Mono 87

WORLD HEALTH ORGANIZATION
INTERNATIONAL AGENCY FOR RESEARCH ON CANCER
IARC Monographs on the Evaluation of

Carcinogenic Risks to Humans
VOLUME 87
Inorganic and Organic
Lead Compounds
LYON, FRANCE
2006
PAGES i-iv DEF.qxp 09/08/2006 10:27 Page i
WORLD HEALTH ORGANIZATION

INTERNATIONAL AGENCY FOR RESEARCH ON CANCER
IARC Monographs on the Evaluation

of Carcinogenic Risks to Humans
VOLUME 87
Inorganic and Organic

Lead Compounds
This publication represents the views and expert opinions

of an IARC Working Group on the
Evaluation of Carcinogenic Risks to Humans,
which met in Lyon,
10–17 February 2004
2006
PAGES i-iv DEF.qxp 09/08/2006 10:27 Page ii
IARC MONOGRAPHS
In 1969, the International Agency for Research on Cancer (IARC) initiated a programme on the evaluation of
the carcinogenic risk of chemicals to humans involving the production of critically evaluated monographs on
individual chemicals. The programme was subsequently expanded to include evaluations of carcinogenic risks asso-
ciated with exposures to complex mixtures, life-style factors and biological and physical agents, as well as those in
specific occupations.
The objective of the programme is to elaborate and publish in the form of monographs critical reviews of data
on carcinogenicity for agents to which humans are known to be exposed and on specific exposure situations; to
evaluate these data in terms of human risk with the help of international working groups of experts in chemical
carcinogenesis and related fields; and to indicate where additional research efforts are needed.
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iarc.fr/
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Research on Cancer (IARC) and does not necessarily express the views of USEPA-ORD.
Published by the International Agency for Research on Cancer,
150 cours Albert Thomas, 69372 Lyon Cedex 08, France
©International Agency for Research on Cancer, 2006
Distributed by WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.:
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IARC Library Cataloguing in Publication Data
Inorganic and Organic Lead Compounds/IARC Working Group on the Evaluation of
Carcinogenic Risks to Humans (2004 : Lyon, France)
(IARC monographs on the evaluation of carcinogenic risks to humans ; v. 87)
1. Carcinogens − congresses 2. Lead − adverse effects 3. Lead − toxicity
I. IARC Working Group on the Evaluation of Carcinogenic Risks to
Humans II. Series
ISBN 92 832 1287 8 (NLM Classification: W1)
ISSN 1017-1606
PRINTED IN FRANCE
PAGES i-iv DEF.qxp 09/08/2006 10:27 Page iii
1 2 5
3 6
1 Leaded gasoline: tetraethyl lead has been used as an additive in gasoline

for decades.
2 Exposure to lead-based paint in older homes: a major source of lead exposure
for children
3 Products like surma and kohl, used in some cultures for cosmetic purposes
and in traditional medicine, often contain large amounts of lead.
4 Lead-acid batteries: the largest single application of lead world-wide
5 Lead-glazed tableware: the bluish-grey crackled glaze of these teacups may
leach considerable amounts of lead.
6 Lead-based paint in older homes
Cover design: Georges Mollon, IARC

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PAGES v-xiv DEF.qxp 09/08/2006 10:36 Page v
CONTENTS
NOTE TO THE READER ..................................................................................................1
LIST OF PARTICIPANTS ..................................................................................................3
PREAMBLE........................................................................................................................7
1. Background..............................................................................................................9
2. Objective and Scope ................................................................................................9
3. Selection of Topics for Monographs ....................................................................10
4. Data for Monographs ............................................................................................11
5. The Working Group ..............................................................................................11
6. Working Procedures ..............................................................................................11
7. Exposure Data........................................................................................................12
8. Studies of Cancer in Humans ................................................................................14
9. Studies of Cancer in Experimental Animals..........................................................17
10. Other Data Relevant to an Evaluation of Carcinogenicity
and its Mechanisms ..............................................................................................20
11. Summary of Data Reported ..................................................................................22
12. Evaluation ..............................................................................................................23
13. References..............................................................................................................28
GENERAL REMARKS ON THE SUBSTANCES CONSIDERED................................33
MONOGRAPH ON INORGANIC AND ORGANIC LEAD COMPOUNDS ................37

1. Exposure Data........................................................................................................39
1.1 Chemical and physical data ........................................................................39
1.1.1 Nomenclature, synonyms, trade names, molecular formulae,
chemical and physical properties ....................................................39
1.1.2 Technical products and impurities ..................................................46
1.2 Production ....................................................................................................48
1.2.1 The ores and their preparation ........................................................48
1.2.2 Smelting ..........................................................................................48
(a) Two-stage processes ..............................................................48
(b) Direct smelting processes ......................................................50
1.2.3 Hydrometallurgical processes ........................................................51
1.2.4 Primary lead refining ......................................................................51
(a) Pyrometallurgical processes ..................................................53
(i) Removal of antimony, arsenic and tin ........................53
(ii) Removal of silver and gold ........................................53
–v–
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vi IARC MONOGRAPHS VOLUME 87
(iii) Removal of zinc ..........................................................53

(iv) Removal of bismuth ....................................................53
(b) Electrolytic processes ............................................................54
1.2.5 Secondary lead production..............................................................54
(a) Secondary lead smelting ........................................................54
(b) Secondary lead refining..........................................................56
1.2.6 Lead production by compound and country ..................................56
1.3 Use ..............................................................................................................56
1.3.1 Lead–acid batteries..........................................................................60
1.3.2 Lead sheet........................................................................................67
1.3.3 Lead pipes ......................................................................................67
1.3.4 Cable sheathing ..............................................................................68
1.3.5 Lead alloys ......................................................................................68
(a) Lead–antimony alloys ............................................................68
(b) Solders ....................................................................................68
(c) Lead for radiation shielding ..................................................69
(d) Other uses of lead alloys ........................................................69
1.3.6 Lead pigments and compounds ......................................................69
(a) Lead pigments ........................................................................70
(b) Lead stabilizers for polyvinyl chloride ................................70
(c) Lead in glass ..........................................................................70
(d) Lead for ceramics ..................................................................71
1.3.7 Gasoline additives ..........................................................................71
1.3.8 Miscellaneous uses..........................................................................72
1.4 Occurrence ..................................................................................................73
1.4.1 Environmental occurrence ..............................................................73
(a) Natural occurrence ................................................................74
(b) Air and dust ............................................................................74
(c) Water ......................................................................................84
(d) Sediments ..............................................................................90
(e) Soil ........................................................................................91
(f) Lead in gasoline ....................................................................98
(g) Lead in paint ........................................................................102
(h) Food......................................................................................103
(i) Contamination of livestock ......................................104
(ii) Contamination from food preparation, storage and
tableware ....................................................................112
(iii) Alcoholic beverages ..................................................116
(iv) Fish and seafood ........................................................117
(v) Rice and cereals ........................................................117
(vi) Daily intake through food..........................................118
(i) Plants and fertilizers ............................................................118
Phytoremediation ................................................................120
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CONTENTS vii
(j) Others ..................................................................................121

(i) Traditional medicine..................................................121
(ii) Cosmetics ..................................................................123
(iii) Ammunition ..............................................................124
(iv) Miscellaneous ............................................................124
(k) Blood lead concentrations from specific sources of
exposure ..............................................................................124
1.4.2 Exposure of the general population ..............................................124
(a) Adults ..................................................................................127
(b) Pregnant women and neonates ............................................138
(c) Children ................................................................................139
1.4.3 Occupational exposure ..................................................................142
(a) Lead–acid battery workers ..................................................165
(b) Workers in mining and primary smelting ............................165
(c) Workers in secondary smelting ............................................165
(d) Workers in leaded-glass manufacturing ..............................165
(e) Workers in welding/soldering ..............................................165
(f) Professional drivers and traffic controllers ..........................166
(g) Firing-range instructors ........................................................166
(h) Other occupational exposures ..............................................166
1.5 Analysis......................................................................................................167
1.5.1 Environmental samples ................................................................167
Use of lead isotope ratios in source attribution and
apportionment................................................................................169
1.5.2 Biological indicators of lead contamination in soil and water ....170
1.5.3 Biological samples ........................................................................170
(a) Analysis in hard tissues........................................................171
(i) Bone ..........................................................................171
(ii) Teeth ..........................................................................171
(iii) Hair and nails ............................................................171
(b) Analysis in soft tissues and body fluids ..............................172
(i) Blood ........................................................................172
(ii) Urine ..........................................................................173
(iii) Placenta......................................................................173
(iv) Sweat and saliva ........................................................173
1.5.4 Biomarkers of lead exposure ........................................................174
(a) Biomarkers related to haeme biosynthesis ..........................174
(i) PBGS (ALAD) activity in blood ..............................174
(ii) ALA in urine and plasma ..........................................175
(iii) Zinc protoporphyrin in blood ....................................175
(b) Biomarkers related to pyrimidine nucleotide metabolism ..176
(c) Other biomarkers..................................................................176
1.6 Regulations and guidelines ........................................................................177
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viii IARC MONOGRAPHS VOLUME 87
2. Studies of Cancer in Humans ..............................................................................183

2.1 Studies among specific occupational groups ............................................183
2.1.1 Battery manufacturing workers ....................................................183
2.1.2 Lead smelter workers ....................................................................201
2.1.3 Lead chromate pigment production ..............................................205
2.1.4 Workers in glass production..........................................................206
(a) Cohort studies ......................................................................206
(b) Case–control studies ............................................................207
2.1.5 Studies in miners ..........................................................................207
2.1.6 Newspaper printers........................................................................208
2.1.7 Exposure to organic lead ..............................................................209
2.1.8 Workers biologically monitored for blood lead concentrations....211
2.1.9 Register linkage studies ................................................................213
2.1.10 Population-based case–control studies..........................................214
(a) Multiple cancer sites ............................................................214
(b) Stomach ................................................................................214
(c) Kidney ..................................................................................215
(d) Brain and nervous system ....................................................215
(e) Other primary sites ..............................................................216
2.1.11 Meta-analyses................................................................................217
2.2 Studies based on general population (environmental) exposures ............219
2.2.1 Cohort studies................................................................................219
2.2.2 Cohort studies of the general population based on blood
lead concentrations........................................................................220
2.2.3 Case–control studies......................................................................221
2.3 Studies on parental exposure and childhood cancer..................................222
2.3.1 Cohort studies................................................................................222
2.3.2 Case–control studies......................................................................223
(a) Wilms’ tumour......................................................................223
(b) Other cancer sites ................................................................224
3. Studies of Cancer in Experimental Animals ......................................................225

3.1 Lead acetate ..............................................................................................225
3.1.1 Mouse ............................................................................................225
(a) Oral administration ..............................................................225
(b) Pre- and perinatal administration ........................................226
(c) Administration with known carcinogens or modifiers
of carcinogenesis ..................................................................226
3.1.2 Rat ................................................................................................227
(b) Subcutaneous administration................................................230
(c) Administration of lead with known carcinogens or
modifiers of carcinogenesis..................................................230
3.1.3 Dog ..............................................................................................232
3.1.4 Monkey..........................................................................................232
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CONTENTS ix
3.2 Lead subacetate..........................................................................................232

3.2.1 Mouse ............................................................................................232
(b) Intraperitoneal administration ..............................................233
(c) Administration of lead with known carcinogens or
3.2.2 Rat ................................................................................................235
(b) Administration of lead with known carcinogens or
3.2.3 Hamster ........................................................................................239
3.2.4 Rabbit ............................................................................................239
3.3 Lead carbonate ..........................................................................................239
3.3.1 Rat ................................................................................................239
Oral administration........................................................................239
3.4 Lead nitrate ................................................................................................240
3.4.1 Mouse ............................................................................................240
Administration of lead with known carcinogens or modifiers
of carcinogenesis ..........................................................................240
3.4.2 Rat ................................................................................................240
3.5 Lead powder ..............................................................................................241
3.5.1 Rat ................................................................................................241
(b) Intramuscular administration................................................241
(c) Intrarenal administration ......................................................241
3.6 Lead oxide..................................................................................................242
3.6.1 Rat ................................................................................................242
Inhalation exposure ......................................................................242
3.6.2 Hamster ........................................................................................242
Intratracheal administration ..........................................................242
3.7 Lead naphthenate ......................................................................................243
3.7.1 Mouse ............................................................................................243
Skin application ............................................................................243
3.8 Lead chromate............................................................................................243
3.8.1 Mouse ............................................................................................243
Intramuscular administration ........................................................243
3.8.2 Rat ................................................................................................244
(a) Subcutaneous injection ........................................................244
(b) Intramuscular administration................................................244
(c) Intrapleural administration ..................................................244
(d) Intrabronchial administration ..............................................245
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x IARC MONOGRAPHS VOLUME 87
3.8.3Guinea-pig ....................................................................................245
3.8.4 Rabbit ............................................................................................246
3.9 Lead phosphate ..........................................................................................246
3.9.1 Rat ................................................................................................246
(a) Subcutaneous injection ........................................................246
(b) Subcutaneous and intraperitoneal administration
combined ..............................................................................247
3.10 Lead arsenate ............................................................................................247
3.10.1 Rat ................................................................................................247
modifiers ..............................................................................248
3.11 Tetraethyl lead............................................................................................248
3.11.1 Mouse ............................................................................................248
Subcutaneous administration ........................................................248

and its Mechanisms ............................................................................................249
4.1 Absorption, distribution, metabolism and excretion ................................249
4.1.1 Inorganic lead compounds ............................................................249
(a) Humans ................................................................................249
(i) Absorption ................................................................249
(ii) Distribution................................................................255
(iii) Metabolism ................................................................263
(iv) Excretion....................................................................263
(v) Mobilization of lead ..................................................264
(b) Animals ................................................................................268
(i) Absorption ................................................................268
(ii) Distribution................................................................276
(iii) Excretion....................................................................279
(c) Experimental systems in vitro..............................................281
4.1.2 Organic lead compounds ..............................................................281
(a) Humans ................................................................................282
(i) Absorption ................................................................282
(ii) Distribution................................................................282
(iii) Metabolism ................................................................282
(iv) Excretion....................................................................283
(b) Animals ................................................................................283
(i) Absorption ................................................................283
(ii) Distribution................................................................283
(iii) Metabolism ................................................................283
(iv) Excretion....................................................................284
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CONTENTS xi
4.2 Toxic effects ..............................................................................................285

4.2.1 Overt symptoms of lead intoxication............................................285
4.2.2 Effects on haeme-containing systems ..........................................286
(a) Humans ................................................................................286
(i) Inhibition of ALAD by lead ......................................288
(ii) ALAD gene polymorphism ......................................288
(iii) Other gene polymorphisms ......................................289
(iv) Lead and coproporphyrins ........................................290
(v) Lead and free erythroprotoporphyrin ........................290
(vi) Lead and pyrimidine 5′-nucleotidase ........................291
(vii) Lead and indicators of anaemia ................................291
(viii) Lead and other haeme-containing systems ..............292
(b) Animal studies......................................................................292
4.2.3 Nephrotoxicity ..............................................................................293
(a) Humans ................................................................................298
(i) General population ....................................................298
(ii) Occupational exposure ..............................................298
(iii) Clinical studies ..........................................................299
(b) Animal studies......................................................................300
4.2.4 Neurological and neurotoxic effects ............................................302
(a) Humans ................................................................................302
(i) Neurological symptoms of high-level exposure
to lead ........................................................................302
(ii) Impact on hearing induced by low-level exposure
to lead ........................................................................304
(iii) Visual functions affected by low-level exposure
to lead ........................................................................305
(iv) Peripheral nervous functions affected by low-level
exposure to lead ........................................................305
(v) Neurotoxicity of lead in children ..............................307
Cross-sectional studies ..............................................307
Prospective studies ....................................................311
Recent studies ............................................................312
Lead and antisocial behaviour ..................................313
(vi) Other effects ..............................................................314
(vii) Neurobehavioural effects of organic lead..................315
(b) Experimental systems ..........................................................315
(i) In-vivo studies with inorganic lead ..........................315
Effects on learning ....................................................316
Effects on visual function ..........................................316
Effects on hearing ......................................................317
Effects on nerve conduction velocity ........................317
Effects on motor function and aggressive
behaviour ..................................................................317
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xii IARC MONOGRAPHS VOLUME 87
Effects on neurochemical parameters........................318

(ii) In-vivo studies with organic lead ..............................320
(iii) In-vitro studies ..........................................................320
4.2.5 Cardiovascular toxicity ................................................................321
(a) Humans ................................................................................321
(i) Blood lead concentrations and blood pressure ..........321
General population ....................................................321
Occupational exposure and lead poisoning ..............321
(ii) Blood pressure and renal function ............................322
(iii) Coronary risk of lead exposure ................................322
(i) Cardiovascular effects of lead ..................................322
(ii) Studies on the etiology of lead-induced
hypertension ..............................................................323
4.2.6 Immunological effects ..................................................................323
(a) Humans ................................................................................324
Studies in exposed workers..................................................324
4.2.7 Other toxic effects ........................................................................328
(a) Lead-induced mitogenesis....................................................328
(b) Effects on regulatory proteins ..............................................330
(c) Apoptosis..............................................................................332
(i) In-vivo studies ..........................................................332
(ii) In-vitro studies ..........................................................333
(d) Effects on hepatic enzymes..................................................334
(e) Effects on endocrine function ..............................................335
(i) Human studies ..........................................................335
(ii) In-vitro study ............................................................336
4.3 Effects on reproduction..............................................................................337
4.3.1 Humans..........................................................................................338
(a) Male fertility ........................................................................338
(b) Effects of lead during pregnancy ........................................341
(c) Effects of lead on abortion ..................................................342
(d) Effects on stature and growth ..............................................344
4.3.2 Animal studies ..............................................................................345
(a) Male fertility ........................................................................345
(b) Effects on pregnancy, fertility and growth and
development in animals........................................................347
4.4 Genetic and related effects ........................................................................348
4.4.1 Human studies ..............................................................................348
4.4.2 Effects in animals..........................................................................354
4.4.3 Mammalian cells in vitro ..............................................................358
4.4.4 Prokaryotic systems ......................................................................363
4.4.5 Yeast and plants ............................................................................363
4.4.6 Cell-free systems ..........................................................................363
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CONTENTS xiii
4.5
Mechanistic considerations........................................................................363
4.5.1 Introduction ..................................................................................363
4.5.2 Toxicokinetics and metabolism of lead ........................................364
(a) Inorganic lead ......................................................................364
(i) Absorption ................................................................364
(ii) Distribution ................................................................364
(iii) Excretion....................................................................365
(b) Organic lead ........................................................................365
(i) Absorption ................................................................365
(ii) Distribution and metabolism ....................................365
(iii) Excretion....................................................................366
4.5.3 Toxicodynamics and mode of action of lead ................................366
(a) Genotoxic mechanisms ........................................................366
Dose considerations..............................................................367
(b) Cell proliferation by mitogenic and regenerative
mechanisms ..........................................................................367
(c) Molecular mechanisms of action ........................................369
5. Summary of Data Reported and Evaluation........................................................370
5.1 Exposure data ............................................................................................370
5.2 Human carcinogenicity data ......................................................................371
5.3 Animal carcinogenicity data ......................................................................372
5.4 Other relevant data ....................................................................................374
5.5 Evaluation ..................................................................................................377
6. References..................................................................................................378
LIST OF ABBREVIATIONS USED IN THIS VOLUME ............................................469
CUMULATIVE INDEX TO THE MONOGRAPHS SERIES ........................................473

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NOTE TO THE READER
The term ‘carcinogenic risk’ in the IARC Monographs series is taken to mean the
probability that exposure to an agent will lead to cancer in humans.
Inclusion of an agent in the Monographs does not imply that it is a carcinogen, only
that the published data have been examined. Equally, the fact that an agent has not yet
been evaluated in a monograph does not mean that it is not carcinogenic.
The evaluations of carcinogenic risk are made by international working groups of
independent scientists and are qualitative in nature. No recommendation is given for
regulation or legislation.
Anyone who is aware of published data that may alter the evaluation of the carcino-
genic risk of an agent to humans is encouraged to make this information available to the
Carcinogen Identification and Evaluation Group, International Agency for Research on
Cancer, 150 cours Albert Thomas, 69372 Lyon Cedex 08, France, in order that the agent
may be considered for re-evaluation by a future Working Group.
Although every effort is made to prepare the monographs as accurately as possible,
mistakes may occur. Readers are requested to communicate any errors to the Carcinogen
Identification and Evaluation Group, so that corrections can be reported in future volumes.
–1–
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IARC WORKING GROUP ON THE EVALUATION

OF CARCINOGENIC RISKS TO HUMANS:
INORGANIC AND ORGANIC LEAD COMPOUNDS
Lyon, 10–17 February 2004
LIST OF PARTICIPANTS
Members
Ahti Anttila, Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer
Research, Liisankatu 21 B, 00170 Helsinki, Finland
Pietro Apostoli, Institute of Occupational Health and Industrial Hygiene, University of
Brescia, P. le Spedali Civili 1, 25123 Brescia, Italy (unable to attend)
James A. Bond, Editor-in-Chief, Chemico-Biological Interactions, 25 Rabbitbrush Road,
Santa Fe, NM 87506, USA (Subgroup Chair, Other Relevant Data)
Lars Gerhardsson, Department of Occupational and Environmental Medicine, Sahlgrenska
University Hospital, St. Sigfridsgatan 85, 412 66 Göteborg, Sweden
Brian L. Gulson, Graduate School of the Environment, Macquarie University, Sydney,
NSW 2109, Australia
Andrea Hartwig, Institute of Food Technology and Food Chemistry, Technical University
Berlin, Gustav-Meyer-Allee 25, D-13355 Berlin, Germany
Perrine Hoet, Unit of Industrial Toxicology and Occupational Medicine, Faculty of Medi-
cine, Catholic University of Louvain, Clos Chapelle-aux-Champs 30-54, 1200 Brussels,
Belgium
Masayuki Ikeda, Kyoto Industrial Health Association, 67 Nishinokyo-Kitatsuboicho,
Nakagyo-ku, Kyoto 604-8472, Japan
Eileen K. Jaffe, Biomolecular Structure and Function Group, Fox Chase Cancer Center,
333 Cottman Avenue, Philadelphia, PA 19111, USA (Subgroup Chair, Exposure Data)
Philip J. Landrigan, Department of Community and Preventive Medicine, Mount Sinai
School of Medicine, 10 East 101 Street, Box 1057, New York, NY 10029-6574, USA
(unable to attend)
Len Levy, Institute of Environment and Health, Cranfield University, Silsoe, Bedfordshire
MK45 4DT, United Kingdom (Overall Chair)
–3–
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4 IARC MONOGRAPHS VOLUME 87
Herbert L. Needleman, Lead Research Group, University of Pennsylvania, 310 Keystone

Bldg, 3520 Fifth Avenue, Pittsburgh, PA 15213, USA
Ellen J. O’Flaherty, Department of Environmental Health, College of Medicine, Uni-
versity of Cincinnati, Cincinnati, OH 45219, USA (retired)
Steve Olin, ILSI Risk Science Institute, One Thomas Circle, NW, 9th Floor, Washington,
DC 20005-5802, USA
Jørgen H. Olsen, Danish Cancer society, Institute of Cancer Epidemiology, Strand-
boulevarden 49, 2100 Copenhagen, Denmark (Subgroup Chair, Cancer in Humans)
Toby G. Rossman, Nelson Institute of Environmental Medicine, New York University
School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA
Tadashi Sakai, Occupational Poisoning Center, Tokyo Rosai Hospital 13-21, Omorimi-
nami-4, Ota-ku, Tokyo, 143-0013, Japan (deceased)
Xiaoming Shen, Research Center for Childhood Lead Poisoning Prevention, Shanghai
Second Medical University, 1665 Kong Jiang Road, Shanghai 200092, People’s
Republic of China (unable to attend)
Tom Sorahan, Institute of Occupational and Environmental Medicine, University of
Birmingham, University Road West, Edgbaston, Birmingham B15 2TT, United
Kingdom
Kyle Steenland, Rollins School of Public Health, Department of Environmental and
Occupational Health, Emory University, 1518 Clifton Road, Atlanta, GA 30322, USA
F. William Sunderman, Jr, Department of Laboratory Medicine, University of Connecticut
Medical School, Farmington, CT, Department of Chemistry and Biochemistry,
Middlebury College, Middlebury, VT 05753, USA (retired)
Tania M. Tavares, Laboratório de Química Analítica Ambiental, Instituto de Química,
Universidade Federal da Bahia, R. Barão de Geremoabo n 147, 4o andar, s/405,
Campus Universitário de Ondina, 40.170-290 Salvador, Bahia, Brazil
Rudra D. Tripathi, Ecotoxicology and Bioremediation Laboratory, National Botanical
Research Institute, Rana Pratap Marg, Lucknow-226001 (UP), India
Michael P. Waalkes, Inorganic Carcinogenesis Section, Laboratory of Comparative
Carcinogenesis, National Cancer Institute at the National Institute of Environmental
Health Sciences, 111 Alexander Drive, P.O. Box 12233, MD F0-09 (South Campus
(101/F095A), Research Triangle Park, NC 27709, USA (Subgroup Chair, Cancer in
Experimental Animals)
Invited Specialist
Ted Junghans, Technical Resources International Inc., 6500 Rock Spring Drive, Suite 650,
Bethesda, MD 20817-1197, USA
Representative
Representative of the US National Institute of Environmental Health Sciences
C. William Jameson, National Toxicology Program, National Institute of Environmental
Health Sciences, 79 Alexander Drive, Research Triangle Park, NC 27709, USA
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PARTICIPANTS 5
Observers
Observer for the International Lead Zinc Research Organization, Inc.1
Craig J. Boreiko, Manager, Environment and Health, International Lead Zinc Research
Organization, P.O. Box 12036, Research Triangle Park, NC 27709-2036, USA
Observer for the Lead Development Association International 2

Vagn Englyst, Rönnskär Smelter, Department of Occupational Health, 932 81 Skellefte-
hamn, Sweden
IARC Secretariat
Robert A. Baan, Carcinogen Identification and Evaluation (Responsible Officer, Rappor-
teur, Subgroup on Other Relevant Data)
Véronique Bouvard, Carcinogen Identification and Evaluation
Vincent J. Cogliano, Carcinogen Identification and Evaluation (Head of Programme)
Catherine Cohet, Carcinogen Identification and Evaluation
Fatiha El Ghissassi, Carcinogen Identification and Evaluation (Co-Rapporteur, Subgroup
on Other Relevant Data)
Tony Fletcher, Visiting Scientist, Environmental Cancer Epidemiology
Marlin Friesen, Nutrition and Cancer
Yann Grosse, Carcinogen Identification and Evaluation (Rapporteur, Subgroup on Cancer
in Experimental Animals)
Jay Hunt, Visiting Scientist, Environmental Cancer Epidemiology
Douglas McGregor, Carcinogen Identification and Evaluation
Dave McLean, Special Training Awardee, Radiation and Cancer
Garnett P. McMillan, Post-doctoral Fellow, Epidemiology for Cancer Prevention
Nikolai Napalkov, Carcinogen Identification and Evaluation
Béatrice Secretan, Carcinogen Identification and Evaluation (Rapporteur, Subgroup on
Exposure Data)
Kurt Straif, Carcinogen Identification and Evaluation (Rapporteur, Subgroup on Cancer
in Humans)
Olga Van der Hel, Post-doctoral Fellow, Environmental Cancer Epidemiology
Rosamund Williams (Editor)
Administrative assistance
Sandrine Egraz, Carcinogen Identification and Evaluation
Michel Javin, Administrative Services
Martine Lézère, Carcinogen Identification and Evaluation
1
A non-profit research foundation for the purpose of conducting research on behalf of the international commu-
nity of lead and zinc miners and smelters.
2
Representative organization for the lead-producing and lead-using industries at the European and global levels.
P 001-006 DEF.qxp 09/08/2006 10:42 Page 6
Jane Mitchell, Carcinogen Identification and Evaluation

Georges Mollon, Communications
Elspeth Perez, Carcinogen Identification and Evaluation
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PREAMBLE
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IARC MONOGRAPHS PROGRAMME ON THE EVALUATION

OF CARCINOGENIC RISKS TO HUMANS
PREAMBLE
1. BACKGROUND
In 1969, the International Agency for Research on Cancer (IARC) initiated a pro-
gramme to evaluate the carcinogenic risk of chemicals to humans and to produce mono-
graphs on individual chemicals. The Monographs programme has since been expanded
to include consideration of exposures to complex mixtures of chemicals (which occur,
for example, in some occupations and as a result of human habits) and of exposures to
other agents, such as radiation and viruses. With Supplement 6 (IARC, 1987a), the title
of the series was modified from IARC Monographs on the Evaluation of the Carcino-
genic Risk of Chemicals to Humans to IARC Monographs on the Evaluation of Carcino-
genic Risks to Humans, in order to reflect the widened scope of the programme.
The criteria established in 1971 to evaluate carcinogenic risk to humans were
adopted by the working groups whose deliberations resulted in the first 16 volumes of
the IARC Monographs series. Those criteria were subsequently updated by further ad-
hoc working groups (IARC, 1977, 1978, 1979, 1982, 1983, 1987b, 1988, 1991a; Vainio
et al., 1992).
2. OBJECTIVE AND SCOPE

The objective of the programme is to prepare, with the help of international working
groups of experts, and to publish in the form of monographs, critical reviews and eva-
luations of evidence on the carcinogenicity of a wide range of human exposures. The
Monographs may also indicate where additional research efforts are needed.
The Monographs represent the first step in carcinogenic risk assessment, which
involves examination of all relevant information in order to assess the strength of the avai-
lable evidence that certain exposures could alter the incidence of cancer in humans. The
second step is quantitative risk estimation. Detailed, quantitative evaluations of epidemio-
logical data may be made in the Monographs, but without extrapolation beyond the range
of the data available. Quantitative extrapolation from experimental data to the human
situation is not undertaken.
The term ‘carcinogen’ is used in these monographs to denote an exposure that is
capable of increasing the incidence of malignant neoplasms; the induction of benign neo-
–9–
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plasms may in some circumstances (see p. 19) contribute to the judgement that the expo-
sure is carcinogenic. The terms ‘neoplasm’ and ‘tumour’ are used interchangeably.
Some epidemiological and experimental studies indicate that different agents may act
at different stages in the carcinogenic process, and several mechanisms may be involved.
The aim of the Monographs has been, from their inception, to evaluate evidence of carci-
nogenicity at any stage in the carcinogenesis process, independently of the underlying
mechanisms. Information on mechanisms may, however, be used in making the overall
evaluation (IARC, 1991a; Vainio et al., 1992; see also pp. 25–27).
The Monographs may assist national and international authorities in making risk
assessments and in formulating decisions concerning any necessary preventive measures.
The evaluations of IARC working groups are scientific, qualitative judgements about the
evidence for or against carcinogenicity provided by the available data. These evaluations
represent only one part of the body of information on which regulatory measures may be
based. Other components of regulatory decisions vary from one situation to another and
from country to country, responding to different socioeconomic and national priorities.
Therefore, no recommendation is given with regard to regulation or legislation,
which are the responsibility of individual governments and/or other international
organizations.
The IARC Monographs are recognized as an authoritative source of information on
the carcinogenicity of a wide range of human exposures. A survey of users in 1988 indi-
cated that the Monographs are consulted by various agencies in 57 countries. About 2500
copies of each volume are printed, for distribution to governments, regulatory bodies and
interested scientists. The Monographs are also available from IARCPress in Lyon and via
the Marketing and Dissemination (MDI) of the World Health Organization in Geneva.
3. SELECTION OF TOPICS FOR MONOGRAPHS

Topics are selected on the basis of two main criteria: (a) there is evidence of human
exposure, and (b) there is some evidence or suspicion of carcinogenicity. The term
‘agent’ is used to include individual chemical compounds, groups of related chemical
compounds, physical agents (such as radiation) and biological factors (such as viruses).
Exposures to mixtures of agents may occur in occupational exposures and as a result of
personal and cultural habits (like smoking and dietary practices). Chemical analogues
and compounds with biological or physical characteristics similar to those of suspected
carcinogens may also be considered, even in the absence of data on a possible carcino-
genic effect in humans or experimental animals.
The scientific literature is surveyed for published data relevant to an assessment of
carcinogenicity. The IARC information bulletins on agents being tested for carcino-
genicity (IARC, 1973–1996) and directories of on-going research in cancer epide-
miology (IARC, 1976–1996) often indicate exposures that may be scheduled for future
meetings. Ad-hoc working groups convened by IARC in 1984, 1989, 1991, 1993 and
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PREAMBLE 11
1998 gave recommendations as to which agents should be evaluated in the IARC Mono-
graphs series (IARC, 1984, 1989, 1991b, 1993, 1998a,b).
As significant new data on subjects on which monographs have already been prepared
become available, re-evaluations are made at subsequent meetings, and revised mono-
graphs are published.
4. DATA FOR MONOGRAPHS

The Monographs do not necessarily cite all the literature concerning the subject of
an evaluation. Only those data considered by the Working Group to be relevant to making
the evaluation are included.
With regard to biological and epidemiological data, only reports that have been
published or accepted for publication in the openly available scientific literature are
reviewed by the working groups. In certain instances, government agency reports that
have undergone peer review and are widely available are considered. Exceptions may
be made on an ad-hoc basis to include unpublished reports that are in their final form
and publicly available, if their inclusion is considered pertinent to making a final
evaluation (see pp. 25–27). In the sections on chemical and physical properties, on
analysis, on production and use and on occurrence, unpublished sources of information
may be used.
5. THE WORKING GROUP

Reviews and evaluations are formulated by a working group of experts. The tasks of
the group are: (i) to ascertain that all appropriate data have been collected; (ii) to select
the data relevant for the evaluation on the basis of scientific merit; (iii) to prepare
accurate summaries of the data to enable the reader to follow the reasoning of the
Working Group; (iv) to evaluate the results of epidemiological and experimental studies
on cancer; (v) to evaluate data relevant to the understanding of mechanism of action; and
(vi) to make an overall evaluation of the carcinogenicity of the exposure to humans.
Working Group participants who contributed to the considerations and evaluations
within a particular volume are listed, with their addresses, at the beginning of each publi-
cation. Each participant who is a member of a working group serves as an individual
scientist and not as a representative of any organization, government or industry. In
addition, nominees of national and international agencies and industrial associations may
be invited as observers.
6. WORKING PROCEDURES
Approximately one year in advance of a meeting of a working group, the topics of
the monographs are announced and participants are selected by IARC staff in consul-
tation with other experts. Subsequently, relevant biological and epidemiological data are
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collected by the Carcinogen Identification and Evaluation Unit of IARC from recognized
sources of information on carcinogenesis, including data storage and retrieval systems
such as MEDLINE and TOXLINE.
For chemicals and some complex mixtures, the major collection of data and the pre-
paration of first drafts of the sections on chemical and physical properties, on analysis,
on production and use and on occurrence are carried out under a separate contract funded
by the United States National Cancer Institute. Representatives from industrial asso-
ciations may assist in the preparation of sections on production and use. Information on
production and trade is obtained from governmental and trade publications and, in some
cases, by direct contact with industries. Separate production data on some agents may not
be available because their publication could disclose confidential information. Infor-
mation on uses may be obtained from published sources but is often complemented by
direct contact with manufacturers. Efforts are made to supplement this information with
data from other national and international sources.
Six months before the meeting, the material obtained is sent to meeting participants,
or is used by IARC staff, to prepare sections for the first drafts of monographs. The first
drafts are compiled by IARC staff and sent before the meeting to all participants of the
Working Group for review.
The Working Group meets in Lyon for seven to eight days to discuss and finalize the
texts of the monographs and to formulate the evaluations. After the meeting, the master
copy of each monograph is verified by consulting the original literature, edited and pre-
pared for publication. The aim is to publish monographs within six months of the
Working Group meeting.
The available studies are summarized by the Working Group, with particular regard
to the qualitative aspects discussed below. In general, numerical findings are indicated as
they appear in the original report; units are converted when necessary for easier compa-
rison. The Working Group may conduct additional analyses of the published data and use
them in their assessment of the evidence; the results of such supplementary analyses are
given in square brackets. When an important aspect of a study, directly impinging on its
interpretation, should be brought to the attention of the reader, a comment is given in
square brackets.
7. EXPOSURE DATA
Sections that indicate the extent of past and present human exposure, the sources of
exposure, the people most likely to be exposed and the factors that contribute to the
exposure are included at the beginning of each monograph.
Most monographs on individual chemicals, groups of chemicals or complex mixtures
include sections on chemical and physical data, on analysis, on production and use and
on occurrence. In monographs on, for example, physical agents, occupational exposures
and cultural habits, other sections may be included, such as: historical perspectives, des-
cription of an industry or habit, chemistry of the complex mixture or taxonomy. Mono-
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PREAMBLE 13
graphs on biological agents have sections on structure and biology, methods of detection,
epidemiology of infection and clinical disease other than cancer.
For chemical exposures, the Chemical Abstracts Services Registry Number, the latest
Chemical Abstracts primary name and the IUPAC systematic name are recorded; other
synonyms are given, but the list is not necessarily comprehensive. For biological agents,
taxonomy and structure are described, and the degree of variability is given, when
applicable.
Information on chemical and physical properties and, in particular, data relevant to
identification, occurrence and biological activity are included. For biological agents,
mode of replication, life cycle, target cells, persistence and latency and host response are
given. A description of technical products of chemicals includes trade names, relevant
specifications and available information on composition and impurities. Some of the
trade names given may be those of mixtures in which the agent being evaluated is only
one of the ingredients.
The purpose of the section on analysis or detection is to give the reader an overview
of current methods, with emphasis on those widely used for regulatory purposes.
Methods for monitoring human exposure are also given, when available. No critical eva-
luation or recommendation of any of the methods is meant or implied. The IARC
published a series of volumes, Environmental Carcinogens: Methods of Analysis and
Exposure Measurement (IARC, 1978–93), that describe validated methods for analysing
a wide variety of chemicals and mixtures. For biological agents, methods of detection
and exposure assessment are described, including their sensitivity, specificity and
reproducibility.
The dates of first synthesis and of first commercial production of a chemical or
mixture are provided; for agents which do not occur naturally, this information may
allow a reasonable estimate to be made of the date before which no human exposure to
the agent could have occurred. The dates of first reported occurrence of an exposure are
also provided. In addition, methods of synthesis used in past and present commercial
production and different methods of production which may give rise to different impu-
rities are described.
Data on production, international trade and uses are obtained for representative
regions, which usually include Europe, Japan and the United States of America. It should
not, however, be inferred that those areas or nations are necessarily the sole or major
sources or users of the agent. Some identified uses may not be current or major appli-
cations, and the coverage is not necessarily comprehensive. In the case of drugs, mention
of their therapeutic uses does not necessarily represent current practice, nor does it imply
judgement as to their therapeutic efficacy.
Information on the occurrence of an agent or mixture in the environment is obtained
from data derived from the monitoring and surveillance of levels in occupational envi-
ronments, air, water, soil, foods and animal and human tissues. When available, data on
the generation, persistence and bioaccumulation of the agent are also included. In the
case of mixtures, industries, occupations or processes, information is given about all
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agents present. For processes, industries and occupations, a historical description is also
given, noting variations in chemical composition, physical properties and levels of occu-
pational exposure with time and place. For biological agents, the epidemiology of
infection is described.
Statements concerning regulations and guidelines (e.g., pesticide registrations,
maximal levels permitted in foods, occupational exposure limits) are included for some
countries as indications of potential exposures, but they may not reflect the most recent
situation, since such limits are continuously reviewed and modified. The absence of
information on regulatory status for a country should not be taken to imply that that
country does not have regulations with regard to the exposure. For biological agents,
legislation and control, including vaccines and therapy, are described.
8. STUDIES OF CANCER IN HUMANS

(a) Types of studies considered
Three types of epidemiological studies of cancer contribute to the assessment of
carcinogenicity in humans — cohort studies, case–control studies and correlation (or
ecological) studies. Rarely, results from randomized trials may be available. Case series
and case reports of cancer in humans may also be reviewed.
Cohort and case–control studies relate the exposures under study to the occurrence
of cancer in individuals and provide an estimate of relative risk (ratio of incidence or
mortality in those exposed to incidence or mortality in those not exposed) as the main
measure of association.
In correlation studies, the units of investigation are usually whole populations (e.g.
in particular geographical areas or at particular times), and cancer frequency is related to
a summary measure of the exposure of the population to the agent, mixture or exposure
circumstance under study. Because individual exposure is not documented, however, a
causal relationship is less easy to infer from correlation studies than from cohort and
case–control studies. Case reports generally arise from a suspicion, based on clinical
experience, that the concurrence of two events — that is, a particular exposure and
occurrence of a cancer — has happened rather more frequently than would be expected
by chance. Case reports usually lack complete ascertainment of cases in any population,
definition or enumeration of the population at risk and estimation of the expected number
of cases in the absence of exposure. The uncertainties surrounding interpretation of case
reports and correlation studies make them inadequate, except in rare instances, to form
the sole basis for inferring a causal relationship. When taken together with case–control
and cohort studies, however, relevant case reports or correlation studies may add
materially to the judgement that a causal relationship is present.
Epidemiological studies of benign neoplasms, presumed preneoplastic lesions and
other end-points thought to be relevant to cancer are also reviewed by working groups.
They may, in some instances, strengthen inferences drawn from studies of cancer itself.
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PREAMBLE 15
(b) Quality of studies considered

The Monographs are not intended to summarize all published studies. Those that are
judged to be inadequate or irrelevant to the evaluation are generally omitted. They may
be mentioned briefly, particularly when the information is considered to be a useful
supplement to that in other reports or when they provide the only data available. Their
inclusion does not imply acceptance of the adequacy of the study design or of the
analysis and interpretation of the results, and limitations are clearly outlined in square
brackets at the end of the study description.
It is necessary to take into account the possible roles of bias, confounding and chance
in the interpretation of epidemiological studies. By ‘bias’ is meant the operation of
factors in study design or execution that lead erroneously to a stronger or weaker asso-
ciation than in fact exists between disease and an agent, mixture or exposure circum-
stance. By ‘confounding’ is meant a situation in which the relationship with disease is
made to appear stronger or weaker than it truly is as a result of an association between
the apparent causal factor and another factor that is associated with either an increase or
decrease in the incidence of the disease. In evaluating the extent to which these factors
have been minimized in an individual study, working groups consider a number of
aspects of design and analysis as described in the report of the study. Most of these consi-
derations apply equally to case–control, cohort and correlation studies. Lack of clarity of
any of these aspects in the reporting of a study can decrease its credibility and the weight
given to it in the final evaluation of the exposure.
Firstly, the study population, disease (or diseases) and exposure should have been
well defined by the authors. Cases of disease in the study population should have been
identified in a way that was independent of the exposure of interest, and exposure should
have been assessed in a way that was not related to disease status.
Secondly, the authors should have taken account in the study design and analysis of
other variables that can influence the risk of disease and may have been related to the
exposure of interest. Potential confounding by such variables should have been dealt with
either in the design of the study, such as by matching, or in the analysis, by statistical
adjustment. In cohort studies, comparisons with local rates of disease may be more
appropriate than those with national rates. Internal comparisons of disease frequency
among individuals at different levels of exposure should also have been made in the
study.
Thirdly, the authors should have reported the basic data on which the conclusions are
founded, even if sophisticated statistical analyses were employed. At the very least, they
should have given the numbers of exposed and unexposed cases and controls in a
case–control study and the numbers of cases observed and expected in a cohort study.
Further tabulations by time since exposure began and other temporal factors are also
important. In a cohort study, data on all cancer sites and all causes of death should have
been given, to reveal the possibility of reporting bias. In a case–control study, the effects
of investigated factors other than the exposure of interest should have been reported.
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Finally, the statistical methods used to obtain estimates of relative risk, absolute rates
of cancer, confidence intervals and significance tests, and to adjust for confounding
should have been clearly stated by the authors. The methods used should preferably have
been the generally accepted techniques that have been refined since the mid-1970s.
These methods have been reviewed for case–control studies (Breslow & Day, 1980) and
for cohort studies (Breslow & Day, 1987).
(c) Inferences about mechanism of action

Detailed analyses of both relative and absolute risks in relation to temporal variables,
such as age at first exposure, time since first exposure, duration of exposure, cumulative
exposure and time since exposure ceased, are reviewed and summarized when available.
The analysis of temporal relationships can be useful in formulating models of carcino-
genesis. In particular, such analyses may suggest whether a carcinogen acts early or late
in the process of carcinogenesis, although at best they allow only indirect inferences
about the mechanism of action. Special attention is given to measurements of biological
markers of carcinogen exposure or action, such as DNA or protein adducts, as well as
markers of early steps in the carcinogenic process, such as proto-oncogene mutation,
when these are incorporated into epidemiological studies focused on cancer incidence or
mortality. Such measurements may allow inferences to be made about putative mecha-
nisms of action (IARC, 1991a; Vainio et al., 1992).
(d ) Criteria for causality

After the individual epidemiological studies of cancer have been summarized and the
quality assessed, a judgement is made concerning the strength of evidence that the agent,
mixture or exposure circumstance in question is carcinogenic for humans. In making its
judgement, the Working Group considers several criteria for causality. A strong asso-
ciation (a large relative risk) is more likely to indicate causality than a weak association,
although it is recognized that relative risks of small magnitude do not imply lack of
causality and may be important if the disease is common. Associations that are replicated
in several studies of the same design or using different epidemiological approaches or
under different circumstances of exposure are more likely to represent a causal relation-
ship than isolated observations from single studies. If there are inconsistent results
among investigations, possible reasons are sought (such as differences in amount of
exposure), and results of studies judged to be of high quality are given more weight than
those of studies judged to be methodologically less sound. When suspicion of carcino-
genicity arises largely from a single study, these data are not combined with those from
later studies in any subsequent reassessment of the strength of the evidence.
If the risk of the disease in question increases with the amount of exposure, this is
considered to be a strong indication of causality, although absence of a graded response
is not necessarily evidence against a causal relationship. Demonstration of a decline in
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PREAMBLE 17
risk after cessation of or reduction in exposure in individuals or in whole populations also

supports a causal interpretation of the findings.
Although a carcinogen may act upon more than one target, the specificity of an asso-
ciation (an increased occurrence of cancer at one anatomical site or of one morphological
type) adds plausibility to a causal relationship, particularly when excess cancer occur-
rence is limited to one morphological type within the same organ.
Although rarely available, results from randomized trials showing different rates
among exposed and unexposed individuals provide particularly strong evidence for
causality.
When several epidemiological studies show little or no indication of an association
between an exposure and cancer, the judgement may be made that, in the aggregate, they
show evidence of lack of carcinogenicity. Such a judgement requires first of all that the
studies giving rise to it meet, to a sufficient degree, the standards of design and analysis
described above. Specifically, the possibility that bias, confounding or misclassification
of exposure or outcome could explain the observed results should be considered and
excluded with reasonable certainty. In addition, all studies that are judged to be methodo-
logically sound should be consistent with a relative risk of unity for any observed level
of exposure and, when considered together, should provide a pooled estimate of relative
risk which is at or near unity and has a narrow confidence interval, due to sufficient popu-
lation size. Moreover, no individual study nor the pooled results of all the studies should
show any consistent tendency for the relative risk of cancer to increase with increasing
level of exposure. It is important to note that evidence of lack of carcinogenicity obtained
in this way from several epidemiological studies can apply only to the type(s) of cancer
studied and to dose levels and intervals between first exposure and observation of disease
that are the same as or less than those observed in all the studies. Experience with human
cancer indicates that, in some cases, the period from first exposure to the development of
clinical cancer is seldom less than 20 years; studies with latent periods substantially
shorter than 30 years cannot provide evidence for lack of carcinogenicity.
9. STUDIES OF CANCER IN EXPERIMENTAL ANIMALS

All known human carcinogens that have been studied adequately in experimental
animals have produced positive results in one or more animal species (Wilbourn et al.,
1986; Tomatis et al., 1989). For several agents (aflatoxins, 4-aminobiphenyl, azathio-
prine, betel quid with tobacco, bischloromethyl ether and chloromethyl methyl ether
(technical grade), chlorambucil, chlornaphazine, ciclosporin, coal-tar pitches, coal-tars,
combined oral contraceptives, cyclophosphamide, diethylstilboestrol, melphalan, 8-
methoxypsoralen plus ultraviolet A radiation, mustard gas, myleran, 2-naphthylamine,
nonsteroidal estrogens, estrogen replacement therapy/steroidal estrogens, solar radiation,
thiotepa and vinyl chloride), carcinogenicity in experimental animals was established or
highly suspected before epidemiological studies confirmed their carcinogenicity in
humans (Vainio et al., 1995). Although this association cannot establish that all agents
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and mixtures that cause cancer in experimental animals also cause cancer in humans,
nevertheless, in the absence of adequate data on humans, it is biologically plausible
and prudent to regard agents and mixtures for which there is sufficient evidence (see
p. 24) of carcinogenicity in experimental animals as if they presented a carcinogenic
risk to humans. The possibility that a given agent may cause cancer through a species-
specific mechanism which does not operate in humans (see p. 27) should also be taken
into consideration.
The nature and extent of impurities or contaminants present in the chemical or
mixture being evaluated are given when available. Animal strain, sex, numbers per
group, age at start of treatment and survival are reported.
Other types of studies summarized include: experiments in which the agent or
mixture was administered in conjunction with known carcinogens or factors that modify
carcinogenic effects; studies in which the end-point was not cancer but a defined
precancerous lesion; and experiments on the carcinogenicity of known metabolites and
derivatives.
For experimental studies of mixtures, consideration is given to the possibility of
changes in the physicochemical properties of the test substance during collection,
storage, extraction, concentration and delivery. Chemical and toxicological interactions
of the components of mixtures may result in nonlinear dose–response relationships.
An assessment is made as to the relevance to human exposure of samples tested in
experimental animals, which may involve consideration of: (i) physical and chemical
characteristics, (ii) constituent substances that indicate the presence of a class of
substances, (iii) the results of tests for genetic and related effects, including studies on
DNA adduct formation, proto-oncogene mutation and expression and suppressor gene
inactivation. The relevance of results obtained, for example, with animal viruses
analogous to the virus being evaluated in the monograph must also be considered. They
may provide biological and mechanistic information relevant to the understanding of the
process of carcinogenesis in humans and may strengthen the plausibility of a conclusion
that the biological agent under evaluation is carcinogenic in humans.
(a) Qualitative aspects

An assessment of carcinogenicity involves several considerations of qualitative
importance, including (i) the experimental conditions under which the test was per-
formed, including route and schedule of exposure, species, strain, sex, age, duration of
follow-up; (ii) the consistency of the results, for example, across species and target
organ(s); (iii) the spectrum of neoplastic response, from preneoplastic lesions and benign
tumours to malignant neoplasms; and (iv) the possible role of modifying factors.
As mentioned earlier (p. 11), the Monographs are not intended to summarize all
published studies. Those studies in experimental animals that are inadequate (e.g., too
short a duration, too few animals, poor survival; see below) or are judged irrelevant to
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PREAMBLE 19
the evaluation are generally omitted. Guidelines for conducting adequate long-term
carcinogenicity experiments have been outlined (e.g. Montesano et al., 1986).
Considerations of importance to the Working Group in the interpretation and eva-
luation of a particular study include: (i) how clearly the agent was defined and, in the
case of mixtures, how adequately the sample characterization was reported; (ii)
whether the dose was adequately monitored, particularly in inhalation experiments;
(iii) whether the doses and duration of treatment were appropriate and whether the
survival of treated animals was similar to that of controls; (iv) whether there were
adequate numbers of animals per group; (v) whether animals of each sex were used;
(vi) whether animals were allocated randomly to groups; (vii) whether the duration of
observation was adequate; and (viii) whether the data were adequately reported. If
available, recent data on the incidence of specific tumours in historical controls, as
well as in concurrent controls, should be taken into account in the evaluation of tumour
response.
When benign tumours occur together with and originate from the same cell type in
an organ or tissue as malignant tumours in a particular study and appear to represent a
stage in the progression to malignancy, it may be valid to combine them in assessing
tumour incidence (Huff et al., 1989). The occurrence of lesions presumed to be pre-
neoplastic may in certain instances aid in assessing the biological plausibility of any neo-
plastic response observed. If an agent or mixture induces only benign neoplasms that
appear to be end-points that do not readily progress to malignancy, it should nevertheless
be suspected of being a carcinogen and requires further investigation.
(b) Quantitative aspects

The probability that tumours will occur may depend on the species, sex, strain and
age of the animal, the dose of the carcinogen and the route and length of exposure.
Evidence of an increased incidence of neoplasms with increased level of exposure
strengthens the inference of a causal association between the exposure and the develop-
ment of neoplasms.
The form of the dose–response relationship can vary widely, depending on the
particular agent under study and the target organ. Both DNA damage and increased cell
division are important aspects of carcinogenesis, and cell proliferation is a strong deter-
minant of dose–response relationships for some carcinogens (Cohen & Ellwein, 1990).
Since many chemicals require metabolic activation before being converted into their
reactive intermediates, both metabolic and pharmacokinetic aspects are important in
determining the dose–response pattern. Saturation of steps such as absorption, activation,
inactivation and elimination may produce nonlinearity in the dose–response relationship,
as could saturation of processes such as DNA repair (Hoel et al., 1983; Gart et al., 1986).
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(c) Statistical analysis of long-term experiments in animals

Factors considered by the Working Group include the adequacy of the information
given for each treatment group: (i) the number of animals studied and the number
examined histologically, (ii) the number of animals with a given tumour type and
(iii) length of survival. The statistical methods used should be clearly stated and should
be the generally accepted techniques refined for this purpose (Peto et al., 1980; Gart
et al., 1986). When there is no difference in survival between control and treatment
groups, the Working Group usually compares the proportions of animals developing each
tumour type in each of the groups. Otherwise, consideration is given as to whether or not
appropriate adjustments have been made for differences in survival. These adjustments
can include: comparisons of the proportions of tumour-bearing animals among the
effective number of animals (alive at the time the first tumour is discovered), in the case
where most differences in survival occur before tumours appear; life-table methods,
when tumours are visible or when they may be considered ‘fatal’ because mortality
rapidly follows tumour development; and the Mantel-Haenszel test or logistic regression,
when occult tumours do not affect the animals’ risk of dying but are ‘incidental’ findings
at autopsy.
In practice, classifying tumours as fatal or incidental may be difficult. Several
survival-adjusted methods have been developed that do not require this distinction (Gart
et al., 1986), although they have not been fully evaluated.
10. OTHER DATA RELEVANT TO AN EVALUATION OF

CARCINOGENICITY AND ITS MECHANISMS
In coming to an overall evaluation of carcinogenicity in humans (see pp. 25–27), the
Working Group also considers related data. The nature of the information selected for the
summary depends on the agent being considered.
For chemicals and complex mixtures of chemicals such as those in some occupa-
tional situations or involving cultural habits (e.g. tobacco smoking), the other data consi-
dered to be relevant are divided into those on absorption, distribution, metabolism and
excretion; toxic effects; reproductive and developmental effects; and genetic and related
effects.
Concise information is given on absorption, distribution (including placental
transfer) and excretion in both humans and experimental animals. Kinetic factors that
may affect the dose–response relationship, such as saturation of uptake, protein binding,
metabolic activation, detoxification and DNA repair processes, are mentioned. Studies
that indicate the metabolic fate of the agent in humans and in experimental animals are
summarized briefly, and comparisons of data on humans and on animals are made when
possible. Comparative information on the relationship between exposure and the dose
that reaches the target site may be of particular importance for extrapolation between
species. Data are given on acute and chronic toxic effects (other than cancer), such as
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PREAMBLE 21
organ toxicity, increased cell proliferation, immunotoxicity and endocrine effects. The
presence and toxicological significance of cellular receptors is described. Effects on
reproduction, teratogenicity, fetotoxicity and embryotoxicity are also summarized
briefly.
Tests of genetic and related effects are described in view of the relevance of gene
mutation and chromosomal damage to carcinogenesis (Vainio et al., 1992; McGregor
et al., 1999). The adequacy of the reporting of sample characterization is considered and,
where necessary, commented upon; with regard to complex mixtures, such comments are
similar to those described for animal carcinogenicity tests on p. 18. The available data
are interpreted critically by phylogenetic group according to the end-points detected,
which may include DNA damage, gene mutation, sister chromatid exchange, micro-
nucleus formation, chromosomal aberrations, aneuploidy and cell transformation. The
concentrations employed are given, and mention is made of whether use of an exogenous
metabolic system in vitro affected the test result. These data are given as listings of test
systems, data and references. The data on genetic and related effects presented in the
Monographs are also available in the form of genetic activity profiles (GAP) prepared in
collaboration with the United States Environmental Protection Agency (EPA) (see also
Waters et al., 1987) using software for personal computers that are Microsoft Windows®
compatible. The EPA/IARC GAP software and database may be downloaded free of
charge from www.epa.gov/gapdb.
Positive results in tests using prokaryotes, lower eukaryotes, plants, insects and
cultured mammalian cells suggest that genetic and related effects could occur in
mammals. Results from such tests may also give information about the types of genetic
effect produced and about the involvement of metabolic activation. Some end-points
described are clearly genetic in nature (e.g., gene mutations and chromosomal aberra-
tions), while others are to a greater or lesser degree associated with genetic effects (e.g.
unscheduled DNA synthesis). In-vitro tests for tumour-promoting activity and for cell
transformation may be sensitive to changes that are not necessarily the result of genetic
alterations but that may have specific relevance to the process of carcinogenesis. A
critical appraisal of these tests has been published (Montesano et al., 1986).
Genetic or other activity detected in experimental mammals and humans is regarded
as being of greater relevance than that in other organisms. The demonstration that an
agent or mixture can induce gene and chromosomal mutations in whole mammals indi-
cates that it may have carcinogenic activity, although this activity may not be detectably
expressed in any or all species. Relative potency in tests for mutagenicity and related
effects is not a reliable indicator of carcinogenic potency. Negative results in tests for
mutagenicity in selected tissues from animals treated in vivo provide less weight, partly
because they do not exclude the possibility of an effect in tissues other than those
examined. Moreover, negative results in short-term tests with genetic end-points cannot
be considered to provide evidence to rule out carcinogenicity of agents or mixtures that
act through other mechanisms (e.g. receptor-mediated effects, cellular toxicity with
regenerative proliferation, peroxisome proliferation) (Vainio et al., 1992). Factors that
P 007-032 DEF.qxp 09/08/2006 10:46 Page 22
may lead to misleading results in short-term tests have been discussed in detail elsewhere
(Montesano et al., 1986).
When available, data relevant to mechanisms of carcinogenesis that do not involve
structural changes at the level of the gene are also described.
The adequacy of epidemiological studies of reproductive outcome and genetic and
related effects in humans is evaluated by the same criteria as are applied to epidemio-
logical studies of cancer.
Structure–activity relationships that may be relevant to an evaluation of the carcino-
genicity of an agent are also described.
For biological agents — viruses, bacteria and parasites — other data relevant to
carcinogenicity include descriptions of the pathology of infection, molecular biology
(integration and expression of viruses, and any genetic alterations seen in human
tumours) and other observations, which might include cellular and tissue responses to
infection, immune response and the presence of tumour markers.
11. SUMMARY OF DATA REPORTED

In this section, the relevant epidemiological and experimental data are summarized.
Only reports, other than in abstract form, that meet the criteria outlined on p. 11 are
considered for evaluating carcinogenicity. Inadequate studies are generally not summarized:
such studies are usually identified by a square-bracketed comment in the preceding text.
(a) Exposure
Human exposure to chemicals and complex mixtures is summarized on the basis of
elements such as production, use, occurrence in the environment and determinations in
human tissues and body fluids. Quantitative data are given when available. Exposure to
biological agents is described in terms of transmission and prevalence of infection.
(b) Carcinogenicity in humans

Results of epidemiological studies that are considered to be pertinent to an
assessment of human carcinogenicity are summarized. When relevant, case reports and
correlation studies are also summarized.
(c) Carcinogenicity in experimental animals

Data relevant to an evaluation of carcinogenicity in animals are summarized. For
each animal species and route of administration, it is stated whether an increased
incidence of neoplasms or preneoplastic lesions was observed, and the tumour sites are
indicated. If the agent or mixture produced tumours after prenatal exposure or in single-
dose experiments, this is also indicated. Negative findings are also summarized. Dose–
response and other quantitative data may be given when available.
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PREAMBLE 23
(d ) Other data relevant to an evaluation of carcinogenicity and its mechanisms

Data on biological effects in humans that are of particular relevance are summarized.
These may include toxicological, kinetic and metabolic considerations and evidence of
DNA binding, persistence of DNA lesions or genetic damage in exposed humans. Toxi-
cological information, such as that on cytotoxicity and regeneration, receptor binding
and hormonal and immunological effects, and data on kinetics and metabolism in
experimental animals are given when considered relevant to the possible mechanism of
the carcinogenic action of the agent. The results of tests for genetic and related effects
are summarized for whole mammals, cultured mammalian cells and nonmammalian
systems.
When available, comparisons of such data for humans and for animals, and parti-
cularly animals that have developed cancer, are described.
Structure–activity relationships are mentioned when relevant.
For the agent, mixture or exposure circumstance being evaluated, the available data on
end-points or other phenomena relevant to mechanisms of carcinogenesis from studies in
humans, experimental animals and tissue and cell test systems are summarized within one
or more of the following descriptive dimensions:
(i) Evidence of genotoxicity (structural changes at the level of the gene): for
example, structure–activity considerations, adduct formation, mutagenicity (effect on
specific genes), chromosomal mutation/aneuploidy
(ii) Evidence of effects on the expression of relevant genes (functional changes at
the intracellular level): for example, alterations to the structure or quantity of the product
of a proto-oncogene or tumour-suppressor gene, alterations to metabolic activation/inac-
tivation/DNA repair
(iii) Evidence of relevant effects on cell behaviour (morphological or behavioural
changes at the cellular or tissue level): for example, induction of mitogenesis, compen-
satory cell proliferation, preneoplasia and hyperplasia, survival of premalignant or mali-
gnant cells (immortalization, immunosuppression), effects on metastatic potential
(iv) Evidence from dose and time relationships of carcinogenic effects and inter-
actions between agents: for example, early/late stage, as inferred from epidemiological
studies; initiation/promotion/progression/malignant conversion, as defined in animal
carcinogenicity experiments; toxicokinetics
These dimensions are not mutually exclusive, and an agent may fall within more than
one of them. Thus, for example, the action of an agent on the expression of relevant genes
could be summarized under both the first and second dimensions, even if it were known
with reasonable certainty that those effects resulted from genotoxicity.
12. EVALUATION
Evaluations of the strength of the evidence for carcinogenicity arising from human
and experimental animal data are made, using standard terms.
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It is recognized that the criteria for these evaluations, described below, cannot
encompass all of the factors that may be relevant to an evaluation of carcinogenicity. In
considering all of the relevant scientific data, the Working Group may assign the agent,
mixture or exposure circumstance to a higher or lower category than a strict inter-
pretation of these criteria would indicate.
(a) Degrees of evidence for carcinogenicity in humans and in experimental

animals and supporting evidence
These categories refer only to the strength of the evidence that an exposure is carcino-
genic and not to the extent of its carcinogenic activity (potency) nor to the mechanisms
involved. A classification may change as new information becomes available.
An evaluation of degree of evidence, whether for a single agent or a mixture, is limited
to the materials tested, as defined physically, chemically or biologically. When the agents
evaluated are considered by the Working Group to be sufficiently closely related, they
may be grouped together for the purpose of a single evaluation of degree of evidence.
(i) Carcinogenicity in humans

The applicability of an evaluation of the carcinogenicity of a mixture, process, occu-
pation or industry on the basis of evidence from epidemiological studies depends on the
variability over time and place of the mixtures, processes, occupations and industries.
The Working Group seeks to identify the specific exposure, process or activity which is
considered most likely to be responsible for any excess risk. The evaluation is focused as
narrowly as the available data on exposure and other aspects permit.
The evidence relevant to carcinogenicity from studies in humans is classified into
one of the following categories:
Sufficient evidence of carcinogenicity: The Working Group considers that a causal
relationship has been established between exposure to the agent, mixture or exposure
circumstance and human cancer. That is, a positive relationship has been observed
between the exposure and cancer in studies in which chance, bias and confounding could
be ruled out with reasonable confidence.
Limited evidence of carcinogenicity: A positive association has been observed
between exposure to the agent, mixture or exposure circumstance and cancer for which
a causal interpretation is considered by the Working Group to be credible, but chance,
bias or confounding could not be ruled out with reasonable confidence.
Inadequate evidence of carcinogenicity: The available studies are of insufficient
quality, consistency or statistical power to permit a conclusion regarding the presence or
absence of a causal association between exposure and cancer, or no data on cancer in
humans are available.
Evidence suggesting lack of carcinogenicity: There are several adequate studies
covering the full range of levels of exposure that human beings are known to encounter,
which are mutually consistent in not showing a positive association between exposure to
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PREAMBLE 25
the agent, mixture or exposure circumstance and any studied cancer at any observed level
of exposure. A conclusion of ‘evidence suggesting lack of carcinogenicity’ is inevitably
limited to the cancer sites, conditions and levels of exposure and length of observation
covered by the available studies. In addition, the possibility of a very small risk at the
levels of exposure studied can never be excluded.
In some instances, the above categories may be used to classify the degree of evi-
dence related to carcinogenicity in specific organs or tissues.
(ii) Carcinogenicity in experimental animals

The evidence relevant to carcinogenicity in experimental animals is classified into
one of the following categories:
Sufficient evidence of carcinogenicity: The Working Group considers that a causal
relationship has been established between the agent or mixture and an increased inci-
dence of malignant neoplasms or of an appropriate combination of benign and malignant
neoplasms in (a) two or more species of animals or (b) in two or more independent
studies in one species carried out at different times or in different laboratories or under
different protocols.
Exceptionally, a single study in one species might be considered to provide sufficient
evidence of carcinogenicity when malignant neoplasms occur to an unusual degree with
regard to incidence, site, type of tumour or age at onset.
Limited evidence of carcinogenicity: The data suggest a carcinogenic effect but are
limited for making a definitive evaluation because, e.g. (a) the evidence of carcino-
genicity is restricted to a single experiment; or (b) there are unresolved questions
regarding the adequacy of the design, conduct or interpretation of the study; or (c) the
agent or mixture increases the incidence only of benign neoplasms or lesions of uncertain
neoplastic potential, or of certain neoplasms which may occur spontaneously in high
incidences in certain strains.
Inadequate evidence of carcinogenicity: The studies cannot be interpreted as showing
either the presence or absence of a carcinogenic effect because of major qualitative or
quantitative limitations, or no data on cancer in experimental animals are available.
Evidence suggesting lack of carcinogenicity: Adequate studies involving at least two
species are available which show that, within the limits of the tests used, the agent or
mixture is not carcinogenic. A conclusion of evidence suggesting lack of carcinogenicity
is inevitably limited to the species, tumour sites and levels of exposure studied.
(b) Other data relevant to the evaluation of carcinogenicity and its mechanisms
Other evidence judged to be relevant to an evaluation of carcinogenicity and of
sufficient importance to affect the overall evaluation is then described. This may include
data on preneoplastic lesions, tumour pathology, genetic and related effects, structure–
activity relationships, metabolism and pharmacokinetics, physicochemical parameters
and analogous biological agents.
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Data relevant to mechanisms of the carcinogenic action are also evaluated. The
strength of the evidence that any carcinogenic effect observed is due to a particular
mechanism is assessed, using terms such as weak, moderate or strong. Then, the Working
Group assesses if that particular mechanism is likely to be operative in humans. The
strongest indications that a particular mechanism operates in humans come from data on
humans or biological specimens obtained from exposed humans. The data may be consi-
dered to be especially relevant if they show that the agent in question has caused changes
in exposed humans that are on the causal pathway to carcinogenesis. Such data may,
however, never become available, because it is at least conceivable that certain com-
pounds may be kept from human use solely on the basis of evidence of their toxicity
and/or carcinogenicity in experimental systems.
For complex exposures, including occupational and industrial exposures, the
chemical composition and the potential contribution of carcinogens known to be present
are considered by the Working Group in its overall evaluation of human carcinogenicity.
The Working Group also determines the extent to which the materials tested in experi-
mental systems are related to those to which humans are exposed.
(c) Overall evaluation

Finally, the body of evidence is considered as a whole, in order to reach an overall
evaluation of the carcinogenicity to humans of an agent, mixture or circumstance of
exposure.
An evaluation may be made for a group of chemical compounds that have been eva-
luated by the Working Group. In addition, when supporting data indicate that other,
related compounds for which there is no direct evidence of capacity to induce cancer in
humans or in animals may also be carcinogenic, a statement describing the rationale for
this conclusion is added to the evaluation narrative; an additional evaluation may be
made for this broader group of compounds if the strength of the evidence warrants it.
The agent, mixture or exposure circumstance is described according to the wording
of one of the following categories, and the designated group is given. The categorization
of an agent, mixture or exposure circumstance is a matter of scientific judgement, reflec-
ting the strength of the evidence derived from studies in humans and in experimental
animals and from other relevant data.
Group 1 — The agent (mixture) is carcinogenic to humans.

The exposure circumstance entails exposures that are carcinogenic to humans.
This category is used when there is sufficient evidence of carcinogenicity in humans.
Exceptionally, an agent (mixture) may be placed in this category when evidence of carci-
nogenicity in humans is less than sufficient but there is sufficient evidence of carcino-
genicity in experimental animals and strong evidence in exposed humans that the agent
(mixture) acts through a relevant mechanism of carcinogenicity.
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PREAMBLE 27
Group 2
This category includes agents, mixtures and exposure circumstances for which, at
one extreme, the degree of evidence of carcinogenicity in humans is almost sufficient, as
well as those for which, at the other extreme, there are no human data but for which there
is evidence of carcinogenicity in experimental animals. Agents, mixtures and exposure
circumstances are assigned to either group 2A (probably carcinogenic to humans) or
group 2B (possibly carcinogenic to humans) on the basis of epidemiological and experi-
mental evidence of carcinogenicity and other relevant data.
Group 2A — The agent (mixture) is probably carcinogenic to humans.

The exposure circumstance entails exposures that are probably carcinogenic to
humans.
This category is used when there is limited evidence of carcinogenicity in humans
and sufficient evidence of carcinogenicity in experimental animals. In some cases, an
agent (mixture) may be classified in this category when there is inadequate evidence of
carcinogenicity in humans, sufficient evidence of carcinogenicity in experimental
animals and strong evidence that the carcinogenesis is mediated by a mechanism that
also operates in humans. Exceptionally, an agent, mixture or exposure circumstance may
be classified in this category solely on the basis of limited evidence of carcinogenicity in
humans.
Group 2B — The agent (mixture) is possibly carcinogenic to humans.

The exposure circumstance entails exposures that are possibly carcinogenic to
humans.
This category is used for agents, mixtures and exposure circumstances for which
there is limited evidence of carcinogenicity in humans and less than sufficient evidence
of carcinogenicity in experimental animals. It may also be used when there is inadequate
evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity
in experimental animals. In some instances, an agent, mixture or exposure circumstance
for which there is inadequate evidence of carcinogenicity in humans but limited evidence
of carcinogenicity in experimental animals together with supporting evidence from other
relevant data may be placed in this group.
Group 3 — The agent (mixture or exposure circumstance) is not classifiable as to its

carcinogenicity to humans.
This category is used most commonly for agents, mixtures and exposure circums-
tances for which the evidence of carcinogenicity is inadequate in humans and inadequate
or limited in experimental animals.
Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inade-
quate in humans but sufficient in experimental animals may be placed in this category
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when there is strong evidence that the mechanism of carcinogenicity in experimental

animals does not operate in humans.
Agents, mixtures and exposure circumstances that do not fall into any other group are
also placed in this category.
Group 4 — The agent (mixture) is probably not carcinogenic to humans.

This category is used for agents or mixtures for which there is evidence suggesting
lack of carcinogenicity in humans and in experimental animals. In some instances, agents
or mixtures for which there is inadequate evidence of carcinogenicity in humans but
evidence suggesting lack of carcinogenicity in experimental animals, consistently and
strongly supported by a broad range of other relevant data, may be classified in this group.
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Updating of Selected IARC Monographs from Volumes 1 to 42, Lyon, IARCPress, pp. 687–696
Wilbourn, J., Haroun, L., Heseltine, E., Kaldor, J., Partensky, C. & Vainio, H. (1986) Response of
experimental animals to human carcinogens: an analysis based upon the IARC Monographs
Programme. Carcinogenesis, 7, 1853–1863
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GENERAL REMARKS ON THE SUBSTANCES CONSIDERED
This eighty-seventh volume of IARC Monographs contains evaluations of inorganic

and organic lead compounds. Lead salts and organic lead compounds were considered by
the first IARC Monographs Working Groups (Volumes 1 and 2; IARC, 1972, 1973) and
they have been reviewed in Volume 23 (IARC, 1980) and updated in Supplement 7
(IARC, 1987). Since 1987, new epidemiological and experimental studies have become
available. An IARC Monographs Advisory Group recommended lead compounds as a
high and urgent priority for re-evaluation (IARC, 2003).
Lead is found at low concentrations in the earth’s crust, predominantly as lead sulfide,
but the widespread occurrence of lead in the environment is largely the result of
anthropogenic activity. As a result, human exposure to lead is universal, and all humans
carry a body burden of lead. Lead has long been of concern for its adverse health effects
other than cancer, in particular its neuro-developmental effects on the fetus, infants, and
children. These health effects are discussed in this Volume in some detail. Nonetheless,
the main focus of this Monograph is on the epidemiological studies and experimental
investigations attempting to determine whether exposure to lead is associated with the
development of some forms of cancer. In this database, however, there are several limita-
tions that complicate the analysis and evaluation of the carcinogenic potential of lead
compounds. Some of these limitations are discussed below.
In occupational studies on lead-exposed workers, exposure assessment is complicated
by the historical fact that workers with high exposure often were removed from the job,
either temporarily or permanently. This may introduce exposure misclassification, making
it difficult to discern dose−response relationships using conventional measures such as
cumulative exposure or duration of exposure to lead. It should be noted also that the
presence of disease can influence the toxicokinetics of lead and, consequently, the
reported concentration of lead in blood. Such effects may well affect the findings of
clinical studies based on lead measurements made after diagnosis of disease.
Although inhalation is an important route of human exposure to lead, the Working
Group noted that there was only one long-term inhalation study in experimental animals
available for evaluation, and data on inhalation toxicokinetics in humans are very limited.
To make inferences about human exposure to lead by inhalation, the Working Group
considered information on the toxicokinetics of lead by the inhalation and ingestion routes
in experimental animals. Likewise, because of the limited data in humans on mechanistic
–33–
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aspects of lead carcinogenicity, the Working Group considered mechanistic data in experi-
mental systems, in order to make inferences regarding mechanisms of lead carcino-
genicity in humans. However, definitive conclusions regarding the mechanism of carcino-
genesis of lead in humans could not be drawn.
In view of the magnitude of human exposure to organic lead, in particular tetraethyl
lead, the Working Group found it remarkable that only a single, inadequately conducted
study in experimental animals was available for evaluation, and that there are no studies
for other organic lead compounds. In addition, in the epidemiological studies of tetraethyl
lead it is not possible to separate with certainty the populations exposed to organic, but
not inorganic, lead. On the other hand, various studies indicate that organic lead com-
pounds are metabolized in vivo, at least in part, to ionic lead. To the extent to which ionic
lead, generated from organic lead compounds, is present in the body, it will be expected
to exert the toxicities associated with inorganic lead.
Despite these limitations and the resulting complexities in the analysis, several aspects
of the database stand out, as discussed below.
• Among the many neurological effects of lead, there appears to be an unusual
propensity for lead to induce brain gliomas in rats. There are also some sugges-
tions from the epidemiological studies that this type of brain tumour may be asso-
ciated with lead exposure in humans.
• Both water-soluble and water-insoluble lead compounds are capable of causing
tumours in animals at sites distant from their administration. This indicates that
biologically effective amounts of lead can be mobilized even from insoluble lead
compounds. In humans, the observation that lead poisoning can occur from
indwelling metallic lead shot indicates that toxicologically relevant amounts of
lead can be mobilized in vivo from metallic lead.
• Unlike several other metals (for example, beryllium, cadmium, chromium, and
nickel), lead compounds have repeatedly been shown to be carcinogenic in
experimental animals by the oral route.
• The evidence indicating that various lead compounds cause renal tumours in male
and female mice and rats cannot be accounted for by a male-rat-specific mecha-
nism of renal carcinogenesis.
• The extensive data on lead in experimental systems support the concept that one
expression of lead toxicity is genetic toxicity. Important mechanisms of lead
genetic toxicity include increases in reactive oxygen species and interaction with
proteins, including those involved in DNA repair.
Studies in experimental animals support the concept that the lead component of lead
compounds is critical to the carcinogenic process. For compounds such as lead arsenate
and lead chromate, whose non-lead moieties have been determined to be carcinogenic to
humans (IARC 1990, 2004), a full characterization of the cancer risk must reflect the
carcinogenic activity of both the lead and the non-lead moieties.
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GENERAL REMARKS 35
References
IARC (1972) IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man,
Vol 1, Some Inorganic Substances, Chlorinated Hydrocarbons, Aromatic Amines, N-Nitroso
Compounds, and Natural Products, Lyon
Vol 2, Some Inorganic and Organometallic Compounds, Lyon
Humans, Vol 23, Some Metals and Metallic Compounds, Lyon
IARC (1987) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Suppl 7,
Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1 to 42,
Lyon
IARC (1990) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol 49,
Chromium, Nickel and Welding, Lyon
IARC (2003) Report of an Ad-Hoc IARC Monographs Advisory Group on Priorities for Future
Evaluations (IARC Internal Report 03/001), Lyon
IARC (2004) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol 84,
Some Drinking-water Disinfectants and Contaminants, including Arsenic, Lyon
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P 033-038 DEF.qxp 09/08/2006 10:50 Page 37
MONOGRAPH ON
INORGANIC AND ORGANIC
LEAD COMPOUNDS
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Metallic lead and several inorganic and organic lead compounds have been considered
by previous working groups convened by IARC (IARC, 1972, 1973, 1976, 1980, 1987).
New data have since become available, and these are included in the present monograph
and have been taken into consideration in the evaluation. The agents considered in this
monograph are some inorganic and organic lead compounds.
1. Exposure Data
1.1 Chemical and physical data

1.1.1 Nomenclature, synonyms, trade names, molecular formulae, chemical and
physical properties
Synonyms, trade names and molecular formulae for lead and some inorganic and
organic lead compounds are presented in Table 1. The lead compounds shown are those for
which data on carcinogenicity or mutagenicity are available or which are commercially
most important. The list is not exhaustive.
Selected chemical and physical properties of the lead compounds listed in Table 1 are
presented in Table 2.
Lead (atomic number, 82; relative atomic mass, 207.2) has a valence +2 or +4. The
alchemists believed lead to be the oldest metal and associated it with the planet Saturn.
Lead is a bluish-white metal of bright lustre, is very soft, highly malleable, ductile and a
poor conductor of electricity. It is very resistant to corrosion; lead pipes bearing the insignia
of Roman emperors, used as drains from the baths, are still in service (Lide, 2003). Natural
lead is a mixture of four stable isotopes: 204Pb (1.4%), 206Pb (25.2%), 207Pb (21.7%) and
208Pb (51.7%) (O’Neil, 2003). Lead isotopes are the end-products of each of the three series
of naturally occurring radioactive elements: 206Pb for the uranium series, 207Pb for the acti-
nium series and 208Pb for the thorium series. Forty-three other isotopes of lead, all of which
are radioactive, are recognized (Lide, 2003).
–39–
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40
Table 1. Synonyms and trade names, registry numbers, molecular formulae, and molecular weights for lead and lead
compounds
Chemical name Synonyms and trade names (Chemical Abstracts Service name in italics) CAS registry Molecular formula Molecular
09/08/2006
numbera weightb
Calcium plumbate Pigment Brown 10 12013-69-3 Ca2PbO4 [351.4]

c
Lead, lead powder C.I. 77575; C.I. Pigment Metal 4; Lead element; Lead Flake; Lead S 2; 7439-92-1 Pb 207.2c
11:04
Pb-S 100; SSO 1
IARC MONOGRAPHS VOLUME 87

Lead acetate Acetic acid, lead(2+) salt; acetic acid lead salt (2:1); dibasic lead 301-04-2 Pb(C2H3O2)2 325.3
acetate; lead bis(acetate); lead diacetate; lead dibasic acetate; lead(2+)
Page 40
acetate; lead(II) acetate; neutral lead acetate; normal lead acetate;
plumbous acetate; salt of Saturn; sugar of lead
Lead acetate Acetic acid, lead(2+) salt, trihydrate; lead diacetate trihydrate; lead(II) 6080-56-4 Pb(C2H3O2)2·3H2O 379.3
trihydrate acetate trihydrate; plumbous acetate trihydrate; sugar of lead
Lead arsenate Arsenic acid (H3AsO4), lead(2+) salt (2:3); lead(2+) orthoarsenate 3687-31-8 Pb3(AsO4)2 899.4
(Pb3(AsO4)2); Nu Rexform; trilead diarsenate
Lead azide Lead azide (Pb(N3)2); lead azide (PbN6); lead diazide; lead(2+) azide; 13424-46-9 Pb(N3)2 291.2
RD 1333 [85941-57-7]
Lead bromide Lead bromide (PbBr2); lead dibromide 10031-22-8 PbBr2 367.0
Lead carbonate Carbonic acid, lead(2+) salt (1:1); lead carbonate (PbCO3); basic lead 598-63-0 PbCO3 267.2
carbonate; dibasic lead carbonate; lead(2+) carbonate; plumbous
carbonate; cerussite; white lead
Lead chloride Lead chloride (PbCl2); lead dichloride; lead(2+) chloride; lead(II) 7758-95-4 PbCl2 278.1
chloride; plumbous chloride; natural cotunite
Lead chromate Chromic acid (H2CrO4), lead(2+) salt (1:1); lead chromate(VI); lead 7758-97-6 PbCrO4 323.2
chromate (PbCrO4); lead chromium oxide (PbCrO4); plumbous [8049-64-7]
chromate; Royal Yellow 6000; chrome yellow
Lead fluoride Lead fluoride (PbF2); lead difluoride; lead difluoride (PbF2); lead(2+) 7783-46-2 PbF2 245.2
fluoride; plumbous fluoride [106496-44-0]
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Table 1 (contd)
09/08/2006
numbera weightb
Lead fluoroborate Borate(1-), tetrafluoro-, lead(2+) salt (2:1); borate(1-), tetrafluoro-, 13814-96-5 Pb(BF4)2 380.8
lead(2+); lead fluoborate; lead tetrafluoroborate; lead boron fluoride; [35254-34-3]
11:04
lead fluoroborate (Pb(BF4)2); lead(II) tetrafluoroborate
Lead hydrogen Arsenic acid (H3AsO4), lead(2+) salt (1:1); lead arsenate (PbHAsO4); 7784-40-9 PbHAsO4 347.1
arsenate acid lead arsenate; arsenic acid lead salt; lead acid arsenate; lead [14034-76-5;
Page 41
arsenate; lead hydrogen arsenate (PbHAsO4); lead(2+) monohydrogen 37196-28-4]
arsenate
Lead iodide Lead iodide (PbI2); C.I. 77613; lead diiodide; lead(II) iodide; plumbous 10101-63-0 PbI2 461.0
iodide [82669-93-0]
Lead naphthenate Naphthenic acids, lead salts; lead naphthenates; naphthenic acid, lead 61790-14-5 Unspecified
salt; Naphthex Pb; Trokyd Lead
Lead nitrate Nitric acid, lead(2+) salt; lead dinitrate; lead nitrate (Pb(NO3)2); 10099-74-8 Pb(NO3)2 331.2
lead(2+) bis(nitrate); lead(2+) nitrate; lead(II) nitrate; plumbous nitrate [18256-98-9]
Lead dioxide Lead oxide (PbO2); C.I. 77580; lead brown; lead oxide brown; lead 1309-60-0 PbO2 239.2
peroxide; lead superoxide; lead(IV) oxide; plumbic oxide; Thiolead A [60525-54-4]
Lead monoxide Lead oxide (PbO); C.I. 77577; C.I. Pigment Yellow 46; lead 1317-36-8 PbO 223.2
monooxide; lead oxide yellow; lead protoxide; lead(2+) oxide; lead(II) [1309-59-7;
oxide; litharge; Litharge S; Litharge Yellow L-28; plumbous oxide; 12359-23-8]
yellow lead ochre
Lead trioxide Lead trioxide (Pb2O3); C.I. 77579; lead sesquioxide; lead sesquioxide 1314-27-8 Pb2O3 462.4
(Pb2O3); plumbous plumbate
Lead phosphate Phosphoric acid, lead(2+) salt (2:3); lead phosphate (Pb3P2O8); C.I. 7446-27-7 Pb3(PO4)2 811.5
77622; C.I. Pigment White 30; lead diphosphate; lead orthophosphate;
lead phosphate (3:2); lead(2+) phosphate (Pb3(PO4)2); lead(II) phosphate
(3:2); Perlex Paste 500; Perlex Paste 600A; Trilead phosphate; lead
phosphate dibasic
41
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42
Table 1 (contd)
09/08/2006
numbera weightb
Lead phosphite, Dibasic lead phosphite; lead dibasic phosphite; dibasic lead 1344-40-7 2PbO·PbHPO3·1/2H2O [743]
dibasic metaphosphate; C.I. 77620; lead oxide phosphonate, hemihydrate
Lead molybdate Lead molybdate(VI); lead molybdate oxide (PbMoO4) 10190-55-3 PbMoO4 367.1
11:04
Lead stearate Octadecanoic acid, lead(2+) salt; 5002G; lead distearate; lead(2+) 1072-35-1 Pb(C18H35O2)2 774.1

octadecanoate; lead(2+) stearate; lead(II) octadecanoate; lead(II) [11097-78-2;
stearate; Listab 28ND; Pbst; SL 1000 (stabilizer); SLG; Stabinex NC18; 37223-82-8]
Page 42
stearic acid, lead(2+) salt
Lead stearate, Dibasic lead stearate; Listab 51; lead, bis(octadecanoato)dioxodi-; 56189-09-4 2PbO·Pb(C17H35COO)2 1220
dibasic stearic acid, lead salt, dibasic
Lead styphnate 1,3-Benzenediol, 2,4,6-trinitro-, lead(2+) salt (1:1); 2,4-dioxa-3- 15245-44-0 Pb(C6H3N3O8) [452.3]
plumbabicyclo[3.3.1]nona-1(9),5,7-triene, 3,3-didehydro-6,8,9-trinitro-; [4219-19-6;
lead, [styphnato(2-)]-; lead tricinate; lead trinitroresorcinate; Tricinat; 6594-85-0;
2,4,6-trinitroresorcinol, lead(2+) salt (1:1) 59286-40-7;
63918-97-8]
Lead subacetate Lead, bis(acetato-êO)tetrahydroxytri-; lead acetate (Pb3(AcO)2(OH)4); 1335-32-6 Pb(CH3COO)2·2Pb(OH)2 807.7
lead, bis(acetato)-tetrahydroxytri-; lead, bis(acetato-O)tetra-hydroxytri-;
bis(acetato)dihydroxytrilead; lead acetate hydroxide (Pb3(OAc)2(OH)4);
lead acetate, basic; monobasic lead acetate
Lead sulfate Sulfuric acid, lead(2+) salt (1:1); Anglislite; C.I. 77630; C.I. Pigment 7446-14-2 PbSO4 303.3
White 3; Fast White; Freemans White Lead; HB 2000; Lead Bottoms; [37251-28-8]
lead monosulfate; lead(II) sulfate (1:1); lead(2+) sulfate; lead(II) sulfate;
Milk White; Mulhouse White; TS 100; TS 100 (sulfate); TS-E;
sublimed white lead
Lead sulfide Lead sulfide (PbS); C.I. 77640; lead monosulfide; lead sulfide (1:1); 1314-87-0 PbS 239.3
lead(2+) sulfide; lead(II) sulfide; natural lead sulfide; P 128; P 37; [51682-73-6]
plumbous sulfide
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09/08/2006
Table 1 (contd)
11:04
numbera weightb
Page 43
Lead tetraoxide Lead oxide (Pb3O4); Azarcon; C.I. 77578; C.I. Pigment Red 105; Entan; 1314-41-6 Pb3O4 685.6
Gold Satinobre; Heuconin 5; lead orthoplumbate; lead oxide (3:4); lead [12684-34-3]
oxide red; lead tetroxide; Mennige; Mineral Orange; Mineral red;
Minium; Minium Non-Setting RL 95; Minium red; Orange Lead; Paris
Red; red lead; red lead oxide; Sandix; Saturn Red; trilead tetraoxide;
trilead tetroxide; plumboplumbic oxide
Lead thiocyanate Thiocyanic acid, lead(2+) salt; lead bis(thiocyanate); lead dithiocyanate; 592-87-0 Pb(SCN)2 323.4
lead(2+) thiocyanate; lead(II) thiocyanate [10382-36-2]
Tetraethyl lead Plumbane, tetraethyl-; lead, tetraethyl-; TEL; tetraethyllead; 78-00-2 Pb(C2H5)4 323.5
tetraethylplumbane
Tetramethyl lead Plumbane, tetramethyl-; lead, tetramethyl-; tetramethyllead; 75-74-1 Pb(CH3)4 267.3
tetramethylplumbane; TML
From IARC (1980); Lide (2003); National Library of Medicine (2003); O’Neil (2003); STN International (2003)
a
Deleted Chemical Abstracts Service numbers shown in square brackets
b
Values in square brackets were calculated from the molecular formula.
c
Atomic formula; atomic weight
43
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44
Table 2. Physical and chemical properties of lead and lead compounds
09/08/2006
Chemical name Physical form Melting-point (°C) Boiling-point Density Solubility (per 100 g H2O)
(°C) (g/cm3)
Lead, lead powder Soft silvery-gray metal; cubic 327.5 1749 11.3 Insol. in water; sol. in conc. acid
Lead acetate White crystal 280 Dec. 3.25 44.3 g at 20 °C; sl. sol. in
ethanol
11:04
Lead acetate trihydrate Colourless crystal 75 (dec) – 2.55 45.6 g at 15 °C; sl. sol. in

ethanol
Lead arsenate White crystal 1042 (dec) – 5.8 Insol. in water; sol. in nitric acid
Page 44
Lead azide Colourless orthorhombic needle ~350 (expl) – 4.7 23 mg at 18 °C; v. sol. in acetic
acid
Lead bromide White orthorhombic crystal 371 892 6.69 975 mg at 25 °C; insol. in
ethanol
Lead carbonate Colourless orthorhombic crystal ~315 (dec) – 6.6 Insol. in water; sol. in acid and
alkaline solutions
Lead chloride White orthorhombic needle or 501 951 5.98 1.08 g at 25 °C; sol. in alkaline
powder solutions; insol. in ethanol
Lead chromate Yellow-orange monoclinic 844 – 6.12 17 µg at 20 °C; sol. in dilute
crystals acids
Lead fluoride White orthorhombic crystal 830 1293 8.44 67 mg at 25 °C
Lead fluoroborate Stable only in aqueous solution – – – Sol. in water
Lead hydrogen arsenate White monoclinic crystal 280 (dec) 5.94 Insol. in water; sol. in nitric acid
and alkaline solutions
Lead iodide Yellow hexagonal crystal or 410 872 (dec) 6.16 76 mg at 25 °C; insol. in ethanol
powder
Lead molybdate Yellow tertiary crystal ∼1060 – 6.7 Insol. in water; sol. in nitric acid
and sodium hydroxide
Lead naphthenate No data available
Lead nitrate Colourless cubic crystal 470 – 4.53 59.7 g at 25 °C; sl. sol. in
ethanol
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Table 2 (contd)
09/08/2006
Chemical name Physical form Melting-point (°C) Boiling-point Density Solubility (per 100 g H2O)
(°C) (g/cm3)
Lead monoxide (PbO); Red tetrahedral crystal Transforms to – 9.35 Insol. in water and ethanol; sol.

litharge massicot at 489 °C in dilute nitric acid
11:04
Massicot Yellow orthorhombic crystal 897 – 9.64 Insol. in water and ethanol; sol.
in dilute nitric acid
Lead trioxide (Pb2O3) Black monoclinic crystal or red 530 (dec) – 10.05 Insol. in water; sol. in alkaline
Page 45
amorphous powder solutions
Lead phosphate White hexagonal crystal 1014 – 7.01 Insol. in water and ethanol; sol.
in alkali and nitric acid
Lead phosphite, dibasic Pale yellow powder 6.1
Lead stearate White powder ~100 – 1.4 Insol. in water; sol. in hot
ethanol
Lead styphnate No data available
Lead subacetate White powder Dec. – – 6.3 g at 0 °C; 25 g at 100 °C
Lead sulfate Orthorhombic crystal 1087 – 6.29 4.4 mg at 25 °C; sl. sol. in
alkaline solutions; insol. in acids
Lead sulfide Black powder or silvery cubic 1113 – 7.60 Insol. in water; sol. in acids
crystal
Lead tetraoxide Red tetrahedral crystals 830 – 8.92 Insol. in water and ethanol; sol.
in hot hydrochloric acid
Lead thiocyanate White to yellowish powder – – 3.82 50 mg at 20 °C
Tetraethyl lead Liquid –136 200 (dec) 1.653 at Insol. in water; sol. in benzene;
20 °C sl. sol. in ethanol and diethyl
ether
Tetramethyl lead Liquid –30.2 110 1.995 at Insol. in water; sol. in benzene,
20 °C ethanol and diethyl ether
From IARC (1980); Lide (2003); Physical and Theoretical Chemistry Laboratory (2004)
Abbreviations: conc., concentrated; insol., insoluble; sl. sol., slightly soluble; sol., soluble; v. sol., very soluble; dec, decomposes; expl., explodes
45
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1.1.2 Technical products and impurities

Lead is produced in purity greater than 99.97% in many countries. Lead oxides and
mixtures of lead and lead oxides are also widely available. Tables 3 and 4 show the
specifications for metallic lead and some lead compounds, respectively, from selected
countries.
Table 3. Specifications for metallic lead from selected countries
Country % Pb (min.) Contaminants with limits (% max.a) Reference
Argentina 99.97 Fe, 0.002; Sb, 0.004; Zn, 0.001; Cu, 0.002; Industrias Deriplom
Ag, 0.0095; Bi, 0.035; Cd, 0.001; Ni, 0.001 SA (2003)
Australia 99.97–99.99 Ag, 0.001; As, 0.001; Bi, 0.005–0.029; Cu, Pasminco Metals
0.001; Sb, 0.001; Zn, 0.001; Cd, 0.001 (1998)
Belgium 99.9–99.95 (ppm) Bi, 90–250; Ag, 10–15; Cu, 5–10; Umicore Precious
As, 5; Sb, 3; Sn, 3; As+Sb+Sn, 8; Zn, 3–5; Metals (2002)
Fe, 3; Cd, 3–10; Ni, 2–3
Bulgaria 99.97–99.99 Ag, 0.001–0.005; Cu, 0.0005–0.003; Zn, KCM SA (2003)
0.0002–0.0015; Fe, 0.001; Cd, 0.0002–
0.001; Ni, 0.0005–0.001; As, 0.0005–0.002;
Sb, 0.0005–0.005; Sn, 0.0005–0.001; Bi,
0.005–0.03
Canada 99.97–99.99 NR Noranda (2003);
Teck Cominco
(2003)
Kazakhstan 99.95–99.9996 NR Southpolymetal
(2003)
Mexico 99.97–99.99 Ag, 0.0015; Cu, 0.0005; Zn, 0.0005; Fe, Penoles (2003)
0.0010; Bi, 0.0250; Sb, 0.0005; As, 0.0005;
Sn, 0.0005; Ni, 0.0002; Te, 0.0001
Republic 99.995 Ag, 0.0003; Cu, 0.0003; As, 0.0003; Sb, Korea Zinc Co.
of Korea 0.0003; Zn, 0.0003; Fe, 0.0003; Bi, 0.0015; (2003)
Sn, 0.0003
USA 99.995– (ppm) Sb, 1; As, 1–5; Bi, 0.2–4; Cu, 1–4; ESPI Corp. (2002)
99.9999 Ag, < 0.1–2; Tl, 1–2; Sn, 0.3–1; Fe, < 0.1–
0.3; Ca, 0.1–0.4; Mg, 0.1–0.3
NR, not reported

a
Unless otherwise specified
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09/08/2006
Table 4. Specifications for some lead compounds from selected countries
Country Compound Contaminants with limits (% max.) Gradea Reference

Argentina Lead oxide Fe, 0.003; Sb, 0.001–0.004; Zn, 0.0005– 5 grades of red lead (Pb3O4 + PbO2 + PbO); Industrias
11:04
0.001; Cu, 0.0005–0.002; Ag, 0.001–0.0095; 3 grades of yellow litharge (PbO, 99.65– Deriplom SA
Bi, 0.003–0.035; Cd, 0.0008–0.001; Ni, 99.96%; free Pb, 0.03–0.30%; Pb3O4, (2003)
0.0008–0.001 0.0048–0.05%); 1 grade of green powder
Page 47
(PbO + Pb, 80%+20% or 62%+38%)
Australia Lead oxide Bi, 0.05–0.06; Ag, 0.001; Cu, 0.001; Sn, VRLA-refinedTM and MF-refinedTM Pasminco
0.0005–0.001; Sb, 0.0001–0.0002; As, Metals (2000)
0.0001; Se, 0.0001; S, 0.0007; Cd, 0.0005;
Ni, 0.0002–0.0003; Zn, 0.0005; Fe, 0.0002–
0.0005; Mn, 0.0003–0.0005; Te, 0.00003–
0.0001; Co, 0.0001–0.0002; Cr, 0.0002;
Ba, 0.0005; V, 0.0004; Mo, 0.0003–0.0005
USA Lead acetate NR 5N ESPI Corp.
Lead bromide 3N and 5N (2002)
Lead chloride 3N and 5N
Lead fluoride 3N
Lead iodide 3N and 5N
Lead molybdate 3N
Lead monoxide 3N and 5N
Lead tetraoxide 3N
Lead sulfide 3N and 5N
VRLA, valve-regulated lead acid; MF, maintenance-free; NR, not reported

a
3N, 99.9%; 5N, 99.999%
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1.2 Production
Commercial lead metal is described as being either primary or secondary. Primary
lead is produced directly from mined lead ore. Secondary lead is produced from scrap lead
products which have been recycled.
1.2.1 The ores and their preparation

The most important lead ore is galena (lead sulfide). Other important ores such as
cerussite (lead carbonate) and anglesite (lead sulfate) may be regarded as weathered
products of galena and are usually found nearer to the surface of the earth’s crust. Lead
and zinc ores often occur together and, in most extraction methods, have to be separated.
The most common separation technique is selective froth flotation. The ore is first
processed to a fine suspension in water by grinding in ball or rod mills — preferably to a
particle size of < 0.25 mm. Air is then bubbled through this pulp contained in a cell or tank
and, following the addition of various chemicals and proper agitation, the required
mineral particles become attached to the air bubbles and are carried to the surface to form
a stable mineral-containing froth which is skimmed off. The unwanted or gangue particles
are unaffected and remain in the pulp. For example, with lead–zinc sulfide ores, zinc
sulfate, sodium cyanide or sodium sulfite can be used to depress the zinc sulfide, while
the lead sulfide is floated off to form a concentrate. The zinc sulfide is then activated by
copper sulfate and floated off as a second concentrate (Lead Development Association
International, 2003a).
Around 3 million tonnes of lead are mined in the world each year. Lead is found all
over the world but the countries with the largest mines are Australia, China and the United
States of America, which together account for more than 50% of primary production. The
most common lead ore is galena (lead sulfide). Other elements frequently associated with
lead include zinc and silver. In fact, lead ores constitute the main sources of silver, contri-
buting substantially towards the world’s total silver output (Lead Development
Association International, 2003b). Table 5 shows mine production of lead concentrate by
country in the year 2000. Table 6 shows the trends in lead mine production by geographic
region from 1960 to 2003.
1.2.2 Smelting
(a) Two-stage processes
The first stage in smelting consists of removing most of the sulfur from the lead con-
centrate. This is achieved by a continuous roasting process (sintering) in which the lead
sulfide is largely converted to lead oxide and broken down to a size convenient for use in
a blast furnace — the next stage in the process. The sinter plant gases containing sulfur
are converted to sulfuric acid (Lead Development Association International, 2003a).
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INORGANIC AND ORGANIC LEAD COMPOUNDS 49
Table 5. Mine production of lead concentrate in 2000a
Country Production Country Production

(tonnes) (tonnes)
Algeria 818 Mexico 137 975

Argentina 14 115 Morocco 81 208c
Australia 739 000 Myanmar 1 200b
Bolivia 9 523 Namibia 11 114c
Bosnia and Herzegovina 200b Peru 270 576
Brazil 8 832 Poland 51 200c
Bulgaria 10 500 Republic of Korea 2 724
Canada 152 765 Romania 18 750c
Chile 785c Russian Federation 13 300
China 660 000b Serbia and Montenegro 9 000
Colombia 226 South Africa 75 262
Democratic People’s 60 000b,c Spain 40 300
Republic of Korea Sweden 106 584c
Ecuador 200b Tajikistan 800b
Georgia 200b Thailand 15 600
Greece 18 235b The former Yugoslav 25 000b
Honduras 4 805 Republic of Macedonia
India 28 900 Tunisia 6 602
Iran 15 000b Turkey 17 270
Ireland 57 825 United Kingdom 1 000b
Italy 2 000 USA 465 000
Japan 8 835 Viet Nam 1 000b
Kazakhstan 40 000 World totald 3 180 000c
From Smith (2002)

In addition to the countries listed, lead is also produced in Nigeria, but information is
inadequate to estimate output.
a
Data available at 1 July 2003
b
Estimated
c
Revised
d
Data from the USA and estimated data are rounded to no more than three significant
digits, so that values may not add to total shown.
The graded sinter (lead oxide) is mixed with coke and flux, such as limestone, and fed
into the top of the blast furnace, where it is smelted using an air blast (sometimes pre-
heated) introduced near the bottom. The chemical processes that take place in the furnace
at about 1200 °C result in the production of lead bullion (lead containing only metallic
impurities) which is tapped off from the bottom of the furnace and either cast into ingots
or collected molten in ladles for transfer to the refining process. In the Imperial Smelting
Furnace process, a very similar procedure is used for the simultaneous production of zinc
and lead.
These traditional two-stage processes largely favour the release of hazardous dusts and
fumes. They necessitate the use of extensive exhaust ventilation and result in large volumes
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Table 6. Trends in lead mine production worldwide
Year Production (thousand tonnes) by geographical regiona
Ab B C Db E Fb Total
1960 370 207 822 84 306 583 2372

1965 366 250 984 99 361 724 2784
1970 476 210 1341 120 441 855 3443
1975 435 165 1340 140 395 1085 3560
1980 482 278 1298 112 382 1030 3582
1985 412 261 1197 155 474 1076 3575
1990 727 175 1184 545 556 NRS 3187
1995 382 186 1047 715 424 NRS 2753
2000 360 178 1053 805 650 NRS 3046
2003 218 123 1043 770 666 NRS 2821
From International Lead and Zinc Study Group (1990, 2004)

NRS, not reported separately
a
Data from following countries:
A, Austria, Denmark, Finland, France, Germany (the Federal Republic of Germany before
reunification), Greece, Ireland, Italy, Norway, Portugal, Spain, Sweden, United Kingdom and
former Yugoslavia
B, Algeria, Congo, Morocco, Namibia, South Africa, Tunisia and Zambia
C, Argentina, Bolivia, Brazil, Canada, Chile, Colombia, Guatemala, Honduras, Mexico,
Nicaragua, Peru and USA
D, Myanmar, India, Iran, Japan, Philippines, Republic of Korea, Thailand and Turkey
E, Australia
F, Bulgaria, China, former Czechoslovakia, Hungary, People’s Democratic Republic of Korea,
Poland, Romania and the former Soviet Union; values for the latter four countries are estimates.
b
From 1990 onwards, data from region F are included in region A (for Belarus, Bulgaria, Czech
Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Romania, the Russian Federation,
Slovakia and Ukraine) or region D (for all former Soviet Republics, China and People’s Demo-
cratic Republic of Korea); lead mine production for 1991 in the former Soviet Union is split as
follows: Europe, 19%; Asia, 81%.
of lead-laden exhaust gases which are usually cleaned before they are discharged into the
atmosphere. The collected dusts are returned to the smelting process (Lead Development
Association International, 2003a).
(b) Direct smelting processes

The environmental problems and inefficient use of energy associated with the sinter/
blast furnace and Imperial Smelting Furnace processes have led to a considerable amount
of research into more economical and less polluting methods for the production of lead.
Most of this research has been aimed at devising processes in which lead is converted
directly from the sulfide to the metal without producing lead oxide. As a result, a number
P 039-074 DEF.qxp 09/08/2006 11:04 Page 51
of direct smelting processes now exist, although at varying stages of development (Lead
Development Association International, 2003a).
Direct smelting processes offer several significant advantages over conventional
methods. The first and most obvious advantage is that sintering is no longer necessary. As
a result, the creation of dust, a major occupational and environmental problem, is avoided.
Moreover, the heat evolved during sintering (for the oxidation of the ore) is no longer
wasted but is used in the smelting operation, thus providing a considerable saving of fuel.
The volumes of gas that require filtering are largely reduced and, at the same time, the
sulfur dioxide concentration of the off-gases is greater and these are therefore more
suitable for the manufacture of sulfuric acid. The major difficulty in all direct smelting
processes lies in obtaining both a lead bullion with an acceptably low sulfur content and
a slag with a sufficiently low lead content for it to be safely and economically discarded.
In several cases, further treatment of the crude bullion or the slag or both is required in a
separate operation. There are several direct smelting processes which come close to
meeting the desired criteria — the Russian Kivcet, the QSL (Queneau–Schuhmann–
Lurgi), the Isasmelt and the Outokumpu processes are examples. The use of these newer
processes will probably increase.
At present, the relative importance of the different smelting methods in terms of
amounts of metal produced is as follows: conventional blast furnace, 80%; Imperial
Smelting Furnace process, 10%; and direct processes, 10% (Lead Development Asso-
ciation International, 2003a).
1.2.3 Hydrometallurgical processes

With the prospect of even tighter environmental controls, the possibilities of utilizing
hydrometallurgical techniques for the treatment of primary and secondary sources of lead
are being investigated. Several processes have been described in the literature, but most
are still in the developmental stage and probably not yet economically viable in compa-
rison with the pyrometallurgical (smelting) processes. The goal of the hydrometallurgical
processes in most cases is to fix the sulfur as a harmless sulfate and to put the lead into a
solution suitable for electrolytic recovery. Most of these processes recirculate leach
solutions and produce lead of high purity. For example, the Ledchlor process can be used
on primary materials; other methods such as Rameshni SO2 Reduction (RSR) and the
processes developed by Engitec (CX-EW) and Ginatta (Maja et al., 1989) are more
concerned with recovery of lead from secondary sources, in particular from battery scrap
(Lead Development Association International, 2003a).
1.2.4 Primary lead refining

Apart from gold and silver, lead bullion contains many other metallic impurities
including antimony, arsenic, copper, tin and zinc. Copper is the first of the impurities to
be removed. The lead bullion is melted at about 300–600 °C and held just above its
P 039-074 DEF.qxp 09/08/2006 11:04 Page 52
melting-point when solid copper rises to the surface and is skimmed off. Sulfur is stirred
into the melt to facilitate the operation by producing a dry powdery dross which is more
readily removed. Once copper has been removed, there are a number of processes
available for the extraction of the other impurities from the bullion. These include pyro-
metallurgical techniques, in which elements are removed one or more at a time in several
stages, and electrolytic processes that remove most of the impurities in one operation.
Although electrolytic methods are used in large-scale production, pyrometallurgical
techniques account for the larger portion of the world’s refined lead production (Lead
Development Association International, 2003c). Table 7 shows the trends in production of
refined lead by geographic region from 1960 to 2003.
Table 7. Trends in refined lead production worldwide
Year Production (thousand tonnes) by geographical regiona
1960 950 70 1114 164 211 718 3227

1965 1046 124 1296 202 223 823 3714
1970 1412 147 1619 301 217 992 4688
1975 1354 124 1661 296 198 1195 4828
1980 1514 156 1776 397 241 1331 5415
1985 1613 159 1708 539 220 1416 5655
1990 2323 150 1900 924 229 NRS 5525
1995 1796 141 2102 1474 243 NRS 5756
2000 1882 125 2216 2163 263 NRS 6650
2003 1606 144 2043 2499 311 NRS 6603

a
Data from the following countries:
A, Austria, Belgium, Denmark, Finland, France, Germany (the Federal Republic of Germany
before reunification), Greece, Ireland, Italy, Netherlands, Norway, Portugal, Spain, Sweden,
Switzerland, United Kingdom and former Yugoslavia
B, Algeria, Morocco, Namibia, South Africa, Tunisia and Zambia
C, Argentina, Brazil, Canada, Mexico, Peru, USA and Venezuela
D, Myanmar, India, Indonesia, Japan, Malaysia, Philippines, Republic of Korea, China (Province
of Taiwan), Thailand, and Turkey
E, Australia and New Zealand
F, Bulgaria, China, former Czechoslovakia, Germany (former Democratic Republic of),
Hungary, People’s Democratic Republic of Korea, Poland, Romania and former Soviet Union;
values for Bulgaria, former German Democratic Republic, Romania, former Soviet Union, China
and People’s Democratic Republic of Korea are estimates.
b
From 1990 onwards, data from region F are included in region A (Belarus, Bulgaria, Czech
Republic, Estonia, Germany (former German Democratic Republic), Hungary, Latvia, Lithuania,
Poland, Romania, Russian Federation and Ukraine) or in region D (China, all other former Soviet
Republics and People’s Democratic Republic of Korea); refined lead production in the former
Soviet Union for 1991 is split as follows: Europe, 24%; Asia, 76%.
P 039-074 DEF.qxp 09/08/2006 11:04 Page 53
(a) Pyrometallurgical processes

(i) Removal of antimony, arsenic and tin
After the removal of copper, the next step is to remove antimony, arsenic and tin.
There are two methods available — the softening process (so-called since these elements
are standard hardeners for lead) and the Harris process. In the softening process, the lead
bullion is melted and agitated with an air blast, causing preferential oxidation of the
impurities which are then skimmed off as a molten slag. In the Harris process, the molten
bullion is stirred with a flux of molten sodium hydroxide and sodium nitrate or another
suitable oxidizing agent. The oxidized impurities are suspended in the alkali flux in the
form of sodium antimonate, arsenate and stannate, and any zinc is removed in the form
of zinc oxide (Lead Development Association International, 2003c).
(ii) Removal of silver and gold
After the removal of antimony, arsenic and tin, the softened lead may still contain
silver and gold, and sometimes bismuth. The removal of the precious metals by the Parkes
process is based on the fact that they are more soluble in zinc than in lead. In this process,
the lead is melted and mixed with zinc at 480 °C. The temperature of the melt is gradually
lowered to below 419.5 °C, at which point the zinc (now containing nearly all the silver
and gold) begins to solidify as a crust on the surface of the lead and can be skimmed off.
An alternative procedure, the Port Pirie process, used at the Port Pirie refinery in Australia,
is based on similar metallurgical principles (Lead Development Association International,
2003c).
(iii) Removal of zinc
The removal of the precious metals leaves zinc as the main contaminant of the lead.
It is removed either by oxidation with gaseous chlorine or by vacuum distillation. The
latter process involves melting the lead in a large kettle covered with a water-cooled lid
under vacuum. The zinc distils from the lead under the combined influence of temperature
and reduced pressure and condenses on the underside of the cold lid (Lead Development
Association International, 2003c).
(iv) Removal of bismuth
After removal of zinc, the only remaining impurity is bismuth, although it is not
always present in lead ore. It is easily removed by electrolysis and this accounts for the
favouring of electrolytic methods in Canada (see below), where bismuth is a frequent
impurity. When pyrometallurgical methods of refining are used, bismuth is removed by
adding a calcium–magnesium alloy to the molten lead, causing a quaternary alloy of
lead–calcium–magnesium–bismuth to rise to the top of the melt where it can be skimmed
off (Lead Development Association International, 2003c).
P 039-074 DEF.qxp 09/08/2006 11:04 Page 54
(b) Electrolytic processes

In the Betts process, massive cast anodes of lead bullion are used in a cell containing
an electrolyte of acid lead fluorosilicate and thin cathode ‘starter sheets’ of high-purity lead.
The lead deposited on the cathodes still contains tin and sometimes a small amount of
antimony, and these impurities must be removed by melting and selective oxidation. For
many years, the Betts process was the only process to remove bismuth efficiently. A more
recent electrolytic process, first used in the 1950s in Italy, employs a sulfamate electrolyte.
It is claimed to be an equally efficient refining method, with the advantage that the
electrolyte is easier to prepare (Lead Development Association International, 2003c).
By combining the processes described above to build up a complete refining scheme,
it is possible to produce lead of very high purity. Most major refiners will supply bulk
quantities of lead of 99.99% purity and, for very specific purposes, it is possible to reach
99.9999% purity by additional processing (Lead Development Association International,
2003c).
1.2.5 Secondary lead production

Much of the secondary lead comes from lead batteries, with the remainder originating
from other sources such as lead pipe and sheet. Lead scrap from pipes and sheet is ‘clean’
and can be melted and refined without the need for a smelting stage. With batteries, the lead
can only be obtained by breaking the case open. This is commonly done using a battery
breaking machine which, in addition to crushing the case, separates out the different com-
ponents of the battery and collects them in hoppers. Thus, the pastes (oxide and sulfate),
grids, separators and fragmented cases are all separated from one another. The battery acid
is drained and neutralized, and the other components are either recycled or discarded (Lead
Development Association International, 2003d).
Table 8 shows trends in recovery of secondary lead by geographic region from 1970
to 1988. Three million tonnes of lead are produced from secondary sources each year, by
recycling scrap lead products. At least three-quarters of all lead is used in products which
are suitable for recycling and hence lead has the highest recycling rate of all the common
non-ferrous metals (Lead Development Association International, 2003a). Almost 50% of
the 1.6 million tonnes of lead produced in Europe each year has been recycled. In the
United Kingdom, the figure is nearer 60% (Lead Development Association International,
2003d).
(a) Secondary lead smelting

The workhorse of the secondary lead production industry used to be the blast furnace.
Conversion from blast to rotary-furnace technology in Europe began in the 1960s and was
largely complete by the 1990s, driven by the high price of metallurgical coke and the
relative difficulty of preventing the escape of dust and fume. The blast furnace was used to
provide a low-grade antimonial lead, which was softened. The high-antimony slags were
accumulated for a subsequent blast furnace campaign to produce a high-antimony bullion
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Table 8. Trends in recovery of secondary lead (refined lead and

lead alloys produced from secondary materials)
Year Recovery (thousand tonnes) by geographical regiona
A B C D E Total
1970 619 21 532 78 37 1287

1975 617 29 610 115 39 1410
1980 742 44 798 192 39 1815
1985 766 44 747 258 20 1835
1988 800 48 921 310 23 2102
From International Lead and Zinc Study Group (1990)

a
A, Austria, Belgium, Denmark, Finland, France, Germany (the Federal Republic of
Germany before reunification), Greece, Ireland, Italy, Netherlands, Portugal, Spain,
Sweden, Switzerland, United Kingdom and former Yugoslavia
B, Algeria, Morocco and South Africa
C, Argentina, Brazil, Canada, Mexico, USA and Venezuela
D, India, Japan and China (Province of Taiwan)
for blending into lead alloys. Although a few secondary smelters today still use furnaces
based on blast furnace technology, most companies now use rotary furnaces in which the
charge can be tailored to give a lead of approximately the desired composition. Alter-
natively, a two-stage smelting procedure can be employed, which yields crude soft lead and
crude antimonial lead. In the latter process, for example, battery plates are first melted and
crude soft lead is tapped off after a few hours while the antimonial slag and lead oxide and
sulfate are retained in the furnace. Further plates are charged and more soft lead is with-
drawn until sufficient slag has accumulated for the slag reduction stage. Then, coke or
anthracite fines and soda ash are added, lead and antimony oxides and lead sulfate are
reduced and the cycle ends with the furnace being emptied of antimonial lead and of slag
for discarding. As with primary smelting, large volumes of gas are produced, carrying
substantial quantities of dust. On leaving the smelter, the gases are cooled from about
900 °C to about 100 °C using air and/or water cooling, and pass into a baghouse where the
dust is collected and eventually fed back into the smelter. The gases subsequently are
released into the atmosphere. In the course of processing one tonne of lead, as much as 100
tonnes of air have to be cleaned in this way (Lead Development Association International,
2003d).
In the semi-continuous Isasmelt furnace process used for secondary lead production,
the furnace is fed with a lead carbonate paste containing 1% sulfur. This is obtained as a
result of the battery paste having gone through a desulfurizing process after battery
breaking. Over the following 36 h, wet lead carbonate paste and coal as a reductant are
continuously fed into the furnace. The soft lead that is produced is tapped every 3 h and
P 039-074 DEF.qxp 09/08/2006 11:04 Page 56
contains 99.9% lead. After 36 h, the paste feed is stopped and the slag is reduced to
produce antimonial lead alloy. As with the two-stage process described above, off-gases
from the furnace are first cooled and then passed into a baghouse for fume and dust
control (Lead Development Association International, 2003d).
(b) Secondary lead refining

The principal impurities that are removed in secondary lead refining are copper, tin,
antimony and arsenic. Zinc, iron, nickel, bismuth, silver and other impurities may also be
present. These impurities are generally removed using the same basic techniques as
described above (Lead Development Association International, 2003d).
1.2.6 Lead production by compound and country

Table 9 summarizes the available information on the number of companies in various
countries producing metallic lead and some lead compounds in 2002.
1.3 Use
Over the centuries the unique properties of lead have resulted in its use in many
different applications. These properties are mainly its high resistance to corrosion, its
softness and low melting-point, its high density and its relatively low conductivity (Lead
Development Association International, 2003b).
Large quantities of lead, both as the metal and as the dioxide, are used in storage
batteries. Lead is also used for cable covering, plumbing and ammunition. The metal is
very effective as a sound absorber and as a radiation shield around X-ray equipment and
nuclear reactors. It is also used to absorb vibration. Lead, alloyed with tin, is used in
making organ pipes. Lead carbonate (PbCO3), lead sulfate (PbSO4), lead chromate
(PbCrO4), lead tetraoxide (Pb3O4) and other lead compounds (see Table 1 for synonyms)
have been applied extensively in paints, although in recent years this use has been curtailed
to reduce health hazards. Lead oxide (usually lead monoxide) is used in the production of
fine ‘crystal glass’ and ‘flint glass’ with a high index of refraction for achromatic lenses.
Lead nitrate and acetate are soluble salts that serve as intermediates and in specialty
applications. Lead salts such as lead arsenate have been used as insecticides, but in recent
years this use has been almost eliminated (Lide, 2003).
In most countries, lead is predominantly used as the metal and it may be alloyed with
other materials depending on the application. Lead alloys are made by the controlled
addition of other elements. The term ‘unalloyed lead’ implies that no alloying elements
have been added intentionally; this may mean that the lead is of high purity, but the term
also covers less pure lead containing incidental impurities (Lead Development Asso-
ciation International, 2003e).
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Table 9. Lead production by compound and country
Compound No. of Countries

companies
Metallic lead 10 Japan

6 USA
5 China, Mexico
4 Belgium, Canada
3 Brazil, Germany, Peru, Russian Federation
2 Kazakhstan
1 Argentina, Australia, Bolivia, Bulgaria, China (Province of
Taiwan), Egypt, India, Ireland, Italy, Netherlands, Republic of
Korea, Spain, Sweden, Turkey
Lead acetate 10 China
8 India
7 Mexico
6 USA
5 Brazil, Japan
3 Spain
2 Germany, Italy
1 Australia, China (Province of Taiwan), France, Romania, Russian
Federation
Lead arsenate 3 Japan
1 Peru
Lead azide 2 Brazil
1 Japan
Lead bromide 1 Germany, India, Japan, United Kingdom, USA
Lead carbonate 6 India
2 China, China (Province of Taiwan), Germany, USA
1 Argentina, Australia, Italy, Japan, Mexico, Republic of Korea,
Romania, Ukraine and United Kingdom
Lead chloride 5 India
4 USA
1 Australia, Belgium, China, China (Province of Taiwan),
Germany, Japan, Mexico, Romania, Spain
Lead chromate 22 China
(Pigment 8 India
Yellow 34) 6 USA
5 China (Province of Taiwan), Japan, Spain
3 Germany, Italy
2 Brazil, Republic of Korea, Netherlands, United Kingdom
1 Argentina, Austria, Belgium, Canada, Colombia, France, Mexico,
Peru, Romania, Russian Federation, Turkey, Venezuela
Lead fluoride 4 China
3 India, Japan, USA
1 Argentina, Canada, France, Germany
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Table 9 (contd)

companies
Lead fluoroborate 7 China, India

5 USA
3 Japan
2 Australia, China (Province of Taiwan), France, Germany
1 Argentina, Brazil, Russian Federation, Spain
Lead iodide 2 Japan, United Kingdom
1 China, India, USA
Lead naphthenate 6 China
5 Japan, Mexico
3 Argentina, USA
2 France, India, Peru, Spain
1 Australia, Belgium, Brazil, Canada, China (Province of Taiwan),
Germany, Italy, Romania, Thailand, Turkey
Lead nitrate 12 India
8 China
7 USA
6 Japan
4 Brazil, Mexico
3 Spain
2 Belgium, Germany
1 Australia, Italy, Russian Federation, Tajikistan
Lead monoxide 24 China
7 Japan
6 India
4 China (Province of Taiwan), Germany, Mexico, USA
3 France, Spain
2 Brazil, Italy, Peru, Republic of Korea, Russian Federation
1 Argentina, Australia, Canada, Kazakhstan, Malaysia, Portugal,
South Africa, Tajikistan, Turkey, United Kingdom
Lead dioxide 6 India
4 Japan
3 USA
2 Germany
1 Australia, Italy, South Africa, Spain, United Kingdom
Lead phosphate 6 China
2 India
1 Japan, Russian Federation
Lead stearate 25 China
17 India
9 China (Province of Taiwan)
4 Japan
3 Germany, Spain, Thailand
2 Mexico, Peru, Philippines, Republic of Korea, USA
1 Albania, Argentina, Belgium, Brazil, Indonesia, Italy, Portugal,
Romania, South Africa, Turkey
P 039-074 DEF.qxp 09/08/2006 11:04 Page 59
Table 9 (contd)

companies
Lead stearate, 15 India

dibasic 8 China
2 Japan, Philippines, Spain, Thailand, USA
1 Belgium, Germany, Indonesia, Peru, Republic of Korea, South
Africa, Turkey, United Kingdom
Lead styphnate 2 Brazil
1 Japan
Lead subacetate 4 India
3 Mexico
2 China
1 Australia, Brazil, China (Province of Taiwan), Romania, Spain,
USA
Lead sulfate 6 India
4 Mexico
3 Germany
2 Spain
1 China, Japan, Romania, USA
Lead sulfide 4 India
2 France, Japan
1 Austria, China, Germany, USA
Lead tetraoxide 22 China
5 India, Japan
3 Mexico, Spain
2 Brazil, France, Germany, Italy, Russian Federation, USA
1 Argentina, Kazakhstan, Peru, Poland, Portugal, Republic of
Korea, South Africa, Tajikistan, Turkey, United Kingdom
Lead thiocyanate 2 USA
Lead trioxide 1 China
Tetraethyl lead 1 Germany, Italy
Tetramethyl lead 2 Russian Federation
1 Italy
From Chemical Information Services (2003)

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Trends in the reported consumption of lead by geographical region between 1960 and
2003 are shown in Table 10. Tables 11 and 12 show the trends in total lead consumption
by country and by major use category, respectively, in selected countries between 1985
and 2001.
For six of the major lead-consuming countries (France, Germany, Italy, Japan, the
United Kingdom, USA), detailed historical data are available from 1960 to 1990 (Tables
13–19). In this period, total consumption of lead reported by these countries rose from 2.06
to 2.94 million tonnes, an overall increase of 43% and an average annual increase of 1.2%.
During those three decades, however, there were marked changes in the rates of lead
consumption. These included: (1) the rapid expansion of consumption during the 1960s
and early 1970s leading to peak levels in 1973 prior to the onset of the first world energy
crisis; (2) the steep reduction in 1974–75 and the subsequent revival in 1977–79, with lead
consumption recovering to its 1973 level; (3) the decrease in 1980–82 during the second
energy crisis; and (4) the sustained growth from 1983 until 1990 in the industrialized world
as a whole, supported by rapid advances in some of the newly-industrializing countries, but
with much more restricted progress in the fully-industrialized countries where the rates of
economic expansion and industrial activity slowed down compared with those previously
achieved (International Lead and Zinc Study Group, 1992).
1.3.1 Lead–acid batteries

By far the largest single application of lead worldwide is in lead–acid batteries. The
most common type of lead–acid battery consists of a heavy duty plastic box (normally
polypropylene) containing grids made from a lead–antimony alloy (commonly containing
0.75–5% antimony) with minor additions of elements such as copper, arsenic, tin and
selenium to improve grid properties. For the new generation of sealed, maintenance-free
batteries, a range of lead–calcium–tin alloys is used. These contain up to 0.1% calcium and
0–0.5% tin. The tin-containing alloys are used in the positive grids to protect against
corrosion. Grids are still manufactured in pairs on special casting machines, but production
of grids in strip form by continuous casting or expansion of rolled sheet is becoming
increasingly popular as it facilitates automation and minimizes the handling of plates. The
spaces in the grids are filled with a paste consisting largely of lead dioxide. When
immersed in sulfuric acid, these pasted grids (plates) form an electric cell that generates
electricity from the chemical reactions that take place. The reactions require the presence
of lead dioxide and lead metal and each cell produces a voltage of 2V. These reactions are
reversible and the battery can therefore be recharged. A rechargeable cell is known as a
secondary cell and provides a means of storing electricity. Lead is well suited for this
application because of its specific conductivity and its resistance to corrosion. The addition
of antimony or calcium gives the lead an increased hardness to resist the mechanical
stresses within the battery caused, for example, by the natural vibration of road vehicles
and by the chemical reactions taking place (Lead Development Association International,
2003e).
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Table 10. Trends in total industrial consumption of refined lead
Year Consumption (thousand tonnes) by geographical regiona
1960 1152 19 986 204 65 654 3080

1965 1306 33 1229 270 70 762 3670
1970 1517 46 1488 360 72 1019 4502
1975 1403 76 1454 413 86 1310 4742
1980 1652 102 1476 600 85 1446 5361
1985 1614 98 1510 735 69 1470 5496
1990 2439 114 1648 1193 59 NRS 5454
1995 1948 112 2017 1718 84 NRS 5879
2000 2022 130 2332 1989 46 NRS 6519
2003 2030 154 2012 2471 45 NRS 6712

a
A, Austria, Belgium, Denmark, Finland, France, Germany (the Federal Republic of Germany
before reunification), Greece, Ireland, Italy, Netherlands, Norway, Portugal, Spain, Sweden,
Switzerland, United Kingdom and former Yugoslavia
B, Algeria, Egypt, Morocco, South Africa, Tunisia and Zambia
C, Argentina, Brazil, Canada, Mexico, Peru, USA and Venezuela
D, India, Iran, Japan, Malaysia, Philippines, Republic of Korea, China (Province of Taiwan),
Thailand and Turkey
F, Albania, Bulgaria, China, Cuba, former Czechoslovakia, Germany (the former German
Democratic Republic), Hungary, People’s Democratic Republic of Korea; Poland, Romania,
former Soviet Union; values for Albania, Cuba, China, Germany (the former German Democratic
Republic), Peoples’ Democratic Republic of Korea, Romania and former Soviet Union are
estimates.
b
From 1990 onwards, data from countries in region F are included in region A (Albania,
Bulgaria, Czech Republic, Hungary, Poland, the former German Democratic Republic, Poland,
Romania, Estonia, Latvia, Lithuania, Belarus, Russian Federation and Ukraine) or in region D
(all other former Soviet Republics, China, Cuba and People’s Democratic Republic of Korea).
Lead metal consumption for 1991 in the former Soviet Union was split as follows: Europe, 86%,
Asia, 14%.
The most common form of lead–acid battery is the so-called SLI battery (starting,
lighting and ignition) used in road vehicles such as cars and trucks. Another form, the
traction battery, is used to power vehicles such as golf carts and airport support vehicles.
Other uses of lead power include larger stationary batteries for stand-by emergency power
storage in hospitals and other critical facilities, and for some electricity utilities to help
meet peak power demands and to maintain a stable electricity supply (Lead Development
Association International, 2003e).
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Table 11. Total industrial lead consumption
Country or region Consumption (thousand tonnes) in year
1985 1990 1996 2001
Australia 49.5 45.9 67.0 41.0

Austria 58.0 65.5 58.0 59.0
Belgium 66.8 67.7 50.6 40.3
Brazil 79.6 75.0 110.0 112.0
Canada 104.5 71.7 93.4 71.8
China NA NA 470.1 700.0
Czech Republic NA NA 25.0 80.0
Finland 22.0 13.4 3.5 2.0
Francea 234.3 261.6 273.8 282.5
Germanya 348.2 375.3 331.0 392.6
India 51.3 51.8 85.0 127.0
Italya 235.0 259.0 268.0 283.0
Japan 397.4 417.0 329.9 284.7
Mexico 90.6 66.8 141.0 205.0
Netherlands 45.1 65.0 57.0 30.0
New Zealand 8.6 8.0 7.0 5.0
Republic of Korea 81.0 150.0 289.8 314.7
Romania NA NA 22.0 20.0
Scandinaviab 55.6 36.3 49.0 13.0
South Africa 48.2 65.9 63.1 59.1
South-East Asiac 125.2 185.0 413.0 427.0
Spain 125.3 126.7 144.0 246.0
Switzerland 10.5 8.7 10.5 12.6
United Kingdoma 303.2 334.0 309.2 266.5
USAa 1148.3 1288.4 1554.4 1587.3
Total 3688.2 4038.7 5225.3 5662.1

NA, not available
a
Data for these countries include total metal usage in all forms, i.e. refined
lead and alloys (lead content), plus re-melted lead recovered from secondary
materials. Data for other countries include refined lead and alloys only.
b
Denmark, Norway and Sweden
c
China, Hong Kong Special Administrative Region, China (Province of
Taiwan), Indonesia, Malaysia, Philippines and Singapore
Since 1960 the manufacture of lead–acid batteries has remained the largest single use
of lead in nearly all countries, accounting for an ever-increasing percentage of total lead
consumption (see Tables 12, 14 and 15) (International Lead and Zinc Study Group, 1992).
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Table 12. Trends in uses of lead in selected countriesa
Use Percentage of total usage in year
1985 1990 1996 2001
Batteries 57.7 63.0 72.5 76.7

Cable sheathing 5.6 4.5 2.1 1.4
Rolled and extruded productsb 7.6 7.7 5.9 6.0
Shot/ammunition 2.8 2.8 2.3 2.1
Alloys 4.2 3.3 3.2 2.5
Pigments and other compounds 14.2 12.8 10.0 8.1
Gasoline additives 3.7 2.1 0.9 0.4
Miscellaneous 4.2 3.8 3.3 2.8
Total 100.0 100.0 100.0 100.0

a
Countries include: Australia, Austria, Belgium, Brazil, Canada, China (Hong Kong
Special Administrative Region), China (Province of Taiwan), Denmark, Finland, France,
Germany, India, Indonesia, Italy, Japan, Malaysia, Mexico, Netherlands, New Zealand,
Norway, Philippines, Republic of Korea, Singapore, South Africa, Spain, Sweden,
Switzerland, United Kingdom and USA.
b
Including lead sheet
Table 13. Trends in total lead consumption in six major

consuming countries
Country Consumption (thousand tonnes) in year
1960 1973 1979 1990
France 196 240 233 262

Germany 281 342 342 375
Italy 108 259 280 259
Japan 162 347 368 417
United Kingdom 385 364 336 334
USA 926 1398 1358 1288
Total 2058 2950 2917 2935

The data include refined metal and direct use of lead in scrap form.
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Table 14. Trends in principal uses of lead in six major

consuming countriesa
Use Percentage of total use in year
1960 1979 1990
Batteries 27.7 50.8 64.4

Cable sheathing 17.9 5.9 3.8
Rolled/extruded products 18.0 7.7 7.8
Shot/ammunition 3.2 3.2 3.8
Alloys 10.5 6.7 3.5
Pigment/compounds 9.9 12.3 10.9
Gasoline additives 9.1 9.8 2.7
Miscellaneous 3.7 3.6 3.1
Total 100.0 100.0 100.0

a
France, Germany, Italy, Japan, United Kingdom and USA
Table 15. Trends in consumption of lead for batteries

in six major consuming countries
1960 1973 1979 1990

France 45.0 90.0 110.7 163.5
Germanya 73.2 132.9 158.3 195.2
Italy 25.5 68.0 93.0 113.2
Japan 30.0 163.1 191.8 294.6
United Kingdom 76.2 106.5 113.9 103.7
USA 320.4 698.0 814.4 1019.6
Total 570.3 1258.5 1481.2 1889.8

a
Excludes consumption by some independent producers of lead oxides
for batteries.
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Table 16. Trends in consumption of lead for rolled/

extruded products in six major consuming countries
1960 1973 1979 1990
France 43.7 31.0 27.2 22.4

Germany 44.3 31.1 32.7 39.1
Italy 29.1 50.3 40.8 21.5
Japan 35.9 39.6 26.7 10.9
United Kingdom 88.0 57.7 48.9 98.6
USA 130.1 90.2 47.7 35.8
Total 371.1 299.9 224.0 228.3
Table 17. Trend in consumption of lead for cable

sheathing in six major consuming countries
1960 1973 1979 1990
France 60.8 41.1 21.4 16.3

Germany 83.9 54.6 31.5 12.2
Italy 24.0 44.8 40.0 48.7
Japan 47.0 28.7 36.8 4.9
United Kingdom 97.0 45.8 26.6 10.4
USA 54.7 39.0 16.4 18.3
Total 367.4 254.0 172.7 110.8

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Table 18. Trends in consumption of lead for alloys in

six major consuming countries
1960 1973 1979 1990
France 17.3 14.8 9.3 3.2

Germany 22.7 22.8 16.5 9.0
Italy 6.0 6.0 5.7 3.5
Japan 7.1 24.2 18.3 18.7
United Kingdom 37.0 35.0 24.5 22.0
USA 125.3 128.8 120.0 46.4
Total 215.4 231.6 194.3 102.8
Table 19. Trends in consumption of lead for pigments

and compounds in six major consuming countries
1960 1973 1979 1990
France 11.9 34.5 33.0 29.4

Germany 38.4 69.6 76.8 100.3
Italy 10.1 45.2 60.4 40.0
Japan 17.2 64.2 62.4 64.0
United Kingdom 35.9 38.8 34.1 28.6
USA 89.3 98.7 90.8 56.5
Total 202.8 351.0 357.5 318.8

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1.3.2 Lead sheet

The use of lead sheet has increased dramatically over recent years, particularly for the
building industry. Lead sheet has been produced for decades by traditional wide lead mills
in which lead slabs are fed through large drum-like rollers, sometimes several times, to
produce lead sheets of the desired thickness. The traditional wide lead mill is being
replaced by more sophisticated rolling mills producing coils of lead 1.2–1.5 m wide. Most
lead sheets in building applications are between 1.3 and 2.2 mm thick, but sheets of
2.6–3.6 mm are used for roofing prestige buildings. Thick sheet alloys are rolled for
applications such as anodes for electrowinning and thin foils are used for sound atte-
nuation. A manufacturing technique other than milling is continuous casting in which a
rotating, water-cooled drum is partly immersed in a bath of molten lead. The drum picks
up a solid layer of lead, which is removed over a knife edge adjacent to the drum as it
rotates. The thickness is controlled by varying the speed of rotation and the temperature of
the drum (Lead Development Association International, 2003e).
In the building industry, most of the lead sheet (or strip) is used as flashings or
weatherings to prevent water from penetrating, the remainder being used for roofing and
cladding. By virtue of its resistance to chemical corrosion, lead sheet is also used for the
lining of chemical treatment baths, acid plants and storage vessels. The high density of
lead sheet and its ‘limpness’ make it a very effective material for reducing the trans-
mission of sound through partitions and doors of comparatively lightweight construction.
Often the lead sheet is bonded adhesively to plywood or to other building boards for con-
venience of handling. A particular advantage of the high density of lead is that only rela-
tively thin layers are needed to suppress the transmission of sound (Lead Development
Association International, 2003e).
Lead sheet is the principal element in the product category ‘rolled and extruded
products’. In many countries, the demand for rolled and extruded lead products declined
in the 1960s and 1970s, due in part to a rapid decline in the use of lead pipe (see Tables
14 and 16). Nevertheless, in a number of countries (see Table 12), lead sheet remains the
third largest use of lead at about 6% of the total reported consumption (International Lead
and Zinc Study Group, 1992, 2003).
1.3.3 Lead pipes

Lead piping, once a substantial use in the ‘rolled and extruded products’ category, has
been replaced progressively by copper tubes for the transport of domestic water and the
supply of gas and by plastic tubing for disposal of wastewater. Lead pipes have not been
used in new supplies of domestic water for about 30 years. However, due to their
corrosion-resistant properties, they are still used for transport of corrosive chemicals at
chemical plants. Also, lead pipe of appropriate composition is extruded for cutting into
short-length ‘sleeves’ used in the jointing of lead-sheathed cables (see below) (Inter-
national Lead and Zinc Study, 1992; Lead Development Association International, 2003e).
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1.3.4 Cable sheathing

Because of its corrosion resistance when in contact with a wide range of industrial and
marine environments, soils and chemicals, lead was one of the first materials to be used to
provide an impervious sheath on electric cables. Lead can be applied to the cable core in
unlimited lengths by extrusion at temperatures that do not damage the most sensitive
conductors (optical fibres) or insulating materials (paper or plastics). Lead is pliable and
withstands the coiling, uncoiling, handling and bending operations involved in the
manufacturing and installation of the cable. A lead sheath can be readily soldered at low
temperatures when cables need to be jointed or new cables installed. With modern screw-
type continuous extruders, unjointed submarine power cables as long as 100 km have been
produced (Lead Development Association International, 2003e).
Until 1960 sheathing of electrical cables was the largest single use of lead in many
countries including France, Germany, Japan and the United Kingdom, representing
25–30% of total lead consumption in these four countries. It was used much less exten-
sively in the USA where, during the late 1950s, lead was replaced by alternative materials,
generally plastics, as the sheathing material for telephone cables. Since the mid-1960s,
however, there has been a gradual decline in the use of lead for cable sheathing in most
countries (Table 17). By 1990, lead consumption for cable sheathing had fallen to 4.5%
of total consumption and, by 2001, to 1.4% (Table 12) (International Lead and Zinc Study
Group, 1992, 2003).
1.3.5 Lead alloys

(a) Lead–antimony alloys
By far the largest use of lead–antimony alloys is in batteries. At one time, antimony
contents of ∼10% were common, but the current generation of lead–acid batteries has a
much lower antimony content. Alloys with 1–12% antimony are used widely in the
chemical industry for pumps and valves, and in radiation shielding both for lining the
walls of X-ray rooms and for bricks to house radioactive sources in the nuclear industry.
The addition of antimony to lead increases the hardness of the lead, and therefore its resis-
tance to physical damage, without greatly reducing its corrosion resistance (Lead Deve-
lopment Association International, 2003e).
(b) Solders
Soldering is a method of joining materials, in which a special metal (solder) is applied
in the molten state to wet two solid surfaces and join them on solidification. Solders are
classified according to their working temperatures. Soft solders, which have the lowest
melting-points, are largely lead–tin alloys with or without antimony, while fusible alloys
contain various combinations of lead, tin, bismuth, cadmium and other low melting-point
metals. Depending on the application, lead–tin solders may contain from a few per cent
to more than 60% tin.
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A substantial proportion of solder is used in electrical or electronic assemblies. The

advances made in the electronics industry have required the development of fast and
highly-automated methods of soldering. Printed circuit assemblies can be soldered by
passing them across a standing wave of continuously-circulating molten solder (Lead
Development Association International, 2003e).
The use of lead solder in plumbing has declined with the replacement of lead piping
by copper tubing and, more recently, as a result of concerns of potential leaching of lead
into water supplies. Similarly, concerns of possible danger to health have restricted the
use of lead solders in the canning industry, formerly an important market.
(c) Lead for radiation shielding

Lead and its alloys in metallic form, and lead compounds, are used in various forms
of radiation shielding. The shielding of containers for radioactive materials is usually
metallic lead (see above). Radioactive materials in laboratories and hospitals are usually
handled by remote control from a position of safety behind a wall of lead bricks. X-ray
machines are normally installed in rooms lined with lead sheet; lead compounds are
constituents of the glass used in shielding partitions to permit safe viewing; and lead
powder is incorporated into plastic and rubber sheeting materials used for protective
clothing (Lead Development Association International, 2003e).
(d) Other uses of lead alloys

A variety of lead alloys are produced for a wide range of applications in various
industries. In the 1990s, these alloys accounted for 130–150 000 tonnes of lead used in
industrialized countries (Table 18). However, the trend in this sector had been one of steady
decline during the previous three decades (Table 14), as some uses have been overtaken by
technological changes or have been restricted by health and environmental regulations.
The use of terne metal (a thin tin–lead alloy coating) for corrosion protection, and the
addition of lead to brass and bronze to assist in free machining, and in bearing metals to
reduce friction and wear in machinery, have declined slowly due to competition from alter-
native materials such as aluminum and plastics. The market for type metal in the printing
industry has largely disappeared as hot metal printing has been replaced by new techno-
logy. In the USA, this use peaked at 30 000 tonnes in 1965 but had fallen to 1–2000 tonnes
by the mid-1980s and is similarly low in other developed countries (International Lead and
Zinc Study Group, 1992).
1.3.6 Lead pigments and compounds

The market for lead pigments and compounds constitutes the second largest use of lead
after lead–acid batteries. The market peaked in the mid-1980s, when over 500 000 tonnes
of lead were used in lead pigments and compounds, mainly by the plastics, glass and
ceramics industries, and accounting for 14% of total lead consumption (Table 14). Since
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then these uses have been restricted by health and environmental concerns while still
remaining the second largest use of lead (8% of total lead consumption) (Table 12).
Besides the six major consuming countries (Table 19), pigments and compounds are
also the second most important use of lead in other countries including Brazil, Canada, the
Republic of Korea, South Africa, Spain and countries of South-East Asia (International
Lead and Zinc Study Group, 1992, 2003).
(a) Lead pigments

The use of lead in paints for domestic purposes and in some commercial and industrial
applications is now severely restricted or banned in view of the potential health risks
caused by exposure to weathered or flaking paint. However, lead tetraoxide (Pb3O4) still
retains some of its traditional importance for rust-inhibiting priming paints applied directly
to iron and steel in view of its anti-corrosion properties, but faces growing competition
from zinc-rich paints containing zinc dust and zinc chromate. The use of lead carbonate
(white lead) in decorative paints has been phased out. Calcium plumbate-based paints are
effective on galvanized steel. Lead chromate (yellow) and lead molybdate (red orange) are
still used in plastics and to a lesser extent in paints. Lead chromate is used extensively as
the yellow pigment in road markings and signs, which are now commonplace in most
European countries and in North America (Lead Development Association International,
2003e).
(b) Lead stabilizers for polyvinyl chloride (PVC)

Lead compounds are used in both rigid and plasticized PVC to extend the temperature
range at which PVC can be processed without degradation. In the building industry, the
widespread adoption of PVC materials for corrosion-resistant piping and guttering in
industrial facilities, for potable water piping (lead content, < 1%), and for windows and
door frames provides a major market for lead sulfate and lead carbonate as stabilizers to
prevent degrading of PVC during processing and when exposed to ultraviolet light.
However, concerns over potential health hazards are limiting the use of lead in PVC water
piping in some countries. Dibasic lead phosphite also has the property of protecting
materials from degradation by ultraviolet light. Normal and dibasic lead stearates are
incorporated as lubricants. All these compounds are white pigments that cannot be used
when clear or translucent articles are required (International Lead and Zinc Study Group,
1992; Lead Development Association International, 2003e). The levels of lead in 16
different PVC pipes used for water supplies in Bangladesh were found to be in the range
of 1.1–6.5 mg/g (Hadi et al., 1996).
(c) Lead in glass

Decorative lead crystal glass was developed in England in the seventeenth century.
Normally added in the form of lead monoxide (PbO) at 24–36%, lead adds lustre, density
and brilliance to the glass. Its attractiveness is further enhanced by decorative patterns that
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can be cut on the surface and by the characteristic ring associated with lead crystal. There
is now a substantial market for a cheaper form of ‘semi-crystal’ containing 14–24% lead
oxide, and such glasses are usually moulded with the decorative pattern rather than being
hand-cut later. Lead is also used in optical glass (e.g. telescopes, binoculars), ophthalmic
glass (e.g. spectacles), electrical glass (e.g. lamp tubing, cathode ray tubes) and radiation
protection glass (e.g. for windows in remote-handling boxes, television tubes) (Lead
Development Association International, 2003e).
(d) Lead for ceramics

Lead is used in a wide range of glaze formulations for items such as tableware
(earthenware and china), wall and floor tiles, porcelain and sanitary-ware and electrical
transistors and transducers. The lead compounds used are mainly lead monoxide (litharge,
PbO), lead tetraoxide and lead silicates. The properties offered by lead compounds are
low melting-points and wide softening ranges, low surface tension, good electrical
properties and a hard-wearing and impervious finish. Lead compounds are also used in
the formulation of enamels used on metals and glass.
Another important application for lead compounds is in a range of ceramics (other than
the glazes) used in the electronics industry. Typical of these are piezoelectric materials such
as the lead zirconate/lead titanate range of compositions known generally as PZI. These
materials have a wide range of applications, such as spark generators, sensors, electrical
filters, gramophone pick-ups and sound generators (International Lead and Zinc Study
Group, 1992; Lead Development Association International, 2003e).
1.3.7 Gasoline additives

Tetraethyl and tetramethyl lead have been used as anti-knock additives in gasoline, at
concentrations up to 0.84 g/L, as an economic method of raising the ‘octane rating’ to
provide the grade of gasoline needed for the efficient operation of internal combustion
engines of high compression ratio (Thomas et al., 1999). However, increasing recognition
of the potential health effects from exposure to lead has led to the reformulation of gasoline
and the removal of lead additives. In addition, lead in gasoline is incompatible with the
catalytic converters used in modern cars to control nitrogen oxides, hydrocarbons and other
‘smog’-producing agents. The use of lead in gasoline in the USA has been phased out
gradually since the mid-1970s, and moves to phase it out in the European Community
began in the early 1980s. Since 1977 in the USA and 1991 in Europe, all new cars are
required to run on unleaded gasoline. By the end of 1999, forty countries or regions had
banned the use of lead in gasoline (Table 20), although it is still permitted in some of these
countries for certain off-road and marine vehicles and for general aviation aircraft (Smith,
2002). Numerous other countries are planning the phase-out of lead in gasoline in the near
future. About 79% of all gasoline sold in the world in the late 1990s was unleaded
(International Lead Management Center, 1999). The market for tetraethyl and tetramethyl
lead has declined considerably (Table 21) and will continue to do so (Lead Development
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Table 20. Countries or regions that had phased out the use of
lead in gasolinea by the end of 1999
Argentina Finland Netherlands

Austria Germany New Zealand
Bahamas Guam Nicaragua
Bangladesh Guatemala Norway
Belize Haiti Portugal
Bermuda Honduras Puerto Rico
Bolivia Hong Kong SAR Republic of Korea
Brazil Hungary Singapore
Canada Iceland Slovakia
Colombia Japan Sweden
Costa Rica Luxembourg Thailand
Denmark Malaysia USA
Dominican Republic Mexico US Virgin Islands
El Salvador
From International Lead Management Center (1999)

a
See Section 1.3.7 for permitted uses of leaded gasoline.
Table 21. Trends in consumption of lead for gasoline

additives in five major consuming countries
1960 1973 1979 1990
France 6.1 13.5 15.1 9.8

Germany NA 9.4 10.8 NA
Italy 4.8 11.8 13.0 3.7
United Kingdom 27.1 54.4 58.9 45.1
USA 148.6 248.9 186.9 20.7
Total 186.6 338.0 284.7 79.3

NA, not available
Association International, 2003e). In 2001, less than 0.5% of lead consumption was for
gasoline additives (Table 12) (International Lead and Zinc Study Group, 2003).
1.3.8 Miscellaneous uses

About 150 000 tonnes of lead are employed each year in a variety of other uses, of
which about 100 000 tonnes are consumed in the production of lead shot and ammunition
in the major consuming countries (excluding Japan where this use is not reported
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separately). Globally, this use has remained relatively stable since the 1960s, at around
3–4% of total lead consumption (Tables 12 and 14).
Lead cames have long been a feature of stained-glass windows in churches and
cathedrals. They consist of H-shaped sections of lead which hold together the individual
pieces of glass. They are now being used more widely in modern homes both in the tradi-
tional way and in the form of self-adhesive strips stuck on to a larger piece of glass to
simulate an integral came.
Lead weights for fishing have been largely phased out but lead stampings, pressings
and castings are widely used for many weighting applications, for example curtain
weights, wheel balance weights, weights for analytical instruments and yacht keels.
Lead wool is made by scratching fine strands from the surface of a lead disc. It is used
for the caulking of joints in large pipes like gas mains and in some specialty batteries.
Lead-clad steel is a composite material manufactured by cold rolling lead sheet onto
sheet steel that has been pretreated with a terne plate. A strong metallurgical bond is
formed between the lead and the steel, which provides a material that combines the
physical and chemical properties of lead with the mechanical properties of steel. Although
primarily aimed at the sound-insulation market, lead-clad steel has also found use in
radiation shielding and in the cladding of buildings.
Lead powder is incorporated into a plasticizer to form sheets of lead-loaded plastic.
This material is used to make radiation-protective clothing and aprons for the medical,
scientific and nuclear industries (see Section 1.4.5.c). It also has sound-insulating
properties. Lead powder is also used as the basis for some corrosion-resistant paints (see
Section 1.4.6).
Smaller amounts of lead are used in galvanizing, annealing and plating (International
Lead and Zinc Study Group, 1992; Lead Development Association International, 2003e).
1.4 Occurrence
1.4.1 Environmental occurrence
Lead was one of the first metals used by man; there is evidence that it has been used
for approximately 6000 years (Hunter, 1978). As a result, although both natural and anthro-
pogenic processes are responsible for the distribution of lead throughout the environment,
anthropogenic releases of lead are predominant. Industrial releases to soil from nonferrous
smelters, battery plants, chemical plants, and disturbance of older structures containing
lead-based paints are major contributors to total lead releases. Lead is transferred conti-
nuously between air, water, and soil by natural chemical and physical processes such as
weathering, run-off, precipitation, dry deposition of dust, and stream/river flow; however,
soil and sediments appear to be important sinks for lead. Lead is extremely persistent in
both water and soil. Direct application of lead-contaminated sludge as fertilizers, and
residues of lead arsenate used in agriculture, can also lead to the contamination of soil,
sediments, surface water and ground water. In countries where leaded gasoline is still used,
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the major air emission of lead is from mobile and stationary sources of combustion.
Besides environmental exposures, exposure to lead may arise from sources such as foods
or beverages stored, cooked or served in lead-containing containers, food growing on
contaminated soils, and traditional remedies, cosmetics and other lead-containing products.
The ubiquity of lead in the environment has resulted in present-day body burdens that
are estimated to be 1000 times those found in humans uncontaminated by anthropogenic
lead uses (Patterson et al., 1991), but exposures have decreased substantially over the past
10–30 years in countries where control measures have been implemented.
The estimated contributions of the common sources and routes of lead exposure to total
lead intake vary from country to country and over time. In 1990, the estimated daily intake
of lead from consumption of food, water and beverages in the USA ranged from 2 to
9 µg/day for various age groups and was approximately 4 µg/day for children 2 years of
age and younger (ATSDR, 1999). For many young children, the most important source of
lead exposure is through ingestion of paint chips and leaded dusts and soils released from
ageing painted surfaces or during renovation and remodeling (CDC, 1997a; Lanphear
et al., 1998). Compared with nonsmokers, smokers have an additional lead intake of
approximately 6 µg/day, based on an estimated exposure of 14 µg/day and absorption of
30–50% of the inhaled lead into the bloodstream (IARC, 2004a).
Lead is absorbed into the body via inhalation and ingestion and, to a limited extent,
through the skin. The uptake of inhaled or ingested lead is dependent on the type of lead
compound involved, particle size, site of contact within the body, acidity of the body fluid
at that site, and physiological status of the individual (see Section 4.1).
(a) Natural occurrence

Lead occurs naturally in the earth’s crust in trace quantities at a concentration of
approximately 8–20 mg/kg (Rudnick & Fountain, 1995; Taylor & McLennan, 1995).
Metallic lead occurs in nature, but it is rare. The most important lead ore is galena (PbS).
Anglesite (PbSO4), cerussite (PbCO3) and minium (Pb3O4) are other common lead
minerals. Small amounts of lead reach the surface environment through natural weathe-
ring processes and volcanic emissions, thus giving a baseline environmental exposure.
However, the abundant and widespread presence of lead in our current environment is
largely a result of anthropogenic activity.
(b) Air and dust

Lead is released into the air by natural processes such as volcanic activity, forest fires,
weathering of the earth’s crust and radioactive decay from radon (WHO, 1995). However,
these natural contributions are of relatively minor consequence. The vast majority of lead
in the atmosphere results from human activity. Globally, the main source of lead in air has
been exhaust from motor vehicles using leaded gasoline (see also Section 1.4.1( f )).
Release of lead also occurs during lead smelting and refining, the manufacture of goods,
and the incineration of municipal and medical wastes (ATSDR, 1999). Almost all lead in
air is bound to fine particles of less than 1 µm diameter, although some may be solubilized
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in acid aerosol droplets. The size of these particles varies with the source and with the age
of the particle from the time of emission (US EPA, 1986a; WHO, 1995).
Concentrations of lead in ambient air range from 76 × 10–6 µg/m3 in remote areas
such as Antarctica (Maenhaut et al., 1979), to 0.2 µg/m3 in rural areas in Chile (Frenz
et al., 1997) and to > 120 µg/m3 near stationary sources such as smelters (Nambi et al.,
1997). Tables 22–27 show examples of lead concentrations in air and dust worldwide by
geographic region. A few studies are detailed below according to the main source of
airborne lead.
Trends in emissions of lead in air in the USA have continued to fall since the late
1970s from both point sources (from 2.9 µg/m3 in 1979 to 0.4 µg/m3 in 1988) and urban
sites (from 0.8 µg/m3 in 1979 to 0.1 µg/m3 in 1988). The large decrease in emissions from
point sources resulted from the use of emission controls in industrial processes as well as
automotive controls; the decrease in emissions from urban sites was primarily the result
of the decreased use of leaded gasoline (ATSDR, 1999). Between 1976 and 1995, overall
ambient air concentrations of lead in the USA declined by 97% (US EPA, 1996a). Lead
concentrations in urban and suburban air in the USA (maximum quarterly mean concen-
trations) decreased between 1986 and 1995 from 0.18 µg/m3 to 0.04 µg/m3; rural air
concentrations of lead during the same period were typically 3- to 5-fold lower (US EPA,
1996a). In remote sites, air lead concentrations as low as 0.001 µg/m3 have been reported
(Eldred & Cahill, 1994).
Urban air lead concentrations are typically between 0.15 and 0.5 µg/m3 in most Euro-
pean cities (WHO, 2000a). In Bulgaria, the Czech Republic, Hungary, Poland, Romania,
Slovakia and Slovenia, exposure to lead is primarily through airborne lead. It is estimated
that in congested urban areas 90% of this is due to leaded gasoline. In 1998, there was a
wide range in use of unleaded gasoline for automobiles, from 100% in Slovakia to 5–7%
in Bulgaria and Romania. Table 22 illustrates improvements in air quality during the 1990s
through a concerted effort by the countries to phase out the use of leaded gasoline
(Regional Environmental Center for Central and Eastern Europe, 1998).
Lead concentration in the thoracic fraction of atmospheric particulate matter (PM10)
— that part of the inspirable fraction that penetrates into the respiratory tract below the
larynx — in the ambient air of Delhi, India, in 1998, was reported to range from 0.1 to
2 µg/m3 (Table 26). Principal component analysis identified three major sources, namely
vehicle emissions, industrial emissions and soil resuspension (Balachandran et al., 2000).
Samples collected from high-exposure areas of Mumbai, India, had higher lead concen-
trations than those collected in other high-exposure areas of the world including Beijing
(China), Stockholm (Sweden) and Zagreb (Serbia and Montenegro) (Parikh et al., 1999).
A recent report of the Central Pollution Control Board (2001–2002) found concentrations
of lead in air in Mumbai, India, to be on the decline. In fact, the introduction of unleaded
petrol reduced lead concentrations in ambient air by about half in seven sites throughout
India (Central Pollution Control Board, 1998–99).
In Semarang, Indonesia, mean urban airborne lead concentrations were found to be
0.35 µg/m3 in a highway zone, 0.95 µg/m3 in a residential zone (mainly due to solid-waste
P 075-140 DEF.qxp 09/08/2006 11:15 Page 76
Table 22. Lead concentrations in ambient air in central and eastern Europe
Country Location Mean concentration (µg/m3)a by year
1990 1991 1992 1993 1994 1995 1996
Bulgaria Sofia 0.3 0.3 0.3 0.3 0.2 0.2

Pernik 0.5 0.4 0.4 0.2 0.2 0.4
Plovdiv 0.6 0.5 0.4 0.3 0.2 0.3
Kardjali 1.2 1.2 1.2 0.9 0.9 0.7
Czech Prague 0.06 0.04 0.01
Republicb Pribram 0.08 0.06 0.02
Usti n. Labem 0.06 0.04 0.03
Brno 0.07 0.08 0.05
Ostrava 0.05 0.08 0.05
Hungary Budapest 0.20 0.22 0.22 0.19
Pecs 0.42 0.44 0.25 0.21
Miskolc 0.18 0.12
Debrecen 0.56 0.30 0.27 0.28
c
Poland Katowice 0.73 0.90 1.16 0.68 0.68 0.78 0.58
Chorzuw 2.69 0.85 0.76 0.44 0.44 0.81 1.00
Pszczyna 0.64 0.55 0.45 0.49 0.49 0.62 0.16
Lodz 1.16 1.48 0.87 0.87 1.85 0.55
Romania Copsa Mica 30.30 21.30 16.07 42.20 18.91 12.70
Bucuresti 60.58 60.58 70.65 7.63
Bala Mare 5.45 8.20 97.50 15.07 16.12 13.34
Medias 10.15 21.80 7.20 4.18 9.99 14.70
Zlatna 22.72 27.10 10.00 14.00 9.44 11.46
Slovakia Bratislava 0.11 0.09 0.11 0.10 0.05 0.06
B. Bystrica 0.11 0.09 0.08 0.05 0.03 0.03
Ruzomberok 0.14 0.05 0.06 0.03 0.04 0.02
Richnava 0.50 0.53 0.46 0.14 0.14 0.21
Slovenia Trbovlje 0.90 0.70 0.30
Zagorje 1.50 0.70 0.30
Hrastnik 0.25 0.45 0.10
From Regional Environmental Center for Central and Eastern Europe (1998)
a
Italicized text denotes short-term maximal concentration.
b
Annual geometric means
c
Maximum average daily concentration
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Table 23. Lead concentration in outdoor air in Latin America and the
Caribbean
Country Location Year of Period covered Concentration Reference

study (µg/m3)
mean or range
of means
Bolivia La Paz NR NR 1.1 Romieu

et al. (1997)
Brazil S. Paulo 1985 Annual average 0.39 Romieu
Osasco 1985 Annual average 0.16 et al. (1997)
S. Caetano do Sul 1985 Annual average 0.31
Santo Amaro, 1989 4-day Tavares
Bahia, near (1990)
smelter
at 526 m 2.8
at 955 m 0.13
S. Francisco July 1994a 5-day 0.029 Tavares
Conde, Bahia Jan. 1995 0.0051 (1996a)
(downwind of oil
refinery)
Lamarao de Passé, July 1994 5-day 0.0162
Bahia (downwind Jan. 1995 0.0054
of petrochemical
complex)
Itacimirim/Praia July 1994 5-day 0.0015
do Forte, Bahia Jan. 1995 0.00025
(Atlantic air
masses)
Chile San Felipe 1996 NR 0.19 Frenz et al.
(1997)
NS 1990 Annual average 1.1 Romieu
et al. (1997)
Colombia Bogota 1990 3-month average 3.0 Romieu
et al. (1997)
Guatemala Tegucigalpa NR NR 0.18 Romieu
NS 1994 Annual average 0.17 et al. (1997)
Honduras NS 1994 Annual average 1.11 Romieu
NS 1994 3-month average 1.83 et al. (1997)
Mexico Mexico City 1988 3-month average 0.34–0.24 Romieu
1990 1.08–1.47 et al. (1997)
1994 0.24–0.37
1988 Annual average 1.95
1990 1.23
1994 0.28
1995 24-h average 0.54
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Table 23 (contd)
Country Location Year of Period covered Concentration Reference

study (µg/m3)
mean or range
of means
Peru NS 1980 3-month average 1.8 Romieu

1985 1.9 et al. (1997)
1990 2.2
1994 2.1
1980 Annual average 1.7
1985 1.5
1990 1.6
1994 1.7
Venezuela Caracas 1982 Annual average 4.5 Romieu
1986 2.6 et al. (1997)
1990 1.9
1994 1.6
NR, not reported; NS, not stated

a
July is in wet season whereas January is during the dry season.
Table 24. Lead concentration in indoor dust in Latin America and the
Caribbean
Country Location Year(s) Source of Concentration Reference

of study contamination (µg/g)
mean ± SD
or range of
means
Mexico Cd. Juarez, 1974 Lead smelter Ordóñez et al.

Chihuahua < 1.6 km 1322 ± 930 (2003)
1.6–4 km 220
Villa de la Paz NR Mining 955 (range, Yáñez et al.
220–5190) (2003)
Mexico City 1983 Multiple urban 587 ± 303 Bruaux &
Svartengren
(1985)
Venezuela Caracas (day- 1997–98 Urban 999–1707 Fernández
care centre) et al. (2003)
NR, not reported; SD, standard deviation

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Table 25. Lead concentrations in outdoor air and dust in Africa

of study contamination (µg/m3)a
mean or range of
means (range)
Egypt Cairo 1983–84 Town centre 3.0 Ali et al. (1986)

Residential/industrial 1.3
Residential district 1.4
Suburban district 0.6
Commercial 2.2
Cairo NR Industrial district 2 Hindy et al.
(1987); Nriagu
(1992)
Nigeria Lagos 1981 Urban setting 770–1820 µg/gb,c Ajayi & Kamson
(1983)
1991 Urban traffic 51–1180 µg/gb Ogunsola et al.
(1994a)
South Cape Town NR High traffic 1.5 (1.3–2.1) von Schirnding
Africa Low traffic 0.8 (0.4–0.9) et al. (1991a)
High traffic 2900–3620b
Low traffic 410–2580b
KwaZulu/ 1995 Industrial/highway 1.84 Nriagu et al.
Natal Commercial 0.86 (1996a)
Park/beach 0.56
Residential 0.44
Rural < 0.03
8 cities 1993–95 Urban setting 0.36–1.1 Nriagu et al.
(1996b)
Zambia Kasanda 1973–74 NR 10 (5–145) Nriagu (1992)
Adapted from Nriagu (1992)

NR, not reported
a
Unless specified otherwise
b
Lead concentrations in dust
c
Median values
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Table 26. Lead concentrations in outdoor air and dust in Asia
Country Location Year(s) Concentration Reference

of study (ng/m3)
mean or range of
means (range)
China Beijing and Shanghai 1984–97 60–980 Zhang, Z.-W. et al.

(1998)b
Provincial capitals 30–13 700
Other regions 8–2800
Beijing 21–318 Parikh et al. (1999)
Taiyuan Yang & Ma (1997)
Winter 490–1125
Summer 115–504
China (Province Tainan 180 [Environment
of Taiwan) Protection
Administration ROC
(1991)]
India Delhi 1998 100–2000 Balachandran et al.
(2000)
Delhi 2000 590 Central Pollution
2001 550 Control Board (2001–
2002)
Kolkata (road dust)c 536 µg/g Chatterjee & Banerjee
(1999)
Mumbai 82–605 (31–1040) Khandekar et al. (1984)
Mumbai 30–440 Raghunath et al. (1997)
Mumbai Nambi et al. (1997)
Industrial 500–120 000
Rural 110
Mumbai Parikh et al. (1999)
High-exposure area 432.4 (131–864)
Low-exposure area 268.2 (147–476)
Mumbai 1984–96 Tripathi et al. (2001)
Urban 100–1120
Industrial 1180–4120
Nagpur 1996 42–65 Patel et al. (2001)
7 cities 1980 60–310 Sadasivan et al. (1987)
Whole country 1994 11 000 Gupta & Dogra (2002)
Indonesia Semarang Browne et al. (1999)
Urban 350–990
Industrial 8410
Japan Tokyo and Kyoto 1996–97 15–81 Environment Agency,
Japan (1997)
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Table 26 (contd)
Country Location Year(s) Concentration Reference

of study (ng/m3)
mean or range of
means (range)
Korea Pusan 902–1596 [Moon & Lee (1992)]

Seoul 1984–93 100–1500d Lee et al. (1994)
Seoul 1986–94 22–1070 Reviewed by Moon &
Ikeda (1996)
Pusan 1990 1310 (210–2870) Cho et al. (1992)
Malaysia Kuala Lumpur 30–462 [Hisham & Pertanika
(1995)]
Kuala Lumpur (urban) 95 Hashim et al. (2000)
Kemaman 27
(semiurban) 15
Setiu (rural)
Pakistanc Karachi 7.9–101.8 µg/g Rahbar et al. (2002)
Philippines Whole country 1993 600–1300 Environmental
Management Bureau
(1996)
1994 300–500
Manila 1994 300–1200d
1995 200–800d
Saudi Arabia Riyadh Al-Saleh (1998)
High traffic 3200
Residential 720
Thailand Bangkok 210–390 [Pollution Control
Department (1996)]
Updated from Ikeda et al. (2000a)

a
b
Review of 15 reports published primarily in China between 1984 and 1997
c
Lead concentration in dust
d
Values read from graphs
References in square brackets could not be retrieved as original papers.
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09/08/2006
Table 27. Lead concentrations in outdoor air in Japan, 1996–97, as monitored in 16 monitoring stations
Statistical Monthly average concentration (ng/m3)
11:15
parameter

1996 1997
Page 82
Apr. May June July Aug. Sept. Oct. Nov. Dec. Jan. Feb. March Averageb
AMa 54.9 56.3 51.1 40.3 34.9 44.2 52.4 62.2 73.5 56.5 49.5 55.3 51.3
ASDa 28.0 23.6 24.3 21.1 13.9 24.9 28.0 31.5 34.2 26.6 23.0 21.3 23.1
Min 16 < 10 < 10 < 10 < 10 11 12 16 20 14 15 19 13
Max 110 100 84 81 59 85 99 120 130 100 77 87 81
GMa 45.0
GSDa 1.78
From Environment Agency, Japan (1997)

AM, arithmetic mean; ASD, arithmetic standard deviation; min, minimum; max, maximum; GM, geometric mean; GSD, geometric standard
deviation
a
Values calculated by the Working Group; values < 10 were not included in the calculations.
b
Mean, standard deviation, min. and max. of local annual arithmetic means among the 16 stations
P 075-140 DEF.qxp 09/08/2006 11:15 Page 83
burning) and 0.99 µg/m3 in a commercial zone. Airborne lead concentrations of 8.41 µg/m3
were recorded in an industrial area; values of this magnitude had not been reported
previously in Indonesia (Browne et al., 1999).
After leaded gasoline, lead mining and the smelting and refining of both primary and
secondary lead are the next highest sources of lead emissions that can cause contami-
nation of the nearby environment. The nature and extent of contamination depend on
many factors, including the level of production, the effectiveness of emission controls,
climate, topography and other local factors. Concentrations are usually highest within
3 km of the point source (US EPA, 1989, cited by WHO, 1995). For example, near a
smelter in Santo Amaro, Bahia, Brazil, 4-day average values in 1989 of 2.8 ± 1.0 µg/m3
(range, 1.8–3.9 µg/m3) were reported 526 m from the smelter chimney in one direction
and 0.13 ± 0.06 µg/m3 (range, 0.08–0.22 µg/m3) 955 m in the opposite direction (see
Table 23; Tavares, 1990). A report from China found that lead concentrations in ambient
air, plants and soil increased proportionally with proximity to a large primary smelter; air
lead concentrations were 1.3 µg/m3 at 1000 m from the source and 60 µg/m3 at 50 m from
the source (Wang, 1984). Some earlier studies have shown air pollution and soil contami-
nation as far as 10 km from lead smelters (Djuric et al., 1971; Landrigan et al., 1975a).
A survey conducted in the vicinity of three lead industries in Maharashtra, India,
showed the highest measured concentration of lead in air of 120 µg/m3 in a residential
area 200 m from one of the industries (see Table 26; Nambi et al., 1997).
High concentrations of lead in household dust in the vicinity of lead smelters or mining
activity, or from vehicles using leaded gasoline, have been reported (see Tables 24, 25 and
26). Lead concentrations in dust inside houses located in the vicinity of a lead smelter at
Cd. Juarez, Chihuahua, Mexico, increased from 220 µg/g at 4 km to 1322 µg/g at less than
1.6 km from the smelter (Ordóñez et al., 2003). An international study coordinated by
WHO found a mean lead concentration (± standard deviation) in indoor dust in Mexico
City of 587 ± 303 µg/g, compared with 440 ± 263 µg/g and 281 ± 500 µg/g in Sweden and
Belgium, respectively (Bruaux & Svartengren, 1985). In 1997–98 lead concentrations of
floor dust in day-care centres in Caracas, Venezuela, ranged from 999 to 1707 µg/g
(Fernández et al., 2003).
Data on lead in air in South America are scarce, and refer only to total lead in suspen-
ded particles. One study of lead concentrations in incoming Atlantic air masses reaching
the north-eastern Brazilian coast in 1994–95 showed concentrations of 1.5 ng/m3 during
the rainy season (April–August) and of 0.25 ng/m3 during the dry season (September–
March) (see Table 23; Tavares, 1996a).
Biomass burning, which takes place during the dry season both for forest clearance
and for agricultural purposes, can be an important source of lead in rural environments
with otherwise low concentrations. Measurements in the Amazon forest during the wet
season (September–March) showed lead concentrations of 0.33–0.61 ng/m3 in particles
smaller than 2.5 µm and 0.26–0.50 ng/m3 in particles 2.5–10 µm in size; corresponding
values during the dry season (June–September) were 0.73 ng/m3 and 0.46 ng/m3, respec-
tively (Artaxo et al., 1990).
P 075-140 DEF.qxp 09/08/2006 11:15 Page 84
Coal contains small amounts of lead, and fly ash from coal combustion and refuse
incineration can leach substantial amounts of lead into ambient air (Wadge & Hutton,
1987). In an urban area of Taiwan, China, where the winter is cold, lead concentrations in
air were reported to be about three times higher in winter (0.49–1.13 µg/m3) than in
summer (0.12–0.50 µg/m3), due to use of lead-containing coal for heating (Yang & Ma,
1997). Surveys of lead in air in seven cities in India indicated concentrations ranging from
0.06 ± 0.02 µg/m3 in Coimbatore to 0.31 ± 0.10 µg/m3 in Kanpur (Sadasivan et al., 1987).
In addition to automobile exhaust, increased fuel burning in the winter and open burning
of refuse were identified as sources of lead contamination (Table 26). In contrast, lead air
concentrations in Japan in 1996–97 averaged 50 ng/m3 and little seasonal variation was
observed (Table 27).
Lead concentrations in indoor air are affected by the presence of smokers, air condi-
tioning and lead-painted surfaces. Two studies conducted in the Netherlands and the United
Kingdom showed that air lead concentrations inside dwellings where there is no major
internal lead source were highly correlated with those outside and averaged approximately
60% of those in the external air immediately outside the house (Diemel et al., 1981; Davies
et al., 1987).
(c) Water
Lead enters groundwater from natural weathering of rocks and soil, indirectly from
atmospheric fallout and directly from industrial sources. Lead can enter freshwater bodies
from municipal sewage, from harbour activities and from lead storage sites and production
plants, particularly mining and smelting. In local aquatic environments, pollution can also
result from leaching of lead from lead shot, shotgun cartridges and fishing weights (WHO,
1995). The concentration of lead in surface water is highly variable depending upon the
sources of pollution, the lead content of sediments and the characteristics of the system
(pH, temperature). An additional and distinct hazard to the water supply is the use of lead
piping or lead solder in plumbing systems. Water with low pH and low concentrations of
dissolved salts (referred to as aggressive or corrosive water) can leach substantial quantities
of lead from pipes, solder and fixtures (ASTDR, 1999). Lead-lined reservoirs, cisterns and
water tanks can be a major source of lead contamination of drinking-water.
Lead concentrations in surface water, groundwater and tap-water in different geo-
graphical regions of the world are presented in Tables 28–31. A few examples are detailed
below, according to the type of water analysed.
Seawater generally contains low levels of lead. It was estimated that lead concen-
trations in the ocean were 0.0005 µg/L in the pre-industrial era and around 0.005 µg/L in
the late 1970s (US EPA, 1982).
Concentrations of lead in surface water and groundwater throughout the USA typi-
cally range between 5 and 30 µg/L and between 1 and 100 µg/L, respectively, although
concentrations as high as 890 µg/L have been measured (US EPA, 1986a). The mean
concentration of lead measured at nearly 40 000 surface-water stations throughout the
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11:15
Table 28. Lead concentrations in water in Latin America and the Caribbean
Country Location Year of Source of contamination Concentration (µg/L) Reference
Page 85
study mean (range)
Argentina La Plata river, Buenos Aires Industry, sewage, harbour Verrengia Guerrero & Kesten
Port 1989 activities 28.1 (2.4–58.6) (1994)
Fishing Club 1989 11.3 (9.9–16.4)
Bolivia Pilcomayo river (at Potosi) 1999 Mine tailings 1399 (911–2111) Smolders et al. (2003)
Tarapaya river 1999 Mine tailings 2291 (1101–3980)
Cachi Mayu 1999 No specific source 1.0 ( 0.6–1.7)
Brazil Ribeira do Iguape river 1994 NR < 20–70 Romieu et al. (1997)
Sao Paulo State 1994 NR 2.8
Chile Antofagasta (household) 1998 Lead storage site Max. 170 Sepúlveda et al. (2000)
Mexico Drinking-water 1983 No specific source 2 ± 1 (1–3) Bruaux & Svartengren (1985)
Uruguay Tap-water 1992 Lead pipes 15 (0.2–230) Schütz et al. (1997)
NR, not reported; max., maximum concentration (µg/L)
85
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Table 29. Lead concentrations in fresh water, seawater and sediment

in the Canary Islands, Egypt and Nigeria
Country Location Type of water/ Concentration Reference

sediment mean or range
of means
(range)
Canary Islands Santa Cruz Seawater 1.4–11.3 µg/L Díaz et al. (1990)
(Spain) (0.42–116.9)
Egypt Lake Nubia Sediment 79 µg/g Lasheen (1987)a
Alexandria Seawater 0.05–0.7 µg/L Abdel-Moati &
Sediment 2–49 µg/g Atta (1991)
Nigeria Agunpa river River water 1.3–46 µg/L Mombeshora
Sediment 62–75 µg/g et al. (1983)
Ona river River water 0.2–17 µg/L
Sediment 25–58 µg/g
Adapted from Nriagu (1992)

a
Original paper was not available.
USA was 3.9 µg/L (Eckel & Jacob, 1988). Lead concentrations in surface water are typi-
cally higher in urban areas than in rural areas (US EPA, 1982).
Lead concentrations in the La Plata river at two sites in Buenos Aires, Argentina,
ranged from 2.4 to 58.6 µg/L at the port area and from 9.9 to 16.4 µg/L at the Fishing Club
(Table 28; Verrengia Guerrero & Kesten, 1994). The Ribeira do Iguape river, in South
Brazil, receiving urban and industrial effluents, showed lead concentrations between < 20
and 70 µg/L in 1994 (Romieu et al., 1997). Intensive mining and tailing releases to the
Pilcomayo and Tarapaya rivers resulted in mean lead concentrations in the water of 1399
and 2291 µg/L, respectively, against 1.0 µg/L in Cachi Mayu, which had not been conta-
minated by specific lead sources (Smolders et al., 2003).
Lead contamination of groundwater around the Hussain Sagar lake, Hyderabad, India,
indicated that the source of pollution was the contaminated lake. Lead was detected at
concentrations in the range of 1–28 µg/L in groundwater and 38.4–62.5 µg/L in the lake
(Table 30). The concentrations were appreciably higher than those for uncontaminated
fresh waters which are generally below 1 µg/L (Srikanth et al., 1993). During a 2-year
study of the Nainital lake, India, the average lead contamination levels in water and
sediment were 600 µg/mL and 50.0 µg/g, respectively (Ali et al., 1999). The lead content
in various bodies of water in India ranged from 35 to 70 µg/L in the Eastern Ghats (Rai
et al., 1996), from 350 to 720 µg/L in various lakes in Lucknow, and from 510 to
1510 µg/L in Unnao (Chandra et al., 1993). In the Gomti river, lead concentrations of
13–26 µg/L were reported (Singh, 1996) and in the Ganga river from 0.98 to 6.5 µg/L
(Israili, 1991). The waters of Vasai Creek (Maharashtra, India) had concentrations of
10.5–29.5 µg/L, which was the result of contamination from 18 major industries that
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Table 30. Lead concentrations in water and sediment in Asia
Country Location Type of water/ Concentration Reference Comments
sediment (µg/L)a
mean or range of

means (range)
11:15
India Pilani Tube well 88 (21–354) Kaphalia et al. (1981) pH of water, 7.5–9.1
Lucknow Tap-water 33 (0–67)
Page 87
River 35 (8–58)
Cambay Tank 6 (0–16)
Kanpur villages Tube well 20 (0–40)
Company Tube well 24 (0–80)
Mumbai Drinking-water 12 ± 3 Khandekar et al.
(1984)
Various cities along Ganga River 0.98–6.5 Israili (1991) Highest concentration in
river Sediment 1.2–16.0 µg/g water and sediment at
Garsh Mukteshwara
5 cities along Yamuna river River (10 samples) 0.76–8.51 Israili & Khurshid
(1991)
Koraput (Orissa) Water stations 15 ± 1 Chandra et al. (1993)
Unnao (Uttar Pradesh) 510 ± 50 (summer)
1510 ± 150 (winter)
Various sites along Gomti River Singh (1996) Highest concentrations at
river unfiltered 13–25 Mohan Meakin, Sultampur
filtered 9–21 and Pipraghat
Hussain Sagar lake, Lake 38.4–62.5 Srikanth et al. (1993)
Hyderabad Ground water
200–1000 m 7–28
from lake
1000–2000 m 1–9
from lake
87
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Table 30 (contd)
88
Country Location Type of water/ Concentration Reference Comments
sediment (µg/L)a
mean or range of
09/08/2006
means (range)
India Eastern Ghats (Koraput Drinking-water facilities Rai et al. (1996)

(contd) Orrisa) adequate 54 ± 5
primitive 35 ± 5
absent 70 ± 37
11:15
Nainital Lake water 150–480 Ali et al. (1999)

Sediment 50.0 µg/g
Vasai Creek, Maharashtra River/sea 10.5–29.5 Lokhande & Kelkar
Page 88
(1999)
Mumbai Drinking-water Parikh et al. (1999)
High exposure area 2.8 ± 0.8
Low exposure area 4.5 ± 1.7
Nagpur Tap-water 2.82 Patel et al. (2001)
Well 3.30
Lucknow Lake and ponds 350–720 Rai & Sinha (2001)
Darbhanga District, North- 9 ponds [147–1056] Rai et al. (2002) Data for 1996–97; highest
Bihar Sediment [72.21–240.95 µg/g] values for water and
sediment in same pond
Indonesia Central Kalimantan 6 rivers 0.41–5.23 Kurasaki et al. (2000) Motor boats are an
3 channels 0.1–1.28 important mode of
3 lakes 0.28–11.48 transport.
1 fish pond 0.51
Malaysia Klang river 1992b 28 APEC (1997)
1993 21
1994 18.6
1995 25.9
1996 8
Pakistan Karachi Drinking-water from 3.1–4.3 Rahbar et al. (2002)
household
a
b
Year of sample collection
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Table 31. Lead concentration in drinking-water, Japan, 2001
Number [%] of samples with lead concentration (µg/L)
Total <5 5–< 10 10–< 15 ≥ 15
Source water 5178 5110 53 5 10

[98.69] [1.02] [0.10] [0.19]
Treated watera 5647 5536 84 14 13
[98.03] [1.49] [0.25] [0.23]
From Ministry of Health, Labour and Welfare, Japan (2001)

a
Concentrations measured at drinking-water treatment plants
Note: A drinking-water standard of < 10 µg/L lead was established in Japan as of
1 April, 2004 (Ministry of Health, Labour and Welfare, Japan, 2003).
collectively released about seven tonnes of lead per year into the creek (Lokhande &
Kelkar, 1999).
Among six locations along four rivers in central Kalimantan, Indonesia, the highest
lead concentrations were found in the Kahayan river (5.23 and 2.09 µg/L at two sampling
sites), followed by Murung river (1.71 µg/L). Of various channel, lake and pond waters
(7 locations), lake Tundai was found to be by far the most contaminated with lead
(11.48 µg/L), followed by channel Dablabup (1.28 µg/L) (Kurasaki et al., 2000).
Surveys in Canada and the USA showed that drinking-water supplies leaving
treatment plants contain 2–8 µg/L lead (US EPA, 1986a; Dabeka et al., 1987). EPA
estimated that less than 1% of the public water systems in the USA have water entering
the distribution system with lead concentrations above 5 µg/L. However, most lead conta-
mination comes from corrosion by-products of lead pipes and lead-soldered joints
(US EPA, 1991). A survey of 1245 drinking-water samples taken from various districts in
the USA showed that average lead concentrations in water in copper, galvanized and
plastic pipes were 9, 4.2 and 4.5 µg/L, respectively. These data show that even plumbing
that did not use lead solder (e.g. plastic pipes) contained significant amounts of lead,
primarily from the brass faucet fixtures which are used in almost all plumbing. The brass
fixtures may account for approximately one-third of the lead in the first-draw water (Lee
et al., 1989).
Following an increased volcanic activity that resulted in the release of acid aerosols,
Wiebe et al. (1991) analysed over 2000 water samples in Hawaii, USA, and found lead
concentrations in drinking-water collected in catchment systems ranging from < 20 to
7000 µg/L.
The use of lead pipes in Uruguay resulted in tap-water concentrations of lead ranging
between 0.2 and 230 µg/L (Schütz et al., 1997). In 1983, lead concentrations in drinking-
water from an underground source in Mexico City, Mexico, ranged between 1 and 3 µg/L,
in spite of the past intensive use of lead in petrol (Bruaux & Svartengren, 1985). Storage
P 075-140 DEF.qxp 09/08/2006 11:15 Page 90
of minerals near urban areas in Antofagasta, Chile, resulted in concentrations of lead in

household water of up to 170 µg/L in 1998 (Sepúlveda et al., 2000).
Water samples collected from tube wells, tanks and taps in India showed lead concen-
trations that varied between 0 and 354 µg/L (Kaphalia et al., 1981). The lead concentration
in drinking-water in Karachi, Pakistan, was found to be in the range of 3.08–4.32 µg/L as
an arithmetic mean for each of five monitored areas (Rahbar et al., 2002). Throughout
Japan, more than 98% of the drinking-water samples had concentrations below 5 µg/L
(Table 31; Ministry of Health, Labour & Welfare, 2001).
Gulson et al. (1997a) measured lead in household water throughout the day in an
unoccupied test house in Australia. Lead concentrations in water ranged from 119 µg/L for
the initial (first-draw) sample to 35–52 µg/L for hourly samples (125 mL) to 1.7 µg/L for
a fully flushed sample.
(d) Sediments
Lead reaching surface waters is readily bound to suspended solids and sediments, and
sediments from both freshwater and marine environments have been studied for their lead
content. Sediments contain considerably higher concentrations of lead than corresponding
surface waters, and provide a unique record of the history of global lead fluxes (WHO,
1995).
Concentrations of lead in sediments in Africa, Asia and Latin America are
summarized in Tables 29, 30 and 32, respectively.
Average concentrations of lead in river sediments in the USA have been reported to
be about 23 mg/kg (Fitchko & Hutchinson, 1975; US EPA, 1982). In coastal sediments a
mean value of 87 mg/kg was measured (range, 1–912 mg/kg) (Nriagu, 1978; US EPA,
1982). Surface sediment concentrations of lead in Puget Sound, near Seattle, were found
to range from 15 to 53 mg/kg (Bloom & Crecelius, 1987). An analysis of sediments taken
from 10 lakes in Pennsylvania indicated that the lead does not principally originate from
parent materials in the watershed (from the native rocks as a result of acid deposition), but
rather from transport of anthropogenic lead through the atmosphere onto the soil surface
and subsequent run-off of soil particulates into the lake (Case et al., 1989).
The main reported sources of lead entering surface-water bodies in Latin America have
been metallurgy, smelter and mining effluents, oil refineries and port activities. In Brazil,
the All Saints bay showed values of 119 mg/kg in sediments at the river mouth downstream
from a smelter; 176 mg/kg at the river mouth downstream from an oil refinery; and
618 mg/kg in the vicinity of metallurgical industries and an industrial port, compared with
35.7 mg/kg in an area with no specific source of lead, away from industries (Tavares,
1996a,b).
Mine tailings in Bolivia were responsible for an increase in lead concentrations from
7.4 mg/kg in Cachi mayu, where no specific source of lead contamination exists, to
average values of 603 mg/kg (range, 292–991 mg/kg) and 902 mg/kg (range, 761–1236
mg/kg), in sediments from the Pilcomayo river at Potosi and from the Tarapaya river,
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Table 32. Lead in sediments in Latin America and the Caribbean

of study contamination (µg/g)
mean (range)
Brazil All Saints bay, 1994 Downstream from 119 Tavares

São Brás lead smelter (1996b)
All Saints bay, 1994 Oil refinery 176
Mataripe river
mouth
All Saints bay, 1994 Metallurgies, 618
Aratu Port industrial port
All Saints bay, 1994 No specific source 35.7
Cabuçu
Ribeira do Iguape 1994 NR (3–240) Romieu et al.
river (1997)
Jacareí, São Paulo 1994 NR (10–9100)
Bolivia Pilcomayo river, 1997–98 Mine tailings 603 Smolders et al.
Potosi (292–991) (2003)
Tarapaya river 1997–98 Mine tailings 902
(761–1236)
Cachi mayu 1997–98 No specific source 7.4
(3.3–9.9)
Honduras Yojoa lake NR NR 371 Romieu et al.
(1997)
Mexico Gulf of Mexico 1983–87 NR (0.29–90.15) Albert &
coast Badilloa (1991)
Uruguay Montevideo NR NR (20–160) Romieu et al.
(1997)
NR, not reported

a
Review of 7 studies at 8 sites
respectively (Smolders et al., 2003). Mean concentrations of lead in sediments from the
Gulf of Mexico were found to range from 0.29 to 90.15 mg/kg (Albert & Badillo, 1991).
(e) Soil
Most of the lead released into the environment from emissions or as industrial waste
is deposited in soil. Lead-containing wastes result from the processing of ores, the pro-
duction of iron and steel, the various end-products and uses of lead, and the removal and
remediation of lead paint (ATSDR, 1999). Lead in soil may be relatively insoluble (as a
sulfate, carbonate or oxide), soluble, adsorbed onto clays, adsorbed and coprecipitated
with sesquioxides, adsorbed onto colloidal organic matter or complexed with organic
moieties present in soil (WHO, 1995). The soil pH, the content of humic and fulvic acids
P 075-140 DEF.qxp 09/08/2006 11:15 Page 92
and the amount of organic matter influence the content and mobility of lead in soils. Since
acidic conditions favour the solubilization and leaching of lead from the solid phase,
acidic soils tend to have lower lead concentrations when analysed as dry soil. Acid rain
promotes the release of lead into groundwater. Humic and fulvic acids can also mobilize
lead, and certain complex organic molecules can act as chelators of lead (WHO, 1995).
Table 33 shows some sources and amounts of lead released in soils worldwide.
Tables 34, 35 and 36 summarize data on lead concentration in soils in Latin America,
Africa and Asia, respectively.
Background concentrations of lead in soil measured across the USA in the 1970s were
estimated to be in the range of < 10–70 mg/kg (Boerngen & Shacklette, 1981). Soil
samples taken at distances of 50–100 m from highways, outside the range of immediate
impact from traffic emissions, usually show concentrations of lead below 40 mg/kg (WHO,
1995).
Studies carried out in Maryland and Minnesota indicate that within large light-
industrial urban settings such as Baltimore, soil lead concentrations are generally highest
in inner-city areas, especially where high traffic flows have long prevailed (Mielke et al.,
1983, 1989); the amount of lead in the soil is correlated with the size of the city, which in
turn is related to traffic density (Mielke et al., 1989; Mielke, 1991). It has been suggested
that the higher lead concentrations in soil samples taken around houses in the inner city
are the result of greater atmospheric lead content from the burning of leaded gasoline in
cars and the washdown by rain of building surfaces to which the small lead particles
adhere (Mielke et al., 1989).
Table 33. Discharge of lead in soil worldwide
Source of lead Amount released (tonnes/year)
Agricultural and food wastes 1500–27 000

Animal wastes, manure 3200–20 000
Logging and other wood wastes 6600–8200
Urban refuse 18 000–62 000
Municipal sewage sludge 2800–9700
Miscellaneous organic wastes, including excreta 20–1600
Solid wastes, metal manufacturing 4100–11 000
Coal fly ash, bottom fly ash 45 000–242 000
Fertilizer 420–2300
Peat (agricultural and fuel use) 450–2600
Wastage of commercial products 195 000–390 000
Atmospheric fallout 202 000–263 000
Mine tailings 130 000–390 000
Smelter slags and wastes 195 000–390 000
Total yearly discharge on land 803 090–1 818 800
From Nriagu and Pacyna (1988)

Many of these discharges remain localized due to the nature of the particulate matter.
P 075-140 DEF.qxp
09/08/2006
Table 34. Lead concentrations in soils in Latin America and the Caribbean
Country Location Year(s) of Source of contamination Concentration (mg/kg) Reference

study mean ± SD (range)
11:15
Argentina Buenos Aires 1975 NR 6–12 Romieu et al. (1997)
Page 93
Brazil Santo Amaro, Bahia a
1980 900 m from smelter, 12 m 10 601 ± 14 611 Tavares (1990)
high chimney (32–107 268)
4415 ± 4.4b
1985 90 m high chimney 4812 ± 8523
(236–83 532)
2529 ± 2.9b
Jacareí, São Paolo 1994 NR (51–338) Romieu et al. (1997)
Chile Antofagasta 1998 Storage of minerals (81–3159) Sepúlveda et al.
(2000)
1998 Upwind from storage site (51–321)
Ecuador Andean village NR Glazing of ceramics Counter et al. (2000)
La Victoria At 1 m 29 213 ± 9458a
At 5 m 172 ± 26
At 10 m 81 ± 13
At 1 km 55 ± 2
At 2 km 19 ± 1
At 6 km 1.4 ± 0.1
Mambija, San Carlos and Control area (2.3–21)
Esmeraldas
93
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94
09/08/2006
Table 34 (contd)
Country Location Year(s) of Source of contamination Concentration (mg/kg) Reference

study mean ± SD (range)
11:15
Mexico N and NE Mexico city 1980–81 Traffic fallout 5.3 ± 1.5 Albert & Badillo

irrigation districts (1991)
Page 94
Mexico city airport 1979 Traffic fallout (739–890)
Mexico city centre 1979 Traffic fallout (6–107)
Mexico city 1979 Traffic fallout (43–578)
Viaducto Piedad
Mexico city 1979 Traffic fallout (2.1–2.7)
Estadio Azteca
Venezuela Caracas, 1997–98 Traffic (high flow) Particle size, 44–62.5 µm: Fernández et al.
Day-care centres 113–375 (2003)
Particle size, < 44 µm:
190–465
Traffic (low flow) Particle size, 44–62.5 µm:
106 ± 3
Particle size, < 44 µm:
142 ± 3
NR, not reported; SD, standard deviation

a
Leachable lead
b
Geometric mean and standard deviation
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Table 35. Lead concentrations in soil in Saudi Arabia and Africa
Country Location Source of contamination Concentration Reference

(mg/kg)
mean or range
of means (range)
Saudi Arabia NR Heavy traffic 95.3 Al-Saleh

Residential 34.5 (1998)
Kenya Nairobi City traffic 137–2196 Onyari et al.
Industrial area 148–4088 (1991)
Zambia Kasanda 2 km from lead smelter 100–> 2400 Nriagu (1992)
Kabwe 5 km from lead smelter (9862–2580) Nwankwo &
Lusaka No specific 16 (11–40) Elinder (1979)
NR, not reported
Lead-based paint can also be a major source of lead in soil. In the state of Maine, USA,
37% of soil samples taken within 1–2 feet (30–60 cm) of the foundation of a building more
than 30 years of age had lead concentrations > 1000 mg/kg (Krueger & Duguay, 1989).
In a study of the association between the concentrations of lead in soil and in blood
samples taken from children in urban and rural areas in Louisiana, USA, blood lead
concentrations in children appeared to be closely associated with soil lead concentration
(Mielke et al., 1997a).
Three prospective studies were conducted in Boston, Baltimore and Cincinnati, USA,
to determine whether abatement of lead in soil could reduce blood lead concentrations of
children. No significant evidence was found that lead reduction had any direct impact on
children’s blood lead concentrations in either Baltimore or Cincinnati (US EPA, 1996b).
In the Boston study, however, a median soil lead reduction from 2075 mg/kg to 50 mg/kg
resulted in a mean decline of 2.47 µg/dL blood lead concentration 10 months after soil
remediation (Weitzman et al., 1993; Aschengrau et al., 1994). A number of factors appear
to be important in determining the influence of soil abatement on blood lead concen-
trations in children, including the site-specific exposure scenario, the extent of the reme-
diation, and the magnitude of additional sources of lead exposure.
Children with pica — a serious eating disorder characterized by repetitive consump-
tion of nonfood items — may be at increased risk for adverse effects through ingestion of
large amounts of soil contaminated with lead. It has been estimated that an average child
may ingest on average between 20 and 50 mg of soil per day through normal hand-to-
mouth activity, whereas a child with pica may ingest up to 5000 mg of soil per day
(LaGoy, 1987). This source can contribute an additional lead intake of 5 µg/day for a
toddler engaging in normal hand-to-mouth activity, and significantly more for a child
demonstrating pica behaviour (ATSDR, 1999).
Davis et al. (1992, 1994), using electron microprobe analysis of soil and waste rock
from the mining district of Butte, Montana, USA, showed that the lead bioavailability of
P 075-140 DEF.qxp
96
Table 36. Lead concentrations in soil and plants in Asia
09/08/2006
Country Location Source of Lead concentration in: Reference Comments
contamination
Soil (mg/kg) Plant (mg/kg)
11:15
China NR Smelter Wang (1984)
50 m 170 29.1

500 m 28 1.7
Page 96
India Mumbai Lead industries 200–3454 145–1048 (grass) Nambi et al.
Control 8.6 1.42 (1997)
Residential area Lead factory 200–46 700 214 ± 17 (leaf) Chatterjee & Soil contaminated at
of greater Kolkata Banerjee (1999) least up to 0.5 km
Coimbatore Sewage Surface: 13.3–22.2 Duraisamy et al. The highest values
Subsurface: 10.26–19.3 (2003) were found in Nov.–
Dec. and the lowest in
March.
Coimbatore Fertilization with 1992: 24–47.2 Kamaraj et al. Fertilizer used during
superphosphate and 2000: 32.4–63.2 (2003) entire period
zinc sulfate
Mongolia Urban 92 Burmaa et al.
Residential 44 (2002)
Philippines Manila Playground Sharma &
contaminated 34.5–281.5 Reutergardh
control 15 (2000)
Thailand Grazing-land site Highway 5.25–14.59 0.76–6.62 (grass) Parkpian et al.
(2003)
P 075-140 DEF.qxp 09/08/2006 11:15 Page 97
these samples is constrained by alteration and encapsulation of the lead-bearing minerals

(galena, anglesite, cerussite and plumbojarosite), which would limit the available lead-
bearing surface area. The inherent chemical properties of soil-lead adsorption sites may
reduce the bioavailability of soil lead compared with that of soluble lead salts and lead
compounds ingested without soil and may explain the low blood lead concentrations
observed in children in this mining community.
Davies (1983) calculated that uncontaminated soils in the United Kingdom have a
(geometric) mean lead concentration of 42 mg/kg, with a maximum of 106 mg/kg.
A study conducted in Wales, United Kingdom, in an area where lead mining began
2000 years ago and ended in the middle of the 20th century, reported concentrations of
lead in garden soils 14 times higher than in uncontaminated areas (Davies et al., 1985).
In Port Pirie, Australia, a community with one of the world’s largest and oldest
primary lead smelters, lead concentrations in soils were found to be grossly elevated,
ranging up to over 2000 mg/kg (McMichael et al., 1985). The frequency of elevated lead
concentrations in the blood of pregnant women and young children in this community
was also increased above that found in other communities in Australia (Wilson et al.,
1986; McMichael et al., 1988).
The main reported sources of lead in soil in Latin America have been from smelter
activities, storage of minerals, glazing of ceramics, and leaded gasoline (Table 34). In
Santo Amaro, Brazil, in 1980, lead concentrations as high as 107 268 mg/kg in soil have
been found in orchards and homes around a smelter (arithmetic mean value for the area
within 900 m from the smelter, 10 601 mg/kg), as a result of the use of dross as paving
material around houses. At that time, the smelter had a 12-m high chimney. Five years later,
after a 90-m high chimney was built, these values dropped to mean values of 4812 mg/kg
(Tavares, 1990). In Antofagasta, in the north of Chile, storage of minerals resulted in lead
concentrations up to 3159 mg/kg in soil around the site compared with values of 51–321
mg/kg upwind from the site (Sepúlveda et al., 2000). Analysis of soil around ceramic
glazing facilities in an Andean Equadorian village showed a significant fall in lead soil
concentration with distance from the baking kilns; concentrations were 29 213 mg/kg at
1 m, 55 mg/kg at 1 km and 1.4 mg/kg at 6 km from the kilns (Counter et al., 2000). In
1979, when tetraethyl lead was still added to gasoline, soil lead concentrations in Mexico
City, Mexico, were determined near avenues in different parts of the city. Higher
concentrations of lead were found in the north and north-west of the city, with the highest
values found at the airport, ranging from 739 to 890 mg/kg. The centre of the city showed
values between 6 and 107 mg/kg (Albert & Badillo, 1991). In 1980–81, agricultural soils
north and north-east of the city, irrigated either directly from wastewaters or with clean
water, were analysed for lead; there was no influence of irrigation on soil lead
concentrations (Albert & Badillo, 1991). Soil lead concentrations in day-care centres near
areas of high traffic flow in Caracas, Venezuela, ranged between 113 and 465 mg/kg, with
higher values in soil particles < 44 µm (Fernández et al., 2003). In Argentina, a study of
phosphate fertilizers imported from different parts of the world showed lead concentrations
P 075-140 DEF.qxp 09/08/2006 11:15 Page 98
between 5.1 and 30.7 mg/kg, which could potentially increase lead concentrations in soils
undergoing continuous fertilization (Giuffré de López Camelo et al., 1997).
A number of studies have reported soil lead concentrations in the proximity of
smelters and mining areas. A report from China found that lead concentrations in ambient
air, plants and soil increased proportionally with proximity to a primary smelter: lead con-
centration in soil was 28.0 mg/kg at 500 m and 170 mg/kg at 50 m distance from the
smelter (Wang, 1984).
Concentrations of lead in soil have been found elevated in many locations in Asia
(Table 36), such as in the vicinity of a lead refinery in Kolkata, India (Chatterjee &
Banerjee, 1999), in sewage-affected soils (Duraisamy et al., 2003), or on a playground in
Manila, Philippines (Sharma & Reutergardh, 2000).
(f) Lead in gasoline

Globally, by far the largest source of lead emissions into air has been exhaust from
motor vehicles using organic lead as an anti-knock agent in gasoline (see Section 1.3.7).
In motor-vehicle exhaust from leaded gasoline, > 90% of the lead emission is inorganic
lead (e.g. lead bromochloride) and < 10% is alkyl lead vapour. Furthermore, alkyl lead
compounds decompose in the atmosphere to lead oxides through a combination of photo-
lysis and oxidation reactions, over a period ranging from a few hours to a few days
(ATSDR, 1999). Vehicle emissions increase lead concentrations in the surrounding air,
and lead compounds adhere to dust particles that settle and increase the lead content of
dusts and soils, thus constituting a major source of exposure of the general population. By
comparing ratios of stable lead isotopes in remote areas with those characteristic of lead
from industrial sources in various regions, investigators have shown that the lead found in
pristine areas such as Greenland and Antarctica originated from motor vehicle exhaust
from North America (Rosman et al., 1994a) and South America (Rosman et al., 1994b),
respectively.
Nriagu and Pacyna (1988) estimated that in 1983 mobile sources worldwide contri-
buted 248 000 tonnes of lead to the atmosphere. This compares with total estimated
emissions to the atmosphere from all sources of 288 700–376 000 tonnes. By 1997, global
emissions from leaded gasoline had been reduced to 40 000 tonnes and are still declining,
as permissible lead contents of gasoline have been lowered and unleaded gasoline has
replaced, or is replacing, leaded fuel in many countries (see Table 20). However, in a
number of countries, leaded gasoline is still in use (see Section 1.3.7). Table 37 shows lead
concentrations in gasoline over time in a number of countries worldwide.
In Japan, the use of lead in gasoline had been phased out since 1974 and reached almost
zero in 1983 (Friberg & Vahter, 1983). The Central Pollution Control Board in India
(1998–1999) reported a 50% reduction of lead concentration in air as unleaded gasoline
came into use. Leaded gasoline has been banned in India with effect from February 2000.
In Pakistan, the addition of lead to gasoline was reduced in 1998–99 from 0.42 to 0.34 g/L
in regular gasoline and from 0.84 to 0.42 g/L in high-octane gasoline. In 2001, a directive
P 075-140 DEF.qxp
Table 37. Lead concentrations in gasoline, air and blood in adults and children worldwide
Country Location Population Year(s) Lead concentration in Reference
09/08/2006
of study
Gasoline Aira Blooda
(g/L) (µg/m3) (µg/dL)
Belgium NR ≥ 20 years 1979 0.45 1.05 17.0b Ducoffre et al. (1990)

1983 0.40 0.66 14.7b
11:15
1987 0.15 0.49 9.0b
Canada Ontario 3–6 years 1984 0.30 NR 11.9c (11.3–12.6)d Loranger & Zayed (1994);
1988 0.09 NR 5.1c (4.8–5.4)d Langlois et al. (1996)
Page 99
1990 0.04 NR 3.6c (3.3–3.9)d
1992 0.00 NR 3.5c (3.1–3.8)d
Finland Helsinki Children 1983 0.35 0.33 4.8 (2.1–8.3) Pönkä et al. (1993); Pönkä
1988 0.14 0.095 3.0 (2.1–4.1) (1998)
1996 0.00 0.007 2.6 (1.7–3.7)
Greece Athens Adults 1979 0.80 3.2 NR Chartsias et al. (1986);
1982 0.40 1.76 16.0 Kapaki et al. (1998)
1984 0.22 0.91 11.8
1988 0.15 0.7 8
1993 0.14 0.43 5.5
Italy Turin ≥ 18 years 1974 0.6 4.7 NR Facchetti (1989); Bono et al.
1980 0.6 3.1 21 (1995)
1985 0.4 2.8 15.1 (± 3.9)e
1989 0.3 1.4 NR
1993 0.11 0.53 6.4 (± 1.7)e
Japan Rural ≥ 20 years 1977–80 0.00 NR 4.9c (± 0.15)e (men) Watanabe et al. (1985)
3.2c (± 0.15)e (women)
Mexico Mexico City 0.5–3 years 1988 0.2 NR 12.2 Octel Ltd (1982, 1988,
1989 0.2 NR 14.6 1990); Driscoll et al. (1992);
1990 0.18 NR 9.8 Mexico City Commission for
1991 0.08 NR 8.6 Prevention and Control of
1992 0.07 NR 9 Pollution (1993); Rothenberg
1993 0.06 NR 7 et al. (1998)
99
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100
Table 37 (contd)

of study
09/08/2006
Nepal Himalayas Adults and NR 0.00 < 0.004g 3.4c Piomelli et al. (1980)
children
11:15
New Zealand Christchurch Adults and 1978–81 0.84 NR 15.2 Hinton et al. (1986);
children 1982–83 0.84 NR 11.8 Walmsley et al. (1988, 1995)

1984–85 0.84 NR 8.1
Page 100
1989 0.45 NR 7.3
1994 0.2 NR 4.9
South Africa Cape Town Adults 1984 0.84 NR 9.7 (3.0–16.0) Maresky & Grobler (1993)
1990 0.40 NR 7.2 (0.62–14.1)
Spain Barcelona 20–60 years 1984 0.60 1.03 18.6 (6.8–38.9) Rodamilans et al. (1996)
19–63 years 1994 0.15 0.24 (0.18–0.3) 8.8 (0.9–31.8)
Tarragona 16–65 years 1990 0.40 2.0 (0.97–3.26) 12.0c (± 1.8)e Schuhmacher et al. (1996a)
1995 0.13 0.23 (0.02–0.43) 6.3c (± 1.8)e
Sweden Trelleborg 3–19 years 1979 0.40 NA 5.6c (2.7–10.4) [Stockholm Municipal
1983 0.15 NA 4.2c (1.9–8.1) Environment and Health
1993 0.00 NA 2.3c (1.0–6.7) Administration (1983)];
Strömberg et al. (1995)
Stockholm Adults 1980 0.40 1.20 7.7 (± 3.3)e Elinder et al. (1986)
1983 0.15 0.50 5.4 (± 3.3)e
Landskrona 3–19 years 1978 0.40 0.12–0.42 6.0c (1.8–25.0) Skerfving et al. (1986);
1982 0.15 0.17 4.8c (1.5–10.0) Schütz et al. (1989);
1984 0.15 NA 4.2c (1.4–12.9) Strömberg et al. (1995)
1988 0.00 NA 3.3c (1.5–7.1)
1994 0.00 NA 2.5c (1.2–12.3)
Switzerland Vaud, 25–74 years 1984–85 0.15 NR 10.3c (8.0–17.2)f Wietlisbach et al. (1995)
Fribourg 1988–89 0.10 NR 7.3c (5.6–12.7)f
1992–93 0.05 NR 5.9c (4.4–10.2)f
P 075-140 DEF.qxp
Table 37 (contd)
09/08/2006
of study
11:15
United England ≥ 11 years 1979 0.42 NR 12.9c Quinn (1985); Quinn &
Kingdom 1981 0.38 NR 11.4c Delves, 1987, 1988, 1989;
1984 0.38 NR 8.0–10.9c Delves et al. (1996)
Page 101
1985 0.38 0.48 9.5c
1986 0.14 0.24 8.4c
1995 0.055 NR 3.1c
USA Countrywide 1–74 years 1976 0.465 0.97 15.9 Annest et al. (1983);
1977 0.394 14.0 [US EPA (1985; 1992)];
1978 0.349 14.6 Brody et al. (1994); Pirkle
1979 0.306 0.71 12.1 et al. (1994)
1980 0.30 0.49 9.5
1988–91 0.00 0.07 (0.05–0.12)d 2.8c (2.7–3.0)d
Venezuela Caracas ≥ 15 years 1986 0.62 1.9 17.4 Cedeño et al. (1990);
1989 0.45 1.3 15.2 Romero (1996)
1991 0.39 1.3 15.6
From Thomas et al. (1999) with minor modifications

NR, not reported
a
Arithmetic mean (range), unless stated otherwise
b
Median value
c
Geometric mean
d
95% confidence interval
e
Standard deviation
f
90% confidence interval
g
Detection limit
101
P 075-140 DEF.qxp 09/08/2006 11:15 Page 102
by the Government of Pakistan established a permissible limit of 0.02 g/L; most of the
petrol produced in Pakistan is now lead-free (Paul et al., 2003).
By 1995, six countries in Latin America and the Caribbean (Antigua and Barbuda,
Bermuda, Bolivia, Brazil, Columbia, and Guatemala) had removed all lead from gasoline
(Pan American Health Organization, 1997). Brazil introduced the national alcohol pro-
gramme [hydrated alcohol used as fuel in a mixture with gasoline] in 1975, leading to
100% of cars running on unleaded fuel by the beginning of the 1980s. This resulted in a
decrease of annual atmospheric lead concentrations from an average of 1.11 µg/m3 in 1980
to 0.27 µg/m3 in 1990 in São Paulo. Similarly, by 1994, 80% of the cars in Guatemala and
46% in Mexico ran on unleaded gasoline, reducing the annual average concentration of
lead in air to 0.17 and 0.28 µg/m3, respectively. In Mexico City, the concentration was
1.95 µg/m3 in 1988 and had decreased by 86% in 1994. Between 1982 and 1990, the city
of Caracas, Venezuela, showed a decrease in the annual average atmospheric lead concen-
trations from 4.5 µg/m3 to 1.9 µg/m3 (57.8% decrease). However, this is still higher than
the value of 1.5 µg/m3 recommended by WHO and established as an air quality standard
by US EPA. According to a survey carried out by the Pan American Center for Human Eco-
logy and Health in Mexico in 1994, lead concentrations in gasoline in participating Latin
American and Caribbean countries ranged from 1.32 g/L in Suriname to 0.03 g/L in
Uruguay (Romieu & Lacasana, 1996; Romieu et al., 1997).
Data on lead in gasoline, lead in air and blood lead concentrations of the local popu-
lation in a number of countries worldwide are summarized in Table 37. An analysis of
17 published studies from five continents (Thomas et al., 1999) found a strong linear
correlation between blood lead concentrations in the population and the consumption-
weighted average concentration of lead in gasoline, with a median correlation coefficient
of 0.94. As the use of lead in gasoline was phased out, blood lead concentrations across
study locations converged to a median of 3.1 ± 2.3 µg/dL, and air lead concentrations
were reduced to ≤ 0.2 µg/m3.
(g) Lead in paint

In the past, the use of lead pigments in paints was widespread, but it is now restricted
in many countries. Dusting, flaking or peeling of paint from surfaces are major sources of
lead contamination of surface dust and soil near houses, and contribute to the amount of
lead in household dust. Exposure occurs not only through the direct ingestion of flaking
and chalking paint but also through the inhalation of dust and soil contaminated with
paint. Renovation and remodelling activities that disturb lead-based paints in homes can
produce significant amounts of lead dust which can be inhaled or ingested. Removal of
lead-based paint from surfaces by burning (gas torch or hot air gun), scraping or sanding
can result, at least temporarily, in high levels of exposure for residents in these homes
(ATSDR, 1999). Lead from paint can constitute the major source of lead exposure, in
particular for young children, and can even make a significant contribution to blood lead
concentrations in children living in areas that are highly contaminated with lead, e.g.
around one of the largest lead mines in the world (Gulson et al., 1994). Consumption of
P 075-140 DEF.qxp 09/08/2006 11:15 Page 103
a single chip of paint with a lead concentration of 1–5 mg/cm2 would provide greater
short-term exposure than any other source of lead (US EPA, 1986a).
An estimated 40–50% of occupied housing in the USA in 1986 was thought to have
lead-based paint on exposed surfaces (Chisolm, 1986). Intervention programmes to
reduce exposures to lead in house dust have been reported (Lanphear et al., 2000a; Galke
et al., 2001; Leighton et al., 2003).
In a study by Schmitt et al. (1988) in the USA, soil samples taken from around the
foundations of homes with wooden exteriors were found to have the highest lead concen-
trations (mean, 522 mg/kg) while concentrations around homes composed of brick were
significantly lower (mean, 158 mg/kg). Lead concentrations up to 20 136 mg/kg were
found in soil samples taken near house foundations adjacent to private dwellings with
exterior lead-based paint. A state-wide study in Minnesota, USA, found that exterior lead-
based paint was the major source of contamination in severely contaminated soils located
near the foundations of private residences, while lead aerosols accounted for virtually all
of the contamination of soils at some distance from the houses. Contamination due to
lead-based paint was found to be highly concentrated over a limited area, while lead
aerosols were less concentrated but more widespread (Minnesota Pollution Control
Agency, 1987). (See also Section 1.4.1(e)).
Many countries have restricted the use of lead in paint. Leroyer et al. (2001) mention
that lead in paint was banned in France in 1948. A lead concentration greater than 0.06%
is not permitted in indoor paints sold in the USA (US DHUD, 1987). However, the lead
content of paint remains unregulated in some countries (Nriagu et al., 1996b). Ten per
cent of lead metal used in India was reported to be used in the manufacture of paint, and
wherever such paint is used there will be the potential for human exposure to lead (van
Alphen, 1999). Results of a study of lead content of paint used in India are shown in
Table 38. Of the 24 samples analysed, 17 had lead concentrations ≥ 0.5%, 13 had concen-
trations ≥ 1% and five had concentrations ≥ 10%. The lead in these paints was predomi-
nantly in the form of lead chromates (van Alphen, 1999).
(h) Food
A major source of lead for non-occupationally exposed adults is food and drink. The
amount of lead intake from food is dependent on the concentration of lead in soil, air,
water and other sources. Lead present in soils is taken up by food crops. Roots usually
contain more lead than stems and leaves, while seeds and fruits have the lowest concen-
trations. In contrast, particulate lead present in air may adhere tenaciously to leafy vege-
tables. Leaves collected in or near urban areas have been shown to contain substantially
elevated concentrations of lead. The use of leaded gasoline or the proximity of industries
producing ambient emissions of lead can greatly influence lead concentrations in food-
stuff. Therefore, caution is required with regard to concentrations of foodborne lead when
extrapolating between regions and countries (WHO, 1995).
Typical lead concentrations in foodstuffs from some 30 countries are given in
Table 39 (Galal-Gorchev, 1991a). Concentrations of lead in a variety of foodstuffs in the
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Table 38. Lead content in some paints used

in India
Paint coloura Lead concentration

(mg/kg)
Ultra white <1

White primer <1
White <1
Brown red 1
White 2
Phiroza 3
Oxford blue 3–6
Phorozi 5
Brown red 5
Brilliant white 6
Signal red 16
Bus green 32
New bus green 40
Deep green 50
Post office red 60–62
Mint green 61
Singal red 78
Tractor orange 114–130
Golden yellow 168–202
Adapted from van Alphen (1999)

a
Paint samples from six companies in Bangalore and
Chennai, India
USA, Canada, Latin America and the Caribbean, Africa, South Asia and Japan are shown
in Tables 40–45, respectively. Lead concentrations of specific food items available in
various countries are given in Tables 46–49. Studies from various countries on dietary
lead intake by children and adults are listed in Tables 50–51. The section below presents
a variety of specific sources of lead contamination in food.
(i) Contamination of livestock
Elevated concentrations of lead in the blood of cattle grazing near a lead smelter have
been reported, although no inferences regarding lead in beef were made. Mean lead
concentrations were highest in animals grazing near the smelter and decreased with
increasing distance. Ingestion of soil along with the forage was thought to be the major
source of lead (Neuman & Dollhopf, 1992).
Evidence has been shown for transfer of lead to milk and edible tissue in cattle
poisoned by licking the remains of storage batteries which had been burned and left in a
pasture (Oskarsson et al., 1992). Concentrations of lead in muscle of eight acutely-sick
cows that were slaughtered ranged from 0.14 to 0.50 mg/kg (wet weight basis). Normal
lead concentrations in bovine meat from Sweden are < 0.005 mg/kg. Eight cows showing
P 075-140 DEF.qxp 09/08/2006 11:15 Page 105
Table 39. Representative concentrations of lead

in foodsa
Food category Typical lead

concentration
(µg/kg)
Cereals 60
Roots and tubers 50
Fruit 50
Vegetables 50
Meat 50
Vegetable oils and fats 20
Fish 100
Pulses 40
Eggs 20
Nuts and oilseeds 40
Shellfish 200
Offal 200
Spices and herbs 300
Drinking-water 20
Canned beverages (lead-soldered cans) 200
Canned food (lead-soldered cans) 200
From Galal-Gorchev (1991a)

a
Data collected from 30 countries in the Global Environ-
mental Monitoring System/Food network
Table 40. Concentrations of lead in various foods

in the USA
Food category Concentration (µg/kg)

range of mean
Dairy products 3–83

Meat, fish and poultry 2–83
Grain and cereal products 2–84
Vegetables 5–74
Fruit and fruit juices 5–53
Oils, fats and shortenings 2–28
Sugar and sweets, desserts 6–73
Canned food 16–649
Beverages 2–41
From US Environmental Protection Agency (1986a) Appendix 7D

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Table 41. Concentrations of lead in various foods in Canada
Food category Concentration (µg/kg)

median (range)
Cereals, bread and toast (as prepared) 32.4 (11.5–78.3)

Water consumed directly 2.0 (0.25–71.2)
Coffee, tea, beer, liquor, sodas, etc. (as prepared) 8.8 (< 0.05–28.9)
Fruit juices, fruits (canned and fresh) 7.9 (1.5–109)
Dairy products and eggs 3.3 (1.21–81.9)
Starch vegetables, e.g. potatoes, rice 16.9 (5.5–83.7)
Other vegetables, vegetable juices and soups 31.7 (0.62–254)
Meat, fish, poultry, meat-based soups 31.3 (11–121)
Miscellaneous (pies, puddings, nuts, snack foods) 33.1 (13.6–1381)
Cheese (other than cottage cheese) 33.8 (27.7–6775)
From Dabeka et al. (1987)
no acute symptoms of poisoning were followed for 18 weeks. The mean lead concen-
tration in milk 2 weeks after exposure was 0.08 ± 0.04 mg/kg; the highest concentration
was 0.22 mg/kg. There was an initial rapid decrease in lead concentrations in milk during
the first 6 weeks after exposure, after which the concentrations remained constant or
increased slightly. Lead concentration in most milk samples was < 0.03 mg/kg 6 weeks
after exposure. Two cows calved at 35 and 38 weeks post-exposure. The lead concen-
tration in the blood of the cows at the time of delivery was high, which suggests mobi-
lization of lead during the later stages of gestation and delivery. Lead concentrations in
colostrum were increased compared to those in mature milk samples taken 18 weeks after
exposure (i.e. during pregnancy), but decreased rapidly after delivery in mature milk to
near the limit of detection.
Lead poisoning was observed in cattle and buffalo grazing near a primary lead–zinc
smelter in India. Affected animals had a history of clinical signs characterized by head
pressing, violent movement, blindness and salivation, and had high lead concentrations in
blood (143 ± 1 µg/dL) and milk (0.75 ± 0.19 mg/L). Animals from the same pasture but
without any history of clinical signs suggestive of lead poisoning had lower blood lead
concentrations than the affected animals, but nonetheless higher than those reported for
cattle in rural and urban areas of India (Dwivedi et al., 2001).
Analysis of animal feed and meat from cattle, horse (an important food animal) and
sheep in a metal-processing region (Oskemen) of eastern Kazakhstan revealed high lead
concentrations in many feed and meat samples (horse > cattle > sheep). The highest
concentrations of lead were found in the liver and kidney, and lower concentrations in
muscle and lung. A lead concentration of 2.2 mg/kg was found in horse liver (Farmer &
Farmer, 2000).
Recreational and subsistence hunters consume a wide range of species including birds
and mammals, some of which represent significant exposure to toxic agents, including
P 075-140 DEF.qxp
Table 42. Lead concentrations in foods in Latin America and the Caribbean
09/08/2006
Country Location Food item Main source of lead Concentration Year(s) Reference
mean ± SD or range of study
of means (range)
Argentina Buenos Aires Cultivated Traffic 2 mg/kg 1975 Romieu et al. (1997)
11:15
vegetables (leaves)
Mixed White wine NR 55 ± 36 µg/L NR Roses et al. (1997)
Red wine NR 85 ± 55 µg/L
Page 107
Brazil Santo Amaro, Vegetables Smelter (0.01–215 mg/kg)a 1980 Tavares (1991)
Bahia
All Saints Bay Mussels 1994 Tavares (1996b)
Mataripe (N) Oil refinery (12.0–57.9 mg/kg)a
Såo Bras (NW) Downstream smelter (1.36–22.5 mg/kg)a
Baiacu (SW) No specific source 5.30 mg/kga
Paraiba valley, Cow’s milk Smelter 0.05 (0.01–0.20 1994 Okada et al. (1997)
S. Paulo mg/L)
Ribeira do Iguape Fish NR 0.03–12 mg/kg 1994 Romieu et al. (1997)
Chile Antofagasta (pre- Vegetables Rural areas, vulcanos 0.6–39.2 µg/kgb NR Queirolo et al. (2000)
Andean region) Potato skin 94 µg/kgb
Temucho Bay Vegetables NR 20 mg/kg NR Romieu et al. (1997)
Ecuador Andean village: Glazing of ceramic NR Counter et al. (2000)
La Victoria Cherries 6.3 ± 2.0 mg/kg
Tomatoes 119 ± 1.2 mg/kg
Corn 61.7 mg/kg
(9.86–118.68 mg/kg)
Wheat grain 23.9 mg/kg
Kernels of wheat 0.75 mg/kg
Honduras Lago Yojoa Fish NR 0.30 mg/kg NR Romieu et al. (1997)
Mexico Vera Cruz, Campeche 4 crustaceae and Industrial region 0.03–5.62 mg/kg 1972 Albert & Badillo
and Tabasco 7 freshwater fish (1991)c
107
P 075-140 DEF.qxp
108
Table 42 (contd)
Country Location Food item Main source of lead Concentration Year(s) Reference
09/08/2006
mean ± SD or range of study
of means (range)
Gulf of Mexico Oyster NR ND–3.0 mg/kg 1976–87

Coatzacoalcos river Fish NR 0.1–2.84 mg/kg 1983
11:15
Laguna de Terminos Oyster March–May 2.4 (0.7–4.1)a mg/kg 1985–86

June–October 5.5 (5.1–5.9)a mg/kg
Dec–Feb 9.5 (8.5–10.5)a mg/kg
Page 108
N and NE Mexico Alfalfa NR (0.4–2.5 mg/kg) 1980–81
districts Beans NR (0.3–3.5 mg/kg)
Commercially Milk in different NR 5–88 µg/L 1982

available forms
Commercially Canned products NR (ND–2.35 mg/kg) 1988
available (fish, fruits and
vegetables)
Commercially Canned fruits NR 0.6–1.6 mg/kg NR Tamayo et al. (1984)
available
Trinidad and Imported Iodized salt NR 6.4 mg/kg NR Romieu et al. (1997)
Tobago
Uruguay Seashore Bivalve shell fish NR 6–32 mg/kg 1992 Romieu et al. (1997)
Venezuela States of Guarico and Rice (commercially NR 0.024–0.21 mg/kg NR Buscema et al. (1997)
Portuguesa available)
SD, standard deviation; NR, not reported; ND, not detectable

a
Dry weight
b
Fresh weight
c
Review including mainly reports and literature not easily accessible
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Table 43. Lead concentrations in food in Africa (Nigeria)

Food item Lead concentration (mg/kg)
Condensed or powdered milk 0.25–0.83

Beef 1.3
Plantains 0.2
Melon seeds 0.43
Water and bitter leaf 0.25–0.3
Gari flour 0.11
Yam tubers 0.35
From Ukhun et al. (1990)
Table 44. Lead concentrations in foods in some Asian countries

Country Place/location Food item Concentration Reference
(mg/kg)a
mean or range of
means (range)
India Nine localities of Cereals 0.23–0.56 Khandekar et al.

Greater Mumbai Pulses 0.54–0.88 (1984)
(high to negligible Leafy vegetables 0.47–1.12
vehicle traffic) Other vegetables 0.042–0.16
Meat 0.40–0.46
Fruit 0.032–0.044
Milk 0.16
Commercially Five brands of beer 10.4–15.7 µg/L Srikanth et al.
available (8.0–18.0) (1995a)
Commercially Rice and other cereal 0.189–0.332 Srikanth et al.
available products (0.128–0.371) (1995b)
Rajasthan Milk from cattle and 0.21–1.47 µg/L Dwivedi et al.
buffalo (2001)
Nagpur Milk Patel et al. (2001)
Infant formula 4.13 µg/L
Dairy 4.75 µg/L
Human 2.73 µg/L
Kazakhstan 4 districts around a Muscle, liver, kidney, 0.49–1.03 (horse) Farmer & Farmer
metal production lung 0.86–2.22 (cattle) (2000)
center 0.06–1.16 (sheep)
Pakistan Karachi Cooked food 1.25–3.90 Rahbar et al. (2002)
b
South Asia 14 regions of south 181 rice samples 0.0048–0.090 Watanabe et al.
Asia (ND–0.269) (1989)
Thailand Grazing land site Milk 14 µg/L Parkpian et al.
near highway (2003)
ND, not detectable

a
b
Dry weight
P 075-140 DEF.qxp 09/08/2006 11:15 Page 110
Table 45. Estimated lead concentrations in foods and dietary lead

intake in Japan, 2001
Food category Lead intake Food intakea Estimated lead

(g/day) concentrationb
(µg/day) (%) (µg/kg)
Rice 6.63 [28.4] 356.3 [18.6]

Other cereals and potatoes 3.42 [14.7] 162.6 [21.0]
Sugar and confectionary 0.55 [2.4] 90.7 [6.1]
Fat and oil 0.25 [1.1] 11.3 [22.1]
Pulses and pulse products 1.06 [4.5] 57.2 [18.5]
Fruits 1.64 [7.0] 132 [12.4]
Green yellow vegetables 1.23 [5.3] 93.6 [13.1]
Other vegetables and algae 2.09 [9.0] 175.7 [11.9]
Beverages 2.39 [10.3] 509.3 [4.7]
Fish and shellfish 1.62 [6.9] 94.0 [17.2]
Meats and eggs 1.25 [5.4] 113.1 [11.1]
Milk and dairy products 0.73 [3.1] 170.0 [4.3]
Prepared foods 0.34 [1.5]
Drinking-water 0.11 [0.5]
Total 23.31 [100.0] 2042
From National Institute of Health Sciences, Japan (2000)

a
From Ministry of Health, Labour and Welfare, Japan (2002)
b
Lead intake divided by food intake
Table 46. Lead concentrations in cow’s milk and infant formula
Product Canadaa Mexicob USAc

1986 1982 late 1980s
median (range) average average
(µg/kg) (µg/kg) (µg/kg)
Fluid milk 1.19 (0.01–2.5) 5

Evaporated milk
Can 71.9 (27–106) 88 10
Cardboard container – 9
Infant formula 13
Ready to use, lead-solder can 30.1 (1.1–122) 10
Ready to use, lead-free can 1.6 (1.5–2) 1
Powder formula 6.6 (3.7–19)
Powdered milkd – 21
Table adapted from WHO (1995)

a
From Dabeka & McKenzie (1987)
b
From Olguín et al. (1982) cited by WHO (1995)
c
From Bolger et al. (1991)
d
The concentration of lead in milk consumed by the infant will be highly depen-
dent on the concentration of lead in water used to dilute the powdered milk.
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Table 47. Distribution of lead concentrations

in table wines produced worldwidea
Range of lead Number of Percentage of

concentrations samples total samples
(µg/L) (n = 432) analysed
0–10 36 8.3
11–25 62 14.4
26–50 105 24.3
51–100 144 33.3
101–250 64 14.8
251–500 12 2.8
501–673 9 2.1
From US Department of the Treasury (1991)

a
Wines produced in 28 different countries and commer-
cially available in the USA
Table 48. Lead concentrations in rice consumed in

various countries
Country/area Lead content (µg/kg fresh weight)
N GM GSD
China 215 22.17 2.31

China (Province of Taiwan) 104 10.84 3.18
Colombia 22 8.09 2.80
Indonesia 24 39.07 2.26
Italy 15 6.97 3.28
Japan 788 5.06 2.64
Malaysia 97 9.31 2.61
Philippines 26 37.60 2.71
Republic of Korea 172 7.95 1.79
Saudi Arabiaa 27 [57.5]b [2.34]b
Thailand 13 8.75 2.28
USA 29 7.42 2.11
From Zhang et al. (1996), Al-Saleh & Shinwari (2001)

GM, geometric mean; GSD, geometric standard deviation; N, no.
of samples
a
Samples of rice imported from Australia (n = 2), Egypt (n = 2),
India (n = 17), Thailand (n = 4) and USA (n = 2)
b
Estimated from arithmetic mean and ± arithmetic SD of 134.8 ±
285.9 mg/kg by the moment method
P 075-140 DEF.qxp 09/08/2006 11:15 Page 112
Table 49. Lead concentrations in a variety of food items
Location Source Lead concentration Reference
Canada Apple juice stored in 65/117 samples > 7 mg/L Klein et al.
glazed earthenware 19/147 samples 500–1000 mg/L (1970)
Ontario, Water boiled in lead- 0.75–1.2 mg/L Ng & Martin
Canada soldered electric kettle (1977)
New York, Alcoholic beverages 0.01–21.5 mg/L Graziano &
USA stored in crystal containers Blum (1991)
South Carolina, Mourning dove Feathers, 465.7–2011.6 µg/kg Burger et al.
USA dry wt (1997)
Muscle, 81.7–142.9 µg/kg wet wt
Liver, 188.3–806.1 µg/kg wet wt
Kuwait Seafood (fish, shrimp) 0.06–0.16 mg/kg wet wt Bu-Olayan &
Al-Yakoob
(1998)
Iowa, USA Mexican candy wrappers 810–16 000 mg/kg Fuortes &
Bauer (2000)
lead. Wild game may be contaminated through the environment or from lead bullets inges-
ted by or embedded in the animal (Burger et al., 1997, 1998).
(ii) Contamination from food preparation, storage and tableware
Lead present in food storage and serving vessels such as lead-soldered cans, ceramic
dishes, cooking vessels, crystal glassware, and labels on food wrap and/or dishes can
contaminate food. Acidic foods tend to leach more lead, but certain foods such as corn and
beans are associated with greater release of lead than would be predicted from their aci-
dity alone. Also, oxygen appears to accelerate the release of lead from food containers
(WHO, 1995).
If food is stored in ceramic or pottery-ware that is lead-glazed and fired in a low-tem-
perature kiln, lead can migrate from the glaze into the food. The glazing process uses a
flux, a material that, at high temperatures, reacts with and helps dissolve the components
of the glaze. Lead oxide is commonly used as flux. Factors determining whether, and to
what extent, lead will migrate include the temperature and extent of firing of the pottery
during the manufacturing process, the temperature and duration of food storage, the age
of the pottery and the acidity of the food. It is extremely difficult to quantify the extent of
such exposures in view of variations in manufacturing processes and quality control
practised in the country of origin; however, exposure can be quite significant, particularly
to infants (WHO, 1995). Gersberg et al. (1997) estimated that dietary exposure to lead
from beans prepared in Mexican ceramic pottery may account for the major fraction of
the blood lead in children whose families use such ceramic-ware.
P 075-140 DEF.qxp 09/08/2006 11:15 Page 113
Table 50. Estimated dietary lead intake in adults and children
Country Population studied Daily intake Reference

(µg/day)a
Adults
Belgiumb Men and women 230 M Fouassin & Fondu (1980)
Belgiumb Men and women 96c D Buchet et al. (1983)
Canada Men and women 43c D Dabeka et al. (1987)
China Women 46 D Vahter et al. (1991a)
Women 24.6 Ikeda et al. (2000a)
China (Province of Taiwan) Women 19.5 Ikeda et al. (2000a)
Croatia Women 15 D Vahter et al. (1991a)
Finland Men and women 66 M Varo & Koivistoinen (1983)
Germany Men and women 54–61 Kampe (1983)
India Men and women 6.4–76.9 Parikh et al. (1999)
Italy Men and women 140 [IAEA (1987)]
Japan Women 31 D Vahter et al. (1991a)
Women 9.3 Ikeda et al. (2000a)
Malaysia Women 7.0 Ikeda et al. (2000a)
New Zealand Men and women 213 M Pickston et al. (1985)
Philippines Women 11.3 Ikeda et al. (2000a)
Republic of Korea Women 21.5 Ikeda et al. (2000a)
Sweden Men and women 27 M Slorach et al. (1983)
Women 26 D Vahter et al. (1991a,b)
Thailand Women 15.1 Ikeda et al. (2000a)
Turkey Men and women 70 [IAEA (1987)]
United Kingdom Men and women 110 M Sherlock et al. (1983)
71 D Sherlock et al. (1983)
USA Men and women 83 M Gartrell et al. (1985a)
Children
India 6–10 years 15.2–23.3 Raghunath et al. (1997)
6–10 years 14.4–19.1 Raghunath et al. (1999)
Poland 0–1 year 225 Olejnik et al. (1985)
1–3 years 259
7–18 years 316
UK Infant 1–2 breast milk Kovar et al. (1984)
or formula
USA < 6 months 16–17 infant Ryu et al. (1983)
formula
Infant 34 M Gartrell et al. (1985b)
Toddler 43 M
Adapted from WHO (1995); Ikeda et al. (2000a)

a
M, market basket survey; D, duplicate diet study
b
Populations studied from the same region
c
Median value
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Table 51. Estimated respiratory and dietary intakes of lead in various cities
in Asia
Country, city Route Lead in air Intakea Uptakeb Total Dietary/

(ng/m3) (µg/day) (µg/day) (µg/day) total (%)
China, Respiratory 60–540 2.70 1.35 2.50 46

Beijing + Shanghai Dietary 23.1 1.16
Japan, Respiratory 70–81 1.13 0.57 1.24 54
Tokyo + Kyoto Dietary 9.0 0.68
Malaysia, Kuala Respiratory 30–462 3.69 1.85 2.37 22
Lumpur Dietary 7.0 0.53
Philippines, Respiratory 648 9.72 4.86 5.69 15
Manila Dietary 11.1 0.63
Thailand, Bangkok Respiratory 210–390 4.29 2.15 3.28 34
Dietary 15.1 1.13
From Ikeda et al. (2000a,b); data are on adult women and were based on studies in 1990s.
a
Respiration volume was assumed to be 15 m3/day.
b
Uptake rates are assumed to be 50% in the lungs and 5–10% in the gastrointestinal tract.
Several studies have shown contamination of foods and beverages from lead used in
the manufacture or repair of metal vessels. Coating the inner surface of brass utensils with
a mixture of lead and tin, described as ‘tinning’, is widely practised by artisans in India.
The tin–lead alloy contains 55–70% lead. Water boiled with tamarind in a tinned brass
vessel for 5 min was found to contain 400–500 µg/L lead (Vatsala & Ramakrishna, 1985).
Zhu et al. (1984) described 344 cases of chronic lead poisoning in Jiansu Province, China,
in people who had drunk rainwater boiled in tin kettles. After boiling, the water contained
0.79–5.34 mg/L lead. Lead concentrations have also been shown to increase when water is
boiled in kettles that contain lead in their heating elements. A study in India showed that
although lead leaching from pressure cookers occurs during cooking, especially from the
rubber gasket and safety valve, it is only a minor source of lead in cooked food (Raghunath
& Nambi, 1998).
Lead-contaminated water may also contribute to foodborne lead where large volumes
of water are used in food preparation and cooking, e.g. in foods prepared in boiling water.
Experiments have shown that vegetables and rice cooked in water containing lead may
absorb up to 80% of the lead in the water (Little et al., 1981).
Trace metals, including lead, have been detected in human breast milk, thus breast-
feeding could deliver lead to an infant. The reader is referred to Section 4.1.1(a)(v) for
information on lead mobilisation in bones and transfer to breast milk during pregnancy and
lactation. In a study in Australia, the mean lead concentration (± standard deviation) in
breast milk from 21 lactating mothers was 0.73 ± 0.70 µg/kg (Gulson et al., 1998a). Ana-
lysis of 210 human milk samples taken across Canada showed a mean lead concentration
P 075-140 DEF.qxp 09/08/2006 11:15 Page 115
of 1.04 µg/kg (range, < 0.05–15.8 µg/kg) (Dabeka et al., 1988). The median lead concen-
tration in breast milk from 41 volunteers in Sweden was 2 µg/kg (range, 0.5–9.0 µg/kg)
(Larsson et al., 1981), whereas the mean value for breast milk 5 days postpartum from
urban residents in Germany in 1983 was 13.3 µg/L (Sternowsky & Wessolowski, 1985).
The concentration in 3-day postpartum milk samples from 114 women in Malaysia ave-
raged 47.8 µg/L (Ong et al., 1985).
Concentrations of lead in human milk vary considerably depending on the mother’s
exposure and occupation. Lead concentrations in the milk of a mother who had worked
in a battery factory until 7 weeks before delivery decreased gradually from 19–63 to
4–14 µg/L in samples taken soon after delivery and those taken up to 32 weeks later,
respectively (Ryu et al., 1978). Lead concentrations in breast milk of 96 mothers in three
districts (urban, mining area and rural) of Hubei, China averaged 76, 101 and 90 µg/L
(geometric mean; n = 21, 11 and 32, respectively). The concentrations were very similar
in colostrum and mature milk, and correlated well with blood lead concentrations (Wang
et al., 2000).
Gulson et al. (1998a) measured lead isotope ratios (207Pb/206Pb and 206Pb/204Pb) in
mothers’ breast milk and in infants’ blood and established that, for the first 60–90 days
postpartum, the contribution from breast milk to blood lead in the infants varied from 36%
to 80%. Maternal bone and diet appeared to be the major sources of lead in breast milk.
Lead has also been reported in home-prepared reconstituted infant formula (breast-
milk substitute). Lead concentrations in cows’ milk and infant formula analysed in
Canada, Mexico and the USA are shown in Table 46. Two of forty samples of infant
formula collected in a study in the Boston area of the USA had lead concentrations
> 15 µg/L. In both cases, the reconstituted formula had been prepared using cold tap-
water run for 5–30 sec, drawn from the plumbing of houses > 20 years old. It was con-
cluded that three preparation practices for infant formula should be avoided: (1) excessive
water boiling, (2) use of lead-containing vessels and (3) use of morning (first-draw) water
(Baum & Shannon, 1997).
Canning foods in lead-soldered cans may increase concentrations of lead in foods
8–10-fold. In 1974, for example, the lead concentration in evaporated milk in lead-
soldered cans was 0.12 µg/g; in 1986, after these cans had been phased out, the concen-
tration dropped to 0.006 µg/g (Capar & Rigsby, 1989). The lead content in canned foods
in the USA dropped from an overall mean of 0.31 µg/g in 1980 to 0.04 µg/g in 1988
(National Food Processors Association, 1992). The production and use of three-piece
lead-soldered cans ceased in 1991 in the USA. However, older lead-soldered cans may
still be present in some households (ATSDR, 1999). Dabeka and McKenzie (1987, 1988)
found that the intake of lead by 0–1 year-old infants fed infant formula, evaporated milk
and concentrated liquid formula stored in lead-soldered cans exceeded the provisional
tolerable weekly intake (PTWI) of 25 µg/kg body weight (bw) lead set by the Joint
FAO/WHO Expert Committee on Food Additives (JECFA) in 1993 (FAO/WHO, 1993).
This value does not include lead in water used to prepare infant formula. Mean intakes far
P 075-140 DEF.qxp 09/08/2006 11:15 Page 116
in excess of the PTWI were obtained in studies carried out in areas with high lead content
in tap-water (Galal-Gorchev, 1991b).
Lozeena, a bright orange powder from Iraq used to colour rice and meat, can contain
7.8–8.9% lead (CDC, 1998).
Lead may leach from lead crystal decanters into the liquids they contain. Three
samples of port wine with an initial concentration of 89 µg/L lead were found to have lead
concentrations of 5331, 3061 and 2162 µg/L after storage for four months in crystal
decanters containing 32%, 32% and 24% lead monoxide, respectively (Graziano & Blum,
1991). Lead was also found to elute from lead crystal wine glasses within minutes. Mean
lead concentrations in wine contained in 12 glasses increased from 33 µg/L initially to 68,
81, 92 and 99 µg/L after 1, 2, 3 and 4 h, respectively (Graziano & Blum, 1991). [See
comments on this article in de Leacy, 1991; Zuckerman, 1991].
(iii) Alcoholic beverages
In addition to contamination from lead crystal glass, contamination of alcoholic
beverages with lead may occur in several ways. For example, from lead solder used to
repair casks or kegs and tap lines, from lead capsules used as seals on wine bottles, or
from residues of lead arsenate pesticides in soils. Alcoholic beverages tend to be acidic
and there is the possibility for large amounts of lead to dissolve during preparation,
storage or serving (WHO, 1995). Wai et al. (1979) showed that wine can react with the
lead capsule to form lead carbonate, which may dissolve in the wine during storage and
pouring. In one study, lead concentrations in wine on the Swedish market ranged between
16 and 170 µg/L (Jorhem et al., 1988). The analysis of 432 table wines originating from
many countries and sold in the USA is summarized in Table 47. In a study of the lead
content of Argentinian wines, red wine was found to have 50% higher lead concentrations
than white wine, average values being 85 and 55 µg/L, respectively (Roses et al., 1997).
Sherlock et al. (1986) found that in the UK the majority of canned and bottled beer (90
and 86% respectively) contained less than 10 µg/L lead. Draught beers typically contained
higher lead concentrations, with 45% having concentrations > 10 µg/L, 16% having
concentrations > 20 µg/L and 4% having concentrations > 100 µg/L. The higher lead
concentrations in draught beers are thought to be due to the draught-dispensing equipment
which may contain brass or gunmetal, both of which contain low but significant amounts
of lead.
The analysis of lead concentration in five different beer brands in India showed that
all brands had a mean lead concentration > 10 µg/L, with an overall mean of 13.2 µg/L.
Assuming the lead concentration in beer to be 13 µg/L, the uptake of lead from beer to be
20% and consumption by three types of consumer to be 1, 5 or 10 L/week, this would
result in a lead uptake of 2.6, 13 and 25 µg/week, respectively (Srikanth et al., 1995a).
Illicit ‘moonshine’ whiskey made in stills composed of lead-soldered parts (e.g. truck
radiators) may contain high concentrations of lead. Lead was detected in 7/12 samples of
Georgia (USA) moonshine whiskey, with a maximum concentration of 5300 µg/L (Gerhardt
P 075-140 DEF.qxp 09/08/2006 11:15 Page 117
et al., 1980). In a more recent study, regular consumers of moonshine whiskey (15/49
subjects) had blood lead concentrations > 50 µg/dL (Morgan et al., 2001).
In general, alcoholic beverages do not appear to be a significant source of lead intake
for the average person.
(iv) Fish and seafood
The uptake and accumulation of lead by aquatic organisms from water and sediment
are influenced by various environmental factors such as temperature, salinity and pH, as
well as humic and alginic acid content of the sediment. In contaminated aquatic systems,
only a minor fraction of lead is dissolved in the water. Lead in fish is accumulated mostly
in gill, liver, kidney and bone. In contrast to inorganic lead compounds, tetraalkyllead is
rapidly taken up by fish and rapidly eliminated after the end of exposure (WHO, 1989).
The Fish and Wildlife Service in the USA reported on the concentration of selected
metals in 315 composite samples of whole fish collected at 109 stations nationwide in
1984–85. For lead, the geometric mean was 0.11 mg/kg (wet weight), with a maximum of
4.88 mg/kg. Lead concentrations in fish declined steadily from 1976 to 1984, suggesting
that reduction in use of leaded gasoline and controls on mining and industrial discharges
have reduced lead concentrations in the aquatic environment (Schmitt & Brumbaugh,
1990).
Recreational and subsistence fishers consume larger quantities of fish and shellfish
than the general population and frequently fish the same waterbodies routinely. Thus, these
populations are at greater risk of exposure to lead and other chemical contaminants if the
waters they fish are contaminated. Ingestion of lead is also a matter of concern in regular
consumers of seafood produced near industrial areas such as in All Saints Bay and Ribeira
do Iguape in Brazil (Tavares, 1996a,b), as well as in Uruguay (Romieu et al., 1997).
(v) Rice and cereals
Rice is an important source of lead intake, particularly in east and south-east Asia
where rice is a staple component of the diet. Lead concentrations in rice consumed in some
areas in Asia, Australia, Europe and North America are summarized in Table 48. The data
show a substantial variation from < 10 to about 40 µg/kg fresh weight (Zhang et al., 1996;
Al-Saleh & Shinwari, 2001a). In a study performed by Watanabe et al. (1989), rice samples
were collected in 15 areas of Asia and Australia (192 samples), and in four areas in other
parts of the world (15 samples). Lead concentrations were distributed log-normally, with a
geometric mean ± geometric standard deviation of 15.7 ± 3.5 µg/kg and concentrations
ranging from 5 µg/kg in Japan to 90 µg/kg in India.
Lead in rice has been estimated to represent 28% (National Institute of Health
Sciences, Japan, 2000; see Table 45), 14% (Zhang et al., 2000), 12% (Moon et al., 1995)
and < 5% (Zhang et al., 1997a) of dietary lead intake in a series of studies in China, Japan
and the Republic of Korea. In Japan, dietary lead intake has decreased on average from
33 µg/day in 1980 to 7 µg/day in 1990, partly as a result of a decrease in rice consumption
(Watanabe et al., 1996).
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Cereals other than rice, e.g. millet and maize, may also be important sources of dietary
lead. The lead concentration in these cereals (43–47 µg/kg) is higher than that in rice
(20–21 µg/kg) or wheat (26–30 µg/kg) (Zhang et al., 1997b). In one study in China, lead
from all cereals accounted for 26% of total dietary lead intake (Watanabe et al., 2000).
Lead intake from rice in Japan was found to be 1.5 times that from wheat in 1998–2000
(Shimbo et al., 2001).
The contribution of lead in rice and cereal products to the total dietary intake of lead
in southern India varies among different socioeconomic groups, based on occupation and
choice of consumption. It has been suggested that rice is the major source of lead among
the rural and economically-deprived populations, but sources of dietary lead appeared to
be more diverse in the urban middle-class and the economically-privileged (Srikanth
et al., 1995b).
(vi) Daily intake through food
Estimates of daily dietary intakes of lead by adults and children worldwide are
presented in Table 50. The available data indicate a general decrease in those areas where
the concentration of lead in gasoline has decreased and those where a concerted effort has
been made to avoid lead-soldered cans for food storage (Bolger et al., 1991; OECD,
1993). Similar decreases in other countries are expected to occur when similar actions to
eliminate these sources of lead exposure are taken.
Dietary lead intake by adult women in several Asian cities, in comparison with
amounts of lead inhaled, is presented in Table 51. The ratio of dietary to total lead intake
varied primarily as a reverse function of the lead concentration in atmospheric air (Ikeda
et al., 2000a). In Mumbai, India, where atmospheric lead concentrations in different zones
of the city varied between 82 and 605 ng/m3, the daily lead uptake by a nonsmoker living
in the city area was estimated to be 33 µg, of which 75% come from food. For a suburban
resident, 85% of the lead intake was estimated to come from food (Khandekar et al., 1984).
(i) Plants and fertilizers

Lead occurs naturally in plants both from deposition and uptake; there is a positive
linear relationship between lead concentrations in soil and in plants. As with other envi-
ronmental compartments, measurement of ‘background’ concentrations of lead in plants
is complicated by the general contamination of the environment from centuries of lead
use, which has included direct application of lead-containing chemicals in agriculture and
contamination of fertilizers with lead (WHO, 1995).
Lead has been detected in a superphosphate fertilizer at concentrations as high as
92 mg/kg (WHO, 1995). Sewage sludge, used as a source of nutrients in agriculture, may
contain concentrations of lead > 1000 mg/kg; concentrations as high as 26 g/kg have been
measured in the USA (WHO, 1995). In a study of soil that had received heavy sludge
applications over years in the United Kingdom, the lead concentration was found to be
425 mg/kg, compared with 47 mg/kg in untreated soil (Beckett et al., 1979).
Lead concentrations in grass and water plants in Asia are shown in Table 52.
P 075-140 DEF.qxp
Table 52. Lead concentrations in terrestrial and aquatic plants in Asia
09/08/2006
Country Location Year(s) Source of Planta Concentration Reference
of study contamination (mg/kg)
mean ± SD or
range of means
11:15
India Koraput NR NR Ipomea aquatic 83.3 ± 4.2 Chandra et al.
Trapa natans 68.5 ± 2.1 (1993)
Unnao (summer) Trapa natans 54.5 ± 2.0
46.6 ± 1.5
Page 119
Ipomea aquatica
(winter) Trapa natans 1030.0 ± 51.5
Ipomea aquatica 845.0 ± 40.0
Eastern Ghats NR Local industries Spirodela polyrrhiza 27 ± 1.6 Rai et al. (1996)
(Koraput, Orrisa) Pistia stratiotes 29 ± 0.8
Mumbai NR Lead industries Grass 145–1048 Nambi et al.
Control grass 1.42 (1997)
Lake Nainital 1997 NR Microcystis aeruginosa 46 ± 2.5 Ali et al. (1999)
Spirogyra adnata 95 ± 4.2
Salix babylonica (root) 37 ± 2.7
Residential area of 1996 Lead factory Leaf samples 214 ± 17 Chatterjee &
greater Kolkata Banerjee (1999)
4 lakes and pounds in 1998 NR Trapa natans 75–375 Rai & Sinha
Lucknow (2001)
Pond in North-Bihar 1996–97 NR Euryale ferox Salisb. 331.6–1256.6 Rai et al. (2002)
Kazakhstan Six districts in the NR Metal production Hay & pasteur grasses 1.6 ± 0.01– Farmer & Farmer
East centre 19.4 ± 6.2 (2000)
Thailand Tropical grazing land NR NR Grass 0.76– 6.62 Parkpian et al.
site (2003)
NR, not reported
119
a
Names in italics are aquatic plants.
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Phytoremediation
Currently, lead-contaminated soils are being remediated by a variety of engineered
technologies such as isolation and containment, mechanical separation, pyrometallurgical
separation, the use of permeable treatment walls, and by soil flushing and soil washing, but
these methods are expensive and not feasible at all sites (Mulligan et al. 2001). Phytoreme-
diation — the use of plants for removal of pollutants and restoration of the environment —
is an emerging clean-up technology for which various reviews provide information on
important aspects (Salt et al., 1995; Cunningham & Ow, 1996; Chaney et al., 1997; Salt
et al., 1998).
For lead remediation, phytoextraction is the more attractive and much better studied
method. Phytoextraction is the uptake of metal by roots and its accumulation in the part
of the plant above ground, i.e. the shoot. Plants that are capable of accumulating more
metal than 0.1% of dry weight of shoot are considered to be suitable for phytoextraction.
There are various reports concerning accumulation and phytoextraction of lead
(Table 53).
The basic problems with lead phytoextraction are the low bioavailability of lead in
soil and its poor translocation from root to shoot. Of all toxic heavy metals, lead is the
least phytoavailable. Water-soluble and exchangeable lead that is readily available for
uptake by plants constitutes only about 0.1% of total lead in most soils (Huang et al.,
1997). Soil properties influence its uptake and translocation. In addition, only a few
higher plants are known to hyperaccumulate lead, mainly owing to the very low trans-
location of lead from the root to the shoot. Piechalak et al. (2002) demonstrated up to 95%
lead accumulation in the roots of Vicia faba, Pisum sativum and Phaseolus vulgaris but
only 5–10% was transported to parts above ground (see Table 53).
To overcome these problems, a chelate is used to increase uptake rate and to increase
lead translocation from roots to shoots. Of the many chelates, EDTA has been found to be
the most appropriate. EDTA solubilizes soil lead and increases its translocation from root
to shoot. It has also been shown to increase rate of transpiration, an important factor in
lead phytoextraction (Wu et al. 1999). However, there are concerns about side-effects
associated with chelate application. Lead EDTA easily percolates through the soil profile
and causes groundwater pollution.
A number of plants used in phytoremediation are crop plants (see Table 53) and thus
there is a potential risk that plants grown as part of phytoremediation programmes will re-
enter the food chain. Furthermore, a number of algae and other plant species accumulate
lead. Such species, if ingested by fish, could also re-cycle lead into the food chain.
Recently, a study presented the development of a plant genetically modified to accumulate
lead, which seems promising for phyto-remediation (Gisbert et al., 2003).
Phytoremediation does have its limitations. It is a slower process than the traditional
methods. Plants remove or degrade only small amounts of contaminants each growing
season, so it can take several decades to clean up a site adequately. There are limits to plant
growth such as temperature, soil type and availability of water. Lastly, most plants are
P 075-140 DEF.qxp 09/08/2006 11:15 Page 121
Table 53. Lead accumulation/biosorption and detoxification by plants
Plant Treatment Lead accumulation/ Reference

phytoextractiona
Zea mays shoot 20–100 µM Pb(NO3)2 Accumulation: Huang &

in nutrient solution 400–500 mg/kg Cunningham
Lead concentration in soil, Phytoextraction: (1996)
2500 mg/kg; treatment with 10 600 mg/kg dw
HEDTA at 2 g/kg for 7 days
Brassica juncea Lead concentration in soil, Accumulation: Blaylock et al.
shoot 1200–1800 mg/kg 45–100 mg/kg (1997)
600 mg/kg Pb: Phytoextraction:
10 mmol/kg EDTA ∼ 15 000 mg/kg
0.5 mmol/kg EDTA 5000 mg/kg
Zea mays, Pisum Lead concentration in soil, Phytoextraction: Huang et al.
sativum shoots 2500 mg/kg; treatment with ∼ 10 000 mg/kg (1997)
HEDTA at 2 g/kg for 7 days
Brassica juncea Lead concentration in soil, Phytoextraction: Vassil et al.
shoot 0.5 mM; treatment with 11 000 mg/kg dwb (1998)
EDTA at 0.75 mM for 48 h
Helianthus annuus 1 mM Pb(NO3)2 in nutrient Accumulation: Kastori et al.
solution from emergence of shoot, 11 027 mg/kg dw (1998)
1st pair of leaves until roots, 17 149 mg/kg dw
growth of 3rd pair of leaves
Vicia faba 1 mM Pb(NO3)2 treatment 46 mg/g dw (in root) Piechalak et al.
for 96 h (2002)
Pisum sativum 50 mg/g dw (in root)
Phaseolus vulgaris 75 mg/g dw (in root)
a
Accumulation refers to the natural lead uptake by the plant from soil or a nutrient solution;
phytoextraction refers to lead uptake following addition of a synthetic chelating agent to the
lead-contaminated soil to improve the bioavailability of the lead.
b
The value was 400 times higher than in untreated controls.
unable to grow on heavily-contaminated soils, thus only lightly-contaminated soils can be

phytoremediated.
( j) Others
Table 54 presents some data on lead concentrations in other sources of exposure.
(i) Traditional medicine
Some traditional medicines and customs have been found to result in exposure to high
concentrations of lead, most of which cannot be quantified with any degree of accuracy.
Rather than occurring as trace ingredients or trace contaminants, various lead compounds
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Table 54. Lead concentrations in various sources of exposure
Location Source Lead concentration Reference
Traditional remedies
Arizona, USA ‘Greta’, ‘azarcon’ 77 000–941 000 mg/kg Baer et al. (1989)
Zabreb, Croatia Metal-mineral tonics 0.90–72 900 mg/kg Prpic-Majic et al.
(1996)
Cosmetics
Morocco, UK, Eye make-up (kohl) from < 100–696 000 mg/kg Parry & Eaton
USA Eastern Mediterranean (1991)
countries
Others
Arizona, USA Pool cue chalk 1–14 080 mg/kg Miller et al. (1996)
Wisconsin, Dental intraoral radiograph 3352 µg (range, 262–34 000)a CDC (2001)
USA film storage boxes (lead
oxide)
a
Average amount of lead present on wipe samples from eight film packets stored in lead-lined boxes
are used as major ingredients in traditional medicines in numerous parts of the world
(Trotter, 1990). Lead concentrations in some traditional and complementary medicines are
shown in Table 55.
Leaded ‘kohl’, also called ‘Al kohl’, is traditionally applied to the raw umbilical
stump of the newborn in the belief of a beneficial astringent action. Lead metal and lead
sulfide are used for inhalation of the fumes (‘Bokhoor’) produced from heating on hot
coals, in the belief that this will ward off the devil and calm irritable infants and children
(Fernando et al., 1981; Shaltout et al., 1981). An Asian remedy for menstrual cramps
known as Koo Sar was reported to contain lead in concentrations as high as 12 mg/kg
(CDC, 1999). The source of lead was thought to be the red dye used to colour the pills.
The Hindus use as a treatment for diabetes ground seeds and roots, which were found to
contain 8000 mg/kg lead (Pontifex & Garg, 1985).
Latin-American countries also report the use of traditional medicines with high lead
concentrations. For example, the Mexican traditional remedies ‘azarcon’ (lead tetroxide)
and/or ‘greta’ (mixed lead oxides), distributed as finely ground powders, may contain
more than 70% lead. They are used in the treatment of ‘empacho’, a gastrointestinal
disorder considered to be due to a blockage of the intestine (Trotter, 1990).
Some Chinese herbal medicines have metallic lead added to them (up to 20 000
mg/kg) to increase their weight and sale price (Wu et al., 1996). Lead contaminants also
are present in some calcium supplements; 17 of 70 brands tested had lead concentrations
leading to a daily intake greater than the provisional total tolerable daily intake of 6 µg
(Bourgoin et al., 1993).
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Table 55. Lead concentrations in herbal and folk

medicines
Medicine Concentration Prescribed for

(µg/g)a (where indicated)
Saptamrut loh 5.12

Keshar gugal 2.08
Punarvadi gugal 1.99
Trifla gugal 4.18
Ghasard 16 000
Bala goli 25
Kandu 6.7
Arogyavardhini 63.2 Liver disease
Sankhvati 13.0
Brahmivati 27 500
Chyavan prash 7.30
Trivanga bhasma 261 200 Diabetes
Diabline bhasma 37 770 Diabetes
Hepatogaurd 0.4 Liver disease
Basant malti 276 to 42 573
Pushap Dhanva Ras 79.3 mg/tablet
Shakti 55.9 mg/tablet
Solution 5.27 µg/mL Leg abscess
Powders 2.6–105 200 Leg abscess
Tablets 1.0–2816.7 Leg abscess
From Dunbabin et al., (1992); Nambi et al. (1997)

a
Unless otherwise specified
Medicinal herbs may be a potential source of lead exposure; analysis of 28 species

showed lead concentrations (arithmetic mean ± arithmetic standard deviation) of
2.6 ± 0.4 mg/kg to 32.8 ± 3.1 mg/kg fresh weight (Dwivedi & Dey, 2002).
(ii) Cosmetics
Hair dyes and some cosmetics may contain lead compounds. Commercial hair dyes
typically contain 3000–4000 mg/kg lead (Cohen & Roe, 1991). A later survey reported
hair dyes formulated with lead acetate, with lead concentrations of 2300–6000 mg/kg
(Mielke et al., 1997b). Lead acetate is soluble in water and easily transferred to hands and
other surfaces during and following application of a hair dye product. Measurements of
150–700 µg of lead on each hand following such applications have been reported (Mielke
et al., 1997b). In addition, lead is transferred by hand to mouth of the person applying the
product, and to any other surface (comb, hair dryer, outside of product container, counter
top) that comes into contact with the product. A dry hand passed through dry hair dyed
with a lead-containing cream has been shown to pick up about 280 µg lead (Mielke et al.,
1997b).
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Some traditional eye cosmetics produced locally may contain lead compounds, and
their application, also to children, may result in lead exposure. Sprinkle (1995) reported
blood lead concentrations of 9–24 µg/dL in nine children aged 3 months–5 years receiving
daily application of such cosmetics, whereas concentrations of 2–6 µg/dL were found in
nine children aged 1–6 years who had no or unknown application. Patel et al. (2001) also
reported elevated blood lead concentrations (20.2 ± 13.0 µg/dL) in 45 children aged
6 months–6 years in India who used eye cosmetics daily.
Cosmetics used by Chinese opera actors may also contain lead (Lai, 1972).
(iii) Ammunition
Use of lead ammunition may result in exposure to lead dust, generated during gun or
rifle discharge, at concentrations up to 1000 µg/m3 (Elias, 1985), from lead pellets
ingested by or embedded in animals that are used as food source (Burger et al., 1997), and
from lead pellets embedded in humans from shooting incidents (Manton, 1994; IARC,
1999). Firing-range instructors and employees may be exposed to high concentrations of
lead and may show elevated blood lead concentrations (see Section 1.4.3.e).
(iv) Miscellaneous
Cigarette tobacco contains 2–12 µg of lead per cigarette (IARC, 2004a); the mean
concentration of lead in filter-tipped cigarettes produced between 1960 and 1980 was
2.4 mg/kg. Up to 6% of lead may be inhaled, while the remainder is present in the ash and
sidestream smoke (IARC, 2004a). Smoking a pack of 20 cigarettes per day, with 12 µg
lead per cigarette, and inhaling 6% of the smoke, would result in daily exposure to 14 µg
lead.
So-called recreational drug users who ‘sniff’ leaded gasoline vapours are at risk of
toxic effects from organolead compounds as well as the hydrocarbon components of gaso-
line (Edminster & Bayer, 1985).
A lead poisoning hazard for young children exists in certain vinyl miniblinds that have
had lead added to stabilize the plastic. Over time, the plastic deteriorates to produce lead
dust that can be ingested when the blinds are touched by children who then put their hands
in their mouths (Consumer Product Safety Commission, 1996; Norman et al., 1997; West,
1998).
(k) Blood lead concentrations from specific sources of exposure

Blood lead concentrations resulting from exposure to a variety of specific sources,
reported mainly as case reports, are presented in Table 56.
1.4.2 Exposure of the general population

Blood lead concentration is the most commonly used estimate of exposure to lead in
the general population. Numerous reports show blood lead concentrations declining over
time in many parts of the world, thereby validating global efforts to reduce lead exposures.
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Table 56. Blood lead concentrations from various sources of exposure
Location Source Blood leada (µg/dL) Reference

individual values or
rangea
Air dust
New York, USA Burning of newspapers in 35 Perkins & Oski
fireplace (1976)
New York, USA Dust at home from Mean, 41.6–73.3 Baker et al. (1977)
workers’ clothing
California, USA Dust on clothes from 31–36 Gerson et al. (1996)
occupational exposure
New York, USA Dust from removal of 20–> 80 CDC (1997a)
lead-based paint
La Victoria and El Tejar, Tile-glazing activities Median, 60 Vahter et al. (1997)
Ecuador (range, 12–106)
Food/food containers
Hawaii, USA Lead-bearing cocktail 131–156 Dickinson et al.
glasses (1972)
Ontario, Canada Water heated in lead- 35–145 Ng & Martin (1977)
soldered electric kettles
Seattle, USA Ceramics from southern 74 and 144 Wallace et al. (1985)
Italy
Nablus district, Israel Contaminated flour Mean, 80–122 Hershko et al. (1989)
(range, 42–166)
Vancouver, Canada Water heated in a lead- 147–154 Lockitch et al.
soldered electric kettle (1991)
Hungary Contaminated paprika 18.8–213 Kákosy et al. (1996)
(lead tetraoxide)
Vermont, USA Apple cider prepared in 33–40 Carney & Garbarino
lead-soldered evaporator (1997)
California, USA Tamarindo candy 26–59 CDC (1998)
Michigan, USA Lozeena (powdered food 25–84 CDC (1998)
colouring)
Georgia, USA Moonshine whiskey > 50b Morgan et al. (2001)
California, USA Tamarindo candy and/or 22–88 CDC (2002)
folk remedies
Cor 126.qxd 01/09/2006 18:04 Page 126
Table 56 (contd)

rangea
Traditional remedies
California, USA Azarcon 27–45 CDC (1981)
Minnesota, USA ‘Pay-loo-ah’ 60 CDC (1983)
Saudi Arabia Traditional remedies 134–277 Abu Melha et al.
(1987)
Guadalajara, Mexico Azarcon (lead tetraoxide) Blood, 29.6; Cueto et al. (1989)
urine, 49.4 µg/L
California, USA Indian herbal medicine 71–80 Smitherman &
Harber (1991)
California, USA Azarcon, greta 20–86 CDC (1993)
New York, USA Contaminated hai ge fen 76 Markowitz et al.
(clamshell powder) (1994); Hill & Hill
(1995)
Zagreb, Croatia Ayurvedic metal-mineral 2.6–92.1 Prpic-Majic et al.
tonics (1996)
Connecticut, USA ‘Koo Sar’ pills (Asian 42–44 CDC (1999)
remedy for menstrual
cramps)
Australia Herbal remedy Mother, 108; Tait et al. (2002)
newborn, 244
Cosmetics
Nottingham, United Surma Mean, 34.2 Ali et al. (1978)
Kingdom
California, USA Traditional eye cosmetics Mean, 12.9 Sprinkle (1995)
(surma, kohl, alkohl)
Ammunition
Texas, USA Old gunshot wound 353 Dillman et al. (1979)
Texas, USA Retained projectiles Blood, 40–525; Linden et al. (1982)
(bullets, shrapnel, urine, 55–720 µg/L
buckshot)
Florida, USA Ingestion of 206 bullets 391 McNutt et al. (2001)
Saskatchewan, Canada Air rifle pellets 35–56 Treble & Thompson
(2002)
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Table 56 (contd)

rangea
Others
Oregon, USA Curtain weight 238 Blank & Howieson
(1983)
Maningrida, Australia Petrol sniffing 42–92 Eastwell et al.
(1983); Watson
(1985)
Australia Petrol sniffing 105 Burns & Currie
(1995)
New York, USA Ornamental clothing 144–150 Esernio-Jenssen
accessory et al. (1996)
Hospital nurseries in the Blood transfusions Mean, 3.5 (range, Bearer et al. (2000,
USA 2–7) 2003)
a
Unless stated otherwise
b
Blood lead concentration in 15/38 patients
Representative data on blood lead concentrations are presented by region in Tables

57–64, and in the text by population subgroup: adults, pregnant women and neonates, and
children.
(a) Adults
The UNEP/WHO Global Study to assess exposure to lead and cadmium through bio-
logical monitoring was one of the first international reliable studies with quality assu-
rance. The geometric mean concentration of lead in blood in different populations ranged
from 6 µg/dL in Beijing (China) and Tokyo (Japan) to 22.5 µg/dL in Mexico City
(Mexico). The values were below 10 µg/dL in Baltimore (USA), Jerusalem (Israel), Lima
(Peru), Stockholm (Sweden) and Zagreb (Serbia and Montenegro), and between 10 and
20 µg/dL in Brussels (Belgium) and Ahmedabad, Bangalore and Kolkata (India) (Friberg
& Vahter, 1983).
Data from central and eastern Europe show relatively high levels of background
exposure to lead at the time of the dissolution of the former Soviet Union (Table 57).
There have been concerted efforts to lower exposure by phasing out the use of leaded
gasoline and by controlling emissions from industries (Regional Environmental Center
for Central and Eastern Europe, 1998).
In the USA, the extent of recent exposures to lead in the general population has been
estimated based on blood lead measurements from the National Health and Nutrition
Examination Surveys (NHANES). Geometric mean blood concentrations in adults aged
P 075-140 DEF.qxp 09/08/2006 11:15 Page 128
Table 57. Lead concentrations in blood in adults and children in central and
eastern European countries
Country City or area Year(s) Population Blood lead (µg/dL)

of study mean or range
Bulgaria Momchilgrad 1991 Children, 5–7 years old 11.4

Momchilgrad 1991 Teenagers, 12–14 years old 11.6
Krichim 1991 Children 9.2
Kurtovo Konare 1991 Children and teenagers 17.0
Haskovo 1995 Children, 5–7 years old 10.1
Haskovo 1995 Teenagers, 11–12 years old 11.4
Nationwide 1995–96 Adults (men+women) 15
Czech Pribram 1992–94 Children, 1–3 years old 14.66; 6.61; 4.95a
Republic Children, 4–7 years old 10.2; 4.95; 4.67
Children, 8–11 years old 12.50; 5.37; 4.51
Teenagers, 12–14 years old 7.21; 4.84; 4.69
Hungary Budapest 1992 – 11.9
Sopron 1993 – 11.6
Local 1994 – 7.4
National 1995 – 6.26
Budapest 1996 – 6.5
Poland Five towns with no 1992–94 Men 4.25–7.68
industrial lead Women 2.38–4.83
emitters Children 2.39–6.23
Based in the vicinity 1992–94 Men 9.85–15.90
of zinc and copper Women 4.94–10.50
mills Children 7.37–11.40
Romania North Railway Station 1983–85 Children 17.1
(six areas of Balta Alba 1983–85 Children 18.40
Bucharest) Center 1983–85 Children 20.20
Giurgiuhu 1983–85 Children 21.93
Militari 1983–85 Children 17.84
Pantelimon 1983–85 Children 20.51
Slovakia Bratislava 1993 Children 3.65
Middle Slovakia 1995 Children 4.5
North Slovakia 1996 Children 3.04
From the final report of the National Integrated Program on Environment and Health Project (1995),
presented in Regional Environmental Center for Central and Eastern Europe (1998)
–, not stated
a
Geometric mean values for subjects living at distances from the lead smelter of less than 3 km, 3–5 km,
and over 5 km, respectively
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Table 58. Lead concentrations in blood in adults and children in the USA
Years of Population No. of Average Smokers Blood lead (µg/dL) Reference

survey subjects age
(years) GM 95% CI
1976–80 Men + women 5537 20–74 Included 13.1 12.7–13.7 Pirkle et al.
(1994)
1988–91 Men + women 6922 20–74 Included 3.0 2.8–3.2 Pirkle et al.
(1994)
1999–2000 Men + women 4207 ≥ 20 Included 1.8 1.67–1.83 CDC (2003a)
1978–80 Children 2271 1–5 – 15.0 14.2–15.8 Pirkle et al.
(1994)
1988–91 Children 2234 1–5 – 3.6 3.3–4.0 Pirkle et al.
(1994)
1991–94 Children 2392 1–5 – 2.7 2.5–3.0 CDC (1997b)
1999–2000 Children 723 1–5 – 2.2 2.0–2.5 CDC (2003a)
a
GM, geometric mean; CI, confidence interval
20 years or older have declined by 87% from 13.1 µg/dL in 1976–80 to 1.75 µg/dL in
1999–2000 (Table 58). Concentrations were higher in men than in women, and higher in
Mexican-Americans and non-Hispanic blacks than in non-Hispanic whites. In general,
blood lead concentrations in adults increase slowly with age (Pirkle et al., 1994; CDC,
1997b, 2003a).
Lead concentrations in the general population in several countries in Africa are
summarized in Table 59. Most values were > 10 µg/dL, except for two rural areas in South
Africa (Grobler et al., 1985; Nriagu et al., 1997a).
Reports from several Asian countries of blood lead concentrations in adults with no
known occupational exposure to lead and no exposure to heavy traffic are summarized in
Table 60. The values were mostly < 10 µg/dL, and few were above 13 µg/dL, with the
exception of one concentration of 24 µg/dL for a rural population in Pakistan (Khan et al.,
1995). One study used urinary lead concentrations to monitor lead exposure in Japan.
A substantial decrease in urinary lead was reported over the last 13 years. The amounts
of lead excreted (geometric means) in 24-h urine samples were 4.74, 2.67 and 1.37 µg for
men in 1985, 1993 and 1998, respectively, and 3.21, 2.14 and 1.02 µg for women in the
same years (Jin et al., 2000).
Blood lead concentrations in adults in Australia are summarized in Table 61. As
observed in other parts of the world, concentrations have declined in the general popu-
lation over the past two decades.
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Table 59. Lead concentrations in blood in the general population in some

countries in Africa
Country City/area Population/ No. of Blood lead Reference

age range subjects (µg/dL)
mean (range)
Egypt Urban area Adults NR 17.0–36.0 Kamal et al.

Rural area 14.0–25.0 (1991)
Cairo No lead 50 18.2 Kamal et al.
exposure (1991)
Nigeria Ibadan Men 11.4 Omokhodion
Women 12.3 (1984)
NR Adults 24 12.9 ± 7.0 Ogunsola et al.
(1.7–32.5) (1994b)
Kaduna 1–6 years 87 10.6 Nriagu et al.
(max. 39) (1997b)
South Urban area Children NR 22 [von Schirnding
Africa Rural area Children NR 11 & Fuggle (1984)]
Remote area 14–16 years 30 3.4 ± 1.5 Grobler et al.
(0.5–7.5) (1985)
Cape Town 1st year-grade 200 12 (white) von Schirnding
18 (mixed) et al. (1991a)c
Cape Town 1st year-grade 104 18b von Schirnding
et al. (1991b)c
Cape Province Children NR 14–16 Nriagu et al.
Mining village Children NR 16 (1996b)
Village 40 km from Children NR 13
mining area
Besters 3–5, 8–10 years 1200 10 Nriagu et al.
Valamehlo (rural) 660 3.8 (1997a)
Johannesburg 6–9 years 433 11.9 (6–26) Mathee et al.
(2002)
Urban areas Children NR 15 Harper et al.
(2003)a
Updated from Nriagu et al. (1996b); reference in square brackets could not be retrieved as original
papers.
NR, not reported
a
Review of several published studies
b
Median value
c
[It was not clear to the Working Group whether the two articles presented data from the same study
population.]
P 075-140 DEF.qxp
Table 60. Lead concentrations in blood in adults in the general population in Asia
09/08/2006
Country City/area Years of Population No. of Smoking Blood lead Reference
study subjects status (µg/dL)
arithmetic meana
(range)
11:15
China Shanghai 1986–88 Women 165 NR 14.1 Jiang et al. (1992)
3 areas 1993–97 Women 250 Nonsmoker 4.6b Zhang et al. (1999)
Hubei NR Women Wang et al. (2000)
urban 33 NR 6.7
Page 131
mining area 28 NR 6.7
rural 44 NR 5.3
Province of 1991–94 ≥ 15 years of age 8828 NR 7.7 (ND–69.1) Liou et al. (1996)
Taiwan 1993–94 Men 1471 Included 7.3 Chu et al. (1998)
Women 1332 Included 5.7
India Ahmedabad NR Men + women 200 Included 13.8 Friberg & Vahter (1983)
Bangalore 73 Included 17.9
Kolkata 100 Included 10.7
Slums of 1994–95 Women 500 NR 14.3 (13.0–15.7) Awasthi et al. (1996; 2002)
Lucknow
Indonesia Bandung 1983 Rural men 20 NR 12 Suzuki (1990)
Iraq Bassora NR Men 60 NR 14.6 Mehdi et al. (2000)
Japan Kanagawa 1991 Adults 62 NR 1.0 (0.6–2.4) Arai et al. (1994)
NR NR Men 70 NR 11.0 (5.0–17.2) Oishi et al. (1996a)
Women 68 NR 6.4 (3.8–11.4)
Kyoto, Sendai 1991–93 Women 72 Nonsmoker 3.2b Zhang et al. (1999)
& Tokyo
30 sites 1991–98 Women 607 Nonsmoker 1.9b Shimbo et al. (2000)
NR NR Women 70 NR 6.4 (3.8–11.4) Nomiyama et al. (2002)
Jordan Irbid City NR Men 21 NR 5.7b Hunaiti et al. (1995)
131
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132
09/08/2006
Table 60 (contd)
Country City/area Years of Population No. of Smoking Blood lead Reference

study subjects status (µg/dL)
11:15
arithmetic meana

(range)
Page 132
Pakistan Rural area 1994–95 Men 36 NR 24.1 Khan et al. (1995)
Philippines Manila 1999 Men + women 50 NR 12.6 Suplido & Ong (2000)
Republic of NR NR NR 26 NR 10.8 Kim et al. (1995a)
Korea Chonan 1997–99 Men + women 135 87% current 5.3 (2–10) Lee, S.-S. et al. (2001);
Schwartz et al. (2001)
Thailand Bangkok 1993 Women 500 NR 6.2 Phuapradit et al. (1994)
NR NR Men 30 NR 6.0 (2.1–9.7) Wananukul et al. (1998)
Chaiyapoom NR Rural 29 Nonsmoker 6.6 (4.0–9.0) Suwansaksri & Wiwanitkit
(2001)
United Arab Abu Dhabi 1999 Men 100 NR 19.8; 13.3b Bener et al. (2001)
Emirates
NR, not reported; ND, not detectable

a
b
GM, geometric mean
P 075-140 DEF.qxp
Table 61. Lead concentrations in blood in adults and children in Australia
Reference Location Period Population No. of Age (years) Blood lead AM (range) Comments
09/08/2006
of study subjects concentration
(µg/dL)
Mencel & Thorp Sydney, NSW 1974 Adults 133 NR 12.4 2.7–51.1
(1976)
Moore et al. Tasmania NR Clerks and students 47 18–61 14.3 SE, 0.72 Capillary blood
11:15
(1976) samples
de Silva & Melbourne, Vic. NR Male office workers 20 42.8 10.9 SD, 2.8 Venous blood
Donnan (1977) samples
Page 133
de Silva & Victoria, Vic. 1979 Children 446 School age 11.4 3–3.7
Donnan (1980)
Calder et al. Adelaide, SA, 1984 Boys and girls 513 ≤ 4 yrs 16.3 2.7% > 30 µg/dL
(1986) industrial suburb
Wilson et al. Port Pirie, SA 1982 Boys and girls 1239 1–14 18.2 15.4% ≥ 25 µg/dL
(1986) 95.4% ≥ 10 µg/dL
Fett et al. (1992) Central Sydney, NSW, 1991–92 Boys and girls 158 9–48 months 11.2 50.6% > 10 µg/dL
inner urban areas
Threlfall et al. Perth, WA 1991 Boys and girls 123 0.2–17 6.9a 3.2–14.7
(1993)
Gulson et al. Broken Hill, NSW 1991–92 Adults and children 146 NR – 2.7–47.1
(1994)
Taylor et al. Victoria, Vic. 1993 Children 252 0.3–14 5.4a 1.0–36.8
(1995)
Mira et al. Central and southern 1992–94 Boys and girls 718 9–62 months 7.0 16.1% > 10 µg/dL
(1996) Sydney, NSW
Chiaradia et al. Goulburn, NSW NR Children of employees 8 2–5 5.7 SD, 1.7 Lead–zinc–copper
(1997) Control children 10 2–5.5 4.1 SD, 1.4 mine employees
Maynard et al. Port Pririe, SA 1993 Boys and girls 679 1–4 13.6 NR Surveys evaluating
(2003) (town with widespread 1994 Boys and girls 551 13.3 NR interventions
contamination from 1995 Boys and girls 803 12.1 NR
lead smelter) 1997 Boys and girls 753 11.4 NR
1998 Boys and girls| 775 10.1 NR
1999 Boys and girls 825 10.6 NR
AM, arithmetic mean; NR, not reported; SE, standard error; SD, standard deviation
133
a
Geometric mean
P 075-140 DEF.qxp
134
Table 62. Lead concentrations in blood in children living near the Santo Amaro smelter in Bahia, Brazil
Year of No. of Age Blood lead Other bioindicators Reference Comments
09/08/2006
study subjects (years) (µg/dL) mean ± SD (range)
mean ± SD
(range)
1980 555 1–9 59.2 ± 25.0 ZPP: Carvalho et al. (1984, Initial survey
(16.0–152.1) 95.3 ± 80.2 µg/dL 1985a); Silvany-Neto
11:15
(3.8–782.8) et al. (1985); Tavares

(1990)
263 Lead in hair: Carvalho et al. (1989)
Page 134
558 ± 644 ppm
1985 250 1–9 36.9 ± 22.9 ZPP: Silvany-Neto et al. 90-m chimney built; population within 300 m
(2.9–150.0) 70.4 ± 43.9 µg/dL (1989); Tavares (1990, from smelter transferred; EDTA treatment for
(10.3–522.7) 1992) 31 children; discontinued donation of smelter
dross and used filters to neighbours; installation
of stack filters; provided working clothes to
employees
1992 100 1–5 ZPP: Silvany-Neto et al. Higher values found in girls; children with
65.5 ± 1.7 µg/dLb (1996); Carvalho et al. darker-skinned racial background; smelter slag
(1996, 1997) present in home; children with pica; children of
smelter workers
1998 47 1–4 17.1 ± 7.3 Carvalho et al. (2003) Smelter closed in 1993
(2.0–36.2) Sources of exposure remaining; higher blood
lead found in: children with pica; smelter slag
present in home; malnutrition; lead intoxication
family history; sewage tubing being placed
with disturbance of slag previously used on
streets
a
ZPP, zinc protoporphyrin; SD, standard deviation
b
Geometric mean
P 075-140 DEF.qxp
09/08/2006
Table 63. Lead concentrations in blood in children in Latin America and the Carribean
Country Location Year(s) Source of exposure No. of Age Mean blood lead Reference
of study subjects (years) (µg/dL)
11:15
Chile Antofagasta 1997–98 Lead storage site 432 0–7 8.7 ± 1.99a Sepúlveda et al.
(railway) (2000)
Port area 54 0–7 6.9 ± 1.94a
Page 135
No exposure 75 0–7 4.2 ± 1.54a
Equador La Victoria NR Ceramic glazing 166 0.3–15 40.0 (6.2–119.1) Counter et al. (2000)
Zamora Province NR No exposure 56 1–15 6.6 (2.0–18.0)
Jamaica NR 1994–95 Rural 242 3–11 9.2b (3–28.5) Lalor et al. (2001)
Urban 90 3–11 14.0b (4–34.7)
Former mining area 61 3–11 35b (18–> 60)
Mexico Mexico City < 1992 Urban 782 girls 5–11 10–17 Olaiz et al. (1996)
801 boys 5–11 14–16.7
Ciudad Juárez, 1974 Smelter 1–9 Ordóñez et al. (2003)
Chihuahua < 1 mile 35 38.7
1–2.5 miles 113 31.6
2.6–4 miles 198 28.7
4.1–6 miles 200 28.5
6.1–8 miles 206 27.7
Total 752 29.3
NR, not recorded

a
Geometric mean
b
Median value
135
P 075-140 DEF.qxp
136
Table 64. Lead concentrations in blood in children in Asia
Country City/area Year(s) Popula- No. of Age Blood lead (µg/dL) Reference Comments
09/08/2006
of study tion subjects (years)
AMa Range
Bangladesh Dhaka 2000 B+G 779 4–12 12.3–17.5b Kaiser et al. (2001)
China Jiangsu NR B+G 27 6–9 8.8 5.9–14.8 Zhou & Chen (1988)c Capillary samples
11:15
Shanghai NR B+G 83 8–13 18.4 ND–55.0 [Wang (1988)c] Capillary samples
Beijing 1990 B+G 287 5–7 7.8–12.3b 3.9–24.8 [Zheng et al. (1993)c] Capillary samples

Multiple sites NR B+G [3746] 1–15 6.6–96.8 Shen et al. (1996) Review of 17 articles published
between 1986 and 1994
Page 136
Shanghai 1997 B+G 1969 1–6 9.6 0.1–69.7 Shen et al. (1999) After removal of lead from
1998 B+G 1972 1–6 8.1 1–23.9 gasoline
Rural area 1998–2001 B+G 959 5–12 49.6 19.5–89.3 Wu et al. (2002) Children exposed to parental
lead-recycling small industry
B+G 207 5–9 12.6 4.6–24.8 Non-polluted area
Rural area NR B+G 469 mean, 8.5 50.5 22.0–93.8 Zheng et al. (2002) Rural area near smelter
Shantou 1999 B+G 332 1–5 10.4 3.4–38.6 Luo et al. (2003) After removal of lead from
2001 B+G 457 1–5 7.9 1.1–29.5 gasoline in 1998
China Kaohsiung 1998–99 B+G 934 8–12 5.5 0.2–25.5 Wang et al. (2002a)
(Province of
Taiwan)
India Delhi NR B+G 82 0.2–13 9.6 Gogte et al. (1991) Control
23 Pica
11.6 Surma
30.8 Pica + surma
New Delhi NR B+G 75 3–5 14 4–40 Kaul (1999) Finger-prick method
Jammu NR B+G 50 3–5 15 4–87
3 sites NR B+G Kumar & Kesaree
urban 25 5–15 32.0 25–43 (1999)
semi-urban 75 5–15 25.0 20–31
rural 50 5–15 15.0 13–22
Mumbai 1986–94 NR 566 6–10 8.6–14.4b Raghunath et al. (1999) Middle-class families
Mumbai 1984–96 [B+G] 560 6–10 8.6–69.2b Tripathi et al. (2001) Capillary samples
Delhi 1998 B+G 190 4–6 7.8 Kalra et al. (2003) Children with ZPP > 50 µg/dL
P 075-140 DEF.qxp
09/08/2006
Table 64 (contd)
Country City/area Year(s) Popula- No. of Age Blood lead (µg/dL) Reference Comments
of study tion subjects (years)
AMa Range
11:15
Indonesia Jakarta < 2001 B+G 397 6–12 8.6b 2.6–24.1 Albalak et al. (2003) Capillary samples
Malaysia Urban 1997 B+G 179 7–11 5.3 0.9–18.5 Hashim et al. (2000) Finger-prick method
Page 137
Semi-urban 112 7–11 2.8 0.1–12.3
Rural 55 7–11 2.5 0.05–5.2
Republic of Ulsan 1997 B+G 426 8–11 4.77b Lee et al. (2002) Lead in gasoline was reduced to
Korea 1999 B+G 250 8–11 5.11b 0.013 g/L in 1993.
2001 B+G 242 8–11 5.21b
Mongolia 6 sites NR NR 142 NR 0.34–1.75 Burmaa et al. (2002) Highest in Ulaanbaatar
Pakistan Karachi NR Boys 77 6–8 16.9 Rahman et al. (2002)
NR Girls 61 6–8 15.12
5 districts in 2000 B+G 400 3–5 12.0–21.6 Rahbar et al. (2002)
Karachi
Saudi Arabia Riyadh NR Girls 533 6–12 8.1 2.3–27.4 Al-Saleh et al. (2001)
Thailand Kanchanaburi, 1997 NR 48 mean, 3.4 27.8 Tantanasrikul et al. Initial survey
downstream 1998 NR 48 30.6 (2002) After environmental deleading
lead refinery 1999 NR 48 30.3 Second survey
plant
NR, not reported; B, boys; G, girls; ZPP, zinc protoporphyrin

a
AM, arithmetic mean, unless stated otherwise
b
Geometric mean
c
Cited by Shen et al. (1996); references in square brackets could not be retrieved as original papers.
137
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(b) Pregnant women and neonates

Lead concentrations were measured in maternal blood and umbilical cord blood from
50 parturient women at delivery in a hospital in Athens, Greece. Lead concentrations
(mean ± standard deviation) for women living in industrial areas with high air pollution
were 37.2 ± 4.7 µg/L in maternal blood and 20.0 ± 3.4 µg/L in umbilical cord blood
(correlation coefficient, r = 0.57), while those for women living in agricultural areas with
low air pollution were 20.5 ± 5.6 µg/L and 12.9 ± 3.6 µg/L, respectively (correlation
coefficient, r = 0.70). The authors concluded that the placenta demonstrates a dynamic
protective function that is amplified when maternal blood lead concentrations are
increased (Dussias et al., 1997).
Data from Kosovo (Serbia and Montenegro) showed that 86% of the pregnant women
living in the vicinity of a lead smelter had blood lead concentrations ≥ 10 µg/dL, while in
a comparable area not near a smelter, only 3.4% of pregnant women showed elevated con-
centrations (Graziano et al., 1990).
Rabinowitz and Needleman (1982) reported an umbilical cord blood lead concen-
tration of 6.6 µg/dL (arithmetic mean), with a range of 0–37 µg/dL, in over 11 000 samples
collected between 1979 and 1981 in Boston, USA. A decrease in the blood lead concen-
tration of approximately 14% per year was noted during the period of collection.
Concentrations of lead (expressed as mean ± standard deviation) in umbilical cord
blood of two groups of women giving birth in a hospital in Boston, USA, in 1980 and
1990, were found to be 6.56 ± 3.19 µg/dL and 1.19 ± 1.32 µg/dL, respectively (Hu et al.,
1996a).
In a study conducted at a medical centre in South Central Los Angeles, one of the
most economically-depressed regions in California, USA, maternal blood lead concen-
trations in the third trimester of pregnancy were significantly higher in a group of 1392
immigrant women (geometric mean, 2.3 µg/dL) than in a group of 489 non-immigrant
women (geometric mean, 1.9 µg/dL). Years living in the USA was the most powerful
predictor of blood lead concentration. Drinking coffee during pregnancy, a history of pica,
and/or low calcium intake were all significantly associated with higher blood lead concen-
trations (Rothenberg et al., 1999).
In a study conducted in the United Arab Emirates, blood samples were collected from
113 mothers of 23 different nationalities and from their neonates (cord blood). Mean
maternal blood lead concentration was 14.9 ± 2.14 µg/dL (range, 6.6–27.8 µg/dL) and
mean cord blood lead concentration was 13.3 ± 2.49 µg/dL (range, 6.0–30.3 µg/dL).
Sixteen per cent of samples from the mothers and 9% of cord blood samples had lead con-
centrations > 20 µg/dL (Al Khayat et al., 1997a).
There are several studies showing high blood lead concentrations in pregnant women
in India (Saxena et al., 1994; Awasthi et al., 1996; Raghunath et al., 2000). The mean blood
lead concentration in a cohort of 500 pregnant women living in the slums of Lucknow,
north India, was 14.3 µg/dL, and 19.2% of women had concentrations ≥ 20 µg/dL. Blood
lead concentration was not associated with age, height, weight, gestation, or history of
P 075-140 DEF.qxp 09/08/2006 11:15 Page 139
abortion, although it was higher with higher parity. Women living in inner-city neighbour-
hoods with heavy vehicular traffic had mean blood lead concentrations significantly higher
than those living in other neighbourhoods (Awasthi et al., 1996). In another study con-
ducted in Lucknow, India, the mean maternal blood lead concentration was significantly
higher in cases of abnormal delivery (22.5 µg/dL) compared with normal deliveries
(19.4 µg/dL). No significant difference in placental blood, cord blood and fetal membrane
lead concentrations was observed between cases of normal and abnormal deliveries
(Saxena et al., 1994).
(c) Children
Data on blood lead concentrations in children are presented in Tables 57–59 and
61–64.
Between 1978 and 1988, decreases of 25–45% in average blood lead concentrations
in children have been reported in Belgium, Canada, Germany, New Zealand, Sweden and
the United Kingdom (OECD, 1993).
Blood lead concentrations were measured in 286 children aged 0–7 years living in the
three largest cities of Finland (n = 172), in rural areas (n = 54) and near a lead smelter
(n = 60) (Taskinen et al., 1981). Mean blood lead concentrations among children in the
urban, rural and lead-smelter areas varied between 6.0 and 6.7 µg/dL, with a range of
2–17 µg/dL. There were no statistically significant differences between groups. The five
children who lived within 500 m of the lead smelter had a mean blood lead concentration
of 9.2 µg/dL, with a range of 5–13 µg/dL, which was significantly higher than the mean
blood lead concentration among 485 children in the rest of the country. In a study carried
out in Sweden, 1395 blood samples were obtained from children living in an urban or rural
area or near a smelter during the period 1978–88. The mean blood lead concentration for
all locations together decreased from 6.4 µg/dL (range, 1.8–25 µg/dL) in 1978 to 4.2 µg/dL
(range, 1.4–12.9 µg/dL) in 1984, to 3.3 µg/dL (range, 1.5–7.1 µg/dL) in 1988. The
decrease was statistically significant for all three areas studied (Skerfving et al., 1986;
Schütz et al., 1989).
In Finland, the mean blood lead concentration for the children in two day-care centres
in Helsinki was 4.8 µg/dL in 1983 (range, 2.1–8.3 µg/dL), 3.0 µg/dL in 1988 (range,
2.1–4.1 µg/dL), and 2.6 µg/dL in 1996 (range, 1.7–3.7 µg/dL) (Pönkä et al., 1993; Pönkä,
1998).
In 1993, almost 30% of 431 children in a lead-mining community in the Upper Silesian
industrial zone of Poland had blood lead concentrations > 10 µg/dL (Zejda et al., 1995). In
Belovo, Russian Federation, lead releases from a metallurgy enterprise decreased between
1983 and 1996 from 120 to 9 tonnes per year, due to almost complete cessation of activity.
In 1983, mean blood lead concentrations in newborn children and their mothers living in
the area were 23.4 and 25 µg/dL, respectively; in 1996, mean blood lead concentrations in
91 children (age, 7–8 years) had decreased to 9.9 µg/dL (range, 0.5–39 µg/dL), with 46%
of values still exceeding 10 µg/dL (Revich et al., 1998).
P 075-140 DEF.qxp 09/08/2006 11:15 Page 140
In a community near a smelter in Bulgaria, blood lead concentrations in 109 children

varied from 8–63 µg/dL. The higher concentrations in these children were correlated with
the consumption of home-grown products. Lower blood lead concentrations were observed
in children whose food came from a distant market (Fischer et al., 2003).
The mean blood lead concentration in children in the USA has dropped dramatically
since the late 1970s (Brody et al., 1994; Pirkle et al., 1994, 1998; CDC, 1997b, 2003a,b).
Results of the NHANES studies in children aged 1–5 years are shown in Table 58.
The NHANES II and NHANES III, Phase I, results showed that from 1976 to 1991,
high blood lead concentrations correlated with low income, low educational attainment
and residence in the north-eastern region of the USA (Pirkle et al., 1994). Data from
Phase II of NHANES III (October 1991 to September 1994) indicated that blood lead con-
centrations in children aged 1–5 years continued to decrease and were more likely to be
elevated among those who were poor, non-Hispanic black, living in large metropolitan
areas or living in older housing (with potential exposure to lead from lead-based paint);
approximately 4.4% of the children aged 1–5 years had blood lead concentrations
≥ 10 µg/dL (CDC, 1997b). In addition, 1.3% of children aged 1–5 years had blood lead
concentrations ≥ 15 µg/dL and 0.4% had concentrations ≥ 20 µg/dL. The downward
trends continued in 1999–2000 (CDC, 2003a). For all periods of this study, mean lead
concentrations were consistently lower among the older age groups, i.e. age 1–5 years,
2.2 µg/dL; 6–11 years, 1.5 µg/dL; 12–19 years, 1.1 µg/dL in the period 1999–2000 (CDC,
2003a).
A study assessing the source of lead exposure during early childhood in the USA
showed that lead-contaminated floor dust was a major source of lead exposure during
early childhood, whereas window sills became an increasingly important source as
children stood upright (Lanphear et al., 2002).
One of the most serious episodes of general population exposure to lead reported in
Latin America occurred in Brazil (Table 62). For 24 years, a lead smelter processing
30 000 tonnes/year operated in the vicinity of Santo Amaro da Purificação (30 000
inhabitants) in the state of Bahia. No proper air pollution control system was used.
Smelter dross (solid wastes) was distributed free of charge to the neighbouring population
and spread over gardens, backyards, schools and streets, and chimney filters from the
smelter were used in homes as carpets, bed spreads and rags. Four cross-sectional studies
in children under 9 years of age were conducted in 1980 (Carvalho et al., 1985a), 1985
(Silvany-Neto et al., 1989), 1992 (Silvany-Neto et al., 1996) and 1998 (Carvalho et al.,
2003). Blood lead concentrations were among the highest reported in the world. Most
children involved in the last study were born after the smelter closed down in December
1993. Five years later, lead concentrations in blood averaged 17.1 ± 7.3 µg/dL, ranging
from 2.0 to 36.2 µg/dL. Blood lead concentrations were approximately 5 µg/dL higher in
children with pica, with visible presence of dross in home premises, with previous history
of lead intoxication in the family and with malnutrition (Carvalho et al., 2003).
In Antofagasta, Chile, a study was conducted with 432 children under 7 years of age
living around a minerals storage site, 54 living near the port and 75 in non-exposed areas
P 141-164 DEF.qxp 09/08/2006 11:26 Page 141
(Table 63). Average concentrations of lead in blood of exposed and unexposed children
were 8.7 µg/dL and 4.2 µg/dL, respectively. Forty-seven per cent of exposed children, but
no unexposed children, had blood lead concentrations > 10 µg/dL. The habit of pica, the
number of cigarettes smoked daily at home, the level of education of the mother and
having a mother working outside the home were variables that partly explained the
variation in blood lead concentrations in the exposed area (Sepúlveda et al., 2000).
In view of airborne lead pollution across the border from a lead smelter in El Paso,
TX, USA, an epidemiological study on lead was conducted in 1974 in Juárez City,
Chihuahua, Mexico, among 752 children aged 1–9 years. The average blood lead concen-
tration was 29.27 ± 7.30 µg/dL in children living within 8 miles of the lead source. Con-
centrations decreased with greater distances from the smelter (Ordóñez et al., 2003; see
Table 24 and Section 1.4.1(b)).
Lead-glazing of ceramics has for many years been a source of exposure of the popu-
lation of La Victoria, Ecuador, where around 70 kilns operate within an area of 250 km2.
One hundred and sixty-six children aged 4 months to 15 years living in the area and many
of them helping their parents in glazing activities had blood lead concentrations ranging
from 6.2 to 119.1 µg/dL (mean, 40.0 µg/dL) compared with an average of 6.6 µg/dL in a
reference population of 56 children aged 1–15 years living 500 km away in the province
of Zamora. Lead isotope ratios of the soil and blood samples were highly similar and
clustered for both study areas, indicating that lead in soil resulting from contamination by
the glazing activities is probably one of the main routes of exposure to lead in these
children (Counter et al., 2000).
Blood lead concentrations among children in several Asian countries (Table 64) were
basically similar to those in adults (Table 60), and were generally between 5 and 15 µg/dL
(geometric mean). It should be noted, however, that finger-prick or capillary blood samples
were employed in some studies (see Section 1.5 for quality assurance). Blood lead concen-
trations in children in Mongolia (Burmaa et al., 2002) were substantially lower than in all
the other studies listed in Table 64.
In a study carried out at 15 sites in India, the highest (69 µg/dL) and second highest
(21 µg/dL) geometric mean blood lead concentrations were observed in children who
lived near a scrap-yard and near a lead smelter, respectively. Values for children in the
remaining sites were in a range of 9–14 µg/dL (Tripathi et al., 2001). Wu, Y. et al. (2002)
observed significantly higher blood lead concentrations in children who lived in an area
polluted by lead from a battery-recycling plant compared with a control group. Similarly,
Zheng et al. (2002) described elevated blood lead concentrations (up to 94 µg/dL) in
children living in an area with heavy lead pollution. Tantanasrikul et al. (2002) found high
blood lead concentrations in children in a Thai village area downstream from a lead
refinery plant. Wang et al. (1998) reported that 22 of 36 children in a kindergarten near a
battery recycling factory in Taiwan, China, had blood lead concentrations in excess of
15 µg/dL in comparison with none of 35 children in a kindergarten in a non-exposed area.
In a study of 566 children aged 6–10 years residing in 13 locations in Mumbai, India,
a correlation coefficient of 0.88 was observed between air lead and blood lead concen-
P 141-164 DEF.qxp 09/08/2006 11:26 Page 142
trations. It was also found that a 1-µg/m3 increase in lead concentration in air resulted in
a 3.56-µg/dL increase in blood lead concentration in children (Raghunath et al., 1999).
In another study among children in India, the differences in the mean blood lead
concentrations were statistically significant (p < 0.001) between the urban, semi-urban
and rural populations. The age-related differences in blood lead concentrations were also
significant for urban, semi-urban and rural children (Kumar & Kesaree, 1999).
In a study comparing children with and without pica in Delhi, India, only six out of
82 children with no symptoms of pica had a mean blood lead concentration ≥ 30 µg/dL
(30–39 µg/dL). Among 88 children with pica, 26 had high blood lead concentrations
(30–92 µg/dL) (Gogte et al., 1991).
Among 400 children aged 36–60 months from the city centre, two suburbs, a rural
community or an island situated in the harbour at Karachi, Pakistan, about 80% had blood
lead concentrations > 10 µg/dL, with an overall mean of 15.6 µg/dL. Housing near a main
intersection in the city centre, application of surma (a lead-containing cosmetic) to
children’s eyes, father’s exposure to lead at the workplace, father’s illiteracy, child’s hand-
to-mouth activity and eating from street vendors were among variables found likely to be
associated with elevated lead concentrations in blood (Rahbar et al., 2002).
The phase-out of leaded gasoline in Indonesia began in Jakarta on 1 July 2001. In a
study conducted before the beginning of the phase-out activities, 35% of children aged
6–12 years in Jakarta had blood lead concentrations ≥ 10 µg/dL and 2.4% had concen-
trations ≥ 20 µg/dL. Lead concentrations in the blood of children who lived near a high-
way or major intersection were significantly higher than those in children who lived near
a street with little or no traffic. The source of household water was also a significant pre-
dictor of blood lead concentrations ≥ 10 µg/dL, after adjustment for age and sex (Albalak
et al., 2003).
Hashim et al. (2000) measured blood lead concentrations in urban and rural primary-
school children in Malaysia; the percentage of children with blood lead ≥ 10 µg/dL was
6.36% overall, and was highest for Kuala Lumpur (11.73%). Urban schoolchildren were
found to have higher blood lead concentrations than their rural and semi-urban
counterparts, even after controlling for age, sex, parents’ education and income levels.
1.4.3 Occupational exposure

Potentially high levels of lead may occur in the following industries or workplaces:
lead smelting and refining industries, battery manufacturing plants, steel welding or
cutting operations, construction, painting and printing industries, firing ranges, vehicle
radiator-repair shops and other industries requiring flame soldering of lead solder, and
gasoline stations and garages.
Workers in many occupations and job activities within or outside these industries have
the potential for relatively high exposures to lead with varying degrees of frequency (Fu
& Boffetta, 1995; ATSDR, 1999; NIOSH, 2001). These exposures and workers are (the
asterisks indicate occupations for which there is at least one epidemiological study of lead
P 141-164 DEF.qxp 09/08/2006 11:26 Page 143
exposure and cancer, as summarized in Section 2 of this volume): on-going exposure —

battery-production workers*, battery-recycling workers*, foundry workers, lead chemical
workers*, lead smelter and refinery workers*, leaded-glass workers*, pigment workers*,
vehicle radiator-repair workers and traffic controllers; moderate frequency of exposure —
firing-range instructors, house renovators, lead miners*, newspaper printers*, plastics
workers*, rubber workers, jewellery workers, ceramics workers and steel welders and
cutters; low frequency of exposure — automobile-repair workers, cable-production
workers, construction workers, demolition workers, firing-range participants, flame-
solder workers, plumbers and pipefitters, pottery-glaze producers, ship-repair workers
and stained-glass producers.
Epidemiological studies have also reported exposure to organic lead compounds, at a
chemical plant in Texas, USA, and at an organic lead manufacturing company in New
Jersey, USA. However, there are a number of activities that present a potential for high
lead exposure but for which no epidemiological data are available.
The most common route of occupational exposure to lead is through inhalation of
lead fumes or lead dusts from ambient air, leading to absorption of lead through the
respiratory system. Lead may also be ingested and absorbed in the gastrointestinal tract.
Organic lead is absorbed through the skin (Bress & Bidanset, 1991).
The lead concentration in air can be measured as a means of monitoring occupational
exposure in work areas. However, occupational exposure is more often inferred from
measurement of blood lead concentrations in individual workers.
Workers occupationally exposed to lead may carry lead home on their body, clothing
and tools. Thus, children of workers exposed to lead can also be at increased risk of expo-
sure. For example, blood lead concentrations of children in households of occupationally-
exposed workers were found to be almost twice those of children in neighbouring homes
whose parents were not exposed to lead in their occupation (median ranges, 10–14 and
5–8 µg/dL, respectively) (Grandjean & Bach, 1986). Exposures to lead in workers’
families have been identified in association with nearly 30 different industries and occu-
pations; the most commonly reported include lead smelting, battery manufacturing and
recycling, radiator repair, electrical components manufacturing, pottery and ceramics and
stained-glass making (NIOSH, 1995).
The results of surveys of occupational exposure to lead in a large variety of industries
in New Zealand, expressed as air lead concentrations and/or blood lead concentrations for
the period 1988–89, are presented in Table 65 (Grant et al., 1992).
Lead concentrations in workplace air and in the blood of exposed workers for specific
job categories are presented in Tables 66–73. Whereas lead concentrations in air were
reported only in a limited number of studies, blood lead concentrations are available for
most studies and the exposure intensity is evaluated in terms of blood lead for the groups
of exposed workers. Examples of extreme exposures reported in the literature include
mean occupational air lead concentrations as high as 1200 µg/m3 for welding structural
steel, 4470 µg/m3 for primary smelting and 5400 µg/m3 within a storage-battery plant
(WHO, 1977).
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Table 65. Occupational exposure to lead in men in New Zealand,

1988–89
Occupation in order of decreasing No. of Blood lead (µg/dL)

mean blood lead concentration workers
Mean SD Range
Radiator repairer 51 78.7 47.6 11–155

Smelter/furnaceman 57 78.7 51.8 14–148
Muffler repairer 33 70.4 33.1 31–109
Scrap metal worker 69 66.2 60.0 14–145
Foundryman general 58 64.2 49.7 23–128
Metal moulder 24 64.2 66.2 14–181
Container repairer 13 60.0 26.9 40–61
Engine reconditioner 33 53.8 33.1 23–154
Panel beater 22 55.9 47.6 23–115
Metal machinist 35 55.9 43.5 18–111
Printer 4 55.9 33.1 28–69
Gas cutter/welder 17 43.5 49.7 6–90
Spray painter 42 43.5 29.0 17–80
Plastic worker 55 43.5 35.2 9–124
Metal polisher 29 43.5 55.9 10–119
Paint removal worker 8 41.4 22.8 19–54
Painter/decorator 208 41.4 51.8 5–181
Leadlight worker 11 39.3 29.0 14–64
Metal extruder 16 35.2 31.1 18–77
Garage mechanic 47 35.2 43.5 9–82
Miscellaneous lead product worker 65 31.1 35.2 5–113
Pottery/ceramics worker 3 29.0 24.8 9–46
Workers exposed to exhaust fumes 6 26.9 26.9 14–47
Plumber 10 26.9 20.7 12–46
Cable jointer 174 26.9 26.9 5–91
Car assembler 25 26.9 31.1 5–76
Electroplater 17 22.8 18.6 9–46
Boat builder 30 20.7 18.6 7–47
Bright solderer 9 20.7 20.7 11–49
Petrol pump attendant 10 20.7 14.5 5–33
Adapted from Grant et al. (1992)

SD, standard deviation
A NIOSH Health Hazard Evaluation (HHE) is a study of a workplace in the USA con-
ducted to learn whether workers are exposed to hazardous materials or harmful condi-
tions. The HHE is not necessarily representative of an industry or general work practices,
since the inspections and measurements are typically done in response to a request by an
employee, an officer of a labour union that represents employees, or any management
official on behalf of the employer. Table 74 presents data from a series of HHE reports
where blood and air concentrations of lead have been measured.
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Table 66. Lead concentrations in blood of occupationally exposed subjects: lead–acid battery factories
Country or Year(s) Job/task Study No. of Age Job history Smoking Blood lead (µg/dL) Lead in air (µg/m3) Reference
area of survey popu- subjects (years) (years) status
lation AMa Range/SD AMa Range/SD
11:26
Brazil [1984] Battery repairb M 5 15–66 ≤1 NR 35.0c NR Carvalho
11 1–3 NR 37.3c et al. (1985b)
23 ≥4 NR 47.7c
Page 145
6 15–18 36.7c
33 19–66 44.0c
Bulgaria 1992–96 Lead–acid battery M 103 39.1 9.7 Included 56.2 NR Vaglenov
et al. (2001)
China 1950–83 Lead–acid battery Wang (1984)
Charging NR 30 NR NR NR 26.2d NR 500
Plate moulding NR 34 NR NR NR 25.6 d NR 60
Printing NR 30 NR NR NR 22.8 d NR 5
China NR Lead–acid battery M 118 37.0 > 6 months 80% 67.0 ± 26 190 Lai et al.
(Province W 101 36.3 > 6 months 2% 45.0 ± 18.7 (1997)
of Taiwan) NR Lead–acid battery M 120 18–67 0.2–35 38% smokers 67.7 ± 28.2 ≥ 0.1 in Wang et al.
W 109 18–71 0.2–17 48.6 ± 17.0 46% of (2002b)
samples
1989–98 Lead–acid battery 17 M 30 38.3 13.1 NR 20–60d,e NR Hsiao et al.
13 W (2001)
1991 Lead–acid battery M+W 284 NR NR Included 34.7 ± 15.0 NR Chuang et al.
1997 M+W 392 NR NR Included 23.9 ± 12.4 NR (1999)
Finland NR Lead–acid battery M+W 91 40.6 12.2 NR 30 NR Erkkilä et al.
(1992)
Irak 1996 Lead–acid battery Mehdi et al.
Charging M 11 NR >4 40% smokers 36.4 ± 11.40 NR (2000)
Repair M 8 NR >4 58.0 ± 13.35 NR
Casting M 18 NR >4 71.7 ± 24.80 NR
145
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146
Table 66 (contd)
09/08/2006
lation AM a
Range/SD AM a
Range/SD
Israel 1975 Administration NR 3 41.3 13.3 Most 28.6 20–34 14.5 11.9–17.0 Richter et al.
Maintenance NR 3 41.3 5.5 smokers 44.0 43–46 23 – (1979)
Assembly NR 6 47.0 9.8 55.0 41–73 49.3 48–50.7
11:26
Miscellaneous NR 17 35.2 4.3 59.5 43–87 84.5 71–98
Grid smelting and NR 10 43.9 13.1 58.4 43–73 190 118–299

casting
Plate drying and NR 15 31.9 4.6 75.2 48–105 399 266–475
Page 146
formation
Oven smelting NR 3 36.3 6.5 76.3 64–90 885 –
Pasting/drying/ NR 4 33.5 6.4 90.7 79–108 1187 1060–1315
oxide formation
Japan NR Lead battery, mostly M 214 NR ≥2 NR 48.9c 17.0–101.0 NR Fukui et al.
W 44 NR ≥2 NR 49.1c 28.0–75.0 NR (1999)
Philippines 1990 Lead–acid battery M 199 33.8 10.7 NR 64.5b 23–121 NR Makino et al.
(1994)
Republic NR Lead–acid battery NR 66 40 ≥ 3 months NR 45.7 ± 15.7 NR Kim et al.
of Korea Casting and 5 39 40.6 ± 8.8 83 40–154 (1995a)
pasting
Plate forming, 17 44 49.2 ± 17.4 170 12–468
finishing
Assembling 22 39 47.2 ± 11.6 145 15–411
Others 22 39 42.6 ± 18.7 NR
NR Lead–acid battery 14 M, 92 40.1 8.6 NR 27.6 19c Hwang et al.
Cast-on-strap 78 W 37 29.6 32c (2000)
Plate processing 3 36.8 29c
Battery cell 19 22.6 13c
setting
Finish processing 21 22.4 9c
Supervisor 12 44.5 27c
1998 Lead–acid battery M 156 36.3 8.8 68% smokers 32.0 ± 13.0 NR Hwang et al.
W 56 47.0 6.2 Nonsmokers 19.8 ± 9.2 NR (2001)
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Table 66 (contd)
11:26
lation AMa Range/SD AMa Range/SD
Page 147
Singapore NR Lead–acid battery M Chia et al.
Chinese 11 39.1 10.8 Included 23.6 12.4 35 ± 31 (1991)
Malay 25 31.7 7.5 Included 34.3 10.5 51 ± 39
NR Lead–acid battery M 50 38.3 10 NR 32.5 19.1–50.9 88.6 ± 176.3 Ho et al.
(1998)
1987–89 Lead–acid battery NR 61 NR NR NR 28.4 12.9 NR Chia et al.
(1993)
South NR Lead–acid battery M 382 41.2 11.6 52% smokers 53.5 23–110 145 10–5480 Ehrlich et al.
Africa (1998)
Turkey NR Lead–acid battery M 71 32.7 NR 73% smokers 34.5 13.4–71.8 NR Süzen et al.
(2003)
USA 1947–72 Lead–acid battery M 1083 NR >1 NR 62.7 NR Wong &
Harris (2000)
NR, not reported; M, men; W, women

a
Arithmetic mean, unless stated otherwise
b
Nineteen different establishments recycling batteries; 76.9% of the workers operating in areas < 30 m2 and involved in fusion of lead
c
Geometric mean
d
Median value
e
Values read from graph
147
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148
Table 67. Lead concentrations in blood of occupationally exposed subjects: mining/primary smelter
Country Year of Job/task Study No. of Age Years of Smoking Blood lead (µg/dL) Lead in air (µg/m3) Reference
09/08/2006
survey popu- subjects years employ- status
lation mean ment AMa Range/ AMa Range
(range) SD
Canada 1994 Primary smelter M+W 368 NR NR NR 22–25 NR NR Fleming

et al. (1998)
11:26
Italy 1977–78 Primary smelter M 1388 NR >1 NR NR 47.6 1–1650 Cocco et al.

(1997)
Japan NR Copper smelter M 42.9 Included Karita et al.
± 5.5
Page 148
Blending 13 (21–60) – 8.9 7 5–8 (2000)
Smelting 51 – 13.5 ± 7.2 29 6–67
Converter 28 – 15.7 ± 7.3 41 17–78
Anode 31 – 25.7 ± 6.1 313 165–436
Current 26.3 14–39
Former 21.0 19–23
Never 25.9 15–34
Kazakhstan 1998 Smelter and mining NR 38 NR NR NR 34 13–> 65 NR Kaul et al.
(2000)
Sweden 1987 Primary smelter Active 70 37.4 14.3 NR 32b 5.0–47.4 NR Gerhardsson
Retired 30 67.9 32.6 NR 9.9b 3.3–20.9 et al. (1993)
Sweden 1950–87 Primary smelter M 3979 NR NR NR 62.1–33.1c NR Lundström
Other metal workers 55.9–16.6c et al. (1997)
Other personnel 53.8–12.4c
United 1970–79 Cadmium plant M 123 NR >1 NR 28 50% Ades &
Kingdom Furnace area M 426 NR >1 NR 59 > 2000 in Kazantzis
Sinter area M 343 NR >1 NR 56 whole plant (1988)
USA 1976 Primary smelter M 173 NR 9.9 NR 56.3 3100 Steenland
et al. (1992)
NR, not reported; M, men; W, women

a
b
Median value
c
Decrease over the study period
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Table 68. Lead concentrations in blood of occupationally exposed subjects: secondary smelter
Country or Year(s) Job/task Study No. of Age Job history Smoking Blood lead (µg/dL) Lead Reference
area of survey popu- subjects years (years) status in air
lation mean AMa Range/ (µg/m3)
AMa

(range) SD
11:26
China NR Battery recycling Wang et al.
(Province Furnace NR 19 37 11 months NR 87 14 NR (1998)
Page 149
of Taiwan) Fragmentation NR 10 35 15 months NR 69 16 NR
Office, guards NR 5 52 31 months NR 38 4 NR
Ghana NR Battery recycling 23 M, 2 W 25 (18–60) ≥5 NR 108 60–270 NR Ankrah et al.
(1996)
Japan NR Secondary lead smelter 19 M, 3 W 22 47 5 NR 43 8–78 NR Tomokuni
(22–63) et al. (1992)
Philippines NR Secondary lead smelter M 107 32.1 6.6 NR 80.8b 19–153 NR Makino et al.
(battery recycling) W 6 27.8 4.0 NR 44.7b 35–61 NR (1994)
Republic 1996 Secondary lead smelter 83 M, 5 W 88 NR > 1 month NR 52.4 17.7 324 Kim et al.
of Korea A M+W 12 47.4 18.8 310 (2002)
B M+W 17 47.2 20.7 194
C M+W 18 49.7 13.1 464
D M+W 25 55.4 19.7 316
E M+W 16 60.0 12.1 290
Sweden 1969–85 Secondary smelter M 664 28 at 2.8b NR 62.1–33.1c NR Gerhardsson
entry et al. (1995a)
USA 1947–72 Smelters (primary, M 254 NR >1 NR 79.7 NR Wong &
second, recycling) Harris (2000)
NR, not reported; M, men; W, women; A–E, five different lead smelters
a
Arithmetic mean, unlewss stated otherwise
b
Median value
c
Decrease over the study period
149
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150
09/08/2006
Table 69. Lead concentrations in blood of occupationally exposed subjects: leaded glass
11:26
Country Years of Job/task Study No. of Age Job Smoking Blood lead (µg/dL) Lead in air (mg/m3) Reference
or area survey population subjects (years) history status
Page 150
(years) AMa Range AMa Range
China NR Lead-coloured glass Women 36 21–35 2–17 Never 55.6 25.8–79.3 NR 0.4–1.2 Murata et al.
(1995)
Japan 1989–90 Lead-coloured glass NR 5 29–55 2–17 NR Hirata et al.
high exposure (15)b 67.1 38–102 1050 741–1658 (1995)
low exposure (60)b 52.3 38–69 286 22–1331
NR Lead glass processing Men 160 36 1–28 NR 55.1 18.1–87.9 NR Oishi et al.
and lead pigment Women 138 28 1–28 NR 54.7 21.5–99.4 NR (1996a)
production
NR, not reported

a
Arithmetic mean
b
Number of samples collected during 15 months
Cor 151.qxd
01/09/2006
Table 70. Lead concentrations in blood of occupationally exposed subjects: welders and solders
Country or Year of Job/task Study No. of Age Job Smoking Blood lead (μg/dL) Lead in air μg/m3) Reference
area survey popu- subjects (years) history status
18:14
lation (years) AMa Range/SD AMa Range

Welding
Page 151
Jordan NR Radiator welding M 22 27.7 1–40 NR 32.8b NR Hunaiti et al. (1995)
Malaysia NR Shipyard welding M 51 > 18 1–17 Includedc 12 4–31 NR Mokhtar et al. (2002)
Mexico NR Radiator repair NR 73 33.2 NR Included 35.5 6.7–79.4 19.1 0–99 Dykeman et al. (2002)
29 Smoker 40.4 13.9–79.4
30 Nonsmoker 32.3 14.6–56.9
Philippines 1999 Radiator mechanic M+W 16 40.2 16.2 NR 20.0 ± 10.6 NR Suplido & Ong (2000)
NR Welding mechanic M 29 NR NR Nonsmoker 9.1 5.0–17.0 NR Suwansaksri et al. (2002)
Thailand NR Mechanic NR 40 NR NR Never 11.2 3.9–17.0 0.1–0.5 Suwansaksri & Wiwanitkit
(2001)
USA 1992 Radiator repair M 63 39 11 39% current 29d 6.6–94 NR Dalton et al. (1997)
NR Radiator repair NR 56 39.5 NR 52% current 37.1 16–73 NR Goldman et al. (1987)
1990 Radiator repair NR 7 NR NR NR NR 17–35 PBZ: 209 < 20–810 Tharr (1993)
TWA:
< 10–> 40
1986 Radiator repair NR 53 37.1 14.3 60% current 31.7 5–58 Area: 40 0–281 Lussenhop et al. (1989)
PBZ: 113 0–590
Soldering
Philippines NR Electronic industry M 21 25.4 1.8 NR 14.9b 7–45 NR Makino et al. (1994)
W 193 21.9 1.8 NR 9.9b 3–47 NR
Singapore 1987 Electronics industry NR 118 NR NR NR 16.1 ± 8.5 110 10–1240 Chia et al. (1993)
NR, not reported; M, men; W, women; PBZ, personal breathing zone; TWA, time-weighted average
a
Arithmetic mean, unless specified otherwise
b
Geometric mean
c
Stratification by smoking did not reveal a significant difference between values.
d
Median value
151
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152
09/08/2006
Table 71. Lead concentrations in blood of occupationally exposed subjects: professional drivers and traffic policemen
Country or Year(s) of Job/task Study No. of Age Job Smoking Blood lead (µg/dL) Lead in air (µg/m3) Reference
area survey popu- subjects (years) history status
a a
lation (years) AM Range/ AM Range
11:26
SD

China 1998 Taxi and bus drivers M 164 NR NR 75% 10.8b ± 1.26 NR Zhou et al.
Page 152
smokers (2001)
Egypt NR Traffic controllers M 45 20–60 Max., 40 NR 68.3 37–97 NR Ahmed et al.
(Alexandria) (1987)
Egypt NR Traffic policemen M 126 48.7 9–36 NR 29.2 7.5 NR Kamal et al.
(1991)
India NR Traffic constables M 88 41.7 2.7 30% 11.2 0.5–40.2 NR Potula & Hu
Bus drivers M 22 43.6 5.6 77% 12.1 0.5–35.7 NR (1996a,b)
Indonesia 1983 Policemen M 24 NR NR NR 31 ± 18 NR 0.7–6.0 Suzuki
Drivers NR 22 NR NR NR 25 ± 17 NR 0.7–6.0 (1990)
Jordan NR Bus drivers, gasoline NR 47 NR NR NR 7.6 NR Hunaiti et al.
station workers (1995)
Pakistan 1994–95 Traffic exposed M 212 19–59 >1 Included 52.2 NR Khan et al.
Traffic police 36 53.4 (1995)
Transportation staff 150 51.1
Shopkeepers 36 52.1
NR, not reported; M, men

a
b
Geometric mean
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09/08/2006
Table 72. Air and blood lead concentrations measured at indoor and outdoor firing ranges
Country Year(s) of study Settings/task No. of Age Job history Blood lead (µg/dL) Lead in air (µg/m3) Reference
subjects (years) (years)
and sex AMa Range AMa Range
11:26
China NR Employees in indoor 10 NR 4–21 37.2 22.4–59.6 GA, 134; PBZ, 413 NR Chau et al.
(Province range (1995)
of Taiwan)
Page 153
New 1990–91 Indoor small-bore rifle 52 M + W 17–68 Recreational End of PBZ, 120 George
Zealand range shooters season, GA, 140–210 et al.
55.0; start of (1993)
season, 33.3
Sweden NR Indoor range Svensson
Powder gun 22 M + W 42.4 10.2 13.8b 6.9–22.8 660 112–2238 et al.
Air gun 21 M + W 46.8 13.7 8.4b 2.0–22.2 4.6 1.8–7.2 (1992)
1994 On- and off-duty police 75 M 43 NR 5.0 1.0–18.2 NR Löfstedt
officers 3W 32 > 9 years 3.7 et al.
(1999)
United NR Indoor range for police 7 NR NR 30–59 30–160 Smith
Kingdom officers (1976)
NR Soldiers 35 21.9 4.2 19.25 9.6–30.1 TWA: 190 Brown
(1983)
USA 1985 Indoor range NR NR Showroom, 2.7 Novotny
Full-time employee 2 59–77 Firing line, 13.6 et al.
Part-time employee 2 17–49 Midway to target, (1987)
57.4;
Target, 90.5
1987 Covered outdoor range 15 NR NR 5.6 (pre- GA, 68.4 3.8–298.6 Tripathi
exposure) PBZ, 128.5 34.7–314.3 et al.
10.7 (day 2) (1989)
14.9 (day 5)
8.7 (day 69)
153
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154
Table 72 (contd)
Country Year(s) of study Settings/task No. of Age Job history Blood lead (µg/dL) Lead in air (µg/m3) Reference
09/08/2006
subjects (years) (years)
and sex AMa Range AMa Range
USA 1987 Indoor range with training 17 M + W 24–40 Trainees Valway

(contd) Jan.-Feb. 3 Feb.–28 April 6.45 < 5–23.1 1483–1860 304–2688 et al.
March (early) 51.4 31.2–73.3 2906–3226 994–5589 (1989)
553–2567c
11:26
March (late) 44.6 27.1–62.3 1231
May 39.8 23.1–51.2

Lead bullet 1410
Nylon-coated 78.3
Page 154
Copper jacketed 43.1
1987 Covered outdoor range 6 NR NR Before GA, 9.53 5.50–14.56 Tripathi
using copper-jacketed shooting, PBZ, 5.88 0.42–7.66 et al.
bullets 6.0 ± 1.7 (1990)
After
shooting,
6.5 ± 1.5
1987–88 Uncovered outdoor range NR NR Goldberg
June 1987 7 28–66 – et al.
July 1987 – 460–510 (3-h TWA) (1991)
Dec. 1987 7 25–70 –
April 1988 5 – 100–170 (3-h TWA)
June 1988 28–38 –
1987 Covered outdoor range NR Instructors Tripathi
Non-jacketed bullets 2 14.2–24.2d 10–27 67.1–211.1 36.7–431.5 et al.
Jacketed bullets 2 13.1–22.1 5.4–8.7 (1991)
1991–93 University rifle range College Recreational Prince &
Old ventilation system students shooters 11.8–16.4 5–21 176 24–239 Horstman
New ventilation system 13.2–13.6 8–23 129 67–211 (1993)
GA, general area; NR, not reported; PBZ, personal breathing zone; TWA, time-weighted average
a
b
Median value
c
New ventilation system installed
d
Range of means of three sampling dates
P 141-164 DEF.qxp
Table 73. Lead concentrations in blood of occupationally exposed subjects: miscellaneous
09/08/2006
Country Year(s) Job/task Sex No. of Age Years of Smoking Blood lead (µg/dL) Lead in air (µg/m3) Reference
of survey subjects (years) employ- status
mean ment AMa Range/SD AMa Range
and/or
range
11:26
Mechanics/garage
Denmark 1976 Automobile mechanics M 138 16–68 NR NR 40.0–44.8 50–125 3.19 0.2–9.2 Clausen & Rastogi (1977)
Ghana NR Automobile mechanics M 25 17–46 2–29 NR 27.8 0–60 NR Ankrah et al. (1996)
Page 155
NR Gasoline retailers M+W 40 20–46 0.1–17 NR 8.6 0–20 NR Ankrah et al. (1996)
India NR Automobile mechanics M 22 20–45 NR NR NR 24.3–62.4 NR Kumar & Krishnaswamy
(1995b)
NR Workers in petrol NR 22 10–15 >1 NR 39.3 ± 3.7 NR National Institute of
storage bunkers Nutrition (1995–96)
Jordan NR Mechanics M 62 NR NR NR 8.1b NR Hunaiti et al. (1995)
Thailand NR Repair mechanics M 23 NR NR Non- 8.4 3.9–14.5 NR Suwansaksri et al. (2002)
smokers
United Arab 1999 Heavy industry, garage M 100 34.8 8.3 NR 77.5 NR Bener et al. (2001)
Emirates and painting
Others
Finland 1973–82 Lead-exposed industry M 18 329 33.8 at 0–46 NR 29.0–14.5b,c NR Anttila et al. (1995)
workers entry
b,c
W 2412 37.5 at 0–46 NR 20.7–6.2
entry
India NR Silver jewellery makers M 9 25–65 5–40 NR 120.8 40.0–210.0 NR Behari et al. (1983)
1981 Papier-mâché workers M+W 30 10–70 NR NR 69.1 23–122 NR Kaul & Kaul (1986)
NR Silver jewellery workers M 7 25–70 12–50 NR 113.4 71.0–208.1 NR Kachru et al. (1989)
NR Printing press M 23 20–50 15–30 NR 41.9 ± 7.0 NR Kumar & Krishnaswamy
(1995a)
NR Papier-mâché workers M 70 17–40 3–26 NR 68.1 18.2–272.7 NR Wahid et al. (1997)
India NR Printing press M+W 25 18–35 3–5 NR 88 ± 30 NR Agarwal et al. (2002)
6–9 59 ± 22
9–15 36 ± 11
Italy NR Electrician M 1 20 6 NR 66 NR Franco et al. (1994)
155
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156
Table 73 (contd)
09/08/2006
and/or
range
Japan NR Ceramic painting M 58 54.7 1–53 Refrain 16.5b 3.5–69.5 NR Ishida et al. (1996)
W 70 52.2 3–47 for 12 h 11.1b 2.1–31.5 NR
11:26
NR Pigment (lead stearate) M 49 48.0 14.5 NR 18.0 7–36 NR Yokoyama et al. (1997)

production (27–63) (2–34)
NR Crystal toy production W 123 27.3 7.2 NR 55.4 22.5–99.4 920 390–1910 Nomiyama et al. (2002)
(17–44) (0.8–25)
Page 156
NR Cloisonné production NR NR NR NR NR Arai et al. (1994)
Glazing 49 47.8 11.3–111
Silver-plating 16 11.3 3.2–19.5
Jordan NR Metal casting M 26 NR NR NR 41.6b NR Hunaiti et al. (1995)
Car painting M 85 NR NR NR 10.7b NR
Malaysia NR Shipyard M > 18 < 1–17 Included NR Mokhtar et al. (2002)
Painting 15 16 8–38
Fabrication 19 12 3–28
Nigeria NR Lead-exposed industry NR 86 24.8 NR Included 56.3 26–97 NR Adeniyi & Anetor
(SW) workers 40% > 60 (1999)
Pakistan 1994–95 Tannery M 46 19–59 >1 Included 60.6 ± 3.8 NR Khan et al. (1995)
Philippines NR Refrigerator production M 59 25.7 4.7 NR 21.5b 8–38 NR Makino et al. (1994)
W 6 21.8 2.1 NR 17.5b 14–22 NR
Republic of 1999 Various (24 facilities) M+W 723 39.4 6.3 61% of 31.7 5.4–85.7 NR Todd et al. (2001a)d
Korea smokers
1997–99 Various (26 facilities) 639 M, 803 40.4 8.2 57% of 32.0 ± 15 NR Schwartz et al. (2001)d
164 W smokers
Singapore 1989 Plastics NR 104 NR NR NR 26.0 ± 15.8 NR Chia et al. (1993)
Metal products NR 70 NR NR NR 32.5 ± 13.1 NR
Solder production NR 22 NR NR NR 25.0 ± 9.1 NR
Paint production NR 88 NR NR NR 14.3 ± 6.8 NR
Telecommunication NR 218 NR NR NR 15.4 ± 5.7 NR
Ship building NR 92 NR NR NR 17.9 ± 6.7 NR
NR PVC compounding M 61 38.3 ca. 10 NR 23.9 6.7–75.8 35.7 ND–277 Ho et al. (1998)
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09/08/2006
11:26
Table 73 (contd)
Page 157
and/or
range
United NR Painters and decorators M 3 22–51 NR NR [85.5] 84.2–87.1 NR Gordon et al. (2002)
Kingdom
Uruguay [1993] Lead–acid battery and M 31 NR 9.5 12 49.7 24.4–87.0 NR 3–1300 Pereira et al. (1996)
lead scrap smeltere
USA 1984 Electronics industry M+W 151 > 11 NR NR 8.0 1–22 NR 61–7000 Kaye et al. (1987)
1994 Custodial activities NR 13 40 8.5 NR 5.4 2.8–10 0.1–3.9 ND–36 Tharr (1997)
1994–96 Labourers M 60 38 15.5 NR 11.2 1.2–50 NR Reynolds et al. (1999)
Painters M 83 39 16.4 NR 7.0 1.5–26.3 NR
NR, not reported; M, men; W, women; ND, not detectable

a
b
Geometric mean
c
Decrease over the 10-year study period
d
[The participants in the study by Todd et al. (2001a) most likely are included in the study by Schwartz et al. (2001).]
e
Two storage battery plants (n = 16, n = 8); lead scrap smelter (n = 6); one self–employed storage battery reconditioner
157
P 141-164 DEF.qxp
158
Table 74. NIOSH Health Hazard Evaluation reports with air and/or blood lead concentration data, 1978–2003
09/08/2006
Industry Year(s) Blood lead (µg/dL) Air lead (µg/m3) Reference
of study
No. of AMa Range No. of Type of AMa Range
workers samples sampling
tested taken
11:26
Bridge, tunnel and elevated highway 1980 Landrigan et al. (1980)
construction: deleading

Grit blasting 13 33 25–47 4 PBZ 305 10–1090
Scraping and priming 19 61 30–96 3 PBZ 391 24–1017
Page 158
Bridge, tunnel and elevated highway 1990–91 Sussell et al. (1992a)
construction: repainting
Inside containment 8 PBZ [13 671] 3620–29 400
Inside containment, inside hood 6 PBZ [78] 9–194
Outside containment 16 PBZ 5–6720b
GA ND–8170
Heavy abrasive blasting Spring 1991 23 5–61
Moderate abrasive blasting Summer 1991 12 13–43
Bridge, tunnel and elevated highway 1993 22 7.2 2.2–16.5 Ewers et al. (1995)
construction: renovation
Blaster/painter 24 PBZ 250 3–1800
Apprentice 11 PBZ 110 1–680
Recycling equipment operator 2 PBZ 140 100–180
Commercial testing laboratories 1986 10 > 17–192 Gunter et al. (1986)
Lakewood, CO 8 PBZ + GA 321 90–800
Sparks, NV 14 PBZ + GA 114 4–490
Copper foundries 1991 10 21 10–39 7 PBZ NA ND–172 Clark et al. (1992)
Electric services 1991 43 20 < 5–43 18 PBZ [9.4] 1.2–55 Venable et al. (1993)
Electric services 1995 NR NR 43 PBZ NA ND–181 Mattorano (1996)
Electronic components 1993 NR NR 3 PBZ NA ND–36 Blade & Bresler (1994)
Electronic components 1993 7 19 9–27 NR Guo et al. (1994)
Fabricated metal products 1987 3 31 25–43 4 PBZ [803] 7.3–1900 Lee (1987)
Fabricated plate work 1991 9 32 10–51 NR Hales et al. (1991)
P 141-164 DEF.qxp
Table 74 (contd)
09/08/2006
of study
tested taken
11:26
Fabricated plate work 1991 17 34 11–77 McCammon et al.
Lead burners 3 PBZ [254] 215–307 (1991)
Tinning 3 PBZ-LT [354] 282–390
Grinding 4 PBZ-LT [32] 0–46
Page 159
General contractors, industrial buildings and 1989 16 [10] 3–21 Stephenson & Burt
warehouses (1992)
Oxyacetylene cutting 6 PBZ 522 160–1300
Other renovation tasks 9 PBZ NA ND–2
General contractors, single family houses: 1989–91 95 ND–27 1402 PBZ 3.1c < 0.4–916 Sussell et al. (1992b)
lead paint abatement 1233 GA 2.0c < 0.4–1296
General contractors, single family houses 1993 53 5.2c NR–17.5 13 PBZ 3.2c 0.05–12 Sussell et al. (1997)
37 GA 0.6c 0.1–25
77 Task-based PBZ 0.2–9.1c 0.03–120
General contractors, single family houses 1998 NR NR Sussell & Piacitelli
Manual paint scraping 5 PBZ-ST NA < 1–250 (1999)
Power paint removal 6 PBZ-ST [5054] 54–27 000
General contractors, single family houses 1996–98 40 16 1–65 20 PBZ 29c 1.5–1100 Sussell et al. (2000)
152 Task-based PBZ 1.3–150 0.17–2000
General contractors, single family houses 1999 NR NR 128 PBZ 22c ND–660 Sussell & Piacitelli
130 GA 1.5c ND–37 (2001)
General contractors, single family houses 1999 NR NR 15 PBZ 100c 39–526 Sussell et al. (2002)
5 GA [2.2] 0.29–6.1
79 Task-based PBZ 71c 1.4–2240
Glass products, stained glass art studio 1986 3 [19] 7–33 7 PBZ + GA 80 10–260 Gunter & Thoburn
(1986a)
Glass products, made from purchased glass 1991 18 12 < 10–24 4 PBZ 18 7–35 Lee (1991)
Glass products, made from purchased glass 1993 2 2 1.8–2.1 17 PBZ NA ND–80 Donovan (1994)
13 GA NA ND–0.7
Gold ores (fire assay) 1987 NR NR 4 PBZ 76 36–117 Daniels (1988)
159
5 GA 48 14–100
P 141-164 DEF.qxp
160
Table 74 (contd)

of study
09/08/2006
tested taken
Gold ores (fire assay) 1989 Daniels & Hales

Assay laboratory personnel 6 42 23–65 1 PBZ 850d (1989)
11:26
Non-assay laboratory personnel 5 18 7–36 6 GA NA ND–110

Gold ores (fire assay) 1989 6 42 23–65 1 PBZ 170 Daniels et al. (1989)
4 GA NA ND–170
Page 160
Gold ores (fire assay) 1989 6 37 13–55 3 PBZ [112] 15–200 Lee et al. (1990a)
5 GA [26] 6–61
Gold ores, assay laboratory 1989 2 < 40 1 PBZ 10d Hales & Gunter (1990)
3 GA 10–30d
Grey iron foundries 1985 NR NR 4 PBZ NA ND–70 Gunter (1985)
3 GA 53 30–70
Heavy construction 1991 6 Sussell et al. (1992c)
Before blasting 34 before 15–44 6 PBZ ND–35
During blasting, outside job 6–43 5 PBZ ND–47
containment 28 during 4 GA 620–3000
During blasting, inside job PBZ
containment, inside helmet 16–25
Industrial inorganic chemicals 1980–81 79 35 NR–69 75 PBZ 13–79 0–359 Landrigan et al. (1982)
Industrial valves 1989 25 15 < 20–33 2 PBZ [91] 87–94 Kinnes & Hammel
4 GA [69.5] 32–120 (1990)
Inorganic pigments 1981 228 8–32 Slovin & Albrecht
Bagging zinc oxide 11 [33] 9–96 (1982)
Mixing zinc oxide 5 [34] 16–68
Mixing barium ores 7 [9] ND–15
Mixing of inert clays 4 [2] ND–8
Motor vehicle parts and accessories 1981 66 23 11–52 25 PBZ 37 7–113 Zey & Cone (1982)
Motor vehicle parts and accessories 1983 14 31 ± 12 7 PBZ [49] 25–104 Ruhe & Thoburn
(1984)
Motor vehicle parts and accessories 1986 5 < 29–60 4 PBZ [172] 40–380 Gunter & Thoburn
4 GA [68] 20–190 (1986b)
P 141-164 DEF.qxp
Table 74 (contd)
09/08/2006
of study
tested taken
11:26
Motor vehicle parts and accessories 1988 8 [29] 8–44 10 PBZ + GA 160 10–290 Gunter & Hammel
(1989)
Motor vehicle parts and accessories 1987–88 28 [9] < 5–43 NR NR Driscoll & Elliott
(1990)
Page 161
Motor vehicle parts and accessories 1989 2 [34] 30–37 2 PBZ [70] 60–80 Gunter & Hales
(1990a)
Motor vehicle parts and accessories 1989 7 32 17–64 Gunter & Hales
Radiator mechanics 5 38 23–64 4 PBZ [28] 10–50 (1990b)
Delivery employees 2 17.5 17–18 2 GA [55] 20–90
Motor vehicle parts and accessories 1989 Gunter & Hales
Radiator mechanics 4 [30] 13–41 4 PBZ [98] 30–220 (1990c)
Delivery employees 2 [18] 14–21
Motor vehicle parts and accessories: 1989 4 [21] 11–33 3 PBZ [43] 20–60 Gunter & Hales
mechanics and delivery employees 1 GA 90 (1990d)
Nitrogenous fertilizers 1991 13 4–13 9 PBZ ND–7 Decker & Galson
7 GA ND–12 (1991)
Non-ferrous foundries (castings) 1988 18 [34] 4–67 6 PBZ [294] 38–520 Montopoli et al. (1989)
Police protection (indoor firing range) 1982 NR NR 5 PBZ [1130]d 940–1300d Bicknell (1982)
6 GA [1120]d 750–1520d
Police protection (indoor firing range) 1987–88 NR NR 4 PBZ 142–2073 102–3361 Reh & Klein (1990)
8-h TWA 13–194d
Police protection (indoor firing range) 1991 NR NR 5 PBZ 14 7–23 McManus (1991)
8-h TWA < 3d
Police protection (indoor firing range) 1991 NR NR Echt et al. (1992)
Student 26 PBZ 26–32d 1–116d
Range officer 14 PBZ 16–18d 0.15–53d
General area 13 GA 0.15–2450
Police protection (indoor firing range) 1991 NR NR 10 5.4d 1–16d Lee & McCammon
(1992)
161
P 141-164 DEF.qxp
162
Table 74 (contd)

of study
09/08/2006
tested taken
Police protection (outdoor firing range) 1991 NR NR 16 PBZ ND–8d NR Rinehart & Almaguer
(1992)
11:26
Police protection (indoor firing range) 1992 NR NR 3 PBZ 6d 5–7d Cook et al. (1993)
13 GA NA ND–845

Police protection (in- and outdoor firing 1989–91 Barsan & Miller
ranges) (1996)
Page 162
Instructor 7–14 8–15 < 4–27 NR PBZ 12.4 ND–52
Technician 5 10–16 6–28 12 PBZ 0.6 ND–2.7
Gunsmith 5–11 11–12 < 4–24 18 PBZ 0.6 ND–4.5
Custodian 6 <4 3 PBZ NA ND–220
Police protection (indoor firing range) 1997–98 NR NR Harney & Barsan
1997 (during shooting) 9 PBZ + GA 144d 4–190d (1999)
1998 (during shooting) 20 PBZ + GAe 230d ND–640d
8 PBZ + GAf 433d 100–960d
Pressed and blown glass and glassware 1984 12 20 2–36 4 PBZ 52 30–60 Gunter & Thoburn
2 GA 75 70–80 (1985)
Pressed and blown glass and glassware 1986 9 13 4–33 16 PBZ + GA NA ND–80 Gunter (1987)
Pressed and blown glass and glassware 1997 NR NR 7 GA [17] 1.6–51 Hall et al. (1998)
Primary smelting and refining of copper 1984 49 11 0–24 15 PBZ + GA NA < 3–60 Gunter & Seligman
(1984)
Secondary smelting and refining of non- 1989 12 29 5–63 5 PBZ NA < 2–40 Gunter & Daniels
ferrous metals 2 GA NA < 2–50 (1990)
Primary and secondary smelting and 1981 3 32 26–37 6 PBZ 123 5–295 Apol (1981)
refining of non-ferrous metals 9 GA NA ND–1334
Refuse systems 1990–91 NR NR 6 PBZ NA ND–30d Mouradian & Kinnes
4 GA NA ND–30d (1991)
Scrap and waste materials 1987 6 4–33 10 PBZ + GA NA ND–2.3 Hills & Savery (1988)
Scrap and waste materials 1991 15 66 9–86 NR Gittleman et al.
(1991)
Scrap and waste materials 1993 16 20 4–40 NR Malkin (1993)
P 141-164 DEF.qxp
Table 74 (contd)
09/08/2006
of study
tested taken

Ship breaking, ship repair, dismantling 1998 NR NR McGlothlin et al.
11:26
ships (1999)
Inside a ship 4 PBZ [355] 253–435
Process area 5 PBZ [189] 41–399
Inside barge tank 5 PBZ [198] 79–356
Page 163
Under a barge 4 PBZ NA < 0.6–2.5
Shipbuilding and repairing 1985 10 38 25–53 7 PBZ 257 108–500 Landrigan & Straub
(1985)
Shipbuilding and repairing 1994 NR NR 14 PBZ-ST [133] 3–900 Sylvain (1996)
Shipbuilding and repairing 1997 67 4.4 0–18 347 PBZ 32 0–1071 Kiefer et al. (1998)
Special trade contractors: cleaning of lead- 1992 NR NR 36 PBZ-ST 66 5–360 Sussell et al. (1993)
based paint 5 PBZ 30 6–73
18 GA-ST 44 4–180
Steel works, blast furnaces (including coke 1984 26 33 27 PBZ 40 < 3–190 Gunter & Thoburn
ovens) (1984)
Steel works, blast furnaces (including coke 1980–82 79 8–15 1–33 42 NR NR NR–79 Hollett & Moody
ovens) (1984)
Steel works, blast furnaces (including coke 1989 22 18 20 PBZ 12 < 3–31 Lee et al. (1990b)
ovens)
Steel works, blast furnaces (including coke 1990 NR NR 12 [PBZ] [16] 1.3–44.2 Tubbs et al. (1992)
ovens)
Storage batteries 1983–84 317 10–39 3–58 675 PBZ 30 1–1600 Singal et al. (1985)
Storage batteries 1987 Matte & Burr (1989a)
Location 1 27 31–47 NR–64 26 PBZ [652] 40–5300
2 GA [7] 4–10
Location 2 12 65c NR–89 10 PBZ [860] 50–3400
Location 3 6 28–> 60 3 PBZ [100] 30–190
3 GA [57] 10–100
Storage batteries 1987 23 64c 28–86 7 PBZ 21c NR–66 Matte & Burr (1989b)
Storage batteries 1991 43 41 12–66 12 PBZ [276] 9–846 Clark et al. (1991)
163
2 GA [59] 10–107
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164
09/08/2006
Table 74 (contd)

of study
11:26
tested taken

Storage batteries 1994–95 111 30–43 Esswein et al. (1996)
Page 164
Pasting operation 19 PBZ 291 68–495
4 GA 1–165
First assembly 12 PBZ 108 15–418
5 GA 13–39
Pouching 7 PBZ 50 31–77
8 GA 11–51
Grid casting 3 PBZ 12–43
6 GA 16–141
Tanks, fabricated plate work 1991 22 23 4–38 22 PBZ [352] 23–1970 McCammon et al.
(1992)
Valves and pipe fittings 1981 2 < 30 2 PBZ [45] 10–80 Ruhe (1982a)
Valves and pipe fittings 1981 2 < 30 2 PBZ [839] 321–1356 Ruhe (1982b)
AM, arithmetic mean; PBZ, personal breathing zone; NA, not applicable; ND, not detected; NIOSH, National Institute for Occupational Safety and Health (USA); NR, not reported; GA,
general area; ST, short-term; TWA, time-weighted average; LT, long-term; [....] calculated by the Working Group
a
Unless otherwise stated
b
Highest value probably a contaminated sample; next highest values at 202 µg/m3
c
Geometric mean
d
8-h TWA value calculated from a short-term sample, assuming no other lead exposure during the day than during sampling
e
Measured with 37-mm cassette
f
Measured with Institute of Occupational Medicine (IOM) sampler
P 165-200 DEF.qxp 09/08/2006 11:30 Page 165
(a) Lead–acid battery workers

Blood lead concentrations have been studied most extensively in workers in lead
storage-battery factories (Table 66). Occupational exposure to lead may occur during the
production of lead–acid batteries, when grids are manufactured either by melting lead
blocks and pouring molten lead into molds or by feeding rolled sheets of lead through
punch presses. In addition, a lead oxide paste is applied into grid spaces. Average lead
concentrations in blood were generally in the range 20–45 µg/dL. Particularly high con-
centrations (> 65 µg/dL) were detected in workers engaged in grid casting in a study in
Iraq (Mehdi et al., 2000), in workers at several workstations in a study from Israel
(Richter et al., 1979) and in a study in Taiwan, China (Wang et al., 2002b).
(b) Workers in mining and primary smelting

The most commonly mined lead ore is galena (87% lead by weight), followed by
anglesite (68%) and cerussite (78%). Workers in lead smelter and refinery operations
such as sintering, roasting, smelting and drossing are exposed to lead sulfide, sulfates and
oxides. Miners of copper and zinc also are exposed to lead.
Relatively high blood lead concentrations (> 60 µg/dL) have been recorded in such
workers, in particular in two studies in Nigeria (Adeniyi & Anetor, 1999) and in Uruguay
(Pereira et al., 1996) (Table 67).
(c) Workers in secondary smelting

Battery-recycling workers in secondary smelters are exposed to lead as they convert
used batteries and other leaded materials to lead of varying purity. From Table 68, it
appears that the mean blood lead concentrations reported for workers in secondary lead
smelters were higher than for workers in other occupations (see Tables 66–73). Of the
different job categories within secondary smelting, the highest mean blood lead concen-
trations (87 µg/dL) were observed in workers in charge of furnace operation (Wang et al.,
1998). In some individual workers, blood lead concentrations in excess of 150 µg/dL were
measured (Makino et al. 1994).
(d) Workers in leaded-glass manufacturing

Leaded glassware is made by combining lead oxide compounds with molten quartz.
This process results in lead fumes and dusts, and glass-blowing is an additional activity
that involves potential contact with lead. Production of leaded glass has been associated
with high lead exposure, with mean blood lead concentrations in excess of 50 µg/dL in
all studies (Table 69).
(e) Workers in welding/soldering

Typical solders contain 60% lead and the high temperatures involved in flame solder
work volatilize some of this lead. Workers repairing vehicle radiators are exposed to lead
P 165-200 DEF.qxp 09/08/2006 11:30 Page 166
dusts during radiator cleaning in addition to lead fumes during flame soldering (Tharr,
1993).
Surveys on welding work in radiator-repair workers (Table 70) generally showed
mean blood lead concentrations in the range of 10–35 µg/dL. A study of 56 mechanics
working in radiator shops in the Boston area, USA, reported that 80% had blood lead con-
centrations greater than 30 µg/dL and 16 had concentrations > 50 µg/dL (Goldman et al.,
1987). Relatively high blood lead concentrations (up to 47 µg/dL) were also reported
among women engaged in soldering in an electronics plant (Makino et al., 1994).
Welders are exposed to lead in the welding fumes generated by gas metal arc welding
of carbon steel. However, in one study, lead concentrations in the welding fumes were
found to range from 1.0 to 17.6 µg/m3, well below the established permissible exposure
limit for the workplace (Larson et al., 1989).
(f) Professional drivers and traffic controllers

Professional drivers (e.g. taxi and bus drivers) and traffic policemen are exposed to
lead in ambient air from vehicle exhausts (Table 71). The blood lead concentrations
reported are distributed over a wide range, from 10 µg/dL (Zhou et al., 2001) to > 60 µg/dL
(Ahmed et al., 1987), probably as a result of variations in traffic intensity and use of leaded
gasoline.
(g) Firing-range instructors

Lead exposure associated with the discharge of firearms at indoor firing ranges began
to be monitored in the early 1970s. Over the last 20 years, numerous exposure assess-
ments have been performed at both indoor and outdoor firing ranges (Table 72). Several
sources of airborne lead have been identified: fragmentation of bullets during firing; the
explosive vaporization of the primer, which can contain both lead styphnate and lead
peroxide; and inadequate ventilation of the range (Landrigan et al., 1975b; Fischbein
et al., 1979; Muskett & Caswell, 1980; Dams et al., 1988). Instructors are generally
exposed to the highest concentrations of airborne lead and tend to have the highest blood
lead concentrations due to their regular duties, which include supervising the range,
cleaning and test-firing weapons, and preparing training ammunition from commercially
purchased components. A positive correlation was reported between exposure of firearms
instructors to elemental lead at covered outdoor firing ranges and increased blood lead
concentrations (Tripathi et al., 1991). Concentrations of airborne lead can be significantly
reduced (97–99%) by using a lead-free primer and bullets jacketed with nylon, brass or
copper (Valway et al., 1989; Robbins et al., 1990; Tripathi et al., 1990, 1991; Goldberg
et al., 1991; Löfstedt et al., 1999; Bonanno et al., 2002).
(h) Other occupational exposures

Several studies have found elevated blood lead concentrations in other occupational
settings, such as in employees working in automobile garages. Mean blood lead
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concentrations in children working in petrol storage bunkers in India for more than one
year were almost double (39.3 ± 3.7 µg/dL) those of age-matched unexposed children
(23.1 ± 0.5 µg/dL) (National Institute of Nutrition, 1995–1996).
Silver jewellery workers are exposed to high concentrations of lead and may have
blood lead concentrations > 200 µg/dL (Behari et al., 1983; Kachru et al., 1989).
People working in arts and crafts may be exposed to lead in paints, ceramic glazes
and lead solder used in sculpture and stained glass (Hart, 1987; Fischbein et al., 1992).
Newspaper printing has been associated with lead exposure (Agarwal et al., 2002). In
one study, more than 3/4 of the monocasters showed some clinical symptoms of lead
poisoning (Kumar & Krishnaswamy, 1995a). Where computerized printing techniques
have replaced the traditional printing techniques, however, lead exposure is no longer a
significant concern in this profession.
1.5 Analysis
Analysis of lead and lead compounds in various matrices has been reviewed (Fitch,
1998).
1.5.1 Environmental samples

Although lead occurs in the environment in the form of a range of inorganic or
organic compounds, it is always measured and expressed as elemental lead. Determi-
nation of lead in environmental samples requires sample collection and sample prepa-
ration, often by wet or dry ashing or acid digestion to solubilize lead in aqueous solution
before analysis. Care must be taken during sampling and sample preparation to avoid
contamination or loss of lead (WHO, 1995).
The techniques most commonly used for the analysis of particulate lead and inorganic
lead compounds in air, water, dust, sediments, soil and foodstuffs include flame atomic
absorption spectrometry (AAS), graphite furnace–atomic absorption spectrometry (GF–
AAS), inductively coupled plasma–mass spectrometry (ICP–MS), inductively coupled
plasma–atomic emission spectrometry (ICP–AES), anode-stripping voltametry (ASV) and
X-ray fluorescence (XRF).
Organic lead species such as tetramethyl lead and tetraethyl lead can be trapped cryo-
genically or by liquid or solid sorbents. Gas chromatography (GC) coupled with GF–AAS
or photoionization detection (PID) can be used to differentiate between organic lead
species (Birch et al., 1980; De Jonghe et al., 1981; Chakraborti et al., 1984; NIOSH,
1994a; ATDSR, 1999).
Selected methods used for the analysis of lead in various matrices are presented in
Table 75.
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Table 75. Selected methods for analysis of lead in various matrices
Matrix Methoda Detection limit Method number Referenceb
Air Flame AAS 2.6 µg/sample Method 7082 NIOSH (1994b)

GF–AAS 0.02 µg/sample Method 7105 NIOSH (1994a)
ICP–AES 0.062 µg/sample Method 7300 NIOSH (2003a)
ASV 0.09 µg/sample Method 7701 NIOSH (2003b)
XRF 6 µg/sample Method 7702 NIOSH (1998)
AAS or 0.01 µg/mL (qual.) Method ID-121 OSHA (2002a)
AES 0.05 µg/mL (anal.)
ICP–AES 2.1 µg/sample (qual.) Method ID-125G OSHA (2002b)
ICP–AES 0.071 µg/mL (qual.) Method ID-206 OSHA (2002c)
0.237 µg/mL (quant.)
XRF 22 µg/sample Method OSS-1 OSHA (2003)
Air (TEL) c
GC–PID 0.1 µg/sample Method 2533 NIOSH (1994c)
Air (TML) d
GC–PID 0.4 µg/sample Method 2534 NIOSH (1994d)
Water ICP–AES 42 µg/L Method D1976 ASTM (2002)
ICP–MS 0.08 µg/L Method D5673 ASTM (2003a)
XRF 1 µg/L Method D6502 ASTM (2003b)
AAS 100 µg/L Method 239.1 US EPA (1978)
Ambient water ICP–MS 0.0081 µg/L Method 1640 US EPA (1997a)
GF–AAS 0.036 µg/L Method 1637 US EPA (1996c)
ICP–MS 0.015 µg/L Method 1638 US EPA (1996d)
Marine water GF–AAS 2.4 µg/L Method 200.12 US EPA (1997b)
ICP–MS 0.074 µg/L Method 200.10 US EPA (1997c)
Soil, wastes and AAS 100 µg/L Method 7420 US EPA (1986b)
groundwater GF–AAS 1 µg/L Method 7421 US EPA (1986c)
Marine sediment GF–AAS 0.2 µg/g Method 140.0 NOAA (1998a)
and soils ICP–MS 0.15 µg/g Method 172.0 NOAA (1998b)
XRF 0.2 µg/g Method 160.0 NOAA (1998c)
Aqueous and solid ICP–AES 28 µg/L Method 6010C US EPA (2000)
matrices
Food GF–AAS 0.1 mg/kg Method 999.10 AOAC (2000a)
AAS NR Method 972.25 AOAC (2000b)
Evaporated milk ASV 5 ng/sample Method 979.17 AOAC (2000c)
and fruit juice
Sugars and syrups GF–AAS 3.3 µg/kg Method 997.15 AOAC (2000d)
Edible oils and fats GF–AAS 18 µg/kg Method 994.02 AOAC (1994)
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Table 75 (contd)
Matrix Methoda Detection limit Method number Referenceb
Ceramic foodware AAS NR Method 4-1 US FDA (2000a)

GF–AAS NR Method 4-2 US FDA (2000b)
Paint, soil, dust, ICP–AES Variable, NR Method E1613 ASTM (1999)
air AAS Variable, NR
GF–AAS Variable, NR
NR, not reported

a
AAS, atomic absorption spectrometry; ASV, anode-stripping voltametry; GD–PD, gas chromato-
graphy–photoionisation detector; GF–AAS, graphite furnace atomic absorption spectrometry; ICP–
AES, inductively-coupled plasma atomic emission spectrometry; ICP–MS, inductively-coupled
plasma mass spectrometry; XRF, X-ray fluorescence
b
NIOSH, National Institute for Occupational Safety and Health; OSHA, Occupational Safety and
Health Administration; ASTM, American Society for Testing and Materials; AOAC, Association of
Official Analytical Chemists; US EPA, US Environmental Protection Agency; NOAA, National
Oceanic and Atmospheric Administration; US FDA, US Food and Drug Administration
c
TEL, tetraethyl lead
d
TML, tetramethyl lead
Use of lead isotope ratios in source attribution and apportionment

Stable lead isotopes have been used to identify the source(s) of lead in environmental
and biological samples (source attribution and apportionment). Lead isotopes vary over
geological time because they are the end-product of radioactive decay of uranium and
thorium. Thus, lead deposits of different geological age have different lead isotope ratios;
e.g. the major Broken Hill lead–zinc–silver mine deposit in Australia formed approxi-
mately 1700–1800 million years ago has an isotope ratio expressed as the 206Pb/204Pb ratio
of 16.0. In contrast, geologically younger deposits formed approximately 400–500 million
years ago, found on the same continent and in various places around the world, have a
206Pb/204Pb ratio of about 18.0 (Gulson, 1986, 1996a).
Techniques have been developed to measure lead isotope ratios in environmental and
biological samples. Lead is extracted from samples by acid digestion and separated from
potentially interfering cations (iron, zinc) by anion-exchange chromatography. Lead iso-
topes are measured as ratios (e.g. 208Pb/206Pb, 207Pb/206Pb, 206Pb/204Pb) by solid source
thermal ionization–mass spectrometry or ICP–MS (Franklin et al., 1997; Eades et al.,
2002).
Lead in the environment and in humans (and animals) is often a mixture of lead origi-
nally derived from different mines, and it is possible to estimate the relative contribution
of the different sources. Where there are two major sources, the estimation is straight-
forward. For example, if the lead present in a blood sample with a 206Pb/204Pb ratio of 17.5
comes from two major sources, the skeleton (ratio of 17.0) and diet (ratio of 18.0), there is
an equal contribution to blood from both sources. For three or more sources, the attribution
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becomes more complex and requires application of specialized computational procedures

(Franklin et al., 1997).
1.5.2 Biological indicators of lead contamination in soil and water

Lead affects many physiological parameters in plants (Singh et al., 1997). Plants and
some fungi synthesize cysteine-rich low-molecular-weight peptides called phytochelatins
(class III metallothioneins) in response to heavy metal stress (Grill et al., 1985). Phyto-
chelatins have the general structure (γ-Glu-Cys)n-Gly (n = 2–11); the majority of legumes
(of the order Fabales), on the other hand, synthesize homophytochelatins in which the
carboxy-terminal glycine is replaced by β-alanine (Grill et al., 1986). For example, when
exposed to lead, roots of Vicia faba synthesize phytochelatins, Phaseolus vulgaris
synthesizes homophytochelatins, and both phytochelatins and homophytochelatins are
induced in Pisum sativum (Piechalak et al., 2002). These peptides are involved in accu-
mulation, detoxification and metabolism of metal ions including lead (Grill et al., 1985;
Mehra & Tripathi, 2000). Phytochelatins detoxify metal by thiolate coordination (Grill
et al., 1987). They are synthesized enzymatically from glutathione or its precursor by the
enzyme γ-glutamyl cysteine dipeptidyl transpeptidase, also called phytochelatin synthase;
the enzyme is present constitutively in cells and is activated by heavy metal ions (Grill
et al., 1989). Thus, phytochelatins are synthesized enzymatically in response to exposure
to many metals including lead (Grill et al., 1987; Scarano & Morelli, 2002).
Phytochelatins can be detected by high-performance liquid chromatography (HPLC)
(Grill et al., 1991) and thus have the potential to be used as plant biomarkers of heavy
metal contamination of soil and water. There are ample laboratory and field data indi-
cating that phytochelatins are biological indicators of exposure to metals, including lead
(Ahner et al., 1994; Pawlik-Skowronska, 2001; Pawlik-Skowronska et al., 2002).
1.5.3 Biological samples

Lead distribution between blood, soft tissue and hard tissue is complex (see Section 4.1
for details). The time required for equilibration of lead between tissues is dependent upon
the type of tissue and varies from hours to decades. In addition, equilibration between
tissues is subject to a variety of physiological states that affect bone metabolism. Hence,
exposure to lead can be estimated by the analysis of various human tissues, either directly
for lead or indirectly for biomarkers of exposure to lead. The tissues include blood, plasma,
urine, saliva, bone, teeth, nails and hair. The following section summarizes the methods
used for the direct determination of lead in tissues and the indirect determination of
exposure to lead using biomarkers. Methods that measure distribution of lead throughout
the body are discussed in Section 4.1.
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(a) Analysis in hard tissues

(i) Bone
Exposure to lead over time results in the progressive accumulation of lead, predomi-
nantly (> 95% of total lead burden) in bones (Barry, 1975). Hence, the analysis of lead in
bones is a suitable approach to determine exposure to lead during the lifetime of an indi-
vidual. Using GF–AAS to measure lead concentrations in bone tissue from individuals
from prehistoric and modern times, it has been estimated that the body burden of lead in
humans in the late 20th century is more than twice that of the late Roman times (Drasch,
1982). Since GF–AAS analysis cannot be performed on human bone in vivo, various XRF
methods have come into use as a direct measure of lead in bone (Todd & Chettle, 1994).
XRF is based on the property of lead to emit X-rays when it is exposed to photons of an
appropriate energy; the fluorescence from lead accumulated in bone provides a low-risk,
non-invasive measure of total lead content. In the 1990s, XRF analysis was limited to
research institutions and was deemed unlikely to become a useful screening tool for expo-
sure to lead (Todd & Chettle, 1994). Intrinsic variability in the instruments used, variability
of lead deposition between the two main compartments of bone (cortical versus trabe-
cular), patients’ bone density and the use of a minimal detectable limit all increase the com-
plexity of data analysis in epidemiological studies (Hu et al., 1995; Kim et al., 1995b).
Efforts continue to improve understanding of the variables that affect the XRF signal
(Hoppin et al., 2000; Todd et al., 2000a, 2001b) and to use XRF for meaningful epidemio-
logical analysis (Hoppin et al., 1997; Roy et al., 1997; Markowitz & Shen, 2001). XRF has
been used successfully to study the factors involved in the mobilization of lead from bone
(Schwartz et al., 1999; Oliveira et al., 2002). With the understanding that bone lead is pro-
bably the best overall indication of lifetime exposure to lead (Börjesson et al., 1997; Hu,
H. et al., 1998), it is reasonable to consider application of XRF to the analysis of the contri-
bution of exposure to lead to the development of cancer.
(ii) Teeth
The dentin of shed deciduous teeth (also known as baby teeth) is a suitable source for
analysis of prior and current lead exposure in children during their teeth-shedding years
(Gulson, 1996a; Kim et al., 1996a) but this method suffers from the limited availability
of samples. It has been estimated that deciduous tooth lead (measured in ppm or µg/g)
correlates with about half the value of blood lead (measured in µg/dL), but that this
correlation does not hold for the permanent, adult teeth (Rabinowitz, 1995). The studies
to determine lead concentrations in teeth each include a specific method for digestion of
the tooth, followed by analysis of lead by ASV, ICP–MS or AAS.
(iii) Hair and nails
Available data on analysis of lead in hair can be divided into three groups. The first
group of studies describe hair analysis as a general toxicological screen for heavy metals.
In this case, the primary concerns are sample preparation, i.e. washing, with the intent to
remove surface contamination. A recent study of six commercial laboratories advertising
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multimineral hair analysis showed high variability between laboratories, thus giving cause
for concern about the validity of these results (Seidel et al., 2001). The second use of hair
lead analysis has been for patients suspected of having chronic, mild or subacute lead
poisoning (Kopito et al., 1967). The third documented use is in epidemiologial studies
(Tuthill, 1996). However, an analysis of the distribution of heavy metals in tissues of 150
corpses concluded that hair was not an appropriate tissue for monitoring exposure to lead
(Drasch et al., 1997). In general, the available data do not support the use of hair as a
resource for analysis of exposure to lead.
The use of nails seems attractive as a non-invasive approach to determining exposure
to lead. However, lead concentrations in nails is not a reliable indicator of exposure to lead
(Gulson, 1996b).
(b) Analysis in soft tissues and body fluids

(i) Blood
The benchmark for analysis of lead exposure is the determination of blood lead
concentrations by AAS. Using this method, lead is typically reported in µg/dL, which can
be converted to concentration in µM (µmol/L) by dividing the value reported in µg/dL by
20.7.
Analytical methods have changed over time because health-based standards and
guidelines have changed. For example, the intervention level set by CDC in the USA has
dropped from 60 µg/dL to 35 µg/dL in 1975, to 25 µg/dL in 1985, and to 10 µg/dL in 1991
(CDC, 1991).
Analytical methods used to determine lead concentrations in whole blood detect both
the lead associated with proteins in the erythrocytes and that in the plasma (Everson &
Patterson, 1980; Cake et al., 1996; Manton et al., 2001). The relationship between lead in
whole blood, in erythrocytes and in plasma is discussed in detail in Section 4.2.1. Lead in
blood is in equilibrium between the plasma and the erythrocytes. Since the plasma fraction
has a greater bioavailability than the lead pool in the red blood cells and is in equilibrium
with extravascular compartments, the lead content of plasma should be considered to be a
better estimate of the internal dose than the concentration of the metal in whole blood
(Cavalleri & Minoia, 1987; Schütz et al., 1996). To obtain an accurate quantification of low
concentrations of lead in plasma, Everson and Patterson (1980) introduced the technique
of isotope-dilution mass spectrometry and concluded that prior studies had grossly over-
estimated the amount of lead in the plasma compartment of blood. ICP–MS was also
shown to be sensitive enough for monitoring low concentrations of plasma lead, and
plasma samples could be frozen prior to analysis without any alteration in the analytical
results (Schütz et al., 1996).
As whole blood became the material of choice for the determination of lead exposure,
various atomic absorption techniques were introduced and evaluated for this purpose. By
the late 1980s, the popularity of GF–AAS stemmed from its high sensitivity (0.05 µg/dL)
and small sample-size requirements (< 50 µL); however, there was considerable variation
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in the different sample preparation techniques and an optimal method could not be defined
(Subramanian, 1989). By 2001, commercial laboratories used predominantly electro-
thermal atomization atomic absorption spectroscopy, ASV and ICP–MS (Parsons et al.,
2001). A comparison of GF–AAS and ICP–MS performed in a Japanese laboratory showed
the two methods to be equally sensitive but the latter took only one fifth of the time.
ICP–MS results tended to be 10–20% lower than those obtained by atomic absorption
analysis (Zhang et al., 1997c).
For screening purposes, the simplest blood lead test is conducted with a capillary
blood sample obtained from a finger-prick. Concerns over false positives due to skin
surface contamination with environmental lead dust have resulted in the recommendation
that a positive capillary blood lead test result be followed by a test on venous blood.
Following the recommendation of universal screening of children in the USA (CDC,
1991; American Academy of Pediatrics, 1998), an analysis of the cost effectiveness of
strategies for screening of lead poisoning concluded that a screening method based on
direct analysis of venous blood was the least expensive (Kemper et al., 1998). Other
studies have shown an excellent correlation between the results of capillary blood lead
analysis and venous blood lead analysis, thus advocating the former as an appropriate
method for screening purposes (Parsons et al., 1997).
Regardless of the method chosen, blood lead analysis is the only diagnostic for lead
exposure for which there exists an international standard for quality control (ACGIH,
2001; WHO, 1996; see Section 1.6) and an external quality assurance programme (Schaller
et al., 2002).
(ii) Urine
Urine is a readily available biological sample for the direct analysis of lead content
by AAS. This method has been used successfully to monitor relative levels of exposure
in workers with chronic occupational exposure to lead (Vural & Duydu, 1995; Jin et al.,
2000). One study argued against the routine use of urine as a surrogate for blood lead
analysis because of the poor correlation between the two values on an individual person
basis, particularly at blood lead concentrations < 10 µg/dL (Gulson et al., 1998b).
(iii) Placenta
During development of biomonitoring methods, non-invasive tissue acquisitions are
frequently sought and analysis of lead in placental tissue has been suggested and evaluated
as a possible indicator of exposure. However, studies show that placenta is not a suitable
tissue for exposure monitoring, because lead is not distributed uniformly throughout the
tissue (Lagerkvist et al., 1996a).
(iv) Sweat and saliva
Lead concentrations in sweat and saliva have been evaluated and are not recommended
for exposure monitoring because of the poor correlation with blood lead concentrations
(Lilley et al., 1988; Koh et al., 2003).
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1.5.4 Biomarkers of lead exposure

(a) Biomarkers related to haeme biosynthesis
It has long been known that lead interferes with haeme biosynthesis (Chisolm, 1964;
Lamola & Yamane, 1974). Aberrations in the haeme biosynthetic pathway form the basis
for many of the methods used for biomonitoring of human exposure to lead.
Haeme is the tetrapyrrole cofactor component of haemoglobin responsible for direct
binding of oxygen. An early step in the pathway of haeme biosynthesis is the synthesis of
the monopyrrole porphobilinogen from δ-aminolevulinic acid (ALA). This reaction is
catalysed by the enzyme porphobilinogen synthase (PBGS) also commonly known as δ-
aminolevulinate dehydratase (ALAD). Despite the fact that the recommended IUPAC
name is PBGS, ALAD is still commonly used in the clinical literature. The inhibition of
PBGS by lead manifests itself in a decrease in measurable PBGS activity in blood and an
accumulation of the substrate ALA in serum, plasma and urine.
Porphobilinogen continues on the pathway to haeme through the action of additional
enzymes to form the immediate haeme precursor protoporphyrin IX, also called free proto-
porphyrin, erythrocyte protoporphyrin (EP) or, erroneously, zinc protoporphyrin (ZPP).
Insertion of iron into protoporphyrin IX is then catalysed by the enzyme ferrochelatase to
form haeme. When iron is lacking, ferrochelatase inserts zinc into protoporphyrin IX to
form ZPP. There is a tight and not fully understood interrelationship between haeme
biosynthesis and iron homeostasis such that exposure to lead is seen to increase ZPP
(Labbé et al., 1999). Hence, between 1974 and 1991, measurement of ZPP was the method
recommended by CDC in the USA for screening for exposure to lead (CDC, 1975).
One limitation in using these biomarkers is that they can be perturbed by conditions
other than exposure to lead. The correlation between these biological parameters and a
direct measure of blood lead may include significant scatter (Oishi et al., 1996b) and may
not be useful at low blood lead concentrations (Schuhmacher et al., 1997). There are both
genetic and environmental factors other than lead that can effect ALA in urine or serum,
PBGS activity in blood and ZPP in blood (Moore et al., 1971; Labbé et al., 1999; Kelada
et al., 2001).
(i) PBGS (ALAD) activity in blood
PBGS activity in blood is the most sensitive biomarker of lead exposure (Toffaletti &
Savory, 1976; Schuhmacher et al., 1997). Human PBGS is a zinc metalloenzyme in which
the catalytically essential zinc is in an unusually cysteine-rich environment that has a very
high affinity for lead relative to the corresponding region in other zinc metalloenzymes.
Although the activity of PBGS in blood shows normal biological variation, a comparison
of the enzyme activity before and after various treatments that displace the inhibiting lead
enables the determination of lead-specific enzyme inhibition (Granick et al., 1973; Chiba,
1976; Sakai et al., 1980). The PBGS assay is either a colorimetric determination of the
complex of porphobilinogen with Ehrlich’s reagent (Berlin & Schaller, 1974) or a quanti-
fication by HPLC of the porphobilinogen formed (Crowne et al., 1981). Despite the sensi-
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tivity of PBGS to inhibition by lead, determination of the enzyme activity is not widely
used in the clinical setting to determine lead exposure. In part, this is due to the fact that
the inhibition of PBGS activity is only observed at low levels of exposure and reaches a
plateau above 50–80 µg/dL lead (Toffaletti & Savory, 1976). The PBGS assay also gained
a reputation for being complex and irreproducible. This may be due to the fact that the
enzyme recovers its activity during the assay procedure, thus producing a variation in
specific activity with incubation time (Jaffe et al., 1991, 2001). Because assays used clini-
cally require the analysis of a stopped mixture, a fixed incubation time is used, which may
vary between laboratories.
PBGS in erythrocytes has a very high affinity for lead (Simons, 1995) and an indivi-
dual’s allotype for the gene encoding PBGS appears to affect the percentage of lead bound
by the protein (Bergdahl et al., 1997). Hence, a variety of epidemiological studies have
suggested that an individual’s PBGS allotype affects the pharmacodynamics of lead
poisoning (Sakai, 2000). PBGS activity in blood can also be affected by the condition of
hereditary tyrosinaemia, wherein an aberrant metabolic by-product of tyrosine acts as a
PBGS inhibitor (Lindblad et al., 1977) (see Section 4.2).
(ii) ALA in urine and plasma
Haeme precursors in urine were among the first biomarkers used for detection of lead
intoxication. The synthesis of ALA is the primary regulatory target for haeme bio-
synthesis: haeme down-regulates ALA synthase expression directly by decreasing the
half-life of ALA synthase mRNA (Hamilton et al., 1991). Thus, inhibition of PBGS by
lead, which results in a decrease in haeme biosynthesis, will upregulate ALA biosynthesis,
and increase ALA concentrations in plasma and urine. An increased concentration of
plasma ALA in turn increases the affinity of zinc for PBGS, thus giving some reprieve
from the lead-induced inhibition of PBGS (Jaffe et al., 2001). This interrelationship
between lead, PBGS and ALA contributes to the complex clinical correlations between
lead exposure and accumulation of ALA in urine. ALA concentrations in plasma increase
slowly below blood lead concentrations of 40 µg/dL and rapidly above this concentration.
Significant correlations are found in both the slow and rapid phases (Sakai, 2000). Plasma
ALA (expressed in µg/L) is generally found to be about five times the value measured in
urine (expressed in mg/g creatinine) (Oishi et al., 1996b).
Analysis of ALA in biological fluids is generally performed either by colorimetry
after chemical transformation of ALA into an Ehrlich’s-positive pyrrole (Tomokuni &
Ichiba, 1988a) or by fluorometry after HPLC analysis using pre- or post-column deriva-
tization (Tabuchi et al., 1989; Okayama et al., 1990; Oishi et al., 1996b).
(iii) Zinc protoporphyrin in blood
In the 1970s, the CDC approved ZPP as the preferred biomarker for the monitoring
of lead exposure in the USA. The approved assay used spectrofluorometry, could readily
be carried out on-site and was widely adopted for screening childhood lead poisoning.
However, ZPP is generally not elevated in individuals with blood lead concentrations
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below 30 µg/dL (Schuhmacher et al., 1997). With the current cut-off for lead poisoning
in young children being 10 µg/dL blood lead (CDC, 1991), ZPP has generally fallen out
of favour in the USA.
Although ZPP is not expected to be elevated in individuals casually exposed to low
concentrations of lead, it continues to be a valuable tool for monitoring occupational
exposure (Lee, 1999; Sakai, 2000) and bioresponse to lead (Lauwerys et al., 1995). Also,
elevation of ZPP is a diagnostic commonly used to detect iron deficiency (Labbé et al.,
1999).
(b) Biomarkers related to pyrimidine nucleotide metabolism

Although it has received far less attention than PBGS, the enzyme pyrimidine 5′-nucleo-
tidase (P5′N), also known as uridine monophosphate hydrolase-1, is extremely sensitive to
inhibition by lead (Paglia & Valentine, 1975). As with other biomarkers, both genetic and
environmental factors can affect P5′N activity (Rees et al., 2003). By analogy to the clinical
manifestations of hereditary deficiencies in P5′N, the majority of the haematological
features of lead poisoning can be explained by inhibition of P5′N (Rees et al., 2003).
Although not yet widely used, recent studies suggest that P5′N activity in blood is an
excellent biomarker for exposure to lead, although less sensitive than PBGS (Kim et al.,
1995a). The three-dimensional structure of human P5′N is not yet known, but the docu-
mented sequence contains a cysteine-rich cluster (Amici et al., 2000), which may be the site
of lead binding.
P5′N catalyses the hydrolysis of pyrimidine nucleoside 5′-monophosphate to pyrimi-
dine nucleoside and monophosphate (inorganic phosphate). Assays for P5′N activity fall
into two categories. Colorimetric assays are based on the determination of inorganic
phosphate. These tests require pre-assay sample dialysis and/or lengthy assay times and
are not used for monitoring purposes (Sakai, 2000). Assays based on determining pyrimi-
dine nucleosides have been introduced, using either a radiolabelled nucleoside (Torrance
et al., 1985) or HPLC analysis of the liberated pyrimidine nucleoside (Sakai & Ushio,
1986). A significant correlation was reported between log P5′N and blood lead concen-
trations over the range of 3–80 µg/dL (Sakai, 2000). Measurements of concentrations of
pyrimidine nucleosides in blood have been suggested as alternative biomarkers for expo-
sure to lead (Sakai, 2000).
(c) Other biomarkers

Nicotinamide adenine dinucleotide synthetase activity in blood has been suggested as
a biomarker for exposure to lead, but this method has received little attention apart from
the work of Sakai (2000). Recent investigations into the biological chemistry of lead
suggest that lead can bind to a variety of proteins that normally bind zinc and/or calcium,
most notably transcription factors. These observations may lead to the future development
of alternative biomarkers for measurement of exposure to lead (Godwin, 2001).
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1.6 Regulations and guidelines

Regulations and guidelines for lead concentrations in blood in non-occupationally
exposed populations, ambient air and drinking-water have been defined in many countries
and are given in Table 76.
Regulations and guidelines for occupational exposure to lead and lead compounds
from several countries are presented in Table 77; maximum permissible lead concen-
trations in blood of occupationally exposed populations for several countries are presented
in Table 78.
Many countries have set guidelines for lead in drinking water, gasoline, paint, foods,
industrial emissions, and other products such as ceramic-ware and solder (Consumer
Product Safety Commission, 1977; US DHUD, 1987; OECD, 1993; US Food and Drug
Administration, 1994).
JECFA first evaluated lead in 1972, when a provisional tolerable weekly intake of
50 µg/kg bw was established. The value was reconfirmed by the Committee in 1978. In
1986, a provisional tolerable weekly intake of 25 µg/kg bw was established for infants
and children for lead from all sources. This value was extended to the general population
in 1993 and was reconfirmed in 1999 (WHO, 2000b; JECFA, 2002).
Analytical methods have changed over time (see Section 1.5) because health-based
standards and guidelines have changed. A historical review of the CDC guidelines in the
USA shows a progressive downward trend in tiered screening and intervention guidelines
for childhood lead poisoning. Maximum permissible blood lead concentrations in the USA
dropped from 35 µg/dL in 1975 to 25 µg/dL in 1985 to 10 µg/dL in 1991 (CDC, 1975,
1985, 1991). Efforts to maintain this downward trend (Bernard, 2003) may continue to
drive development of increasingly sensitive analytical techniques.
The Commission of European Communities reports the following binding biological
limit values [maximum allowed lead levels] and health surveillance measures for lead and
its ionic compounds: (1) biological monitoring must include measuring the blood lead
concentration using absorption spectrometry or a method giving equivalent results. The
binding biological limit is 70 µg lead/dL blood; (2) medical surveillance is carried out
when exposure occurs to a concentration of lead in air that is greater than 0.075 mg/m3,
calculated as a time-weighted average over 40 h per week, or when a blood lead concen-
tration greater than 40 µg/dL is measured in individual workers; (3) practical guidelines
for biological monitoring must include recommendations of biomarkers (e.g. ALA, ZPP,
ALAD) and biological monitoring strategies (European Commission, 1998).
The American Conference of Governmental Industrial Hygienists (ACGIH)
recommends a biological exposure index (BEI) for lead in blood of 30 µg/dL. Women of
childbearing age whose blood lead exceeds 10 µg/dL are at risk of delivering a child with a
blood lead concentration above the current CDC guideline of 10 µg/dL (ACGIH World-
wide, 2003). The ACGIH considers analysis of lead in blood by GF–AAS, ASV or ICP–MS
to be sufficiently sensitive for concentrations below the recommended BEI (ACGIH, 2001).
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Table 76. International standards and guidelines for lead concen-

trations in blood, air and drinking-water
Country Blood (µg/dL) Air (µg/m3) Drinking-water (µg/L)
Australia 10 (GP) 0.5 (federal) 10–50 (OECD)

1.5 (states)
Austria 50
Belgium 2.0
Brazil 10
Canada 10 (GP) 1.0–2.5 (BC) 10
2.0 (QC)
5.0 (MB, NF, ON)
Czech Republic 0.5 50
Denmark 0.4 50
European Union 40a 1.0; 40a 50
Finland 0.5 10
France 2.0 50
Germany 15 (GP) 2.0 40
10 (C+W)
India 100
Ireland 2.0 50
Israel 0.5 50
Italy 2.0 50
Japan 10
Mexico 50
Namibia 1.5 50
Netherlands 0.5 50
New Zealand 1.0 50 (OECD)
Norway 20
Republic of Korea 1.5 50
Russian Federation 0.3
Serbia and Montenegro 100–200 50
South Africa 4.0 50–100
Spain 2.0 50
Sweden 10 (OECD)
Switzerland 10–15 (F) 1.0 50 (OECD)
10 (C)
United Kingdom 2.0 50
USA 10 (GP) 1.5 15 (OECD)a
WHO 20 (GP) 10
From OECD (1993); International Lead and Zinc Study Group (2000); Ministry of
Health, Brazil (2004); IOMC (1998)
BC, British Columbia; C, children; F, fetus; GP, general population; MB, Manitoba; NF,
Newfoundland; ON, Ontario; QC, Quebec; W, women of childbearing age
a
Action level
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Table 77. Regulations and guidelines for occupational exposure to

lead and lead compounds
Country/Agency Exposure limit (mg/m3) Interpretationa
Lead
Argentina 0.15 TWA
Australia 0.15 (dust and fume) TWA
Austria 0.10 (men); 0.02 (women) TWA
Belgium 0.15 TWA
Canada 0.15
Alberta 0.05 (dust and fume) TWA
Ontario 0.05 (excluding tetraethyllead) TWA
Quebec 0.15 TWA
China 0.3 (fume) Ceiling
0.05 (dust) Ceiling
Czech Republic 0.05 TWA
Denmark 0.10 TWA
European Union 0.15 TWA
0.10 (dust and fumes < 10 µm) TWA
Finland 0.10 TWA
France 0.15 TWA
Germany 0.1 (excluding lead arsenate and TWA (MAK)
8 lead chromate) STEL (MAK)
India 0.15–0.20 TWA
Ireland 0.15 (excluding tetraethyl lead) TWA
Israel 0.10 (men); 0.05 (women of fertile age) TWA
Italy 0.15 TWA
Japan 0.10 (excluding alkyls) TWA
Malaysia 0.05 TWA
Mexico 0.15 (dust and fume) TWA
Morocco 0.20 TWA
Namibia 0.15 TWA
Netherlands 0.15 (dust and fume) TWA
New Zealand 0.1 (dust and fume) TWA
Norway 0.05 TWA
Peru 0.20 TWA
Poland 0.05 TWA
Republic of Korea 0.05 TWA
Serbia and Montenegro 0.05 TWA
South Africa 0.15 TWA
Spain 0.15 TWA
Sweden 0.10 (total) TWA
0.05 (respirable) TWA
Thailand 0.20 TWA
United Kingdom 0.15 Ceiling (OES)
0.15 TWA
USA
ACGIH 0.05 TWA (TLV)
NIOSH < 0.1 TWA (REL)
OSHA 0.05 TWA (PEL)
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Table 77 (contd)
Lead acetate
Norway 0.05 (dust and fume) TWA
Lead hydrogen arsenate (PbHAsO4)
Canada
Alberta (as As) 0.15 TWA
0.45 STEL
China, Hong Kong SAR 1.5 TWA
(as PbHAsO4)
Mexico (as Pb) 0.15 TWA
0.45 STEL
USA (as As)
NIOSH 0.002 Ceiling (REL)
OSHA 0.01 TWA (PEL)
Lead arsenate (as Pb3(AsO4)2)
Australia 0.15 TWA
Belgium 0.15 TWA
Canada
Quebec 0.15 TWA
China 0.05 (dust) TWA
New Zealand 0.15 TWA
USA
NIOSH (as As) 0.002 Ceiling (REL)
OSHA (as As) 0.01 TWA (PEL)
Lead chromate (as Cr)
Australia 0.05 TWA
Belgium 0.012 TWA
Canada
Alberta 0.05 TWA
0.15 STEL
Ontario 0.012 TWA
Quebec 0.012 TWA
China 0.012 TWA
Finland 0.05 TWA
Germany 0.1 (dusts and aerosols) TWA (TRK)
0.05 (NOSb) TWA (TRK)
Malaysia 0.012 TWA
Netherlands 0.025 STEL
New Zealand 0.05 TWA
Norway 0.02 TWA
Spain 0.012 TWA
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Table 77 (contd)
USA
OSHA 0.001 TWA (REL)
Lead chromate (as Pb)
Belgium 0.05 TWA
Canada
British Columbia 0.012 TWA
Malaysia 0.05 TWA
Spain 0.05 TWA
USA
Lead (II) oxide
Finland 0.1 TWA
Lead phosphate (as Pb)
Norway 0.05 TWA
USA
OSHA 0.05 TWA (PEL)
Lead sulfide
China 5 Ceiling
Tetraethyl lead (as Pb)
Australia 0.1 (skc) TWA
Belgium 0.1 (sk) TWA
Canada
Alberta 0.1 (sk) TWA
0.3 (sk) STEL
British Columbia 0.075 (sk) TWA
Quebec 0.05 (sk) TWA
China 0.02 (sk) TWA
0.06 (sk) STEL
China, Hong Kong SAR 0.1 (sk) TWA
Finland 0.075 (sk) TWA
0.23 (sk) STEL
Germany 0.05 (sk) TWA (MAK)
0.1 (sk) STEL (MAK)
Ireland 0.1 (sk) TWA
Japan 0.075 (sk) TWA
Malaysia 0.1 (sk) TWA
Mexico 0.1 (sk) TWA
0.3 (sk) STEL
Netherlands 0.05 (sk) TWA
New Zealand 0.1 (sk) TWA
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Table 77 (contd)
Norway 0.01 (sk) TWA

Poland 0.05 (sk) TWA
0.1 (sk) STEL
Spain 0.1 (sk) TWA
Sweden 0.05 (sk) TWA
0.2 (sk) STEL
USA
ACGIH 0.1 (sk) TWA (TLV)
NIOSH 0.075 (sk) TWA (REL)
OSHA 0.075 (sk) TWA (PEL)
Tetramethyl lead (as Pb)
Australia 0.15 (sk) TWA
Belgium 0.15 (sk) TWA
Canada
Alberta 0.15 (sk) TWA
0.5 (sk) STEL
Quebec 0.05 (sk) TWA
China, Hong Kong SAR 0.15 (sk) TWA
Finland 0.075 (sk) TWA
0.23 (sk) STEL
Germany 0.05 (sk) TWA (MAK)
0.1 (sk) STEL (MAK)
Ireland 0.15 (sk) TWA
Malaysia 0.15 TWA
Mexico 0.15 (sk) TWA
0.5 (sk) STEL
Netherlands 0.05 (sk) TWA
New Zealand 0.15 (sk) TWA
Norway 0.01 (sk) TWA
Spain 0.15 (sk) TWA
Sweden 0.05 (sk) TWA
0.2 (sk) STEL
USA
ACGIH 0.15 (sk) TWA (TLV)
NIOSH 0.075 (sk) TWA (REL)
OSHA 0.075 (sk) TWA (PEL)
From ACGIH Worldwide (2003); European Commission (1998); International Lead

and Zinc Study Group (2000)
ACGIH, American Conference of Governmental Industrial Hygienists; NIOSH,
National Institute for Occupational Safety and Health; OSHA, Occupational Safety
and Health Administration
a
TWA, time-weighted average; STEL, short-term exposure limit; MAK, maximum
allowable concentration; OES, occupational exposure standard; TLV, threshold limit
value; REL, recommended exposure limit; PEL, permissible exposure limit; TRK,
technical exposure limit
b
NOS, not otherwise specified
c
sk, skin notation
Note: For the most current information on these regulations and guidelines, the reader
is referred to the relevant regulatory authority.
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Table 78. Regulations and guidelines for maximum lead concentrations in

blood in occupational settings
Country MLLa (µg/dL) Country MLLa (µg/dL)
Australia 50 (men, and women not Japan 60

capable of reproduction);
20 (women of reproductive
capacity)
Austria 45–70 Luxembourg 70
Belgium 80 Morocco 60
Canada 50–80 Namibia 80
Czech Republic 50 Netherlands 70
Denmark 50–70 Norway 2 µmol/L [41.4 µg/dL]
(men)
Finland 50 Peru 60 (men)
France 70–80 South Africa 80 (men);
40 (women)
Germany 70 (men); Spain 70
30 (women under 45 years)
Greece 70–80 Sweden 50 (men and women over
50 years);
30 (women under 50 years)
Ireland 70 Thailand 80
Israel 60 (men); United Kingdom 60 (men);
30 (women of reproductive 50 (adolescents under
age) 18 years);
30 (women of reproductive
capacity)
Italy 70 USA 50

a
MLL, maximum lead level
2. Studies of Cancer in Humans
2.1 Studies among specific occupational groups

A summary of the epidemiological findings reviewed in this section is presented in
Tables 79 (cohort studies) and 80 (population-based case–control studies).
2.1.1 Battery manufacturing workers

Fanning (1988) obtained the cause-specific distribution of 867 deaths (in-service
deaths and pensioner deaths) occurring in male workers in the United Kingdom who were
considered to have been exposed to high or moderate levels of lead whilst engaged in lead
battery manufacturing. This distribution was compared with that of 1206 male decedants
P 165-200 DEF.qxp 09/08/2006 11:30 Page 184
who had been employed either by other companies that participated in the same pension
scheme, or in the lead battery factory but with little potential for exposure to lead. The
deaths occurred during the period 1926–85 and the study incorporated data reported
previously by Dingwall-Fordyce and Lane (1963) and Malcolm and Barnett (1982). After
adjusting for age by 10-year-age groups, there were no significantly elevated proportional
mortality odds ratios for cancer risk in relation to lead-exposed employment. A slightly
elevated risk was suggested for cancer of the stomach.
There has been an extended study of lead battery and lead smelter workers in the USA
(Cooper & Gaffey 1975; Cooper, 1976; Kang et al., 1980; Cooper, 1981; Cooper et al.,
1985; Cooper, 1988; Wong & Harris, 2000). The original cohort (Cooper & Gaffey, 1975)
included 4680 battery workers from 10 plants; the most recent update (Wong & Harris,
2000) relates to a reduced cohort of 4518 battery workers. All subjects manufacturing lead
batteries were employed for at least 1 year during the period 1947–70, and the most recent
follow-up has been analysed for the period 1947–95. There were 195 battery workers
(4.3%) who were untraced on the closing date of the study. Exposure data were limited
but blood lead and urinary lead measurements were taken, mainly after 1960. For lead
battery workers with three or more blood lead measurements, the mean blood concen-
tration was 63 µg/dL and, for those with 10 or more urinary lead measurements, the mean
urine concentration was 130 µg/dL. Standardized mortality ratios (SMRs) were calculated
after comparison with the mortality rates for the male population in the USA, and were
adjusted for age and calendar period. For all cancers, the overall SMR was 104.7 (624
observed; 95% CI, 96.6–113.2). There was a significantly elevated SMR for stomach
cancer (152.8; 45 observed; 95% CI, 111.5–204.5) and non-significantly elevated SMR
for lung cancer (113.9; 210 observed; 95% CI, 99.0–130.4). [The Working Group noted
that it is possible that ethnicity, dietary habits, prevalence of Helicobacter pylori infection,
or socioeconomic status played a role in the excess of stomach cancer.] Findings were also
reported for a nested case–control study of stomach cancer, using 30 cases and 120 age-
matched controls from a single large battery factory. [The authors noted a large percentage
of Italian- and Irish-born members of the study population (23% of the controls in the
case–control study). Being Italian- or Irish-born was associated with a twofold excess risk
for stomach cancer in this population. The Working Group considered that confounding
by place of birth (which is not available for the whole cohort) would probably account for
only a proportion of the 1.5-fold excess reported for this whole population.] The nested
case–control study did not show any significantly increased odds ratios or trends for any
of the three exposure indices that were investigated (duration of employment at the plant,
duration of employment in intermediate or high exposure areas of the plant, [crudely]
weighted cumulative exposure). [The Working Group noted that the analysis by duration
of employment needs to be interpreted with caution, especially among workforces that
were subject to active surveillance and potential removal from work.]
P 165-200 DEF.qxp
Table 79. Cohort studies on cancer risk among occupational groups exposed to lead or lead compounds
09/08/2006
Reference, Cohort description Assessment or indices Cancer site Exposure No of cases Relative 95% CI Comments
location of exposure to lead categories or deaths risks
Battery factory workers

Fanning Proportional mortality Low (1206 men) and PMOR Limited to deaths in service and
11:30
(1988) study; 2073 men; high (867 men) All sites 195 0.95 in pensioners
United frequency-matched by exposure groups; Stomach 31 1.34
Kingdom 10-year age group; defined by job– Lung 76 0.93
1926–85 exposure matrix
Page 185
Wong & 4518 men employed for No exposure data; bio- SMR Expected deaths based on male
Harris (2000) > 1 year during 1947–70; monitoring 1947–72: All sites 624 104.7 96.6–113.2 mortality rates in the USA
USA follow-up 1947–95; vital urinary lead (2275 Lung 210 113.9 99.0–130.4
status, 95.7%; cause of men), blood lead (1863 Stomach 45 152.8 111.5–204.5
death, 99.5% (death men); mean blood lead, Large intestine 59 103.9 79.1–134.0
certificates) 63 µg/dL (n = 1083); Rectum 14 84.7 46.3–142.1
mean urinary lead, Central nervous 10 75.0 35.9–137–9
130 µg/dL (n = 1550) system
Kidney 7 50.2 20.2–103.4
Lead smelter workers
Wong & 2300 men employed in No exposure data; bio- SMR Expected deaths based on male
Harris (2000) 6 smelters for > 1 year monitoring 1947–72: All sites 273 101.8 90.1–114.6 mortality rates in the USA
USA during 1947–70; follow-up, urinary lead (2275 Lung 107 121.5 99.5–146.8
1947–95; vital status, 93%; men), blood lead (1863 Stomach 15 133.4 74.6–220.0
cause of death, 99.5% men); mean blood lead, Large intestine 22 89.0 55.8–134.7
(death certificates) 80 µg/dL (n = 254); Rectum 8 123.0 53.1–242.4
mean urinary lead, Central nervous 5 74.5 24.2–173.9
173 µg/dL (n = 1550) system
Kidney 6 92.3 33.9–201.0
McMichael & 241 male smelter workers Lead poisoning; mean All sites Lead- SPMR Reference group: 695 deceased
Johnson employed 1–30 years, urinary lead, 173 µg/L poisoned 9 0.59 smelter workers without lead
(1982) diagnosed with lead workers poisoning
Australia poisoning 1928–59, versus other
followed through 1977; workers
140 deaths identified
through death registration
records
185
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186
Table 79 (contd)
09/08/2006
Steenland 1990 male smelter workers Mean blood lead, SMR Further follow–up of the cohort
et al. (1992) employed > 1 year, at least 56 µg/dL (n = 173); All sites Total cohort 192 98 84–112 from Selevan et al. (1985)
USA 1 day at the smelter 1940– mean air lead, Stomach 15 136 75–224 National standard population
11:30
65; subcohort with heavier 3.1 mg/m3 (n = 203); Lung 72 118 92–148 No information on smoking
exposure (n = 1436); vital mean air arsenic, Colorectal 9 48 22–90

status ≤ 31 December 1979 14 µg/m3 (n = 89) Kidney 9 193 88–367
(95.5%); cause of death,
All sites Subcohort 137 98 81–115
Page 186
96.3%
Stomach with high 10 128 61–234
Lung lead exposure 49 111 82–147
Colorectal 8 59 25–116
Kidney 8 239 103–471
Gerhardsson Retrospective cohort study; SMR National and regional standards
et al. (1986) 3832 men followed up All sites Cohort 270 [114] [100–128] specified for cause, sex, age and
Sweden 1950–81; subcohort of Subcohort 23 [87] [55–131] calendar period
437 workers employed High mean 15 [100] [56–165] Potential exposure to arsenic,
≥ 3 years in high-exposure blood lead chromium and nickel; cohort
jobs, 1950–74; based on High peak 16 [89] [51–145] update in Lundström et al.
median value of the blood lead (1997)
cumulative blood lead
Lung Cohort 90 [218] [176–269]
concentration, subcohort
Subcohort 8 [160] [69–315]
further divided into high
High mean 5 [172] [56–402]
(n = 218) and low (n = 219)
blood lead
mean blood lead (high
High peak 4 [118] [32–301]
> 478.5 µg × yr/dL > low)
blood lead
and high (n = 288) and low
(n = 149) peak blood lead Stomach Cohort 46 [143] [105–191]
(high > 70 µg × yr/dL Subcohort 3 [94] [19–274]
> low) High mean 2 [111] [13–401]
blood lead
High peak 3 [136] [28–399]
blood lead
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09/08/2006
Table 79 (contd)
11:30
Lundström 3979 workers employed Blood lead level 1950– Total cohort (n = 3979) SMR Follow-up of the cohort reported
et al. (1997) > 1 year 1928–79; sub- 69 (AES) and 1967–87 All sites 126 120 100–150 in Gerhardsson et al. (1986)
Sweden cohort of 1992 workers (AAS); mean blood Lung 39 280 200–380 Regional standard specified for
from the lead department lead in 1950, 62 µg/dL; cause, sex, age and calendar
Highest (n = 1026)
Page 187
and other lead-exposed mean blood lead in period
All sites exposed 55 120 90–150
departments; mortality, 1987, 33 µg/dL Multifactorial exposure pattern
Lung subgroup 19 280 180–450
1955–87; vital status, and lack of smoking data
88.5%; incidence, 1958–87 ≥ 15 year latency Total cohort (n = 2353) SIR
period All sites 172 110 90–120
Lung 42 290 210–400
Central nervous 6 110 40–230
system
Gastrointestinal 31 80 50–110
Kidney 7 90 40–190
Highest (n = 650)
All sites exposed 83 110 90–140
Lung subgroup 23 340 220–520
system
Kidney 3 90 20–250
Lead-only workers or Total cohort (n = 1005) SIR
lead department and All sites 44 90 60–120
other lead-exposed Lung 14 310 170–520
departments; ≥ 15 year Central nervous 2 110 10–380
latency period system
Kidney 0 0 0–150
187
P 165-200 DEF.qxp
188
Table 79 (contd)
09/08/2006
Lundström Highest (n = 163)
et al. (1997) All sites exposed 19 120 80–200
(contd) Lung subgroup 7 510 200–1050
system
11:30
Kidney 0 0 0–500

Englyst et al. 3979 workers in primary Estimate based on Subcohort (1) SIR Workers also exposed to arsenic.
(2001) copper and lead smelter; cumulative blood lead All sites 47 100 70–130 County population reference.
Page 188
Sweden follow-up 1958–87; index Lung 10 240 120–450 Same cohort as Lundström et al.
subcohort (1): 710 workers Kidney 2 90 10–320 (1997)
employed in lead Central nervous 1 60 2–360
department and other system
departments during work Subcohort (2)
history; subcohort (2): All sites 18 120 70–190
383 workers from Lung 5 360 120–830
subcohort (1) only Kidney 1 130 3–720
employed in lead Central nervous 0 0 0–650
department system
Gerhardsson 664 male secondary lead Blood lead sampling SIR Regional standard population:
et al. (1995) smelter workers employed starting 1969 All sites 40 127 91–174 county rates specified for cause,
Sweden > 3 months 1942–87; Stomach 3 188 39–550 sex, age and calendar year
incidence 1969–89 Kidney 1 80 2–448
system
Respiratory tract 6 132 49–288
Cocco et al. 1345 male lead and zinc Mean blood lead 1988– Total cohort SMR Regional reference (Sardinia)
(1996) smelting plant workers 92 and mean Lung 2 [57] [7–206] Possible healthy worker effect;
Italy followed 1973–91; environmental lead Stomach 2 [333] [40–1204] smoking not addressed
subcohort of 1222 with in 1991
Standardized mortality
known G6PDa phenotype
rates × 10–4
All sites Wild-type 10 25.7 21.4–30.6
G6PD
G6PD- 2 17.9 4.3–30.1
deficient
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09/08/2006
Table 79 (contd)
Cocco et al. 1388 male lead smelter Lead concentration SMR National reference (1950–92)

(1997) workers, employed > 1 year in respirable dust; All sites 149 69 58–81
11:30
Italy 1932–71; mortality follow- air arsenic below Lung 35 62 43–86
up 1950–92; vital status level of detection Stomach 17 49 29–79
97.3%; cause of death 96% (23/24 samples); Brain 4 125 34–319
geometric mean air Kidney 5 142 46–333
Page 189
lead, 48 µg/m3
All sites 132 93 78–110 Regional reference (1965–92)
Lung 31 82 56–116
Stomach 14 97 53–162
Brain 4 217 57–557 Exposure to other agents, e.g.
Kidney 4 175 48–449 cadmium; no smoking data
Ades & 4173 zinc–lead–cadmium Mean blood lead in Lung SMR Regional standard population.
Kazantzis smelter workers; employed cadmium plant, Overall 182 125 107–144 Exposure to lead highly
(1988) > 1 year; all staff employed 28 µg/dL (3% of Duration of correlated with exposure to
United 1 January 1943 + all staff cohort); 59 µg/dL in employment arsenic.
Kingdom subsequently employed furnace (10% of (years):
< 1970; born < 1940; 0.7% cohort); 56 µg/dL in 1–4 43 86 62–116
lost to follow-up; 3.2% sinter (8% of cohort) 5–9 23 107 68–161
emigrated; ≥ 10 years Years employed 10–19 36 122 86–170
follow-up 20–29 44 190 138–256
30–39 28 142 94–205
≥ 40 8 292 126–575
Nested case–control study Job–exposure matrix; Lung RR Estimated RR associated with
with 174 lung cancer cases ordered exposure cate- Background 57 1.25 10 years employment at each
and 2717 controls gories Low 73 1.28 exposure level; no. of cases
frequency-matched on age, Medium 72 1.36 working at least 1 year
employment start date, High 27 1.54
surviving the case. Subjects
followed up < 10 years
excluded to allow for
latency
189
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190
Table 79 (contd)
09/08/2006
Lead chromate pigment production

Sheffet et al. 1946 men (1296 Caucasian Exposure to chemical Caucasian National standard population.
(1982) and 650 non-Caucasian) dust air samples All sites 50 1.03 Adjusted to include cases with
USA employed ≥ 1 month in a (airborne chromium) Lung 21 1.6 unknown cause of death
11:30
pigment plant 1940–69; Stomach 5 2.0
followed until 1979 Large intestine 2 0.5

Non-
All sites Caucasian 25 1.01
Page 190
Lung 10 1.6
Stomach 3 1.6
Large intestine 0 0.0
Davies et al. 1152 male pigment workers Jobs categorized into Lung Date of first SMR High and medium exposure
(1984a) first employed 1933, 1949, exposure grades: high, employment combined.
United 1947 and followed until medium and low Reference: specially compiled
Kingdom 1981; factories A and B Factory A quinquennial national rates.
exposure to zinc and lead 1932–45 13 222 120–380 Adjusted for duration of service
chromate; factory C 1946–54 8 223 100–440
exposure to lead chromate 1955–mid- 2 100 10–360
only 1963
mid-1963–67 0 –
Factory B
1948–60 6 373 140–810
1961–67 5 562 180–1310
Factory C
1946–60 1 48 0–270
Davies et al. 57 male pigment workers Not estimated Lung SMR Same factories as in Davies et al.
(1984b) with non-fatal clinical lead 4 145 [39–370] (1984a)
United poisoning; followed from National reference
Kingdom date of poisoning or earliest
available record, through
31 December 1981
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Table 79 (contd)
09/08/2006
Glass workers
Cordioli et al. 468 workers in the glass Not estimated SMR National standard population
(1987) industry employed ≥ 1 year All sites 28 127 [84–184]

Italy 1953–1967 and followed Lung 13 209 [111–357]
11:30
until 1985; vital status Larynx 4 449 [122–1150]
98.3% Stomach 2 61 [7–220]
Sankila et al. Cohort of 3749 (1803 men Not estimated Total SIR National standard population
Page 191
(1990) Finland and 1946 women) Stomach cohort 34 93 64–129
employed ≥ 3 months in Kidney 3 35 7–102
2 glass factories, followed Central nervous 6 60 22–131
1953–86; subcohort of 235 system
glass blowers (201 men Lung 69 128 99–162
and 34 women) Colon 7 46 19–96
Rectum 14 113 62–189
Lung 5 85 28–198
Stomach Subcohort 6 231 85–502
Skin of glass 3 625 129–1827
blowers
Wingren & 625 male art glassworkers Air measurements of SMR County reference. Smoking
Englander employed ≥ 1 month lead All sites 26 138 [90–202] status lower than in the general
(1990) 1964–85 Lung 6 240 [88–522] population
Sweden Colon 4 250 [68–640]
Miners
Cocco et al. 4740 men employed Not estimated SMR Regional reference
(1994a) ≥ 1 year 1932–71 in All sites 293 94 83–105 Exposure to silica and radon
Italy 2 lead/zinc mines; Lung 86 95 76–117 Includes 1741 subjects of the
mortality 1960–88; vital Stomach 27 94 62–137 study reported by Carta et al.
status 99.5%; cause of Bladder 17 115 67–184 (1994).
death 99.4% Intestine and 12 64 33–112
rectum
Peritoneum; retro- 6 367 135–798
peritoneum
Kidney 7 128 52–264
Nervous system 8 117 50–230
191
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192
09/08/2006
Table 79 (contd)
483 women employed ≥ 1 year
11:30
Cocco et al. Not estimated All sites 32 70 48–99 National reference; availability
(1994b) 1932–71 in the same 2 lead/zinc Lung 6 232 85–505 of death records not mentioned

Italy mines as in Cocco et al. Stomach 2 32 4–115
(1994a); mortality 1951–88;
Page 192
vital status 96.0%
Newspaper printers
Bertazzi & 700 men employed ≥ 5 years Not estimated SMR National reference
Zocchetti before 1955 in production All sites 51 123 [92–162] Increase in lung cancer risk
(1980) department of newspaper plant; Lung 13 148 [79–253] confined mainly to packers and
Italy mortality 1956–75; vital status Duration of forwarders possibly exposed to
96.7% employment vehicle exhausts
(years):
≤9 2 167 [20–602]
10–19 5 106 [34–247]
≥ 20 6 207 [76–450]
Digestive organs
and peritoneum 19 120 [72–188]
Michaels 1261 men members of Not estimated SMR Regional standard (New York
et al. (1991) typographical union, employed All sites 123 84 69–100 City rates)
USA 1 January 1961, followed-up Lung 37 89 62–122 Lead phased out during 1974–78;
1961–84, vital status 96.9% Stomach 5 55 18–128 before: low-level exposures
Bladder 8 151 65–297 documented from other printing
Leukaemia and 5 104 34–244 industry plants (ranging from
aleukaemia < 2% to 40% of the occupational
standard)
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09/08/2006
Table 79 (contd)
Organic lead

Sweeney Retrospective study; 2510 men Not estimated National reference.
11:30
et al. (1986) (2248 Caucasian and 262 non- Employment 1952– Lung 14 112 68–1.75 One brain tumour appeared to
USA Caucasian) employed at 77, all workers Larynx 2 364 65–1145 be a metastasis according to
chemical plant (tetraethyl lead combined Brain and central 4 213 73–487 pathology reports.
manufacture) > 1 day 1952–77; nervous system
Page 193
vital status 99.3%, cause of Lymphatic 4 85 36–343
death 98.7%
Employment Lung 13 122 73–194
1952–60, Caucasian Brain 3 186 51–482
only
Employment prior to Respiratory 14 154 [84–258]
1960 and 15 year < 10 years 6 199 [73–432]
latency; duration of > 10 years 8 132 [57–260]
employment
Fayerweather Case–control study in a Employment in Exposed OR 90% CI
et al. (1997) tetraethyl lead manufacturing tetraethyl lead areas Digestive Ever 45 1.3 0.9–1.9 Incidence among active workers
USA site; 735 male cases and 1423 (ever versus never) Cumulative only
controls matched on age, sex, exposure: Quartiles of cumulative
payroll class; 1956–87; High 10 1.3 0.7–2.7 exposure (low, medium, high,
company mortality registries Very high 16 2.2 1.2–4.0 very high) defined as no. of
and employment rosters years × rank weight of
Rectum Ever 9 3.7 1.3–10.2
exposure, ranking variables
Cumulative
originating from a variety of
exposure:
sources
High to 7 5.1 1.6–16.5
very high
Colon Ever 16 1.3 0.7–2.5
Cumulative
exposure:
High to 8 1.7 0.8–4.0
very high
193
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194
Table 79 (contd)
09/08/2006
Biomonitoring
Anttila et al. 20 741 workers (18 329 men, Highest blood lead Blood lead SIR Men only
11:30
(1995) 2412 women) with monitored (µmol/L) (µmol/L) [test for trend borderline
Finland blood lead; 1973–83; 2318 Lung, trachea < 1.0 25 70 50–110 significant]

industrial plants or workplaces 1.0–1.9 35 140 100–190
2.0–7.8 11 110 60–200
Page 194
Stomach < 1.0 11 100 50–190 Men only
1.0–1.9 11 140 70–250 OR for estimated mean lifetime
2.0–7.8 1 30 0–180 blood lead ≥ 0.8 µmol/L:
1.1 (95% CI, 0.4–3.2), based on
14 cases
Kidney < 1.0 4 60 20–150 Men only
1.0–1.9 5 100 30–240 OR for estimated mean lifetime
2.0–7.8 0 0 0–200 blood lead ≥ 0.8 µmol/L: 0.5
(95% CI, 0.2–1.7), based on
7 cases
Nervous system < 1.0 8 130 60–260 Men only
1.0–1.9 6 130 50–270
2.0–7.8 3 160 30–460
Highest blood lead RR Internal comparison; Poisson
(µmol/L) Lung, trachea < 1.0 26 1.0 ref regression
1.0–1.9 36 2.0 1.2–3.2
2.0–7.8 11 1.5 0.8–3.1
Nested case–control study Cumulative exposure Lung OR Test of trend NS
1973–90; 53 cases and 156 (µmol × yr/L) 0 16 1.0 ref Includes pleural cancer
controls matched on sex, year 1–6 6 0.9 0.2–3.6 Adjusted for smoking
of birth and vital status 7–17 15 1.2 0.4–3.1
18–70 16 1.4 0.6–3.7
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Table 79 (contd)
09/08/2006
Reference, Cohort description Assessment or Cancer site Exposure No of cases Relative 95% CI Comments
location indices categories or deaths risks
of exposure to lead
Anttila et al. Same cohort as Anttila et al. Blood lead (µmol/L) Nervous system SIR Entire cohort analysis
(1996) (1995) ≤ 0.9 12 [90] [47–158]

Finland 1.0–1.9 10 [130] [62–239]
11:30
2.0–7.8 4 [138] [38–353]
Nested case–control study Highest blood lead Nervous system OR Internal comparison,
1973–90 with 26 cases and (µmol/L) 0.1–0.7 7 1.0 ref 200 controls
Page 195
200 controls matched on sex, 0.8–1.3 9 1.4 0.5–4.1
year of birth and vital status 1.4–4.3 10 2.2 0.7–6.6
p for trend 0.17
Glioma OR Internal comparison,
0.1–0.7 1 1.0 ref 125 controls.
0.8–1.3 8 6.7 0.7–347 Adjusted for year of first
1.4–4.3 7 11.0 1.0–626 personal measurement
p for trend 0.037
Cumulative exposure Glioma OR 49 controls
(year × µmol/L) 0 1 1.0 ref Adjusted for year of first
1–6 2 2.0 0.1–116 personal measurement
7–14 2 6.2 0.1–816
15–49 5 12.0 0.9–820
p for trend 0.02
Lifetime mean lead Glioma 0.1–0.7 1 1.0 ref 49 controls
(µmol/L) 0.8–1.3 5 3.5 0.4–171 Adjusted for gasoline and
1.4–3.4 4 23.0 0.8–2441 cadmium exposure
p for trend 0.041
Duration of occupa- Glioma 0 1 1.0 ref 49 controls
tional exposure to 1–9 1 0.9 0–122 Adjusted for gasoline and
lead (years) 10–19 3 3.7 0.2–244 cadmium exposure
20–42 5 6.9 0.6–400
p for trend 0.029
AAS, atomic absorption spectroscopy; AES, atomic emission spectroscopy; RR, relative risk; PMOR, proportional mortality odds ratio; SMR, standardized mortality ratio; SPMR,
standardized proportional mortality ratio; SIR, standardized incidence ratio; OR, odds ratio; NS, not significant; [....] calculated by the Working Group
a
G6PD, glucose-6-phosphate dehydrogenase
195
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196
09/08/2006
Table 80. Population-based case–control studies on cancer risk in relation to exposure to lead or lead compounds
Reference, Characteristics of cases and controls Assessment or indices of Cancer site No. of Odds 95% CI Comments
location and exposure to lead cases ratio
years of study
Multiple cancer sites
11:30
Siemiatycki Men aged 35–70 years, resident in the Expert assessment 90% CI; cancer controls for all
(1991) Montreal metropolitan area; hospital Lead compounds: exposures and sites, except

Canada records and population files (multi-site Anya Lung 326 1.1 0.9–1.4 lead fumes and lung cancer
1979–85 cancer and population controls Substantialb 42 1.5 1.0–2.2 (population controls)
Page 196
available); response rates: cancer cases Any Lung, squamous-cell 146 1.3 1.0–1.6
82%, population controls 72% [others Substantial 18 1.5 0.8–2.6 No data on central nervous
not available]; incident cases Any Stomach 126 1.2 1.0–1.6 system/brain cancer
histologically confirmed Substantial 17 1.8 1.1–2.8
Any Bladder 155 1.3 1.0–1.6
Substantial 17 1.1 0.7–1.8
Any Kidney 88 1.2 1.0–1.6
Lead dust:
Any Stomach 5 4.7 1.9–11.7
Lead oxides:
Any Lung 22 1.9 1.1–3.4
Lead carbonate: any Lung, adenocarcinoma 7 1.9 0.9–4.0
Lead chromate: any Lung 26 1.6 1.0–2.7
Bladder 17 1.8 1.1–3.1
Kidney 6 2.1 1.0–4.5
Lead fumes: any Lung, oat-cell 12 1.8 1.0–3.2
Lung, squamous-cell 16 1.8 0.9–3.6
Stomach 10 1.7 0.9–3.0
Pancreas 7 1.9 1.0–3.8
Non-Hodgkin lymphoma 13 1.8 1.1–3.0
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Table 80 (contd)
09/08/2006
years of study
Stomach
11:30
Cocco et al. Population-based study; 24 states; Occupation and industry Stomach Matching by geographic
(1999b) 41 957 deaths (20 878 Caucasian men, titles on death certificates region, race, sex and age (5-
USA 14 125 Caucasian women, 4215 plus job–exposure matrix year)
1984–96 African-American men, 2739 African- High probability of lead
American women) aged ≥ 25 years at
Page 197
exposure:
the time of death; 2 controls per case, Caucasian men 1503 0.92 0.86–0.99
having died from non-malignant African-American men 453 1.15 1.01–1.32
diseases White women 65 1.53 1.10–2.12
African-American women 10 1.76 0.74–4.16
High intensity of lead
exposure:
Caucasian men 290 1.10 0.95–1.27
African-American men 52 0.81 0.59–1.13
Caucasian women 37 1.02 0.68–1.51
African-American women 3 1.25 0.30–5.23
Cocco et al. Same design as in Cocco et al. Occupation and industry Stomach Gastric cardia cancer.
(1998b) (1999b); 1056 cases (1023 Caucasian titles on death certificates [Intercorrelation with other
USA men and 33 African-American men) + job–exposure matrix exposures not described]
1984–92 and 5280 controls High probability of
exposure with intensity:
Unexposed 841 1.0
Low 77 1.3 1.0–1.8
Medium 10 1.1 0.5–2.2
High 1 – –
Kidney
Partanen et al. Population-based study; 408 incident Summary indicators Kidney 4 2.77 0.49–15.6 Lead + inorganic lead
(1997) cases (male and female) aged 1920–68; industrial compounds; adjusted for
Finland ≥ 20 years and 819 controls matched hygienist smoking, coffee consumption
1977–78 on year of birth, sex, survival status; and obesity
response rate 69% (cases), 68%
(controls)
197
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198
Table 80 (contd)
09/08/2006
years of study
Pesch et al. Population-based study; 935 cases Two job–exposure Renal-cell carcinoma Adjusted for age, study centre
(2000) (570 men, 365 women); 95% histo- matrices (lead and lead and smoking
Germany logically confirmed; 4298 controls compounds) used for jobs
11:30
1991–95 (2650 men, 1648 women) matched by held > 1 year
region, sex and age; response rates Job–exposure matrix 1c:

84–95% (cases), 63–75% (controls) Men
Page 198
High 71 1.2 0.9–1.6
Medium 84 1.2 1.0–1.6
Women
High 14 1.0 0.6–1.9
Medium 8 0.7 0.4–1.6
Job–exposure matrix 2d:
Men
High 81 1.2 0.9–1.6
Medium 69 0.9 0.7–1.2
Brain and nervous system
Cocco et al. Population-based study; 24 states; Occupation and industry Brain The group with high intensity
(1998a) 27 060 deaths (Caucasian and African- titles on death certificates (estimated mean blood lead
USA American men and women) and plus job–exposure matrix: > 1.4 µmol/L) and high
1984–92 108 240 controls who died from non- High intensity and high probability of exposure
malignant diseases (aged ≥ 35 years) probability of lead comprised typesetters and
exposure: compositors.
Caucasian men 14 2.1 1.1–4.0 Adjusted for age, marital
Caucasian women 4 1.4 0.4–4.2 status, residence (urban versus
rural) and socioeconomic status
Cocco et al. Same design as in Cocco et al (1998a), Occupation and industry CNS 366 1.1 1.0–1.2 Reference: no exposure
(1999a) 12 980 women titles on death certificates Meningioma 9 1.9 1.0–3.9
USA plus job–exposure matrix
1984–92
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Table 80 (contd)

11:30
years of study
Hu, J. et al. Hospital-based study; 218 cases Self-reported exposure to Glioma 0 [4 controls]
Page 199
(1998), histologically confirmed (139 lead
Heilongjiang astrocytoma and 79 other brain
Province, glioma, male and female)
China 436 controls with non-neoplastic non-
1989–95 neurological diseases, matched on sex,
age, residence (rural/urban); 100%
response rates for cases and controls
Hu, J. et al. Same design as in Hu, J. et al. (1998) Self-reported exposure to Meningioma Adjusted for income,
(1999), 183 cases, 366 controls lead education, fruit and vegetable
Heilongjiang Men 6 7.20 1.00–51.72 consumption (men), further
Province, Women 10 5.69 1.39–23.39 adjusted for smoking (women)
China
1989–96
Other primary sites
Risch et al. Population-based study; 835 cases Partially self-reported Bladder
(1988) histologically confirmed (male and exposure to lead
Canada female) and 792 controls, response compounds, men
1979–82 rates 67% and 53%, respectively; Ever exposed 61 2.00 1.16–3.54 Adjusted for lifetime cigarette
cases and controls matched by year of OR for trend per 10 years 1.76 0.91–3.51 consumption; exposure during
birth, sex and area of residence of duration full-time job ≥ 6 months
Exposed ≥ 6 months 1.45 1.09–2.02
8–28 years before
diagnosis
199
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200
09/08/2006
11:30
Table 80 (contd)

Page 200
years of study
Kauppinen Population-based study; 344 cases Job–exposure matrix: Liver

et al. (1992) histologically confirmed (male and Low exposure to lead and 52 0.91 0.65–1.29 Men and women combined
Finland female), 476 stomach cancer controls its compounds
1976–78 and 385 coronary infarction controls, Expert assessment:
1981 matched to cases by age and sex; 71% Any exposure to lead and 6 1.14 0.44–2.98 Adjusted for alcohol
response rates for both cases and its compounds consumption; no cases with
controls heavy exposure; moderate
exposure, OR 2.28 (95% CI,
0.68–7.67; 5 cases)
CNS, central nervous system; OR, odds ratio

a
Any, any exposure
b
Substantial exposure
c
Job–exposure matrix 1: British
d
Job–exposure matrix 2: German
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2.1.2 Lead smelter workers

The extended study of lead battery and lead smelter workers in the USA (Cooper &
Gaffey, 1975; Cooper, 1976; Kang et al., 1980; Cooper, 1981; Cooper et al., 1985;
Cooper, 1988; Wong & Harris, 2000) originally included 2352 lead smelter workers from
six plants (Cooper & Gaffey, 1975); the most recent update (Wong & Harris, 2000) relates
to a reduced cohort of 2300 smelter workers. All lead smelter workers were employed for
at least 1 year during the period 1947–70, and the most recent follow-up has been
analysed for the period 1947–95. There were 161 lead smelter workers (7.0%) who were
untraced on the closing date of the study. Lead exposure data were limited, but blood lead
and urinary lead measurements were taken, mainly after 1960. For smelter workers with
three or more blood lead measurements, the mean blood concentration was 80 µg/dL and,
for those with 10 or more urinary lead measurements, the mean urine concentration was
173 µg/dL. Other exposures may have included cadmium, arsenic and sulfur dioxide.
SMRs were calculated after comparison with the mortality rates for the male population
in the USA, and were adjusted for age and calendar period. For all cancers, the overall
SMR was 101.8 (273 observed; 95% CI, 90.1–114.6). There were non-significantly
elevated SMRs for stomach cancer (133.4; 15 observed; 95% CI, 74.6–220.0) and lung
cancer (121.5; 107 observed; 95% CI, 99.5–146.8). SMRs were also shown for the lead
battery workers and smelter workers combined in relation to three categories of duration
of employment (< 10 years, 10–19 years, ≥ 20 years). Positive trends were not found for
cancer of the stomach or cancer of the lung. Corresponding findings were not shown sepa-
rately for smelter and battery workers.
Rencher et al. (1977) studied the mortality at a large copper smelter in western USA
during the period 1959–69. Death certificates were used to determine the causes of death.
The death pattern was compared with regional (state) death rates. [The Working Group
did not report the results because the methods of analysis rendered the study uninterpre-
table and person–time was not defined.]
In a study at a lead smelter in Australia (McMichael & Johnson, 1982), 241 male
workers diagnosed with lead poisoning during the period 1928–59 were identified. The
list was cross-checked against death registration records in South Australia for the period
1930–77, thereby identifying 140 deaths. Age-standardized proportional mortality rates
(SPMR) were calculated after comparison with the mortality pattern in 695 other workers
in non-office production jobs at the same smelter, and with the male population in
Australia. The SPMR for all cancer mortality was 0.59, based on nine cancer deaths. [The
Working Group noted that the low SPMR for cancer may be explained by a very high
SPMR for chronic nephritis.]
Selevan et al. (1985) studied mortality in a cohort of 1987 men employed between
1940 and 1965 at a primary lead smelter in the USA. Other exposures included zinc,
cadmium, arsenic, sulfur dioxide and, in some departments, airborne free silica. In an
extended follow-up study of this cohort (Steenland et al., 1992), 1990 male hourly-paid
smelter workers were identified. They had worked in a lead-exposed department for at
P 201-252 DEF.qxp 09/08/2006 11:36 Page 202
least 1 year, with at least 1 day of employment at the smelter between 1940 and 1965. The
vital status of the cohort was determined via the Social Security Administration and the
National Death Index. The population of the USA was used as a reference group. For all
cancers, the overall SMR was 98 (192 observed; 95% CI, 84–112). There were non-signi-
ficantly elevated SMRs for stomach cancer and lung cancer. In the subcohort (1436
subjects) with heavier exposure to lead (departments with mean airborne lead concen-
trations in 1975 that exceeded 0.2 mg/m3), the SMRs were similar. Eight of the nine
kidney cancer deaths occurred in the subcohort with heavier exposure to lead (SMR, 239;
95% CI, 103–471). Analyses by duration of exposure failed to show any significant posi-
tive trends with site-specific cancer risks. Detailed data about individual lead exposures
were lacking as well as information about potential confounders such as concomitant
exposure to cadmium, arsenic and other exposures at the primary smelter. However, some
data were available. In 1975, the mean airborne arsenic concentration was 14 µg/m3,
whereas the mean airborne lead concentration was 3.1 mg/m3. These means were based
on 89 and 203 personal 8-h samples, respectively. [This level of arsenic exposure is
approximately an order of magnitude lower than that seen in most of the historical cohort
studies of arsenic-exposed workers that have shown lung cancer excesses (Steenland
et al., 1996). No lung cancer excess was seen in workers with similar average exposure
levels (between 7 and 13 µg/m3) in copper smelters studied by Enterline et al. (1987).
Similarly, little or no lung cancer excess was seen among workers with this level of expo-
sure in another copper smelter in the USA studied by Lubin et al. (2000).] Data on
smoking were lacking.
In a study in Sweden (Gerhardsson et al., 1986), 3832 male workers first employed
before 1967 at a primary copper smelter in northern Sweden were followed from 1950 to
1981. A subcohort of 437 workers employed for more than 3 years in jobs with high lead
exposure had a mean blood lead concentration of 58 µg/dL in 1950, which had decreased
to 34 µg/dL in 1974. Workers were also potentially exposed to carcinogenic substances
such as arsenic, chromium and nickel. A significant excess of lung cancer and stomach
cancer mortality was observed in the whole cohort but was not sustained in the high-
exposure subcohort.
In a follow-up study at the same smelter (Lundström et al., 1997), the total cohort was
extended to comprise 3979 workers who had been employed for at least 1 year during the
period 1928–79 and who had been monitored for blood lead concentrations since 1950. A
subcohort of 1992 workers was defined by excluding workers ever employed in the
roaster departments, machine shop and any other departments with appreciable exposures
to arsenic and nickel. This subcohort comprised workers from the lead department and
other lead-exposed departments. Airborne concentrations of arsenic ranged from 0.35 to
1.5 mg/m3 at the roasters during the late 1940s and decreased to 0.1–0.5 mg/m3 during the
1950s; those of sulfur dioxide ranged from 70 to 560 mg/m3 during the 1940s and
decreased to 5–10 mg/m3 during the 1960s. [This subcohort is described in the paper as
one of ‘lead-only workers’, but these workers would have been exposed to some degree
to arsenic and nickel.] Expected mortality in 1955–87 and cancer incidence in 1958–87
P 201-252 DEF.qxp 09/08/2006 11:36 Page 203
were calculated relative to county rates, specified for cause, sex, 5-year age groups and
calendar year. Information on mortality was obtained from the Cause-of-Death Register
at Statistics Sweden. The death certificates were coded according to the 8th revision of
the International Classification of Diseases (ICD-8). Information on the incidence of
malignant tumours was gathered from record linkage with the National Swedish Tumour
Registry, established in 1958. The most highly-exposed subgroup was selected on the
basis of a cumulative blood lead dose, which was calculated by summing the annual mean
blood lead values for each worker during the period of employment (≥ 207 µg×yr/dL).
For the total cohort (n = 3979), the overall SMR for all cancers was 120 (126 observed;
95% CI, 100–150). There was a significantly elevated SMR for lung cancer (280; 39
observed; 95% CI, 200–380). The SMR for lung cancer in the most highly-exposed
subgroup (n = 1026) was 280 (19 observed; 95% CI, 180–450). For cancer incidence in
the total cohort (with a 15-year minimum latency period), the overall standardized
incidence ratio (SIR) for all cancers was 110 (172 observed; 95% CI, 90–120). There was
a significantly elevated SIR for lung cancer (42 observed; SIR, 290; 95% CI, 210–400).
The SIR for lung cancer in the most highly-exposed subgroup was 340 (23 observed;
95% CI, 220–520). The risk estimates for lung cancer were further elevated in the
subgroup of ‘lead-only workers’ with the highest exposure (7 observed; SIR, 510;
95% CI, 200–1050). No significantly elevated SIRs were observed for other malig-
nancies. [The multifactorial exposure pattern and the lack of smoking data make it diffi-
cult to separate the effects of lead from the effects of other agents, in particular arsenic,
in the working environment.]
This cohort from Sweden (described above) was further analysed by Englyst et al.
(2001) forming two subcohorts from the original cohort of 3979 male smelter workers
(Lundström et al., 1997). Subcohort 1 consisted of 710 workers who had been employed
in the lead department. Subcohort 2 was nested within subcohort 1 and the subcohort of
the 1992 workers defined by Lundström et al. (1997) and consisted of 383 workers who
had been employed in the lead department at any time but never in the arsenic plant,
nickel plant, the roaster department or the machine shop. SIRs for 1958–87 were calcu-
lated relative to county rates. The lung cancer incidence was raised in both lead sub-
cohorts. Incidence for all cancers was close to expectation. A detailed study of company
records revealed that nine of the 10 lung cancer cases in subcohort 1 and four of the five
lung cancers in subcohort 2 had also had some considerable exposure to arsenic. [The
Working Group noted that such information on exposure to arsenic was not available for
the rest of the cohort.]
Gerhardsson et al. (1995) studied the mortality and cancer incidence among workers
exposed to lead at a secondary lead smelter in southern Sweden. There was no known
concomitant exposure to arsenic, hexavalent chromium, nickel or cadmium. Annual mean
blood lead values declined during the follow-up period, from 62 µg/dL in 1969 to
33 µg/dL in 1985. The cohort consisted of 664 male lead smelter workers who had been
employed for at least 3 months from 1942 to 1987. The causes of death in 1969–89 were
obtained from Statistics Sweden. Death certificates were coded according to ICD-8.
P 201-252 DEF.qxp 09/08/2006 11:36 Page 204
Yearly cancer incidence from 1969 to 1989 was obtained from the National Swedish
Tumour Registry, with calendar year-, sex- and 5-year age group-specific incidences for
the county population. For all cancers, the overall SIR was 127 (40 observed; 95% CI,
91–174). There were non-significantly elevated SIRs for stomach cancer and cancers of
the respiratory tract. [The Working Group noted that the results must be interpreted with
caution due to small numbers and lack of data on smoking.]
In a study of 1345 male smelter workers at a lead and zinc smelting plant in south-
western Sardinia, Italy, mortality was followed from 1973 to 1991 (Cocco et al., 1996).
Death certificates were provided for all deceased subjects by the local health units. SMRs
were calculated after comparison with death rates in the general male population in
Sardinia. No significant excess of mortality was noted for any single cancer site. There
were two deaths from stomach cancer and lung cancer mortality was lower than that
expected. The overall SMR was not presented. [The study interpretation is hampered by
limited numbers of expected deaths, lack of detailed information about individual expo-
sures to lead, zinc and other substances at the smelter, as well as a lack of data on smoking.]
Cocco et al. (1997) also studied 1388 lead workers from another lead smelter in Italy.
An industrial hygiene survey carried out in 1977–78 reported concentrations of cadmium
in respirable dust below the limit of detection (1 µg/m3) in 9/39 samples and below
10 µg/m3 in 28/39 samples. In addition, concentrations of arsenic were reported to be
below the limit of detection (1 µg/m3) in 23/24 samples; the remaining reading was
3 µg/m3 in the agglomeration area. Concentrations of lead in respirable dust had a wide
range of values (1–1650 µg/m3) with a geometric mean for all work areas of 48 µg/m3.
Vital status of the workers was followed from 1950 to 1992. Fifty-five per cent of the
cohort members had died by the end of follow-up. Death certificates were available for
96% of the deceased men. The underlying causes of death were coded according to the
9th revision of the International Classification of Diseases (ICD-9). SMRs were calcu-
lated for specific causes of death after comparison with national and regional reference
rates. On the basis of national rates, mortality for all cancers, stomach cancer and lung
cancer were lower than expected. On the basis of regional rates for a more limited period
of follow-up (1965–92), mortality rates for all cancers, stomach cancer and lung cancer
were close to those expected.
Lung cancer mortality was investigated in a cohort study of men employed at a
zinc–cadmium smelter in the United Kingdom (Ades & Kazantzis, 1988). The study
comprised all hourly-paid male workers employed at the smelter on 1 January 1943 and
those who subsequently started work before 1970. All subjects were born before 1940 and
worked for at least 1 year before 1970. Average arsenic concentrations assessed by static
samplers between 1981 and 1983 ranged from 1 to 3 µg/m3 in the sinter and from 4 to
7 µg/m3 in the furnace. Airborne cadmium exposure before 1970 was assessed to be
200 µg/m3 in the sintering plants and 80 µg/m3 in the cadmium plant. By 1977, these con-
centrations had decreased to 15 µg/m3 in both departments. Biological monitoring results
showed mean blood lead concentrations of 28 µg/dL in the cadmium plant workers,
59 µg/dL in the furnace workers (10% of the cohort) and 56 µg/dL in the sinter workers
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(8% of the cohort). In total, 4173 men were followed up for more than 10 years. SMRs
were calculated using regional comparisons. The SMR for lung cancer was 125 (182
observed; 95% CI, 107–144). The lung cancer mortality was positively related to duration
of employment. On the basis of a matched case–control study nested in this cohort, the
cumulative arsenic and lead exposure (both estimated crudely in terms of
‘level–decades’), but not cumulative cadmium exposure, were positively related to lung
cancer mortality. [It was not possible, however, to elucidate the independent relationships
for arsenic, lead or other concomitant exposures at the smelter.]
2.1.3 Lead chromate pigment production

Workers producing lead chromate pigments have been the subject of two cohort
studies focused on possible lung carcinogenicity resulting from exposure to hexavalent
chromium, which was classified as Group 1 human carcinogen by IARC (IARC, 1990).
[It is not possible to separate the effects of chromium on the lung from those of lead in
these studies, limiting their usefulness in the evaluation of the carcinogenicity of lead.]
Sheffet et al. (1982) studied mortality among 1296 white and 650 non-white men in a
pigment plant producing lead and zinc chromates in the USA who were employed for at
least 1 month between 1940 and 1969, and followed through 31 March 1979. Moderate
exposure was defined as work in jobs with an average exposure of 0.5–2 mg/m3 airborne
chromium, while high exposure was defined as > 2 mg/m3 airborne chromium; 76% of the
cohort had high or moderate exposure. A statistically significant relative risk of 1.6
(95% CI, 1.1–2.2; 31 deaths) for lung cancer was found among male employees,
increasing to a significant 1.9 for those exposed for at least 2 years to moderate or high
exposure. Stomach cancer had a SMR of 2.0 (95% CI, 0.9–3.6; 8 deaths). SMRs varied
depending on whether or not those decedents with cause of death unknown (15%) were
excluded from the observed count of lung cancers or added in proportion corresponding to
the distribution of observed deaths with known causes. [SMRs for other cancers were
calculated, but numbers were small and there were no significant findings.]
Davies et al. (1984a) studied 1152 men at three pigment plants in the United Kingdom;
two of the plants produced zinc and lead chromates, the third only lead chromate. Workers
had at least 1 year of employment between the beginning of complete plant records (1933,
1949 and 1947 for the three plants) and 1967 (with the exception of a few late entrants
1968–74), and were followed up until 1981. Exposure was categorized into high, medium
and low grades: jobs in dry departments and full-time stove drying with heavy exposure to
chromate-containing dust (high); slight or occasional exposure to chromate, including jobs
in management, laboratory, shops, maintenance, etc. (low); and other jobs, e.g. wet depart-
ments, men going all over the factories (medium). There was a statistically significant
excess of lung cancer mortality at the two factories producing zinc and lead chromate, but
no excess was observed at the plant producing only lead chromate, despite small numbers.
The authors speculated that zinc chromate was responsible for the lung cancer excess at the
first two plants. No quantitative data on exposure were given, although it was mentioned
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that lead concentrations were high enough to result in frequent lead poisoning until the
1950s.
Davies et al. (1984b) studied 57 men with documented lead poisoning who were part
of the larger cohort of workers at three pigment plants (Davies et al., 1984a; see above).
There were four cases of lung cancer (SMR, 145; 95% CI, 39–370). [Due to small
numbers, this study is essentially non-informative regarding cancer risk among these
highly-exposed workers.]
2.1.4 Workers in glass production

Glass work involves smelting and foundry work, and glass blowing, grinding and
polishing with potentially high exposures to lead but also to a variety of other metals
(arsenic, cadmium, chromium, antimony, copper), as well as some exposure to silica and,
to a lesser extent, possible exposure to asbestos used in insulation. An earlier Working
Group (IARC, 1994) concluded that the manufacture of art glass, glass containers and
pressed ware entails exposures that are probably carcinogenic to humans (Group 2A) and
that occupational exposures in flat-glass and special glass manufacture are not classifiable
as to their carcinogenicity to humans (Group 3).
Numerous linkage studies on occupation and cancer have been conducted. Some gave
positive results for glass workers and lung cancer (Milne et al, 1983; Lynge et al., 1986;
Levin et al., 1988) or brain cancer (Mallin et al., 1989).
(a) Cohort studies

Cordioli et al. (1987) studied 468 male workers with at least 1 year of employment in
a glass factory in Italy between 1953 and 1967 and followed them for mortality until 1985.
A SMR for lung cancer of 209 [95% CI, 111–357] was observed, based on 13 lung cancer
deaths. An excess of laryngeal cancer was also observed (SMR, 449 [95% CI, 122–1150]),
based on four cases.
Sankila et al. (1990) studied 3749 workers (1803 men, 1946 women) employed for at
least 3 months in two glass factories in Finland and followed them for cancer incidence
from 1953–86. An excess of lung cancer was found (SIR, 128; 95% CI, 99–162; 69 cases,
62 men and seven women). The authors noted that a similar excess of lung cancer was
found when comparing industrial workers in general with the general population in
Finland, suggesting confounding by smoking as a possible explanation of the observed
excess. An excess of stomach cancer (SIR, 231; 95% CI, 85–502; six cases) and skin
cancer (SIR, 625; 95% CI, 129–1827; three cases) was found in the subcohort of glass
blowers (n = 235), but no excess of lung cancer was observed in this group.
Wingren and Englander (1990) studied 625 male glass workers employed in Sweden
for at least 1 month between 1964 and 1985, for cancer incidence and mortality. Slag from
blow pipes contained lead, manganese and nickel. Mortality was emphasized in the results
because the follow-up period covered by incidence was shorter, and the incidence results
tended to parallel the mortality results. Both national and county (local) standards were
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used, with county rates being considerably lower for lung cancer. Lung cancer was found
in excess using national rates (SMR, 144; 95% CI, 52–311) as well as country rates
(SMR, 240; 95% CI, [88–522]), based on small numbers (six lung cancer deaths). Colon
cancer (SMR, 250; 95% CI, [68–640]; four deaths) was also elevated, based on county
rates. Smoking status was known for 60 workers employed in the 1960s, showing a lower
proportion of smokers than in the general population.
(b) Case–control studies

There have been three case–control studies of glass workers in Sweden, conducted by
the same authors, based on death certificates and with some overlapping data (Wingren &
Axelson, 1985; 1987; 1993). Initially, three rural parishes in which glass works were
common were studied from 1950 to 1982. The initial investigation was expanded to 11
parishes, which included most of the glass works in Sweden, again studying the period
1950–82. To assess past and present exposure, a questionnaire regarding use of different
metals was sent to 13 existing glass works of which seven replied. Cancer was not more
common in the parishes than in the whole of Sweden in cohort analyses, but in case–
control analyses (controls were non-cardiovascular, non-cancer deaths) based on occupa-
tion on the death certificate [no information was given on how many were missing], glass
workers had elevated odds ratios. There was an excess of lung cancer (odds ratio, 1.7;
90% CI, 1.1–2.5; 21 exposed cases), stomach cancer (odds ratio, 1.5; 90% CI, 1.1–2.0; 44
exposed cases) and colon cancer (odds ratio, 1.6; 90% CI, 1.04–2.5; 18 exposed cases).
More detailed data on jobs were available for about half of those who died, and analyses
by specific job title suggested that the excess of stomach and colon cancer appeared most
strongly among glass-blowers, while the excess of lung cancer was about the same among
glass blowers and glass workers without specified job title. However, all glass workers
used several metals, which were often used in combination, and it was difficult to identify
particular metals as being responsible for particular cancer excesses. Measurement of lead
in several worksites showed high air concentrations, with a mean of 61 µg/m3 in one
foundry for heavy crystal glass.
2.1.5 Studies in miners

Carta et al. (1994) followed mortality among active male employees in two lead and
zinc mines in Sardinia, Italy. The study was performed particularly to test the relation-
ships between silica and radon exposures and lung cancer risk. Later, Cocco et al.
(1994a,b) enlarged the study to include male (n = 4740) and female (n = 483) workers in
the mines with at least 1 year of employment between 1932 and 1971. Follow-up of the
male cohort was from January 1960 to the end of November 1988, and eligible subjects
were men who were still employed on 1 January 1960 or who had worked for a minimum
of 12 months during 1960–71. In the study among female workers, follow-up was from
1951 to 1988, and eligible subjects were women who were alive at the onset of follow-
up. Vital status was known for 99.5% of the male and 96% of the female cohort members,
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and death certificates were available for all deceased members. In both mines, the ores
mainly consisted of blende and galena (zinc and lead sulphides). The concentrations of
in-air respirable dust averaged 2.5 and 2.6 mg/m3 in 1962–70 and 1.6 and 1.8 mg/m3 from
1971 onwards in the two mines, respectively. Dust concentrations at surface workplaces
were less than 1 mg/m3 in the 1970s. Expected rates were derived from the regional rates
in the study among men and from the national rates in the study among women. Among
men, the overall SMR was 104 (1205 observed; 95% CI, 98–110). The SMR for deaths
from all cancers was 94 (293 observed; 95% CI, 83–105) and 95 (86 observed; 95% CI,
76–117) for lung cancer. Except for cancers of the peritoneum and retroperitoneum (SMR,
367; six deaths observed; 95% CI, 135–798), none of the cancer sites studied had a
significantly increased SMR. In the study among women, 163 deaths occurred in total
(SMR, 78; 95% CI, 67–91); the SMR for lung cancer was 232 (95% CI, 85–505; six
deaths observed). Information on lifetime smoking habits were available for 1741 male
employees included in a cross-sectional survey in 1973 (Carta et al., 1994). About 65%
were current smokers. Further details on exposures to lead were not available.
2.1.6 Newspaper printers

Two studies among newspaper printers are described here; these studies aimed at
describing explicitly long-term exposures to lead in cohorts not exposed to other known
carcinogens (such as other metals, benzene, organic solvents). Other studies of printing
workers potentially exposed to lead have not been reviewed in this monograph.
Bertazzi and Zocchetti (1980) studied mortality among workers in a newspaper plant
in Milan, Italy. Male workers employed in the production department as of 31 December
1955 and having at least 5 years of employment were considered eligible (n = 700).
Mortality follow-up covered the years 1956–75. Follow-up and tracing was successful for
96.7% of the eligible workers. Persons not traced were assumed to be alive at the end of
the follow-up period. The expected numbers were calculated using the national rates. For
10 deaths, no specific cause was mentioned on the death certificate. The overall SMR was
108 (199 deaths observed; 95% CI, 94–124). The SMR for any cancer was 123 (51 deaths
observed; 95% CI, 92–162), that for lung cancer was slightly elevated (SMR, 148; 13
deaths observed; 95% CI, 79–253) and that for cancers of the digestive organs and peri-
toneum was 120 (19 observed; 95% CI, 72–188). There were two deaths from brain
cancer (expected number not given). SMRs for lung cancer were 167 (two deaths
observed), 106 (five deaths observed) and 207 (six deaths observed) in the groups for
whom length of employment was 5–9, 10–19 and 20 or more years, respectively. Risk for
lung cancer was highest among packers and forwarders (SMR, 250; six deaths; 95% CI,
92–544), who were possibly exposed to vehicle exhausts. Among compositors and stereo-
typers, who were thought to be the group most probably exposed to moderate concen-
trations of lead, no excess mortality was found but the study size was small (for lung
cancer, there was one death observed and two expected). [The Working Group noted that
no data were available on exposure to lead for this cohort.]
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Michaels et al. (1991) followed mortality among 1261 newspaper printers in New
York, USA. The cohort was composed of male members of a typographical union
employed at two newspaper printing plants on 1 January 1961. The cohort consisted prima-
rily of compositors and make-up workers, and exposure to lead was assumed to be similar
in both groups. No measurements were reported from these two plants, but the authors
described measurements of airborne lead at other printing plants in the USA in 1942 as
varying from < 1 µg/m3 to 20 µg/m3, i.e. below the occupational standard of 50 µg/m3.
According to a survey in 11 plants in the USA in the 1970s, airborne lead concentrations
were generally < 10 µg/m3, most of them < 1 µg/m3. Of the 1309 male members
potentially eligible for the study, 48 (3.7%) were not traced and were excluded. Vital status
was known for 1222 subjects (96.9% of the traced). Those with unknown vital status were
assumed to be alive at the end of follow-up. Follow-up through death certificates was
carried out until December 1984. New York City mortality rates were used as the reference.
The overall SMR was 74 (498 deaths observed; 95% CI, 68–81); the SMR for any cancer
was 84 (123 deaths observed; 95% CI, 69–100) and that for lung cancer was 89 (37
observed; 95% CI, 69–100). There were no clear increases in SMRs for any of the primary
cancer sites studied. [The Working Group noted that the hot lead process was phased out
of newspaper printing during the period 1974–78.]
2.1.7 Exposure to organic lead

Organo-lead compounds such as tetraethyl and tetramethyl lead have been used histo-
rically as components in gasoline. Gasoline engine exhaust has been previously evaluated
as possibly carcinogenic to humans (Group 2B) (IARC, 1989). Studies on gasoline are not
further reviewed here as there are mixed exposures and the effects of lead cannot be
characterized separately. A cohort study and a nested case–control study of workers
employed in the manufacture of tetraethyl lead are described below.
Sweeney et al. (1986) investigated the mortality of 2510 men employed at a chemical
plant in east Texas, USA. Tetraethyl lead was produced during the study period from 1952
to 1977, together with ethylene dichloride and chloroethane. Vinyl chloride monomer was
also manufactured from 1960 to 1975. Other chemicals (ethylene dibromide, ethylene,
inorganic lead, dyes) were used in the manufacturing processes of tetraethyl lead. Male
employees who had worked at least 1 day at the factory between 1952 and 1977 were
eligible from company records and workers’ union files. More than 50% of the total work-
force had been employed at the plant for at least 5 years. Vital status was ascertained for
99.3% of the cohort members. Expected numbers were calculated from the national rates
by ethnicity, age groups and 5-year calendar periods. Mortality from all causes of death
was lower than expected (SMR, 74; 156 observed; 95% CI, 64–84). The SMR for malig-
nant neoplasms was 103 (38 deaths observed; 95% CI, 77–135). The SMR for lung cancer
was 112 (14 observed; 95% CI, 68–175). There was a slight excess of laryngeal cancers
(SMR, 364; two deaths observed; 95% CI, 65–1145) and of brain and central nervous
system tumours (SMR, 213; four deaths observed; 95% CI, 73–487). Among white men
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employed between 1952 and 1960, when the manufacture of tetraethyl lead was the
principal process, the SMR for lung cancer was 122, based on 13 deaths (95% CI, 73–194)
and the SMR for brain tumours was 186 (three deaths observed; 95% CI, 51–482). When
deaths among male workers employed before 1960 were restricted to those deaths occur-
ring 15 or more years after first employment, the SMR for respiratory cancers was 154
(14 observed; 95% CI, 84–258); for length of employment < 10 years, the SMR was 199
(six observed; 95% CI, 73–432); and for employment > 10 years, the SMR was 132 (eight
observed; 95% CI, 57–260). [There were no further details on mortality by employment at
departments using tetraethyl lead or with other chemical exposures.]
Fayerweather et al. (1997) reported a case–control study among employees who
worked at a tetraethyl lead manufacturing company in New Jersey, USA. The plant began
producing tetraethyl lead in 1923 and production was closed in 1991; thereafter, the
tetraethyl lead plant was involved in lead remediation. The study subjects, 735 male cases
of cancer other than non-melanoma of the skin, and 1423 controls matched by year of
birth, sex, and most recent payroll class, were drawn from the cancer and mortality
registries of the company and from employment rosters. Neoplasms that occurred during
1956–87 were included. The cancer registry mainly covered active workers; workers who
left the company were missing from the registry (but those who left the active workforce
and were put on the company’s disability rolls were included in the registry). The
mortality registry covered all active and pensioned employees since 1957. Information on
ever having worked in the tetraethyl lead area, years of employment in tetraethyl lead
manufacture, rank (degree) of exposure to tetraethyl lead and cumulative exposure to
tetraethyl lead were estimated using employment information from the personnel records,
industrial hygiene data and records of biological measurements available at the factory.
Tetraethyl lead exposure ranks were based on job titles. Employees manufacturing tetra-
ethyl lead could have been exposed both to organic and inorganic lead compounds, but it
was not possible to distinguish between these in the exposure assessment because of
insufficient data. Exposure (ever/never) to other known or suspected carcinogens (such as
aromatic amines, nitriles, benzene, asbestos, radioactive materials) was also assessed.
Smoking histories were available from reports of periodical pulmonary function tests for
38% of the cases and 51% of the controls. Cases and controls for whom there was no
available information on employment from personnel records were excluded. Odds ratios
for cancer of the digestive tract were elevated for the group who had ever worked in the
tetraethyl lead manufacturing area compared with the group who had never worked in that
area (odds ratio, 1.3; 45 cases observed; 90% CI, 0.9–1.9); the risk was increased for high
(odds ratio, 1.3; 90% CI, 0.7–2.7) and very high (odds ratio, 2.2; 90% CI, 1.2–4.0) esti-
mated cumulative exposure. Further latency analyses, adjustments for smoking, and expo-
sure to aromatic amines, radioactive materials and asbestos did not markedly change the
results. Risk for rectal cancer was increased (odds ratio, 3.7; nine cases observed; 90% CI,
1.3–10.2), and was associated with high cumulative exposure to tetraethyl lead. The odds
ratio for colon cancer was 1.3 (16 observed; 90% CI, 0.7–2.5) and was moderately
elevated for the highest cumulative exposure category. [Not all workers exposed to
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organic lead were followed-up, e.g. workers who had terminated their employment
without pension eligibility. Losses in tracing and follow-up were not described in this
study. Quantitative information on the exposure categories was not available. Detailed
results on other primary cancer sites were not reported.]
2.1.8 Workers biologically monitored for blood lead concentrations

Anttila and co-workers (Anttila, 1994; Anttila et al., 1995, 1996) studied mortality and
cancer incidence among a worker population biologically monitored for occupational
exposure to lead. The biological monitoring programme was undertaken by the Institute of
Occupational Health in Finland in order to evaluate the uptake of lead, with the aim parti-
cularly to prevent lead poisoning. The database included 63 700 blood lead measurements
performed during 1973–83 on workers in approximately 2318 industrial plants or work-
places from all over Finland. Personal identity was traced for 97.0% of the measurements
(those for whom the identity could not be traced were excluded). The study population
included 20 741 employees, 18 329 men and 2412 women. In the cohort analyses, follow-
up was done through cause-of-death records, and records from the nationwide cancer
registry from 1973 to 1988. In addition to the cohort follow-up, a nested case–control study
was performed, extending the incidence follow-up to 1990. The case–control study
included 10 common primary cancer sites and controls were selected from monitored
workers not registered for cancer. Controls were matched with the cases by sex, year of
birth, age and vital status. In the case–control study, information on occupational histories
and on smoking and alcohol consumption were requested from the study subjects or their
next-of-kin using a postal questionnaire. Lifetime exposures to lead, and eight other groups
of occupational carcinogens, were estimated by an industrial hygienist; the assessment was
blinded as to the case–control status. Assessment of lifetime exposures to lead was based
on a combination of average individual blood lead values and exposure profiles within
lead-exposed worker groups/industries.
Yearly median concentrations of blood lead decreased from 1.4 µmol/L in 1973 to
0.7 µmol/L in 1982 among men and from 1.0 µmol/L to 0.3 µmol/L among women. The
blood lead concentrations exceeded 1.0 µmol/L (the administrative reference value of
‘occupationally unexposed’ during that time) in 9100 (42%) of the employees. Workers
monitored most regularly for blood lead concentrations were from the lead battery
industry (about 1300 employees from five plants), lead smelting and metal scrap business
(692 employees from 36 plants), metal foundries (419 employees from 30 plants), rail-
road equipment machine shops (434 employees from 14 plants) and manufacture of some
industrial chemicals (100 employees from seven plants). Lead-exposed employees moni-
tored less frequently were those working, for example, in automobile repair shops and
related industries (1290 employees from 292 workplaces), the graphics industry (1238
employees from 166 plants), the manufacture of glass, pottery, PVC plastics and paints
(1220 employees from 68 plants), shipyards (1113 employees from 23 plants) and mis-
cellaneous metal and engineering (2844 employees from 335 plants) (Anttila, 1994).
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Altogether 1082 deaths (1007 men and 75 women; SMR, 84; 95% CI, 79–89) and 469
incident cancer cases (SIR, 99; 95% CI, 90–108) were observed in the cohort follow-up.
Three exposure categories, based on the highest personal blood lead concentration, were
used: low, < 1.0 µmol/L; intermediate, 1.0–1.9 µmol/L; and high, 2.0–7.8 µmol/L. [Com-
pared with many other occupational cohorts, there were rather low levels of exposure to
lead in this cohort and small numbers of highly-exposed employees; there were only a few
cancer cases among women.] In the low exposure group, the SIR for any cancer was 80
(95% CI, 70–100; p < 0.05); the SIRs were 120 (95% CI, 100–140) and 100 (95% CI,
70–140) in the intermediate and high exposure categories, respectively. The SIRs for lung
cancer were, respectively, 70 (95% CI, 50–110), 140 (95% CI, 100–190) and 110
(95% CI, 60–200) for the three groups. [The Working Group noted that the reference
population has a deficit in all cancers and lung cancer incidence, which affects internal
comparisons.] In the internal comparison, there was a twofold risk for lung cancer (rela-
tive risk, 2.0; 95% CI, 1.2–3.2) for the intermediate and a 1.5-fold risk (relative risk, 1.5;
95% CI, 0.8–3.1) in the high exposure groups, compared with the low exposure group [no
p-value for trend available]. Additional analyses were done by cumulative exposure for
which the p-value for trend was not statistically significant (Anttila et al., 1995).
In the nested case–control study on lung cancer, there were initially 121 male cases
and 363 controls. The final population was restricted to 53 cases and 156 controls for
whom complete occupational histories were obtained. The nested case–control analyses
gave results similar to those of the cohort analyses. There was a positive trend, although
not statistically significant, of odds ratios increasing with increasing cumulative exposure
to lead, with odds ratios for lung cancer being 0.9, 1.2 and 1.4 for three groups of esti-
mated lifetime cumulative exposure to lead of 1–6, 7–17 and 18–70 µmol/L × year as
compared with the unexposed, adjusted for smoking and vital status. Compared with non-
adjusted results, the odds ratio for lung cancer increased slightly in the highest exposure
group and remained unaltered in the intermediate category when adjusted for smoking and
vital status, suggesting that smoking was not a confounder in the internal comparison. In
this study (Anttila et al., 1995), a significant fourfold difference was reported between the
risk for lung cancer for raised blood lead alone and raised blood lead with estimated co-
exposure to exhaust. [The Working Group noted that information on exposure to engine
exhaust was of limited quality and the results were difficult to interpret.] There were no
clear increases in risk for stomach or kidney cancer associated with lead exposure.
In a further study on brain and nervous system cancers in the same cohort (Anttila
et al., 1996), the observed/expected numbers of brain and other nervous system cancers
were 12/13.3, 10/7.7 and 4/2.9 over three categories of blood lead (< 1.0, 1.0–1.9, 2.0–
7.8 µmol/L). Internal analyses using Poisson regression showed 1.6-fold (95% CI, 0.7–3.8)
and 1.8-fold (95% CI, 0.6–5.8) risks for the intermediate and high blood lead categories in
comparison with the low. Histology-specific risk estimates could be computed only in the
case–control design. There was a statistically significant increase in the risk for gliomas in
the high blood lead category (p-value for trend = 0.037; 16 gliomas in total), whereas there
were no associations between exposure to lead and cancers with other or unknown histo-
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logy (10 cases; p-value for trend = 1.00). Among those subjects for whom lifetime expo-
sures could be assessed (including 10 of the glioma cases), the risk was associated with the
estimated level and duration of lifetime occupational exposure to lead as well as with the
cumulative exposure (p-values for trend = 0.041, 0.029 and 0.020, respectively).
2.1.9 Register linkage studies

McLaughlin et al. (1987) studied the occurrence of meningioma in men using the
Cancer–Environmental Registry of Sweden, which linked cancer incidence from 1961–79
with 1960 census information on employment. Analyses included all intracranial and
intraspinal meningiomas (n = 1092), 98% of which were coded as histologically benign.
Among glassmakers, a regionally-adjusted fivefold risk was observed (6 cases; SIR, 5.2;
p < 0.01).
Navas-Acién et al. (2002; discussed in a letter to the editor by Costa, 2003) investi-
gated occupational risks for gliomas and meningiomas in Sweden. The study was based
on a linkage of census records with cancer registry files, and exposures were estimated
based on the occupational and industrial titles in the 1970 census. A job–exposure matrix
was used that classified probability (no/possible/probable) of exposure, based on esti-
mated proportions of exposed workers. Possible exposure meant that between 10 and 66%
of the subjects were exposed at a level > 10% of the threshold limit value. Probable expo-
sure meant that more than 66% of the subjects were exposed. The job–exposure matrix
was aimed to be representative for the labour force in Sweden. There were 3363 gliomas
and 1166 meningiomas in men, and 1561 gliomas and 1273 meningiomas in women in
the follow-up from 1971 to 1989, including those aged 25–64 years at the beginning of
follow-up. Risk for glioma in men with possible exposure to lead was not increased
(10 cases; relative risk, 1.08; 95% CI, 0.58–2.01; adjusted for age, period, geographical
category, town size and other chemical exposures); there were no cases with probable
exposure to lead. Risk for meningioma was elevated (seven cases; relative risk, 2.36;
95% CI, 1.12–4.96) for possible exposure to lead; no cases had probable exposure. There
were fewer than four cases exposed to lead in the female study population, and the risk
estimates were not reported. [The Working Group noted that it is difficult to be confident
about the exposure classification.]
Wesseling et al. (2002) carried out a study on brain and nervous system cancer risk
among women in Finland, based on linkage of census and cancer registry data. Occupation
titles were drawn from the 1970 census, and follow-up was performed from 1971 to 1995
among a cohort of 413 887 women with blue-collar occupations. There were 693 cases of
brain and nervous system cancers, 43% of which were meningiomas, 29% gliomas and
28% of other types. In a Poisson regression model with multiple agents, adjusted for year
of birth, period of diagnosis, and turnover rate, exposure to lead was not statistically signi-
ficantly elevated: the SIR for low exposure (blood lead < 0.3 µmol/L) was 1.24 (95% CI,
0.95–1.62) and the SIR for medium/high exposure (blood lead > 0.3 µmol/L) was 1.27
(95% CI, 0.81–2.01).
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2.1.10 Population-based case–control studies

(a) Multiple cancer sites
A population-based case–control study of cancer associated with occupational expo-
sure among male residents of Montreal, Canada, aged 35–70 years, included histologically-
confirmed cases of several types of cancer newly diagnosed between 1979 and 1989 in 19
hospitals (Siemiatycki, 1991). Interviews were carried out with 3730 cancer patients
(response rate, 82%) and 533 age-stratified controls from the general population (response
rate, 72%). The main cancer sites included were oesophagus, stomach, colon, rectum,
pancreas, lung, prostate, bladder, kidney, skin melanoma and non-Hodgkin lymphoma. For
each cancer site analysed, two controls were available: a population control and a control
selected among cases of cancer at other sites. The interview was designed to obtain lifetime
job histories and information on potential confounders. Each job was reviewed by a team
of chemists and industrial hygienists who translated the jobs into occupational exposures
using a checklist of 293 substances found in the workplace. For exposure to lead
compounds or various other forms of lead, no excess risk of cancer was seen for most of
the primary sites examined. For substantial exposure to lead compounds, there was a
statistically significant 1.8-fold increase in the risk of stomach cancer and a statistically
significant 1.5-fold increase in the risk of lung cancer. Substantial exposure to lead dust
was associated with an increased risk of stomach cancer, but there were only three exposed
cases. The odds ratio for kidney cancer for any exposure to lead was 1.2 (90% CI, 1.0–1.6;
88 exposed cases) and that for substantial exposure was 0.8 (90% CI, 0.4–1.7; six cases).
For other forms of exposure to lead, there were smaller numbers, and there were some
excess risks reported only with the category ‘any exposure’. [The Working Group noted
that this study reported significant associations between estimated exposure to lead com-
pounds and both stomach cancer and (to a lesser extent) lung cancer. However, the study
involved multiple comparisons of exposures and cancer sites, as well as some uncertainties
in exposure classifications, and so reliance has been placed in this monograph primarily on
the results from cohort studies of lead-exposed populations.]
(b) Stomach
Cocco et al. (1999b) reported a population-based case–control study on occupational
risk factors for stomach cancer associated with 12 workplace exposures, based on informa-
tion from a national surveillance programme for occupational diseases at the National
Cancer Institute, USA. The main study included 41 957 deaths from stomach cancer during
1984–96. Two controls per case were selected from those who died from non-malignant
diseases; controls were matched to cases by geographic region, race, sex and 5-year age
group. An investigation of deaths from cancers of the gastric cardia (ICD-9 code 151.1),
including 1056 cases during 1984–92 and 5280 controls, was also undertaken (Cocco et al.,
1998b). The study classified probability and intensity of exposures to lead with help of a
job–exposure matrix composed from occupational and industry titles reported as the
‘usual’ occupation and industry on the death certificate. Overall, risk for stomach cancer
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was not increased among Caucasian men with either increasing probability or intensity of
exposure to lead. There were some slight increases in the risk among African-American
men, Caucasian women and African-American women with high probability of lead expo-
sure. Risk for gastric cardia cancer was slightly elevated with increasing probability or
intensity of exposure to lead. There was only one case, however, in the group with high
probability and intensity and the risk estimate was not provided. [The reliability of the lead
exposure data and intercorrelations with other exposures were not described.]
(c) Kidney
A population-based case–control study among residents of Finland (Partanen et al.,
1991) was conducted in 1977–78 involving 672 incident cases of primary renal adeno-
carcinoma and 1344 controls matched on age, sex and survival status. A questionnaire
including information on job history, smoking and obesity was sent to all participants or to
the next-of-kin of deceased participants. Response rates for cases and controls were 69%
and 68%, respectively. After exclusion of non-eligible subjects, 408 cases and 819 controls
remained in the study. Summary indicators of occupation were calculated for the period
1920–68 to allow for a 10-year latency and occupational histories were scored by an
industrial hygienist. The annual exposure to lead and inorganic lead compounds was cate-
gorized as background (< 0.001 mg/m3), low (0.001–0.05 mg/m3), high (> 0.05 mg/m3)
and ‘not known’. Four cases of kidney cancer (all men) had been exposed to lead and
inorganic lead compounds. After adjusting for smoking, coffee consumption and obesity,
an odds ratio of 2.77 (95% CI, 0.49–15.6) was observed in subjects with at least 5 years of
high- or low-level exposure before 1968, or less than 5 years of exposure but at least 1 year
of high-level exposure during 1920–68, versus background exposure. When the white-
collar and farming occupations were excluded, the odds ratio was 5.6 (95% CI, 0.6–54.8).
A population-based case–control study on renal-cell cancer from 1991 to 1995 (Pesch
et al., 2000) enrolled 935 cases from five regions in Germany and 4298 population
controls, matched to the cases by region, sex and age. Information on occupational history
and other risk factors was collected in face-to-face interviews. The response rates were
84–95% and 63–75% for cases and controls, respectively. Information on occupational
risk factors was based on two job–exposure matrices (British and German) and used on
every job task held for at least 1 year. For each job title and job task the exposure matrix
provided an expert rating in terms of the probability and the intensity of exposure to an
agent. Slight increases were suggested in the renal-cell cancer risk for estimated expo-
sures to lead, with some dose–response patterns. [Descriptions of tasks with estimated
exposures were not provided. Inter-correlations or confounding from other occupational
exposures were not tested. It was not possible to check whether differential response rates
between cases and controls affected the results.]
(d) Brain and nervous system

A population-based case–control study using information from a national surveillance
programme for occupational diseases at the National Cancer Institute, USA, classified
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probability and intensity of exposures to lead with help of a job–exposure matrix composed
from occupational and industry titles (Cocco et al., 1998a). No information on the duration
of exposure was available. Cases were 27 060 Caucasian and African-American subjects
(14 655 men and 12 405 women) who died during the period 1984–92 from cancer of the
brain at age 35 years or older. Four controls per case were selected from among subjects
who died from non-malignant diseases. When all levels of exposure to lead were
combined, brain cancer risk did not increase with increasing probability of exposure. When
all probabilities of exposure were combined, there was no overall increase in the risk by
exposure level, except among the African-American population (for most of whom low
probability of exposure was coded, however, if the estimated level was medium or high).
The risk estimate for brain cancer with high probability and level of exposure to lead was
2.1 (95% CI, 1.1–4.0; 14 cases observed) among Caucasian men and 1.4 (95% CI, 0.4–4.2;
four cases observed) among Caucasian women. Among Caucasian men, the category with
high probability and level of exposure appeared to be only one occupational group, i.e.
typesetters and compositors. In a later study on central nervous system tumours in women
in the USA, Cocco et al. (1999a) reported a slightly increased risk for meningiomas (odds
ratio, 1.9; 95% CI, 1.0–3.9; nine cases observed) for any versus no exposure to lead.
Hu, J. et al. (1998) performed a hospital-based case–control study on risk factors for
glioma in the province of Heilongjiang, China. Altogether 218 consecutive incident cases
of primary glioma diagnosed between 1989 and 1995 were identified from six hospitals,
and two controls were recruited per case from patients with non-neoplastic, non-neural
disease. The reported response rates were 100% for both cases and controls. Based on self-
reported exposure (request to describe chemical or other occupational exposures using a
pre-specified list of agents), there was no increase in the risk related to lead exposure (no
cases and four controls). The study was extended to December 1996 with 183 cases of
meningioma and 366 controls (Hu et al., 1999). This study suggested an increased risk for
meningioma with exposure to lead. [Only self-reported exposure was available. Occupa-
tions or exposure levels among lead-exposed respondents were not detailed.]
(e) Other primary sites

Risch et al. (1988) conducted a population-based case–control study of bladder cancer
during 1979–82 in Canada. Cases aged 35–79 years diagnosed through the tumour registry
or hospital files were eligible (n = 1251) and population controls were used (n = 1483).
Information on occupational history and jobs held in some pre-selected industries, together
with self-reported exposure to fumes, dusts, smoke or chemicals, were collected for 835
(67%) eligible cases and 792 (53%) controls through face-to-face interviews. Information
on family, medical and residential histories, use of tobacco, socioeconomic factors and diet
was also collected. Among men who had worked full-time for at least 6 months, exposure
to lead compounds was associated with risk for bladder cancer (twofold risk among ever
exposed, adjusted for smoking) and there was a trend with duration of exposure/employ-
ment as estimated per 10 years. [Exposure to lead was not reported among women. Expo-
sures were partially self-reported. It was not clearly stated if the information on work tasks
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was used in defining exposure status in the assessment. It was not possible to check
whether the differential response rate affected the results.]
Kauppinen et al. (1992) conducted a population-based case–control study on primary
liver cancer and occupational exposures in Finland. Cases were drawn from 1976–78 and
1981 from the files of the nationwide cancer registry (cases from 1979–80 had been used
in another study by the same group); two reference groups were formed from patients
with stomach cancer in 1977 and persons who had died from coronary infarction. There
were 344 liver cancer cases, 476 controls with stomach cancer and 385 controls with
coronary infarction. Controls were matched to cases by age and sex. Information on work
history was collected, with the aid of a postal questionnaire, from the closest next-of-kin
traced for the study subjects. Response rates were 71% for both cases and controls.
Exposure assessment was made using a job–exposure matrix and by a team of
occupational hygienists. In the analyses using the job–exposure matrix, no association
between the risk for liver cancer and exposure to lead and lead compounds was seen (odds
ratio, 0.91; 95% CI, 0.65–1.29 for a combined group of low level or probability of
exposure). Based on the hygienists’ assessments, the odds ratio for any exposure to lead
was also close to unity (1.14; 95% CI, 0.44–2.98 after adjustment for alcohol
consumption). No cases and four controls had had heavy exposure to lead (they were all
typesetters with more than 10 years of employment) and five cases had had moderate
exposure (odds ratio, 2.28; 95% CI, 0.68–7.67). Moderate exposure was defined as a
duration of at least 10 years with low-level exposure or a duration of less than 10 years
with high-level exposure; the group included workers in plumbing, welding and crystal
glass manufacture. [Comparison between stomach cancer and infarction controls as to
their exposures to lead was not available.]
2.1.11 Meta-analyses
Fu and Boffetta (1995) reviewed reports of 16 cohort studies and 13 case–control
studies (nested and population-based) relating to lead exposure and cancer risk. Meta-
analyses were performed for all cancers (12 studies), stomach cancer (10 studies), lung
cancer (15 studies), kidney cancer (five studies) and bladder cancer (five studies). [The
Working Group noted that most of the studies included in the meta-analyses of Fu and
Boffetta (1995) and Steenland and Boffetta (2000) (see below) have been considered in
this monograph. Neither meta-analysis included exposures to organo-lead or in the mining
industry, both of which are discussed in detail in this volume. The meta-analysis of Fu and
Boffetta (1995) included two studies of oil mist exposure in the printing industry
(Goldstein et al., 1970; Pasternack & Ehrlich, 1972), which have not been discussed here.
These two studies lacked specific lead exposure data, did not adjust for smoking nor for
other occupational exposures and did not have appropriate reference groups.] Fu and
Boffetta (1995) included only the most recent publications if several reports were available
for the same study population. Fixed-effect models were used; random-effect models were
also applied when there was significant heterogeneity in a set of relative risks. The meta-
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analysis was limited to overall study findings (SMRs from cohort studies, and odds ratios
from case–control studies); quantitative data or analyses in relation to categories of cumu-
lative exposure were not considered. The meta-analyses (fixed-effect models) provided
significantly elevated summary relative risks for all cancers (relative risk, 1.11; 95% CI,
1.05–1.17), stomach cancer (relative risk, 1.33; 95% CI, 1.18–1.49), lung cancer (relative
risk, 1.29; 95% CI, 1.10–1.50) and bladder cancer (relative risk, 1.41; 95% CI, 1.16–1.71).
A non-significantly elevated risk was shown for kidney cancer (relative risk, 1.19; 95% CI,
0.96–1.48). Significant heterogeneity in the set of study-specific relative risks was only
shown for lung cancer (p < 0.001) but a highly significant summary relative risk was also
obtained for this cancer from a random-effect model (odds ratio, 1.29; 95% CI, 1.10–1.50).
When meta-analysis was restricted to studies conducted in industries involving higher lead
exposures (battery and smelter industries), significantly elevated summary relative risks
were shown for all cancers (five studies: relative risk, 1.08; 95% CI, 1.02–1.15), stomach
cancer (four studies: relative risk, 1.50; 95% CI, 1.23–1.83) and lung cancer (random-effect
model applied to three studies: relative risk, 1.42; 95% CI, 1.05–1.92). A non-significantly
increased relative risk was shown for kidney cancer (three studies: relative risk, 1.26; 95%
CI, 0.70–2.26). [Most of the studies included in this meta-analysis were of occupational
groups with exposure to carcinogens such as chromium and arsenic as well as lead. Most
of the studies were cohort studies entailing comparison with the general population without
adjustment for potential confounding from smoking or diet. Many of the cohort studies did
not report data for all of the cancers of interest and there is considerable scope for
publication bias for the meta-analyses of kidney and bladder cancer; however, this is not
an issue for the lung cancer findings.]
In their review of lead and cancer in humans, Steenland and Boffetta (2000) included
a meta-analysis of eight cohort studies of highly exposed workers. Four studies analysed
cancer mortality (of which one study used a nested case–control design); the remaining
four studies analysed cancer incidence (cancer registrations). The results of meta-analyses
for all cancers (n = 1911) and cancers of the lung (n = 675), stomach (n = 181), kidney
(n = 40) and brain (n = 69) were presented. The investigators first determined whether
there was significant heterogeneity in each set of cause-specific relative risks (estimated
by overall site-specific SMRs, summary relative risks or odds ratios obtained from
internal comparison). There was an absence of such heterogeneity for all cancers, and
cancers of the stomach, kidney and brain. Therefore, fixed-effect models were used for
these groupings of cancer sites to combine relative risks across the studies. A significantly
elevated relative risk was shown for cancer of the stomach (relative risk, 1.34; 95% CI,
1.14–1.57) but not for kidney cancer (relative risk, 1.01; 95% CI, 0.72–1.42), brain cancer
(relative risk, 1.06; 95% CI, 0.80–1.40) or all cancers (relative risk, 1.04; 95% CI,
1.00–1.09). There was significant heterogeneity in the set of relative risks for lung cancer
and the investigators applied a random-effect model, leading to an overall relative risk of
1.30 (95% CI, 1.15–1.46). A previous study (Englyst et al., 1999) had shown that there
was significant arsenic exposure in the outlier study (Lundström et al., 1997), and exclu-
sion of this study led to a much lower summary relative risk for lung cancer (1.14;
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95% CI, 1.04–1.25). [This meta-analysis is limited to overall summary findings; quanti-
tative data or possible dose–response effects within the eight studies were not available
for meta-analysis. It was not possible to adjust for potential confounders such as smoking
and occupational exposure to arsenic and other chemicals.]
2.2 Studies based on general population (environmental) exposures

Studies in the general population involve exposures to lead in the environment which
are usually much lower than lead exposures in occupational studies, sometimes by as
much as an order of magnitude. Exposure effects at low doses can differ from those at
high doses with regard to the type of cancer. Furthermore, low-dose effects may involve
biological mechanisms different from those involved in high-dose effects, even for the
same cancer site. Nevertheless, when considering the same cancer site, in general, one
should expect that higher doses should cause more disease than lower doses.
Five ecological studies deal with exposure to lead and cancer. Correlations between
levels of trace metals in water supplies and cancer mortality in the USA were investigated
by Berg and Burbank (1972). Lung cancer mortality rates for Caucasian men and women
in the former ‘Tri-State mining district’ of the USA (Cherokee County, KS; Jasper County,
MO and Ottawa County, OK) were investigated by Neuberger and Hollowell (1982).
Correlations between lead concentrations (and other aspects of air pollution) and lung
cancer incidence rates (standardized for age, sex and race) were investigated in 1973–76
by Vena (1983) for 125 census tracts in New York State, USA. Correlations between
blood lead concentrations and age were investigated by Hussain et al. (1990) for cancer
patients and other residents of the Lahore district in India. Relationships between mineral
and trace elements in drinking-water and gastric cancer mortality in 34 municipalities in
the Aomori Prefecture of Japan were investigated by Nakaji et al. (2001). [The Working
Group judged these studies to be uninformative due to the poor classification of exposure
and the considerable scope for confounding.]
2.2.1 Cohort studies

McDonald and Potter (1996) conducted a mortality study in a cohort of 454 paediatric
patients resident in Massachusetts, USA, and diagnosed with lead poisoning at Boston
Children’s Hospital between 1923 and 1966. Diagnosis of lead poisoning was based on the
presence of at least two of the following clinical criteria: (1) history of lead exposure or of
lead poisoning in a sibling; (2) radiographic lead lines in the bones; (3) gastrointestinal,
haematological and/or neurological symptoms of lead poisoning. Cohort members were
traced until 1991 to ascertain mortality; 153 (33.7%) were lost to follow-up. Numbers of
observed deaths were compared with those expected, based on population statistics in the
USA. Eighty-six deaths were observed (observed/expected, 1.74; 95% CI, 1.40–2.15), 10
of which were due to cancer (observed/expected, 1.14; 95% CI, 0.55–2.10). Seventeen
deaths were directly attributed to lead poisoning. Mortality from cardiovascular disease
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was elevated (observed/expected, 2.09; 95% CI, 1.29–3.19). [The study is limited by the
high percentage of cohort members lost to follow-up.]
2.2.2 Cohort studies of the general population based on blood lead

concentrations
The National Health and Nutrition Examination Survey (NHANES II) conducted two
studies between 1976 and 1980 on the same population in the USA, based on a national
probability sample of the civilian non-institutionalized population, aged 6 months to 74
years at baseline (n = 27 801) (Jemal et al., 2002; Lustberg & Silbergeld, 2002) (see also
Section 1.6). Data were obtained from standardized questionnaires, physical examinations
and laboratory tests. Single blood lead measurements were made for all children below 7
years of age and for a random subsample of half of the subjects aged 7 years or more.
Mortality was investigated for the period 1976–92 via internal comparisons of rates for
those with high blood lead concentrations versus those with low blood lead concentrations
[a single blood lead estimation may misrepresent long-term exposure].
Jemal et al. (2002) restricted their analyses to 3592 Caucasian subjects (1702 men,
1890 women) aged 30 years or more at baseline. The study had a complex sample design
with multistage stratified cluster sampling and sample weighting of study participants. Cox
proportional hazard regression models were used to estimate dose–response relationships
between blood lead and mortality from all cancers (203 deaths), as well as some specific
cancers. Log-transformed blood lead was both categorized into quartiles and treated as a
continuous variable in a cubic regression spline. Median blood lead concentrations for the
quartiles were 7.3, 10.6, 13.8 and 19.7 µg/dL. In analyses that adjusted for baseline values
of age (continuous variable), poverty, annual alcohol and tobacco use, region and year of
examination, there were no significant trends between blood lead concentrations (quartile
analyses) and risk for cancer mortality in men and women combined (p = 0.16), men (p =
0.57) or women (p = 0.22). None of the examined site-specific cancer risks showed a signi-
ficant association with blood lead at baseline. For lung cancer (71 deaths), the rate ratio
comparing subjects with blood lead concentrations above the median versus below the
median, adjusted for smoking and age, was 1.5 (95% CI, 0.7–2.9). Based on five stomach
cancer deaths, the relative risk for those with blood lead concentrations above the median
versus those below the median was 2.4 (95% CI, 0.3–19.1). [The Working Group noted the
strong reported correlation between smoking and baseline blood lead concentration and
that adjustment for smoking did not consider duration of smoking, which may have led to
some residual confounding.]
NHANES II was used by another research group to analyse associations between blood
lead concentrations at baseline and subsequent mortality (Lustberg & Silbergeld, 2002).
This report made use of data for non-Caucasian as well as Caucasian subjects. A total of
4292 male and female participants aged 30–74 years with baseline blood lead concen-
trations were considered; follow-up identified 929 deaths (240 cancer deaths) before the
end of 1992. In order to exclude those with high blood lead concentrations due to possible
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occupational exposure, the authors did not consider subjects who had blood lead
concentrations ≥ 30 µg/dL. [The Working Group noted that elimination of those with
highest exposure may weaken dose–response analyses.] In analyses that adjusted for base-
line values of age, sex, race, education, income, smoking, body mass index, exercise and
location (urban, rural, suburban), there was a positive trend with blood lead concentration
for all causes of death (referent < 10 µg/dL; 10–19 µg/dL: relative risk, 1.17; 95% CI,
0.90–1.52; 20–29 µg/dL: relative risk, 1.46; 95% CI, 1.14–1.86), for diseases of the circu-
latory system (referent < 10 µg/dL; 10–19 µg/dL: relative risk, 1.10; 95% CI, 0.85–1.43;
20–29 µg/dL: relative risk, 1.39; 95% CI, 1.01–1.91) and for all cancers (referent
< 10 µg/dL; 10–19 µg/dL: relative risk, 1.46; 95% CI, 0.87–2.48; 20–29 µg/dL: relative
risk, 1.68; 95% CI, 1.02–2.78). The only specific cancer for which results were given was
lung cancer, for which rate ratios were 1.70 (95% CI, 0.60–4.81) and 2.20 (95% CI,
0.80–6.06), for the middle and high exposure groups, respectively. [The Working Group
noted that residual confounding by smoking may have resulted from failure to consider
duration in the adjustment for smoking. Data for all cancers show large decreases in rate
ratios after control for smoking, suggesting that better control over smoking might lead to
further decreases, especially for lung cancer. The Working Group also noted that the
generalized increase in all deaths, all cancers and all circulatory diseases with increasing
blood lead concentration suggests possible residual confounding by socioeconomic status.]
2.2.3 Case–control studies

The possible relationship between laryngeal cancer and subclinical lead intoxication
(assessed both by blood lead concentrations and ALAD activity in the blood) has been
investigated (Kandiloros et al., 1997). A total of 58 patients underwent surgery for cancer
of the larynx over a period of 8 months at a hospital in Athens, Greece. After excluding
patients with a history of lead intoxication, professional exposure to lead, previous renal or
haematological diseases, or with other health problems, a total of 26 patients (24 men, two
women) aged 42–75 years were included in the study. All patients had histologically-con-
firmed squamous-cell laryngeal carcinoma; none of the patients had received chemotherapy.
Fifty-three patients with no history of cancer, suffering from other diseases, mainly otitis
media, comprised the control group. There was no significant difference in the mean blood
lead concentration between the two groups (patients: mean, 8.5 µg/dL; controls: mean,
7.9 µg/dL). However, ALAD activity was significantly lower (0.001 < p < 0.01) in the cases
(patients: mean, 50.9 U/L; controls: mean, 59.8 U/L). [The Working Group noted that the
exclusion of lead-exposed cases may have biased the results and that the ALAD concen-
tration could have been affected by the case–control status.]
The possible relationships between cancer of the gallbladder and biliary concen-
trations of heavy metals have been investigated (Shukla et al., 1998). Cases comprised 38
patients (11 men, 27 women) with histologically-diagnosed cancer of the gallbladder
admitted to the surgical unit of the University Hospital, Varanesi, India, from January
1995 to March 1996. Controls comprised 58 patients with gallstones (14 men, 44
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women). The mean age of the cases was 53.5 years and that of the controls was 48.3 years.
Bile was taken by needle aspiration from the gallbladder of all patients at the time of
surgery for estimation of cadmium, chromium and lead concentrations. Statistical compa-
risons were made using Student’s t-test. Highly significant differences between cases and
controls (p < 0.001) were observed for the mean values of all the metals under study
(cadmium: cases, 0.19 mg/L; controls, 0.09 mg/L; chromium: cases, 1.26 mg/L; controls,
0.55 mg/L; lead: cases, 58.4 mg/L; controls, 3.99 mg/L). There was no overlap in the
observed ranges of biliary lead concentrations (cases, 35–76 mg/L; controls, 0–19 mg/L).
[The Working Group noted that age and sex differences in the two groups (cases were on
average 5 years older than controls and included a higher percentage of men) were not
taken into account, but judged this to be an unlikely explanation of the study findings. The
results could indicate that lead exposure is an important risk factor for cancer of the gall-
bladder, but no attempt was made to determine whether the cases had been more exposed
to lead than had the controls. Alternatively, the lead concentration findings may reflect a
consequence of gallbladder cancer or gallstones.]
At a hospital clinic in Lucknow, India, blood lead, zinc and copper concentrations in
17 patients undergoing surgery for cancer of the prostate, 41 patients undergoing surgery
for benign hyperplasia of the prostate and 20 controls (men without any symptoms of
bladder flow obstruction) were investigated (Siddiqui et al., 2002). Patients (mean age:
cancer cases, 71.0 years; benign disease, 70.0 years) were older than controls (mean age,
53.1 years) [no information was supplied on how controls were selected]. Mean blood
lead concentrations were significantly higher (p < 0.05) in patients with prostate diseases
(cancer cases, 28.2 µg/dL; benign hyperplasia, 23.4 µg/dL) than in controls (10.2 µg/dL).
Blood concentrations of zinc and copper were significantly lower (p < 0.05) both in
prostate cancer cases and cases of benign hyperplasia than in controls. [The comparisons
were unadjusted for age.] None of the subjects reported any previous occupational or
accidental exposure to lead. [The Working Group noted that the disease status may have
affected the blood lead concentrations.]
2.3 Studies on parental exposure and childhood cancer

2.3.1 Cohort studies
Wulff et al. (1996) conducted a cancer incidence study among a cohort of 30 644
children born between 1961 and 1990 in the municipality of Skellefteå, Sweden, to deter-
mine whether children born to women living near the Rönnskär smelter during pregnancy
(n = 4400) had an increased incidence of cancer compared with children born to women
living at a distance from the smelter (n = 26 244). The Rönnskär smelter is a significant
source of environmental pollutants, including lead, arsenic, copper, cadmium and sulfur
dioxide. People living in two parishes within a 20-km radius of the smelter (St. Örjan and
Bureå) were considered to be the exposed group, based on environmental sampling data.
People in all other parishes within the municipality were considered to be unexposed.
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Through linkage to the Swedish Cancer Registry, cancer diagnoses were obtained and
compared with expected numbers based on national incidence rates in Sweden. Thirteen
cases of childhood cancer (four leukaemia, three brain, one kidney, one eye and four other
cancers) were identified among children born in the exposed area, versus 6.7 expected
(SIR, 195; 95% CI, 88–300). Among children born to women living in the unexposed
area, the observed number of cancer cases (n = 42) was similar to that expected (n = 41.8).
[The focus on incidence of disease, the large size of the population and the linkage to
national data sets are strengths of this study, but the lack of individual exposure data or
blood lead concentrations are weaknesses. The presence of multiple contaminants makes
etiological assignment difficult.]
In a study in Norway, Kristensen and Andersen (1992) used multistep register linkage
to measure cancer incidence in a cohort of children who were the offspring of men who
were members of the Oslo printers’ unions. A file of these workers’ children was esta-
blished through linkage with the Central Population Register. Children born between
1950 and 1987 (n = 12 440) were traced for cancer incidence during the years 1965–87
in the Cancer Registry of Norway (193 406 person–years). Thirty-three incident cases of
cancer were found. To account for the fact that the use of lead in the Oslo printing industry
ended in the mid-1970s, an examination of cancer incidence was undertaken in the
subcohort of 3221 children born before 1975. In this group, none developed cancer before
age 15 (32 532 person–years) compared with 3.7 expected (upper limit of the 95% CI,
100). [The Working Group noted that exposure was uncertain.]
2.3.2 Case–control studies

(a) Wilms’ tumour
In a case–control study of Wilms’ tumour incidence (Kantor et al., 1979), 149 children
born in Connecticut, USA, aged 0–19 years (80 males, 69 females) with Wilms’ tumour
recorded in the Connecticut Tumor Registry during the period 1935–73 were compared
with 149 matched controls selected from Connecticut birth certificates and matched by sex,
race and year of birth. The occupation of the father at the time of the child’s birth was deter-
mined from the birth certificate and used as an indicator of potential sources of exposure
to carcinogens. An association was found between paternal occupations related to lead
(driver, motor-vehicle mechanic, service-station attendant, welder, solderer, metallurgist
and scrap metal worker) in the children with Wilms’ tumour compared with the controls.
Fathers of 22 cases and of six controls had been employed in lead-related occupations
(odds ratio, 3.7; 95% CI, 1.5–11.1). Fathers of five cases and of one control had been
employed in jobs with potential exposure to lead (odds ratio, 5.75). [The Working Group
noted that no confidence interval was given and that exposure was uncertain.]
In a case–control study conducted by Wilkins and Sinks (1984a,b), an occupation–
exposure linkage system was used to examine the possible association between paternal
occupation and Wilms’ tumour incidence. The study was undertaken in Ohio, USA, and was
based on 62 cases with histologically-confirmed tumours, registered through the Columbus
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Children’s Hospital Tumor Registry between 1950 and 1981. Cases from certain counties in
Ohio were excluded from analysis because they fell outside a particular catchment area. Two
controls per case were selected from birth certificate files in Ohio and matched on year of
birth, sex and race. Job-related exposure of the father was inferred from the occupational and
industry notation on the birth certificates, using a job–exposure matrix developed by Hoar
et al. (1980). The first part of the study was designed to test the hypothesis that paternal
exposure to lead is a risk factor for Wilms’ tumour in offspring. There was no statistical
difference in the frequency of occupational exposure to lead (odds ratio, 1.1; 95% CI,
0.6–2.0), lead alkyls (odds ratio, 1.3; 95% CI, 0.5–3.3) or lead salts (odds ratio, 0.7; 95% CI,
0.1–4.1) between fathers of children with Wilms’ tumour and fathers of controls. Occu-
pations associated with exposure to lead were examined by calculating odds ratios, all of
which were greater than unity but not statistically significant. For exposure to lead, the odds
ratio was 1.25 (95% CI, 0.56–2.70).
Olshan et al. (1990) undertook a case–control study in the USA to examine the
possible relationship between Wilms’ tumour and paternal occupational exposure. Cases
consisted of 200 children with Wilms’ tumour diagnosed by histopathological exami-
nation, who were registered at selected National Wilms’ Tumour Study institutions
between 1 June 1984 and 31 May 1986. The National Wilms’ Tumour Study registers an
estimated 84% of all cases of Wilms’ tumour diagnosed in the USA. Disease-free controls
(n = 233) of the same age (± 2 years) and geographic area were matched to each case using
a random-digit dialling procedure. To ascertain history of occupational exposure, the
parents of cases and controls completed a self-administered questionnaire that provided
information on all jobs held for more than 6 months since 18 years of age. Questionnaires
were completed by the parents of 234 cases (61% of eligible cases), but only 200 (52% of
eligible) were successfully matched with a control. Questionnaires were completed by
parents of 233 controls (52% of eligible). Paternal exposures were assessed for three
separate time periods in the period between birth and diagnosis: preconception, during
pregnancy and postnatal. Exposure was determined by juxtaposition of each occupational
exposure history with a job–exposure matrix developed by NIOSH. Specific analyses
linking exposure to lead with the incidence of Wilms’ tumour gave odds ratios of 1.07 (37
exposed cases/33 exposed controls; 95% CI, 0.58–1.98) for preconception exposure; 1.14
(24/24; 95% CI, 0.56–2.36) for exposure during pregnancy; and 1.31 (21/22; 95% CI,
0.61–2.77) for postnatal exposure.
(b) Other cancer sites

Buckley et al. (1989) conducted a case–control study to examine the incidence of acute
non-lymphocytic leukaemia in relation to parental occupational exposures in children in
the USA and Canada under 18 years of age. Of 262 eligible cases, mothers of 204 children
(78%) were interviewed successfully. Controls were obtained through random-digit
dialling and matched on date of birth (± 2 years for children aged more than 4 years and
± 12 months for children aged 1–3 years) and race. Information on occupational exposure
was sought through interview with the mother, and exposures were ascertained either by
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direct reporting of chemical name or inference from job title. The fathers of five cases and
five controls had been exposed to lead between 1 and 1000 days (odds ratio, 1.0; 95% CI,
0.3–3.5); the fathers of six cases and of none of the controls had had exposure to lead for
more than 1000 days (p for trend = 0.03). [The Working Group noted that the positive trend
with increasing duration is based on a small number of cases and on retrospective ascer-
tainment of exposure without any blood lead data.]
A case–control study conducted during 1976–87 in the USA included all residents of
New York State, excluding New York City, diagnosed with neuroblastoma (Kerr et al.,
2000). A total of 216 cases aged < 15 years and born to Caucasian mothers was ascertained
from the NY State Cancer Registry. Controls were sampled from the NY State Department
of Health live birth certificate registry and matched on ethnicity of the mother and age.
Telephone interviews were conducted with the mothers during 1992–93 with a completion
rate of 85% (final number of cases = 183). Interviews gathered information on gestation,
drug use and medical history during pregnancy, parents’ lifestyle, occupation, and socio-
demographic attributes. Using self-reported occupational exposure and a list of industries
and occupations with potential for exposure, exposure certainty indexes were coded for
each of 25 physical and chemical agents as: category 1, reported exposure and potential for
exposure; category 2, no report of exposure but potential for exposure; category 3, report
of exposure but no potential for exposure; category 4 (no reported exposure and no poten-
tial for exposure) was used as reference. Odds ratios of 4.7 (95% CI, 1.3–18.2) for self-
reported maternal exposure to lead (nine cases, four controls) and 2.4 (95% CI, 1.2–4.8)
for self-reported paternal exposure (21 cases, 18 controls) were observed. Odds ratios for
categories 1, 2 and 3 for maternal exposure were 3.5 (95% CI, 0.7–22.6), 0.8 (95% CI,
0.4–1.8) and 8.3 (95% CI, 0.8–412.1), respectively, and for paternal exposure, 2.2 (95%
CI, 0.9–5.4), 1.0 (95% CI, 0.7–1.6) and 3.3 (95% CI, 1.0–11.5), respectively.
3. Studies of Cancer in Experimental Animals
3.1 Lead acetate

3.1.1 Mouse
(a) Oral administration
In a study by Waszynski (1977), a total of 137 male and female F1(RIII × C57Bl) mice,
6–8 weeks of age, were divided into four groups and fed diets containing lead acetate
(analytical grade) (daily intake, 6 mg/mouse), sulfathiazole (daily intake, 0.3 mg/mouse),
lead acetate plus sulfathiazole, or unaltered diet (control) for 18 months and were observed
for an additional 7 months. Some animals died during the observation period. Histological
analysis revealed that none of the treatments produced renal tumours. [The Working Group
noted that the group sizes were not specified.]
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Blakley (1987) exposed groups of 42–46 female albino Swiss mice, 8 weeks of age, to
lead acetate [purity unspecified] in drinking-water at concentrations of 0 (control), 50 or
1000 µg/mL for up to 280 days. This mouse strain has a high spontaneous incidence of lym-
phocytic leukaemia. Mice that died during exposure or were killed at the end of the study
were examined grossly for evidence of lymphocytic leukaemia of thymic origin (enlarged
thymus). Survival was significantly reduced (p = 0.007, Lee-Desu survival statistic) in the
lead-treated mice, suggesting that lead enhanced death due to leukaemia. [The Working
Group noted the absence of histological analysis of the tumours.]
(b) Pre- and perinatal administration

In a study by Waalkes et al. (1995), groups of 10–15 primigravid C57Bl/6NCr mice,
previously bred with C3H/HeNCr males to produce B6C3F1 offspring, were given ad libi-
tum drinking-water containing lead acetate [purity unspecified] at doses that provided lead
concentrations of 0 (control), 500, 750 and 1000 ppm, from gestation day 12 through to
birth and until 4 weeks postpartum when offspring were weaned. Exposure to lead acetate
did not alter litter size. The offspring were placed into same-sex groups of 23–25 based
on maternal exposure level to lead acetate. They were given water without added lead and
with or without 500 ppm sodium barbital as a renal tumour promoter and observed for a
total of 112 weeks postpartum. Exposure to lead acetate did not alter body weight of the
offspring nor the survival of any group during the observation period. A complete
necropsy was performed on each animal. In male offspring, histological examination of
the kidneys revealed that exposure to lead acetate was associated with a dose-related
increase (p = 0.0006, Cochran-Armitage test for trend) in the incidence of proliferative
lesions (including atypical tubular-cell hyperplasia) and a significant increase in the
incidence of renal adenomas (p < 0.05, two-tailed Fisher’s exact test) and occasional renal
carcinomas. In female offspring, exposure to lead acetate was associated with a significant
dose-related increase (p = 0.017; Cochran-Armitage test for trend) in the incidence of
renal proliferative lesions, including hyperplasia, adenoma and carcinoma. Proliferative
lesions were exclusively of renal tubular cell origin. Sodium barbital did not increase the
incidence of renal proliferative lesions in any group. The authors noted that the
transplacental/translactational lead acetate-induced tumours arose in the absence of exten-
sive chronic nephropathy typically seen in lead carcinogenesis in rodents chronically
exposed as adults. Exposure to lead acetate was not associated with tumours at extra-renal
sites in any of the experimental groups (Waalkes et al., 1995).
(c) Administration with known carcinogens or modifiers of

carcinogenesis
Bull et al. (1986) tested various chemicals with potential to initiate tumours, including
lead acetate (purity, > 99%), in groups of 30 female SENCAR mice, 6–8 weeks of age.
The mice received a single oral dose of 600 mg/kg bw [presumably by gastric intubation;
vehicle either emulphor, saline or water] or a single dermal application of 600 mg/kg bw
to the shaved back [vehicle either acetone or ethanol]. Two weeks later, mice received
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dermal applications of 1.0 µg of the skin tumour promoter, 12-O-tetradecanoyl phorbol-

13-acetate (TPA), in 0.2 mL acetone three times per week for up to 52 weeks. Skin
tumours were assessed histologically; other tumours were not reported. Oral and topical
applications of lead acetate did not affect the incidence of skin tumours. [The Working
Group noted that the study was limited by the use of a single dose and the inadequate
reporting of experimental details.]
Blakley (1987) also studied the effects of oral administration of lead acetate on the
incidence of urethane-induced lung adenoma in female Swiss mice. Groups of 19–25
mice, 3 weeks of age, were exposed to lead acetate [purity unspecified] in the drinking-
water at concentrations of 0 (control), 50, 200 or 1000 µg/mL for 15 weeks. A single intra-
peritoneal injection of 1.5 mg/kg bw urethane was administered 3 weeks after the start of
lead treatment. The lead acetate and urethane treatments did not alter water consumption
or body weight gain. The animals were killed at the end of the lead exposure period
(15 weeks). Lungs were inflated, fixed and inspected visually for the number and size of
adenomas. Treatment with lead acetate did not alter average lung tumour size or multi-
plicity (tumours/animal). [The Working Group noted that the absence of a group treated
with lead acetate alone limited the utility of this study.]
3.1.2 Rat
Boyland et al. (1962) fed a group of 20 male Wistar rats, 10 weeks of age, a diet con-
taining 1% lead acetate [purity unspecified] for 1 year and observed them for up to 629
days. Histological evaluation of rats that died revealed the first renal tumour after 331
days. Subsequently, 14 more rats died with renal tumours. Among the total of 15 renal
tumours, 14 were carcinomas. [The Working Group noted the absence of a control group
but the remarkable incidence of renal carcinomas in lead acetate-exposed animals.]
In a lifetime study testing metals for nutritional essentiality, groups of 50 male and 50
female Long Evans rats [age unspecified] were exposed to 5 ppm lead as lead acetate
[purity not specified] in drinking-water from weaning to natural death and compared with
control animals given water without added lead. Lead acetate significantly increased
mortality in both sexes (p < 0.05, Student’s t-test). Not all animals underwent necropsy
and only grossly visible tumours were evaluated microscopically [tumour location not
specified]. The authors indicated no significant differences in total tumour incidence
between control and lead acetate-treated rats (Chi-squared test) (Schroeder et al., 1965;
Kanisawa & Schroeder, 1969). [The Working Group noted the low dose used, the limited
pathological evaluation, that animals would have been deficient in other metals, and that
the data were inconsistent between the two reports.]
Zawirska and Medras (1968) gave groups of 94 male and 32 female Wistar rats [age
not specified] a diet supplemented with lead acetate [purity unspecified] to achieve a dose
of lead of 3 mg/rat per day for 2 months followed by a dose of 4 mg/rat per day for 16
months. The groups were compared with 19 male and 13 female control rats fed unaltered
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diets. After 18 months, 40 of the lead acetate-treated rats [sex unspecified] were killed
while the rest were allowed to live to a natural death. Weight loss was evident in the lead
acetate-treated rats [actual body weight data not given; survival data not given]. Extensive
histological examination was performed on all animals. The authors stated that no
tumours were observed in control rats except for one adenoma and one carcinoma of the
mammary gland. This included an absence of spontaneous tumours of the kidney and
endocrine organs in control animals. The 94 lead acetate-treated male rats had 58 renal
tumours (43 adenomas, 15 carcinomas), 23 adrenal gland tumours (22 adenomas, one
carcinoma), 23 interstitial-cell tumours of the testes, 22 prostatic tumours (21 adenomas,
one carcinoma), 10 lung tumours (eight adenomas, two carcinomas), four pituitary adeno-
mas, three liver tumours, three brain gliomas, three thyroid adenomas, two spermatic duct
carcinomas, one leukaemia and one sarcoma [given a tumour incidence of 0/19 in control
males, incidences of renal, adrenal, testes and prostatic tumours were significantly
increased in lead acetate-treated male rats (p < 0.05, two-tailed Fisher’s exact test)]. The
32 lead acetate-treated female rats had 14 renal tumours (12 adenomas, two carcinomas),
nine adrenal gland adenomas, five lung tumours (four adenomas, one carcinoma), three
mammary gland tumours, two liver tumours, two thyroid tumours, one pituitary adenoma,
one oesophageal carcinoma, one leukaemia and two sarcomas [given a tumour incidence
of 0/13 in control females, incidences of renal and adrenal tumours were significantly
increased in lead-treated female rats (p < 0.05, two-tailed Fisher’s exact test)]. [The
Working Group noted that the spontaneous incidence of gliomas in rats is a very rare
event.]
In further studies (Zawirska & Medras, 1972; Zawirska, 1981), groups of 47 male and
47 female Wistar rats, 31 weeks of age, were fed lead acetate [purity unspecified] in the
diet to achieve a dose of lead of 3 mg per day [based on 20 g food/rat given to 10 rats/cage]
for periods ranging between 60 and 504 days and were observed for times ranging from 60
days to the point of natural death (maximum 572 days). Control animals [stated variously
as 31 males and 31 females or 47 males and 47 females] were fed unaltered diet and were
observed for up to 800 days [survival was imprecisely defined]. All rats were examined
histologically. No tumours were reported in the control group. In the 94 lead acetate-treated
rats, examination revealed 102 tumours including 12 rats with kidney adenomas, 15 with
lung adenomas, 17 with pituitary adenomas, 10 with brain gliomas, 11 with thyroid adeno-
mas, five with parathyroid adenomas, 11 with prostate adenomas, eight with mammary
adenomas and 13 with adrenal cortical adenomas [all incidences were significantly
increased, except parathyroid adenoma incidence, versus 0/62 control animals (p < 0.05,
two-tailed Fisher’s exact test)]. The authors stated that renal tumour incidence appeared to
be related to length of treatment with lead acetate. [The Working Group noted some incon-
sistencies between the two reports. The Working Group also noted that the spontaneous
incidence of kidney adenomas and brain gliomas is a very rare event.]
Azar et al. (1973) fed groups of 50 male and 50 female rats [strain and age unspecified]
diets containing concentrations of lead acetate [purity unspecified] to give 10, 50, 100 or
500 ppm lead for 2 years. A control group of 100 males and 100 females remained untreated.
Cor 229.qxd 01/09/2006 18:01 Page 229
In a second study, started shortly after the first, groups of 20 male and 20 female rats were
fed 0, 1000 and 2000 ppm lead [presumably as lead acetate] for 2 years. Weight gain was
depressed in animals receiving 1000 and 2000 ppm lead. Data on survival rates at 2 years
indicated increased mortality in males fed 500 and 2000 ppm lead [test not specified].
Complete necropsy with histological examination was carried out on all animals. No patho-
logical lesions were reported in rats fed up to 100 ppm lead. No renal tumours occurred in
either male or female control rats. In male rats treated with lead, the incidence of renal
tumours was 5/50, 10/20 and 16/20 in groups fed 500 ppm, 1000 ppm and 2000 ppm,
respectively [all three incidences were statistically significant, two-tailed Fisher’s exact test;
a χ 2 test for trend proved significant (p < 0.001)]. In female rats treated with lead, the inci-
dence of renal tumours was 0/50, 0/20 and 7/20 in the groups fed 500 ppm, 1000 ppm and
2000 ppm, respectively [the incidence in the last group was significantly increased; two-tail
Fisher’s exact test]. Most renal tumours were adenomas derived from the tubular epi-
thelium. The doses of lead acetate used resulted in the following blood lead concentrations:
no treatment, 12.7 µg/dL; 10 ppm lead acetate, 11.0 µg/dL; 50 ppm, 18.5 µg/dL; 100 ppm,
35.2 µg/dL; 500 ppm, 77.8 µg/dL.
Waszynski (1977) fed groups of 15–20 male and 19–26 female [individual group size
not specified] Wistar rats, aged 2–2.5 months, diets containing either lead acetate (analy-
tical grade) alone, sulfathiazole alone, lead plus sulfathiazole or unaltered diet (control) for
18 months and observed them for an additional 7 months. Diets were prepared to give a
dose of 3 mg/rat per day lead acetate and 54 mg/rat per day sulfathiazole. Some animals
died during the observation period. Histological examination of the 42 male and female
rats that survived until the end of the observation period showed that lead acetate treatment
alone induced 14 renal tumours including five carcinomas in males and one carcinoma in
a female. In 43 male and female rats that survived until the end of the observation period,
lead plus sulfathiazole treatment induced 17 renal tumours including one renal carcinoma
in a female. Controls and rats fed sulfathiazole alone did not develop renal tumours. [The
Working Group noted some deficiencies in reporting. The Working Group also noted that
the spontaneous occurrence of renal carcinomas in rats is a very rare event.]
Nogueira (1987) fed groups of 10–12 male Wistar rats, 6 weeks of age, diets contai-
ning 0 (control), 0.5 or 1.0% lead acetate [purity unspecified] for up to 24 weeks. Survival
and body weight were unaltered by lead acetate treatment. At necropsy, kidneys were
assessed histologically in a median transverse section and tumours were categorized as
basophilic or chromophobic, and the incidence was reported separately. Renal tumours
were not reported in the 10 control rats [the Working Group noted the absence of other data
on tumours in controls]. Renal tumours did not occur in the 12 rats fed 0.5% lead acetate,
but of the 10 rats fed 1.0% lead acetate, two developed basophilic tumours and seven
developed chromophobic tumours [it is unclear if any rats had both types of tumours].
In a study by Fears et al. (1989) on carcinogenic mixtures, groups of 24 male and 24
female Fischer 344 rats [age unspecified] were fed 500, 2000 or 8000 ppm lead as lead
acetate [purity unspecified] in the diet for up to 725 days. Control groups of 213 male and
214 female rats received unaltered diet. Other groups of male and female rats received
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lead together with various other carcinogens (N-butyl-N-(4-hydroxybutyl)nitrosamine

[NBBN], aflatoxin B1 or thiouracil) in the diet to evaluate carcinogenic synergy. Survival
of lead-treated rats did not differ from that of controls. All animals underwent complete
necropsy. Tissues were examined histologically, and only malignant tumours were tabu-
lated [pathological type not specified]. No malignant renal tumours were found in the 213
male and 214 female control rats. In male rats treated with lead acetate alone, the inci-
dence of malignant renal tumours was 0/24, 11/24 [statistically significant, two-tailed
Fisher’s exact test, p < 0.05], and 19/24 [statistically significant; two-tailed Fisher’s exact
test, p < 0.05; χ 2 test for trend, p < 0.0001] in animals that received 500 ppm, 2000 ppm
and 8000 ppm lead, respectively. In female rats treated with lead acetate alone, the inci-
dence of malignant renal tumours was 0/24, 1/24, and 4/24 [statistically significant, two-
tailed Fisher’s exact test] in animals that received 500 ppm, 2000 ppm and 8000 ppm lead,
respectively. No carcinogenic interactions were observed between lead and NBBN, afla-
toxin B1 or thiouracil.
(b) Subcutaneous administration

In a study undertaken by Teraki and Uchiumi (1990) to analyse the metal content in
metal-induced injection-site tumours, a group of 13 male Fischer 344/NSle rats, 5 weeks
of age, received subcutaneous dorsal injections of 60 mg/kg bw lead acetate [purity un-
specified] in distilled water weekly for 5 weeks. Another group of 13 rats was injected
with saline and served as controls. Rats were observed for 80 weeks following the start of
the injections [survival data not given]. [Although not explicitly stated, histological ana-
lysis appears to have been performed.] Of the rats injected with lead acetate and available
for review, 42% [probably five rats with tumours/12 rats injected] developed injection-site
sarcomas [No data were given for the incidence of injection-site tumours in controls and
the Working Group noted the incomplete reporting of experimental details.]
(c) Administration of lead with known carcinogens or modifiers of

carcinogenesis
Hinton et al. (1979) fed groups of 150 male Fischer 344 rats, weighing 125–175 g [age
unspecified], unaltered diet (control) or diets containing 1% lead as lead acetate [purity
unspecified], 0.04% N-(4′-fluoro-4-biphenyl) acetamide (FBPA) or 1% lead acetate plus
FBPA. Ten to 20 rats from each group were killed after 3, 7 and 14 days and 4, 8, 16, 24,
36 and 52 weeks of exposure [survival unspecified] and a gross examination of the kidneys
and livers for the appearance of tumours was made. This revealed one mass in the kidney
of a rat fed lead acetate alone for 52 weeks. Lead acetate treatment also appeared to
increase FBPA-induced gross renal tumour multiplicity [not statistically evaluated]. Upon
histological examination, these lesions were confirmed as renal adenocarcinomas. [The
Working Group noted that the experimental design and reporting was insufficient to eva-
luate the role of lead acetate on FBPA-induced carcinogenesis.]
Tanner and Lipsky (1984) fed groups of male Fischer 344 rats [initial group size of 50
but substantially reduced due to lead-induced mortality], weighing 125–175 g, diets con-
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taining either 10 000 ppm lead as lead acetate [purity unspecified], 400 ppm FBPA, FBPA
plus lead, or unaltered diet (control). Five to 10 animals per group were killed after 16,
24, 36 and 52 weeks of feeding and kidneys were examined microscopically. No details
were given on survival. The number of control animals killed at each time point was 5–10
[exact number unspecified]. No renal lesions were seen in the controls at any time. The
incidence of renal hyperplasia, adenoma and adenocarcinoma was reported irrespective of
concurrent lesions in the same animal. Of the 26 rats fed FBPA alone, 19 had hyperplasia,
eight had adenomas and eight had carcinomas. Of the 29 rats fed lead alone, 21 had hyper-
plasia, two had adenomas and one had an adenocarcinoma. Of the 27 rats fed FBPA and
lead, 27 had hyperplasia, 18 had adenomas and 10 had carcinomas. Statistical evaluation
was not carried out. [The Working Group noted the incomplete reporting and the high
early mortality of the treated rats.]
Koller et al. (1985) gave groups of 7–16 male weanling Sprague-Dawley rats 0, 26 or
2600 ppm lead as lead acetate [purity unspecified] in drinking-water continuously for a
total of 76 weeks. Twenty-eight weeks after start of lead acetate exposure, each group was
simultaneously exposed to diets containing sodium nitrite (6.36 g/kg diet) and ethyl urea
(2.0 g/kg diet) for 20 weeks and thereafter to unaltered diet until the end of the study (76
weeks). A control group received unaltered water and feed, and a group received
2600 ppm lead acetate alone for 76 weeks. Of the lead-exposed animals, 3/36 were lost
to observation due to early death. All rats were subjected to histological examination.
Renal tumours occurred with the following incidence (tumour bearing rats/number of rats
examined): control, 0/7; ethyl urea and sodium nitrite only, 0/8; 26 ppm lead acetate plus
ethyl urea and sodium nitrite, 0/7; 2600 ppm lead acetate plus ethyl urea and sodium
nitrite, 6/10 [statistically significant versus controls, two-tailed Fisher’s exact test];
2600 ppm lead acetate only, 13/16 [statistically significant versus controls, two-tailed
Fisher’s exact test]. All kidney tumours were classified as renal tubule carcinomas with
the exception of a clear cell adenoma in the group of rats treated with 2600 ppm lead plus
ethyl urea and sodium nitrite.
Nogueira (1987) fed groups of 10–12 male Wistar rats, 6 weeks of age, diets containing
0 (control), 0.5 or 1.0% lead acetate [purity unspecified] for up to 24 weeks. Separate groups
were given 0.01 or 0.025% N-nitrosodiethylamine (NDEA) in water at a dose of 5 mg/kg
per day [presumably 5 mg of solution/kg per day by intubation] with or without 0.5 or 1.0%
lead acetate. Lead acetate did not appear to affect NDEA-induced carcinogenesis.
In a study of the effects of calcium and lead on blood pressure, Bogden et al. (1991)
fed groups of 4–8 male weanling Wistar rats diets containing either 0.2% or 4.0% calcium.
The animals were given drinking-water containing 0, 1 or 100 µg/mL lead as lead acetate
[purity unspecified]. After 31 weeks, rats were killed and one kidney from each rat was
prepared for histological examination. Proliferative lesions of the kidney were observed
only in rats fed the 4.0% calcium diet and given 100 µg/mL lead in drinking-water; among
five rats there were three with transition cell hyperplasia and two with invasive carcinoma.
[The Working Group noted the small group sizes.]
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3.1.3 Dog
Azar et al. (1973) fed groups of four male and four female beagle dogs [age unspe-
cified] diets containing 0 (control), 10, 50, 100 and 500 ppm lead acetate [purity unspeci-
fied] for 2 years, at which time the experiment was terminated. These doses of lead did not
affect weight gain or mortality. A complete necropsy with histological examination was
carried out on all animals. There were no pathological effects of dietary lead in any organ
system in the females. Two male dogs fed 500 ppm lead showed a slight degree of cyto-
megaly in the proximal convoluted tubule of the kidneys. No tumours of any type were
reported. [The Working Group noted the small group sizes and the short duration of
treatment.]
3.1.4 Monkey
A case of a rhesus macaque (Macaca mulatta) that developed chronic myelocytic
leukaemia after having been exposed to lead acetate has been reported by Krugner-Higby
et al. (2001). The malignancy occurred in a female monkey that had received daily oral
exposures to lead for a total of 2 years in order to achieve a target blood lead concentration
of 35 µg/dL. Beginning at day 8 postpartum and continuing for the next 6 months, lead
was given to the monkey mixed in a commercial milk formula [dose unspecified]. After
weaning at 6 months, lead was administered in a fruit-flavoured diet for an additional 18
months [dose unspecified]. Regular blood samples were drawn to test for blood lead
concentrations. The mean concentration of lead in blood over the lifetime of the
leukaemic macaque was 37.6 µg/dL. The first symptoms of haematopoietic abnormality
developed when the monkey was 25 months of age and, after an attempt at chemo-
therapeutic intervention, the animal was sacrificed 4 months later. The author noted that
this was the first report of chronic myelocytic leukaemia in this species and that it is a rare
malignancy in non-human primates. The animal was seronegative for several retroviruses
that have been associated with lymphoid neoplasia in non-human primates.
3.2 Lead subacetate

3.2.1 Mouse
Van Esch and Kroes (1969) fed groups of 25 male and 25 female Swiss mice, 5 weeks
of age, diets containing either 0 (control), 0.1% or 1.0% lead subacetate [purity un-
specified] for up to 2 years. The higher dose caused an early decrease in survival. Although
the dose was reduced to 0.5% at 92 days of treatment for male mice and 114 days for
female mice, few animals survived beyond 1 year. Survival was similar in controls and
mice fed 0.1% lead subacetate. In the latter group, histological examination showed renal
tumours in six males (two adenomas, four carcinomas) and one female (adenoma) while
none occurred in controls. One carcinoma occurred in a female fed 1.0/0.5% lead
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subacetate. [The Working Group noted that the number of mice subjected to pathological
analysis was not specified].
Stoner et al. (1986) gave groups of 16 male and 16 female strain A/J mice, 6–8 weeks
of age, three oral doses of lead subacetate [purity unspecified] per week for up to 24
weeks (total dose, 190 mg/kg bw) and compared them with untreated controls. Of the
lead-treated mice, 81% of the females and 100% of the males survived to the end of the
study. At the end of the experiment, lungs were removed, fixed, and gross lesions repre-
senting lung tumours were counted. A few lesions were subjected to histological exami-
nation to confirm typical histopathology of pulmonary adenoma. Lead subacetate-treated
mice did not show a significant lung tumour response.
(b) Intraperitoneal administration

In an earlier study, Stoner et al. (1976) gave groups of 20 male and female strain
A/Strong mice, 6–8 weeks of age, intraperitoneal injections of lead subacetate (> 97% pure)
dissolved in tricaprylin, three times per week for 5 weeks (total doses, 30, 75 or 150 mg/kg
bw) and observed them for up to 30 weeks after the first injection. The high dose was
considered to be a maximum tolerated dose. Of the lead-treated mice, 60–75% survived to
the end of the study compared with 90% of the controls. At the end of the experiment, lungs
were removed, fixed, and gross lesions representing lung adenomas were counted. A few
lesions were subjected to histological examination and confirmed the typical histopathology
of pulmonary adenoma. Lung tumour multiplicity (average number of tumours/mouse) was
increased approximately threefold in mice given the highest dose of lead subacetate
compared with controls given vehicle alone (1.47 ± 0.38 versus 0.50 ± 0.12; p < 0.05,
Student’s t-test) (Stoner et al., 1976; Shimkin et al., 1977).
Poirier et al. (1984) gave groups of 30 (equal numbers of male and female) strain
A/Strong mice, 6–8 weeks of age, intraperitoneal injections of lead subacetate (reagent
grade) dissolved in tricaprylin (0.04 mmol/kg per injection) three times per week (total of
20 injections; total dose, 0.8 mmol/kg) and observed them for up to 30 weeks after the
first injection. This dose schedule was said to constitute a maximum tolerated dose of lead
in this strain of mouse. To define potential antagonism, separate groups received intraperi-
toneal injections of calcium acetate or magnesium acetate at 1:1, 3:1 and 10:1 molar ratios
with lead subacetate. Calcium or magnesium were admixed with the lead prior to injec-
tion and given with the same dosage schedule as lead subacetate. Survival of mice to the
end of the study was 70–87% in controls, 67% in mice treated with lead alone and
53–77% in mice treated with combined calcium and lead. Survival ranged from 43–60%
in mice given magnesium at 3:1 or 10:1 molar ratios with lead. When magnesium was
given as an equimolar mixture with lead, only 1/30 mice survived, preventing further ana-
lysis of this group. At the end of the experiment, surviving animals were killed, lungs
were removed and fixed, and gross lesions representing lung adenomas were counted. A
few lesions were subjected to histological examination and confirmed the typical histo-
pathology of pulmonary adenoma. Lead alone caused a significant increase (p < 0.05,
Student’s t-test) in lung tumour multiplicity compared with controls (0.86 ± 0.20 versus
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0.32 ± 0.12). At all doses used, calcium significantly reduced lead-induced increases in
lung tumour multiplicity (p < 0.05). In the study with magnesium, lead alone caused a
significant increase in lung tumour multiplicity (p < 0.05) compared with mice given the
vehicle while magnesium given at molar ratios of 3:1 or 10:1 with lead significantly
reduced lead-induced increases in lung tumour multiplicity (p < 0.05).
Stoner et al. (1986) gave groups of 16 male and 16 female strain A/J mice, 6–8 weeks
of age, intraperitoneal injections of lead subacetate [purity unspecified] dissolved in water
three times per week for up to 24 weeks (total doses, 38, 95 or 190 mg/kg bw) and com-
pared them with water-treated controls. Of the lead-treated mice, 81–100% survived except
in the group of males that received the high dose, of which only 3/16 (19%) survived to the
end of the study. At the end of the experiment, surviving animals were killed, lungs were
removed and fixed, and gross lesions representing lung tumours were counted. A few
lesions were subjected to histological examination and confirmed the typical
histopathology of pulmonary adenoma. Lung tumour multiplicity was significantly
increased in the males at the low dose (38 mg/kg bw; 0.5 ± 0.18) and at the high dose
(190 mg/kg bw; 0.67 ± 0.33), compared with controls (0.07 ± 0.07) (p < 0.05; Wilcoxon
nonparametric rank test). The four other lead-treated groups did not show a significant lung
tumour response. [The Working Group noted the mortality in the high dose-treated male
group.]
(c) Administration of lead with known carcinogens or modifiers of

carcinogenesis
Sakai et al. (1990) gave groups of 14–18 of male ddy mice [age unspecified],
weighing 22–24 g, weekly intraperitoneal injections of 10 mg/kg bw lead subacetate
[purity, > 99.99%] suspended in 50% glycerine solution for 18 weeks with or without
either two or three intraperitoneal injections of 10 mg/kg bw N-nitrosodimethylamine
(NDMA) in saline per week. Controls received injections of vehicles alone (saline and
50% glycerine solution). The treatments did not affect survival [test unspecified]. Lung
tumours were evaluated histologically [stage was not specified, but included adenomas
and adenocarcinomas]. Control mice and mice given lead alone did not develop lung
tumours. Although lead did not alter NDMA-induced lung tumour incidence, lung tumour
multiplicity was significantly increased in groups given lead compared with those that
received NDMA alone. Animals given two injections of NDMA per week developed an
average of 0.33 tumours/lung compared with 0.78 tumours/lung in mice also receiving
lead (p < 0.05, Student’s t-test) [descriptive statistics not given]. Mice injected three times
a week with NDMA developed an average of 3.4 tumours/lung compared with 5.7
tumours/lung in mice also receiving lead subacetate (p < 0.05, Student’s t-test) [standard
errors not given].
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3.2.2 Rat
Van Esch et al. (1962) fed groups of 11–16 male and 11–16 female Wistar rats [age
incompletely specified] diets containing 0.1% lead subacetate [purity unspecified] or
unaltered diet (control) for 29 months or 1.0% lead subacetate or unaltered diet (control)
for 24 months. Both concentrations of lead reduced body weight (p < 0.005, Wilcoxon’s
test) and 1.0% dietary lead subacetate reduced survival [test unspecified]. The incidence
of renal tumours in rats fed 0.1% lead subacetate was 5/16 in males and 6/16 in females
compared with 0/14 in control males and 0/15 in control females [incidences in both
males and females were significantly elevated, Fisher’s exact test]. The incidence of renal
tumours in rats fed 1.0% lead subacetate was 6/13 in males and 7/11 in females compared
with 0/13 in control males and 0/13 in control females [incidences in both males and
females were significantly elevated, Fisher’s exact test; χ 2 test for trend for both male and
female, and p < 0.006 and p < 0.0004 respectively]. Three carcinomas occurred in rats fed
0.1% lead subacetate and six occurred in rats fed 1.0% lead subacetate; the remainder
were adenomas. In the group fed 1.0% lead subacetate, one animal had a carcinoma with
multiple metastases.
Mao and Molnar (1967) fed a group of 40 male Wistar rats (weighing ~200 g) [age
unspecified] a diet containing 1% lead subacetate [purity unspecified] and a group of 20
rats an unaltered diet. Rats were killed or died from 238 to 690 days (controls) or from
213 to 677 days (lead-treated) [average survival unspecified]. Necropsies were performed
on all animals and kidneys were examined histologically. Evaluation [presumably of the
kidney only] revealed a single renal sarcoma among the 20 control rats while 31/40 lead-
treated rats developed renal tumours [significantly different from controls, Fisher’s exact
test], including adenomas and carcinomas. One lead-treated rat with a renal tumour
showed a pulmonary metastasis.
In a study by Oyasu et al. (1970) in which the effects of 2-acetylaminofluorene
(2-AAF) in combination with lead subactate was studied, two groups of male CD
Sprague-Dawley rats, 5–8 weeks of age, were fed diets containing 1.0 % lead subacetate
[purity unspecified] or 1.0% lead subacetate and 1.6% indole and were observed for
12–17 months. Average survival in these groups was 53–69 weeks. A pool of various
control groups (age range, 58–67 weeks) was used, including a mixed group of 130 male
and female CD Sprague-Dawley ex-breeders over 60 weeks of age, a mixed group of 155
male and female CD Sprague-Dawley rats fed unaltered diets, 23 Wistar rats [sex
unspecified] fed 3.2% indole in the diet and 17 CD Sprague-Dawley rats [sex unspecified]
fed unaltered diets but whose cerebrum was damaged by focal freezing. Necropsy and
histological examination was performed on all animals. The authors pooled the groups of
rats fed lead subacetate alone with those fed lead acetate plus indole for statistical
analysis. The reported incidence (tumour bearing rats/rats examined) of cerebral gliomas
was: 1/325 (0.3%) in control rats; and 5/58 (8.6%) (p < 0.05, test unspecified) in rats fed
either lead subacetate alone or lead subacetate plus indole. Two of 17 rats fed lead sub-
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acetate alone developed gliomas and 3/41 rats fed lead subacetate + indole developed
gliomas. [The Working Group considered there were only 285 untreated controls, in
which one glioma occurred.] The incidence of renal cortical tumours [pathological stage
undefined] was: 13/17 (76%) in rats fed lead subacetate alone and 25/41 (61%) in rats fed
lead subacetate plus indole. The incidence of renal tumours in controls was not reported.
[The Working Group noted the unusual design of analysis and incomplete reporting of this
investigation.]
In a study of the histopathology of chemically-induced renal tumours carried out by
Ito et al. (1971), a group of 10 male Wistar rats, 6–8 weeks of age, was fed 1.5% lead sub-
acetate [purity unspecified] in the diet for 48 weeks and renal tumours were assessed
histologically. All 10 rats developed either renal adenomas (60%) or renal carcinomas
(40%). [The Working Group noted the absence of a control group.]
In another study by Ito (1973) focusing on the histopathology of tumours of the uri-
nary system of rats, groups of 11–13 male Wistar rats, 6–8 weeks of age, some of which
were also subjected to unilateral nephrectomy, were fed 1.5% lead subacetate [purity un-
specified] in the diet for 23 weeks (intact or nephrectomized) or 48 weeks (intact).
Tumours of the urinary system were assessed histologically. In the 13 intact rats fed the
lead subacetate-containing diet for 23 weeks, no renal tumours were observed while 2/11
lead subacetate-treated unilaterally-nephrectomized rats developed renal tumours. After
48 weeks of exposure, renal tumours developed in 9/11 lead subacetate-treated intact rats.
Lead subacetate-induced tumours were either renal-cell adenomas (64%) or carcinomas
(36%). [The Working Group noted the absence of control groups.]
In a study performed by Kasprzak et al. (1985) of the effects of dietary calcium on the
carcinogenicity of lead subacetate in the kidney, groups of 28–30 male Sprague-Dawley
rats were fed 1% lead subacetate (AR grade) admixed with 0, 0.3, 1, 3 or 6% calcium
acetate in the diet and observed for 79 weeks. Controls received unaltered basal diet and
a separate group was fed 3% calcium acetate alone. All additions to the basal diet caused
significant suppression of weight gain ranging from 7 to 46% (p < 0.05, Student’s t-test).
No significant differences in survival were observed (two-tailed Fisher’s exact test). At
the time of the detection of the first renal tumour (58 weeks), surviving rats were killed,
tissues were examined microscopically and renal tumour incidence was determined.
Renal tumours did not occur in control rats or rats fed calcium alone. In rats fed lead
subacetate alone, 13/29 (45%) developed renal tumours [statistically significant; Fisher’s
exact test, p < 0.05] including 11 adenomas and two adenocarcinomas. Addition of 0.3, 1,
3 or 6% calcium (calcium reduced renal lead content by up to 72%) to the diet signi-
ficantly increased (p = 0.035–0.014, two-tailed Fisher’s exact test) the incidence of renal
tumours in lead-treated rats to 62–79%. The number of rats with bilateral renal tumours
was also significantly increased (p < 0.05, two-tailed Fisher’s exact test) in comparison
with rats treated with lead subacetate alone.
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(b) Administration of lead with known carcinogens or modifiers of

carcinogenesis
The effects of lead subacetate in combination with 2-AAF, indole or boiled linseed oil
containing ‘lead drier’ [lead drier is a compound made of lead, cobalt and manganese
naphthenates that was added to improve the drying qualities of oil-based paints made with
boiled linseed oil] on renal carcinogenesis were studied by Hass et al. (1967) in male CD
rats, 6–8 weeks of age. For up to 74 weeks the animals were fed diets supplemented with
two or more of the following components: 0.06% 2-AAF, 1.6% indole, 1.0% lead sub-
acetate [specified as ‘chemically pure’] and 10.0 g/100 mL [presumably mL of diet] com-
mercial boiled linseed oil containing ‘lead drier’. Some animals in each group were killed
at 52 weeks. The concentrations of naphthenates in the linseed oil were given as 0.20%
lead, 0.35% manganese and 0.30% cobalt. In total, 64 rats received 2-AAF plus indole, 24
rats received lead subacetate plus indole, 50 rats received lead subacetate, indole and
linseed oil, and 74 rats received lead subacetate, 2-AAF, indole and linseed oil. A few rats
died during exposure [precise survival and body weight data not given]. Complete
autopsies were done and tissues from all tumours were examined microscopically. None of
the animals fed diets containing 2-AAF and indole developed renal tumours. All of the
groups fed diets containing lead subacetate developed renal cortical tumours. Of the 24 rats
fed lead subacetate plus indole, 22 had ‘cystomas’ [presumably cystic adenomas], 19 had
adenomas [presumably solid adenomas] and 11 (46%) had adenocarcinomas. Of the 50 rats
fed lead acetate, indole and linseed oil, 30 had cystomas, 20 had adenomas and 14 (28%)
had adenocarcinomas. Of the 74 rats fed lead subacetate, indole, linseed oil and 2-AAF, 37
had cystomas, 29 had adenomas and 25 (34%) had adenocarcinomas. [The Working Group
noted the absence of a control group or a group receiving lead subacetate alone].
Oyasu et al. (1970) fed three groups of male CD Sprague-Dawley rats, 5–8 weeks of
age, diets containing 1.0 % lead subacetate [purity unspecified], or 1.0% lead subacetate
and 1.6% indole, or 1.0% lead subacetate, 1.6% indole (added to prolong the lifespan of
2-AAF-treated rats) and 2-AAF. The animals were observed for 12–17 months. Average
survival was 53–69 weeks. Histological examination was performed on all animals that
died or were killed at the end of the experiment. For statistical analysis the authors pooled
the groups of rats fed lead subacetate alone with those fed lead acetate plus indole. The
reported incidence (tumour bearing rats/rats examined) of cerebral gliomas was 5/58
(8.6%) in rats fed either lead subacetate alone or lead subacetate plus indole (2/17 rats fed
lead subacetate alone developed gliomas and 3/41 rats fed lead subacetate + indole deve-
loped gliomas), and 6/72 (8.3%) in rats fed lead subacetate, indole and 2-AAF. The inci-
dence of renal cortical tumours [pathological stage undefined] was 13/17 (76%) in rats
fed lead subacetate alone; 25/41 (61%) in rats fed lead subacetate plus indole, and 36/72
(50%) in rats fed lead subacetate, indole and 2-AAF. [The Working Group noted the
unusual design of analysis and incomplete reporting of this investigation.]
Hiasa et al. (1983) studied the development of renal tumours in groups of 17–24 male
Wistar rats, 6 weeks of age, fed diets containing 500 or 1000 ppm N-ethyl-N-hydroxyethyl-
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nitrosamine (EHEN) for 2 weeks followed by 1000 ppm lead subacetate (purity, 99.5%) for
20 weeks with an additional observation period of 10 weeks (total duration, 32 weeks).
Two groups were fed EHEN alone (1000 ppm) and lead subacetate alone, respectively.
Controls received unaltered diets for 32 weeks. Rats that died before the end of the study
were excluded from evaluation; these included two rats given EHEN alone and four rats
given EHEN plus lead subacetate. All groups fed lead subacetate and the group fed
1000 ppm EHEN alone showed significant reduction (p < 0.05, test unspecified) of final
body weight (maximum, 14%). Histological examination revealed the following renal
tumour incidence (tumour-bearing rats/rats examined): 500 ppm EHEN, 0/24; 1000 ppm
EHEN, 9/18 (p < 0.05 versus control, χ 2 test); 500 ppm EHEN plus lead subacetate, 10/22
(p < 0.05 versus 500 ppm EHEN alone); 1000 ppm EHEN plus lead subacetate, 17/17
(p < 0.05 versus 1000 ppm EHEN alone); lead subacetate alone, 0/24; control 0/24. No
adenocarcinomas occurred in rats fed EHEN alone, one renal adenocarcinoma occurred in
a rat fed EHEN 500 ppm plus lead subacetate and 10 adenocarcinomas in rats fed
1000 ppm EHEN and lead subacetate. [The Working Group noted the short duration of the
study for the assessment of lead-induced tumours.]
The effects of various nephrotoxic chemicals, including lead subacetate, in promoting
EHEN-induced renal carcinogenesis were studied by Shirai et al. (1984) in groups of
23–25 male Fischer 344 rats [age unspecified; weighing ~130 g] that were given 0.1%
EHEN in the drinking-water for 1 week followed by 0.1% lead subacetate [purity un-
specified] in the diet for 35 weeks. A separate group received lead subacetate alone from
week 2 to week 36. All rats were subjected to unilateral nephrectomy during the third
week of the experiment. All rats were killed after 36 weeks and five transverse kidney
sections from each animal were taken for histological evaluation. Lead subacetate alone
did not induce renal tumours. EHEN alone induced renal-cell tumours [size and histology
unspecified] in 5/23 rats (22%); exposure to lead subacetate after EHEN increased the
incidence of renal-cell tumours to 13/25 (p < 0.05 versus EHEN alone, test unspecified).
[The Working Group noted that no untreated control group was included and noted the
short duration of the study for the assessment of lead subacetate-induced tumours.]
Groups of 15 male Wistar rats, 6 weeks of age, were fed diets containing 1000 ppm
EHEN for 2 weeks. Unilateral nephrectomies were then performed on all rats and they
were provided with unaltered diets or diets containing 1000 ppm lead subacetate [purity
unspecified] for up to 18 additional weeks. Five animals from each group were killed at
weeks 8, 12 and 20 of the experiment. In rats given EHEN alone, 2/15 had simple renal
hyperplasia (hyperplasia with a tubular pattern), 0/15 had renal ‘adenomatous
hyperplasia’ (hyperplasia with loss of tubular pattern) and 0/15 had renal tumours. In rats
given EHEN plus lead subacetate, 11/15 had simple hyperplasia, 8/15 had adenomatous
hyperplasia and 1/15 had a renal-cell tumour. Incidence and multiplicity (lesions/rat) of
simple hyperplasia was increased in the rats fed EHEN plus lead and killed at week 20
versus rats fed EHEN alone (p < 0.05, tests unspecified) (Hiasa et al., 1991; Nishii 1993).
[The Working Group noted that no untreated control group was included and noted the
short duration of the study for the assessment of lead subacetate-induced tumours.]
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3.2.3 Hamster
Van Esch and Kroes (1969) fed groups of 22 male and 23–24 female Syrian golden
hamsters, 3–4 weeks of age, either 0 (control), 0.1 or 0.5% lead subacetate [purity un-
specified] in the diet for up to 2 years. The higher dose in females and both doses in males
appeared to reduce survival, mostly during the first year [not statistically evaluated]. At
the end of the experiment all animals were killed and underwent histological examination.
No renal tumours or hyperplasia occurred in any group, although pleomorphic cells with
hypertrophic nuclei were commonly observed in the kidneys of lead-treated hamsters.
3.2.4 Rabbit
Hass et al. (1967) fed a total of 85 male rabbits (primarily New Zealand albino with
a few German Checker and Belgian Hare), 3 months of age, diets containing 0.5–1.0%
lead subacetate (specified as chemically pure) for 3–78 weeks. Twenty-one animals
received lead alone while the others were given various other compounds (linseed oil con-
taining lead drier, 2-AAF, cholesterol, chloroform, carbon tetrachloride and vitamin D) in
the diet or by injection. Precise survival and body weight data were not given. None of
the lead-treated rabbits developed renal tumours, although chronic lead nephropathy was
common. [The Working Group noted the absence of a control group, the use of a variety
of strains of rabbits and the incomplete reporting of the study.]
3.3 Lead carbonate

3.3.1 Rat
Oral administration
Fairhall and Miller (1941) fed male albino rats, 70–90 g, [strain and age unspecified]
diets that contained 0.1% lead arsenate (49 rats) (see section 3.10 for assessment of the
lead arsenate experiment) or an equivalent amount of lead as lead carbonate (55 rats) for
up to 2 years. A control group of 24 rats of similar age and weight was fed the same diet
without the test substances. At the end of the first year, approximately half of the survi-
ving rats in each group were killed, and tissues were taken for histological examination.
The remaining rats in each group were maintained on the same treatments and were killed
at the end of the second year; their tissues were examined similarly. Histological exami-
nations performed at 1 and 2 years showed moderate to marked kidney changes (enlarge-
ment of cells in the convoluted tubules, intranuclear inclusions and accumulation of
brown pigment in cells of the convoluted, proximal and distal tubules), but no tumours in
the rats fed lead carbonate. No pathological changes of note were observed in other
tissues and organs in the lead carbonate-treated rats compared with controls. No tumours
were observed at any site in any of the groups. [The Working Group noted the incomplete
reporting of the study.]
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3.4 Lead nitrate

3.4.1 Mouse
Administration of lead with known carcinogens or modifiers of carcinogenesis
Litvinov et al. (1984) gave groups of 50 female CBA × C57/BL6 mice [age un-
specified] 10 mg/L NDMA or 0.3 mg/L lead nitrate or both compounds together in
drinking-water for either 26 or 39 weeks. None of the mice receiving lead nitrate alone
for 39 weeks developed tumours. Treatment with lead nitrate did not appear to impact
NDMA-induced renal tumours. [The Working Group noted the short duration of the study
for assessment of lead-induced tumours.]
3.4.2 Rat
Schroeder et al. (1970) gave groups of male Long-Evans rats [age and initial number
unspecified] 25 ppm lead nitrate (25 mg/L lead) in the drinking-water from weaning until
death. An epidemic of pneumonia of 3 weeks duration killed 22 lead-treated rats and 19
controls. Sufficient rats survived in each group (52 lead-treated rats and 52 controls) to
continue the experiment. After corrections for the early mortality, the survival of lead-
treated rats was lower (p < 0.05) than that of the controls. Grossly visible tumours [type
and location unspecified] were found in 7/43 lead-treated rats at necropsy; the tumour inci-
dence (10/50) in controls was not significantly different. [The Working Group noted the
low dose of lead nitrate that was used and the incomplete reporting of this experiment.]
(b) Administration of lead with known carcinogens or modifiers of

carcinogenesis
Litvinov et al. (1982) gave groups of 50 albino outbred male rats, weighing 150–200 g,
NDMA in the drinking-water (effective dose, 0.5 mg/kg bw per day) alone or in the
presence of lead nitrate (0.5 mg/L drinking-water). A group of 50 control rats were given
drinking-water only; no group treated with lead nitrate alone was available. The experiment
lasted 19 months. A complete necropsy was performed on all animals and tissues were
examined histologically. No renal or liver tumours occurred in control animals. Renal
tumours occurred in 8/42 rats treated with NDMA alone and in 19/41 rats treated with
NDMA and lead nitrate. Liver tumours occurred in 15/42 rats receiving NDMA alone
compared with 5/41 rats receiving NDMA and lead nitrate combined. The authors
concluded that lead nitrate increased the incidence of kidney tumours and decreased the
incidence of liver tumours.
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3.5 Lead powder

3.5.1 Rat
Furst et al. (1976) gave groups of 25 male and 25 female young Fischer 344 rats [age
unspecified] weighing ≤ 119 g, lead powder (99.9% pure; 10 mg lead; particle size
unspecified) in corn oil by stomach tube twice a month for 12 months and observed them
for 24 months. Groups of 20 male and 20 female control rats were given 0.5 mL corn oil
by stomach tube according to the same schedule. A complete necropsy was performed on
all of the animals that were killed and included histological examination of suspicious
tissues. Survival data were not reported. One lymphoma and four leukaemias were found
at necropsy in 47 lead powder-treated rats; this did not differ significantly from the inci-
dence of three lymphomas found at necropsy of 29 controls. No other neoplasms were
reported in the lead powder-treated or control rats.
(b) Intramuscular administration

In a similar experiment, Furst et al. (1976) gave groups of 25 male and 25 female
young Fischer 344 rats [age unspecified], weighing ≤ 111 g, monthly intramuscular injec-
tions of 10 mg lead powder (99.9% pure; particle size unspecified) in trioctanoin for 9
months and then monthly injections of 5 mg lead powder for 3 months and observed the
animals until the end of the experiment (24 months). Equal numbers of rats were given
the trioctanoin vehicle alone and served as controls. A complete necropsy was performed
on all animals that were killed and included histological examination of suspicious
tissues. Fibrosarcomas developed at the injection site in one of the lead powder-treated
rats and in one of the control rats. The incidences of lymphoma were 6/50 in the lead
powder-treated rats and 3/50 in the trioctanoin-treated controls. The authors noted the
following tumours in the lead powder-treated rats that were not seen in the controls: a
metastasis of an osteogenic sarcoma in the lungs without primary site identification, a
mesothelioma of the urogenital tract and two tumours of the pancreas (a fibrolipoma and
a villous adenoma). Statistical analyses were not reported, but the authors concluded that
‘lead powder did not seem to produce any appreciable number of tumours’.
(c) Intrarenal administration

Jasmin and Riopelle (1976) gave a group of 20 young female Sprague-Dawley rats,
weighing 120–140 g, injections of 5 mg lead powder [purity and particle size not
specified] suspended in 50 µL glycerine into the cortical sections of both poles of the right
kidney (total dose, 10 mg lead powder/rat). A negative control group of 16 rats received
similar intrarenal injections of 50 µL glycerine alone and a positive control group of 16
rats received intrarenal injections of 5 mg nickel subsulfide powder (total dose, 10 mg/rat)
in 50 µL glycerine. The experiment lasted 12 months, during which time the animals were
examined at regular intervals for development of erythrocytosis and renal tumours. All of
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the kidneys were removed at necropsy for histological examination. No erythrocytosis or

renal tumours developed in the lead powder-treated rats or in the negative controls,
whereas marked erythrocytosis (p < 0.05 versus controls) developed in all of the 16 posi-
tive control rats, and renal carcinomas were found in 7/16 of these near the nickel sub-
sulfide injection sites [p-value not reported].
3.6 Lead oxide

3.6.1 Rat
Inhalation exposure
Monchaux et al. (1997) exposed a group of 50 male Sprague-Dawley rats, 12 weeks
of age, to lead oxide particles [purity unspecified] (mean particle size, 0.69 µm; mass
median aerodynamic diameter (MMAD), 5.1 µm) in a whole-body chamber. The mean
airborne concentration of lead oxide measured within the chamber was 5.3 ± 1.7 mg/m3,
and rats were exposed for 6 h per day on 5 days per week for 1 year. The authors estimated
that this exposure was approximately equivalent to the dose of oral lead acetate that would
give rise to a 10% incidence of kidney cancers in rats, according to the experiments of
Azar et al. (1973). A group of 785 untreated rats served as the control. In addition to the
rats treated with lead oxide alone, a group of 63 rats was initially exposed to 0.6 Gy fission
neutrons by placing the animals at a distance of 4 m from a Silene experimental reactor
core (time unspecified); another group of 50 rats was exposed to fission neutrons and 2
months later to lead oxide by inhalation. A fifth group of 25 rats was exposed to lead oxide
by inhalation and then received six intramuscular injections of 25 mg/kg bw 5–6 benzo-
flavone (βNF) [schedule unspecified] for lung tumour promotion starting 1 month after
lead exposure ended. All animals were kept until moribund [precise survival time un-
specified] except those exposed to lead oxide and βNF, which were killed 100 days after
the last injection of βNF. A complete necropsy was performed on each animal. Lungs were
fixed by intratracheal instillation of fixative. Lead oxide exposure did not reduce survival
compared with controls. No lung tumours occurred. One renal tumour occurred among the
group of animals receiving lead oxide alone. The addition of βNF did not alter lead oxide-
induced tumours. Lead oxide did not alter cancer rates induced by neutron exposure.
3.6.2 Hamster
Intratracheal administration
Kobayashi and Okamoto (1974) gave groups of 15 male and 15 female Syrian golden
hamsters, 6 weeks of age, intratracheal instillations weekly for 10 weeks of either 1 mg
lead oxide powder (99.8% purity; particle diameter < 20 µm), or a mixture of 1 mg benzo-
[a]pyrene and lead oxide, or 1 mg benzo[a]pyrene alone. Each treatment sample was
suspended in 0.2 mL isotonic saline plus 0.5% carboxymethylcellulose solution. One
group received vehicle alone. All suspensions were ultrasonicated and homogenized, so
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that the final size of most of the particles (95%) within the mixture was < 10 µm. Fifteen
males and 15 females were kept as untreated controls. The hamsters were killed when
moribund or at 60 weeks after the initial intratracheal instillation. The hamsters treated
with lead oxide alone, benzo[a]pyrene alone or the combination showed lower survival
rates than those that received the vehicle alone or untreated controls. At necropsy, in addi-
tion to examination of any visible tumour foci, the five pulmonary lobes of each hamster
were sectioned for histological examination. Atypical epithelial proliferations, adenomas
(11 in males and females) and an adenocarcinoma (in a female) were observed in the
lungs of hamsters given benzo[a]pyrene mixed with lead oxide. The neoplastic changes
originated mostly in the bronchiolo-alveolar area. No neoplastic changes were found in
the other groups. Lead oxide alone induced hyperplastic and squamous metaplastic foci
of the alveolar area, while benzo[a]pyrene alone affected the lung only slightly. Although
statistical confirmation was not provided, the authors concluded that lead oxide showed a
cocarcinogenic effect with benzo[a]pyrene in the bronchiolo-alveolar area of hamster
lungs. [The Working Group noted that lead could have acted as a carrier for benzo[a]-
pyrene as in other particle studies, but this does not exclude other lead-related mecha-
nisms of carcinogenesis.]
3.7 Lead naphthenate

3.7.1 Mouse
Skin application
Baldwin et al. (1964) painted a 20% solution of lead naphthenate [purity unspecified]
in benzene on shaved dorsal skin of a group of 59 adult male Schofield albino mice. The
total dose of 6 mL was administered over 12 months as weekly or twice-weekly appli-
cations [dosing schedule unclear]. Kidney damage [no further details reported] was
observed in treated animals and, after 648 days, less than 50% of the mice had survived.
Of the 59 treated animals, two developed skin papillomas, one developed renal carcinoma
and four showed tubular adenomas of the kidney. [The Working Group noted that no
vehicle-control group was included and that a known carcinogen was used as the vehicle.]
3.8 Lead chromate

Chromium[VI] was previously evaluated as carcinogenic to humans (Group 1) in the
Monograph on Chromium and Chromium Compounds (IARC, 1990).
3.8.1 Mouse
Intramuscular administration
Furst et al. (1976) gave a group of 25 female weanling NIH-Swiss mice intramuscular
injections of 3 mg/mouse lead chromate (98% pure) in trioctanoin (tricaprylin; total dose,
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12 mg/mouse) monthly for 4 months. The authors noted that a higher dose (8 mg/mouse)
of lead chromate was not tolerated. Two control groups of mice were included; one
received the vehicle alone and the other served as uninjected controls. Necropsies were
performed at termination of the study at around 25 months, and showed that 2/17 mice in
the lead chromate-treated group had developed lymphoma and 3/17 had alveologenic
carcinomas [further details not reported]. Necropsies of 22/25 mice in the vehicle-control
group revealed two animals with lymphocytic leukaemia and one with an alveologenic
carcinoma. In the uninjected controls, necropsies of 15/25 mice showed one lymphoma,
five lymphocytic leukaemias and one alveologenic carcinoma. [The Working Group noted
the incomplete reporting of the study.]
3.8.2 Rat
(a) Subcutaneous injection
Groups of 40 male and 40 female Sprague-Dawley rats, 13 weeks of age, were given
a single subcutaneous injection of 30 mg/rat lead chromate (chromium yellow) or basic
lead chromate (chromium orange) [purity unspecified] suspended in saline. Within 150
weeks, 26/40 animals injected with lead chromate and 27/40 injected with basic lead
chromate had developed sarcomas (rhabdomyosarcomas and fibrosarcomas). No
sarcomas developed in 60 control animals (Maltoni, 1976; Maltoni et al., 1982).
(b) Intramuscular administration

Hueper (1961) gave a group of 33 rats [strain, age and sex unspecified] intramuscular
implantations of lead chromate [amount and purity unspecified] in sheep fat. One tumour
was reported at the implantation site [no further details stated]. None of the rats in two
vehicle-control groups developed tumours. [The Working Group noted the incomplete
reporting of the study.]
Furst et al. (1976) gave groups of 25 male and 25 female weanling Fischer 344 rats
intramuscular injections of 8 mg lead chromate (98% pure) in trioctanoin (tricaprylin) once
a month for 9 months. At the termination of the study at around 25 months, two lym-
phomas, 11 injection-site fibrosarcomas, 10 injection-site rhabdomyosarcomas and one
osteogenic sarcoma had developed in 24 lead-chromate-treated female rats. Among 23 lead
chromate-treated male rats, three injection-site fibrosarcomas, seven rhabdomyosarcomas
and three renal carcinomas had developed. In the vehicle-control group, necropsy revealed
two lymphomas among 16 females and one lymphocytic leukaemia and one injection-site
fibrosarcoma among 12 males. [The Working Group noted the development of tumours of
the kidney distant to the site of administration in male rats.]
(c) Intrapleural administration

Hueper (1961) also gave a group of 33 rats [strain, age and sex unspecified] intra-
pleural implantations of lead chromate [amount and purity unspecified] in sheep fat. Three
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tumours were reported at the implantation site [no further details stated]. None of the rats
in two vehicle-control groups developed tumours. [The Working Group noted the incom-
plete reporting of the study.]
(d) Intrabronchial administration

In a study to investigate the potential carcinogenicity of a range of chromium-contai-
ning materials, groups of 50 male and 50 female Porton-Wistar rats, 8–10 weeks of age,
received intrabronchial implantations of stainless-steel mesh pellets (5 × 1 mm) loaded
with about 2 mg of a series of seven commercial types of lead chromate test materials (lead
chromate (99.8% pure), primrose chrome yellow, Supra LD chrome yellow, molybdate
chrome orange, light chrome yellow, medium chrome yellow and silica-encapsulated
medium chrome yellow). The lead chromates contained between 60–64% lead with the
exception of the silica-encapsulated medium chrome yellow (40% lead). Groups of 50
male and 50 female rats receiving pellets loaded with cholesterol alone acted as negative
controls and similar groups receiving pellets loaded with 2 mg calcium chromate (96.7%
purity) suspended in 50:50 cholesterol acted as positive controls. Animals were maintained
for 24 months at which time surviving animals were killed and full necropsies were
performed. All lungs and any suspected lesions were examined histologically. Survival was
95.7% at 400 days and overall, 53.9% at 700 days. No bronchial carcinomas (0/100) were
seen in the cholesterol-alone control group whilst 25/100 bronchial carcinomas (24
squamous-cell carcinomas and one adenocarcinoma) were found in the calcium chromate
positive control group. Among the seven lead chromates tested, one squamous-cell tumour
of the lung was found in one male in each of the four groups which received lead chromate
(99.8% pure), primrose chrome yellow, Supra LD chrome yellow or medium chrome
yellow, respectively (in each of the four groups, incidence was 1/100, males and females
combined; p = 0.37; χ 2 test) (Levy & Venitt, 1986; Levy et al., 1986).
3.8.3 Guinea-pig
Steffee and Baetjer (1965) gave a group of 13 guinea-pigs [strain and sex unspecified],
3 months of age, 0.3-mL intratracheal instillations of 1% lead chromate [purity and particle
size unspecified] in saline at 3-monthly intervals for 18 months with no further exposure
until death or termination of the experiment. After an experimental period of 40–50
months, none of the lead chromate-exposed animals and none of the vehicle-control
animals (18 guinea-pigs) had developed pulmonary tumours. [The Working Group noted
the small numbers of animals and the insufficient experimental details provided.]
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3.8.4 Rabbit
Steffee and Baetjer (1965) gave a group of seven rabbits [strain and sex unspecified],
4 months of age, 1-mL intratracheal instillations of 1% lead chromate [purity and particle
size unspecified] in saline at 3-monthly intervals for 9–15 months with no further exposure
until death or termination of the experiment. After an experimental period of 40–50
months, none of the lead chromate-exposed animals and none of the vehicle-control
animals (five rabbits) had developed pulmonary tumours. [The Working Group noted the
small numbers of animals and the insufficient experimental details provided.]
3.9 Lead phosphate

3.9.1 Rat
(a) Subcutaneous injection
Zollinger (1953) gave groups of 10 albino randomly-bred rats [strain, age and sex un-
specified] weekly subcutaneous injections of 20 mg lead phosphate [purity unspecified]
as a 2% suspension in 1 mL [vehicle unspecified] for up to 16 months (total doses,
40–760 mg/rat). No kidney epithelial tumours were reported for the 40 rats in an untreated
control group. Among treated rats, many animals died during the experiment and the inci-
dence of renal tumours (adenomas, cystadenomas, papillomas and cortical carcinomas)
was 19/29 for rats surviving ≥ 10 months from the start of treatment. Each of the 19 had
received a total dose of 120–680 mg lead phosphate. Histological analysis revealed that
21/112 treated rats had renal tumours (the earliest developing 4 months after the start of
treatment), and in 11, the renal tumours were bilateral. The author reported that tumour
incidence increased with time. [The Working Group noted the renal tumour response with
a water-insoluble lead compound.]
Tönz (1957) gave groups of 36, 33, 14 and 29 albino rats [strain, age and sex un-
specified] subcutaneous injections of 20 mg lead phosphate [purity unspecified] suspended
in pectin weekly for up to 9.5 months and observed them for a total experimental period of
up to 16.5 months after the start of the injections. Total doses were: 340 mg over 4 months;
440 mg over 4–9.5 months; 250 mg over a total experimental period of 10 months or less;
and 360 mg from a total experimental period of 10 to 16.5 months; for the above four
groups, respectively. Kidney weight increased in all animals given lead phosphate. All 36
rats that received a total dose of 340 mg and all 33 rats that received a total dose of 440 mg
lead phosphate died during or shortly after the treatment. The incidences of renal adenomas
and carcinomas were 19/29 and 3/29 respectively in the group that received an average
total dose of 360 mg lead phosphate. Spontaneous epithelial kidney tumours were not
observed in more than 2000 historical control animals in the author’s laboratory. [The
Working Group noted that no concurrent control group was included but noted the renal
tumour response with a water-insoluble lead compound.]
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Baló et al. (1965) gave a group of 80 albino rats [age and sex unspecified] subcuta-
neous injections of lead phosphate [purity and vehicle unspecified] at weekly or fort-
nightly intervals for 18 months. Rats surviving to the end of treatment had received a total
dose of 1.3 g lead phosphate. Renal adenomas developed in 29 lead phosphate-treated rats
and in none of 20 control animals. [The Working Group noted the renal tumour response
with a water-insoluble lead compound.]
(b) Subcutaneous and intraperitoneal administration combined

Roe et al. (1965) gave three groups of 24 male Chester Beatty Wistar rats [age un-
specified] combined subcutaneous and intraperitoneal injections of a technical grade of
lead phosphate in distilled water at repeated intervals for 34 weeks (total doses, 29, 145
and 450 mg lead phosphate for the three groups, respectively). No carcinoma developed
in the 23 rats that survived to 200 days in the lowest-dose group. Twenty-one animals in
the highest-dose group died before 200 days and two of the three remaining animals deve-
loped renal adenomas. In the mid-dose group, 14/23 rats surviving to 200 days developed
renal tumours (13 adenomas, seven adenocarcinomas and one undifferentiated malignant
renal tumour) [statistically significant, Fisher’s exact test; p < 0.05]. Two of the 24 control
rats developed renal tumours (one undifferentiated malignant tumour and one
transitional-cell carcinoma in the renal pelvis).
3.10 Lead arsenate

Arsenic compounds were previously evaluated as carcinogenic to humans (Group 1)
in Supplement 7 of the IARC Monographs (IARC, 1987) and in the Monograph on Arsenic
in Drinking-Water (IARC, 2004b).
3.10.1 Rat
Fairhall and Miller (1941) fed a group of 49 white male rats [strain unspecified],
weighing 70–90 g, a diet containing 10 mg/animal lead arsenate [purity unspecified] daily
for 2 years (total approximate dose, 7.2 g). Of the animals that were given lead arsenate
45% had died after 1 year and 61% at 2 years [cause of death unspecified]. No tumours
were reported from necropsies of the experimental animals nor from the 24 animals in the
control group. [The Working Group noted the high early mortality.]
Kroes et al. (1974) fed groups of 40 or 29 male and 40 or 19 female weanling Wistar
rats a diet containing 463 or 1850 ppm, respectively, of technical-grade lead arsenate (60%
lead; 20.9% arsenic) for up to 120 weeks. At necropsies of 17 surviving males that had
received the higher dose, one bile duct adenocarcinoma, one renal cortical adenoma and
one lymphangioma were observed. No tumours were seen at necropsies of 11 surviving
females that received the higher dose. In 38 males in the low-dose group, one renal
hamartoma and two pituitary adenomas were observed. Among 40 females in the low-dose
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group, eight developed pituitary adenomas. In the control groups, necropsy of 39 males
revealed one nephroblastoma, one pituitary adenoma, one lymphatic leukaemia and one
lymphoblastosarcoma, and among 59 females, one thoracic sarcoma and 13 pituitary ade-
nomas were observed. The authors stated that no definite conclusions could be drawn from
the study.
(b) Administration of lead with known carcinogens or modifiers

Kroes et al. (1974) also fed two groups of 40 male and 40 female weanling SPF-derived
Wistar rats a diet containing 463 ppm technical-grade lead arsenate (60% lead; 20.9%
arsenic) and 0.3 mL water by intubation (five times/week for the duration of the study) for
up to 120 weeks. One of the groups also received 5 µg/rat NDEA in water by intubation
five times/week for the duration of the study. Control groups comprised 50 male and 60
female rats receiving 0.3 mL water by intubation and 50 male and 60 female rats receiving
5 µg/day NDEA as well as 0.3 mL water by intubation (five times/week for the duration of
the study). Necropsies were performed on all the animals at the end of the study. In the
group that received lead arsenate plus NDEA, one heart endothelial sarcoma and one pitui-
tary adenoma were seen among 34 male rats; in the corresponding 40 females, seven pitui-
tary adenomas were observed. In the water-only control group, one nephroblastoma, one
pituitary adenoma, one lymphatic leukaemia and one lymphoblastosarcoma were observed
among 39 males. In the corresponding group of 59 females, one thoracic sarcoma and 13
pituitary adenomas were observed. In the water plus NDEA control groups, one splenic
lymphosarcoma, three pituitary adenomas, one lymphosarcoma and one lymphatic leukae-
mia were observed among 40 males. In the corresponding female group of 58 rats, one renal
hamartoma, 14 pituitary adenomas and one lymphosarcoma were observed. [The Working
Group noted the absence of an effect of lead arsenate on NDEA-induced tumours.]
3.11 Tetraethyl lead

3.11.1 Mouse
Subcutaneous administration
Epstein and Mantel (1968) gave groups of 109, 79 and 69 male and female randomly
bred neonatal (0–21 days old) Swiss mice subcutaneous injections of total doses of 0.6,
1.2 and 2.0 mg/mouse, respectively, of tetraethyl lead [purity unspecified] in tricaprylin
into the nape of the neck. The low-dose group received 0.1 mg on days 1 and 7 and 0.2 mg
on days 14 and 21; the mid-dose group received 0.2 mg on days 1 and 7 and 0.4 mg on
days 14 and 21; and the high-dose group received a single injection of 2 mg on day 1. All
69 mice injected with 2 mg, 92% of the 79 mice injected with 1.2 mg and 20% of the 109
mice injected with 0.6 mg tetraethyl lead died prior to weaning. At 36 weeks, the inci-
dence of lymphomas in the mice that survived treatment with 0.6 mg tetraethyl lead (low
dose) was 1/26 males and 5/41 females. The incidence of lymphomas in vehicle-control
animals was 1/39 males and 0/48 females. Thus the incidence of lymphomas in treated
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female mice was significantly elevated (p < 0.05, χ 2 test) compared with female control
mice but not in treated male mice compared with male control mice. [The Working Group
felt that this study was limited by high mortality and the lack of concordance in tumour
response between lead-treated male and female mice.]

and its Mechanisms
4.1 Absorption, distribution, metabolism and excretion

4.1.1 Inorganic lead compounds
(a) Humans
(i) Absorption
Absorption of lead is influenced by the route of exposure, the physicochemical charac-
teristics of the lead and the exposure medium, and the age and physiological status of the
exposed individual (e.g. fasting, concentration of nutritional elements such as calcium, and
iron status). Inorganic lead can be absorbed by inhalation of fine particles, by ingestion
and, to a much lesser extent, transdermally.
Inhalation exposure
Smaller lead particles (< 1 µm) have been shown to have greater deposition and
absorption rates in the lungs than larger particles (Hodgkins et al., 1991; ATSDR, 1999).
In adult men, approximately 30–50% of lead in inhaled air is deposited in the respiratory
tract, depending on the size of the particles and the ventilation rate of the individual. The
proportion of lead deposited is independent of the absolute lead burden in the air. The half-
life for retention of lead in the lungs is about 15 h (Chamberlain et al., 1978; Morrow et al.,
1980). Once deposited in the lower respiratory tract, particulate lead is almost completely
absorbed, and different chemical forms of inorganic lead seem to be absorbed equally
(Morrow et al., 1980; US EPA, 1986).
In two separate experiments, male adult volunteers were exposed to aerosols of lead
oxide (prepared by bubbling propane through a solution of tetraethyl lead in dodecane and
burning of resulting vapour) containing 3.2 µg/m3 lead (15 subjects) or 10.9 µg/m3 lead
(18 subjects) in a room for 23 h/day for up to 18 weeks (Griffin et al., 1975a). Six un-
exposed controls were included in each experiment. For those volunteers who remained
until the end of the study, blood lead concentrations increased for about 12 weeks and then
remained at ∼37 µg/dL and ∼27 µg/dL for the groups with higher and lower exposure,
respectively. The concentration in the blood of controls was ∼15 µg/dL. Lead content in
blood declined after cessation of exposure, returning to near pre-exposure concentrations
after 5 or 2 months for higher and lower exposure, respectively. Chamberlain et al. (1978)
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suggested that some residual unburnt tetraethyl lead vapour may have been present in these
experiments.
Twelve volunteers exposed to 150 µg/m3 lead as lead oxide for 7.5 h per day on 5 days
per week for 16–112 weeks exhibited elevated concentrations of lead in blood and urine,
with one subject achieving a blood lead concentration of 53 µg/100 g (Kehoe, 1987). An
average respiratory intake of 14 µg lead per day was reported for five male volunteers
while exposed to an ambient concentration of 0.4–2.1 µg/m3 airborne lead (Rabinowitz
et al., 1977).
Oral exposure
Most data on gastrointestinal absorption of lead are available for adults; there have been
very few studies in children. Absorption of lead occurs primarily in the duodenum (reviewed
in Mushak, 1991). The mechanisms of absorption have yet to be determined but may
involve active transport and/or diffusion through intestinal epithelial cells (transcellular) or
between cells (paracellular), and may involve ionized lead (Pb2+) and/or inorganic or organic
complexes of lead (Mushak, 1991). The extent and rate of gastrointestinal absorption are
influenced by physiological conditions of the exposed individual such as: age, fasting, the
presence of nutritional elements including calcium, phosphorus, copper and zinc, iron status,
intake of fat and other calories; and physicochemical characteristics of the medium ingested,
including particle size, mineral species, solubility and lead species.
Studies in adults
The experimental studies in adults have mainly employed lead chloride and radio-
active tracers (212Pb and later 203Pb). Other evidence, often indirect, comes from stable
lead isotope methods and epidemiological studies. Representative studies in adults are
summarized in Table 81. The experimental studies generally had small numbers of
subjects, ranging from one to 23 and the studies with 203Pb were very short-term, due to
the short half-life of the tracer (52 h). There was a wide variation in absorption between
individuals in most studies; absorption was up to 96% in subjects who ingested lead with
alcohol whilst fasting (Graziano et al., 1996) but was generally less than 10% in subjects
who received lead with food.
Studies in children
Dietary data for very young infants (< 6 months old) are scarce; results of some
studies are listed in Table 82. For example, of the eight children investigated by Alexander
et al. (1974), only one was aged less than 6 months. In the study by Ziegler et al. (1978),
only one infant was studied from 14 days of age, two were studied from 72 and 83 days
of age, respectively, and the rest were over 118 days (∼4 months) old. In a study by Gulson
et al. (2001a), 15 newborn infants were monitored for at least 6 months postpartum.
Infants were breastfed or formula-fed or both and, aged about 91–180 days, usually fed
solid foods (baby food called beikost). Daily lead intake ranged from 0.04 to 0.83 µg/kg
bw with a geometric mean of 0.23 µg/kg bw and the excretion/intake ratio ranged from
0.7 to 22 with a geometric mean of 2.6. In a stable-isotope study, the mean value of blood
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Table 81. Absorption of lead in adults after ingestion

No. and sex Percentage ± SD Exposure conditions Reference
of subjects absorption (range)
Radioactive tracer 203PbCl2a or 203PbAca

11 men + 65 Fasting James et al. (1985)
12 women 3.5 Meal with calcium + phosphorus
16 3 h after breakfast
43 5 h after breakfast
10 men 21 ± 16 (10–67) 2 h after meal Blake (1976)
6 men 8 (4–11) Meal Chamberlain et al.
45 ± 17 (24–65) Fasting (1978)
7 men 21 (10–48) 2 h after meal Moore et al. (1979)
4 women 70 (67–74) Fasting Blake & Mann (1983)
17 (7–26) Fasting + 175 mg calcium/250 mg
phosphorus
2 (1–5) Fasting + 1750 mg calcium/2500 mg
phosphorus
8 men 63 (59–67) Fasting Heard & Chamberlain
6 men 3 (2–5) In liver and kidney of lambb (1982)
2 men 44 (37–56) Fasting Heard et al. (1983)
9 men 5.5 (2–14) In spinachc
8 men 10 (5–15) Normal meal + 200 mg calcium/
140 mg phosphorus
2 men 14 (3–28) With coffee and tea (and normal meal)
(nine tests)
4 men 19.5 (11–23) With beer 10 min before light lunch
9 men 14 ± 3 (8–18) Tracer given 2 h after meal Newton et al. (1992)
d
Stable lead isotopes
9 men 13.8 ± 3.1 ‘Contaminated’ beer, 0.5 L/d for 5 d Newton et al. (1992)
5 men 10 ± 2.7 (6.5–14) With food: lead nitrate Rabinowitz et al. (1976)
4 men 8.2 ± 2.8 (6–10) With food: lead nitrate/cysteine Rabinowitz et al. (1980)
4 men 35 ± 13 (30–37) Fasting: lead nitrate/sulfide/cysteine
2 men, 76 (46–96) Fasting: Sherry in lead crystal decanter Graziano et al. (1996)
4 women
1 man 34 Fasting: Wine doped with tracer 207Pb Gulson et al. (1998c)
2.3 Wine doped with 207Pb consumed
with meal
a
Volunteers ingested 203Pb as lead chloride or lead acetate in various media, e.g. in water, beverages
and meal, with varying amounts of calcium and phosphorus under fasting and non-fasting conditions.
Venous blood samples were taken at various times, e.g. 24 and 48 h. Body burden was measured by γ-
ray counting, 4–9 days after dosing.
b
Portions of liver or kidney from lamb injected with 203Pb as lead chloride and butchered after 6 days
were cooked and served in meals to volunteers.
c
The plants of spinach were placed in water containing the 203Pb as lead chloride for 48 h. The tops
were then harvested, cooked and eaten with normal meal.
d
Volunteers ingested non-radioactive enriched lead isotopes 204Pb, 206Pb or 207Pb as lead nitrate, lead
cysteine or lead sulfide in various media, e.g. in water, beverages and meal. Lead in samples (blood,
urine or faeces) was determined by thermal ionization mass spectrometry.
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09/08/2006
Table 82. Daily lead intakes in children and absorption of lead after ingestion
Study group Exposure Daily intakes Mean absorptiona (%) Mean Reference
retentionb
11:36
(µg/kg bw per day)
mean (range) (%)
Page 252
4 boys and 4 girls, aged 11 balance studies in own 10.6 (5–17) 53 18 Alexander
3 months to 8 years homes. One child was studied et al. (1974)
4 times from 3 months to
1.08 years.
6 boys and 6 girls, aged 2 separate balance studies 11– >5 42 32 Ziegler et al.
14–746 days 18 days apart in metabolic unit; (1978)
61 studies with variable lead
intakes > 5 µg/kg bw per day
9 children in hospital, 104 balance studies with 6.5 [1.5–17] Between –79% and 12% for the Barltrop &
aged 3–13 weeks; part 29 children 9 subjects, but high inter- Strehlow
of group of 29 children subject variability, some in (1978)
aged 3 weeks–14 years negative balance; –40% for all
29 children
a
Absorption denotes total intake minus faecal excretion
b
Retention denotes total intake minus total excretion
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lead coming from diet was 50% (Ryu et al., 1983, 1985). This value was consistent with
earlier estimates of uptake of lead in blood in newborn infants when environmental lead
concentrations were much higher (Alexander et al., 1974; Ziegler et al., 1978). In
contrast, Manton et al. (2000) suggested that the absorption in one child aged 4 months
was only 1–5%. [The Working Group noted that the percentage absorption observed in
this study is at variance with the majority of observations in infants.]
It should be noted that no absorption studies have been conducted in children older
than 8 years. However, the changes in stable isotope tracers of blood lead in mothers and
their children present similar profiles; both reach equilibrium with a unique exogenous
lead isotope profile suggesting that children aged 6–11 years and their mothers may
absorb a similar percentage of ingested lead from dietary sources (Gulson et al., 1997a).
Nutritional factors affecting absorption
Mineral content is one factor that may lower the absorption of lead when it is ingested
with food. For example, the presence and amount of calcium and phosphorus in a meal
depress the absorption of ingested lead. The effect is greater for the two elements together
than for either alone, with calcium showing a stronger effect than phosphorus (Blake &
Mann, 1983; Heard et al., 1983; James et al., 1985). In children, an inverse relationship
has been observed between dietary calcium intake and retention of lead, suggesting that
children who are deficient in calcium may absorb more lead than calcium-replete children
(Ziegler et al., 1978). Several studies have drawn attention to the potential toxicity of lead
in calcium or vitamin supplements (Capar & Gould, 1979; Roberts, 1983; Boulos & von
Smolinski, 1988; Bourgoin et al., 1993; Rogan et al., 1999; Scelfo & Flegal, 2000).
However, a study using isotope differences between lead in two types of calcium supple-
ments and that in the blood of adults showed that the supplements did not increase blood
lead concentration over a 6-month trial (Gulson et al., 2001b).
A higher dietary intake of iron is associated with lower blood lead concentrations
among children and iron deficiency may result in higher absorption of lead (Watson et al.,
1980; Mahaffey & Annest, 1986; Watson et al., 1986; Marcus & Schwartz, 1987;
Hammad et al., 1996; Wright et al., 2003). Evidence for the effect of iron deficiency on
lead absorption has been provided also from animal studies (see Section 4.1.1(b)).
In a metabolic study of 10 adult subjects who ingested copper, zinc or iron supple-
ments incorporated into a basal diet, higher faecal lead losses and lower blood lead con-
centrations were observed only with the copper supplements (Kies & Ip, 1991). [This
could be an effect on either absorption or retention.]
A positive correlation has been observed between blood lead in children and total and
saturated fat and caloric intake (Lucas et al., 1996; Gallichio et al., 2002). No relationship
between intake of fat and protein and lead concentrations in bone and blood was found in
middle-aged to elderly men in the Normative Aging Study (Cheng et al., 1998).
Ascorbic acid is known to enhance the urinary elimination of lead from blood, liver
and kidney in rats (Flora & Tandon, 1986). However, evaluation of the data from the
Third National Health and Nutrition Examination Survey showed that there is no signi-
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ficant relationship between ascorbic acid intake in diet and blood lead concentrations in
humans (Simon & Hudes, 1999; Houston & Johnson, 2000).
Absorption of lead from soil
In a study to mimic the soil ingestion habits of children, six adult subjects ingested
soil (particle size less than 250 µm) from the Bunker Hill (ID, USA) mining site, resulting
in a dose of 250 µg lead/70 kg bw. Based on stable lead isotope analysis, the subjects
absorbed 26 ± 8% of the lead in the soil when they were in the fasted state and 2.5 ± 1.7%
when the same soil lead dose was ingested with a meal (Maddaloni et al., 1998). There
are no reported measurements of the absorption of soil-borne lead in infants or children.
Evidence for a lower absorption of soil-borne lead compared with dissolved lead is
provided from studies in laboratory animals (see Section 4.1.1(b)). Experiments with
lead-bearing mine waste soil suggested that surface area characteristics determine disso-
lution rates for particles < 90 µm in diameter, whereas dissolution of 90–250-µm particles
appeared to be controlled more by surface morphology (Davis et al., 1994). Similarly,
in-vitro experiments showed that the solubility of 30-µm particles of lead sulfide in real
gastric fluid [origin not specified] was much greater than that of 100-µm particles (Healy
et al., 1982).
Dermal exposure
Little information is available regarding absorption of lead in humans after dermal
exposure. Moore et al. (1980a) conducted a study in which commercially-available lead
acetate solution (6 mmol/L lead acetate) or skin cream (9 mmol/kg lead), labelled with
[203Pb]acetate, was applied to the forehead skin of eight male volunteers for 12 h and then
washed off. Blood and urine samples were collected. The percentage of absorption was
estimated by measuring the 203Pb activity in blood samples, by counting over the subject’s
calf region using a whole-body monitor, and also by counting 24-h and 48-h urine
samples. Absorption through intact skin was 0.18 ± 0.15% of the dose applied; that
through scratched skin was 0.26 ± 0.46%. Lead exposure from the use of hair-colouring
agents containing lead acetate was reported to be insignificant (Moore et al., 1980a;
Cohen & Roe, 1991). However, this assumes that only adults will be in contact with the
colouring agents and ignores human behaviour in the home environment (Mielke et al.,
1997b). Measurements of lead on hands and surface wipes (including combs, hair dryer,
faucet) from subjects using hair-colouring agents showed between 150 and 700 µg lead
per hand and more than 100 µg/9.3 dm2 [∼10 µg/dm2] on the surfaces. At such concen-
trations, there is a potential for hand-to-mouth and hand-to-surface transfer of lead not
only to adults but also to children (Mielke et al., 1997b).
The dermal absorption studies of Florence and colleagues (1988), although limited in
subject numbers (nine workers), remain the most comprehensive to date. Following obser-
vations that workers in a lead battery factory exhibited high concentrations of lead in
sweat, Florence et al. (1988) and Lilley et al. (1988) showed that finely-powdered lead
metal and lead oxide (20 mg; particle size < 0.45 µm) or 60 µL of 0.5 M lead nitrate solu-
tion (6 mg lead) placed on the skin of one arm was rapidly absorbed. The absorbed lead
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appeared in sweat (induced by pilocarpine iontophoresis) on the other arm and in saliva,
but was not detectable in blood or urine. The authors found that the rate of lead absorption
through the skin increased with increased sweating and, as observed by Moore et al.
(1980a), suggested that the mechanism was one of rapid diffusion through filled sweat
ducts followed by a slower diffusion through the stratum corneum (Lilley et al., 1988).
The authors (as also observed by Moore et al., 1980a) noted that the absorbed lead must
be transported in the plasma and concentrated quickly into the extracellular pool (sweat
and saliva), that its mean residence time in the plasma is very short and that little lead
enters the erythrocytes (Lilley et al., 1988). [No quantification of the amount of lead
absorbed was undertaken and there were inconsistencies between the concentrations of
lead in sweat from the two arms on certain days.]
In later experiments using compounds made with 204Pb tracer and employing the
sensitive thermal ionization–mass spectrometry (TIMS) and ICP–MS methods, lead
acetate or lead nitrate was applied to the skin of four volunteers and perspiration induced
by either pilocarpine iontophoresis or thermally in a sauna (Stauber et al., 1994). The lead
compounds were rapidly absorbed through the skin and detected in sweat, blood and urine
within 6 h of application. In one subject, 4.4 mg lead (as lead nitrate) was applied to the
skin under a patch and perspiration induced by iontophoresis. Of the applied dose, 1.3 mg
lead was not recovered from skin washings, indicating that 29% of the applied dose was
absorbed into or through the skin. The authors suggested that some of the absorbed lead
was still present in the epidermis and had not entered the circulatory system as the other
experiments indicated that an equivalent of only 0.2% of the 204Pb applied to the skin was
detected in blood. However, no measurable increase of total lead in blood or urine was
found in this study. [The Working Group agreed with the authors in their concern about
this lack of increase in total lead in blood or urine, since blood lead is the accepted bio-
marker of exposure.]
(ii) Distribution
Lead enters and leaves most soft tissues reasonably freely. The clearance from the
blood into both soft tissues and bone dominates lead kinetics during the first few weeks
after an exposure, with an apparent half-life of several weeks (Table 83). Once an
approximate equilibrium is reached between soft tissues and blood, the concentration of
lead in blood is determined almost entirely by the balance among absorption, elimination,
and transfer to and from bone. In the absence of continuing exposure, the whole-body
half-life represents the loss of lead from bone. Lead enters and leaves bone by physio-
logically-distinguishable mechanisms (reviewed and summarized in O’Flaherty, 1991a,
1992, 1993), which include rapid exchange between blood plasma and bone at all bone
surfaces, incorporation of lead into forming bone and its loss during bone resorption, and
very slow diffusion of lead throughout undisturbed bone. Slow diffusion accounts for the
gradual build-up of large quantities of bone-seeking elements such as lead in quiescent,
largely cortical bone (Marshall & Onkelinx, 1968).
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Table 83. Kinetic parameters for lead in blood of non-occupationally exposed

adults and young children
Study group and No. and sex of Age Lead half-life Comments Reference
exposure subjects range in days ± SD
(years) (range)
Adults
Inhalation of lead 24 men 24–49 ∼1 month 10.9 µg/m3 lead Griffin et al.
oxide 21 men 24–50 ∼1 month 3.2 µg/m3 lead (1975a)
Ingestion of stable 5 men 25–53 25 ± 3 With meals Rabinowitz
204
Pb and 207Pb as et al. (1976)
nitrate
Ingestion of lead- 9 men 23–65 30 ± 4 No standardiza- Newton et al.
contaminated beer (19–46) tion of meals (1992)
for 28 days
Ingestion of wine 1 man NR 23 With meals Gulson et al.
doped with 207Pb (1998c)
tracer
Exposed to 7 (of 8) women 26–36 59 ± 6 Isotopic changes Gulson et al.
environments with (immigrantsa) (50–66) in blood lead (1995, 1999)
different lead monitored
isotopes monthly
Children
Newborn infants of 9 0–0.5 91 ± 19 Isotopic changes Gulson et al.
immigrant mothersa (65–131) in blood lead (1999)
monitored every
2 months
NR, not reported

a
The Working Group noted the longer half-lives of lead in blood for the immigrant women and their
newborn infants. The timing of sampling for the immigrant women, usually at least 1 month after their
arrival in Australia, suggests that the longer half-life observed was a whole-body half-life, reflecting a
primary contribution from bone.
Bone formation and bone resorption are generally tightly coupled. During infancy and
childhood, the bones grow rapidly and they are continually reshaped. Although the forma-
tion rate may greatly exceed the resorption rate, both processes are active throughout bone.
When full growth is reached in the late teens, bone formation and resorption rates are equal.
Subsequently, resorption of old bone and formation of new bone, which take place
throughout the entire bone volume, serve to maintain healthy bone tissue and to restructure
the bone in response to changing physical demands. The bulk of this activity takes place in
trabecular bone. The coupling of bone formation and bone resorption is a two-edged sword:
it is necessary to think of bone as both a sink for lead and a source of endogenous lead,
since both processes operate simultaneously. During childhood, when the formation rate is
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high, so is the resorption rate, so that little bone lead from an early childhood exposure will
persist into adulthood. On the other hand, generally whenever resorption is high, so is
formation, so that return of lead to blood plasma with resorbing bone will be partially com-
pensated by its redeposition into forming bone. Since trabecular bone generally turns over
more rapidly than cortical bone, the lead content of trabecular bone should respond more
rapidly than the lead content of cortical bone to changes — either increases or decreases —
in lead exposure (O’Flaherty, 1993).
Beginning as early as at age 25–30 years, bone resorption rate rises slightly while
bone formation rate does not change, so that slow net bone loss begins in early adulthood
(Jowsey et al., 1965; Mazess, 1982). There are also physiological states in which bone
resorption and formation become temporarily partially uncoupled. During the first five or
more years following menopause in women, the bone resorption rate is temporarily
increased without a compensatory increase in bone formation rate, after which bone
resorption rate drops back to a level about the same as that observed in older men (and in
women before menopause) (Mazess et al., 1987; Nilas & Christiansen, 1988). During
pregnancy and lactation, the bone resorption rate is increased in order to supply calcium
to the fetus and neonate.
The distribution of lead in various body compartments is considered in greater detail
below.
Blood
Lead in blood is found primarily in the red blood cells (> 99%) rather than the plasma
(Hursh & Suomela, 1968; Everson & Patterson, 1980; DeSilva, 1981; US EPA, 1986;
Bergdahl et al., 1997a). Bergdahl et al. (1997b,c, 1998a) showed that the principal lead-
binding protein was delta-aminolevulinic acid dehydratase (ALAD), also known as
porphobilinogen synthase (PBGS). Human ALAD has two alleles, ALAD-1 and ALAD-2,
with three phenotypes (and their percentages in Caucasian populations): ALAD 1-1 (80%),
ALAD 1-2 (19%) and ALAD 2-2 (1%) (Battistuzzi et al., 1981; Benkmann et al., 1983).
It has been proposed that this polymorphism causes differential sensitivity to lead exposure
(see Section 4.2.2).
Half-life of lead in blood
The half-life of lead in human blood has been determined experimentally, primarily in
adult men. These studies were carried out on small numbers of subjects, usually fewer than
ten, exposed only for up to 124 days. There are very limited data for children. A summary
of estimated half-lives from experimental studies is given in Table 83. The mean half-lives
of loss of lead from the blood immediately following an exposure are similar across studies
and are independent of the route of exposure, although there are large differences between
individuals. The mean half-lives for adult men in these studies ranged from 19–30 days.
However, in lead workers exposed for periods of up to 10 years, with high blood lead
concentrations, the half-life of initial loss from the blood following cessation of exposure
is of the order of 20–130 days; the half-life in lead workers was a function of cumulative
occupational exposure (O’Flaherty et al., 1982).
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When equilibrium is reached between soft tissues and blood, the net rate of loss of
lead from the blood decreases. Subsequently, the rate-determining step for whole-body
loss is the return of lead from the bone; in environmentally exposed subjects at equili-
brium with their environment, 40–70% of lead in blood derives from bone (Manton, 1985;
Gulson et al., 1995; Smith et al., 1996). Because of the nature of the mechanisms respon-
sible for return of lead from bone to blood, the overall process is not correctly described
by a half-life; however, it is convenient to continue to use half-lives to characterize whole-
body loss as expressed by the decline of blood lead concentrations. In adult women of
child-bearing age, Gulson et al. (1995, 1999) determined a mean whole-body half-life of
59 ± 6 days. Infants born to mothers immigrant to Australia had whole-body half-lives of
65–131 days, considerably longer than the 50–66-day half-lives observed for the adult
women (Gulson et al., 1999). Manton et al. (2000) observed longer whole-body half-lives
of lead during the first 2 years of life in the blood of two groups of children who had been
exposed to lead from residential remodelling over varying periods of time. Half-lives of
lead in children exposed for unspecified brief periods of time were between 8 and 11
months, while half-lives in those with longer exposures varied from 20 to 38 months.
Whole-body half-lives of lead in blood estimated for workers occupationally exposed
to lead are commonly much greater than those shown in Table 83 for non-occupationally
exposed individuals, and reflect a much greater loading of the skeleton with lead
(O’Flaherty et al., 1982; Hryhorczuk et al., 1985; Schütz et al., 1987; Nilsson et al., 1991;
Fleming et al., 1997, 1999). They are comparable to half-lives of lead measured in cortical
bone (Christoffersson et al., 1986; Erkkilä et al., 1992).
Serum–whole blood relationships
Several authors have proposed that measurement of lead in serum may better reflect the
fraction of lead that is available in the circulation for exchange with target organs such as
the central nervous system and kidneys, and with the developing fetus (Manton & Cook,
1984; Schütz et al., 1996; Hernandez-Avila et al., 1998; Hu, H. et al., 1998; O’Flaherty,
1998; O’Flaherty et al., 1998; Smith et al., 1998; Bergdahl et al., 1999). A stronger asso-
ciation was found between the ratio plasma lead/blood lead with bone lead concentrations
(measured by X-ray fluorescence) than with whole blood lead concentrations (Cake et al.,
1996; Hernandez-Avila et al., 1998). Using urine as a proxy for plasma, Tsaih et al. (1999)
observed significant associations between bone lead and urinary lead.
The low concentration of lead in plasma, relative to red blood cells, has made it
extremely difficult to measure accurately plasma lead concentrations in humans, parti-
cularly at blood lead concentrations less than 20 µg/dL (Schütz et al., 1996; Hernandez-
Avila et al., 1998). Serum analyses, especially at lower blood lead concentrations, are
complicated by erythrocyte contamination (haemolysis), sampling and laboratory conta-
mination, measurement error and misinterpretation of the data (Manton et al., 2001).
Plasma is generally accepted as the source of lead available to distribution and excretion
processes. Urinary lead excretion in humans is directly proportional to plasma lead concen-
tration but not to blood lead concentration (O’Flaherty, 1993). Breast milk lead has been
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considered an indirect measure of plasma lead. A number of studies have shown significant
linear relationships between lead in human breast milk and whole blood collected at
delivery (cord blood) or post partum (Moore et al., 1982; Ong et al., 1985; Rabinowitz
et al., 1985; Namihira et al., 1993; Palminger Hallén et al., 1995a; Gulson et al., 1998a).
Physiologically-based kinetic models in which transfers of lead (other than into bone)
are assumed to be proportional to plasma lead concentration have been successful in a
variety of different applications (O’Flaherty, 1998, 2000).
The relationship between serum lead and blood lead concentrations is not linear, due
at least in part to limited availability of lead binding sites in the erythrocyte (DeSilva, 1981;
Marcus, 1985; O’Flaherty, 1993). This binding is highly variable among individuals; it is
influenced by extrinsic factors, such as iron nutritional status; and there is some evidence
for its inducibility (Raghavan et al., 1980; Marcus & Schwartz, 1987). The saturable
binding of lead to erythrocytes has been interpreted as binding to three principal com-
ponents, the tightest binding of which is to ALAD (Bergdahl et al., 1998a). Thus, the
fraction of blood lead in the plasma, the driving compartment for transfer into tissues,
increases disproportionally with increasing blood lead concentration (Figures 1 and 2). The
disproportionality becomes more pronounced as blood lead concentrations increase above
about 40 µg/dL. Below this concentration, the relationship of serum lead concentration to
blood lead concentration can be approximated by a straight line (Manton et al., 2001).
Figure 1. The relationship between plasma lead and blood lead
Adapted from O’Flaherty (1993)

Data points are from DeSilva (1981) as shown in Marcus (1985). Curve A is the model simulation. Curve B
is Marcus’ fit to the data, using a no-intercept model (Marcus’ Model 4) consistent with the concept of a maxi-
mum erythrocyte binding capacity for lead.
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Figure 2. Plot of serum lead concentration vs blood lead concentration for

73 subjects
Adapted from Manton et al. (2001)

The line fitted to the points has the equation y = 0.00246 + 0.00236x (r = 0.82). Curves for workers obtained
by Schütz et al. (1996) and Hernandez-Avila et al. (1998) are those calculated by Manton et al. (2001). The
curves of both groups of workers were defined down to blood lead concentrations of 23 µg/dL so that at the
lower end of their ranges, the observations for the workers overlap with those of Manton et al. (2001). See
Manton et al. (2001) for further details.
In summary, in more recent investigations within this apparently linear range, there is
convergence towards a percentage of serum lead/whole blood lead of < 0.3% (Cake et al.,
1996; Bergdahl & Skerfving, 1997; Bergdahl et al., 1997a; Hernandez-Avila et al., 1998;
Bergdahl et al., 1999; Manton et al., 2001; Smith et al., 2002; see Table 84). These
investigations confirm earlier studies with radioactive 203Pb tracers that showed that 0.2%
of the 203Pb was present in plasma at 50–100 h after exposure (Heard & Chamberlain,
1984).
Soft tissues
Lead has been measured in a variety of tissue samples in humans but care needs to be
taken when comparing results because of the different reporting of measures for wet, dry
and ashed weights.
In a study of lung tissues collected at autopsy from individuals with no known occupa-
tional exposure to lead [no details given], an average lead concentration of 0.22 ± 0.11 µg/g
tissue was found (Barry, 1975). In 42 non-occupationally exposed subjects, Gross et al.
(1975) detected 0.36 ± 0.12 µg/g wet weight (ashed, 23.9 ± 10.6 µg/g) in lung tissue. In a
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Table 84. Analyses of blood lead concentrations in serum and whole blood
samples
Subjects (no.) Analytical Blood lead % serum/whole Curvilinear Reference

exposed or not to methoda concentration blood (mean or relationship
lead (µg/dL) range)
Women, non- TIMS 0.6–12.6 0.1–0.4 Linear Manton et al.

exposed (73) < 10 µg/dL (2001)
Women and men, ICP-MS 2.3–41.6 0.2–0.7 Yes Hernandez-Avila
non-exposed (26) et al. (1998)
Women, non- ICP-MS < 25 0.099–0.48 For samples Smith et al.
exposed (63) > 10 µg/dL (2002)
Men, exposed ICP-MS 10–30 0.4 (read from Yes Bergdahl et al.
(143) the graph) (1997a);
30–90 0.35 (read from Bergdahl &
the graph) Skerfving (1997)
Men, exposed TIMS 16.5–55.2 0.8–2.5 Not stated Cake et al.
(49) (1996)
Children (44), ICP-MS Yes (for Bergdahl et al.
exposed (31) 9.9–92 0.24–2.0 exposed and (1999)
Considerably (median, 0.79) unexposed
lower exposed: 3.9–12 0.23–0.49 children)
‘Unexposed’ (13) (median, 0.36)
a
TIMS, thermal ionization–mass spectrometry; ICP–MS, inductively-coupled plasma mass spectrometry
similar study, Mylius and Ophus (1977) reported an average of 0.56 µg/g dry weight (range,
0.28–1.14 µg/g) in lung tissue from 10 non-occupationally exposed individuals.
Gerhardsson et al. (1995b) showed that in 32 deceased smelter workers with known
lead exposure history, the major soft tissue organs of lead accumulation were: liver >
kidney > lungs > brain. Lyon et al. (2002) measured lead in liver tissue of 157 subjects
aged < 1 day to 6 years. Lead concentrations ranged from 0.0083 to 0.407 µg/g wet
weight. The median fetal liver concentration in 10 subjects was 0.0256 µg/g dry weight
(Lyon et al., 2002), comparable with the value in a Canadian study of 21 fetal livers of
0.061 ± 0.023 µg/g dry weight as calculated by Lyon et al. (2002) from the reported value,
0.243 ± 0.092 µg/g wet weight (Gélinas et al., 1998). These values are considerably lower
than those found in adults before 1994 (0.25–2.30 µg/g; Caroli et al., 1994), in 73 adults
in Canada (0.01–1.2 µg/g; Treble & Thompson, 1997) and in children aged 0–10 years for
the period 1975–89 (0.08–1.37 µg/g; Patriarca et al., 2000).
Barregård et al. (1999) measured lead in the renal cortex from 36 living healthy
kidney donors in Sweden and found mean values of 0.18 µg/g dry weight. This was the
first study of heavy metals in kidney cortex of living, healthy subjects.
Al-Saleh and Shinwari (2001b) measured concentrations of lead in tumour tissue from
23 patients (17 women, six men) with malignant brain tumours and 21 patients (11 women,
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10 men) with benign brain tumours who were undergoing treatment at a Saudi Arabian hos-
pital. Mean lead concentrations were similar in malignant and benign tumours (0.65 ± 1.7
and 0.61 ± 1.7 µg/g, respectively). In a study of a population in the USA, however, the
concentration of lead in brain was below the limit of detection of 0.0008 µg/g (Bush et al.,
1995). [The Working Group noted the lack of a proper control group and other indices of
cumulative lead exposure, and the limited statistical analyses of this study.]
Bone
In human adults, more than 90% of the total body burden of lead is found in the bone,
whereas bone lead accounts for ~70% of the body burden in children (Barry, 1975). Lead
is not distributed uniformly in bone (Somervaille et al., 1986; Wittmers et al., 1988;
Aufderheide & Wittmers, 1992; Hoppin et al., 2000; Todd et al., 2000b, 2001c,d, 2002).
Estimates of the half-life of lead in trabecular bone are partly dependent on the tissue
analysed and the ‘purity’ of the trabecular component [patella, calcaneus, finger bone
(phalanx)]; current estimates range from about 12–16 years although earlier estimates
ranged from 2–7 years (Christoffersson et al., 1986; Schütz et al., 1987; Gerhardsson et al.,
1993; Bergdahl et al., 1998b). Earlier estimates for the half-life of lead in cortical bone were
of the order of 13–27 years (Rabinowitz, 1991; Gerhardsson et al., 1993; Bergdahl et al.,
1998b).
Studies over the past two decades using X-ray fluorescence methods have shown that
trabecular bone — which has a faster turnover rate — (measured at the calcaneus or
patella) has higher concentrations of lead/mg bone mineral than cortical bone (measured
at the tibia) in the same subjects. The ratio of the concentration of lead in trabecular vs
cortical bone generally ranges from 1.1 to 2.0; it appears to be independent of duration of
exposure, occupation, age, sex, life-stage, pregnancy status, trabecular bone site, or blood
lead concentration (Hu et al., 1996b,c; Bergdahl et al., 1998b; Fleming et al., 1998;
Hernandez-Avila et al., 1998; Tsaih et al., 1999; Brown et al., 2000; Hu et al., 2001;
Elmarsafawy et al., 2002; Korrick et al., 2002; Rothenberg et al., 2002; Hernandez-Avila
et al., 2003; Garrido Latorre et al., 2003). A ratio of 3.6 in trabecular/cortical bone lead
was measured in active workers exposed to lead in Finland (Erkkilä et al., 1992). The
higher ratio is consistent with the more rapid turnover of trabecular bone, which would be
expected to be responsive to current exposure. [There may be a possible bias in the studies
reported here since the majority of the subjects were from the Normative Aging Study].
Maternal patella bone lead concentrations have been shown to be superior to tibia
bone lead concentrations in predicting lower infant birth weight (Gonzalez-Cossio et al.,
1997) and reduced growth rate from birth to 1 month of age (Sanín et al., 2001).
In two of three adult males studied after cessation of occupational exposure to lead,
lead concentrations in the patella (representative of trabecular bone) decreased more
rapidly than those in the tibia (representative of cortical bone), consistent with the esti-
mates of a shorter lead half-life in trabecular bone (Hu et al., 1991).
Fleming et al (1997) and, in a follow-up study, Brito et al (2001) observed non-linear
relationships between cumulative blood lead index (CBLI) and bone lead concentrations
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in groups of 367 and 519 active lead-smelter workers. By subdividing their study groups
by date of hire, the authors showed that the apparent half-life of bone lead increased with
length of employment (Brito et al., 2001). They suggested that the increase was attri-
butable to the age-dependence of bone turnover; i.e. that turnover was lower in the older
men with longer employment histories. However, since blood lead concentrations in both
groups of smelter workers exceeded 60 µg/dL during their earlier employment years
(before the mid-1970s) and declined thereafter, the curvilinearity in the bone lead concen-
tration/CBLI relationship could also be explained simply as a reflection of that of the
plasma lead/whole blood lead relationship. This curvilinearity would have led to a dispro-
portionate loading of bone with lead relative to blood lead concentrations (but not relative
to plasma lead concentrations) during the early employment years when blood lead con-
centrations were high (Fleming et al., 1997).
Cortical bone lead concentrations gradually increase with age whereas concentrations
in trabecular bone (rib, vertebrae) level-off in the fifth decade of life and then may
decrease (Gross et al., 1975; Drasch et al., 1987; Wittmers et al., 1988; Kosnett et al.,
1994; Hu et al., 1996c).
Analyses of bone and teeth can provide an integrated biomarker of previous lead
exposure and can be used in a variety of investigations. For example, K-X ray fluo-
rescence (K-XRF) analysis of bone has shown strong associations between bone lead and
hypertension, cognitive functioning (e.g. Korrick et al., 1999; Cheng et al., 2001; Gerr
et al., 2002; Rothenberg et al., 2002) and delinquency (Needleman et al., 2002).
(iii) Metabolism
Ionic lead in the body is not known to be metabolized or biotransformed. It does form
complexes with a variety of proteins and non-protein ligands (US EPA, 1994; ATSDR,
1999).
(iv) Excretion
Lead in the faeces includes both lead that has not been absorbed in the gastrointestinal
tract and lead excreted in the bile (endogenous faecal excretion). When lead exposure is
by ingestion, more than 90% of excreted lead is found in the faeces (Kehoe, 1987; Smith
et al., 1994). Biliary clearance is also a major route of excretion of absorbed lead. Excre-
tion of lead does not appear to depend on exposure pathway (ATSDR, 1999), but the ratio
of urinary to faecal excretion is variable. Values of from 1:1 to 3:1 have been reported for
the ratio of urinary lead clearance to endogenous faecal lead clearance in adult humans
after injection, inhalation or ingestion of 203Pb-lead (Chamberlain et al., 1978; Campbell
et al., 1984).
Excretion of lead through sweat is a minor process. Concentrations of lead in sweat
vary depending on exposure and can be significantly elevated in workers in the lead
industry (Stauber & Florence, 1988; Omokhodion & Howard, 1991; Omokhodion &
Crockford, 1991a) compared with unexposed subjects (Omokhodion & Howard, 1991;
Omokhodion & Crockford, 1991b). In healthy subjects who volunteered to ingest small
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amounts of lead, the lead concentrations in sweat were less than 10 µg/L and were about
20% of the concentrations found in urine and 6% of those in blood (Rabinowitz et al.,
1976; Omokhodion & Crockford, 1991b). [The Working Group noted the possibility of
contamination of samples during collection and/or the lack of baseline lead concentrations
reported in some of these studies.]
(v) Mobilization of lead
Although earlier investigators (Brown & Tompsett, 1945; Ahlgren et al., 1976) had
suggested that the skeleton was a potential endogenous source of lead poisoning, the
opposing concept of the skeleton as a ‘safe’ repository for lead persisted until the mid-
1980s and early 1990s. Potential mobilization of lead from the skeleton can occur at times
of physiological stress associated with enhanced bone remodelling, such as during
pregnancy and lactation (Manton, 1985; Silbergeld, 1991; Hertz-Picciotto et al., 2000),
menopause (Silbergeld et al., 1988; Silbergeld, 1991), extended bed rest (Markowitz &
Weinberger, 1990), hyperparathyroidism (Kessler et al., 1999) and weightlessness. The
lead deposited in the bone of adults can serve to maintain blood lead concentrations long
after exposure has ended (O’Flaherty et al., 1982; Manton, 1985; Kehoe, 1987; Schütz
et al., 1987; Nilsson et al., 1991; Gulson et al., 1995; Inskip et al., 1996; Smith et al.,
1996; Fleming et al., 1997).
Pregnancy and lactation
During pregnancy, the mobilization of bone lead increases. The increase in blood lead
concentrations during the third trimester has been attributed to increased bone resorption
to meet the calcium requirements of the developing fetal skeleton (Manton, 1985;
Rothenberg et al., 1994; West et al., 1994; Lagerkvist et al., 1996b; Schuhmacher et al.,
1996b; Gulson et al., 1997b; Hertz-Picciotto et al., 2000).
Manton (1985) monitored blood lead of one woman by use of high-precision
measurement of stable lead isotopes and attributed the almost doubling of blood lead
concentrations during pregnancy to skeletal sources. In subjects who had been exposed in
their earlier life to lead from sources different from their current environment, Gulson
et al. (1995) and Smith et al. (1996) — using the same methods — estimated that 40–70%
of lead in blood is derived from the skeleton. In Australia, Gulson et al. (1997b) monitored
two immigrant cohorts longitudinally during and after pregnancy over a 10-year period
using the same study design and monitoring protocols. The first cohort (Gulson et al.,
1997b, 1998a), comprising 16 pregnant immigrants, six long-term Australian women and
six non-pregnant immigrant controls, showed that concentrations of blood lead increased
during pregnancy by an average of about 20% compared with the non-pregnant immigrant
controls. The increases were attributed to release of lead from the skeleton associated with
increased bone remodelling, and were possibly related to the low calcium intake of most
of the subjects.
Berglund et al. (2000) determined lead in blood and urine in relation to bone turnover
in pregnant and lactating women in Stockholm, Sweden. In contrast to many of the studies
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cited above, no increase in blood lead during pregnancy was detected. The authors
suggested that this could be attributed to normal physiological haemodilution (Hytten,
1985), a diet relatively high in calcium and low in lead, transfer of lead to the fetus and a
possibly relatively low body burden of lead in younger women in Sweden. However, signi-
ficant increases in concentrations of blood during pregnancy have been observed in women
whose blood lead concentrations were also low (Gulson et al., 1997b, 1998a; Rothenberg
et al., 2000). In addition to increases in blood lead during later stages of pregnancy, blood
lead concentrations have been observed to decrease in the early stages of pregnancy. The
mechanisms for these changes are not understood, although increased mobilization of bone
lead during pregnancy may contribute partly to the increase (Lagerkvist et al., 1996b;
Schuhmacher et al., 1996b; Gulson et al., 1997b, 1998a). Increased blood volume and
haemodilution may contribute to the decrease observed in the first half of pregnancy,
whereas increased absorption of lead during pregnancy or decreased elimination may also
occur (Rothenberg et al., 1994; Franklin et al., 1997; Gulson et al., 1997b).
Transplacental transfer/breast milk
Transplacental transfer of lead in humans has been demonstrated in a number of
studies indicating that the ratio of cord/maternal blood lead concentration at delivery
ranges from about 0.6 to 1.0 (Barltrop, 1969; Rabinowitz et al., 1984; McMichael et al.,
1986; Goyer, 1990a; Graziano et al., 1990; Al-Saleh et al., 1995; Schuhmacher et al.,
1996b; Gulson et al., 1997b). Diffusion has been proposed as the primary mechanism for
transplacental lead transport (Goyer, 1990a).
Evidence for maternal-to-fetal transfer of lead in humans can be gained from stable
lead isotope measurements. For example, a 0.99 correlation in lead isotopic ratios for
maternal and cord blood (Manton, 1985; Gulson et al., 1997b) and similarity of isotopic
ratios in maternal blood and in blood and urine of newborn infants provide strong evi-
dence of placental transfer (Gulson et al., 1999; Gulson et al., 2004). The presence of lead
in neonatal liver provides further direct evidence that it crosses the human placental
barrier (Lyon et al., 2002).
Breast milk can also be a vehicle for maternal excretion of lead. However, given the
very low lead concentrations and the analytical difficulties arising from the high fat content
of breast milk, lead analyses require careful attention (Gulson et al., 1998a). For breast
milk collected serially, the mean lead concentration was found to be 0.73 ± 0.70 µg/L for
mothers whose blood lead concentration was less than 5 µg/dL. For the first 60–90 days
postpartum, the contribution from breast milk to blood lead in the infants varied from
36–80%. Gulson et al. (1998a) evaluated studies published over the last 15 years of lead
concentrations in breast milk and suggested that studies in which the ratio of lead concen-
tration in breast milk to lead concentration in maternal whole blood were greater than 0.15
should be viewed with caution because of potential contamination during sampling and/or
laboratory analyses. Several studies appear to show a linear relationship between lead in
breast milk and maternal whole blood lead. The percentage of lead in breast milk was com-
parable with that in whole blood in subjects with blood lead concentrations ranging from
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2–34 µg/dL. Gulson et al. (1998a) suggested that breastfed infants are only at risk if the
mother is exposed to high concentrations of lead contaminants either from endogenous
sources such as the skeleton or exogenous sources.
Reduction of lead mobilization during pregnancy and lactation
Studies that focused on the reduction of lead mobilization during pregnancy and lacta-
tion in humans have usually employed calcium supplementation. Increased intake of
calcium has been suggested as a measure to prevent mobilization of extra lead during
pregnancy and lactation (Farias et al., 1996; Hernandez-Avila et al., 1996; Gulson et al.,
1998d; Hertz-Picciotto et al., 2000; Gulson et al., 2003). Calcium supplementation at the
recommended level of approximately 1000 mg/day (NIH, 1994) was found to almost
halve the extra lead released during pregnancy but offered no benefit during lactation
(Gulson et al., 2004). In contrast, calcium carbonate supplementation of 1200 mg/day ele-
mental calcium during lactation gave a modest reduction of 16% in blood lead concen-
trations amongst women with relatively high bone lead burdens (Hernandez-Avila et al.,
2003). In an earlier report that apparently used the same cohort but with smaller numbers,
there did not seem to be any benefit from calcium supplementation during lactation
(Téllez-Rojo et al., 2002). Using concentrations of cross-linked N-telopeptides of type I
collagen (NTX), a sensitive biomarker of bone resorption, Janakiraman et al. (2003)
observed that a 1200-mg calcium supplement taken at bedtime during the third trimester
of pregnancy reduced maternal bone resorption by an average of 14%.
Menopause
Increases in blood lead in postmenopausal women have been attributed to release of
lead from the skeleton associated with increased bone resorption during menopause
(Silbergeld et al., 1988; Symanski & Hertz-Picciotto, 1995; Muldoon et al., 1994;
Weyermann & Brenner, 1998; Hernandez-Avila et al., 2000). Most of these studies were
based on blood lead concentrations. More recent investigations employing bone X-ray
fluorescence measurements as well as blood lead concentrations have supported an endo-
genous contribution of bone lead to blood (Webber et al., 1995; Korrick et al., 2002;
Garrido Latorre et al., 2003). Postmenopausal women using hormone replacement
therapy may have lower blood lead concentrations and higher bone lead values than non-
users (Webber et al., 1995; Garrido Latorre et al., 2003). In contrast, in a cross-sectional
study of 264 women (46–74 years old) in Boston, USA, both tibia and patella lead values
were significantly and positively associated with blood lead but only among postmeno-
pausal women not using estrogen (Korrick et al., 2002). In a pilot study of immigrant
women in Australia, Gulson et al. (2002) found a decrease in blood lead concentrations
and changing lead isotopic composition in women treated for 6 months with a powerful
anti-bone resorptive bisphosphonate drug. Upon cessation of treatment, the blood lead
concentrations increased and the isotopic composition changed.
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Preferential partitioning of bone lead into plasma

Several authors have proposed that lead released from the skeleton is preferentially
partitioned into serum rather than erythrocytes; one explanation being that the lead from
endogenous sources was in a different form to that from exogenous sources (Cake et al.,
1996; Hernandez-Avila et al., 1998; Tsaih et al., 1999). In a study employing similar
methods, Bergdahl and Skerfving (1997) disputed the findings of Cake et al. (1996).
Chettle et al. (1997) also challenged the hypothesis of Cake et al. (1996) that the ratio of
serum lead to whole blood lead increases with increasing amounts of lead released from
bone. Using urine as a proxy for serum, Gulson et al. (2000) compared lead isotopic ratios
and lead concentrations in 51 matched blood and spot urine samples from 13 subjects,
covering the interval from before pregnancy through 180 days postpartum. There was no
evidence for preferential partitioning of lead into serum compared with whole blood.
Pharmacokinetic models
Several pharmacokinetic models for lead have been proposed to explain and predict
physiological processes, including intercompartmental lead exchange rates, retention of
lead in various pools, and relative rates of distribution among the tissue groups. Compre-
hensive discussions of these models have been published by ATSDR (1999). One of the
earliest was a three-compartment model based on stable lead isotope tracer experiments and
balance data from five healthy men (Rabinowitz et al., 1976). A physiologically-based phar-
macokinetic (PBPK) model developed initially for rats by O’Flaherty (1991a,b,c, 1993,
1995) uses physiologically-based parameters to describe the volume, composition and
metabolic activity of blood and tissues that determine the disposition of lead in the human
body. The compartments and pathways in the O’Flaherty model are shown in Figure 3
(ATSDR, 1999). Two other models in current use are compartmental pharmacokinetic
models; the integrated exposure uptake biokinetic (IEUBK) model for lead in children
(Figure 4) (US EPA, 1994) and the Leggett model (Leggett, 1993), which simulate the same
general processes as those in the PBPK model, although transfer rate constants and kinetic
coefficients may not have precise physiological correlates. All three models have been cali-
brated, to varying degrees, against empirical physiological data from animals and humans,
and blood lead concentrations observed in exposed populations of children and adults.
Pharmacokinetic models have been used to estimate the probability distribution of blood
lead concentrations in children potentially exposed to lead via multiple exposure pathways
at hazardous waste sites. The O’Flaherty and Leggett models have accurately reproduced
adult blood lead concentrations, and may be modified to reflect changes in lead associated
with pregnancy, ageing, or disease states (Pounds & Leggett, 1998; O’Flaherty, 2000).
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Figure 3. Compartments and pathways of lead exchange in the O’Flaherty model
From ATSDR (1999), derived from O’Flaherty, 1991b, 1993, 1995
(b) Animals
(i) Absorption
Ingestion
Absorption of lead from the gastrointestinal tract in experimental animals is age-
dependent and is influenced by the amount of food intake.
Prior to weaning, rodents absorbed from 50% to more than 80% of a single oral dose
of radiolabelled lead, while older rodents absorbed < 1–15% (Forbes & Reina, 1972;
Garber & Wei, 1974; Kostial et al., 1978; Flanagan et al., 1979).
In rats receiving a carrier-free oral dose of 0.02 µCi 212Pb, absorption of lead from the
gut declined steadily from 74–89% in animals 16–22 days of age to 15–42% in animals
24–32 days old and to only 16% in 89-day-old animals (Forbes & Reina, 1972). [It was
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Figure 4. Structure of the IEUBK model for children
From ATSDR (1999)
unclear whether the study was conducted with fasted animals.] A single oral dose of 203Pb-
lead chloride resulted in 52% absorption in 1-week-old suckling rats compared with 0.4%
in 6-week-old adults on a standard diet (Kostial et al., 1978). Lead absorption from an
intragastric dose of 2 µCi 210Pb-lead acetate was 5.4% and 9.7% in adult C56Bl/6 Jax mice
that were given an iron-supplemented diet or an iron-deficient diet, respectively (Flanagan
et al., 1979).
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The presence of food in the intestine was shown to reduce by more than 80% the
absorption of a 10-mg/kg oral dose of lead acetate in Sprague-Dawley rats (Aungst &
Fung, 1981). In Swiss-Webster mice, food reduced lead absorption from 14% to 7.5%,
when a single tracer dose of 210Pb-lead acetate (3 µg/kg bw) was administered. However,
the absorption rate (4–5%) was similar in fasted and non-fasted mice receiving a higher
dose of lead (2 mg/kg bw) (Garber & Wei, 1974).
In non-human primates, the absorption of lead ranged from 38–65% in young animals
and from ∼3–40% in mature animals (Willes et al., 1977; Pounds et al., 1978; O’Flaherty
et al., 1996; Cremin et al., 2001).
Fasted young monkeys (Macaca fascicularis; 10 days of age) absorbed 64.5% of an oral
dose of 10 µg/kg bw 210Pb-lead nitrate, while only 3.2% was absorbed by fasted mature
adults (Willes et al., 1977). Similarly, the gastrointestinal absorption of an oral dose of
72.6 µg 206Pb-lead acetate (352 nmol) in 12 mL apple juice was ~65% in fasted infant rhesus
monkeys (Cremin et al., 2001). Fasted adult cynomolgus monkeys absorbed 22–44% of a
single dose of lead given as 210Pb-lead nitrate, depending on the dose (O’Flaherty et al.,
1996). In fed juvenile rhesus monkeys (5–7 months old), lead absorption was 38% versus
26.4% in fed adults following a single gavage dose of 10 mg/kg bw 210Pb-lead acetate
(Pounds et al., 1978).
Experiments in mice and rats provide evidence that lead absorption is increased in the
later stages of pregnancy and during lactation (Donald et al., 1986; Maldonado-Vega
et al., 1996). The gastrointestinal absorption of 203Pb in lactating rats was found to be
about 2–3.5 times that in controls (Kostial & Momcilovic, 1972; Momcilovic, 1979).
There is experimental evidence that gastrointestinal absorption of lead is a saturable
process. In mice, single administrations of 0.2, 2 or 20 mg/kg 210Pb-lead acetate resulted
in similar absorption rates (Garber & Wei, 1974). Duodenal perfusate experiments in mice
have shown that lead uptake from the lumen increased in proportion to lead concentration
in the perfusate but that the transfer of lead across isolated mouse duodenum to the carcass
was saturable (Flanagan et al., 1979).
The extent of absorption decreased from 42% in fasted adult Sprague-Dawley rats
administered a single oral dose of 1 mg/kg bw lead (as lead acetate) to 2% when the dose
was increased to 100 mg/kg bw. Furthermore, the percentage of the dose recovered from
the tissues (brain, liver, kidneys, blood) decreased from 6.9% after 1 mg/kg bw lead to
0.6% after 100 mg/kg bw in adults and from 11.0% to 0.6% in pups (Aungst et al., 1981).
A 100-fold increase in a single oral dose from 10 µg to 1 mg 203Pb-lead chloride was
accompanied by an increase of only 20-fold in the quantity of lead absorbed in fasted
Wistar rats (Conrad & Barton, 1978). Studies by Polák et al. (1996) demonstrated a dose-
dependent biovailability in rats of both soluble lead and lead in mine waste or in mine
waste-contaminated soils. Fractional absorption decreased as lead intake increased,
regardless of the source of the lead, but the magnitude of this dose dependence was lead
source-dependent. Fractional absorption varied from 4–5% at low exposure rates
(1–2 mg/kg bw lead per day) when lead acetate was added to the diet, to 0.24% at a high
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exposure rate (24 mg/kg bw lead per day) when a test soil of mine waste contaminated
with lead was added to the diet (Polák et al., 1996).
The absorption of an intraluminal dose of 203Pb-lead acetate in chicks was impaired
by the presence of lead (as lead chloride) in the diet, in a dose-dependent fashion from
43% at a dietary concentration of 0.1% lead to 16 % at a dietary concentration of 0.8%
(Fullmer, 1991).
Fractional absorption of 210Pb-lead nitrate decreased from 44% of a single oral dose
of 750 µg/kg bw to 22–28% of a dose of 1500 µg/kg bw in fasted adult cynomolgus
monkeys (O’Flaherty et al., 1996).
The bioavailability of lead is dependent on its chemical form and its particle size as
well as the matrix and the source of environmental lead. Absorption of lead from the
gastrointestinal tract of Wistar rats (30-day-old) varied greatly with chemical form; lead
carbonate administered in the diet showed a 12-fold greater absorption coefficient than
metallic lead. Relative to the absorption of lead acetate taken as 100%, the absorption
coefficients of lead salts were: 44% for lead chromate, 62% for lead octoate, 64% for lead
naphthenate, 67% for lead sulfide, 121% for lead tallate and 164% for lead carbonate
(basic) (Barltrop & Meek, 1975). In studies performed by Dieter et al. (1993), rats were
fed ≤ 38-µm size particles of lead sulfide, lead oxide, lead acetate and a lead ore concen-
trate from Skagway, Alaska, USA, mixed into the diet at doses of 0, 10, 30 and 100 ppm
for 30 days. Bioavailability was found to be highest for lead acetate, intermediate for lead
oxide and lowest for lead sulfide and Alaskan mixed-ore concentrate. Lead concentrations
in bone and kidney were about 20- and 10-fold greater, respectively, in rats fed the more
soluble compared with the less soluble lead compounds (Dieter et al., 1993). Experi-
mental studies on fed young rats showed that the mean relative bioavailability (compared
with lead acetate) of lead in the Butte mining waste soil was 20%, 9% and 8% based on
measurements of lead in blood, bone and liver, respectively (Freeman et al., 1992). In
further studies by these authors, the absolute bioavailability of ingested lead acetate in
feed was estimated to be 15% based on measurements of blood lead concentrations after
oral administration. The addition of control soil to the diet with lead acetate resulted in a
significant decrease in lead bioavailability. The absolute bioavailability to rats of mining
waste lead in soil administered in feed was approximately 3% based on blood lead con-
centration and less than 1% based on bone and liver lead concentrations (Freeman et al.,
1994). The bioavailability of lead sulfide was found to be approximately 10% that of lead
acetate (Freeman et al., 1996).
In immature swine, the relative bioavailability (compared with lead acetate) of lead
from soil samples from the Smuggler Mountain Superfund Site in Aspen (CO, USA) was
shown to range from 57% based on blood lead area-under-the-curve (AUC) to about 80%
based on liver lead concentration. The absolute bioavailability was estimated to be from
28% (via blood AUC) to about 40% (via liver uptake) (Casteel et al., 1997).
An inverse relationship was found between the particle size of metallic lead
(6–250 µm) administered in the diet and absorption in rats. This relation was more
marked in the 6–100-µm range; a fivefold enhancement of absorption was observed when
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rats were fed with lead particles of mean size 6 µm compared with 197-µm particles.
A marked enhancement of absorption (1.5–1.8-fold) was also found on feeding lead chro-
mate and lead octoate when particle size was reduced from 500–1000 µm to less than
50 µm (Barltrop & Meek, 1979).
The bioavailability of lead is influenced by dietary habits. Regular rat chow attenuates
the absorption of lead by the strong binding or precipitative action of the chow diet
(Freeman et al., 1996). Lead absorption of a single oral dose of 203Pb-lead chloride in
adult rats fed several ‘human’ diets ranged from about 3% to more than 20% above that
in controls receiving regular rat chow food. Highest absorption values were observed in
animals fed fruit and cow’s milk (Kello & Kostial, 1973; Kostial et al., 1978; Kostial &
Kello, 1979).
Palminger Hallén and Oskarsson (1995) studied the effects of milk on lead absorption
in rat pups. At 2 h after gastric intubation of various liquid diets labelled with 203Pb, the
lead bioavailability was 47% from water, 42% from human milk, 40% from infant
formula, 31% from cows’ milk and 11% from rat milk. After 6 h, the bioavailability of
lead was about 50% from water and human milk, 45% from infant formula and cow’s milk
and 36% from rat milk. Rat pups given lead in human milk had lead concentrations in
blood and brain approximately twice as high as those of pups given lead in rat milk.
Other investigators have not found any effect of milk on lead absorption in suckling
or adult rodents (Garber & Wei, 1974; Meredith et al., 1977; Henning & Leeper, 1984).
Kinetic analysis of pups’ blood lead concentration revealed a rate-limited absorption in
suckling mice exposed to milk from mothers administered lead, with a slower absorption
of lead in the offspring compared with dams. The conflicting evidence on whether milk
influences absorption of lead in infant rodents might be resolved, at least in part, by
measurements of lead absorption at different time periods after its administration to the
animals (Palminger Hallén et al., 1996a).
Nutritional status has been shown to influence lead absorption and/or retention in
experimental animals. Vitamin D, calcium and phosphorus have complex and interrelated
effects on lead absorption (Fullmer, 1990, 1991, 1997). Diets deficient in calcium and/or
phosphate are associated with increased intestinal absorption and/or retention of lead in
experimental animals (mice, rats, chicks, monkeys) (Six & Goyer, 1970; Quarterman &
Morrison, 1975; Jacobson & Snowdon, 1976; Barton & Conrad, 1981; Mykkänen et al.,
1984; Aungst & Fung, 1985; Van Barneveld & Van den Hamer, 1985). Simultaneous
reduction of both dietary calcium and phosphate content produced an additive effect on
absorption of lead (Quarterman & Morrison, 1975; Barltrop & Khoo, 1976). However,
experimental studies in chicks have shown that variations in the extent and duration of
lead ingestion and calcium deficiency may result in increases or decreases in lead
absorption (Fullmer, 1991). In chicks fed standard diet but administered a single injection
into the lumen of the intestine of 203Pb-lead acetate, lead absorption increased from 18.8%
in animals with adequate calcium content in the diet to 54.5% in animals fed a severely
calcium-deficient diet. In calcium-deficient chicks on a diet containing lead, a biphasic
response was observed; intestinal absorption of lead was enhanced by calcium deficiency
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initially, in a manner similar to the groups not fed lead, but this response was inhibited by
prolonged dietary lead intake (Fullmer, 1991).
Calcium supplemention has been shown to reduce lead absorption in several animal
species when administered at the same time as lead (Barltrop & Khoo, 1976; Meredith
et al., 1977; Barton et al., 1978a; Varnai et al., 2001) but not when administered sepa-
rately (Quarterman et al., 1978; Aungst & Fung, 1985; Van Barneveld & Van den Hamer,
1985). Calcium supplementation caused a statistically significant dose-related decrease in
lead in tissues (liver, kidneys, brain and carcass) of suckling rats exposed to lead orally
but had no effect on lead incorporated in tissues after parenteral exposure to lead, sugges-
ting that calcium primarily reduced lead absorption from the gastrointestinal tract (Varnai
et al., 2001).
Administration of cholecalciferol (vitamin D3) or 1,25-dihydroxycholecalciferol
(1,25-(OH)2D), the active metabolite of vitamin D3, was found to increase gastrointestinal
absorption of lead in rats and chicks (Smith et al., 1978; Hart & Smith, 1981; Mykkänen
& Wasserman, 1982; Edelstein et al., 1984; Fullmer, 1990). Dietary vitamin D deficiency
or depletion resulted in increased intestinal absorption of lead in intact animals, but the
manipulation of dietary phosphate and vitamin D3 content had no significant effect upon
the absorption of lead from isolated gastrointestinal segments of rats. Hence, this increased
absorption was attributed to a decrease of gastrointestinal motility with a prolonged transit
time (Barton et al., 1980; Barton & Conrad, 1981). However, the administration of
cholecalciferol to rachitic chicks resulted in an increase in the transepithelial transport of
203Pb in the intestine (Mykkänen & Wasserman, 1982). The vitamin D-induced intestinal
calcium-binding proteins bind lead with higher affinity than calcium suggesting a co-
transport mechanism whereby lead absorption would be increased by calcium deficiency
(Fullmer et al., 1985; Fullmer, 1997). However, the effect of 1,25-(OH)2D appeared to be
dependent upon the duration of exposure to lead and the magnitude of lead stores in the
body. The efficiency of intestinal 203Pb absorption was significantly diminished by dietary
lead in an apparently dose-dependent fashion (Fullmer, 1990).
Iron status also influences the absorption and/or retention of dietary lead in rodents
(Six & Goyer, 1972; Ragan, 1977; Barton et al., 1978b; Conrad & Barton, 1978; Robertson
& Worwood, 1978; Flanagan et al., 1979; Morrison & Quarterman, 1987; Crowe &
Morgan, 1996). Lead absorption was found to be promoted by iron deficiency and
inhibited by iron loading (Barton et al., 1978b). Rats fed iron-deficient diets had increased
concentrations of lead in kidney and bone (femur) when compared with rats ingesting
equivalent quantities of lead (as lead acetate) in drinking-water while being fed an iron-
adequate diet (Six & Goyer, 1972). The degree of iron deficiency does not need to be
severe to increase lead retention. A sixfold increase in tissue lead was demonstrated in rats
when body iron stores were reduced, but before frank iron deficiency developed (Ragan,
1977). 203Pb absorption in fasted rats was found to be increased by a short period of severe
iron restriction before any change in haematological parameters became apparent. An
extended period of moderate iron restriction, causing a reduction in haemoglobin con-
centration, resulted in increased iron and lead absorption. When iron dietary concentrations
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were made adequate to meet essential requirements produced by blood loss or hypoxia,
lead absorption was similar to that in controls (Morrison & Quarterman, 1987). The ion
lead Pb++ is a substrate for the divalent-cation metal transporter 1 (DMT1). This transporter
is expressed most significantly in the proximal duodenum in the rat and is upregulated by
dietary iron deficiency (Gunshin et al., 1997). In a yeast model, it was demonstrated that
DMT1 transports lead and iron with similar affinity and that iron inhibits the transport of
lead (Bannon et al., 2002).
Other dietary factors reported to influence absorption of lead in experimental animals
are lipids (Barltrop & Meek, 1975; Barltrop & Khoo, 1976; Quarterman et al., 1977; Ku
et al., 1978), amino acids and proteins (Conrad & Barton, 1978; Quarterman et al., 1980),
citrate and ascorbic acid (Garber & Wei, 1974; Conrad & Barton, 1978; Spickett et al.,
1984) and lactose (Bushnell & DeLuca, 1983).
Blood lead concentrations measured in rats after controlled oral exposure to lead as
lead acetate are given in Table 85.
Table 85. Blood lead concentrations in rats during chronic oral exposure to
lead acetate
Strain Age at Duration of Lead acetate added Blood lead Reference

of rat start of exposure to diet (ppm as concentration
exposure (days) lead) (µg/dL ± SD)
Fischer 6–7 weeks 30 0 – Dieter et al.

344/N 10 16 ± 1.7 (1993)
30 31.8 ± 3.8
100 84.8 ± 8.9
Fischer 4 weeks 7 0 5.0 ± 0.9 Freeman
344 17.6 32.0 ± 6.9 et al. (1996)
42.8 37.6 ± 5.4
127 77.1 ± 11.2
15 0 2.7 ± 0.3
17.6 20.5 ± 1.6
42.8 42.4 ± 8.4
127 67.6 ± 8.1
44 0 1.2 ± 0.1
17.6 24.9 ± 1.9
42.8 40.5 ± 2.8
127 70.6 ± 3.4
Sprague- 24 days 31 In drinking-water Read from graph O’Flaherty
Dawley 60 1000 ~100 (1991c)
1000 ~100
22 days 418 In drinking-water Read from graph
1000 ~120
2000 ~135
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Intratracheal instillation, inhalation

The bioavailability of lead from inhaled particles depends on the particle size and is
affected by the particle matrix.
A study by Eaton et al. (1984) showed that five weeks after exposure by intratracheal
instillation, the vast majority of a lead chromate paint particulate suspension (median
particle diameter, 6 µm) remained in the lung of rats (ratio lung lead:bone lead, 540). In
contrast, after exposure to lead acetate, little remained in the lung, but significant eleva-
tions were found in bone (ratio lung lead:bone lead, 0.5) and kidney. Intratracheal
instillation of lead tetraoxide showed an intermediate absorption rate (ratio lung lead:bone
lead, 73).
Grobler et al. (1988) showed that in rats exposed to aerosols of lead chloride (0.05,
77, 249 and 1546 µg lead/m³) (mass median diameter (MMD), < 5.8 µm; 56% of the total
particles at 77 µg/m³, 44% at 249 µg/m³, 37% at 1546 µg/m³) for 28, 50 and 77 days,
blood lead concentrations reached relatively stable plateaux, which differed significantly
with lead exposure. Stability was reached after 10 days at the highest exposure concen-
tration and after 30 days when rats were exposed to 249 µg/m³. When exposure ceased,
blood lead concentrations declined with a half-life of 3–5 days.
In baboons, the rate of absorption of lead into the bloodstream after exposure to
coarse (mean particle size, 1.6 µm; MMD, 5.9 µm) airborne particles of lead oxide was
faster and the concentration reached was higher than that after exposure to fine (mean
particle size, 0.8 µ; MMD, 2 µm) particles (Rendall et al., 1975). This finding contrasts
with the greater deposition and absorption rates of fine particles (< 1 µm) reported in
humans exposed by inhalation (ATSDR, 1999; see also Section 4.1.1(a)(i)).
Blood lead concentrations measured in the studies by Rendall et al. (1975) and Grobler
et al. (1988) are given in Table 86.
Skin absorption
After application of a solution of lead acetate or nitrate (6.4 mg of lead) to the skin of
female BALB/c mice, an analysis of the organs, faeces and urine showed that 0.4% of the
applied dose was absorbed through the skin and entered the circulatory system. In less than
24 h significant increases in lead concentrations were observed in the skin, muscle,
pancreas, spleen, kidney, liver, caecum, bone, heart and brain but not in the blood (Florence
et al., 1998).
Sun et al. (2002) measured the urinary lead content of rats after application of a patch
of linen cloth containing lead compounds (100 mg lead in petrolatum on a 2 × 6-cm cloth),
under occlusive conditions, for 12 days. Total amounts of lead in urine increased from
10.8 ng in the controls to 3679.3 ng for lead naphthenate, 146.0 ng for lead stearate,
736.6 ng for lead nitrate, 123.1 ng for lead sulfate, 115.9 ng for lead oxide and 47.8 ng for
lead metal powder.
In studies by Bress and Bidanset (1991), in-vivo absorption was measured by applying
300 mg/kg bw tetrabutyl lead, lead nuolate, lead naphthenate, lead acetate or lead oxide to
the shaved backs of guinea-pigs for 7 days under occluded wrappings. Tetrabutyl lead was
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Table 86. Blood lead concentrations in baboons and rats during

and after inhalation exposure
Species Exposure protocol Mean blood lead Reference

concentration
(µg/dL ± SD)
Baboon Dust clouds of Pb3O4; target At the end of exposure: Rendall

(Papio conc., 2 mg/m3 lead; mean group A, ~50*; et al.
ursinus) particle size: group A, 1.6 µm; group B, ~18* (1975)
group B, 0.8 µm; 5 days/week 6 weeks after end of
for 4 weeks exposure:
group A, 40 ± 19.7;
group B, 20 ± 7.7
BD IX rats Aerosol of lead chloride; During exposure Grobler
4 groups; (plateau conc.) et al.
0.05 µg/m3 lead (controls) 0.5–4 (1988)
77 µg/m3 lead for 77 days ~15*
All groups, 22 h/day,
7 days/week
*Read from the graph
present in blood, brain, liver and kidney in the highest quantities. Lead nuolate was found
in greater amounts than lead naphthenate in the liver and kidneys. Lead acetate was poorly
absorbed while lead oxide showed no absorption (see also Section 4.1.2(b)(i)).
(ii) Distribution
Experimental studies have shown that lead is rapidly distributed into soft and minera-
lizing tissues after acute and chronic exposures. The initial distribution of lead into soft
tissues has a half-life of 3.5 days in rats (O’Flaherty, 1991c).
In rodents and non-human primates, 98–99% of the blood lead content is associated
with erythrocytes, the remainder being found in the plasma (Morgan et al., 1977; Willes
et al., 1977; Keller & Doherty, 1980a; Palminger Hallén & Oskarsson, 1993). As in
humans, plasma lead is the source of lead available to distribution and excretion pro-
cesses. Keller and Doherty (1980a) found that milk lead concentration in lactating mice
was linearly related to plasma lead concentration but not to blood lead concentration.
Similarly, Oskarsson et al. (1992) were able to fit the relationship between lead concen-
trations in whole blood and milk in cows with an exponential expression, demonstrating
its nonlinearity.
A physiologically-based model in which soft-tissue distribution and excretion of lead
are assumed to be proportional both to the rate of blood flow to the tissue (which is pro-
portional to plasma flow) and to the concentration of lead in blood plasma has successfully
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reproduced the time-profile of concentration changes in blood lead after cessation of

chronic feeding of lead to rats (O’Flaherty, 1991c). Because of the high dose rates used in
these studies (blood lead concentrations in excess of 100 µg/dL) and the disproportionality
between plasma lead and blood lead, a model that assumed distribution to be proportional
to whole blood lead could not have duplicated the observed blood lead concentration
profiles.
After acute exposure by inhalation, lead content expressed as percentage of the dose in
rats has been shown to be highest in kidneys, liver and lung, with concentrations increasing
in bone as those in soft tissues declined and stabilized (Morgan & Holmes, 1978). After
oral exposure, lead concentrations in rats were highest in kidneys (Aungst et al., 1981).
After intravenous injection of 203Pb-lead chloride to rats, 20% of the dose was found ini-
tially in the kidney; subsequently, long-term deposition of 25–30% occurred in bone
(Morgan et al., 1977). At steady state, the pattern of distribution of lead is bone > kidney
> liver > brain (Griffin et al., 1975b; Morgan et al., 1977; Conrad & Barton, 1978; Kostial
et al., 1978; Aungst et al., 1981; Rader et al., 1981; Mykkänen et al., 1982; Cikrt et al.,
1983; Miller et al., 1983; Cory-Slechta et al., 1989; P’An & Kennedy, 1989).
When Sprague-Dawley rats (44–48 days old at the beginning of the study, mature adult
at the end) were given intraperitoneal injections of lead acetate (10 or 20 mg/kg bw) at 1,
2, 4, 8, 12, 16, 20 and 24 weeks, lead accumulated steadily in the bone, kidney and brain
and reached high concentrations in bone and kidney, but remained low in brain. The
authors suggested that although brain lead values increased, some regulatory mechanisms
limited access of lead to the adult brain (P’An & Kennedy, 1989). In a study reported by
Crowe and Morgan (1996), rats were exposed to lead acetate from 3 days prior to birth (day
18 of pregnancy) until 15, 21 or 63 days postpartum, via the placenta, and then via the
milk. This was achieved by giving a diet containing 0 or 3% lead acetate to pregnant Wistar
rats, as well as 0.2% lead acetate in their drinking-water. After weaning, 0.2% lead acetate
in the drinking-water became the sole source of dietary lead for the offspring. To study the
effect of iron deficiency on lead absorption, low-iron diets were given to mothers from day
18 of pregnancy and were continued with the young offspring rats after weaning. It was
found that iron deficiency did not increase lead deposition in the brain and brain lead
concentrations were relatively low (< 0.1 µg/g) in all rats. Lead concentrations in the liver
were below 2 µg/g, whereas kidneys had almost 20-fold higher concentrations. Compared
with other tissues, the blood–brain barrier appeared to restrict lead uptake by the brain
independent of the iron status of the animals; the functional blood-brain barrier is present
very early in development, possibly before birth (Crowe & Morgan, 1996). In other studies
in rats, following intravenous administration, lead has been shown to cross the blood–brain
barrier (Bradbury & Deane, 1993).
In rats exposed almost continuously (22 h/day, 7 days/week) to lead oxide particles
(MMD, 86% ≤ 0.18 µm) at an average concentration of 21.5 µg/m³ for 12 months, the
concentrations of lead in blood, kidney and liver were found to reach a maximum at 3–4
months of exposure and did not increase significantly after that time. The concentration
of lead in soft tissues decreased after the exposure, but remained elevated in bone (Griffin
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et al., 1975b). In a subsequent study in which rats were exposed to lead oxide particles
(20 µg/m3) for 15 months, a small increase in tissue lead was found between the sixth and
the fifteenth months of exposure, but in the femur the increase during this period was
nearly 70% (Russell et al., 1978).
In studies conducted by Maldonado-Vega et al. (1996), rats were given 100 ppm
[100 µg/mL] lead acetate in distilled water either before and during lactation (during 158
days), or before lactation only (144 days), or during lactation only (14 days). Results were
compared with those obtained from non-pregnant lead-exposed matched rats and non-
exposed pregnant and non-pregnant control rats. During lactation, lead concentrations in
blood, liver and kidney increased while those in bone decreased. The increase in tissue
concentrations was shown to result from increased intestinal absorption (exogenous expo-
sure) and bone resorption (endogenous exposure). Significant deposition of lead in bone
was observed in rats exposed to lead only during lactation indicating that both processes
(deposition and bone resorption) take place in this period (Maldonado-Vega et al., 1996,
2002).
There is experimental evidence of lead mobilization from bones to blood (Grobler
et al., 1991). In studies in monkeys, 17–20% of the total blood lead originated from histo-
rical bone stores (Inskip et al., 1996; O’Flaherty et al., 1998). Increased lead release from
the skeleton occurs during pregnancy and lactation (Buchet et al., 1977; Maldonado-Vega
et al., 1996; Franklin et al., 1997; Maldonado-Vega et al., 2002). Maternal-to-fetal transfer
of lead appears to be related partly to the mobilization of lead from the maternal skeleton.
Evidence for transfer of maternal bone lead to the fetus has been provided by studies with
stable lead isotopes in cynomolgus monkeys (Macaca fascicularis). The study by Franklin
et al. (1997) showed that 7–39% of the maternal lead burden that is transferred to the fetus
appears to derive from the maternal skeleton (see Section 4.1.1(a)(v)).
The mean half-life of lead in bone was found to be 3.0 ± 1.0 years in the rhesus
monkey (McNeill et al., 1997). Injection of 25 µCi of an aqueous solution of 210Pb and its
daughters into adult rats and analysis of bone tissue over the subsequent 140 days showed
a half-life of lead in bone of 64–109 days (Torvik et al., 1974).
Age-related differences in the distribution of lead have been reported in experimental
animals. After intraperitoneal injection of 203Pb, marked differences were observed in the
kinetics of lead retention and distribution in suckling as compared with adult rats. Com-
pared with older rats, suckling rats showed 2.3-fold higher whole-body retention, higher
blood concentrations and an almost 8-fold greater accumulation in the brain. Retention in
the kidneys was one third lower in the suckling rats (Momcilovic & Kostial, 1974; Kostial
et al., 1978).
Similar findings have also been reported for kidney and bone in neonatal monkeys
exposed to a single oral dose of 210Pb lead nitrate. Bone lead concentrations and bone:blood
lead ratios were significantly higher in infant monkeys than in adults. Brain:blood lead
ratios were significantly greater in 10-day-old infants than in adult monkeys. The liver lead
concentration was also higher in neonates and young monkeys than in adults (Willes et al.,
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1977). Lead concentrations in fetal bone of monkeys have been reported to exceed
maternal bone lead concentrations (Franklin et al., 1997).
Ageing has also been shown to alter the pattern of distribution of lead in rats admi-
nistered lead acetate in drinking-water. In studies reported by Cory-Slechta et al. (1989),
blood lead concentrations in adult (8-month-old) and old (16-month-old) rats showed
different trends over the course of exposure; values in adults declined, while those of old
rats tended to increase. Brain lead concentrations and, to a marginally significant extent,
liver lead concentrations were higher in old rats than in adult rats, while bone lead
concentrations were significantly lower in old rats than in adult rats. The pattern of
distribution, namely femur > liver > brain, was similar in all age groups, but age-related
increases in lead concentrations in brain and kidney were noted, along with decreases in
femoral bone lead content. This shift did not appear to reflect enhanced lead uptake from
the gastrointestinal tract but rather a change in bone physiology with age, combined with
altered patterns of urinary lead excretion over time (Cory-Slechta, 1990).
The intracellular bioavailability of lead in major target organs such as the kidney and
brain appears to be determined largely by formation of complexes with a group of low-
molecular-weight proteins. Several distinct high-affinity cytosolic lead-binding proteins
(PbBP) have been identified in the rat kidney and brain that appear to act as receptors for
lead (Oskarsson et al., 1982; DuVal & Fowler, 1989). The PbBP from rat kidney has been
shown to be a specific cleavage product of α2u-globulin, produced most extensively in the
livers of male rats and to a much lesser extent in female rats of breeding age. The PbBP
was shown to migrate to the nucleus and form complexes with nuclear chromatin (Mistry
et al., 1985; 1986; Fowler & DuVal, 1991). The renal PbBP is selectively localized in only
certain nephrons and only specific segments of the renal proximal tubule. Short-term,
high-dose lead exposure (1% or 7% lead acetate in drinking-water for 7 weeks) resulted
in increased excretion of this protein in the urine with a concomitant decrease in renal
concentrations of PbBP (Fowler & DuVal, 1991). The brain PbBP appears to be a chemi-
cally similar but distinct molecule (DuVal & Fowler, 1989). High-affinity PbBPs have
also been identified in the kidney and brain of monkeys (Fowler et al., 1993).
(iii) Excretion
Excretion of lead occurs mainly in the faeces and urine (WHO, 1985). Adult mice
were found to excrete about 62% of intravenously injected lead within 50 days; cumu-
lative lead concentrations in faeces were 25–50% of the administered dose (Keller &
Doherty, 1980b). Adult rats excreted 24.4% and 9.5% of intravenously injected lead in
faeces and urine, respectively, within 48 h (Kostial & Momcilovic, 1974). In rats and
monkeys exposed by inhalation to lead oxide (21.5 µg/m³) for 1 year, lead excretion was
greater in faeces than in urine, but wide variations between individual animals were noted
(Griffin et al., 1975b). Five days after a single intravenous dose of 203Pb in rats, total lead
excretion was found to amount to 53%, with similar amounts being excreted in urine and
faeces, except on day 2 (ratio faeces:urine, 2) (Morgan et al., 1977). Studies on rats
exposed for 30–45 min to an ‘urban-like’ aerosol of 210Pb-dibenzoylmethane (added to
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gasoline and burned in a tubular furnace heater at 600 °C) showed that, 6 days after inha-
lation, less than 1% of the total absorbed dose of lead was retained in lung, 40% had been
eliminated in faeces and 15% in urine, 40% was fixed in the skeleton and 4–5% in soft
tissue (Boudene et al., 1977).
Studies on dogs after intravenous administration of 210Pb showed that 56–75% of the
total dose of lead was excreted in the faeces (Hursh, 1973; Lloyd et al., 1975).
Adult monkeys have been shown to excrete more absorbed lead in faeces than young
animals (13% versus 3.45%), while urinary excretion was similar (5.31% versus 3.84%)
(Pounds et al., 1978).
Marked species differences in the biliary excretion of lead have been reported
(Castellino et al., 1966; Klaassen & Shoeman, 1974; Conrad & Barton, 1978; Cikrt et al.,
1983; Gregus & Klaassen, 1986). A relatively high biliary excretion of lead was reported in
rats (Klaassen & Shoeman, 1974). About 6.5–8.5% of a dose of 210Pb-lead nitrate or 203Pb-
lead chloride administered intravenously to rats was excreted in the bile within 24 h; biliary
excretion thus plays an important role in the enterohepatic circulation of lead in rats (Cikrt,
1972; Cikrt & Tichy, 1975). In a further study, biliary excretion of lead was analysed in three
groups of rats given drinking-water containing lead acetate (at 100, 250 and 2500 mg
lead/L) for 80 days. Biliary excretion of lead in the exposed groups reached 0.08 ± 0.01,
0.20 ± 0.04 and 1.46 ± 0.09 µg/mL, respectively, compared with 0.05 ± 0.04 µg/mL in a
control group (Cikrt et al., 1983). Rabbits have been shown to excrete lead in the bile at
< 50% and dogs at < 2% of the rates of biliary excretion of lead in rats (Klaassen &
Shoeman, 1974).
Studies on the renal handling of lead (203Pb) in dogs showed that plasma lead is
filtered and reabsorbed but that there is no evidence of tubular secretion of lead (Vander
et al., 1977). Urinary clearance of lead was calculated to be 19% of the estimated glome-
rular filtration rate in two cynomolgus monkeys (O’Flaherty et al., 1996).
In rodents, lead is transferred across the placenta to fetuses and during lactation to the
litter (Kostial & Momcilovic, 1974; McClain & Siekierka, 1975; Hackett et al., 1982a,b;
Donald et al., 1986; Maldonado-Vega et al., 1996, 2002). The lactational transfer after
current or recent exposure of dams to lead is considerably higher than the placental
transfer (Kostial & Momcilovic, 1974; Palminger Hallén et al., 1995b). A high transfer of
lead into milk was demonstrated in rodents, as well as a high uptake of lead in the tissues
of suckling pups. About 20–33% of an initial maternal dose of lead was transferred to
suckling rats or mice (Momcilovic, 1978; Keller & Doherty, 1980a; Palminger Hallén
et al., 1996b). In a study by Palminger Hallén & Oskarsson (1993), rat and mouse dams
were administered a single intravenous dose of 203Pb on day 14 of lactation in four or five
doses ranging from 0.0005 to 2.0 mg/kg bw. The concentration of 203Pb in plasma was
linearly correlated with that in milk. The milk:plasma ratios were 119 and 72 in mice and
89 and 35 in rats at 24 and 72 h after administration, respectively. Excretion into milk
appeared more efficient in mice than in rats, but rat pups had higher tissue concentrations
than mouse pups; this may be due to a higher bioavailability and/or a lower excretion of
lead in rat pups (Palminger Hallén & Oskarsson, 1993). Continuous exposure of rats to
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lead in drinking-water during gestation and lactation resulted, at day 15 of lactation, in

milk lead concentrations about 2.5-fold higher than blood lead concentrations. When
exposure to lead was terminated at parturition, the milk lead concentrations were similar
to those of blood lead at day 15 of lactation, and were only 10% of the milk lead concen-
trations found after continuous exposure to lead during gestation and lactation. Exposure
of offspring to lead via placenta and milk from dams exposed continuously resulted in
blood and brain lead concentrations sixfold higher than those in offspring exposed via the
placenta only. Exposure of offspring via milk only from dams exposed to lead until par-
turition resulted in blood lead concentrations that were higher than those in offspring
exposed to lead via the placenta only (Palminger Hallén et al., 1995b).
(c) Experimental systems in vitro

In vitro, intestinal permeability to lead has been shown to be similar in intestines from
fasted and fed rats (Aungst & Fung, 1981).
Healy et al. (1982) showed that the rate of dissolution of lead sulfide in gastric acid
in vitro was dependent on particle size, being much greater for particles of 30 µm
diameter than for particles of 100 µm diameter.
Studies in kidneys of rats in vitro have shown that the kidney PbBP facilitates the
nuclear uptake of lead followed by its binding to chromatin (Mistry et al., 1985, 1986;
Fowler & DuVal, 1991; Goering, 1993; Fowler, 1998).
Bress and Bidanset (1991) measured the degree of in-vitro penetration of lead acetate
and lead oxide, using diffusion tubes in excised guinea-pig skin and human skin from
autopsy. The percentage recovery of lead acetate in guinea-pig skin and human skin was
0.03% and 0.05%, respectively. There were no measurable amounts of lead oxide
absorbed in either species.
Steady-state kinetic analyses of 210Pb in hepatocytes from rats demonstrated three
compartments, more than 85% of the lead being found in the kinetic pool associated with
mitochondria (Pounds et al., 1982). In osteoclastic bone cells from mouse calvaria, three
similar kinetic pools of intracellular lead containing approximately 10%, 12% and 78%
of total cellular lead were identified; as in hepatocytes, the bulk of cellular lead was asso-
ciated with mitochondria. The half-times for isotopic exchange were 1, 27 and 480 min,
respectively (Pounds & Rosen, 1986).
4.1.2 Organic lead compounds

The toxicity of organic lead compounds is generally high, but varies widely between
animal species and according to the chemical structure of the compound. Most of the
information available concerns tetraethyl lead, but the toxicity of tetramethyl lead and
some of its metabolites is also well described. Organic lead compounds are toxico-
kinetically distinct from inorganic lead compounds in terms of absorption and distribution
and, owing to their greater lipophilicity, they are rapidly partitioned into soft tissues.
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(a) Humans
(i) Absorption
Inhalation exposure
Inhaled tetraethyl and tetramethyl lead vapours behave as gases in the respiratory tract
and, as a result, their pattern and extent of deposition and absorption differ from that of
inhaled inorganic lead particles (US EPA, 1994; ATSDR, 1999). These differences result
in a higher fractional absorption: approximately 60–80% of the deposited tetraethyl and
tetramethyl lead was absorbed by the lungs (Heard et al., 1979).
Dermal exposure
Tetraethyl lead is a lipophilic substance that can penetrate intact skin in lethal quan-
tities. The amount absorbed is proportional to the surface area exposed and the con-
centration. Accidents involving transdermal absorption of tetraethyl lead and tetramethyl
lead in humans have been described (Hayakawa, 1972; Gething, 1975). Due to its higher
lipophilicity, tetraethyl lead is more readily absorbed than tetramethyl lead.
(ii) Distribution
Inhalation of tetraethyl lead results in much higher concentrations of lead in the brain
than does inhalation exposure to inorganic lead.
Distribution of organic lead in humans has been observed to be highly variable and
measurements are complicated by metabolism of the alkyl lead to inorganic lead. For
example, in a man who ingested a chemical mixture containing 59% tetraethyl lead (38%
lead w/w), the highest concentrations of triethyl lead and inorganic lead were found in the
liver and kidneys followed by the brain, pancreas and heart (Bolanowska et al., 1967). In
another report in which a man and a woman accidentally inhaled a solvent containing 31%
tetraethyl lead (17.6% lead w/w), concentrations of triethyl lead and inorganic lead were
highest in the liver and lower in the kidney, brain, pancreas, muscle and heart
(Bolanowska et al., 1967), although the liver/kidney ratio for triethyl lead was 5:1 in the
woman compared with that of 1.3:1 in the man. Trialkyl lead metabolites have also been
detected in brain tissue of subjects not occupationally exposed to air pollution (Nielsen
et al., 1978).
Organic lead compounds are ultimately metabolized to inorganic lead and the latter is
stored in the bones (Schwartz et al., 1999, 2000a).
(iii) Metabolism
Alkyl lead compounds are actively metabolized in the liver through oxidative de-
alkylation catalyzed by cytochrome P-450. Relatively few human studies that address the
metabolism of alkyl lead compounds were found in the available literature (Bolanowska
et al., 1967; Nielsen et al., 1978; ATSDR, 1999).
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(iv) Excretion
Tetraethyl lead is excreted in the urine as diethyllead and inorganic lead
(Turlakiewicz & Chmielnicka, 1985; Vural & Duydu, 1995). Following inhalation
exposure, exhalation of tetraalkyl lead compounds is a major pathway of elimination in
humans. Heard et al. (1979) showed that 48 h after inhalation exposure, 40% and 20% of
inhaled tetramethyl and tetraethyl lead doses, respectively, that were initially deposited in
the lung, were exhaled, and there was little urinary excretion.
(b) Animals
(i) Absorption
Bress and Bidanset (1991) measured absorption in vivo by applying 300 mg/kg tetra-
butyl lead, lead nuolate, lead naphthenate, lead acetate or lead oxide to the shaved backs
of guinea-pigs for 7 days under occluded wrappings. Tetrabutyl lead was present in
tissues in the highest quantities: mean (± SD) total lead concentration reached 7.46
(± 0.68) µg/g in blood, 8.52 (± 0.46) µg/g in kidney, 4.31 (± 0.21) µg/g in liver and 4.02
(± 0.29) µg/g in brain (see also Section 4.1.1(b)(i)).
(ii) Distribution
Previous monographs (IARC, 1972; 1980) have summarized many studies on the
distribution of lead published before 1980. In more recent studies in rabbits (Arai et al.,
1998), total lead in the brain 1 day after intravenous injection of triethyl neopentoxy lead
consisted of triethyl lead alone; total lead in liver and kidney was about 72–78% triethyl
lead, about 14–19% inorganic lead and about 8–9% diethyl lead. Lead in blood was about
34% triethyl lead, about 38% inorganic lead and about 28% diethyl lead. In bile, it was
about 2% triethyl lead, about 9% inorganic lead and about 89% diethyl lead. These ratios
of lead species in the organs were similar 7 days after injection, but only inorganic lead
was detected in blood.
Studies by Morgan and Holmes (1978) using adult rats exposed for 40–60 min by
inhalation to an aerosol containing 203Pb-tetraethyl lead added to lead-free petrol showed
that less than 2% of the dose was present in the lungs after 1 week. Mean total deposition
of lead was calculated to be 30.5%. At least half of the 203Pb deposited in the lungs was
absorbed with a half-life of less than 1 h. To investigate whether lead in ingested exhaust
particles is absorbed from the gastrointestinal tract, exhaust particles from an engine
running on 203Pb tetraethyl-enriched gasoline were collected on millipore filters, which
were then fed to rats. Less than 0.5% of the 203Pb lead associated with the particles was
found to be absorbed.
(iii) Metabolism
Tetraethyl and tetramethyl lead undergo oxidative dealkylation and are metabolized
to the highly neurotoxic metabolites triethyl and trimethyl lead, respectively. In rabbit
liver, the reaction is catalysed by a cytochrome P-450-dependent monoxygenase system
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(Kimmel et al., 1977). Complete oxidation of alkyl lead to inorganic lead also occurs in
rat, mouse and rabbit (Bolanowska, 1968; ATSDR, 1999).
(iv) Excretion
Previous monographs have summarized many studies on the excretion of lead
published before 1980 (IARC, 1972; 1980). Kozarzewska and Chmielnicka (1987) studied
the excretion of tetraethyl lead in rabbits. After intragastric or intravenous administration
to rabbits of 12 mg/kg bw tetraethyl lead, diethyl lead constituted 70–90% and 50%,
respectively, of the total lead excreted in urine during the first seven days, and 70% and
40%, respectively, after 30 days. Maximum diethyl lead excretion occurred on the first
three days regardless of the route of the administration. After administration of a 3 mg/kg
bw dose, excretion of diethyl lead did not vary so much between the intragastric and the
intravenous routes of administration; in this case, during 30 days of observation, diethyl
lead constitued about 40% of the total lead excreted in urine. In rabbits exposed for 5 h to
tetraethyl lead by inhalation at a concentration of 200 µg/m³ in air, maximum diethyl lead
excretion was recorded on day 2 after exposure and constituted about 20% of total lead
excreted in the urine. On day 7, only trace quantities of this metabolite were found.
Arai and Yamamura (1990) showed that in rabbits, after a single intravenous dose of
9.9 mg/kg bw tetramethyl lead (7.7 mg/kg bw lead), the mixture of lead compounds
excreted in urine was composed of about 73% dimethyl lead, 19% trimethyl lead, 6% in-
organic lead and 2% tetramethyl lead on the day following injection. The excretion on day
7 was entirely composed of trimethyl lead. In rabbits injected with 39.7 mg/kg bw tetra-
methyl lead (30.8 mg/kg bw lead), total urinary lead excretion was composed of about
67% dimethyl lead, 14% trimethyl lead, 17% inorganic lead and 2% tetramethyl lead on
the day following administration and about 8% dimethyl lead, 74% trimethyl lead, 17%
inorganic lead and 1% tetramethyl lead on day 7 after dosing. In both groups of rabbits,
total lead excretion in faeces during the 7 days after injection was entirely composed of
inorganic lead. During the same period, 1–3% of either administered dose of tetramethyl
lead was excreted in the urine and 7–19% in the faeces.
Further studies (Arai et al., 1998) showed that about 4% of an intravenous dose of
triethyl neopentoxy lead (10 mg/kg bw; 4 mg/kg bw lead) administered to rabbits was
excreted in the urine within 7 days and about 68% in the faeces. Urinary excretion of total
lead was composed of about 85% diethyl lead, 8% triethyl lead and 7% inorganic lead.
The 7-day faecal excretion was composed of about 92% inorganic lead, 4% diethyl lead
and 4% triethyl lead. Hence, the major chemical species of lead excreted in the urine was
diethyl lead, while the major species excreted in the faeces was inorganic lead.

Bress and Bidanset (1991) measured the degree of in-vitro penetration of tetrabutyl
lead, lead naphthenate, lead nuolate, lead acetate and lead oxide, using diffusion tubes in
excised guinea-pig skin and human skin from autopsy. The percentage recovery of lead in
guinea-pig skin ranged from 1.3% with tetrabutyl lead, demonstrating the highest skin
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penetration, followed by lead naphthanate (0.45%), lead nuolate (0.25%), lead acetate
(0.03%) and lead oxide (< 0.01%). The same rank order of recovery was seen in excised
human skin where recovery of tetrabutyl lead was 6.3%.
4.2 Toxic effects

The extensive literature on the toxic properties of lead up until 1998 has been
reviewed in the Toxicological Profile for Lead (ATSDR, 1999) and earlier by the National
Research Council (NRC, 1993).
4.2.1 Overt symptoms of lead intoxication

Mankind has been using lead for over 6000 years and the widespread contamination
of the environment with lead is solely the result of anthropogenic activities. In 370 BC,
the Greek physician Hippocrates was probably the first to recognize lead as the cause of
colic in a man who was a metal worker. In the 1st century AD, Dioscorides, another Greek
physician, noted that exposure to lead could cause paralysis and delirium in addition to
intestinal problems and swelling (Cilliers & Retief, 2000; Hernberg, 2000). In Roman
times winemakers used lead pots or lead-lined kettles to boil the crushed grapes, and
added lead acetate to their wine as a sweetener (Aitchinson, 1960). References to
paralysis in miners exposed to lead increased in Europe in the 1600s, as did reports of
colic in wine-drinkers (Lin-Fu, 1992).
One of the earliest manifestations of lead intoxication in adults is so-called lead-
induced colic, which is a syndrome characterized by a combination of abdominal pain,
constipation, cramps, nausea, vomiting, anorexia and weight loss. Various pathogenic
mechanisms have been proposed for this syndrome: it may result from changes in visceral
smooth muscle tone secondary to the action of lead on the visceral autonomic nervous
system; from lead-induced alterations in sodium transport in the small-intestinal mucosa;
and from lead-induced interstitial pancreatitis. The possible presence of this syndrome
should be considered in the differential diagnosis of abdominal pain of obscure etiology,
and whenever a disparity is observed between the symptoms and the abdominal findings
in a patient with abdominal pain, especially in the presence of a history of occupational
exposure to lead (Janin et al., 1985).
Many cases of acute lead intoxication have been described in the literature (for re-
views, see Srianujata, 1998; Vig & Hu, 2000; Matte, 2003). Only a few studies are dis-
cussed below.
The effects on health of occupational exposure to lead have been investigated in 92
exposed workers in a lead–acid battery factory and 40 non-exposed workers who served
as a control group. The two groups were closely similar in age, stature, body weight and
socioeconomic status. In the factory, concentrations of lead in air varied between 1.8 and
2.2 mg/m3. In 46 workers, average concentrations of lead in blood were 48–81 µg/dL,
depending on job title. In 12 controls, an average blood lead concentration of 21 µg/dL
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was measured. A highly significant increase (p < 0.01) was also recorded in urinary copro-
porphyrin and basophilic stippled red blood cells of the exposed group in comparison with
the control group. Central nervous system symptoms (insomnia, fatigue, weakness and
drowsiness) were reported by 50% of the workers, and other symptoms such as abdominal
colic and constipation were noted by 41% of the exposed group (Awad el Karim et al.,
1986).
Three cases of acute lead poisoning in adults were reported to be caused by exposure
to old leaded paint. Initial concentrations of lead in blood in the three subjects were 84.2,
85.2 and 87.1 µg/dL, respectively, and all complained of abdominal pain, malaise and
nausea. The patients received sodium calcium edetate and/or succimer for three weeks,
which reduced their blood lead concentrations by 50–75%. Despite removal from the
source of exposure, lead concentrations remained elevated in two cases, which may be
explained by release of lead from the skeleton (Gordon et al., 2002).
A case of severe lead poisoning in a young woman was reported to be caused by
prolonged use of eye make-up (‘kohl’) made of lead sulfide. Clinically, the patient
presented with abdominal cramps, anxiety and irritability, and microcytic sideropenic
anaemia. Emergency chelate treatment improved her condition and decreased lead concen-
trations in blood from their initial value of 490 µg/dL to 49 µg/dL 6 weeks after treatment
(Bruyneel et al., 2002).
4.2.2 Effects on haeme-containing systems

(a) Humans
Interaction with enzymes and high-affinity metal-binding proteins is probably the
most important mechanism of lead toxicity. This interaction usually consists of reversible
binding of lead to sulfhydryl groups or to other protein sites capable of binding divalent
cations. In this regard, the most well-known example is the inhibition by lead of δ-amino-
levulinic acid dehydratase (ALAD) (also known as porphobilinogen synthase, PBGS), a
key enzyme in the pathway of haeme synthesis (Figure 5). This enzyme has a unique zinc
binding site (Jaffe et al., 2001) that confers a very high affinity for Pb2+ (Simons, 1995).
Over the past 10 years, attention has been paid increasingly to early, subtle (sub-
clinical) effects of lead on haeme systems, the hypothesis being that these form a physio-
pathogenetic continuum with the clinical or overt effects. The only difference between
early and clinical effects of a given type depends on their degree and not on their nature
(Goyer, 1990b). The effects on haeme synthesis and haematological effects are dose-
dependent (Table 87) and become manifest at blood lead concentrations < 10 µg/dL
(ALAD inhibition), at 15–30 µg/dL (inhibition of iron chelation in haeme), and 50–
60 µg/dL (reduction of haemoglobin concentrations).
Effects of lead, such as inhibition of ALAD, elevation of aminolevulinic acid (ALA)
in urine and increase of free erythrocyte protoporphyrin in blood, have been observed in
humans exposed to lead (Lauwerys et al., 1973; Alessio et al., 1976; Tomokuni & Ogata,
1976; Horiguchi et al., 1981; Moore, 1988). These biological indicators correlate more or
P 285-336 DEF.qxp 09/08/2006 12:30 Page 287
Figure 5. Haeme biosynthesis in the cell
Modified from Moore (1988)

Lead inhibits ALA dehydratase, coproporphyrinogen oxidase and ferrochelatase with consequent increases in
the urinary excretion of ALA and coproporphyrin III together with accumulation of protoporphyrin 9 in the
erythrocyte. Primary control of the rate-limiting enzyme, 5-aminolaevulinate synthase is vested in the end
product of the pathway, haeme through the ‘pool’ of free haeme in the cell. This pool is depleted in lead
poisoning through diminished synthesis of haeme and enhanced catabolism of the haeme by haeme oxy-
genase. The net result is increased synthesis of ALA synthase and excessive production of pathway inter-
mediates. There is, in addition, some deleterious influence on haemoprotein synthesis because of the lack of
haeme substrate for their formation.
less closely with the concentration of lead in peripheral blood (see Section 1.6.2), and are
therefore useful in evaluating the effect of lead in individuals exposed occupationally or
environmentally to the metal. They have also been used for assessing exposure to lead.
In addition to effects on haeme in erythropoiesis, attention has also been paid to the
possible effects of lead on other haeme-containing enzymatic systems, such as P450 cyto-
chromes or systems involved in the metabolism of vitamin D (Silbergeld et al. 1988;
Goyer, 1990b). Such effects result in a decreased availability of cytochromes for the respi-
ratory chain and the accumulation of toxic metabolites such as ALA.
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Table 87. Effects of lead on haeme synthesis in adults and

relative concentrations of lead in blood at which they become
manifest
Lowest observed effect Haeme synthesis and haematological effects

level (blood lead
concentration, µg/dL)
80 Frank anaemia
50 Reduced haemoglobin production
40 Increased urinary ALA and elevated coproporphyrins
25–30 EP elevation in men
15–20 EP elevation in women
< 10 ALAD inhibition
Adapted from US EPA (1986)

ALA, delta-aminolevulinic acid; ALAD, delta-aminolevulinic acid dehydratase; EP,
erythrocyte protoporphyrin
(i) Inhibition of ALAD by lead

Inhibition of ALAD by lead is discussed in Section 1.6.2. It is responsible in part for
increases in ALA in plasma, in blood and in urine. ALA synthase is induced by negative
feedback from the depression of haeme synthesis. ALA in plasma and blood should reflect
the effects of lead more directly than ALA in urine (Moore et al., 1980b; WHO, 1980; see
Section 1.6.2 for analytical methods).
In subjects recently exposed to lead, there is a latency period of about 2 weeks before
ALA in urine increases. After cessation of exposure, the excretion of ALA in urine returns
to normal relatively quickly; thus this parameter is not suitable for detecting past exposure
to lead (Tola et al., 1973; Haeger-Aronsen et al., 1974; Benson et al., 1976).
(ii) ALAD gene polymorphism
ALAD is a well-known enzyme that is essential to tetrapyrrole biosynthesis (e.g.
haeme, chlorophyll and vitamin B12). In humans, ALAD is a polymorphic enzyme with
two common alleles, ALAD1 and ALAD2 (Battistuzzi et al., 1981; Petrucci et al., 1982).
The enzyme is polymorphic due to a G-to-C transversion of nucleotide 177 in the coding
region, which results in replacement of lysine by asparagine at position 59 in the protein
(Wetmur et al., 1991a).
Numerous studies have investigated the role of the ALAD polymorphism in relation
to blood lead concentrations. The data indicate that at equivalent exposures, homozygotes
or heterozygotes for ALAD2 have significantly higher mean blood lead concentrations,
and lower concentrations of ALAP (only at high blood lead concentrations, 40−60 µg/dL)
than homozygotes for ALAD1 (Wetmur et al., 1991b; Smith et al., 1995; Sithisarankul
et al., 1997; Sakai, 2000). However, no differences in the net accumulation of lead in bone
were found (Fleming et al., 1998). Lead (Pb2+) has been shown to bind the ALAD enzyme
P 285-336 DEF.qxp 09/08/2006 12:30 Page 289
by displacement of zinc (Zn2+) (Simons, 1995; Bergdahl et al., 1998a). The difference in
haeme precursor concentrations in people carrying different ALAD genotypes is thought
to be due to a difference in binding affinity of lead for the ALAD isoenzymes (Bergdahl
et al., 1997b). However, the model of human ALAD based on homologous crystal
structure showed no obvious structural variation that would affect either metal binding to,
or catalytic function of, the different ALAD isoenzymes. In in-vitro binding experiments,
no differential displacement of Zn2+ by lead (Pb2+) was found between the ALAD1 (K59)
and ALAD2 (N59) protein variants (Jaffe et al., 2000), but the two allozymes show a small
difference in the kinetics of lead displacement by zinc (Jaffe et al., 2001). This implies
that differences in susceptibility to lead of subjects carrying different ALAD genotypes
may be related to a difference in direct binding of lead to the gene products. However,
other indirect mechanisms leading to differences in lead retention in carriers of the diffe-
rent genotypes cannot be ruled out.
(iii) Other gene polymorphisms
An additional polymorphism that may modify the toxicity of lead involves the vita-
min D receptor (VDR) gene. This gene can exist in two alleles (B and b) and experimental
data suggest that bone calcium content increases with increasing copy number of the b
allele. Because lead can substitute for calcium in many biological systems, and since both
lead and calcium are divalent cations, it has been suggested that the toxicity of lead may
be modified by polymorphisms in the VDR gene which could explain the increased con-
centrations of lead in dense cortical bone in populations occupationally exposed to lead
(Schwartz et al., 2000b). The VDR gene is involved in the absorption of calcium through
the gut and into calcium-rich tissue such as bone. However, effects of VDR polymorphism
on a number of parameters of lead toxicity were not observed in a recent study of 798
workers exposed to lead (Weaver et al., 2003).
Schwartz et al. (2000b) evaluated the association of tibial lead concentration with poly-
morphisms in the vitamin D receptor (VDR) gene in 504 former organolead manufacturing
workers (mean age, 57.4 years). Tibial lead concentrations were measured by X-RF spectro-
metry in subjects with different VDR genotypes, adjusting for confounding variables. All
study subjects had low tibial lead concentrations (mean, 14.4 µg/g bone mineral) and there
were only small differences by VDR genotype. In a multiple linear regression model, the
VDR genotype modified the relation between tibial lead concentration and age or years since
last exposure. Although the influence of the VDR genotype on bone mineral density is a
matter of debate, the data suggest that variant VDR alleles modify lead concentrations in
bone.
Another gene that may influence the absorption of lead is the haemochromatosis gene
encoding the HFE protein. Mutations in the HFE gene give rise to haemochromatosis in
homozygous individuals. Because of the associations between iron and lead transport, it
is possible that polymorphisms in the HFE gene may also influence the absorption of
lead. Patients homozygous for the HFE mutation accumulate more lead than those who
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do not carry two mutated alleles (Barton et al., 1994). The role of these genes in the effects
of lead is not fully understood (Onalaja & Claudio, 2000).
(iv) Lead and coproporphyrins
Lead may inhibit other enzymes in the metabolic pathway of haemoglobin synthesis.
Inhibition of coproporphyrinogen decarboxylase results in accumulation of copropor-
phyrins and their increased urinary excretion. Urinary coproporphyrin is not, however, a
specific indicator of exposure to lead, since it may also result from porphyria cutanea tarda,
liver disease, haemolytic anaemia, infectious disease and alcohol consumption. The
influence of lead on disorders of porphyrin metabolism, which are more evident in women
than in men, have been documented among lead-exposed workers.
No effects are detected on urinary coproporphyrin at blood lead concentrations
≤ 40 µg/dL and, in constantly exposed subjects, blood lead and urinary coproporphyrin
correlate well, with a positive linear relation (Williams et al., 1969; US EPA, 1986).
Increased excretion of urinary coproporphyrin occurs with a latency of about 2 weeks,
when blood lead concentrations are slightly higher than those at which ALAU increases
(Tola et al., 1973; Benson et al., 1976). After cessation of exposure, the urinary copropor-
phyrin concentrations normalize with a few weeks (sometimes within a few days). The
validity of urinary coproporphyrin to predict different blood lead concentrations is rather
modest, so its use as a screening test is limited. In addition, subjects with severe lead expo-
sure may in some cases show normal concentrations of urinary coproporphyrin (Alessio
et al., 1976).
(v) Lead and free erythroprotoporphyrin
Lead causes an increase in free protoporphyrin IX in blood, which is measured as zinc
protoporphyrin (ZPP). This is possibly due to the interrelationship between iron availabi-
lity and haeme biosynthesis (Labbé et al., 1999). An increase in ZPP results from the ferro-
chelatase enzyme inserting Zn2+ in place of Fe2+ (Bloomer et al., 1983).
ZPP is a normal metabolite that is formed in trace amounts during haeme biosynthesis.
During periods of iron insufficiency or impaired iron utilization, zinc becomes an alterna-
tive metal substrate for ferrochelatase, leading to increased ZPP formation. Evidence
suggests that this zinc-for-iron substitution occurs predominantly within the bone marrow,
and the ZPP:haeme ratio in erythrocytes reflects the iron status in the bone marrow. In addi-
tion, ZPP may regulate haeme catabolism through competitive inhibition of haeme oxy-
genase, the rate-limiting enzyme in the haeme degradation pathway that produces bilirubin
and carbon monoxide (Labbé et al., 1999).
Roh et al. (2000) showed that ZPP concentrations measured by haematofluorometry
were consistently higher than those measured by HPLC and spectrofluorometry in non-
exposed adults, but were lower in exposed workers. They also found a positive correlation
between blood lead and ZPP in workers exposed to high concentrations of lead, but not in
non-exposed controls. The increase in ZPP is observed only at exposures resulting in blood
P 285-336 DEF.qxp 09/08/2006 12:30 Page 291
lead concentrations > 20 µg/dL and good correlations have been found with blood lead
concentrations > 40 µg/dL (Leung et al., 1993; Froom et al., 1998) (see also Section 1.6.2).
The best-fitting correlation between blood lead and ZPP is an exponential curve, with
an r-value ranging from 0.38 to 0.69. In a group of 97 subjects selected in a stratified
sample, in whom the blood lead values ranged from 10–120 µg/dL, there was a very good
correlation between blood lead and log ZPP (r = 0.87). When the diagnostic validity of
the ZPP test was analysed in various groups of workers, a high number of false negatives
was observed at various ZPP cut-off values. ZPP cannot be applied in screening of
workers with medium or low exposures to lead. In such situations, it is considered advi-
sable to use blood lead as an indicator (Apostoli & Maranelli, 1986).
At blood lead concentrations < 20 µg/dL, ZPP concentrations were not found to be
significantly different between the genotypes ALAD1 and ALAD2. Furthermore, ALAD
genotypes did not affect the concentrations of haeme precursors at low blood lead concen-
trations (Alexander et al., 1998; Zhang et al., 1998). At blood lead concentrations of
20–60 µg/dL, ZPP concentrations in ALAD1 homozygotes were significantly higher than
those in ALAD2 carriers (Schwartz et al., 1995; Alexander et al., 1998).
(vi) Lead and pyrimidine 5′-nucleotidase
Lead may affect haematocrit and haemoglobin concentrations also via the haemolytic
effect of pyrimidine nucleotide accumulation due to the inhibition of pyrimidine 5′-nucleo-
tidase (P5N) (Sakai, 2000). Following initial observations on the inhibitory effects of lead
on P5N (Paglia et al., 1975; Angle & McIntire, 1978), a number of studies have been
carried out mainly to develop adequate analytical methods for measuring P5N activity in
the general population and to study its relationship with blood lead concentrations and with
other enzymes such as deoxy-P5N and arginase (Cook et al., 1985, 1986; Sakai & Ushio,
1986). It was reported that ALAD is more sensitive to lead than P5N (Tomokuni & Ichiba,
1988b; Ong et al., 1990; Pagliuca et al., 1990; Kim et al., 1995a). It has been suggested
that P5N is the 45-kDa protein component in the lysate from erythrocytes of exposed
workers that is seen to bind Pb2+ (Bergdahl et al., 1998a).
(vii) Lead and indicators of anaemia
Anaemia following exposure to lead is caused by the decreased synthesis of both
haeme and globin and by a haemolytic mechanism that is due partly to inhibition of P5N
(Sakai, 2000). Anaemia induced by lead poisoning is normocytic in children and women
and commonly associated with iron deficiency, which may produce a more severe micro-
cytic hypochromic anaemia (Clark et al., 1988). Anaemia may also result in part from the
inhibitory action of lead on erythropoietin (Graziano et al., 1991).
A threshold lead-in-blood concentration resulting in a decrease in haemoglobin has
been estimated to be 50 µg/dL for occupationally exposed adults (US EPA, 1986).
A cross-sectional epidemiological study was conducted to assess the association
between blood lead concentration (11–164 µg/dL) and hematocrit value in 579 children
(age, 1–5 years) living near a primary lead smelter. There was a non-linear dose–response
P 285-336 DEF.qxp 09/08/2006 12:30 Page 292
relationship between blood lead concentration and hematocrit, which was influenced by
age. In one-year-olds, the age group most severely affected, the risk of having an hema-
tocrit < 35% — indicative of anemia — was 2% at a blood lead concentration of 20–
39 µg/dL, 18% at 40–59 µg/dL, and 40% at a PbB > 60 µg/dL. The data suggest that lead-
induced anemia is an important consequence of lead absorption, even at low exposure
levels (Schwartz et al., 1990).
(viii) Lead and other haeme-containing systems
Lead inhibits the synthesis of cytochromes, such as cytochrome C, in both animal and
human systems (Bull et al., 1983). It also affects other haeme-requiring enzymes, such as
cytochrome C oxidase in muscle (Goldberg et al., 1985).
A decrease in haeme will also alter the activity of other haeme-requiring proteins
(Figure 6).
(b) Animal studies

The effects of lead on the haematopoietic system in experimental animals have been
studied extensively (see WHO, 1995; ATSDR, 1999).
A decrease in ALAD activity in erythrocytes was observed in rats given lead acetate
at 1000 ppm in the drinking-water for 6 days. Blood lead concentrations increased to
44 µg/dL after the first day and remained within 10 µg/dL of that value until the end of
the exposure period (Simmonds et al., 1995).
In subchronic exposure studies, decreased haematocrit values and impaired haeme
synthesis were reported, the lowest effective dose being dependent on the exposure route
and on the chemical form of lead. When administered to rats by gavage, lead acetate caused
a decrease in haematocrit values at a dose of 30 mg/kg bw per day given for 19 days
(Overmann, 1977). When rats received 1% lead acetate in the diet for 7 weeks, a similar
decrease in haematocrit value was seen (Walsh & Ryden, 1984). In contrast, rats that
received lead acetate in their drinking-water at 34 mg lead/kg bw per day did not show
adverse effects on haematocrit (Fowler et al., 1980).
Urinary excretion of ALA was significantly increased in rats that received lead acetate
or lead oxide at 5 mg lead/kg bw per day for 30 days, but no effect was seen with lead
sulfide or a lead ore (Dieter et al., 1993). Likewise, ALAD activity in serum was more
strongly inhibited by lead acetate than by lead sulfide or lead-contaminated soil (Freeman
et al., 1996).
The effect of ingestion of lead on haematological parameters was investigated in male
and female Swiss mice. Eight different doses of lead were administered through prepa-
ration of different feeds. The amounts of lead in the diet were designed to provide blood
lead concentrations below (0.6–< 2.0 µg/dL) and above (> 2.0–13 µg/dL) the normal
background. One litter of mice was exposed to each dose by feeding the mother with the
lead-containing diet starting 1 day after mating, and mother and offspring continued to
receive the feed until the litter was 90 days old. Male and female mice receiving concen-
trations of dietary lead below normal background displayed enhanced erythrocyte produc-
P 285-336 DEF.qxp 09/08/2006 12:30 Page 293
tion as measured by higher cell numbers and increased haemoglobin and haematocrit
values. However, as the blood lead concentrations approached 10 µg/dL, there was a
marked decrease in erythrocyte production. These findings are significant since lead
appeared to stimulate erythrocyte production at low concentrations (2.0 µg/dL) while
adversely affecting red cell synthesis at higher concentrations (7.0–13 µg/dL) (Iavicoli
et al., 2003).

Acute toxic effects of lead (at 0.5, 1.0, 2.5 and 5.0 µM for 24 h) on coproporphyri-
nogen oxidase activity have been evaluated in an in-vitro model using HepG2 cells, a
hepatoma cell line of human origin (Hernández et al., 1998). The cells were treated with
150 µM ALA to induce porphyrins. Cellular protoporphyrin increased in a dose-dependent
manner, reaching a maximum at 2.5 µM lead, but no changes in extracellular proto-
porphyrin were found. Extracellular coproporphyrin concentration was increased two-fold
at all concentrations of lead, without changes in cellular content. The coproporphyrinogen
oxidase activity was depressed in a dose-dependent manner to 62% of control activity at
5.0 µM lead. The dose-dependent increase in coproporphyrin secretion accompanied by
the depression of coproporphyrinogen oxidase activity supports the hypothesis that lead
inhibits coproporphyrinogen oxidase.
4.2.3 Nephrotoxicity
The renal effects of lead in humans and experimental systems have been reviewed
(Goyer, 1989; Nolan & Shaikh, 1992; Goyer, 1993; WHO, 1995; Loghman-Adham,
1997). Acute and chronic effects of lead on the kidney are summarized in Figure 7. Acute
exposure to high concentrations of lead results in disruption of proximal tubular architec-
ture with disturbances in proximal tubular function. Histological changes include intra-
nuclear inclusions in proximal tubular cells and mitochondrial swelling. Renal manifesta-
tions of acute lead poisoning include glycosuria, aminoaciduria and phosphaturia, collec-
tively presented as the Fanconi syndrome. Chronic exposure to low concentrations of lead
is also associated with increased urinary excretion of low-molecular-weight proteins and
lysosomal enzymes. Chronic exposure to high concentrations of lead results in irrever-
sible changes in the kidney, including interstitial fibrosis, tubular atrophy, glomerular
sclerosis and ultimately chronic renal failure. It has also been implicated in the develop-
ment of gout and hypertension secondary to nephropathy.
It has become evident that concentrations of lead as low as 10 µg/dL in blood, pre-
viously considered to be safe, may also be associated with renal function abnormalities,
such as changes in serum creatinine concentration or in creatinine clearance (Staessen et al.,
1992; Kim et al., 1996b). Whether such small changes in renal function result in clinically-
significant health problems is uncertain.
The renal effects of lead in humans and experimental systems reviewed below are
summarized in Table 88.
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Figure 6. Multiorgan impact of reduction of haeme body pool by lead
Pb
Reduction of
haeme body pool
Erythropometic Reduced haemoglobin Anaemia reduced

synthesis oxygen transport
effects to all tissues
Neural Reduced haemoproteins Impaired cellular

(e.g. cytochromes) energetics
effects
Disturbed immuno-
regulatory role
of calcium
Renal endocrine Reduced 1.25 (OH)2• Disturbed calcium

effects vitamin D metabolism
Disturbed role in
tumorigenesis
control
Impaired detoxification
of xenobiotics
Hepatic Reduced haeme for

haeme-regulated
effects transformations
Impaired metabolism
of endogenous
agonists
Modified from ATSDR (1999)

P 285-336 DEF.qxp 09/08/2006 12:30 Page 295
Figure 6 (contd)
Anaemia reduced Exacerbation of Cardiovascular

oxygen transport hypotoxic effects of dysfunction and
to all tissues other stress agents other hypoxic effects
Effects on neurons,
axons, and
Schwann cells
Impaired cellular Impaired myelination

energetics and nerve conduction
Impaired development
of nervous system
Disturbed immuno- Impaired mineral Impaired bone and

regulatory role tissue homeostasis tooth development
of calcium
Impaired calcium
Disturbed calcium
role as second
metabolism
messenger
Disturbed role in Impaired calcium

tumorigenesis role in cyclic
control nucleotide metabolism
of environmental
toxins
of xenobiotics
of drugs
Altered metabolism Elevated brain

of tryptophan levels of tryptophan,
serotonin, and HIAA
Impaired metabolism
of endogenous
agonists
Impaired hydroxylation Disturbed indoleamine
of cortisol neurotransmitter
function
P 285-336 DEF.qxp
Figure 7. Consequences of excessive lead exposure
296
Lead
09/08/2006
Chronic Acute
Distal RAS
Glomeruli Proximal tubule
tubule Ca++ signaling
12:30
Intranuclear
Normal inclusions
Page 296
histology Mitochondrial
swelling
Increased Excretion of low Aminoaciduria

urate Vasoconstriction Hyperfiltration MW proteins and Glycosuria
secretion enzymes (NAG) Phosphaturia
Glomerulosclerosis
Chelation and/or
Hyperuricaemia Interstitial fibrosis
abatement
Tubular atrophy
?
Hypertension Persistent No renal
Gout CRF
dysfunction dysfunction
Lead nephropathy
Modified from Loghman-Adham (1997); CRF, chronic renal failure; NAG, N-acetyl-β-D-glucosaminidase
Acute lead poisoning results in proximal tubular dysfunction; these changes usually disappear with chelation therapy or removal from lead sources. Chronic lead poisoning can
affect glomerular function when blood lead levels exceed 60 µg/dL. After an initial period of hyperfiltration, the glomerular filtration is reduced and nephrosclerosis and chronic
renal failure ensue. Prolonged lead exposure also interferes with distal tubular secretion of urate, leading to hyperuricaemia and gout. Finally, chronic lead exposure may cause
hypertension, resulting from vasoconstriction due to the action of lead on the renin–angiotensin system (RAS) and on calcium signaling.
P 285-336 DEF.qxp
Table 88. Summary of published studies of the renal effects of lead
Effects General population Occupational exposure Clinical studies Animal studies
09/08/2006
Acute
Hypophosphaturia, aminoaciduria, – – Chisholm (1962) –
glycosuria (Fanconi syndrome)
Glomerular filtration rate – – Wedeen et al. (1979) Khalil-Manesh et al.
12:30
(1992a, 1994)
γ-Glutamyl transferase – – – Huguet et al. (1982)
natriuria
Tubular change (inclusion bodies, – Cramér et al. (1974) Biagini et al. (1977) Moore & Goyer (1974);
Page 297
mitochondria) Goyer & Wilson (1975);
Fowler et al., (1980)
Chronic
S-Creatinine Staessen et al., (1990); Ong et al. (1987) – –
Kim et al. (1996)
Creatinine clearance Staessen et al. (1992) Ong et al. (1987) – –
S-Urea (BUN) Campbell et al. (1977) Baker et al. (1979); Maranelli – –
& Apostoli (1987); Ong et al.
(1987)
Hyperuricaemia Campbell et al. (1977) Maranelli & Apostoli (1987) – –
α1-Microglobulin Chia et al. (1995) – –
β2-Microglobulin Staessen et al. (1992) Huang, J.-X. et al. (1988) – –
N-Acetyl-β,D-glucosaminidase Verberk et al. (1996) Meyer et al. (1984); Ong et al. – –
(1987); Verschoor et al. (1987)
Glutathione S-transferase – – – Khalil-Manesh et al.
(1992a); Moser et al.
(1995)
Serum proline – Cramér et al. (1974) – –
6-kPGF1α, TXB2, tubular antigen – Cárdenas et al. (1993) – –
Gout – Batuman et al. (1981); Pollock – –
& Ibels (1988)
Renal mortality – McMichael & Johnson (1982) – –
297
–, no data; BUN, blood urea nitrogen; 6-kPGF1α, 6-ketoprostaglandin F1 alpha; TXB2, thromboxane B2
P 285-336 DEF.qxp 09/08/2006 12:30 Page 298
(a) Humans
(i) General population
In a longitudinal study of 459 men, Kim et al. (1996b) reported a positive correlation
between blood lead concentration and impairment of renal function measured by serum
creatinine concentrations. A weak positive correlation between serum creatinine and blood
lead concentrations had also been found by Staessen et al. (1990) in a study conducted
among civil servants not subject to industrial exposure to heavy metals. Staessen et al.
(1992) examined a random population sample, including 965 men and 1016 women (geo-
metric mean blood lead concentrations, 11.4 µg/dL and 7.5 µg/dL, respectively), and
reported that creatinine clearance was inversely correlated with blood lead concentrations.
A positive correlation was found in this study between serum β2-microglobulin and blood
lead concentrations in men.
Verberk et al. (1996) reported a positive relationship between concentration of lead in
blood (mean ± standard deviation, 34.2 ± 22.4 µg/dL) and the activity of N-acetyl-β-D-
glucosaminidase (NAG) in urine in 151 children (3–6 years old) who resided at different
distances from a lead smelter in Romania. There was a 13–14% increase of urinary NAG
activity per 10 µg/dL increase in blood lead concentration, which was indicative of renal
tubular damage. Campbell et al. (1977) found that increased blood lead concentrations
were associated with increased serum urea concentrations and hyperuricaemia in 283
people living in houses known or believed to have lead plumbing systems, with lead con-
centrations in the drinking-water > 0.1 mg/L.
(ii) Occupational exposure
Buchet et al. (1980) examined 25 male lead-smelter workers (blood lead concentration
range, 33.8–61.3 µg/dL; mean (range) duration of exposure, 13.2 (3.1–29.8) years) and 88
male controls (blood lead concentration range, 5.5–34.2 µg/dL), and found no differences
in renal function between the groups and no clinical signs of renal impairment. The authors
concluded that blood lead concentrations less than 62 µg/dL were not associated with renal
toxicity.
Ong et al. (1987) examined renal function in 158 male and 51 female lead-exposed
workers (age range, 17–68 years) with mean (± SD) blood lead concentrations of 42.1
(± 16.6) and 31.9 (± 14.3) µg/dL, respectively. Serum creatinine, blood urea nitrogen and
creatinine clearance were significantly correlated with blood lead concentrations. After
adjusting for age of the subjects, the increase in NAG excretion with increasing blood lead
concentration was found to be statistically significant (p < 0.001).
Meyer et al. (1984) found significant increases in median urinary NAG activity in 29
workers exposed to lead, but there was no correlation with blood lead concentrations. In a
later study by Verschoor et al. (1987), the excretion of NAG was reported to be a consistent
and sensitive parameter of early effects on renal tubular function in workers occupationally
exposed to low concentrations of lead. No significant differences were found in various
indicators of renal function between 148 male workers exposed to lead (blood lead,
2.29 µM (geometric mean); range, 1.63–3.21 µM) [47.4 µg/dL; range, 33.8–66.5 µg/dL]
P 285-336 DEF.qxp 09/08/2006 12:30 Page 299
and 125 non-exposed workers (blood lead, 0.40 µM (geometric mean); range, 0.27–
0.58 µM) [8.3 µg/dL; range, 5.6–12.0 µg/dL] matched for age, smoking habits, socioeco-
nomic status and duration of employment. There were no differences in protein excretion
patterns and no signs of renal impairment. However, regression and matched-pair analyses
suggested that renal tubular parameters as measured by NAG excretion might be more
strongly influenced by exposure to lead than the glomerular parameters. Changes in renal
function parameters may occur at blood lead concentrations below 60 µg/dL.
Chia et al. (1995) suggested that time-integrated blood lead indices were the most
important descriptors of the variability in urinary α1-microglobulin, urinary β2-micro-
globulin and urinary retinol binding protein in 128 workers exposed to lead (current blood
lead concentration range, 7.6–66.2 µg/dL). Urinary α1-microglobulin was the only marker
that was significantly higher in the lead-exposed group than in controls, with a good dose–
response and dose–effect relationship with the time-integrated blood lead indices.
No clinical signs of renal impairment were observed among active and retired lead-
smelter workers with long-term exposure whose blood lead concentrations were below
70 µg/dL (Gerhardsson et al., 1992; see also Roels et al., 1999)
Elevated concentrations of blood urea nitrogen (≥ 20 mg/dL) were reported in 28 of
160 lead-exposed workers whose blood lead concentrations ranged from 16–280 µg/dL
(Baker et al., 1979). Maranelli and Apostoli (1987) reported significantly higher concen-
trations of blood urea nitrogen and serum uric acid in 60 workers with lead poisoning
(mean ± SD of blood lead, 71.9 ± 16.5 µg/dL) compared with 76 control subjects.
Cramér et al. (1974) found significantly lower plasma concentrations of proline,
valine, tyrosine and phenylalanine, but no excessive aminoaciduria in five men with
heavy occupational exposure to lead (blood lead concentration range, 71–138 µg/dL)
compared with non-exposed controls. Typical lead-induced intranuclear inclusion bodies
were found only in renal biopsies of the workers with short exposure. Mitochondrial
changes were found in all subjects.
Cárdenas et al. (1993) reported interference of lead (mean blood lead concentration,
48 µg/dL) with the renal synthesis of eicosanoids, resulting in lower urinary excretion of
6-keto-prostaglandin F1α and an enhanced excretion of thromboxane. As this was not asso-
ciated with any sign of renal dysfunction, it may represent a reversible biochemical effect
or contribute to the degradation of renal function after the onset of clinical lead nephro-
pathy. The urinary excretion of some tubular antigens (BBA, BB50 and HF5) was posi-
tively associated with duration of exposure to lead.
(iii) Clinical studies
Chisholm (1962) examined renal tubular injury in 23 lead-intoxicated children and
compared the pattern of aminoaciduria with that seen in 56 patients with other diseases that
impair renal function. Acute lead intoxication in children produced disorders of renal
tubular function similar to those of Fanconi syndrome. Hypophosphataemia, aminoaci-
duria and glycosuria were found in 8/23 children, and most frequently in those with severe
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clinical manifestations. The abnormalities disappeared within 2 months, showing that the
effect of lead was reversible.
Biagini et al. (1977) studied renal morphology in eight patients with chronic lead
poisoning (blood lead concentration range, 90–200 µg/dL). The ultrastructural changes,
which mainly involved the proximal tubules, were (1) a degenerative pattern (swollen
mitochondria, dilated endoplasmic reticulum and scanty microvilli), (2) signs of metabolic
hyperactivity (intranuclear granular inclusions, oddly shaped nuclei) and (3) a regenerative
pattern (poorly differentiated cells with few microvilli, shallow infoldings of basal cell
membranes). In the glomeruli, the most characteristic finding was a mesangial reaction. In
some cases, the basement membrane appeared to be thickened and the visceral epithelial
cells were hypertrophic. Interstitial fibrosis was present, as well as a certain degree of arte-
riolar hyperplasia. These findings appear to confirm chronic lead nephropathy.
Wedeen et al. (1979) reported reduced glomerular filtration rates (GFR; < 90 mL/min/
1.73 m2; see McIntosh et al., 1928) in 21 of 57 workers with excessive lead body burdens
(urinary lead > 1000 µg/24 h, after edetate disodium calcium lead mobilization test). In
seven of eight renal biopsy specimens examined by immunofluorescence microscopy, the
finding of glomerular and tubular immunoglobulin deposition raises the possibility that an
autoimmune response may contribute to the interstitial nephritis that occurs in occupational
lead nephropathy.
Batuman et al. (1981) examined 44 male patients with gout by using the ethylene-
diaminetetracetic acid (EDTA) lead-mobilization test. The amount of mobilizable lead
was significantly greater in patients with gout who had renal impairment than in patients
with gout who had normal renal function, although lead blood concentrations were not
significantly different between the groups (26 ± 3 and 24 ± 3 µg/dL, respectively). Renal
function (determined by the serum creatinine concentration) correlated with mobilizable
lead in all 44 patients. The data indicate that lead plays a role in gout nephropathy. If lead
nephropathy with gout or hypertension is suspected, the diagnosis may be confirmed
using an EDTA chelation test (Pollock & Ibels, 1988).
An age-standardized proportional mortality analysis was conducted among 241 lead-
smelter workers diagnosed with ‘lead poisoning’ between 1928 and 1959. Among the 140
deaths in this group, the study showed a substantial excess in the numbers of deaths from
chronic renal disease, particularly prior to 1965 (see also Section 2.1.2). A moderate excess
was also apparent for other smelter workers, not diagnosed with lead poisoning. In recent
years, these excesses of mortality in lead-exposed workers have largely disappeared
(McMichael & Johnson, 1982).
(b) Animal studies

Chronic intoxication with lead is associated with the presence of characteristic intra-
nuclear inclusions in proximal tubular epithelial cells of the kidney. Chemical analysis of
these inclusion bodies has indicated the presence of lead as well as of protein, presumably
of the non-histone type. The inclusion bodies are eosinophilic and do not appear to contain
DNA or RNA. Lead-induced formation of nuclear inclusion bodies has been observed in
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kidneys of rabbits (Hass et al., 1964), rats (Goyer et al., 1970; Choie & Richter, 1972a,b),
monkeys (Allen et al., 1974) and dogs (Stowe et al., 1973).
Moore and Goyer (1974) used differential centrifugation to isolate inclusion bodies
from renal tubular cells of rats exposed to lead and studied their biochemical composition.
The inclusion bodies contain about 40–50 µg lead/mg protein and may function as an intra-
cellular depot of non-diffusible lead. Further studies indicated that protein-bound lead in
renal tubular cells may be partitioned between insoluble and non-diffusible, morpho-
logically-discrete inclusion bodies and a soluble, extractable fraction that is presumably
diffusible.
Goyer and Wilson (1975) demonstrated that the nuclear inclusion bodies formed in
lead-treated rats could be disrupted and removed from the nuclei by the administration of
EDTA and that this removal corresponded to peak urinary excretion of lead. The sharp
increase in urinary lead following EDTA therapy is the result, at least in part, of chelation
and excretion of sequestered lead bound to nuclear protein and indicates that the formation
of inclusion bodies is reversible.
The lowest chronic exposure to lead resulting in a detectable renal effect in rats has
been reported to be 5 mg/L in drinking-water, which resulted in a median blood lead con-
centration of 11 µg/dL (Fowler et al., 1980). At this exposure level, cytomegaly and karyo-
megaly were found in renal proximal tubular cells. Proximal tubular cells from rats
exposed to 50 and 250 ppm lead for 6 or 9 months showed intranuclear inclusion bodies.
Inhibition of renal mitochondrial respiration and swollen mitochondria were seen at
9 months of exposure, but these changes were not evident at 6 months.
Huguet et al. (1982) reported acute kidney damage following intraperitoneal adminis-
tration of lead acetate (0, 0.05, 0.15 and 0.30 mmol Pb2+/kg bw) to groups of five male
and five female rats. Minimal kidney damage shown by increased urinary γ-glutamyl
transferase activity was observed only in males given the highest dose. In all animals and
at all doses, natriuria was significantly decreased on the first day (from 4 h after adminis-
tration). Such changes evoke mild tubular abnormalities but glomerular disturbances may
also be involved.
Khalil-Manesh et al. (1992a) studied the progression of lead nephropathy in rats given
lead acetate at a high dose (5% in drinking water) for 1–12 months. Control animals were
pair-fed. In the exposed rats, the glomerular filtration rate (GFR) was significantly higher
than in the controls after 3 months of lead exposure, but was lower than the controls after
12 months. Lead inclusion bodies were found in nuclei of proximal convoluted tubules and
the pars recta in all lead-treated animals from 1 month onwards. Tubular atrophy and inter-
stitial fibrosis first appeared at 6 months, and increased in severity thereafter. Brush borders
of proximal tubules were disrupted at 1 and 3 months, but recovered thereafter. After 3 and
6 months of lead exposure, urinary NAG and glutathione S-transferase (GST) concen-
trations were elevated in the exposed rats compared with controls, but at 9 and 12 months
the differences were not all significant. Concentrations of urinary brush border antigens
were also increased above controls at 1 and 3 months, but were decreased at 6 and 12
months, correlating with morphological changes in the brush border. The authors concluded
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that a high dose of lead in rats may initially stimulate both renal cortical hypertrophy and an
increase in GFR. Later, the adverse effects of lead on the tubulointerstitium predominate,
and the GFR decreases. The urinary marker, NAG, was found to be abnormal in the early
stages post-exposure, but age-related changes obscured this abnormality at later stages and
urinary GST appeared to be a more consistent marker of injury.
In the same experimental system, administration of the chelator dimercaptosuccinic
acid (DMSA) resulted in an improvement in GFR and a decrease in albuminuria, together
with a reduction in size and number of nuclear inclusion bodies in proximal tubules
(Khalil-Manesh et al., 1992b). Overall, treatment with DMSA improved renal function
but had less effect on pathological alterations.
In rats exposed via drinking-water to 5000 mg/L or 100 mg/L lead acetate for 1–12
months, GFR and blood lead concentrations correlated positively during the first 6 months
of treatment. GFR and red blood cell membrane Na-K-ATPase correlated negatively at 6
and 12 months in rats given the high dose (Khalil-Manesh et al., 1994).
Moser et al. (1995) reported effects of acute and chronic exposure to lead on GST iso-
forms during kidney development in rats. In the acute exposure experiment, rats of 14 and
50 days of age were given three daily intraperitoneal injections of lead acetate (114 mg/kg
bw) for 3 days and were sacrificed 24 h after the third injection. In the chronic exposure
studies, rats received lead acetate in drinking-water (50–500 ppm) from the day after con-
ception. Acute and chronic lead exposure were found to have similar effects, causing
increases in all but one GST isoform (Yb3); these increases were markedly higher under
conditions of dietary calcium depletion. Lead-related increases in GSTs were partially
reversed by transferring the animals to lead-free water for a 4-week period.
4.2.4 Neurological and neurotoxic effects

(a) Humans
(i) Neurological symptoms of high-level exposure to lead
Neurological and neurotoxic effects of lead are well recognized in both adults and
children. High-level exposure to lead causes symptomatic lead poisoning.
Both the peripheral and the central nervous system are targets for lead, although peri-
pheral neural effects (wrist drop and slowing of nerve conduction velocities) have, so far,
been described largely in adults in occupational settings. Lead encephalopathy has been
reported to occur in cases of acute symptomatic lead poisoning and its severity depends
on a combination of factors, including the intensity and duration of exposure.
Children are more vulnerable than adults to the effects of lead for several reasons: a
greater proportion of ingested lead is absorbed from the gastrointestinal tract of children
than of adults, more lead gains access to the brain of children than of adults, and the deve-
loping nervous system is far more vulnerable to the toxic effects of lead than the mature
brain (Leggett, 1993).
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The symptoms of severe lead poisoning in children are typically associated with a blood
lead concentration of 70 µg/dL, but can occur in some children at a concentration of
50 µg/dL (Adams & Victor, 1993). The early symptoms include lethargy, abdominal
cramps, anorexia and irritability. Over a period of days or weeks, in children younger than
2 years of age, there is progression to vomiting, clumsiness and ataxia; then to alternating
periods of hyperirritability and stupor; and finally coma and seizures. Children who survive
are either severely cognitively compromised or frankly mentally retarded (reviewed by
Lidsky & Schneider, 2003).
Rahman et al. (1986) described six infants, three of them neonates, diagnosed as
having acute lead poisoning; four had acute encephalopathy. All had been given an indi-
genous preparation, ‘Bint Al Zahab’ (Daughter of Gold), for abdominal colic and early
passage of meconium after birth. Chemical analysis of this powder revealed a lead content
of 82.5%. The index case had anaemia with punctate basophilia, dense metaphysial lines
on X-ray and markedly raised blood lead concentrations, arousing a strong index of suspi-
cion for the early diagnosis of subsequent cases. Computerized axial tomography (CAT)
scan in three cases showed signs of early cerebral cortical atrophy. The picture of cerebral
oedema was absent in the four cases of acute lead encephalopathy.
In a later study by Al Khayat et al. (1997b), a group of 19 infants (mean age, 3.8 months)
showed symptoms consistent with acute lead encephalopathy following the use of traditional
medicines. All children presented with convulsions, and CAT scans of the brain showed
oedema in four patients and atrophy in four others. Cerebrospinal fluid of nine children was
analysed and showed pleocytosis in six and a high protein content in eight cases. The median
lead concentration in the blood of these 19 infants was 74.5 µg/dL, and seven children had a
mean lead concentration of 57 µg/dL which is below the proposed threshold (70 µg/dL) for
encephalopathy. The children received chelation therapy. During follow-up 13 infants were
observed to have developed brain damage. The results indicate that acute encephalopathy
may occur in very young infants at lead concentrations lower than previously reported.
Blood concentrations of lead below that which produces clear clinical symptoms are
also neurotoxic in children and have lasting effects on neurobehavioural function. Lead
poisoning at these lower levels of exposure is far more common and is particularly insi-
dious because of its lack of diagnostically-definitive physical signs. Some children com-
plain of stomach pains and loss of appetite and may or may not have anaemia. Neurobeha-
vioural deficit resulting from exposure to lead can occur in the absence of clinical symp-
toms (reviewed by Lidsky & Schneider, 2003).
The characteristic acute and predominantly cerebellar encephalopathy associated with
high exposure to lead in neonates contrasts to the subtle, axo-dendritic disorganization
shown to be associated with low-level exposure of infants to inorganic lead. In both low-
level exposure to inorganic lead and exposure to organolead, there is a preferential
involvement of the hippocampus, and the clinical syndromes of irritability, hyperactivity,
aggression and seizures are common features of disturbed hippocampal function. Neuro-
transmitter system abnormalities and changes in glutamate, dopamine and/or γ-amino-
butyric acid (GABA) uptake, efflux and metabolism have been described following expo-
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sure to inorganic lead. Among these effects, abnormalities of GABA and glutamate meta-
bolism are also found after exposure to organolead. While inorganic lead produces a clini-
cally-definable encephalopathy and neuropathy dependent upon age, route of exposure
and dose, the clinical syndrome caused by organolead — i.e. triethyl lead, the neurotoxic
metabolite of tetraethyl lead — is characterized by lethargy, tremors, hyperexcitability,
hypermotility, aggression, convulsions, ataxia, paralysis and death (Verity, 1990).
(ii) Impact on hearing induced by low-level exposure to lead
Lead-induced impairment of the auditory brain and cochlea is believed to contribute
substantially to the cognitive disorders and learning disabilities associated with low-level
exposure to lead. However, the specific effects of elevated blood lead concentrations on
central nervous system physiology and sensory systems, particularly the auditory system
have not been clearly elucidated. Furthermore, earlier studies on the effects of lead intoxi-
cation on brainstem physiology and auditory sensory-neural functions have resulted in
conflicting results (Otto & Fox, 1993).
Several investigations have reported that humans exposed to lead develop auditory
brainstem abnormalities and significant hearing loss.
Holdstein et al. (1986) recorded auditory brainstem evoked potentials (ABEP; in res-
ponse to 75-dBHL (decibels hearing level) clicks presented at rates of 10/sec and 55/sec)
from 29 adults and children (age range, 8–56 years) (blood lead concentration range, 30–
84 µg/dL) who were accidentally exposed to lead in food until approximately 1 year prior
to the study. A prolonged interpeak latency difference (between peaks I and III) was the most
significant recurring result, with longer intervals in lead-exposed children compared with
the control group. Increasing stimulus rate, on the other hand, affected exposed adults to a
greater extent than the children. The results may imply an impairment of the peripheral
portion of the auditory system with axonal and myelin involvement.
Otto et al. (1985) evaluated 49 children aged 6–12 years for residual effects of lead
exposure using the ABEP test. The initial blood lead concentration range in these children
was 6–59 µg/dL, the range at the time of ABEP testing was 6–30 µg/dL. A linear relation-
ship between blood lead concentration and slow brain wave voltage during sensory condi-
tioning was observed at initial evaluation and at follow-up after 2 years. No significant
relationship between blood lead concentration and slow wave voltage during passive condi-
tioning was found at the 5-year follow-up. A significant linear relationship between the
original blood lead concentrations and the latency of waves III and V of the ABEP was also
reported. The latency of both waves increased as a function of the initial blood lead concen-
tration, which is suggestive of subclinical pathology of the auditory pathway.
Schwartz and Otto (1987) used NHANES data to confirm the relationships previously
observed between blood lead concentration and hearing threshold and found that the
probability of elevated hearing thresholds at 500, 1000, 2000 and 4000 Hz increased
significantly for both ears with increasing blood lead concentration. However, others have
reported a lack of effects on auditory sensory-neural function.
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Counter et al. (1997a) investigated blood lead concentrations and auditory sensory-
neural function in 62 schoolchildren living in a lead-contaminated area of Ecuador and 14
children in a neighbouring area with no known lead exposure. The median blood lead
concentration in the lead-exposed group was 52.6 µg/dL (range, 9.9–110.0 µg/dL) com-
pared with 6.4 µg/dL (range, 3.9–12.0 µg/dL) in the non-exposed group (p < 0.001).
Auditory thresholds for the lead-exposed group were normal at the pure tone frequencies
of 2500–8000 Hz over the entire range of blood lead concentrations. Auditory tests in
seven of the children with high blood lead concentrations showed normal absolute peak
and interpeak latencies. In a more extensive neurophysiological and audiological study
conducted by the same research group, the exposed children showed normal wave
latencies and neural transmission times, with no statistical correlation between blood lead
concentrations and interpeak latencies. Audiological tests indicated normal cochlear
function and no statistical relation between auditory thresholds and blood lead
concentration (Counter et al., 1997b).
(iii) Visual functions affected by low-level exposure to lead
In 19 gun metal founders occupationally exposed to lead (initial blood lead concen-
trations, 16–64 µg/dL), Araki et al. (1987) found that the N2 latency — conduction time
from the retina to the visual cortex — of the visual-evoked potential (VEP) was signifi-
cantly prolonged. Twelve months later, after improvement of the work environment, the
N2 latency had returned to the normal level. This change was correlated positively with
absorption indicators of lead and inversely with those of zinc and copper. This suggests that
lead interferes with visual function, and that this interference is antagonized by zinc and
copper. In another study, an increase in P100 latency — i.e. the latency of the VEP-posi-
tive peak 100 msec after stimulus onset — was reported in 17 lead-exposed workers (non-
smokers, blood lead concentrations, 25–52 µg/dL) compared with 27 unexposed controls,
while the N75 latency — i.e. the latency of the VEP-negative peak 75 msec after stimulus
onset — was not affected. However, no significant effects of lead were observed for the
smokers or for the total subject population (31 exposed, 54 controls) (Solliway et al.,
1995). The results indicate that lead affects neural function even at permitted levels of
exposure.
Altmann et al. (1998) investigated 384 children (age, 5.0–7.8 years) from lead-polluted
areas for the impact of lead on the visual system. The range of blood lead concentrations
in these children was 1.4–17.4 µg/dL. Statistically significant lead-related changes were
found only for some of the VEP interpeak latencies after adjusting for confounding effects.
All other outcome variables were not significantly related to lead concentrations.
(iv) Peripheral nervous functions affected by low-level exposure to
lead
Nerve conduction studies have been carried out in chronically-exposed industrial
workers with elevated blood lead concentrations but with no clinical evidence of neuro-
pathy. In one of the first studies of this kind, Seppäläinen et al. (1975) found evidence for
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asymptomatic slowing of the motor nerve conduction velocity in 26 exposed workers

whose blood lead concentrations had never exceeded 70 µg/dL. In a further study among
78 workers with maximal blood lead concentrations (ever recorded) in the range
≤ 40 µg/dL up to ≥ 70 µg/dL, Seppäläinen et al. (1979) found that ulnar nerve conduction
velocity was depressed in workers whose blood lead concentrations had never exceeded
50 µg/dL. A third study reported slowing of ulnar nerve conduction velocity at blood lead
concentrations just above 30 µg/dL (Seppäläinen et al., 1983). Jeyaratnam et al. (1985)
found that mean maximum motor conduction velocities of the median nerve were signifi-
cantly lower in workers exposed to lead (mean blood lead concentration, 48.7 µg/dL) than
in controls (mean blood lead concentration, 15.8 µg/dL). Other studies have also reported
reduction in peripheral nerve conduction velocities in workers exposed to lead (Chen et al.,
1985; Murata et al., 1987).
Triebig et al. (1984) studied 148 male workers exposed to lead from the manufacture
of storage batteries, and 66 non-exposed controls. Statistically significant differences in
nerve conduction velocities were seen only for the distal sensory fibres of the ulnar and
median nerves. In contrast to the reports mentioned above, the authors concluded that at
blood lead concentrations below 70 µg/dL, no functionally significant lead-induced
reduction of nerve conduction velocity is to be expected. These findings repeated and con-
firmed the earlier results of Spivey et al. (1980) and Nielsen et al. (1982).
Schwartz et al. (1988) demonstrated a negative correlation between blood lead concen-
tration and motor nerve conduction velocity in 202 asymptomatic children aged 5–9 years
living near a lead smelter in Idaho, USA, whose blood lead concentrations ranged from
13–97 µg/dL. The authors found evidence for a threshold in three regression analyses: at a
blood lead concentration of 30 µg/dL in ‘hockey stick’ regression, at 20 µg/dL in logistic
regression and at 25–30 µg/dL in quadratic regression. Age, sex, socioeconomic status or
duration of residence near the smelter did not significantly modify the relationship. The
study confirmed that, in the absence of symptoms, increased lead absorption caused
slowing of nerve conduction in children, but also indicated that measurement of maximal
motor nerve conduction velocity is an insensitive screen for low-level lead toxicity.
All the above studies relate the findings on nerve conduction velocity to ‘current’
blood lead concentrations in humans. This practice is not ideal as the toxicity of lead to
the peripheral nerves progresses over time. Chia et al. (1996a) studied 72 workers in a
lead-battery manufacturing plant and 82 non-exposed referents. At the time of the study,
mean blood lead concentrations in these groups were 36.9 (range, 7.3–68.5) and 10.5
(range, 4.4–19.8) µg/dL, respectively. Past blood lead measurements were available for
62 workers, for whom the mean cumulative blood index was 136.8 (range, 6.7–1087.0)
µg-year/dL. There was a significant reduction in sensory conduction velocity of the
median nerve of the dominant forearm for the group of 49 workers with mean cumulative
blood lead index > 40 µg-years/dL. Current blood lead concentrations, however, did not
show any trends against the nerve conduction parameters.
Ishida et al. (1996) studied 58 male and 70 female ceramic painters, aged 29–75 years,
with lead concentrations in blood ranging from 2.1–69.5 µg/dL. They examined maximal
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conduction velocity in the median nerve of the forearm as a measure of motor nerve
function, the variation in the cardiac cycle time in electrocardiography as a measure of
parasympathetic function, and changes in finger blood-flow volume and drop velocity
with change in posture from the supine to standing position as a measure of sympathetic
function. No significant association was found between blood lead concentrations and the
results of these neurophysiological tests.
(v) Neurotoxicity of lead in children
The neurotoxicity of lead was recognized as early as the 1st century AD when
Dioscorides, physician to Nero, wrote that “Lead makes the mind give way.” Childhood
lead poisoning was first reported at the end of the 19th century (Lockhart Gibson et al.,
1892). Until the 20th century, it was generally thought that lead-exposed individuals who
did not die during the acute illness were left without any trace of their exposure. When a
study of children who had recovered from acute lead poisoning showed impaired cogni-
tion, poor school performance and increased antisocial behaviour (Byers & Lord, 1943),
the long-term effects of lead toxicity were established and the modern era of lead toxico-
logy began. Until the 1970s, it was thought that these residua were found only in children
who had displayed clinical signs of encephalopathy. Among studies in the early 1970s of
children in the USA who had no overt symptoms, four found lead-associated deficits in
intelligence quotient (IQ) (David, 1974; Perino & Ernhart, 1974; De la Burdé & Choate,
1975; Landrigan et al., 1975c), while three found no significant differences between
exposed and unexposed children (Kotok, 1972; Lansdown et al., 1974; Baloh et al.,
1975). These early studies tended to have small sample sizes and low statistical power;
many used insensitive measures of cognition; covariate control was limited; and the expo-
sure measure was lead in blood, which is a short-term storage system for lead. Later
studies, using larger samples, more appropriate and sensitive outcome measures and
better covariate control, tended to report impaired cognition at concentrations of lead in
blood well below those associated with clinical symptoms. Not all studies reported signi-
ficant effects, and the issue of silent lead exposure has continued until quite recently to be
a source of contention.
Cross-sectional studies
Byers and Lord (1943) were alerted to the possibility of long-term effects of lead
poisoning when two children were referred for aggressive behaviour. They were
recognized as children who had in the past been treated for lead poisoning and discharged
as recovered. A further 20 children with similar histories were then identified and it was
found that 19 had school failure, behavioural disorders or mental retardation.
David (1974) compared blood and penicillamine-provoked urinary lead concen-
trations in 54 children with hyperactivity with corresponding values in 37 controls and
found that the hyperactive children had increased lead concentrations in blood and urine.
Perino and Ernhart (1974) compared 30 children with blood lead concentrations
> 40 µg/dL with 50 children with concentrations ranging from 10–30 µg/dL. Using
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multiple regression to control for age, parental intelligence and birth weight, they found a
significant inverse relationship between blood lead concentrations and McCarthy intelli-
gence scores.
De la Burdé and Choate (1975) compared 67 children who had been exposed to lead,
but displayed no acute symptoms, with a group of 70 controls with no known exposure.
Exposed children had deficits in global IQ and associative abilities, visual and fine motor
coordination and behaviour. School failure due to learning and behavioural problems was
more frequent in the lead-exposed than in the control group.
Landrigan et al. (1975c) compared a group of children who lived in the vicinity of a
smelter and had blood lead concentrations > 40 µg/dL with children of similar socioeco-
nomic status with blood lead concentrations < 40 µg/dL. The children with the higher lead
concentrations were found to have significantly lower scores in performance and full-scale
IQ tests, as well as in a finger–wrist tapping test, which measures fine motor function.
At the end of the 1970s and the beginning of the 1980s, studies were conducted with
larger sample sizes, better covariate control and more sophisticated use of statistics.
Needleman et al. (1979), using lead in shed deciduous teeth as marker of exposure, com-
pared 58 children with high concentrations of lead in their dentine (> 24 µg/g) with 100
children with low concentrations (< 6 µg/g). After control for covariates, children with high
lead concentrations had significantly lower IQ scores, impaired attention and reduced
language function than those with low concentrations. Teachers’ negative ratings of 2146
children on a forced-choice classroom behavioural rating scale were related to higher
dentine lead concentrations (Figure 8).
Yule et al. (1981) classified 166 children by their blood lead concentrations (range,
7–33 µg/dL) and found significant negative associations with IQ, reading and spelling.
A later study used the teachers’ rating scale employed by Needleman (see Figure 8) and
found the same results (Yule et al., 1984).
Winneke et al. (1982) studied 458 school-age children whose dentine lead concen-
trations had been measured (range, 1.4–12.7 µg/g). From this group, two subgroups of 26
children each (mean age, 8.5 years) were chosen with low (means, 2.4 µg/g) and high
(means, 9.2 µg/g) tooth lead concentrations, respectively. The groups were matched for
age, sex and father’s occupational status. The high-lead group scored significantly lower
(p < 0.05) in two perceptual motor-integration tests and had a 5–7 point lower IQ (nearly
significant, p < 0.1) than the low-lead group. In a further study (Winneke et al., 1983) of
115 school-age children living in a lead-smelter area (mean tooth lead concentration,
6.2 µg/g; range, 1.9–38.5 µg/g), inverse associations — some of which were significant,
p < 0.05 — were found between tooth lead values and outcomes of perceptual motor-inte-
gration and reaction-performance tests. After correction for confounding, there remained a
tendency for children with tooth lead > 10 µg/g to have on average a 4.6-point lower IQ
than children with tooth lead ≤ 4 µg/g.
Smith et al. (1983) measured dentine lead in 402 schoolchildren in London and
reported that, after covariate adjustment, children with high lead concentrations (mean,
11 µg/g) had lower verbal IQ, performance IQ and full-scale IQ scores than those with
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Figure 8. Teachers’ ratings on forced-choice behavioral items classified by ascending dentine lead
09/08/2006
level
12:30
Page 309
Modified from Needleman et al. (1979)
The group boundaries were chosen to obtain symmetrical cell sizes for the median (groups 1 and 6 = 6.8 per cent, groups 2
and 5 = 17.6 per cent, and groups 3 and 4 = 25.6 per cent).
309
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intermediate (mean, 6 µg/g) and low dentine lead (mean, approx. 3 µg/g). The exact p-
values were not given, and the differences were reported as ‘not significant’. Children with
high lead concentrations also had lower scores (also reported as ‘not significant’) on a word
reading test.
Lansdown et al. (1986) found no significant associations between lead and IQ in a
study of 194 children classified by blood lead concentrations in the range 7–24 µg/dL.
Fulton et al. (1987) evaluated 501 primary-school children aged 6–9 years in
Edinburgh, United Kingdom, using the British Ability Scales combined scores. Lead
burden was measured by blood lead concentrations (range, 3.3–34 µg/dL), and 33 co-
variates were controlled for in the multiple regression model. A significant inverse
relationship between lead and cognitive scores was found with no evidence of a threshold.
Silva et al. (1988) studied 579 children and found no association between blood lead
concentration (mean ± SD, 11.1 ± 4.9 µg/dL; range, 4–50 µg/dL) and IQ, but a significant
association with behavioural problems, including inattention and hyperactivity as reported
by teachers and parents.
Hansen et al. (1989) studied the relationship between dentine lead concentration
(average, 10.7 µg/g; range, 0.4–168.5 µg/g) and IQ in 162 schoolchildren in Denmark.
After adjustment for covariates, significant inverse associations were found between lead
and IQ (p < 0.01) and visual motor performance (p < 0.001).
Wang et al. (1989) studied 180 elementary-school children in China and found a signi-
ficant inverse relationship between blood lead concentration (mean, 21.1 µg/dL; range,
4.5–52.8 µg/dL) and IQ as measured by the revised Wechsler intelligence scale for children
(WISC-R).
Greene and Ernhart (1993) obtained IQ scores of 164 children aged 4 years and 10
months and measured lead concentrations in blood and in dentine of shed deciduous teeth.
Using multiple regression, the association was measured with and without controlling for
Home Observation for Measurement of the Environment (HOME) scores. Verbal IQ and
performance IQ were inversely related (p < 0.001 and p = 0.025, respectively) to dentine
lead concentration in the absence of HOME score adjustment. When HOME was entered
into the model, the relationship between lead and performance IQ was no longer signifi-
cant (at p = 0.590). An errors-in-variables analysis was applied, and verbal IQ continued
to be significantly (but inversely) related with dentine lead (p = 0.011).
Some critics of the association between lead and intelligence have argued that the
effect of lead is small and therefore inconsequential (Ernhart et al., 1989). Figure 9 shows
the cumulative frequency distribution of IQ scores in subjects with high and low lead con-
centrations in the study of Needleman et al. (1982). It can be seen that a median difference
of six points is associated with a fourfold increased rate of severe deficit (IQ < 80). In
addition, 5% of the subjects with high lead concentrations were prevented from achieving
superior function (IQ > 125).
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Figure 9. Cumulative frequency distribution of verbal IQ scores in subjects with low

or high levels of lead
Modified from Needleman et al. (1982)
Prospective studies
McMichael et al. (1988) followed a cohort of 537 children living in the vicinity of a
lead smelter in Australia from birth onwards. At 4 years of age, an inverse association was
found between body lead burden and mental development, as measured according to the
McCarthy Scales of Children’s Abilities. At 11–13 years of age, the inverse association of
blood lead concentrations with WISC scores continued to be significant (Tong et al.,
1996).
Ernhart et al. (1989) studied a group of 242 infants, and reported no significant
covariate-adjusted associations between intelligence test scores of these preschool
children and lead concentrations in maternal blood, umbilical cord blood or venous blood
of the children up to 4 years of age. The strength of the negative inference is lessened by
the use of a sample in which half of the mothers were alcohol abusers.
Needleman et al. (1990) followed-up 132 adolescents (mean age, 18.4 years) from the
group first tested 11 years before (see above). At the time of the re-examination, blood lead
concentrations were measured for 48 subjects; all were < 7 µg/dL. Subjects were grouped
in quartiles according to their earlier dentine lead concentrations (< 5.9, 6.0–8.2, 8.3–22.2
and > 22.2 µg/g). Higher lead concentrations (> 20 µg/g) were associated with lower class
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standing in the senior year in high school, increased absenteeism, lower vocabulary and
grammatical reasoning scores, poorer eye–hand coordination, longer reaction times and
slower finger tapping. Having an elevated dentine lead concentration in childhood was
associated with a sevenfold increased risk for failing to graduate from high school and a
sixfold risk for reading disability.
Bellinger et al. (1992) studied a group of 148 infants at birth and at 6,12, 18, 57 and
120 months of age. Blood lead concentrations at 2 years, but not at other ages, were signi-
ficantly associated with a reduced IQ score at both 57 and 120 months of age. Over the
range 0–25 µg/dL, a 10-µg/dL increase in blood lead concentration at 24 months was
associated with a 5.8-point decline in WISC-R score.
Fergusson et al. (1997) followed a birth cohort of 1265 children in New Zealand until
18 years of age. Lead burden was measured at age 6–8 years by deciduous teeth analysis.
At age 18, after adjustment for confounders and errors in measurement, subjects with
elevated dentine lead concentrations had significantly poorer reading scores, lower levels
of success in school examinations and greater likelihood of failure to graduate.
Schnaas et al. (2000) followed a group of 112 children in Mexico at 6-month intervals
from 6 to 60 months. After adjustment for covariates, lead was significantly related to the
general cognitive index on the McCarthy scales. The postnatal lead concentrations (mean
value of measurements at 6, 12 and 18 months) had a maximum effect on the cognitive
index at 4–5 years of age.
Wasserman et al. (2000) followed 442 children in a lead-exposed and a non-exposed
area in Serbia and Montenegro from before birth until 7 years of age and found that ele-
vations in both prenatal and postnatal blood lead concentrations were related to reduced
scores in cognitive ability tests (McCarthy scales; WISC).
Coscia et al. (2003) followed a cohort of 196 children from birth to 15 years of age,
and applied growth-curve analysis to study the association between exposure to lead and
cognition parameters measured at 6.5, 11 and 15 years of age. Blood was collected
prenatally from the mother near the end of the first trimester of pregnancy, approximately
10 days after birth, every 3 months until the age of 5 years, at 66, 72 and 78 months, and
at approximately 15 years of age. The highest mean blood lead concentration for this
group of children was 17.03 ± 8.13 (SD) µg/dL, measured at 2 years of age. Children with
higher lead concentrations showed lower verbal IQ scores over time, and greater decline
in the rate of vocabulary development.
Recent studies
Following the removal of lead from gasoline, blood lead concentrations in the general
population — first in the USA and then in Europe — began to decline. Mean blood lead
concentrations in the USA were 15 µg/dL in 1975, 9 µg/dL in 1980 and 2 µg/dL in 2000
(NHANES IV). This decline has permitted investigators to compare exposed subjects to
reference groups at 1 µg/dL, an opportunity that was foreclosed when the mean blood lead
concentration in the general population was 15 µg/dL.
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Two recent studies of the effects of extremely low concentrations of lead have been
published. Lanphear et al. (2000b) examined data from the NHANES III on 4853 children
between the ages of 6 and 16 years. The association between scores on arithmetic and
reading skills, achievement scores, and blood lead concentration was measured; adjustments
were made in the multiple regression analysis for age, race, sex, region of the country,
parental marital status and education, poverty level and serum cotinine concentration. The
geometric mean blood lead concentration was 1.9 µg/dL. Significant inverse relationships
were found for arithmetic and reading tests at blood lead concentrations < 5 µg/dL, for
block design at blood lead concentrations < 7.5 µg/dL and for digit span at blood lead con-
centrations < 10 µg/dL.
Canfield et al. (2003) examined the association between blood lead concentrations and
Stanford-Binet Intelligence Scale (SBIS) scores in a prospective study of 172 children aged
6–60 months. A longitudinal analysis, adjusting for sex, birth weight, blood iron status,
mother’s IQ, education, race, tobacco use, income and HOME scores, was conducted.
Mean blood lead concentrations were 3.4 µg/dL at 6 months, 9.7 µg/dL at 24 months and
6.0 µg/dL at 60 months. A significant inverse relationship between these average blood
lead concentrations and SBIS scores was found.
The studies by Lanphear et al. (2000b) and Canfield et al. (2003) support the meta-
analysis of Schwartz (1994) who reanalysed the data from the Boston prospective study
(Bellinger et al., 1992) and several others. Using non-parametric regression, Schwartz
(1994) found an inverse relationship between IQ and blood lead concentrations below
5 µg/dL.
Lead and antisocial behaviour
Suggestions that lead exposure may have a role in antisocial behaviour are not new.
Parents of lead-poisoned children have frequently complained that, after recovery from the
acute illness, their children became oppositional, aggressive or violent. In the first follow-
up study of lead-poisoned children, Byers and Lord (1943) found that 19/20 subjects had
severe behavioural problems or learning disorders. Denno (1990) found that the strongest
predictor of arrest of youths enrolled in the Collaborative Perinatal Disease Study in
Philadelphia, USA, was a history of lead poisoning.
Needleman et al. (1996) studied a cohort of 301 boys in the school system in
Pittsburgh, USA. Bone lead concentrations, measured by X-RF spectrometry at 12 years
of age, were significantly related to parents’ and teachers’ child behaviour checklist ratings
of aggression, attention and delinquency. The subjects’ self-reports of delinquent acts were
also positively associated with bone lead concentrations. Dietrich et al. (2001) studied 195
urban youths and found that prenatal exposure to lead was significantly related with
covariate-adjusted increases in parental reports of delinquent and antisocial behaviour.
Prenatal and postnatal exposure to lead was associated with self-reports of such behaviour.
Needleman et al. (2002) conducted a case–control study of bone lead concentrations
in 194 male youths arrested and adjudicated as delinquents. Cases had significantly higher
mean concentrations of lead in their bones than controls (11.0 ± 32.7 µg/g versus
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1.5 ± 32.1 µg/g). Logistic regression analysis found an unadjusted odds ratio of 1.9
(95% CI, 1.1–3.2) for a lead concentration ≥ 25 µg/g versus < 25 µg/g. After adjustment
for covariates and interactions, adjudicated delinquents were four times more likely to
have bone lead concentrations > 25 µg/g (odds ratio, 4.0; 95% CI, 1.4–11.1). In addition,
self-reports of delinquency were positively associated with bone lead concentrations.
Two recent ecological studies have reported positive associations between environ-
mental concentrations of lead and antisocial behaviour. Stretesky and Lynch (2001)
measured the association between estimated air lead concentrations for all 3111 conti-
guous counties in the USA (range, 0–0.17 µg/m3) and homicide data (average over the
period 1989–91) from the National Center for Health Statistics. After adjusting for 15 con-
founding variables, they reported a fourfold increase in homicide in the counties with the
highest lead concentrations compared with those with the lowest lead concentrations.
Nevin (2000) reported a statistically significant association between sales of leaded
gasoline and violent crime after adjustment for unemployment and percentage of popu-
lation in the high-crime age group. Figure 10 shows the rates of violent crime in the USA
by year in relation to the yearly sales of leaded gasoline.
Figure 10. Violent crime rates and sales of lead gasoline in the USA
Modified from Nevin (2000)
(vi) Other effects

Since the late 1980s, several studies have explored the effect of lead exposure on pos-
tural stability. Motivated by a positive pilot study with 33 children (Bhattacharya et al.,
1988), Bhattacharya et al. (1990, 1993; with 63 and 109 children, respectively) confirmed
an association between postural sway abnormalities and lead intoxication. There was a
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significant relationship between postural sway response recorded at 6 years of age and
maximum blood lead concentrations during the second year of life. Chia et al. (1994) ini-
tially reported lead-induced postural instability among a group of workers exposed to lead
compared with non-exposed workers. However, a significant relation between current
blood lead concentrations and postural sway parameters could not be established. In a later
study (Chia et al., 1996b), there was a significant association between most of the postural
sway parameters and the cumulative blood lead concentrations in the 2 years prior to the
date of the postural assessment. Current blood lead concentrations were poorly correlated
with most of the postural sway parameters. It was concluded that the adverse effect of lead
on postural stability is the result of chronic rather than acute exposure to lead.
(vii) Neurobehavioural effects of organic lead
To investigate the relationship between bone lead concentration after exposure to
organic lead compounds and neurobehavioural test scores, a study was conducted with
529 former organolead workers of mean age 57.6 years. The mean time since last expo-
sure was 16 years. X-RF spectrometry of the tibia was used to estimate accumulated bone
lead concentration. Lead-exposed workers had significantly lower scores on visuocons-
truction tasks, verbal memory and learning. Peak tibial lead concentrations were asso-
ciated with decline in verbal and visual memory, executive function and manual dexterity.
These effects of lead were reported to be more pronounced in individuals who had at least
one ε4 allele of the apolipoprotein E4 gene (Stewart et al., 2002).
(b) Experimental systems

(i) In-vivo studies with inorganic lead
Several of the neurological and neurotoxic effects of lead described in humans have
been investigated and confirmed in animal model systems. This section reviews a limited
number of relevant studies in this area.
Acute lead encephalopathy has been induced experimentally in various animal
species, such as the rat, the guinea pig, the baboon and the rhesus monkey.
Five-day-old rats that received the highest non-lethal dose of aqueous lead acetate
(1 mg lead/g bw per day) on two consecutive days were found to develop haemorrhagic
encephalopathy (Toews et al., 1978).
Lead administered to newborn rats postnatally on days 1–15 by daily intraperitoneal
injections of 10 mg lead nitrate/kg bw was found to cause haemorrhagic encephalopathy
in the cerebellum at 15 days (Sundström & Karlsson, 1987).
Bouldin and Krigman (1975) induced acute lead encephalopathy in adult guinea-pigs
that received 2, 3, 5 or 6 consecutive daily oral doses of lead carbonate (155 mg per dose).
Clinical signs of intoxication started after 2–3 doses and became more severe with higher
doses.
Lead encephalopathy in the baboon (Papio anubis) was reported by Hopkins and Dayan
(1974). Two adult animals received 6–8 injections of lead carbonate (1 g per injection;
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approx. 90 mg/kg initial weight) over a period of 8–12 months. Seizures were observed to
begin at 3 and 5 months, respectively, in these two animals.
In rhesus monkeys, encephalopathy was induced by doses of 0.5 g lead subacetate,
given by gastric gavage on alternate days, three times a week, for 6–18 weeks (Clasen
et al., 1974). Vitamin D (1000 units) was given together with each dose to enhance the ali-
mentary absorption of lead (Sobel & Burger, 1955).
Effects on learning
Experimental studies, primarily with rodent and non-human primate models, have
provided evidence that chronic low-level exposure to lead affects learning abilities and
behaviour, in particular in the developing animal. The magnitude of these effects appears
to be strongly dependent on the developmental period in which exposure takes place (for
a review, see Cory-Slechta, 2003). Since learning requires the remodelling of synapses in
the brain, lead may specifically affect synaptic transmission, and it has been proposed that
the learning deficits caused by lead are due to events regulated by a calcium-dependent
protein kinase C (PKC), most likely at the synapse (Bressler et al, 1999). However, the
effects of lead on PKC studied in brain homogenates in vitro may not accurately reflect
effects of chronic in-vivo exposure to lead (Cremin & Smith, 2002).
In a study by Altmann et al. (1993), rats were exposed chronically to low concentrations
of lead at different stages of development, and tested with respect to active-avoidance
learning and hippocampal long-term potentiation. When exposure comprised the prenatal
and the early postnatal period and was continued into adulthood, both processes were
impaired. However, when exposure started at 16 days after birth, neither learning nor hippo-
campal potentiation was affected. These results reflect the higher vulnerability of the imma-
ture hippocampus to lead-induced functional deficits compared with the mature hippo-
campus.
Effects on visual function
In a study by Kohler et al. (1997), rhesus monkeys were exposed pre- and postnatally
to 0, 350 or 600 ppm lead acetate in the diet for 9 years. Lead exposure was followed by a
35-month period of lead-free diet. During this period, blood lead concentrations of the
treated animals declined to nearly equal those of untreated controls. Lead exposure affected
the dopaminergic amacrine cells in the retina by reducing the tyrosine hydroxylase content
in these neurons. This neurotoxic effect persisted beyond the end of exposure.
Rice and Hayward (1999) exposed monkeys to lead acetate at 500 or 2000 µg lead/kg
bw per day from birth onwards. Spatial and temporal contrast-sensitivity functions were
assessed at adulthood and during ageing, by measuring the frequency and amplitude at
peak sensitivity and the high-frequency cut-off value. Compared with controls, lead-
exposed monkeys exhibited reduced temporal visual function at the first assessment but
not the second. There was no evidence of an accelerated decline in contrast sensitivity as
a result of exposure.
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Effects on hearing
Yamamura et al. (1984) gave guinea-pigs intraperitoneal injections of 1% lead acetate
once a week for 5 weeks. The animals were examined electrophysiologically using
cochlear microphonics and action potential. There were no significant changes in the
thresholds of cochlear microphonics. The thresholds of maximum voltage of N1 in the
action potential of the animals injected with a total of 100 mg lead acetate were elevated
by about 15 dB and increased N1 latency was also observed.
Rice (1997) determined pure tone detection thresholds in a group of six monkeys
(Macaca fascicularis) dosed with lead acetate (2.8 mg lead/kg bw, 5 days per week) from
birth until testing at 13 years of age. Blood lead concentrations at the time of testing were
60–170 µg/dL. Pure tone detection thresholds were determined at six frequencies between
0.125 and 31.5 kHz. Three lead-exposed monkeys had thresholds outside the control
range at some frequencies. The findings are consistent with reports of elevated pure tone
detection thresholds in lead-exposed humans, although the effect is smaller than might
have been predicted given the concurrent blood lead concentrations of the monkeys in this
study.
Effects on nerve conduction velocity
Conduction velocity of the optic nerve has been studied in rats that received 7.6 or
15.8 µg lead/kg bw daily by intraperitoneal injection during the first 2 weeks of postnatal
life. Optic nerve conduction velocity was examined at 30 days of age in 14 rats taken from
10 different litters. The mean conduction velocities for the two faster axonal groups were
16.8 and 5.4 m/s in control rats, 10.3 and 5.8 m/s in rats given the lower dose and 9.4 and
5.2 m/s in rats given the higher dose of lead. The reduction in conduction velocity for the
fastest axons was significant in both dose groups (Conradi et al, 1990).
Purser et al. (1983) maintained five cynomolgus monkeys at blood lead concen-
trations of 90–100 µg/dL for 9 months by daily oral dosing with lead acetate (12–15 mg
lead/kg bw). The animals showed no clinical or behavioural evidence of lead poisoning
at any time during the study, although there was a decrease in packed cell volume, haemo-
globin and erythrocyte concentration in the blood. The maximal motor nerve conduction
velocity of the ulnar nerve remained constant throughout the study, although changes
were observed in the conduction velocity of slowly-conducting nerve fibres. At the end of
the study, focal areas of myelin degeneration were found in the ulnar and sciatic nerves.
Effects on motor function and aggressive behaviour
Two groups of rats were given 50 ppm sodium acetate and 50 ppm lead acetate, respec-
tively, in the drinking-water for 3 months. Ocular motor function was tested by rotating the
animals on a platform at an increasing angular velocity and measuring ocular nystagmus
when the rotation is abruptly stopped. The lead-exposed animals showed a reduction in
post-rotatory nystagmus that was significantly related to blood lead and brain lead concen-
trations, while no such alterations were observed in animals treated with sodium acetate.
The results show that low concentrations of lead may impair both sensory and motor
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functions, and indicate that these measurements provide a screening tool for neurotoxic
effects of lead even in the absence of clinical signs of lead intoxication (Mameli et al.,
2001).
Young rats (3–4 weeks old) were treated with lead acetate (daily oral doses of 10 mg
lead/kg bw) and ethanol (10% v/v in drinking-water), either alone or in combination, for
8 weeks. Motor activity, the number of fighting episodes and several lead-sensitive bio-
chemical indices were measured. Spontaneous locomotor activity and aggressive
behaviour were significantly increased in the group ingesting ethanol plus lead compared
with the controls. The lead concentrations in blood, liver, kidney and brain were signifi-
cantly higher in rats exposed simultaneously to lead and ethanol compared with the group
treated with lead alone (Flora et al., 1999).
The effects of lead exposure on a feline model of aggression were investigated by Li
et al. (2003). Five cats were stimulated with a precisely controlled electrical current via
electrodes inserted into the lateral hypothalamus. The response measure was the predatory
attack threshold, i.e. the current required to elicit an attack response in 50% of the trials.
Lead was mixed (as lead acetate) into cat food at doses of 50–150 mg/kg bw lead per day
for 4–5 weeks. Blood lead concentrations were < 1, 21–77 and < 20 µg/dL before, during
and after lead exposure, respectively. The predatory attack threshold decreased signifi-
cantly during lead exposure in three of the five cats and increased after cessation of expo-
sure in four of the five cats (p < 0.01). There was a significant (p = 0.0019) negative asso-
ciation between threshold current and blood lead concentration. These data show that lead
exposure enhances predatory aggression in cats.
Effects on neurochemical parameters
While neurological and neurotoxic effects are difficult to define and quantify
precisely, neurochemical effects are easy to define and to quantify but their interpretation
remains elusive. Most neurochemical studies have been conducted since the 1970s and
1980s (see Tables 89 and 90); in this section, only the most recent and important findings
are reported.
Neurochemical parameters were measured in discrete brain areas of rat pups whose
mothers were intoxicated with lead in drinking-water (300 ppm) from day 1 of pregnancy
until postnatal day 12. This treatment produced a significant reduction in the activity of
alkaline phosphatase and ATPase in the brain, and reduced the concentration of adenine
nucleotides, most notably in the striatum, but not in the hypothalamus. Lead also reduced
the concentration of neurotransmitters throughout the brain, especially in the hippo-
campus (Antonio & Leret, 2000).
In a study to investigate the effects of lead on antioxidant enzyme activities in the
developing brain, female Wistar rats were given drinking-water containing 500 ppm lead
(as lead acetate) or 660 ppm sodium acetate during pregnancy and lactation. The activities
of superoxide dismutase (SOD), glutathione peroxidase and glutathione reductase were
determined in the hypothalamus, hippocampus and striatum of male pups at 23 or 70 days
of age. In 23-day-old pups, the activity of SOD was decreased in the hypothalamus. There
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Table 89. Effects of lead on catecholamines
Reference Animal Major results
Silbergeld & Goldberg (1975) Mouse Increase in norepinephrine in forebrain,

midbrain, brainstem
Silbergeld & Chisolm (1976) Mouse Increase in VMA in whole brain
Sauerhoff & Michaelson (1973) Rat No change in norepinephrine, decrease in
dopamine in whole brain
Golter & Michaelson (1975) Rat Increase in norepinephrine, no change in
dopamine in whole brain
Sobotka & Cook (1974) Rat No change in norepinephrine in brain
Hrdina et al. (1976); Dubas Rat Decrease in norepinephrine in hypothalamus,
et al. (1978); Jason & Kellog striatum, brainstem
(1981)
Sobotka & Cook (1974) Rat No change in dopamine in cortex, brainstem,
hypothalamus, striatum and forebrain
VMA, vanillylmandelic acid
Table 90. Cholinergic effects of lead
Reference Animal Cholinergic effects
Silbergeld & Goldberg Mouse No change in acetylcholine in whole brain

(1975)
Modak et al. (1975); Rat No change in choline and acetylcholine in
Shih & Hanin (1978) cerebellum, hippocampus, midbrain, pons-medulla,
cortex, and striatum
Modak et al. (1975); Rat Increase in acetylcholine in diencephalon and cortex
Hrdina et al. (1976)
Modak et al. (1978) Rat Decrease in acetylcholine in whole brain and
cerebellum, medulla, diencephalon, cerebrum,
striatum, and midbrain.
was no significant effect of the treatment on any of the enzymes and brain regions eva-
luated in adult (70-day-old) animals. Oxidative stress due to decreased antioxidant
function may occur in lead-treated rats at weaning (23 days) but it is not likely to be the
main mechanism involved in the neurotoxicity of lead (Moreira et al., 2001).
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(ii) In-vivo studies with organic lead

The neurotoxic properties of organic lead compounds and their neurobehavioural
effects have been reviewed by Walsh and Tilson (1984). The behavioural effects produced
by organic lead compounds resemble the sequelae of damage in the limbic system. Altera-
tions in sensory responsiveness or behavioural reactivity and task-dependent changes in
avoidance learning are observed following both exposure to organic lead and experimental
disruption of the limbic system. In addition, the neurochemical changes induced by organic
lead compounds are site-specific and restricted to the limbic forebrain and frontal cortex.
Rat pups (age, 5 days) received 15% ethanol or 3 or 6 mg/kg bw triethyl lead chloride by
subcutaneous injection (LD50, 13 ± 1 mg/kg bw). Controls were sham-injected with ethanol.
Transient effects included reduced olfactory discrimination on day 7, decreased incidence of
nipple attachment on day 9, and fine whole-body tremor on day 10. Persistent hypo-activity
was observed on days 15, 22, 24, 26 and 29 in males that received the high dose. A reduction
in number, but not in magnitude, of startle responses was also noted in the lead-treated
animals. Thus a single postnatal injection of triethyl lead produced transient effects possibly
reflecting direct pharmacological activity, as well as long-term effects suggesting potentially
permanent alterations in behavioural function (Booze et al., 1983).
Cragg and Rees (1984) administered tetramethyl lead dissolved in olive oil to pregnant
rats by subcutaneous injection on days 7, 14 and 21 of gestation. Pups were born on day
22 and received similar injections 7 and 14 days after the last prenatal dose. The total lead
concentration in the brain was about 1 µg/g at 28 days. Birth weight was unaffected, but
postnatal brain growth was reduced relative to body growth, resulting in a higher
body:brain weight ratio. Brain myelination, dendritic growth, granule cell production and
retinal receptor development were unchanged. The body:brain weight ratio appeared to be
a sensitive parameter for detecting effects on neurological development of exposure to low
concentrations of tetramethyl lead, which is neurotoxic at higher concentrations.
(iii) In-vitro studies
Various in-vitro studies implicate second-messenger metabolism and protein kinase
activation as potential pathways for the disruptive action of lead on nervous system
function. These reactions could contribute to the subtle defects in brain function asso-
ciated with low-level lead poisoning.
To investigate the effects of acute lead exposure on evoked responses in the hippo-
campus of the rat in vitro, field potentials in response to paired-pulse stimulation were
measured in rat hippocampal slices perfused with medium containing 0.2–53 µM lead.
The evoked population excitatory postsynaptic potentials and the orthodromically-evoked
population spike showed a dose-dependent decrease during lead exposure, whereas the
presynaptic fibre volley remained unchanged. Within 20 min after the start of exposure,
the recorded responses had reached the control level again in spite of further lead perfu-
sion. These results show that lead acts pre-synaptically in the hippocampus, and that it
interferes with non-synaptic processes at the pyramidal neurons (Altmann et al., 1988).
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Excessive glutamate release in the brain and subsequent neuronal stimulation cause
increased production of reactive oxygen species (ROS), oxidative stress, excitotoxicity
and neuronal damage. The interaction between glutamate and lead may result in neuronal
damage, as glutamate-induced production of ROS is greatly amplified by lead in cultured
neuronal cells. Alterations in the activity of protein kinase C seem to play an important
role in this process. The neurotoxic effects of lead may be amplified through glutamate-
induced neuronal excitation (Savolainen et al., 1998).
Lead can substitute for calcium in several intracellular regulatory events associated
with neurological function. At nanomolar concentrations, lead activates calmodulin-
dependent phosphodiesterase and calmodulin inhibitor-sensitive potassium channels. At
picomolar concentrations it activates calmodulin-independent protein kinase C. There is
evidence to support the hypothesis that activation of PKC underlies some aspects of lead
neurotoxicity (Goldstein, 1993).
4.2.5 Cardiovascular toxicity

Cardiovascular effects of lead in humans and experimental systems have been reviewed
(Victery, 1988; Goyer, 1993; Hertz-Picciotto & Croft, 1993; WHO, 1995).
(a) Humans
(i) Blood lead concentrations and blood pressure
The literature discussed in the reviews mentioned above can be divided into studies on
the general population and occupational cohort studies. Surveys of the general population
have been conducted in Belgium, Canada, Denmark, the United Kingdom and the USA.
Results of most of the studies suggest positive associations between blood lead concen-
trations and blood pressure, but some of the studies do not show any significant association.
General population
Staessen et al. (1995) carried out an extensive meta-analysis including 23 studies with
a total of 33 141 subjects. Among the studies were 13 surveys of the general population
and 10 of occupational groups. Most studies took into account confounding factors. The
association between blood pressure and blood lead was similar in men and women. For
all groups and both sexes combined, a twofold increase in blood lead concentration was
associated with a 1.0-mmHg rise in systolic pressure (95% CI, 0.4–1.6 mmHg; p = 0.002)
and with a 0.6-mmHg increase in diastolic pressure (95% CI, 0.2–1.0 mmHg; p = 0.004).
A recent update comprising 31 studies (19 surveys in the general population, 12 occupa-
tional studies) largely confirmed these results (Nawrot et al., 2002).
Occupational exposure and lead poisoning
In a longitudinal study of > 500 lead-foundry workers who had been examined annually
for periods of up to 14 years, Neri et al. (1988) found an association between short-term
changes in an individual’s blood lead concentration and contemporary changes in diastolic
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pressure. The average increase in diastolic blood pressure per 1-µg/dL increase in blood lead
concentration was 0.3 mm Hg. The association remained significant after allowance for age
or time trends and for effects related to changes in body weight.
Parkinson et al. (1987) examined the relationship between occupational exposure to
lead and diastolic and systolic blood pressure in randomly-selected samples of 270 exposed
and 158 non-exposed workers. After controlling for other known risk factors such as age,
education, income, cigarette usage, alcohol consumption and exercise, the associations
between exposure and blood pressure were small and non-significant.
(ii) Blood pressure and renal function
Batuman et al. (1983) used the EDTA lead-mobilization test to study the etiological
role of lead burden in 48 men diagnosed as having essential hypertension. Patients who had
hypertension and a reduced renal function (i.e. serum creatinine > 1.5 mg/dL) had signi-
ficantly larger amounts of mobilizable lead than did patients who had hypertension without
renal impairment. The increase in mobilizable lead was not due to the renal disease itself.
(iii) Coronary risk of lead exposure
Silver and Rodriguez-Torres (1968) studied electrocardiograms in 30 children (aged
17–60 months) with lead poisoning (blood lead concentration range, 60–200 µg/dL).
Twenty-one patients (70%) had at least one abnormal electrocardiographic finding (mostly
myocardial damage) before treatment [details of this treatment were not reported], which
persisted in only four (13%) after treatment. The most significant findings were increased
heart rate (six patients), and atrial arrhythmia (five patients). More frequent abnormalities
were found in children with higher blood lead concentrations.
Kirkby and Gyntelberg (1985) studied the coronary risk profile in 96 heavily-exposed
workers (mean ± SD blood lead concentration, 51 ± 16 µg/dL) employed at a lead smelter
for 9–45 years. The reference group (mean blood lead, 11 ± 3 µg/dL) was not exposed to
lead but was comparable with respect to age, sex, height, weight, social grouping, occupa-
tional status and alcohol and tobacco consumption. The exposed workers had slightly
higher diastolic blood pressure, significantly more ischaemic electrocardiographic
changes, and lower high-density lipoprotein levels than the reference group. The exposed
workers with electrocardiographic changes had higher blood pressure than the referents
with corresponding changes. These findings indicate a higher coronary risk profile for lead
smelter workers, and support the hypothesis of a positive association between lead expo-
sure and arteriosclerosis and high blood pressure.

(i) Cardiovascular effects of lead
A number of animal experiments have suggested a biphasic response of blood pressure
to lead dose (Victery et al., 1982; Victery, 1988; Staessen et al., 1994). Rats were exposed
to lead in utero and after birth until weaning by giving their mothers 100 or 500 ppm lead
(as lead acetate) in drinking-water. This regimen was then continued for the offspring after
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weaning. Male rats receiving 100 ppm developed a significant elevation of systolic blood
pressure at 3.5 months and remained hypertensive until sacrifice at 6 months; male rats
exposed in this way to 500 ppm lead and female rats exposed to 100 or 500 ppm lead
remained normotensive. At 6 months, plasma renin activity was significantly reduced in
the low-dose male group but was normal in the high-dose group (Victery et al., 1982).
In several experiments involving high doses of lead, hypertension was observed, but
the nephrotoxicity of lead may have contributed to its development. However, in other
high-dose experiments, no hypertension was seen. In contrast, the experiments conducted
with lower doses of lead consistently demonstrated a hypertensive effect (Victery, 1988).
Evis et al. (1985) reported that chronic (3 or 12 months) low-level exposure of spon-
taneously hypertensive rats to lead (25 ppm lead (as lead acetate) in the drinking-water)
enhanced the susceptibility of the heart to ischaemia-induced arrhythmias at 3 but not at
12 months. In contrast, chronic (3 months) high-level exposure of these rats to lead (250
or 1000 ppm in the drinking-water) resulted in slightly enhanced susceptibility of the
heart to arrhythmias induced by myocardial ischaemia (Evis et al., 1987).
In experiments in which rats were exposed to lead (0.25, 0.5 and 1.0% lead acetate in
the drinking-water) for 90 days, Lal et al. (1991) found that the two higher doses of lead
resulted in increased arterial blood pressure and calcium influx in atrial trabeculae and
papillary muscles. No marked pathological or histochemical changes were observed in
heart tissue except congestion (build-up of fluid) and a slightly reduced activity of succinic
dehydrogenase in the high-dose group.
(ii) Studies on the etiology of lead-induced hypertension
Chai and Webb (1988) reviewed a number of animal studies on the possible role of
lead in the etiology of hypertension. The main results indicate that the response of isolated
vascular smooth muscle to adrenergic agonists is increased in rats with lead-induced hyper-
tension, and that alterations in the regulation of intracellular calcium concentration may
contribute to the abnormal vascular function associated with lead-induced hypertension.
Boscolo and Carmignani (1988) reported that blood pressure was increased in rats
receiving 30 and 60 ppm lead (as acetate) in drinking-water for 18 months. The contractile
activity of the heart was augmented only in those animals receiving the higher dose of lead,
and the heart rate was not modified. Exposure to lead affected the renin-angiotensin system
and induced sympathetic hyperactivity by acting on central and peripheral sympathetic
junctions and by increasing the reactivity to stimulation of cardiac and vascular β-
adrenergic and dopaminergic receptors.
4.2.6 Immunological effects

In a recent review by Singh et al. (2003), the immunomodulatory role of lead on
cellular and humoral components of the immune system is discussed, with particular refe-
rence to effector cells such as B cells, T cells, natural killer (NK) cells and soluble media-
tors such as cytokines, chemokines and nitric oxide (NO).
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(a) Humans
Studies in exposed workers
Ewers et al. (1982) examined the sera of 72 male lead-exposed workers (mean age, 36.4
years; range, 16–58 years; blood lead concentration range, 18.6–85.2 µg/dL) and of 53 refe-
rence subjects (mean age, 34.8 years; range, 21–54 years; blood lead concentration range,
6.6–20.8 µg/dL) for immunoglobulins IgM, IgG and IgA and complement C3 by radial
immunodiffusion. IgA in the saliva was measured in samples from 33 workers and 40
controls. The workers had a mean duration of exposure of 10.2 years (range, 1–34 years).
Lead-exposed workers had lower serum IgM (p = 0.008) and lower salivary IgA concen-
trations (p = 0.008) than the controls. A significant negative correlation was found between
blood lead concentrations and serum concentrations of IgG and complement C3 in the lead-
exposed group.
Jaremin (1990) studied the effects on the humoral immune response of exposure to
lead in 77 men (mean age, 38.1 years) occupationally exposed to lead for 0.5–24 years.
The ambient concentration of lead in air ranged from 0.06 to 1.6 mg/m3. Three subgroups
were distinguished: Group 1 (mean blood lead concentration, 40.1 µg/dL) without traits
of lead poisoning; Group 2 (mean blood lead, 72.2 µg/dL) with biochemical features of
lead poisoning; and Group 3 (mean blood lead, 106.7 µg/dL) with clinical signs of lead
poisoning. Decreased concentrations of IgG and IgM in serum and reduction of the peri-
pheral B lymphocyte pool were observed in Groups 2 and 3.
Queiroz et al. (1994a) examined the immunological status of 33 male lead acid–battery
workers (mean age, 32.4 years; range, 18–56 years; mean exposure period, 5.8 years;
range, 0.5–20 years) compared with that of 20 non-exposed, age-matched controls, all with
blood lead concentrations < 10 µg/dL. The workers’ blood lead concentrations ranged from
12–80 µg/dL, with 21 of them having concentrations between 40–60 µg/dL. Serum con-
centrations of IgG, IgA and IgM did not differ between the groups and there was no corre-
lation between blood lead concentrations or urinary ALA concentrations and serum immu-
noglobulin levels. In addition, there was no difference between the groups in the capacity
of peripheral blood mononuclear cells (PBMCs) to respond to the mitogen phyto-
haemagglutinin (PHA), a correlate of T-cell function. There was also no correlation
between mitogenic response and blood lead concentration. These data suggest that chronic
exposure to lead does not compromise lymphocyte function.
In a further study, Queiroz et al. (1994b) investigated phagocytosis and intracellular
killing of Candida albicans and C. pseudotropicalis by neutrophils and splenic phagocytic
function in blood samples from a similar group of lead-exposed workers (see above). The
Candida assay is used to identify myeloperoxidase-deficient subjects who have neutrophils
that are unable to kill C. albicans, whereas C. pseudotropicalis can be effectively lysed.
Lysis of C. albicans, but not C. pseudotropicalis, was impaired in lead-exposed workers
with blood lead concentrations and urinary ALA concentrations below 60 µg/dL and
6 mg/L, respectively, as well as in toxic ranges. This suggests that lead exposure may result
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in myeloperoxidase deficiency. There was no difference between the groups in any of the
other parameters examined.
Ündeger et al. (1996) compared peripheral blood lymphocytes, serum immunoglobu-
lins (IgG, IgA and IgM), and C3 and C4 complement protein concentrations of 25 male
lead-exposed workers (mean age, 33 years; range, 22–55 years) employed in storage-
battery plants (mean exposure period 6 years; range, 0.5–15 years; average blood lead con-
centration, 74.8 µg/dL) with those of 25 male controls with no history of lead exposure
(mean age, 33 years; range, 22–56 years; average blood lead concentration, 16.7 µg/dL).
The numbers and the percentage of T, T-suppressor, B, and NK cells, were not different
between the groups, but the numbers of T-helper lymphocytes and the serum concen-
trations of IgG, IgM, C3 and C4 complement components were significantly lower in lead-
exposed workers compared with controls (p < 0.05). These results suggest that chronic
exposure to lead may be detrimental to the human immune system.
Pinkerton et al. (1998) evaluated a number of immune parameters in 145 lead-exposed
workers (mean age, 32.9 ± 8.6 years) with a median blood lead concentration of 39 µg/dL
(range, 15–55 µg/dL) and 84 unexposed workers (mean age, 30.1 ± 9.3 years; mean blood
lead, < 2 µg/dL; range, < 2–12 µg/dL). After adjusting for covariates, no major differences
were found between the two groups in the percentage of CD3+ cells, CD4+ T cells,
CD8+ T cells, B cells, NK cells, serum immunoglobulin levels, salivary IgA, serum C3
complement levels or lymphoproliferative responses. However, among exposed workers,
serum IgG was negatively associated with cumulative lead exposure, and the percentage
and number of CD4+/CD45RA+ cells were positively associated with cumulative lead
exposure. This study found no evidence of a marked immunotoxic effect of lead, although
subtle differences in some immunological parameters were noted.
The immunological effects of occupational exposure to lead have been studied by
measurement of lymphocyte proliferation, NK cell cytotoxicity and interferon (IFN)-γ pro-
duction in PBMCs of three groups of lead-exposed workers: drivers of three-wheelers (30,
eight of whom had blood lead > 10 µg/dL; average blood lead, 6.5 ± 4.7 µg/dL), battery
workers (34, all with blood lead > 10 µg/dL; average blood lead, 128.11 ± 104 µg/dL) and
silver-jewellery makers (20, 12 with blood lead > 10 µg/dL; average blood lead,
17.8 ± 18.5 µg/dL). Unexposed healthy volunteers (30, none with blood lead > 10 µg/dL;
range, 1.6–9.8 µg/dL) served as controls. Lymphocyte proliferation in response to PHA sti-
mulation was lower in lead-exposed individuals than in controls, but there was no corre-
lation with blood lead concentrations. NK cell cytotoxicity was not different between
groups. In contrast, the concentration of IFN-γ was significantly elevated in culture super-
natants collected from PHA-stimulated PBMCs of lead-exposed individuals, showing a
significant positive correlation with blood lead concentrations. This study demonstrates
that lead can affect the immune response of exposed workers (Mishra et al., 2003).

Swiss Webster mice that received 130 or 1300 mg/L lead as lead acetate in drinking-
water for 70 days showed decreased β-lymphocyte responsiveness and humoral antibody
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titres (Koller & Kovacic, 1974; Koller & Brauner, 1977). Similar findings were obtained
by Luster et al. (1978) in rats exposed to 25 or 50 mg/L lead acetate in drinking-water for
35–45 days.
In CBA mice exposed to lead in drinking-water (13–1300 mg/L, as lead acetate) for
10 weeks, the ability of the mitogens lipopolysaccharide and purified protein derivative to
induce lymphocyte proliferation in the kidney was inhibited, but the response to conca-
navalin A was not significantly affected (Koller et al., 1979).
To analyse the effect of lead on the immune system and to determine the ability of α-
tocopherol to reverse lead-induced immunotoxicity, Fernandez-Cabezudo et al. (2003)
treated groups of six TO mice intraperitoneally for 2 weeks with saline alone, lead acetate
alone, lead acetate plus α-tocopherol or with α-tocopherol alone. Spleens were then ana-
lysed for (i) cellular composition by flow cytometry, (ii) cellular response to B and T cell
mitogens and (iii) production of NO. The treatment with lead acetate resulted in a significant
splenomegaly associated mainly with an influx of CD11b+ myeloid cells, but these cells
exhibited no up-regulation of activation markers and did not produce NO. The mitogenic
responses of the lymphocytes were inhibited by ≥ 70% in the lead-treated group. Concurrent
treatment with lead acetate and α-tocopherol resulted in an almost complete reversal of the
lead-induced splenomegaly, but the mitogenic response in this case was approximately 50%
of that observed in saline-treated controls.
The effects of lead on the immune system of the developing embryo were assessed by
Miller et al. (1998) in 9-week-old female Fischer 344 rats exposed to lead acetate (0, 100,
250 and 500 ppm lead) in their drinking-water during breeding and pregnancy. Exposure
was discontinued at parturition and offspring received no additional lead treatment. At 13
weeks, tumour necrosis factor (TNF)-α and NO production were elevated in the female off-
spring of dams exposed to 250 ppm lead, while cell-mediated immune function was
depressed, as shown by a decrease in delayed-type hypersensitivity (DTH) reactions. IFN-γ
concentrations were lower in the offspring of the 500-ppm treatment group than in controls.
Serum IgE levels were increased in rats exposed in utero to 100 ppm lead. The lead-exposed
dams did not show chronic immune alterations. These results indicate that exposure of
pregnant females to moderate levels of lead produces chronic immune modulation in their
offspring.
Bunn et al. (2001) gave adult female Sprague-Dawley rats 500 ppm lead as lead
acetate in the drinking-water early (days 3–9) or late in gestation (days 15–21). Signifi-
cantly depressed DTH responses and elevated interleukin (IL)-10 production, higher rela-
tive monocyte numbers and increased relative thymic weights were observed when female
offspring exposed during late gestation were assessed as adults. In contrast, male off-
spring had increased IL-12 production and decreased IL-10 production, while the DTH
response, relative monocyte numbers and thymic weights were unchanged. Exposure
during early gestation decreased NO production in lead-treated male, but not female off-
spring. These results suggest that the rat embryo may be more sensitive to lead-induced
immunotoxic effects when exposed during late gestation, with the effects on DTH
function being more pronounced in females.
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Differential embryonic sensitivity to lead-induced immunotoxicity was studied by

Lee, J.-E. et al. (2001) by injection of sublethal doses of lead (5–400 µg) into fertilized
Cornell K Strain White Leghorn chicken eggs via the air sac on days 5, 7, 9 and 12 of
incubation, designated as E5, E7, E9 and E12, respectively. In 5–6-week-old chickens,
splenic lymphocyte production of IFN-γ was significantly suppressed (measured for E7
and E9 exposures only, p < 0.05) among lead-treated groups compared with controls. Pro-
duction of NO by macrophages (measured as nitrite production) was significantly
depressed (p < 0.05) after E5, E7 and E9 lead exposures but not following E12 lead expo-
sure. In contrast, DTH function was unaltered following the E5, E7 and E9 exposures, but
was significantly depressed (p < 0.05) after E12 exposure. The findings indicate that lead
exposure during different stages of embryonic development results in different immuno-
toxic outcomes in the juvenile chicken.
In turkey poults fed 100 ppm dietary lead acetate, the concentration of arachidonic acid
in macrophage phospholipids increased to twice that of controls. In-vitro production of eico-
sanoids by these macrophages was substantially increased, and this effect was most pro-
nounced following lipopolysaccharide stimulation: prostaglandin F2α increased 11-fold,
thromboxane B2 3-fold and prostaglandin E2 1.5-fold. The in-vitro phagocytic potential of
these macrophages was only half that of control macrophages. The results show that lead
influences immunological homeostasis in birds (Knowles & Donaldson, 1997).
The combined effects of a non-pathogenic immunological challenge and exposure to
lead shot were investigated in three groups of 24 Japanese quail chicks (Coturnix coturnix
japonica) that were given either one lead shot (0.05 g) or four lead shots (0.2 g) orally, at
the age of 8 days. Controls did not receive lead. As immunological challenge, a third of
each group of chicks was injected intraperitoneally with either 0.075 mL 10% chukar
partridge (Alectoris graeca) red blood cells, Newcastle disease virus, or a placebo vaccine
at 13 and 35 days of age. Lead did not affect antibody production or cell-mediated
immune response. Granulocyte numbers were significantly higher in the lead-treated
birds than in controls, and both antigen-treated groups had lower granulocyte numbers
than controls. At the 0.2-g dose, lead increased haematocrit values, lowered plasma
protein concentrations and increased granulocyte numbers in the quail (Fair & Ricklefs,
2002).
The effects of lead nitrate (0.1 µM–1 mM) on proliferative responses of B and T lym-
phocytes of mouse, rat and human origin were investigated. T cells were stimulated by
PHA or by monoclonal antibodies directed at the T cell receptor/CD3 complex, while B
cells were activated by T-independent mitogens (Staphylococcus aureus cells,
Escherichia coli lipopolysaccharide and Salmonella typhimurium mitogen for human,
mouse and rat lymphocytes, respectively). Large differences in proliferative responses
were observed for lead nitrate across species; rat lymphocytes were very sensitive to
immunomodulation by lead, whereas human cells were found to be relatively resistant
(Lang et al., 1993).
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4.2.7 Other toxic effects

(a) Lead-induced mitogenesis
Endogenous DNA damage is present in every living cell and may remain relatively
harmless — even when it is not, or very slowly, repaired — as long as the cell does not
replicate its DNA prior to mitosis. However, when cell proliferation is induced, endo-
genous DNA damage may be converted into mutations, some of which may lead to distur-
bance of cellular growth control and, ultimately, to carcinogenesis. Stimulation of cell
proliferation (mitogenesis) may, therefore, play an important role in the mode of action of
carcinogens that do not directly interact with DNA (Cohen & Ellwein, 1990). The mito-
genic activity of lead and lead compounds has been studied extensively.
Choie and Richter (1974a) showed that a single dose of 5 mg lead/kg bw, given as
lead acetate by intracardiac injection produced a 45-fold increase in DNA synthesis in the
kidney of mice, followed by a wave of mitoses. This effect was found to be preceded by
a general increase in synthesis of RNA and protein (Choie & Richter, 1974b). A single
intracardiac dose of lead acetate (40 mg lead/kg bw) induced a 25-fold increase in mitosis
of mouse hepatocytes within 5 hours. The prompt appearance of a mitotic wave and the
relatively large number of mitoses suggest that the mitotic cells were from a hepatocyte
sub-population arrested in the G2 phase (Choie & Richter, 1978).
The effects of a single intraperitoneal dose of lead acetate (0.04 mg lead/kg bw) on
the proliferation of the proximal tubule epithelium of the rat kidney were investigated by
autoradiographic analysis of [3H]thymidine incorporation, over a 3-day period after injec-
tion. Within 2 days, the labelling index increased approximately 40-fold compared with
controls. Three days after injection of lead 14.5% of the proximal tubular epithelial cells
were labelled (Choie & Richter, 1972c).
In a subsequent study, the same authors investigated the effects of chronic adminis-
tration of lead. Rats received intraperitoneal injections once a week for 6 months, at doses
of 1–7 mg lead per rat. At the end of this period, the proliferative activity of the proximal
tubular epithelium was 15 times higher in treated than in untreated rats. Epithelial hyper-
plasia was seen in some proximal tubules, with occasional atypia. The results suggest that
the renal carcinogenicity of lead (see Section 3) may be due to lead-induced stimulation
of renal cell proliferation (Choie & Richter, 1972a).
Stevenson et al. (1977) showed that a single intraperitoneal injection of 10 mg/kg bw
lead chloride into rats caused a transient twofold increase in synthesis of RNA and DNA
in the kidney after 1 and 3 days, respectively; RNA synthesis in liver and lung was also
increased twofold, but DNA synthesis was decreased in these organs.
Columbano et al. (1983, 1984) gave groups of seven male Wistar rats a single dose of
lead nitrate (100 µmol/kg bw) by intravenous injection and sacrificed them 1, 2, 3, 4 and 7
days later. The treatment caused a marked enlargement of the liver, which reached a maxi-
mum of 71% at the third day after treatment. This effect was accompanied by an increase
in total hepatic protein and DNA content, with a maximum at 3 and 4 days, respectively.
An increase in DNA synthesis, as monitored by the incorporation of [3H]labelled thy-
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midine, was observed at 24 h, reaching a maximum at 36 h after administration of lead

nitrate, with a 30-fold higher level than in control rats. DNA synthesis returned to normal
within 3 days. The lead-induced stimulation of liver-cell proliferation was reflected in a
significant increase in the number of parenchymal and non-parenchymal cells entering
mitosis, with a peak at 48 h. No histologically detectable liver-cell necrosis was seen,
which suggested that the cell proliferation induced by lead is not due to a regenerative
response. The stimulatory effect of lead on liver growth was reversible; during return to
normal size, cell death, morphologically similar to apoptosis, was observed in histological
sections of liver from animals sacrificed 4–7 days after treatment.
A series of studies by the same research group investigated the effect of different
types of cell proliferation on the development of enzyme-altered preneoplastic hepatic
foci in male Wistar rats. In the first experiment, animals were given a single intraperi-
toneal injection of N-nitrosodiethylamine (NDEA; 100 mg/kg bw). After a 2-week reco-
very period liver cell proliferation was induced by repeated doses of carbon tetrachloride
(2 mg/kg bw, by intragastric intubation), or by repeated mitogenic treatments with lead
nitrate (100 µmol/kg bw, by intravenous injection). Histologically-altered hepatocytes
were monitored as γ-glutamyltransferase-positive or adenosine triphosphatase-negative
foci. The results indicated that compensatory cell proliferation induced by carbon tetra-
chloride enhanced the growth of NDEA-initiated hepatocytes to enzyme-altered foci. On
the contrary, repeated waves of cell proliferation induced by lead nitrate did not result in
any significant number of enzyme-altered foci (Columbano et al., 1990).
In follow-up studies, the same authors determined the efficacy of different types of
cell-proliferative stimuli given during several liver tumour-promoting regimens, with
respect to the formation of enzyme-altered hepatocyte foci. Male Wistar rats were initiated
with NDEA (150 mg/kg bw, by intravenous injection). After recovery, the animals were
subjected to different promoting regimens, i.e. the resistant hepatocyte model (Solt &
Farber, 1976), the phenobarbital model (Peraino et al., 1971) and the orotic acid model
(Laurier et al., 1984). While the rats were on these regimens, they received different types
of liver cell-proliferative stimuli, either a compensatory type (two-thirds partial hepatec-
tomy or a necrogenic dose of carbon tetrachloride) or a direct hyperplastic stimulus by lead
nitrate. Initiated cells thus promoted were monitored as foci of enzyme-altered hepa-
tocytes. While compensatory cell regeneration induced by carbon tetrachloride and partial
hepatectomy stimulated the promoting ability of the regimens used, direct hyperplasia
induced by lead nitrate did not stimulate the formation of foci and/or nodules from initiated
hepatocytes. Incorporation of [3H]thymidine showed that there was no significant
difference in the extent of DNA synthesis resulting from the different proliferative stimuli,
irrespective of the promoting procedure used. These results suggest that the two types of
cell-proliferative stimuli may involve different cell growth and signal-transduction path-
ways, or they may act on different cell populations (Ledda-Columbano et al., 1992; Coni
et al., 1993a).
An enhanced susceptibility of renal tubular epithelial cells in rats to lead-induced
mitogenicity was reported at doses comparable to those used in the cancer bioassay. This
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may contribute to the carcinogenic response seen in the kidney following exposure to
lead. It is of interest to note that the liver — an organ that is not susceptible to lead-
induced carcinogenicity — showed a significantly lower mitogenic response towards lead
exposure (Calabrese & Baldwin, 1992).
To evaluate the effect of pre-exposure to mitogens on carbon tetrachloride-induced
hepatotoxicity, Calabrese et al. (1995) gave male Wistar rats a single intraperitoneal injec-
tion of carbon tetrachloride (0.3 mL/kg bw in corn oil) 48 h after either a single intravenous
injection of lead nitrate (0.33 mg/kg bw) or distilled water. The rats pre-treated with lead
nitrate showed markedly lower serum alanine aminotransferase (ALT) and aspartate amino-
transferase (AST) activities at 24, 48 and 72 h after administration of carbon tetrachloride
than rats pre-treated with distilled water. However, treatment with the anti-mitotic agent
colchicine did not alter the lead-induced protection. These findings suggest that the lead-
induced protection is not associated with the major mitogenic response of lead, despite its
strong temporal association.
Bell et al. (1993) tested lead nitrate and lead acetate for mitogenic effects in the liver of
adult male and female rainbow trout. Groups treated with a single intraperitoneal injection
of lead nitrate or lead acetate (up to 375 mg/kg bw) or a single intravenous injection of lead
nitrate (up to 5 mg/kg bw) showed no statistically significant alterations in liver:body weight
ratio. There was no change in hepatic DNA content of the fish that received the intraperi-
toneal injections. The results suggest significant interspecies differences between the mito-
genic response of the liver in rainbow trout and Wistar rats exposed to lead.
(b) Effects on regulatory proteins

The steady-state levels of c-fos and c-jun messenger RNA have been investigated in
rat liver tissue after various proliferative stimuli, i.e. compensatory cell regeneration
induced by partial hepatectomy or carbon tetrachloride, and direct hyperplasia induced by
different hepatomitogens, one of which was lead nitrate. Whereas c-fos and c-jun
expression increased soon after partial hepatectomy or administration of carbon tetra-
chloride, an increased expression of c-jun in the absence of c-fos expression was seen
during direct hyperplasia induced by lead nitrate. These results suggest that, depending on
the nature of the proliferative stimulus, an increased expression of these regulatory genes
may not be necessary for in-vivo induction of liver cell proliferation (Coni et al., 1993b).
The influence of lead on various protein factors involved in cell signalling has been
studied in relation to its neurotoxic effects. Male Long-Evans rats (aged 21 days; n = 40)
received lead acetate (50 ppm) in drinking-water for 90 days. Control animals (n = 40)
received sodium acetate. After this period, mean ± SD blood lead concentrations in the
control and lead-exposed groups were 4 ± 0.2 and 18 ± 0.2 µg/dL, respectively. Compared
with controls, the lead-exposed animals showed a significantly higher accumulation of
lead in the frontal cortex, brain stem, striatum and hippocampus, as well as a three- to
fourfold increase in the concentrations of NF-κB and activator protein 1, a four- to 10-fold
activation of c-Jun N-terminal kinase, a five- to sixfold activation of mitogen-activated
protein kinase kinase (MAPKK) and an enhanced activity of caspases in these four brain
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regions, which is consistent with apoptosis. These effects may contribute to the neuro-
toxicity of lead (Ramesh et al., 2001).
To identify genes that are upregulated in PbR11 cells (a lead-resistant variant of rat
glioma C6 cells), Li and Rossman (2001) applied the method of suppression subtractive
hybridization between mRNAs of C6 and PbR11 cells. Three upregulated genes were
identified, i.e. thrombospondin-1, heparin sulfate 6-sulfotransferase, and neuropilin-1,
which play important roles in angiogenesis and axon growth during neuronal development.
It is of interest to note that all these genes are functionally related to heparin sulfate. The
effects of short-term lead exposure (24 h, up to 600 µM) on the expression of these genes
were examined in C6 cells. While thrombospondin-1 is repressed by lead in a dose-depen-
dent manner, neuropilin-1 and heparin sulfate 6-sulfotransferase showed low constitutive
expression in C6 cells, which was not altered by exposure to lead. Since low concentrations
of lead inhibit the sulfation of heparin (Fujiwara & Kaji, 1999), the results suggest that
heparin sulfate 6-sulfotransferase may be the lead-sensitive enzyme responsible for this
inhibition. In addition to this enzyme, neuropilin-1 and thrombospondin-1 may also be
targets for lead-induced developmental neurotoxicity (Li & Rossman, 2001).
Bouton et al. (2001) used cDNA microarrays to analyse the effects of acute lead expo-
sure (10 µM lead acetate, 24 h) on large-scale gene expression patterns in immortalized rat
astrocytes. Control cells were treated with 10 µM sodium acetate. Many genes previously
reported to be differentially regulated by lead exposure were identified in this system. In
addition, novel putative targets of lead-mediated toxicity were identified, including calcium/
phospholipid binding annexins, angiogenesis-inducing thrombospondins, collagens, and
t-RNA synthetases. In a biochemical assay, the phospholipid binding activity of the protein
annexin A5 was shown to be induced by nanomolar concentrations of lead.
Lead acetate (100 nM–100 µM) stimulated DNA synthesis and cell-cycle progression
in human astrocytoma cells through selective lead-induced activation of protein kinase
Cα (PKCα) (Lu et al., 2001). In a further study, the same authors investigated the ability
of lead to activate the mitogen-activated protein kinase (MAPK) cascade. Exposure of
these astrocytoma cells to lead acetate (1–50 µM) resulted in a concentration- and time-
dependent activation of MAPK, as was evident from increased phosphorylation and
increased kinase activity. This effect was significantly reduced by specific inhibition or
down-regulation of PKCα. Lead also activated MAPK MEK1/2 kinase, an effect that was
mediated by PKCα. Addition of specific MEK inhibitors blocked lead-induced MAPK
activation and inhibited lead-induced DNA synthesis, as measured by [3H]thymidine
incorporation. The results of this study suggest that lead may act as a tumour promoter in
transformed glial cells (Lu et al., 2002).
The effect of divalent lead on protein phosphorylation in bovine adrenal chromaffin
cells and human SH SY5Y cells has been examined. Cells were incubated with inorganic
[32P] for 1 h in the presence of lead acetate (1, 5 and 10 µM) and proteins were separated
by two-dimensional polyacrylamide gel electrophoresis. Among the spots that were indi-
cative of increased protein phosphorylation, three proteins, with an apparent molecular
weight of 25 kDa and iso-electric points in the range 4.0–4.5, were immuno-identified as
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isoforms of the heat-shock protein 27 (Hsp27). The effect of lead on Hsp27 phosphory-
lation was blocked by the p38MAPK inhibitor SB203580 (1 µM) and phosphorylation of
p38MAPK was increased by lead. The results were similar for both cell types studied.
Thus lead can modulate the phosphorylation state of Hsp27 via activation of the
p38MAPK pathway. Since Hsp27 in its non-phosphorylated form confers resistance
towards oxidative stress (Rogalla et al., 1999) this effect of lead may result in a higher
vulnerability of cells to oxidative damage (Leal et al., 2002).
The zinc finger, a major structural motif involved in protein–nucleic acid interactions,
is present in the largest super-family of transcription factors (Zeng & Kagi, 1995). Zinc
(Zn2+) ions coordinate this finger-like structure through interaction with cysteine and histi-
dine residues. Factors containing such motifs are potential targets for perturbation by
divalent lead (Büsselberg, 1995; Guilarte et al., 1995; Tomsig & Suszkiw, 1996). Lead has
been shown to interfere with the DNA-binding properties of the zinc finger-containing
transcription factors Sp1 and Egr-1, both in vivo and in vitro. More recently, the inhibitory
effects of lead on the DNA-binding of the zinc finger protein transcription factor IIIA
(TFIIIA) have been demonstrated (Hanas et al., 1999). The interaction of lead with Sp1,
Egr-1, and TFIIIA shows that lead can also target other cellular proteins that contain the
zinc-finger motif and that this protein domain is a potential mediator for lead-induced
alterations in protein function. Thus by specifically targeting zinc-finger proteins, lead is
able to produce multiple responses through its action on a common site that is present in
enzymes, channels and receptors (Zawia et al., 2000).
(c) Apoptosis
(i) In-vivo studies
Apoptosis or programmed cell death is induced by various physiological or patho-
logical stimuli. Mitochondria and a specific class of proteins, the caspases, play an impor-
tant role in this process. At an early stage of apoptosis, the mitochondrial permeability
transition pore is opened, which leads to depolarization of the mitochondrion and to the
release of cytochrome C. Subsequently, caspases activate endonucleases that cleave the
genomic DNA into the high-molecular-weight fragments that are characteristic of apoptotic
cells. Although the detailed molecular mechanism of lead-induced apoptosis is still
unknown, calcium overload and the generation of ROS may be important triggers. These
and other mechanistic aspects of lead-induced apoptosis are discussed in recent reviews
(Waalkes et al., 2000; Pulido & Parrish, 2003).
Columbano et al. (1985) showed that in male Wistar rats, a single intravenous injec-
tion of lead nitrate (100 µmol/kg bw) caused liver enlargement associated with hepatic cell
proliferation. The subsequent involution of the liver hyperplasia was studied by histo-
logical examination of liver sections prepared during regression of the liver. There was no
sign of massive lytic cell necrosis, and no change in serum concentrations of glutamate
pyruvate transaminase. Apoptotic bodies were observed in the involuting liver by micros-
copy and ultrastructural examination. A marked increase in the number of apoptotic bodies
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was noted 5 days after administration of lead, when the liver was already regressing, while
very few were observed in control animals or in rats 2 days after lead injection, when the
mitotic index reached its maximum, or at 15 days, when the liver had returned to normal.
These findings suggest that the removal of excess liver tissue that follows the initial lead-
induced hyperplasia is due to apoptosis.
Fox et al. (1998) showed that exposure to lead resulted in the selective apoptotic loss
of rods and bipolar cells in the retina of rats. Lead-exposed rats were reared from dams that
received 0.02% or 0.2% lead acetate in drinking-water during lactation only. At 21 days of
age (weaning), the mean blood lead concentrations in the non-exposed rats and the two
dose-groups were 1, 19 and 59 µg/dL, respectively. During and following lead exposure,
rod/retinal cGMP phosphodiesterase expression and activity were delayed in onset and
decreased, the concentration of calcium was elevated, and mitochondrial ATP synthesis
was decreased in the infant rats.
(ii) In-vitro studies
The role of apoptosis in the effects induced by lead (lead acetate, 0.01–100 µM) and
glutamate (0.1 and 1 mM) has been studied in mouse hypothalamic GT1-7 neurons.
Loikkanen et al. (2003) found that glutamate alone had no effect on cell viability, but it
enhanced neuronal cell death induced by lead (at concentrations 1–100 µM) at 72 h. Gluta-
mate alone did not induce caspase-3-like protease activity or internucleosomal DNA frag-
mentation which are both biochemical hallmarks of apoptosis. However, combined expo-
sure to lead (10 or 100 µM) and glutamate (1 mM) resulted in more prominent caspase-3-
like protease activity than that caused by lead alone, with the highest activity measured at
48 h. Internucleosomal DNA fragmentation caused by lead (10 or 100 µM) was enhanced
by glutamate (1 mM). Immunoblotting did not reveal any changes in p53 protein concen-
tration in cells exposed to lead, glutamate, or their combination at any time point (3–72 h).
These results suggest that lead-induced neurotoxicity may be mediated partially through
p53-independent apoptosis and enhanced by glutamate.
Cultured granule cells from newborn rat cerebellum were used to study whether apop-
totic or necrotic death is the major consequence of exposure to low concentrations of lead.
At a dose of 1 µM, lead did not affect glutamate-induced neuronal necrosis but promoted
neuronal apoptosis, as characterized by cell shrinkage and chromatin condensation, inter-
nucleosomal DNA fragmentation and by dependence on de-novo synthesis of macro-
molecules. The low concentrations of lead that promoted apoptosis in this study were
within the range of blood lead concentrations reported to impair the cognitive function in
children and to alter synaptogenesis in the neonatal rat brain. These in-vitro results suggest
that the highly neurotoxic action of lead may depend on a facilitation of apoptosis (Oberto
et al., 1996).
In-vitro studies using rat retinas incubated in the presence of calcium or lead showed
increased high molecular weight DNA fragmentation and a higher number of apoptotic
rods. In addition, retinal mitochondrial ATP synthesis was decreased, mitochondrial cyto-
chrome C was released and caspase activity was increased. These effects were additive in
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the presence of physiological concentrations of both calcium and lead. These results
suggest that lead-induced rod and bipolar cell apoptosis is triggered by calcium and lead
overload and that mitochondrial alterations play a central role in this process (Fox et al.,
1998).
An in-vitro model using isolated rat retinas was used to determine the mechanisms
underlying retinal degeneration induced by calcium and/or lead. Confocal microscopy and
histological and biochemical analyses established that elevated amounts of calcium and/or
lead were concentrated around photoreceptors and produced rod-selective apoptosis. Mito-
chondrial depolarization, swelling and cytochrome C release were also seen, followed by
activation of caspase-9 and caspase-3, but not caspase-7 or caspase-8. The effects of calcium
and lead were additive. The concentrations of reduced and oxidized glutathione and pyridine
nucleotides in rods were unchanged. These results show that rod mitochondria are the target
sites for calcium and lead, and suggest that these metals bind to the internal binding site of
the mitochondrial permeability transition pore, which then opens up, initiating the cyto-
chrome C-caspase cascade of apoptosis (He et al., 2000).
The effects of extracellular lead supplementation on the cellular lead content and on cell
proliferation and survival have been studied in normal rat fibroblasts. The culture medium
contained a background level of 0.060 µM lead and the normal cellular concentration of lead
was 3.1 ± 0.1 ng/107 cells. Cells were exposed to 0.078–320 µM lead acetate, which caused
a dose-dependent inhibition of cell proliferation after 48 h, which was apparent at 0.312 µM
(p = 0.122) and became statistically significant at concentrations > 0.625 µM (p = 0.0003 at
5 µM). DNA fragmentation, a hallmark of apoptosis, increased significantly at lead concen-
trations from 2.5–10.0 µM. The occurrence of apoptosis was confirmed by flow cytometry,
which showed a sub-diploid peak at 5–20 µM lead. There was a dose-dependent accumu-
lation of cells in the G0/G1 phase, mainly compensated by a decrease in the percentage of
cells in S phase. These results demonstrate that induction of apoptosis contributes to the
lead-induced inhibition of cell proliferation in rat fibroblasts (Iavicoli et al., 2001).
De la Fuente et al. (2002) incubated human peripheral blood mononuclear cells with
increasing concentrations of cadmium, arsenic or lead, and determined apoptosis by flow
cytometry and DNA electrophoresis. Arsenic (15 µM) induced a significant level of apop-
tosis after 48 h of incubation, while cadmium had a similar effect at higher concentrations
(65 µM). In contrast, lead concentrations as high as 500 µM were non-toxic and did not
induce a significant degree of apoptosis.
(d) Effects on hepatic enzymes

Alvares et al. (1975) determined metabolizing capacities in 10 normal adults and in 10
children aged 1–8 years with two test drugs, antipyrine and phenylbutazone. Eight children
had biochemical evidence but no clinical expression of lead poisoning. Among the children,
there were no differences in their capacities to metabolize the two drugs. The mean anti-
pyrine half-life in the children, 6.63 h, was significantly lower than the mean half-life of
13.58 h in adults. The mean phenylbutazone half-lives in the children and adults, 1.68 and
3.16 days, respectively, also differed significantly. In two other children who showed
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clinical as well as biochemical manifestations of acute plumbism, antipyrine half-lives were

significantly longer than normal.
Saenger et al. (1984) investigated the possible inhibitory effects of lead on the meta-
bolism of 6β-hydroxycortisol (6βOHF, a highly polar metabolite of cortisol) by analysis
of urinary excretion of 6βOHF in 26 children with mildly to moderately elevated blood
lead concentrations (average, 44 µg/dL; range 23–60 µg/mL). The EDTA provocative test
was used to assess the size of chelatable and potentially toxic lead stores in these children.
Children with elevated urinary lead excretion after an EDTA provocative test, i.e. elevated
tissue lead stores, had markedly decreased urinary excretion of 6βOHF (178 ± 15 µg/m2
body surface area in 24 h) compared with children who had negative tests
(333 ± 40 µg/m2 in 24 h; p < 0.01); the urinary cortisol excretion in both these groups of
children was not different from that of age-matched controls. These findings suggest that
lead, at relatively low concentrations, may interfere with hepatic microsomal formation
of a cortisol metabolite.
(e) Effects on endocrine function

(i) Human studies
Gustafson et al. (1989) carried out a study in Sweden in a group of secondary lead
smelter workers and appropriately selected controls, and found a complex effect on the
endocrine system induced by moderate exposure to lead, possibly mediated by changes at
the hypothalamic–pituitary level. It should be noted that all the hormone values were
within the normal range for the Swedish population.
The possible neuroendocrine effects of lead were studied in six children with high
blood lead concentrations (range, 41–72 µg/dL) and in four children with low blood lead
(0–30 µg/dL). The first group received EDTA chelation therapy. The growth rate of these
children increased considerably after the chelation therapy, from 4.2 ± 0.9 cm/year before
treatment to 9.0 ± 0.9 cm/year after treatment (data for 2–3-year-olds, n = 5). The children
with low blood lead concentrations had a growth rate of 8.9 ± 1.0 cm/year (2–2.3-year-
olds, n = 3) (Huseman et al., 1992)
Thyroid function tests were performed in 58 petrol-pump workers or automobile
mechanics (mean age, 31.7 ± 10.6 years; mean duration of exposure to lead, 13 ± 10 years).
Their mean blood lead concentration was 51.9 ± 9.4 µg/dL, which was approximately five-
fold higher than that in 35 non-exposed control subjects. There was no difference in serum
concentrations of triiodothyronine (T3) or thyroxine (T4) between the groups. Interes-
tingly, T3 was significantly lower with longer exposure times (210 versus 29 months). The
mean thyroid-stimulating (TSH) concentrations were significantly higher (p < 0.01) in
exposed workers. This was independent of exposure time, but more pronounced in indivi-
duals with higher blood lead values. However, TSH concentrations remained within the
normal range. The results suggest that elevated blood lead concentrations could enhance
the pituitary release of TSH without having a significant effect on circulating levels of T3
and T4 (Singh et al., 2000).
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The effects of lead on the endocrine system were studied in 77 lead-smelter workers (62
active, 15 retired) compared with 26 referents. Lead concentrations were determined in
plasma (i.e. giving an index of recent exposure), in blood and in finger-bone (i.e. giving an
index of long-term exposure). In addition, the serum concentrations of pituitary hormones,
thyroid hormones and testosterone were determined. Nine exposed workers and 11 referents
were challenged with gonadotrophin-releasing hormone and thyrotrophin-releasing
hormone, followed by measurement of stimulated pituitary hormone concentrations in
serum. Median blood lead concentrations were 33.2 µg/dL in active workers, 18.6 µg/dL in
retired workers and 4.1 µg/dL in controls. Respective median bone lead concentrations were
21 µg/g, 55 µg/g and 2 µg/g. Concentrations of pituitary hormones, thyroid hormones and
testosterone were similar in the three groups. In the challenge test, stimulated follicle-stimu-
lating hormone (FSH) concentrations were significantly lower in lead workers (p = 0.014)
than in referents, indicating an effect of lead in the pituitary. The results show that moderate
exposure to lead was associated with only minor changes in male endocrine function, parti-
cularly affecting the hypothalamic–pituitary axis (Erfurth et al., 2001).
(ii) In-vitro study
To examine the in-vitro effects of lead on cytochrome P450 aromatase and on
estrogen receptor β, human ovary granulosa cells were collected from women undergoing
in-vitro fertilization and cultured with 10 µM lead acetate. Lead content in these cells
increased to 85 µg/g after 5 h of culture, 390 µg/g after 24 h and 1740 µg/g at 72 h. Aro-
matase activity was significantly reduced, as were the amounts of P450 aromatase
enzyme, estrogen receptor β and their mRNAs. Inhibition of protein synthesis by cyclo-
heximide (10 µg/mL) did not eliminate the effects of lead. The results suggest that the
effects of lead on female fertility may result, in part, from the down-regulation of P450
aromatase and estrogen receptor β gene transcription in ovarian granulosa (Taupeau et al.,
2003).
4.3 Effects on reproduction

It is generally accepted from the older literature that lead adversely affects the repro-
ductive process in both men and women. The evidence is however mostly qualitative and
dose–effect relationships have not been established.
Most of the information is based on studies among workers with high occupational
exposure to lead, while low-dose effects have been reported from occupational cohorts or
groups in the general population living in polluted areas.
Some factors make it difficult to extrapolate animal data to the human situation. These
difficulties are due mainly to differences among species in reproductive end-points and to
the level of exposure.
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4.3.1 Humans
(a) Male fertility
Studies have focused mainly on the quality of semen, endocrine function and birth
rates in occupationally-exposed subjects, and have shown that concentrations of inorganic
lead > 40 µg/dL in blood can impair male reproductive function by reducing sperm count,
volume and density, and by affecting sperm motility and morphology.
Dose–response relationships, in particular at a threshold level, are poorly understood,
and site, mode or mechanism of action are often unknown. Also, the effects were not
always the same or associated in the same way, although the prevalent effects were on
sperm count and concentration.
The classic study by Lancranjan et al. (1975) performed in Romania first provided
some evidence of impaired spermatogenesis in men with blood lead concentrations
> 40 µg/dL. The subjects were classified into four groups: ‘men with lead poisoning’
(n = 23), men with ‘moderate’ (n = 42), ‘slight’ (n = 35) or ‘physiological’ (n = 50) lead
absorption. The major finding of this study was the suggestion of a dose–response relation-
ship for the decrease in sperm count (hypospermia) and sperm motility (asthenospermia)
and the increase in abnormal sperm morphology (teratospermia) with increasing lead
absorption. The strengths of this study were the use of a standardized questionnaire to
collect the data, the relative comparability of controls and the relatively large number of
subjects involved. On the other hand, assessment of the dose–response relationship was
limited by the overlap between exposure groups, by the relatively high blood lead concen-
trations in control subjects, by the inclusion of coitus interruptus as a means to collect
semen and by lack of information on sperm counts.
Similar findings were reported by Lerda (1992) in Argentina, although no dose–
response relationship was found. The result should be noted, mainly because selection of
subjects and characterization of exposure to lead were well conducted, as were the collec-
tion and analysis of the semen and the statistical analyses of the results.
The cross-sectional study by Alexander et al. (1996) showed that blood lead concen-
trations > 40 µg/dL may affect spermatogenesis by reducing sperm concentration and
total sperm count. No association was found between exposure to lead and sperm
morphology or motility, or serum concentration of reproductive hormones. The strengths
of the study were mainly the size and careful selection of the study population,
availability of historical data of lead exposure, the control for all the relevant confounding
factors (e.g. age, smoking, a1cohol consumption, period of abstinence before semen
collection, blood concentrations of other metals such as cadmium and zinc), the statistical
analysis, and the validity of the semen analysis.
A study by Rodamilans et al. (1988) in Spain showed no clear correlation between
blood lead concentrations and endocrine variables. Smelter workers were divided into
three groups according to duration of exposure: < 1 year (group 1, n = 5), 1–5 years
(group 2, n = 8) and > 5 years (group 3, n = 10). In group 3, serum testosterone was signi-
ficantly lower, steroid binding globulin (SBG) was higher and there was a clear reduction
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in the free testosterone index (testosterone/SBG). In group 2, there was a significantly

lower free testosterone index but there were no clear differences between testosterone and
SBG concentrations compared to the controls. There was an increase in serum luteinizing
hormone (LH) concentration in the first group, but this did not persist with longer dura-
tions of lead exposure. The authors suggested an initial testicular toxicity followed by a
dysfunction in the hypothalamus or the pituitary gland, which disrupts the hypo-
thalamic–pituitary feedback mechanism associated with prolonged exposure (Rodamilans
et al., 1988).
A study by McGregor and Mason (1990) suggested that lead may cause subclinical
primary toxic damage to the seminiferous tubules in the testis at blood lead concentrations
> 47 µg/dL. In this study, testosterone concentrations were normal, in contrast to the
findings of Rodamilans et al. (1988).
Ng et al. (1991) carried out a study in Singapore and found that concentrations of LH
and FSH showed a moderate increase in relation to blood lead concentrations in the range
of 10–40 µg/dL, thereafter reaching a plateau or declining. An increase in concentrations
of LH and FSH, with normal testosterone, was noted in subjects with < 10 years of expo-
sure to lead whereas men exposed for 10 or more years had normal FSH and LH and low
testosterone concentrations. The main conclusion was that moderate exposure to lead
resulted in small changes in endocrine function in a dose-related manner, reflecting
primary and secondary effects of lead on the testes and the hypothalamus–pituitary axis.
Gennart et al. (1992) assessed the thyroid, testes, kidney and autonomic nervous
system function in 98 battery workers in Belgium (mean blood lead concentration,
51 µg/dL; range, 40–75 µg/dL) and found no abnormalities.
Several of the studies described above (Lancrajan et al., 1975; Lerda, 1992;
Alexander et al., 1996) and that of Assennato et al. (1987) reported effects on testicular
function in groups of men with mean blood lead concentrations above 40–50 µg/dL.
These results are consistent with a likely threshold of about 45–55 µg/dL (Bonde et al.,
2000). In contrast, the findings of a study of semen (Robins et al., 1997) in 97 men
employed in a South African lead–acid battery plant, with blood lead concentrations
ranging from 28–93 µg/dL, did not support an effect of lead on sperm concentration and
total sperm count. However, the authors noted that their results should be interpreted with
caution because of the relatively high range of current blood lead concentrations, the high
prevalence of abnormalities in semen quality and the lack of a control population.
In a cross-sectional survey (Telisman et al., 2000) of workers exposed to lead and
non-occupationally exposed controls, a significant negative association was found
between sperm count and mean blood lead concentrations in six subgroups stratified by
blood lead concentration. The mean blood lead concentrations in the six subgroups ranged
from 5–35 µg/dL. In contrast, in a longitudinal study (Viskum et al., 1999) of battery
workers in Denmark, no improvement was found in sperm concentration or in the propor-
tion of morphological abnormalities with a decline in blood lead concentration from about
40 to 20 µg/dL.
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Bonde et al. (2002) undertook a cross-sectional survey on some fertility parameters

of 503 workers employed by 10 companies in Belgium, Italy and the United Kingdom, as
part of the ASCLEPIOS project. Volume of semen and concentration of sperm were deter-
mined in a fresh semen sample according to an agreed protocol of quality assurance.
Measurement of dose indicators in blood and seminal fluid and its fractions and the sperm
chromatin structure assay were all performed by centralized laboratories. Abnormal chro-
matin structure of the spermatozoa was analysed by flow cytometric measurement of red
(denaturated single stranded DNA) and green (native DNA) fluorescence in sperm cells
stained with acridine, and expressed by the ratio of red to total (red + green) fluorescence
(Garner et al., 1986). Extraneous determinants including centre, period of sexual absti-
nence and age were taken into account in the statistical analysis. If appropriate, possible
thresholds were examined by iterative threshold slope linear regression. The mean blood
lead concentration was 31.0 µg/dL (range, 4.6–64.5 µg/dL) in 362 workers exposed to
lead and 4.4 µg/dL (range, below the detection limit to 19.8 µg/dL) in 141 workers not
exposed to lead. The median sperm concentration was reduced by 49% in men with blood
lead concentrations > 50 µg/dL. The findings were consistent across the three centres and
the sample size was larger than in earlier studies thus strengthening the findings.
However, in this study and in previous ones, the authors noted that the low participation
rate at two of the three sites is a major limitation conferring risk of selection bias as men
who perceived themselves to be less fertile may have been more motivated to take part
(Bonde et al., 1996; Larsen et al., 1998; Bonde et al., 2002).
The concentration of inorganic lead in blood may not reflect the concentration in the
target organs and therefore lead measured in seminal fluid and its fractions might be better
correlated with testicular lead and histopathological alterations. Apostoli et al. (1999) and
Bonde et al. (2002) found a high content of lead within spermatozoa and a low concen-
tration in seminal fluid, indicating that lead is either taken up by spermatozoa or is incor-
porated into the sperm cells during spermatogenesis. The analyses based on lead in semen
largely corroborated the findings based on analysis of lead concentration in blood, but
men with the highest concentration of lead in spermatozoa also had higher mean αT, and
a higher proportion of sperm cells outside the main population, indicating alterations of
the sperm chromatin structure (Bonde et al., 2002).
Zinc contributes to sperm chromatin stability and binds to protamine 2. It has recently
been shown that lead competes with zinc and binds human protamine 2 (HP2) causing
conformational changes in the protein (Quintanilla-Vega et al., 2000). This decreases the
extent of HP2-DNA binding, which probably results in alterations in sperm chromatin
condensation. Alteration of sperm chromatin structure by increased in-situ denaturation is
strongly correlated with the presence of sperm DNA strand breaks (Aravindan et al.,
1997) and is associated with reduced fecundity in humans (Spanò et al., 2000).
There appears to be a direct negative correlation between seminal plasma lead con-
centrations and in-vitro fertilization rates (Benoff et al., 2000, 2003). Lead concentrations
are also negatively correlated with standard semen parameters (sperm count, motility and
morphology) and sperm function biomarkers (mannose receptor expression and mannose-
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stimulated acrosome reaction), and positively correlated with premature acrosome

breakdown.
Positive relationships between blood lead concentrations and seminal plasma lead or
sperm lead concentrations have been reported after both occupational exposures (Aribarg
& Shukcharoen, 1996; Telisman et al., 2000; Bonde et al., 2002) and environmental expo-
sures (Telisman et al., 2000) to lead.
Another way to verify the possible effect of lead on male fertility is through retrospec-
tive evaluation of time to pregnancy. A French cohort study (Coste et al., 1991) of 229
workers exposed to lead (mean blood lead concentration, 46.3 µg/dL) compared with 125
unexposed subjects did not provide clear evidence of adverse effects of occupational expo-
sure to lead on male fertility as studied by recording live births.
Apostoli et al. (2000) found decreased fertility among men with blood lead concentra-
tions of at least 40 µg/dL, but this was statistically significant only in a subgroup analysis
restricted to subjects with just one child. Fertility was not reduced in men with blood lead
concentrations in the range 30–40 µg/dL.
Sallmén et al. (2000) conducted a retrospective study on time to pregnancy among the
wives of men who had been monitored for lead to assess whether paternal occupational
exposure to inorganic lead was associated with decreased fertility. Lead exposure was
assessed by blood measurements and by questionnaires. The final study population
consisted of 502 couples who did not use contraception at the beginning of the pregnancy.
The fecundability density ratios, adjusted for potential confounders, were 0.92 (95% CI,
0.73–1.16), 0.89 (95% CI, 0.66–1.20), 0.58 (95% CI, 0.33–0.96) and 0.83 (95% CI,
0.50–1.32) for blood lead categories in men of 0.5–0.9, 1.0–1.4, 1.5–1.8 and ≥ 1.9 µmol/L,
respectively. This study provided limited support for the hypothesis that paternal exposure
to lead is associated with decreased fertility.
In a study by Joffe et al. (2003) as part of the ASCLEPIOS project, a total of 1104
subjects in four European countries took part, of whom 638 were occupationally exposed to
lead at the relevant time. Blood lead concentrations were mainly < 50 µg/dL. No consistent
association between time to pregnancy and lead exposure was found in any of the exposure
models. It may be concluded from this multicentric survey that there are no detectable
effects on male fertility at the levels of lead exposure currently measured in European
worksites.
Lead may be determined in Leydig cells, thus in possible relation with testosterone
levels in serum. Lead may also be detected in germ cells, demonstrating that it passes
through the blood–testis barrier, which is functionally very similar to the blood–brain
barrier, and affects the germ cells at different degrees of differentiation (spermatogonia,
primary spermatocytes, spermatids or spermatozoa). In this regard, it is still an open
question whether lead in cells or in fluids is a result of a breakdown of the blood–testis
barrier or whether lead normally passes this barrier.
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(b) Effects of lead during pregnancy

Wibberley et al. (1977) studied placental lead concentrations in a series of births in
Birmingham, United Kingdom, classified by stillbirth, neonatal death or survival beyond
one week. Average results showed higher lead concentrations in those neonates who failed
to survive both birth and the neonatal period. There was no association of placental lead
with impaired birth weight among survivors.
Placental transfer of lead and its effects on newborns were examined by Clark (1977).
Following delivery, blood from 122 mothers and cord blood from their infants were taken
to measure lead, haemoglobin, packed cell volume and mean corpuscular haemoglobin
concentration. All were resident in Kasanda, Zambia, a lead mine and smelter town. The
mean blood lead concentrations were 41.2 µg/dL and 37 µg/dL for maternal blood and
cord blood, respectively, with a significant correlation (r = 0.77, p < 0.001). The increased
lead transfer, however, did not appear to affect adversely birth weight or red cell values
of the newborn.
Nordström et al. (1979a) investigated the frequencies of congenital malformations in
the offspring of female employees at a smelter in northern Sweden and in a reference
population near the smelter. In the population of the area, no significant variation in the
total frequency of malformations or in any particular group of malformations was found.
Among the women who worked at the smelters, the risk for malformations was about two
times as high and the risk for multiple malformations about four times as high as in the
reference population.
In a study of the relationship between prenatal lead exposure and congenital ano-
malies, Needleman et al. (1984) measured lead concentration in umbilical cord blood
from 5183 consecutive deliveries of at least 20 weeks’ gestation. The demographic and
socioeconomic variables of the mothers, including exposure to lead, which were shown
on univariate analysis to be associated with increased risk for congenital anomalies, were
evaluated in a stepwise logistic-regression model with malformation as the outcome.
Coffee, alcohol, tobacco and marijuana use, which were associated with lead concen-
trations, but not with risk for malformation in offspring, were also taken into account. The
model was reduced in steps by eliminating the variables with the highest p-value, until the
most parsimonious model was created. The relative risk for anomalies associated with
lead was then calculated while holding other covariates constant. Lead was found to be
associated, in a dose-related fashion, with an increased risk for minor anomalies, but the
risk for major malformations was not increased.
Bellinger et al. (1991) evaluated the relationship between prenatal low-level lead
exposure and fetal growth in 4354 pregnancies in which the mean lead concentration in
umbilical cord blood was 7.0 µg/dL (SD, 3.3; 10th percentile, 3.4 µg/dL; 90th percentile,
10.9 µg/dL). Higher cord blood lead concentrations were significantly associated with
gestations of slightly longer duration. Comparing infants with cord blood lead concen-
trations ≥ 15 µg/dL with those with < 5 µg/dL, adjusted risk ratios of 1.5–2.5 were
observed for low birth weight (< 2500 g) and for fetal growth indices that express birth
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weight as a function of length of gestation (e.g. small for gestational age, intrauterine
growth retardation). The 95% confidence intervals of these risk ratios included 1, but pre-
cluded rejection of the null hypothesis of no association. The authors concluded that the
risk for adverse fetal growth is not increased at cord blood lead concentrations < 15 µg/dL
but that modest increases in risk may be associated with concentrations ≥ 15 µg/dL.
Factor-Litvak et al. (1991) tested the hypothesis that exposure to lead during pregnancy
is associated with reduced intrauterine growth and an increase in preterm delivery. The
sample comprised women, recruited at mid-pregnancy, residing in Titova Mitrovica, a lead
smelter town, or in Pristina, a non-exposed town 25 miles away, in the province of Kosovo,
Serbia and Montenegro. Mean blood lead concentrations at mid-pregnancy were
0.92 µmol/L (± 0.38, n = 401) in women in the exposed town and 0.26 µmol/L (± 0.09,
n = 506) in women in the comparison town. No differences were found between towns for
either birth weight or length of gestation: mean birth weight was 3308 (± 566) g in Titova
Mitrovica and 3361 (± 525) g in Pristina; mean length of gestation was 274 (± 18.8) days
in Titova Mitrovica and 275 (± 15.6) days in Pristina. After adjustment for the effects of
potential confounders, no significant relationships were found between maternal blood lead
measured at mid-pregnancy, at delivery or in the umbilical cord, and either birth weight or
length of gestation or preterm delivery (< 37 weeks). The authors concluded that exposure
to environmental lead does not impair fetal growth or influence length of gestation.
The relation between paternal occupational exposure to lead and low birth weight/pre-
maturity was also examined in a retrospective cohort study (Lin et al., 1998). Birth weight
and gestational age, obtained from New York State birth certificates (1981–92), were
compared for children born to lead-exposed and non-exposed workers. The exposed group
(n = 4256) consisted of births to male workers of reproductive age reported to the New
York State Heavy Metals Registry. The control group (n = 2259) consisted of the offspring
of a random sample of male bus drivers, frequency matched by age and residence. There
were no statistically-significant differences in birth weight or gestational age between the
exposed and the control groups. However, workers who had elevated blood lead concen-
trations for more than 5 years had a higher risk of fathering a child of low birth weight (risk
ratio, 3.40; 95% CI, 1.39–8.35) or who was premature (risk ratio, 3.03; 95% CI, 1.35–6.77)
than did controls after adjustment for paternal age, low maternal education, race, residence,
gravidity, maternal spontaneous abortion history, perinatal complications, adequacy of pre-
natal care and sex of the infant.
The effect of maternal bone lead on length and head circumference of newborns and
infants aged one month was evaluated by Hernandez-Avila et al. (2002). Birth length of
newborns was found to decrease as tibia lead concentrations increased. Patella lead was
positively and significantly related to the risk of a low head circumference score; this
score remained unaffected by inclusion of birth weight.
(c) Effects of lead on abortion

As a whole, the literature on this topic provides consistent evidence in the form both
of case series and epidemiological studies, that the risk for spontaneous abortion (defined
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as a pregnancy loss occurring before the 20th week of gestation, but after the stage of
unrecognized, subclinical loss) is increased by maternal exposure to high concentrations
of lead. The data on male exposures and spontaneous abortions in their partners are more
sparse and less consistent.
Torelli (1930) provided data on pregnancies in Milan, where the printing industry was
a source of lead exposure. The risk for spontaneous abortion was reported to be 4.5% in
the general population, 14% in partners of men employed in the printing industry and
24% in women who themselves were so employed; these data yield relative risks of 3.1
and 5.3. The infant mortality was more than doubled among exposed women as compared
with the rate in all of Italy: 320 versus 150 per 1000 livebirths (cited by Hertz-Picciotto,
2000).
Nordström et al. (1978a) reported an increased frequency of spontaneous abortion in
women living close to a smelter in northern Sweden. In a later report, Nordström et al.
(1979b) described the responses to a questionnaire completed by 511/662 women who had
worked at the smelter and were born in 1930–59. Spontaneous abortion rates were high in
those pregnancies in which the mother was employed during the pregnancy (13.9%) or had
been employed before and was living close to the smelter (17%); the rate was higher
(19.4%) when the father worked at the smelter. It should be noted that the smelter produced
copper and lead in addition to a number of other metallurgical and chemical products
(Nordström et al., 1978a) and that the effects reported may not necessarily be attributable
exclusively to lead.
A study of pregnancies in the centre and surrounding areas of the lead smelter town
of Port Pirie, Australia, found that incidence of miscarriages (22/23) and stillbirths (10/11)
was higher in women living close to the smelter (McMichael et al., 1986). Two studies
found a decreased length of gestation in women whose blood lead concentrations were
> 0.58 µmol/L (12 µg/dL) (Dietrich et al., 1986) or 0.68 µmol/L (14 µg/dL) (McMichael
et al., 1986). However Needleman et al. (1984), Bellinger et al., (1984) and Factor-Litvak
et al. (1991) did not find differences in gestational length of pregnancy in women with
higher blood lead concentrations.
Murphy et al. (1990) analysed the rates of spontaneous abortion among women living
in the vicinity of a lead smelter with those of women living in a town where exposure to
lead was low. The data were taken from the obstetric histories of both groups of women
when they sought prenatal care for a subsequent pregnancy. A total of 639 women (304
exposed, 335 unexposed) had at least one previous pregnancy and had lived at the same
address since their first pregnancy. The geometric mean blood lead concentrations at the
time of the interviews were 0.77 µmol/L [16 µg/dL] in women in the exposed town and
0.25 µmol/L [5 µg/dL] in women in the unexposed town. The rates of spontaneous abor-
tions in first pregnancies were similar: 16.4% of women in the exposed town and 14.0%
in the unexposed town . The adjusted odds ratio relating town of residence to spontaneous
abortion was 1.1 (95% CI, 0.9–1.4).
A case–referent study conducted by Lindbohm et al (1991) focused on whether occu-
pational exposure of men to inorganic lead is related to their partners’ spontaneous
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abortion. The cases (213 spontaneous abortions) and referents (300 births) were identified
from medical registers. Lead exposure was assessed by blood lead measurements and data
obtained from a questionnaire. The results did not show a statistically-significant relation-
ship between spontaneous abortion and paternal exposure to lead among the study subjects.
In a comparison of placental lead concentrations in 71 normal deliveries and 18 births
with adverse outcomes (premature birth or premature rupture of membranes) significantly
higher placental lead concentrations were found in the adverse birth groups
(153.9 ± 71.7 ng/g dry weight compared with the placentas from normal deliveries
(103.2 ± 49.5 ng/g dry weight) (Falcón et al., 2003).
Hu (1991) provided data from Boston, MA, USA, on the pregnancies of women who
themselves experienced lead poisoning during their childhood in the years 1930–44. The
rationale for this study lay in the fact that lead is stored in bone tissue for decades, and the
possibility that demineralization of the skeleton takes place during pregnancy. Thirty-five
cases of childhood plumbism were identified from hospital records. These women were
traced in the 1980s, and interviewed regarding their pregnancy histories. Matched control
subjects were included for 22 of the 35 women with childhood plumbism. The proportion
of pregnancies reported to have ended in spontaneous abortion or stillbirth was 22%
(11/51) among cases with matched plumbism, 29% (8/28) among the cases with non-
matched plumbism and 13% (6/48) among matched control subjects. The matched-pairs
odds ratio was 1.6 (95% CI, 0.6–4.0) reflecting the small size of the study. Inclusion of
unmatched plumbism subjects did not alter the results.
In conclusion, the studies reviewed here show that the effects of lead on fertility and
abortion were not always the same either morphologically or quantitatively, neither did
they always vary in the same direction. Those on sperm count and concentration were the
most frequent in showing effects of lead. It is not yet clear whether the mechanism is a
direct effect of lead on reproductive organs or on the endocrine control of reproduction, or
both. The mechanism for inducing pregnancy loss is also not clear. Besides preconcep-
tional chromosomal damage to the sperm or a direct teratogenic effect on the fetus, inter-
ference with the maternal–fetal hormonal environment is possible, as endocrine-disrupting
activity associated with lead has been observed in rodents, primates, and humans. Vascular
effects on the placenta are also plausible, given the literature on lead and hypertension
(Hertz-Picciotto & Croft, 1993). Developmental toxicity to the fetus is also possible.
(d) Effects on stature and growth

The effects of low to moderate prenatal and postnatal lead exposure on children’s
growth in stature were studied by Shukla et al. (1989, 1991) in 235 subjects assessed
every 3 months for lead exposure (blood lead concentration) and stature (recumbent
length) up to 33 months of age. Fetal lead exposure was indexed by maternal blood lead
concentration during pregnancy. Adverse effects of lead on growth during the first year of
life were observed. Mean blood lead concentrations during the second and third years of
life were negatively associated with attained height at 33 months of age (p = 0.002), but
only among those children who had mean blood lead concentrations above the cohort
P 337-378 DEF.qxp 09/08/2006 13:47 Page 345
median (> 10.77 µg/dL) during the 3–15-month period. The results suggest that the
effects of lead exposure (in utero and during the first year of life) are transient provided
that subsequent exposure to lead is not excessive. An average blood lead concentration of
25 µg/dL or higher during the second and third year of life was detrimental to the child’s
attained stature at 33 months of age. Approximately 15% of this cohort experienced these
levels of lead exposure.
The relationship between blood lead concentration and stature was evaluated for a
group of 1454 Mexican-American children (age, 5–12 years), from data sets of the
1982–84 Hispanic Health and Nutrition Examination Survey. An inverse relationship was
found between blood lead concentration in the range 0.14–1.92 µmol/L [3–40 µg/dL] and
stature, which suggests that growth retardation may be associated even with moderate
concentrations of blood lead (Frisancho & Ryan, 1991).
Concentrations of lead, zinc and lysozyme, a factor of non-specific immunity, were
determined in blood and placental tissue from 50 pregnant women with intrauterine fetal
growth retardation (IUGR) and from 27 pregnant women in a control group. Statistically-
significant differences in zinc and lead concentrations were found between the groups,
with the IUGR group having lower zinc and higher lead concentrations. A significant nega-
tive correlation between zinc and lead concentrations was observed, as well as a statis-
tically significant relationship between placental lead concentrations and the age of the
pregnant women. Greater age was associated with higher lead concentrations in placental
tissue, whereas zinc concentrations decreased. Higher lysozyme concentrations were
found in placental tissues of women in the IUGR group (Richter et al., 1999).
The possible role of environmental pollutants in the incidence of IUGR in India was
investigated by measurement of lead and zinc concentrations in blood collected at parturi-
tion from mothers and neonates. Both maternal and cord blood lead concentrations were
significantly higher in IUGR cases than in normal cases (p < 0.05). The mean concen-
tration of zinc was also higher in maternal blood of IUGR cases. The mean cord blood lead
concentration was > 10 µg/dL in 54% of newborns. A good correlation (r = 0.53; p < 0.01)
between maternal and cord blood lead concentrations confirmed the transfer of lead from
mother to fetus. There was a weak but significant inverse relationship between cord blood
lead concentrations and birth weight of newborns (r = –0.23, p < 0.05) (Srivastava et al.,
2001).
4.3.2 Animal studies

(a) Male fertility
Many studies in experimental animals have generated results that are consistent with
direct toxic effects of lead on seminiferous tubules or Leydig cells, but one study reported
simultaneous impairment of spermatogenesis and reduced pituitary content of FSH,
which points to a primary action at the extratesticular level.
The male reproductive organs of Sprague-Dawley rats and NMRI mice are apparently
rather resistant to the toxicity of inorganic lead. However, several studies of other rat
P 337-378 DEF.qxp 09/08/2006 13:47 Page 346
strains and other rodent species indicate fairly consistently that exposures to lead that result
in blood lead concentrations > 30–40 µg/dL for at least 30 days are associated with impair-
ment of spermatogenesis and reduced concentrations of circulating androgens. The great
variations in hormone concentrations, whether they are circadian, age-related, seasonal,
individual or even strain-related make it difficult to draw valid conclusions on hormonal
effects (Lee et al., 1975; Ellis & Desjardins, 1982; Heywood & James, 1985).
Age and sexual maturity of the animal may have a bearing on the results in several
ways. It has been shown that prepubertal rats are less sensitive to the toxic effects of lead
on testosterone and sperm production than animals exposed to lead after puberty (Sokol
& Berman, 1991).
Momcilovic and Kostial (1974) found marked differences in lead distribution in
suckling rats compared with adult rats. Age-related changes should also be considered:
Heywood and James (1985) showed that up to 7% of rats maintained for 52 weeks showed
spermatogenesis not proceeding beyond the spermatocyte stage. At 104 weeks, 20% of rats
had developed atrophy of the seminiferous epithelium.
Of the 21 experimental studies reviewed by Apostoli et al (1998), 15 mentioned the
age of the animals at the start of the experiment. However, animals were sexually mature
(i.e. 90 days old) at the start of the experiment in only two studies. In four other studies,
age at start was described only as ‘mature’. Descriptions of subchronic effects should be
interpreted with caution when the test period is shorter than 77 days for rats, 53 days for
mice, 64 days for rabbits and 57 days for monkeys. Taking this into account, about half of
the animal studies reviewed by Apostoli et al. (1998) can be considered to assess only
acute effects.
Schroeder and Mitchener (1971) have shown that mice are more vulnerable to the
toxic effects of lead on reproduction than rats. Exposure of sexually-mature animals to
lead caused varying degrees of impaired spermatogenesis (Chowdhury et al., 1984;
Barratt et al., 1989), premature acrosome reaction and reduction of fertility (Johansson,
1989) or hormonal disorders (Sokol & Berman, 1991) at widely varying (30–187 µg/dL)
blood lead concentrations (Apostoli et al., 1998).
Ivanova-Cemišanska et al. (1980) reported changes in levels of enzymatic activity
and ATP in testicular homogenate of rats given 0.2 and 20 mg/kg bw solutions of lead
acetate, over a 4-month period.
Chowdhury et al. (1984) found testicular atrophy and cellular degeneration in rats
with blood lead concentrations > 70 µg/dL, but not in rats with blood lead concentrations
of 54.0 µg/dL.
A comprehensive study in rabbits (Moorman et al., 1998) estimated a threshold for
effects on total sperm count of 23.7 µg/dL lead in blood.
Groups of cynomolgus monkeys with mean blood lead concentrations of 10 ± 3 µg/dL
(n = 4) and 56 ± 49 µg/dL (n = 7) after treatment with lead acetate from birth to the age of
15–20 years had increased abnormal sperm chromatin as expressed by the αT distribution
(shift from green to red fluorescence) with a larger SD αT when compared with a reference
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group with blood lead < 1 µg/dL. However, there were no effects of treatment on para-
meters of semen quality such as sperm count, viability, motility (Foster et al., 1996).
The results of studies on the lead content of testicular or seminal fluid are inconclusive
(Hilderbrand et al., 1973; Der et al., 1976; Chowhury et al., 1984; Sokol et al., 1985;
Saxena et al., 1987; Boscolo et al., 1988; Barratt et al., 1989; Saxena et al., 1990; Sokol &
Berman, 1991; Nathan et al., 1992; Pinon-Lataillade et al., 1993; Thoreux-Manlay et al.,
1995). Although a relation between testicular lead content and histopathological changes
has been noted, the lack of uniformity regarding age of the animals, duration of exposure,
assessment of internal doses, identification of reproductive end-points, and methods to
measure effect indicators, makes it impossible to draw any clear conclusions on mecha-
nisms and dose–response relationships.
(b) Effects on pregnancy, fertility and growth and development in

animals
Many early studies identified effects on spermatogenesis in rats exposed to lead and
also indicated that high exposure of dams to lead can reduce numbers and size of offspring.
There may also be paternally-transmitted effects resulting in reductions of litter size,
weights of offspring and survival rate (for references, see WHO, 1995). Other important
topics are the exposure periods, the sites of action, and growth and development.
Lead (as lead acetate) was administered to mouse dams via the drinking-water (at
10 mg/mL) during three periods: (1) when target mice were born (postnatal); (2) after con-
ception of target mice (gestational); or (3) during the mothers’ own pre-weaning age (pre-
mating). These experiments showed variable effects of lead exposure on brain weight,
DNA per brain and protein per brain (Epstein et al., 1999).
Exposure of female rats to lead produced irregular estrous cycles at blood lead
concentrations of 30 µg/dL and morphological changes in ovaries including follicular
cysts and reduction in numbers of corpora lutea at blood lead concentrations of 53 µg/dL
(Hilderbrand et al., 1973).
Grant et al. (1980) reported delayed vaginal opening in rats whose mothers were
given 25, 50 and 250 ppm lead in drinking-water. The vaginal opening delays in the
25-ppm group occurred in the absence of any growth retardation or other developmental
delays and were associated with median blood lead concentrations of 18–29 µg/dL.
Testicular homogenates from 2–3-week-old male offspring of lead-exposed female
rats (mean blood lead concentration in the pups, 6.3 µg/dL) showed decreased ability to
metabolize progesterone (Wiebe et al., 1982).
In a study by McGivern et al. (1991), Sprague-Dawley dams were given lead acetate
(0.1%) in drinking-water from day 14 of gestation until parturition to determine whether
exposure of the fetus to elevated lead concentrations during a period of rapid differen-
tiation of the hypothalamic–pituitary–gonadal (HPG) axis would disrupt HPG function in
adulthood. Female offspring from lead-treated dams were found to have a significant
delay in the day of vaginal opening and prolonged and irregular periods of diestrous
accompanied by an absence of observable corpora lutea at 83 days of age. Male offspring
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from these dams were found to have decreased sperm counts at 70 and 165 days of age,
exhibit enlarged prostates at 165 days and ∼35% reduction in the volume of the sexually
dimorphic nucleus of the preoptic area of the hypothalamus. Pulsatile release of gonado-
tropins, measured in castrated male and female adult animals, revealed irregular release
patterns of both FSH and LH in some lead-treated animals which were not observed in
controls. The overall pattern of data suggested to the authors that multiple functional
aspects of the HPG axis can be affected by exposure to lead during a period of gestation
when structures related to the HPG axis are undergoing rapid proliferation.
The reproductive toxicity and growth effects of lead exposure in developing rats have
also been assessed by Ronis et al. (1996). Lead exposure was initiated in utero, prepuber-
tally, or postpubertally. In male animals, weights of testis and all secondary sex organs were
significantly decreased in animals exposed prepubertally. Serum testosterone levels were
significantly suppressed, most severely in animals exposed in utero. In female animals
exposed prepubertally, delayed vaginal opening and disrupted estrous cycling was
observed in 50% of the animals. The group treated in utero had suppression of circulating
estradiol accompanied by significant decreases in both circulating LH concentrations and
pituitary LH protein concentration, but no effect on LHβ mRNA was observed. These
findings suggested to the authors a dual site of action for lead: (a) at the level of the hypo-
thalamic pituitary unit; and (b) at the level of gonadal steroid biosynthesis. Prepubertal
growth in both sexes was suppressed by 25% in the group exposed in utero. The effects of
lead on growth are possibly due to a delay in the development of sex-specific pituitary
growth hormone secretion rather than a persistent developmental defect.
Studies on female monkeys have shown that pre- and/or postnatal exposure to lead can
affect pubertal progression and hypothalamic–pituitary–ovarian–uterine functions. Chronic
exposure to lead of nulliparous female monkeys, resulting in blood concentrations of
approximately 35 µg/dL, induced subclinical suppression of circulating LH, FSH and
estradiol without producing overt effects on general health and menstrual function (Foster,
1992).
4.4 Genetic and related effects

4.4.1 Human studies (see Table 91)
In human genotoxicity studies, co-exposures to lead and other compounds could not
be discounted and thus it is difficult to attribute genetic and other related effects to lead
alone. A general description of lead concentrations in air and blood in various exposure
situations is given in Section 1.
The single-cell gel electrophoresis assay (Comet assay) provides data that are indicative
of DNA damage; either direct strand breaks or alkali-labile sites. Five studies of DNA
damage using the Comet assay on blood leukocytes in lead-exposed workers gave positive
results. In workers in a secondary lead smelter in India with blood lead concentrations of
24.8 ± 14.7 µg/dL, there was a significant increase in the percentage of leukocytes showing
P 337-378 DEF.qxp
Table 91. Genetic and related effects in humans occupationally or non-occupationally exposed to lead
09/08/2006
Subjects No. of exposed/controls End-point Air lead Mean blood lead Reference
Resulta concentration concentration
(µg/m3) (µg/dL)
Occupationally exposed
DNA damage (SCGE (Comet) assay)
13:47
Secondary lead smelter 45 exposed % of cells with tail length increased, 4.2 24.8 ± 14.7 Danadevi et al.
workers, Hyderabad, India 44.6 ± 8.5 (p < 0.05); (2003)
36 controls 21.1 ± 11.7 2.75 ± 1.52
Page 349
Secondary lead smelter 46 exposed Significant increase in tail length, – Range of medians in Ye et al.
workers, China dose-related (p < 0.05) different subgroups, (1999)
28 controls < 13–> 37; median in
controls, 9
Battery plant workers, Italy 37 exposed Significant increase in tail moment – 39.6 ± 7.6 Fracasso et al.
29 controls (p = 0.011), dose-related 4.4 ± 1.7 (2002)
Battery plant workers, 43 exposed Significant increase in tail length, no – 98.5 ± 25.3 De Restrepo
Colombia 13 controls dose–response (p < 0.05) 5.4 ± 3.6 et al. (2000)
Battery plant workers, 44 exposed % of cells with tail length increased, – 50.4 ± 9.2 Palus et al.
Poland 15.6 ± 4.1 (p < 0.05) (2003)
40 controls 11.3 ± 5.0 5.6 ± 2.8
Other DNA damage
DNA–protein crosslinks
Battery plant workers, 23 high exposed 1.8 ± 0.7%S; 1.4 ± 0.5NS (p < 0.05) 0.2–10.3 32.5 ± 14.5 Wu et al.
Taiwan, China 34 low exposed 1.2 ± 0.4S; 1.1 ± 0.5NS 9.3 ± 2.9 (2002)
30 controls 1.0 ± 0.2S; 1.0 ± 0.3NS 4.2 ± 1.4
DNA single strand break
Workers exposed at 10 78 exposed No significant effects 1.6–50 2.8–13.7 Hengstler et al.
facilities in Hessen, 22 controls Median, 3 Median, 4.41 (2003)
Germany
(Cd and Co co-exposed)
Micronuclei (% of cells with micronuclei)
Battery plant workers, 73 exposed 38.6 ± 16.8% (p < 0.05) 193–700 67 ± 23 Vaglenov et al.
Bulgaria 23 controls 19.1 ± 16.2% 60 25 ± 6 (1997)
349
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350
Table 91 (contd)
09/08/2006
(µg/m3) (µg/dL)
Battery plant workers, 22 exposed 62 ± 3% (p < 0.001) 447 ± 52 61 ± 3 (SE) Vaglenov et al.
Pazardzik, Bulgaria 19 external controls 20 ± 2% 73 ± 22 18 ± 0.6 (SE) (1998)
13:47
19 internal controls 26 ± 3% 58 ± 5 2.8 ± 1.6 (SE)
40 ± 18

Metal powder factory 31 exposed 0.65/cell (p < 0.01) – Hamurcu et al.
(exposure to Pb, Zn, Cd), 20 controls 0.24/cell 12 ± 4 (2001)
Turkey
Page 350
Battery plant workers (may 103 workers 43 ± 2% (p < 0.001) – 56 ± 2 Vaglenov et al.
include some subjects from 78 controls (43 internal, 22 ± 1% 19 ± 0.8 (2001)
previous study), Pazardzik, 35 external combined)
Bulgaria
Battery plant workers, 30 exposed 18.6 ± 5.0% (p < 0.01) – 50.4 ± 9.2 Palus et al.
Poland 42 controls 6.6 ± 3.9% 5.6 ± 2.8 (2003)
Chromosomal aberrations
Lead oxide workers, 8 exposedb Significant increase in various types of – 74.7 ± 9.4 Schwanitz
Germany 14 controls chromosome damage 14.9 ± 4 et al. (1970)
(p < 0.01)
Lead manufacturing 32 exposed No significant effect – NR (3 with lead Schmid et al.
workers, Germany 20 controls intoxication) (1972)
Ship-breaking workers, UK Chromatid absc Chromosomal absc – O’Riordan &
35 exposed 5.16% 0.69% Range, 40–> 120 Evans (1974)
31 controls 4.46% 0.42% < 40
285 other survey controls 2.18% 1.16%
Steel plant workers, 105 exposed No significant correlation with blood lead or – 37.7 ± 20.7 Schwanitz
Germany no control group urine ALA et al. (1975)
Battery plant workers 11 exposed Significant increase in chromosomal < 800 After 1 month: Forni et al.
(prospective study), Italy (same subjects, aberrations 45 ± 17.3 (1976)
pre-employment) (p < 0.05) Pre-employment:
34 ± 12.6
P 337-378 DEF.qxp
Table 91 (contd)
09/08/2006
(µg/m3) (µg/dL)
Lead smelter workers, 18 exposed 1.3% 50–500 48.7 ± 1.7 Mäki-

Finland 12 controls 1.8% < 10 Paakkanen
13:47
no significant effect et al. (1981)
Smelter workers (exposed Chromatid abs/cell Chromosomal abs/cell – Nordenson
to Pb, As), Rönnskär, 26 exposed 0.023 0.027 (p < 0.001) High: 64.77 ± 10.95 et al. (1978)
Sweden 0.019 0.004 Medium: 39.19 ± 7.13
Page 351
0.006 0.000 Low: 22.48 ± 1.77
Historical controls 0.004 0.001
Battery plant workers, Chromatid abs Chromosomal abs – NR Al-Hakkak
Baghdad, Iraq 19 exposed 3.4 ± 2.4% 3.3 ± 2.3% et al. (1986)
9 controls 1.5 ± 3.0% 2.0 ± 2.3%
Battery plant workers, 7 high exposed 3.71 (p < 0.01) – 86.9 ± 16.5 Huang, X.-P.
China 7 medium exposed 2.71 52.1 ± 7.3 et al. (1988)
7 low exposed 1.43 33.7 ± 5.9
7 controls 1.14 7.8 ± 2.3
Sister chromatid exchange
Lead smelter workers, 18 exposed 11.7 ± 0.4S; 9.8 ± 0.7NS (p < 0.05 in smokers 50–500 48.7 ± 1.7 Mäki-
Finland only) Paakkanen
12 controls 10.4 ± 0.4S; 9.2 ± 0.4NS < 10 et al. (1981)
Battery plant workers, 10 long-term exposed Long-term exposed: lower frequency after a 4- – 29.0–74.5 Grandjean
Denmark 18 new employees wk vacation 6.2–29.0 et al. (1983)
New employees: no significant increase after
2–4 months employment
Battery plant workers, 54 exposed 7.9 ± 1.5 – 45.2 ± 16.6 Leal-Garza
Monterrey, Mexico 13 controls 7.0 ± 1.2 25.5 ± 6.4 et al. (1986)
Battery plant workers, 7 high exposed 7.06 ± 0.39 (p < 0.001) – 86.9 ± 16.5 Huang, X.-P.
China 7 medium exposed 4.48 ± 0.75 52.1 ± 7.3 et al. (1988)
7 low exposed 3.93 ± 0.53 33.7 ± 5.9
7 controls 4.04 ± 0.33 7.8 ± 2.3
Printers, India 13 exposed No increase – NR Rajah & Ahuja
351
16 controls (1995)
P 337-378 DEF.qxp
352
Table 91 (contd)
09/08/2006
(µg/m3) (µg/dL)
Metal-powder factory 32 exposed 8.9 ± 1.4S; 8.2 ± 0.9NS (p < 0.01 in – 13.8 ± 9.2 Donmez et al.
workers, Turkey 20 controls nonsmokers only) (1998)
8.7 ± 1.0S; 7.2 ± 0.6NS 2.4 ± 0.9
13:47
Battery plant workers, 23 high exposed 6.4 ± 0.5S; 5.9 ± 0.7NS (p < 0.05) 0.2–10.3 32.5 ± 14.5 Wu et al.
5.8 ± 0.4S; 5.5 ± 0.7NS 9.3 ± 2.9

Taiwan, China 34 low exposed (2002)
30 controls 5.7 ± 0.3S; 4.9 ± 0.4NS 4.2 ± 1.4
Page 352
Battery plant workers, 71 exposed Significant increase in group with blood lead – 34.5 ± 1.5 Duydu &
Ankara, Turkey 20 controls > 50 µg/dL (p < 0.05) 10.4 ± 0.4 Süzen (2003)
Battery plant workers, 30 exposed 7.6 ± 0.9S; 7.1 ± 0.9NS (p < 0.05) – 50.4 ± 9.2 Palus et al.
Poland 43 controls 6.5 ± 1.1S; 5.9 ± 0.8NS 5.6 ± 2.8 (2003)
Non-occupationally exposed
Oxidative DNA damage
Citizens of Bremen, 141 No increase in oxidative DNA damage (Fpg- – Median, 4.6 Merzenich
Germany sensitive sites) et al. (2001)
Sister chromatid exchange
Children living near a lead 19 exposed No effect – 29.3–62.7 Dalpra et al.
smelter, Milan, Italy 12 controls 10.0–21.0 (1983)
Chromosomal aberrations
Male volunteers, 11 ingestedd No significant effect – 40 ± 5 × 7 wks Bijlsma &
Netherlands 10 controls de France
(1976)
Children living near lead 20 exposed No significant effect – > 30 Bauchinger
smelter, Germany 20 controls 7–19 et al. (1977)
–, No data; S, smoker; NS, nonsmoker; SE, standard error; NR, not reported; ALA, δ-aminolevulinic acid; Fpg, formamidopyrimidine-DNA glycosylase
a
Dose–response refers to blood lead concentrations.
b
Exposed workers have significantly increased mitotic index.
c
Chromatid/chromosomal abnormalities
d
Daily ingested lead acetate to give mean blood lead concentration of 40 ± 5 µg/dL for 7 wks
P 337-378 DEF.qxp 09/08/2006 13:47 Page 353
DNA damage and increased Comet tail length compared with controls (non-exposed).
Blood lead was positively associated with the percentage of DNA-damaged cells (Danadevi
et al., 2003). [The Working Group noted that the air lead level was unexpectedly low.]
Significantly increased percentages of DNA-damaged leukocytes and tail length, as well as
increased malondialdehyde concentrations were also seen in workers in a secondary lead
smelter in China. The effects were dose-related, with minimal blood lead concentrations of
27–37 µg/dL being associated with genotoxicity (Ye et al., 1999). Similar results were seen
in workers in battery plants in Italy, Columbia and China, Province of Taiwan (De Restrepo
et al., 2000; Fracasso et al., 2002; Wu, F.-Y. et al., 2002) where significant increases in tail
moment, tail length and/or DNA in the tail were observed in workers’ lymphocytes. In one
study, the Comet assay results were correlated with blood lead concentrations, and with
decreased concentrations of reduced glutathione (GSH) in blood (Fracasso et al., 2002). The
DNA damage occurred at blood lead concentrations > 40 µg/dL in the workers in Columbia
and sister chromatid exchange occurred at blood lead concentrations > 15 µg/dL in workers
in China, Province of Taiwan.
In a single study, evidence for increased DNA–protein crosslinks was seen at high
blood lead concentrations in the highly-exposed group (blood lead, 32.5 ± 14.5 µg/dL) of
battery plant workers (Wu, F.-Y. et al., 2002). DNA single-strand breaks (measured with
the alkaline elution assay) were not increased in lymphocytes of workers with median
blood lead concentrations of 4.41 µg/dL (Hengstler et al., 2003). [The Working Group
noted that the air lead level was unexpectedly low.] However, in the latter study, lead
exposure increased the effects of cadmium in inducing DNA strand breaks.
All of five studies of micronuclei in blood lymphocytes of exposed workers found
increases. These occurred in battery plant workers exposed to at least 193 µg/m3 lead in
air (resulting in 3.16 µM [65.5 µg/dL] in blood) (Vaglenov et al., 1997). A second study
confirmed these results and demonstrated a reduction in micronucleus frequency in
workers given a vitamin and mineral supplement (Vaglenov et al., 1998). The authors
suggested that oxidative DNA damage may be responsible for the micronuclei. Battery
plant workers in Poland were shown to have increased micronuclei in both centromere-
positive and centromere-negative classes, indicating both a clastogenic and aneugenic
effect of lead (Palus et al., 2003).
Studies of chromosomal aberrations in lead-exposed workers gave mixed results.
Chromosomal aberrations were evaluated in 105 lead-exposed workers in Germany and
found to be slightly but not significantly increased (Schwanitz et al., 1975). In an earlier
report from this group with a small number of subjects, chromosomal aberrations were
positively correlated to excretion of ALA (Schwanitz et al., 1970), but a higher mitotic
index in lymphocytes from workers was noted. Negative results for chromosomal aberra-
tions were reported by Schmid et al. (1972) and O’Riordan and Evans (1974) for workers
in lead manufacturing and ship breaking, respectively. In a prospective study in which 11
battery plant workers acted as their own controls, a doubling of chromosomal aberrations
(mostly chromatid and one-break aberrations) was seen after 1 month of employment.
There was a further increase in the second month, but then the level remained the same
P 337-378 DEF.qxp 09/08/2006 13:47 Page 354
for at least 7 months. The increased frequency of chromosomal aberrations was correlated
to inhibition of ALAD in red blood cells (Forni et al., 1976). The authors speculated that
culture conditions may have been responsible for the DNA damage, whose repair is inhi-
bited by lead because, in a previous study in which the bone-marrow cells were not
cultured, exposure to lead did not result in increased chromosomal aberrations (Forni &
Secchi, 1972). Mäki-Paakkanen et al. (1981) also found evidence of ‘culture-born aberra-
tions’, and noted that these may have influenced the outcome of the study.
In a study in which primary copper and lead smelter workers were stratified by blood
lead concentrations, increased frequencies of chromatid-type aberrations were seen in the
intermediate group (mean blood lead, 39.19 µg/dL); and chromosome-type aberrations were
seen only in the ‘high’ group (mean blood lead, 64.77 µg/dL) (Nordenson et al., 1978). The
authors estimated that a blood lead concentration of 25 µg/dL is the minimum required to
produce any chromosomal effects. Huang et al. (1988) only saw an increased frequency of
chromosomal aberrations in their intermediate group (mean blood lead, 52.1 µg/dL).
The results of studies measuring sister chromatid exchange in workers exposed to lead
are mostly positive but, in some studies, positive responses were seen only in smokers.
For example, a small increase in sister chromatid exchange was seen only in lead smelter
workers who smoked (Mäki-Paakkanen et al., 1981). No significant increase in sister
chromatid exchange was seen in printers (confounded by smoking) (Rajah & Ahuja,
1995), whereas there was a significant increase in battery plant workers after controlling
for smoking (Duydu & Süzen, 2003). In these studies, there was also inconsistency in the
correlations with blood lead concentrations. In one study, the level of sister chromatid
exchange decreased in battery plant workers after a 4-week vacation (Grandjean et al.,
1983). The same authors also monitored newly-employed workers and found no increases
in sister chromatid exchange after 2–4 months of employment.
In general, studies in which a variety of genotoxic end-points were measured in non-
occupationally exposed subjects (children living near plants, volunteers, general popu-
lation) gave negative results (Table 91).
4.4.2 Effects in animals (see Table 92)

DNA damage was assessed in kidney cells of male rats by use of the Comet assay
(single-cell gel electrophoresis). In cells isolated from the kidneys of rats that had received
three doses of lead acetate by oral administration, a larger Comet tail was seen than in
cells from animals that had been given the same amount of lead in a single dose. The same
study also showed an increased level of sister chromatid exchange in kidney cells, with
the single high dose being more effective (Robbiano et al., 1999). When mice were
exposed for three generations to lead acetate in the drinking-water, Comet tail length
increased in blood cells in the F1 and F2 generations, but not in the dams (Yuan & Tang,
2001). With an inhalation protocol in mice, DNA damage was detected in the liver and
lung after a single exposure to lead acetate, whereas kidney, brain, nasal cells, bone
P 337-378 DEF.qxp
Table 92. Genetic and related effects of lead compounds in animals in vivo
09/08/2006
Test system Result Dosea Reference
(LED or HID)
Lead acetate

DNA damage, female Kunming mouse leukocytes (SCGE) – 1 µg/mL water approx. 3–4 mo Yuan & Tang (2001)
13:47
DNA damage, Kunming mouse leukocytes (SCGE), 2nd and 3rd generations of + 1 µg/mL water in utero to sexual Yuan & Tang (2001)
multigeneration study maturity
DNA damage, male CD-1 mouse liver, kidney, nasal cavity, brain, bone-marrow w+ 6800 µg/m3, inhal., 60 min × 2/wk, 4 wk Valverde et al. (2002)
Page 355
cells (SCGE)
DNA damage, male CD-1 mouse testicle cells, leukocytes (SCGE) – 6800 µg/m3, inhal., 60 min × 2/wk, 4 wk Valverde et al. (2002)
DNA damage, male CD-1 mouse lung cells (SCGE) ?* 6800 µg/m3, inhal., 60 min × 2/wk, 4 wk Valverde et al. (2002)
DNA damage, unilaterally nephrectomized Sprague-Dawley rat kidney (SCGE) + 78 mg/kg bw po × 3 Robbiano et al. (1999)
Sister chromatid exchange, rabbit lymphocytes – 0.5 mg/kg bw sc 3×/wk, 14 wk Willems et al. (1982)
Micronucleus formation, female C57BL mouse bone marrow – 25 mg/kg bw ip × 2 Jacquet et al. (1977)
Micronucleus formation, female C57BL/6 × C3H/He F1 mouse bone marrow – 1000 mg/kg bw ip Bruce & Heddle (1979)
Micronucleus formation, male and female Sprague-Dawley rat bone marrow w+ 104 mg/kg bw ip Tachi et al. (1985)
Micronucleus formation, rabbit bone marrow erythrocytes – 0.5 mg/kg bw sc 3×/wk, 14 wk Willems et al. (1982)
Micronucleus formation, unilaterally nephrectomized Sprague-Dawley rat kidney + 78 mg/kg bw po × 3 Robbiano et al. (1999)
Chromosomal aberrations, female C57B1 mouse bone marrow – 0.5% diet × 1 mo Jacquet et al. (1977)
Chromosomal aberrations, male C57B1 mouse bone marrow – Normal diet + 0.5% × 1 mo Deknudt & Gerber (1979)
Chromosomal aberrations, male C57B1 mouse bone marrow + Low Ca diet + 0.5% × 1 mo Deknudt & Gerber (1979)
Chromosomal aberrations, female Sprague-Dawley rat bone marrow + 104 mg/kg bw ip Tachi et al. (1985)
Chromosomal aberrations, male Sprague-Dawley rat bone marrow – 104 mg/kg bw ip Tachi et al. (1985)
Chromosomal aberrations, female Sprague-Dawley rat bone marrow – 104 mg/kg bw ip × 5 Tachi et al. (1985)
Chromosomal aberrations, male Sprague-Dawley rat bone marrow w+ 104 mg/kg bw ip × 5 Tachi et al. (1985)
Chromosomal aberrations, Wistar rat bone marrow – 10 mg/kg bw po 5×/wk, 4 wk Nehéz et al. (2000)
Chromosomal aberrations, male and female A/sw mouse leukocytes + 1% diet × 2 wk Muro & Goyer (1969)
Chromosomal aberrations, cynomolgus monkey lymphocytes ± 6 mg/d po × 10 mo Deknudt et al. (1977)
Chromosomal aberrations, cynomolgus monkey leukocytes – 5 mg/kg bw po/d × 12 mo Jacquet & Tachon (1981)
Aneuploidy, Wistar rat bone marrow + 10 mg/kg bw po 5×/wk, 4 wk Nehéz et al. (2000)
Aneuploidy, cynomolgus monkey lymphocytes ± 6 mg/d po × 10 mo Deknudt et al. (1977)
Sperm morphology, C57BL/6 F1 × C3H/He F1 mice + 125 mg/kg bw ip Bruce & Heddle (1979)
Sperm morphology, rabbits – 0.5 mg/kg bw sc 3×/wk, 14 wk Willems et al. (1982)
Sperm abnormality, cynomolgus monkey (acid denaturation of DNA) + 50 µg/kg bw/d for 100–200 db Foster et al. (1996)
355
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356
09/08/2006
Table 92 (contd)
13:47
(LED or HID)

Lead chloride
Page 356
Dominant lethal mutations, NMRI mice – 1.33 g/L dw Kristensen et al. (1993)
Lead nitrate
Sister chromatid exchange, pregnant female Swiss Webster mouse bone marrow + 150 mg/kg bw iv Nayak et al. (1989)
Sister chromatid exchange, liver and/or lung of fetus of maternal Swiss Webster – 200 mg/kg bw iv Nayak et al. (1989)
mice
Sister chromatid exchange, male Swiss albino mouse bone marrow + 10 mg/kg bw ip Dhir et al. (1993)
Micronucleus test, male and female Swiss albino mouse bone marrow ? 80 mg/kg bw ip Jagetia & Aruna (1998)
Chromosomal aberrations, maternal bone marrow and fetal liver cells of Swiss + 100 mg/kg bw iv Nayak et al. (1989)
Webster mouse
Aneuploidy, maternal bone marrow and fetal liver cells of Swiss Webster mouse + 100 mg/kg bw iv Nayak et al. (1989)
Induction of nondisjunction, Drosophila melanogaster – 200 ppm feed Ramel & Magnusson
(1979)
+, positive; –, negative; ±, equivocal; w+, weak positive; ?, significant variation from dose to dose, no clear dose–response relationship; ?*, significant variation from
week to week; po, oral; inhal., inhalation; dw, drinking-water; sc, subcutaneous; iv, intravenous; d, day; wk, week; mo, month; SCGE, single-cell gel electrophoresis;
bw, body weight
a
Lowest effective dose or highest ineffective dose
b
Dose resulted in blood lead concentrations of 6–20 µg/dL.
P 337-378 DEF.qxp 09/08/2006 13:47 Page 357
marrow and leukocytes required more than one exposure before DNA damage was seen.
No damage to testicular cells was seen after 4 weeks (Valverde et al., 2002).
No increases in sister chromatid exchange in rabbit lymphocytes were seen after sub-
cutaneous injections of lead acetate (Willems et al., 1982). The same treatment also failed
to cause sperm abnormalities or micronucleus formation in bone-marrow erythrocytes.
However, intravenous injection of lead nitrate on day 9 of gestation increased sister
chromatid exchange frequency in the bone marrow of F1 mice, but not in fetal liver and/or
fetal lung cells, although the lead was shown to cross the placenta (Nayak et al., 1989).
In this study, lead nitrate caused chromosomal aberrations, mostly deletions, in both dams
and fetal cells, as well as aneuploidy, increased embryonic resorptions and reduced
placental weights. Dhir et al. (1993) showed that intraperitoneal injection of low doses of
lead nitrate caused a significant increase in sister chromatid exchange in bone marrow in
male Swiss albino mice. The lowest dose that caused micronucleus formation in bone
marrow (but without a dose–response relationship) was 0.63 mg/kg bw lead nitrate. Male
mice were found to be more sensitive than females (Jagetia & Aruna, 1998).
Feeding mice a diet containing lead acetate resulted in increased frequencies of chro-
mosomal aberrations in leukocytes, particularly involving single chromatids (Muro &
Goyer, 1969). Similar results were seen in a study in female C57BL mice (Jacquet et al.,
1977) but, in a further study, only when mice were given a low-calcium diet (Deknudt &
Gerber, 1979).
Female (but not male) rats given a single intraperitoneal injection of lead acetate had
increased chromosomal aberrations (mostly gaps) (Tachi et al., 1985). In the same study,
both male and female rats showed an increased frequency of micronuclei following
treatment with lead acetate. The nature of the micronuclei was not determined, but lead
acetate-induced chromatid gaps may reflect mostly clastogenicity rather than aneuploidy.
Aneuploidy was induced in pregnant mice and their offspring (maternal bone marrow and
fetal liver cells) by intravenous administration of lead nitrate on day 9 of gestation (Nayak
et al., 1989) and in rats (bone marrow) given lead acetate orally (Nehéz et al., 2000), but
nondisjunction did not increase in Drosophila given lead acetate in feed (Ramel &
Magnusson, 1979).
Increased frequencies of chromosomal aberrations (gaps and fragments) and enhanced
aneuploidy were seen in lymphocytes of monkeys given lead acetate orally or by
intubation in one study (Deknudt et al., 1977) but not in another (Jacquet & Tachon, 1981).
In a single in-vivo mutagenesis study, lead chloride in the drinking-water had no
effect in the dominant lethal assay in mice (Kristensen et al., 1993).
Increased abnormal sperm morphology was seen in mice given lead acetate intraperi-
toneally (Bruce & Heddle, 1978). Increased sperm abnormality (analysed by sperm chro-
matin structure assay) was seen in monkeys given lead acetate resulting in blood lead con-
centrations of up to 20 µg/dL (Foster et al., 1976). However, subcutaneous administration
of lead acetate did not induce sperm abnormalities in rabbits (Willems et al., 1982).
P 337-378 DEF.qxp 09/08/2006 13:47 Page 358
4.4.3 Mammalian cells in vitro (for references, see Table 93)

The genetic effects of lead compounds have been reviewed (Hartwig, 1994;
Silbergeld et al., 2000). Equivocal results have been published with respect to the muta-
genicity of water-soluble lead compounds in mammalian cells in culture; in most classical
test systems, the effects were rather weak and/or restricted to toxic doses. Nevertheless,
in AS52 Chinese hamster ovary cells carrying a single copy of an Escherichia coli gpt
gene, lead chloride induced mutations in a dose-dependent manner at non-cytotoxic con-
centrations of < 1 µM (Ariza & Williams, 1996, 1999; Ariza et al., 1998). More detailed
studies revealed predominantly point mutations with increasing frequencies of partial and
complete deletions, in the dose range 0.5–1.0 µM (Ariza & Williams, 1999). Increased
mutant frequencies in the Hprt gene were also observed in a study in Chinese hamster
ovary K1 cells, but at higher, although still not cytotoxic concentrations of lead acetate,
starting at 0.5 mM. Analysis of mutation spectra revealed base substitutions predomi-
nantly at G-C sites, as well as small and large deletions resulting from DNA damage
induced by ROS (Yang et al., 1996). Furthermore, two studies revealed an increase in
mutation frequency in combination with ultraviolet (UV) C irradiation or treatment with
N-methyl-N-nitro-N-nitrosoguanidine (MNNG) (Roy & Rossman, 1992). One potential
mechanism may be the interaction with DNA repair processes; although results are equi-
vocal, different outcomes may depend on incubation conditions. Thus, in human HeLa
cell lines, two independent studies showed repair inhibition of X-ray-induced or UVC-
induced DNA damage after 24 and 20 h preincubation, respectively (Skreb & Habazin-
Novak, 1977; Hartwig et al., 1990), while one study did not show an effect after 30 min
preincubation (Snyder et al., 1989).
With respect to the induction of chromosomal aberrations by lead acetate, treatment of
human leukocytes showed clearly elevated frequencies of achromatic lesions, chromatid
breaks and isochromatid breaks in 72-h cultures but not 48-h cultures (Beek & Obe, 1975);
other studies with lead nitrate and lead glutamate were mostly negative. However, consis-
tently positive results were obtained with lead chromate, which the authors related to the
probable action of chromate (Wise et al., 1994). Concerning the induction of micronuclei,
a recent study reported a dose-dependent increase starting at concentrations of 1.1 µM lead
chloride or 0.05 µM lead acetate. Both positive and negative results have been reported for
the induction of sister chromatid exchange; nevertheless, similar to the enhancement of
UVC-induced mutagenicity noted above, lead acetate also increased the UVC-induced
frequency of sister chromatid exchange. More consistently, lead acetate as well as particu-
late lead chromate induced cell transformation in several studies; in the case of lead chro-
mate, the effect was thought by the authors to be not due solely to the action of chromate
(Elias et al., 1989; Sidhu et al., 1991). The induction of DNA damage in mammalian cells
by lead acetate and lead nitrate has been investigated repeatedly, yielding negative or
(mostly weakly) positive results for DNA strand breaks; one study did not find 8-OH-
deoxyguanosine (8-OH-dG) in nuclear DNA, and one suggested the induction of DNA–
protein crosslinks. Besides genotoxic effects, there is growing evidence for altered gene
P 337-378 DEF.qxp
Table 93. Genetic and related effects of lead and lead compounds; in-vitro studies
09/08/2006
(LED or HID)
Without With
exogenous exogenous
metabolic metabolic
system system
13:47
Lead acetate
DNA strand breaks, isolated plasmid DNA +b NT 1 mM Roy & Rossman (1992)
DNA strand breaks, isolated plasmid DNA + NT 0.1 mM Yang et al. (1999)
Page 359
8-OH-dG, calf thymus DNA +b NT 0.5 mM Yang et al. (1999)
Escherichia coli WP2, rec-assay – NT 50 mM Nishioka (1975)
Salmonella typhimurium TA100, TA1535, TA1537, TA1538, TA98, reverse mutation – NT 333 µg/plate Dunkel et al. (1984)
Salmonella typhimurium TA1535, TA1538, reverse mutation – – 250 µg/plate Rosenkranz & Poirier (1979)
Escherichia coli WP-2 uvrA, reverse mutation – NT 333 µg/plate Dunkel et al. (1984)
Saccharomyces cerevisiae D3, mitotic recombination – – 50 000 µg/mL Simmon (1979)
Plant cuttings of Tradescantia clone 4430 (exposed to lead tetraacetate), micronucleus + 0.44 ppm Sandhu et al. (1989)
formation
DNA strand breaks, primary rat kidney cells in vitro + NT 560 µM Robbiano et al. (1999)
DNA strand breaks, Chinese hamster ovary (CHO) cells in vitro (+) NT 1 mM Robison et al. (1984)
DNA strand breaks, transgenic cell lines G12 from Chinese hamster V79 cells in vitro + 1.7 mM Roy & Rossman (1992)
8-OHdG in nuclear DNA, Chinese hamster ovary (CHO K1) cells in vitro – NT 100 µg/mL Yusof et al. (1999)
Gene mutation, Chinese hamster ovary (CHO K1) cells, Hprt locus in vitro + NT 0.5 mM Yang et al. (1996)
Gene mutation, Chinese hamster V79 cells, Hprt locus in vitro – 5 µM Hartwig et al. (1990)
Gene mutation, transgenic cell lines G12 from Chinese hamster V79 cells, Gpt locus (+) 1.7 mM Roy & Rossman (1992)
in vitro
Sister chromatid exchange, Chinese hamster V79 cells in vitro – 10 µM Hartwig et al. (1990)
Enhancement of UVC-induced sister chromatid exchange, Chinese hamster V79 cells + 1 µM Hartwig et al. (1990)
in vitro
Micronucleus formation, Chinese hamster V79 cells in vitro + 0.05 µM Thier et al. (2003)
Chromosomal (structural) aberrations, Chinese hamster ovary (CHO) cells in vitro – 1 mM Bauchinger & Schmid (1972)
Cell transformation, Syrian hamster embryo (SHE) cells + 10 µM Zelikoff et al. (1988)
DNA strand breaks, human kidney cells in vitro + 1.8 mM Robbiano et al. (1999)
DNA strand breaks, human HeLa cells in vitro – 500 µM Hartwig et al. (1990)
DNA single- and double-strand breaks, human lymphocytes in vitro (+) 1 µM Wozniak & Blasiak (2003)
DNA-protein cross-links, human lymphocytes in vitro + 100 µM Wozniak & Blasiak (2003)
Effect on the resealing of X-ray induced DNA single-strand breaks, human HeLa cells – 100 µM Snyder et al. (1989)
359
in vitro
P 337-378 DEF.qxp
360
Table 93 (contd)

(LED or HID)
09/08/2006
Without With
exogenous exogenous
metabolic metabolic
system system
Effect of pyrimidine dimer removal induced by UVC, human – 10 mM Snyder et al. (1989)
13:47
Inhibition of UVC-induced DNA repair, human HeLa cells in vitro + 500 µM Hartwig et al. (1990)
Gene mutation, diploid human fibroblasts, HPRT locus in vitro – 2 mM Hwua & Yang (1998)

Sister chromatid exchange, human leukocytes in vitro – 10 µM Beek & Obe (1975)
Chromosomal aberrations, human lymphocytes in vitro – 1 mM Schmid et al. (1972)
Page 360
Chromosomal aberrations, human lymphocytes in vitro ? 1 mM Deknudt & Deminatti (1978)
Chromosomal aberrations, human lymphocytes in vitro – 1 mM Gasiorek & Bauchinger (1981)
Achromatic lesions, chromatid breaks and isochromatid breaks, human leukocytes in vitro + 10 µM Beek & Obe (1974)
Cell transformation, diploid human fibroblasts (anchorage-independent growth) + 0.5 mM Hwua & Yang (1998)
Lead bromide
Salmonella typhimurium TA1535, reverse mutation + 9.0 µg/plate Maslat & Haas (1989)
Salmonella typhimurium TA1537, reverse mutation – 68.0 µg/plate Maslat & Haas (1989)
Serratia marcescens, reverse mutation + 1.91 mM Maslat & Haas (1989)
Escherichia coli KMBL 1851, reverse mutation, met+ and his+ + 3.27 mM Maslat & Haas (1989)
Lead chloride
Escherichia coli WP2, rec-assay – 50 mM Nishioka (1975)
Escherichia coli K12, Trp+ reversion plate test – 1 mM Nestmann et al. (1979)
Salmonella typhimurium TA98, TA100 reverse mutation – – 580 µg/plate Nestmann et al. (1979)
Saccharomyces cerevisiae D7, mitotic cross-over + 0.3 mM Fukunaga et al. (1982)
Gene mutation, Chinese hamster ovary AS52 cells, Gpt locus in vitro + 0.1 µM Ariza & Williams (1996);
Ariza et al. (1998); Ariza &
Williams (1999)
Micronucleus formation, Chinese hamster V79 cells in vitro + 1.1 µM Thier et al. (2003)
Inhibition of X-ray-induced DNA repair, human HeLa cells in vitro +c 250 µM [70 µg/mL] Skreb & Habazin-Novak
(1977)
Lead chromate
Escherichia coli K12 Gal+ forward mutation – 100 µg/mL Nestmann et al. (1979)
Escherichia coli Trp+ reversion plate test – 1 mM Nestmann et al. (1979)
Escherichia coli WP2 Uvr– Trp+ reversion fluctuation assay + 5 µM Nestmann et al. (1979)
P 337-378 DEF.qxp
Table 93 (contd)
09/08/2006
(LED or HID)
Without With
exogenous exogenous
metabolic metabolic
system system
13:47
Salmonella typhimurium TA100, reverse mutation – – 200 µg/plate Nestmann et al. (1979)
Salmonella typhimurium TA1535, reverse mutation – – 100 µg/plate Nestmann et al. (1979)
200 µg/plate
Page 361
Salmonella typhimurium TA1537, reverse mutation + – Nestmann et al. (1979)
Salmonella typhimurium TA1538, TA98, reverse mutation + + 200 µg/plate Nestmann et al. (1979)
Saccharomyces cerevisiae D5, mitotic recombination + – 63 µg/mL Nestmann et al. (1979)
DNA strand breaks, DNA–protein crosslinks, Chinese hamster ovary (CHO) cells in vitro + 0.08 µg/cm2 (1 µM) Xu et al. (1992)
Gene mutation, C3H 10T1/2 mouse cells, ouabain resistance in vitro – 100 µM Patierno et al. (1988)
Gene mutation, Chinese hamster ovary (CHO) cells, 6-thioguanine resistance and ouabain – 100 µM Patierno & Landolph (1989);
resistance in vitro Patierno et al. (1988)
Chromosomal aberrations, Chinese hamster ovary (CHO) cells in vitro + 0.4 µg/cm2 (5 µM) Xu et al. (1992)
Chromosomal aberrations, Chinese hamster ovary (CHO) cells in vitro + 0.4 µg/cm2 (5 µM) Wise et al. (1992); Wise et al.
(1994)
Cell transformation, C3H 10T1/2 mouse cells + 25 µM Patierno & Landolph (1989);
Patierno et al. (1988)
Cell transformation, Syrian hamster embryo (SHE) cells, simian adenovirus SA7 viral + 80 µM Schechtman et al. (1986)
enhancement
Cell transformation, Syrian hamster embryo (SHE) cells + ~0.8 µg/mL Elias et al. (1989)
Chromosomal aberrations, human foreskin fibroblasts in vitro + 0.08 µg/cm2 (1 µM) Wise et al. (1992)
Cell transformation, nontumorigenic human osteosarcoma (HOS) TE85 cells + 2 µg/mL Sidhu et al. (1991)
Lead glutamate
Chromosomal aberrations, Chinese hamster ovary (CHO) cells in vitro ? 1 mM Wise et al. (1994)
Lead nitrate
Saccharomyces cerevisiae D7, mitotic gene conversion, reverse mutation – 60 µg/mL Kharab & Singh (1985)
Allium cepa L, chromosomal aberrations + 10 ppm Lerda (1992)
Drosophila melanogaster, non-disjunction – 200 ppm Ramel & Magnusson (1979)
Gene mutation, Chinese hamster V79 cells, Hprt locus in vitro + 500 µM Zelikoff et al. (1988)
Gene mutation, transgenic cell lines G12 from Chinese hamster V79, Gpt locus in vitro – 1.7 mM Roy & Rossman (1992)
Sister chromatid exchange, Chinese hamster V79 cells in vitro – 3 mM Zelikoff et al. (1988)
361
P 337-378 DEF.qxp
362
09/08/2006
Table 93 (contd)

(LED or HID)
Without With
exogenous exogenous
13:47
metabolic metabolic
system system

Sister chromatid exchange, Chinese hamster ovary (CHO) cells in vitro + 3 µM Lin et al. (1994)
Page 362
Sister chromatid exchange, Chinese hamster ovary (CHO) cells in vitro + 100 nM Cai & Arenaz (1998)
Micronucleus formation, Chinese hamster ovary (CHO) cells in vitro – 30 µM Lin et al. (1994)
Chromosomal aberrations, Chinese hamster ovary (CHO) cells in vitro – 30 µM Lin et al. (1994)
Chromosomal aberrations, Chinese hamster ovary (CHO) cells in vitro – 2 mM Wise et al. (1994)
DNA strand breaks, transgenic cell lines G12 from Chinese hamster V79 cells in vitro + 1.7 mM Roy & Rossman (1992)
Lead sulfide
Gene mutation, Chinese hamster V79 cells, Hprt locus in vitro + 376 µM Zelikoff et al. (1988)
Sister chromatid exchange, Chinese hamster V79 cells in vitro – 938 µM Zelikoff et al. (1988)
Lead, diethyl dichloride
Drosophila melanogaster, non-disjunction + 16 ppm Ramel & Magnusson (1979)
Lead, triethyl chloride
Drosophila melanogaster, non-disjunction + 8 ppm Ramel & Magnusson (1979)
SCGE, Single-cell gel electrophoresis

+, positive; (+), weakly positive; –, negative; ?, inconclusive; NT, not tested
a
LED, lowest effective dose; HID, highest ineffective dose unless otherwise stated; in-vitro tests, µg/mL; in-vivo tests, mg/kg bw/day; ip, intraperitoneal; po, oral; NG, not
given
b
In the presence of H2O2
c
Incorporation of [3H]thymidine or [3H]uridine triphosphate
P 337-378 DEF.qxp 09/08/2006 13:47 Page 363
expression resulting from low-level exposure to lead (Bouton et al., 2001; Li & Rossman,
2001).
4.4.4 Prokaryotic systems (for references, see Table 93)

Lead acetate and lead chloride were not mutagenic in bacterial test systems. In
contrast, lead chromate was mutagenic in E. coli and Salmonella typhimurium, indicating
that chromate may be the active component. Furthermore, one study demonstrated lead
bromide to be mutagenic which may be due to bromination of uracil subsequently incor-
porated into DNA (Maslat & Haas, 1989).
4.4.5 Yeast and plants (for references, see Table 93)

In yeast, lead acetate and lead nitrate usually gave negative results in test systems
assessing mitotic recombination. One study demonstrated a limited number of mitotic
gene conversions at growth inhibitory concentrations; however, among the convertants
there were significantly higher frequencies of mitotic crossing-over. Chromosomal
aberrations and micronuclei were observed in plants after exposure of roots to lead nitrate
or cuttings to lead tetraacetate, respectively.
4.4.6 Cell-free systems (for references, see Table 93)

The effect of lead acetate on isolated DNA has been investigated in detail. A dose-
dependent increase in DNA strand breaks was observed in plasmid DNA as well as an
increase in 8-OH-dG in calf thymus DNA in the presence of hydrogen peroxide as deter-
mined by HPLC-electrochemical detection. Studies with different radical scavengers
suggested the participation of singlet oxygen (1O2) and hydrogen peroxide in DNA damage
induction. A Fenton-like reaction, involving the reduction of Pb2+ to Pb1+ and/or lead-
oxygen or lead-peroxide complexes, has been proposed to play a role in this process (Yang
et al., 1999). One other mode of action with potential relevance for genetic stability consists
of interactions with zinc-binding motifs in DNA-binding proteins. In this context, zinc
finger 3 of transcription factor TFIIIA exerts a higher binding constant for Pb2+ than for
Zn2+, and lead chloride has been shown to inhibit DNA binding of transcription factor
TFIIIA and Sp1 (Petering et al., 2000; Razmiafshari et al., 2001). However, the zinc finger-
containing repair proteins XPA and Fpg were not inhibited by lead (Asmuss et al., 2000).
4.5 Mechanistic considerations

4.5.1 Introduction
A considerable number of experiments have been conducted to elucidate the toxico-
kinetic and toxicodynamic mechanisms by which exposure to lead may result in cancer.
Chemical form and route, patterns and magnitude of exposure are important factors in eva-
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luating the toxicokinetic mechanisms relevant to the carcinogenic potential of lead. Issues
such as mode of action, genotoxicity and the mitogenic and/or cytotoxic potential of lead
must be considered in describing the toxicodynamics of lead carcinogenicity.
4.5.2 Toxicokinetics and metabolism of lead

(a) Inorganic lead
(i) Absorption
Lead absorption from the gastrointestinal tract in both humans and experimental ani-
mals is strongly influenced by age (neonates and the young absorb a larger fraction than do
adults), fasting/fed status (fasting experimental animals and humans absorb much greater
fractions), nutritional status (fat and caloric intakes, and phosphorus, copper, zinc and
especially iron and calcium status all affect absorption), solubility (soluble compounds are
better absorbed) and particle size (in controlled studies in rats, lead absorption from mining
wastes was shown to be inversely proportional to particle size).
The fraction of lead absorbed from an inhalation exposure is not known to be depen-
dent on the amount of lead in the lung. Patterns and rates of deposition are highly depen-
dent on particle size and ventilation rate, but all lead deposited deep in the lung is even-
tually absorbed.
Limited studies indicate that dermal absorption of inorganic lead is negligible, al-
though slightly enhanced by high perspiration rates.
Intravenous, intraperitoneal or subcutaneous administration of lead salts gives no useful
information about the kinetics of lead, because metal salts administered by these routes are
distributed and excreted very differently from the same salts absorbed by a more physio-
logical or natural route.
(ii) Distribution
In both experimental animals and humans, absorbed lead is distributed from blood
plasma rapidly and simultaneously into erythrocytes, soft tissues, and bone. Once the lead
in soft tissues has reached an approximate equilibrium with that in blood, the concentra-
tion of lead in blood is determined almost entirely by the balance among absorption, eli-
mination, and transfers to and from bone. Initially, however, distribution into soft tissues
dominates the shape of the blood lead concentration–time curve, with a half-life of 20–
130 days in adult humans and 3.5 days in rats. In both humans and rats, the highest soft-
tissue concentrations of lead are found in the liver and kidney, with considerably lower
concentrations in the brain.
After equilibration with soft tissues and in the absence of continuing exposure, the
blood lead concentration–time profile mirrors the return of lead from bone. Because of the
nature of the several processes that mediate bone lead uptake and release, loss of lead from
bone is not a first-order process, and in principle neither return of lead from bone nor
whole-body loss can be characterized by a single half-life. Nonetheless, half-lives are
commonly used for this purpose. While the bone can be a significant source of endogenous
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lead, exposures must be both moderately high and extended in time to load the bone with
lead.
Plasma, rather than whole blood, is generally accepted as the source of lead available
for distribution and excretion processes. The fraction of whole blood lead that is in the
plasma is substantially larger at high blood lead concentrations than at low blood lead
concentrations. Although the relationship of plasma lead to whole blood lead is curvi-
linear at all points, it can be approximated by a straight line at low blood lead concentra-
tions. In one group of 73 adult women, it has been established that the slope of the plasma
lead to whole blood lead regression line is 0.00246 at whole blood lead concentrations
below about 6 µg/dL; up to this concentration, the relationship between plasma lead and
whole blood lead can be approximated by a straight line, and the mean plasma lead
concentration is 0.24% of the whole blood lead concentration. The most marked outlier
in this group of women had a plasma lead concentration of 0.017 µg/dL at a whole blood
lead concentration of about 3 µg/dL (0.56%). At whole blood lead concentrations excee-
ding about 40 µg/dL, the fraction of blood lead found in the plasma increases. For
example, at a whole blood lead concentration of 60 µg/dL, plasma lead concentration is
about 0.8 µg/dL (1.3%); at 80 µg/dL in whole blood, it is about 1.5 µg/dL (nearly 2%);
and at 100 µg/dL in whole blood, it may be as high as 3 µg/dL (3%) (Manton et al., 2001).
In certain physiological states, such as pregnancy, lactation and the period just after
menopause in women, an increase in bone resorption rate takes place without a fully com-
pensatory increase in bone formation rate. In general, it appears that whenever any of these
situations has been studied, significant increases in markers of bone resorption have been
observed along with comparable increases in that fraction of blood lead coming from bone.
(iii) Excretion
Absorbed lead is excreted both in the urine and in faeces (by secretion in the bile).
Excretion in the urine is by filtration and reabsorption, and the rate of excretion is propor-
tional to the concentration of lead in plasma. Excretion in bile is highly variable among
experimental animal species. In humans, biliary excretion has been reported to be
between 25% and 50% of urinary excretion.
Absorbed inorganic lead is not exhaled from the lung.
(b) Organic lead

(i) Absorption
Organic lead compounds, such as tetraethyl lead and tetramethyl lead, behave as gases
in the respiratory tract, and are absorbed to a greater extent than are inorganic lead particles.
Organic lead compounds are also absorbed through the skin in both humans and experi-
mental animals.
(ii) Distribution and metabolism
Tetraethyl lead and tetramethyl lead are oxidatively dealkylated in the body. Any
inorganic lead produced endogenously is distributed in the same pattern as administered
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inorganic lead, but the parent compounds and the intermediate dealkylated products are
distributed quite differently and in accordance with their lipophilicity. In humans exposed
to tetraethyl lead, concentrations of the parent compound and its metabolites, including
inorganic lead, are highest in the liver and kidneys followed by the brain and heart. The
rates of metabolite production are not known in detail for either humans or experimental
animals. In rats, however, production of the toxic metabolite triethyl lead appears to be
fairly rapid (in the order of hours), while production of subsequent metabolites is much
slower (in the order of weeks). The highest concentrations of total lead in rats after expo-
sure to alkyl leads are found in the kidney and liver, followed by the brain.
(iii) Excretion
In humans, tetraethyl lead was found to be excreted in the urine as diethyl lead and
inorganic lead. In rats and rabbits, dialkyl lead is the major metabolite found in urine.
Tetraalkyl leads would also be excreted in the faeces as inorganic lead, the end product of
metabolism.
In humans, exhalation of tetraethyl lead and tetramethyl lead from the lung is a major
route of excretion, accounting for 40% (tetramethyl lead) and 20% (tetraethyl lead) of the
inhaled dose at 48 h after inhalation.
4.5.3 Toxicodynamics and mode of action of lead

(a) Genotoxic mechanisms
In considering the possible mechanisms whereby lead compounds could be muta-
genic, it is important to keep in mind the doses at which different biological responses are
seen. Since those mechanisms that occur only at highly toxic doses are not relevant
carcinogenesis, the mechanisms discussed below emphasize findings at lower doses.
In most commonly-used test systems, effects were rather weak and/or restricted to
toxic lead doses. In two published studies, in Chinese hamster ovary AS52 cells carrying
a single copy of an Escherichia coli gpt gene, lead chloride induced mutations in a dose-
dependent manner, at concentrations less than 1.0 µM. High mutant frequencies after
exposure to lead were also observed in a different study in Chinese hamster ovary CHO
K1 cells at higher but non-cytotoxic concentrations of lead starting at 0.5 mM. The muta-
tion spectrum included base substitutions predominantly at G-C sites, as well as small and
large deletions similar to DNA damage induced by ROS. Furthermore, two studies
revealed an increase in mutant frequency when non-mutagenic concentrations of lead
were used in combination with UVC irradiation or MNNG. One potential mechanism may
be the interference with DNA repair processes. Two independent studies revealed an
inhibition by lead of repair of UVC-induced or X-ray-induced DNA damage.
In addition to inducing gene mutations, lead appears to be an effective clastogen
in vivo (although not consistently) and in vitro. Human studies are mostly confounded by
the presence of other genotoxic compounds. Lead can induce aneuploidy, chromosomal
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aberrations, micronuclei, sister chromatid exchange and DNA damage (as measured most
frequently with the Comet assay).
There is some evidence to suggest that one of the mechanisms of the genotoxicity
seen after exposure to lead may be mediated by ROS. Lead appears to stimulate lipid
peroxidation in vivo. ROS can be increased in cells through a number of mechanisms. For
example, ALA, the haeme precursor whose levels are increased by lead exposure as a
result of inhibition of the enzyme ALAD, can generate free radicals in cells and cause the
formation of oxidative DNA lesions. Another mechanism may be depletion of cellular
antioxidants such as glutathione. The loss of protection against ROS generated by other
events may result in increased free radical and oxidative damage to DNA. Another aspect
of lead that will result in oxidative DNA damage is the ability of lead to undergo Fenton-
type reactions in the presence of hydrogen peroxide, leading to DNA strand breaks. One
study suggested that singlet oxygen may be involved, since singlet oxygen quenchers, but
not hydrogen peroxide or hydroxyl radical quenchers, blocked the reaction.
Dose considerations
As indicated earlier (see Distribution, above), the usual concentration of lead
measured in blood is almost entirely accounted for by the fraction present within and
bound to erythrocytes. Only a small fraction of blood lead is present in plasma, the precise
proportion depending on the concentration in whole blood. In people heavily exposed to
lead, with blood lead concentrations of about 100 µg/dL, plasma lead may be as high as
3 µg/dL (about 140 nM), whereas human populations in less contaminated environments
may have whole blood lead concentrations of about 10 µg/dL, which corresponds to
0.024 µg/dL (about 1 nM) in plasma. These values are important in considering the
human and non-human applicability of genetic toxicity data obtained from in-vitro
experiments (see Tables 92 and 93).
(b) Cell proliferation by mitogenic and regenerative mechanisms

Cell proliferation can occur either as a regenerative response to cytotoxicity or by a
process termed mitogenesis which does not involve cytotoxicity. Lead can increase proli-
feration of rat and mouse kidney cells, rat liver cells, vascular smooth muscle cells and
spleen cells as well as cultured human astrocytoma cells. Often, these proliferative effects
occur in the absence of cytotoxicity, although, at higher doses, lead is clearly causing cell
death. Thus, tritiated thymidine incorporation was significantly increased in human astro-
cytoma cells at 1 µM lead concentrations, while lactate dehydrogenase activity in the
medium (a measure of cytotoxicity) was not significantly increased until a concentration
of 20 µM lead was reached (10 µM having no effect). In the kidneys of mice treated with
intracardiac doses of lead acetate, there was a dose-related increase in tritiated thymidine
incorporation into DNA that was evident at 1 mg/kg bw lead and maximal at 5 mg/kg bw
lead in the absence of tubular necrosis. It is therefore plausible that lead exposure can
induce proliferation by both mechanisms and could act as a tumour promoter. It is also
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plausible, given the demonstration of lead-induced proliferation in such a wide variety of

cells, that any cell capable of replication in any tissue could be stimulated to do so by lead.
Lead has been shown to activate PKC, which comprises a large family of isozymes.
Activation of PKC has multiple consequences, including neurotransmitter release and the
induction of cell proliferation or differentiation and apoptosis. In human astrocytoma cells
specifically, lead induces the translocation of the PKCα isoform from the cytosolic to the
membrane fraction and stimulates DNA synthesis by a signal transduction cascade of the
form PKCα → Raf-1 → MEK1/2 → ERK1/2 → p90RSK, a protein that stimulates DNA
synthesis. The authors of the study stress, however, that this mechanism might not be
applicable to other cell types.
In rat kidneys, the early toxic effects of lead appear to be localized primarily in cells of
the proximal tubule, where lead is taken up by extensive membrane binding and possibly by
a passive transport mechanism. Studies in rats have demonstrated proximal tubular damage,
which is characterized by the development of intranuclear inclusion bodies in cells that
remain capable of division. Renal tumours have been observed in rodents after high-dose
exposure to lead. The inclusion bodies, which mainly consist of lead and lead-binding
proteins (PbBPs), are thought to act as intracellular depots of non-diffusible lead. A number
of high-affinity renal PbBPs have been identified, one of which is a cleavage product of α2u-
globulin, a male rat-specific protein. A cytolethal mechanism in the development of tumours
after lead exposure that involves α2u-globulin is, however, unlikely, since lead induces
tumours in male and female mice as well as male and female rats. Several other cytosolic
PbBPs have been found in kidneys from environmentally exposed humans. These include
thymosin β4 and the 9-kDa acyl-coenzyme A binding protein. Other similar low molecular
weight proteins bind lead in brain and analogous proteins exist in several species. A common
feature seems to be that they are rich in aspartic and glutamic dicarboxylic acid residues. In-
vitro studies using rat cells have shown that the renal PbBP facilitate the intranuclear
transport of lead and provide evidence of chromatin binding of the lead binding complex. It
has been suggested that this could lead to the altered gene expression associated with the
mitogenic effects of lead in the kidney.
Lead can induce significant functional impairments in vivo in major target organs at
doses below those associated with cytotoxicity. Significant increases in proliferative
lesions of the kidneys, including tubular cell carcinomas, were observed after lead acetate
exposures that did not result in pathological changes in adjacent tissues. Chronic nephro-
pathy was not observed in any of the studies at doses that produced tumours. Thus, non-
specific target organ toxicity, resulting in cell death, does not appear to be responsible for
the production of tumours due to lead exposure. On the other hand, other evidence
suggests that some form of cytotoxicity might play a role in renal carcinogenesis.
Cystic hyperplasia, a late morphological manifestation of chronic lead nephropathy, is
a risk factor for renal cancer. Renal adenocarcinoma in experimental animals occurs against
a background of proximal tubular cell hyperplasia, cytomegaly and cellular dysplasia.
Cystic hyperplasia was reported to occur prior to adenoma formation in animals treated
with renal carcinogens. One hypothesis regarding the progression from hyperplasia to
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cancer is that cells lining cysts become transformed and proliferate abnormally in response
to increased volumes of intracystic fluid. Both human and experimental studies suggest
that renal cyst formation contributes to an increased incidence of renal adenocarcinomas.
In the case of lead, adenocarcinoma may be a consequence of the cystic change in the renal
cortex that follows chronic lead-induced nephropathy.
More subtle types of cytotoxicity may also play roles in the carcinogenic process.
Oxidative stress may contribute to some aspects of the cellular toxicity of lead by disrup-
ting the pro-oxidant–antioxidant balance that exists within cells. For example, lipid oxi-
dation is significantly elevated in animals exposed to inorganic lead. These results suggest
that lead exerts its toxic effects by enhancing peroxidative damage to the membranes, thus
compromising cellular functions.
(c) Molecular mechanisms of action

The main mutagenic mechanisms of lead at non-cytotoxic concentrations demons-
trated to date are: (1) those involving ROS; and (2) interference with DNA repair pro-
cesses. It has been shown in many systems that exposure to lead results in altered ROS
levels and species. The mechanisms by which this can occur include inhibition of antioxi-
dant defence systems, catalysis of Fenton-type reactions, and via accummulation of ALA.
Nucleotide excision repair has been shown to be blocked by exposure to lead. This type
of inhibition would be expected to enhance the mutagenicity of agents such as polycyclic
aromatic hydrocarbons, UV and other agents causing bulky lesions in DNA. The co-muta-
genicity of lead with UVC or MNNG is consistent with the hypothesis that both nucleo-
tide excision repair and base excision repair may be affected by lead.
One mechanism for lead interaction with proteins could be via displacement of
metals, such as zinc or calcium, from their respective binding sites. In cell-free systems,
lead has been shown to reduce DNA binding of transcription factors TFIIIA and Sp1,
presumably by replacing zinc in zinc fingers. However, the zinc finger-containing repair
proteins XPA and Fpg were not inhibited by lead. Thus, zinc finger proteins cannot be
considered as a general target, but interactions depend on the specific protein. Further-
more, these interactions have not yet been demonstrated in intact cells.
Another mechanism that may be relevant for carcinogenesis by lead is its ability to
alter gene expression. One pathway by which this could occur is via activation of PKC,
which occurs at low concentrations of lead. PKC activation starts a signaling pathway that
leads to upregulation of ‘immediate early response’ genes, which ultimately results in a
proliferative response.
In conclusion, lead is a toxic metal and one expression of this property is genetic toxi-
city. There is, however, little evidence that it interacts directly with DNA at normally
encountered concentrations. The genetic toxicity of lead appears to be modified in part by
increases in and modulation of ROS. In addition, lead itself can interact with proteins,
including those involved in DNA repair. This latter mechanism might be responsible for
the enhancement of genotoxicity caused by other agents. These properties could result in
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mutation, changes in gene expression and cell proliferation, all of which would contribute
to a carcinogenic response if exposure is sustained.
5. Summary of Data Reported and Evaluation
5.1 Exposure data

Lead is found at low concentrations in the earth’s crust predominantly as lead sulfide
(galena), but the widespread occurrence of lead in the environment is largely the result of
anthropogenic activity. The utility of lead and lead compounds was discovered in pre-
historic times. Lead has been used in plumbing and tableware since the time of the Roman
Empire. Lead usage increased progressively with industrialization and rose dramatically
with the widespread use of the automobile in the twentieth century. Lead has found major
uses in pipes and plumbing, pigments and paints, gasoline additives, construction materials
and lead–acid batteries. The uses of lead in pipes, paints and gasoline additives have
resulted in substantial introductions of lead into the environment and human exposure, and
are being phased out in many countries. The predominant use of lead is now in lead–acid
batteries and, to a lesser extent, in construction materials and lead-based chemicals.
As a result of anthropogenic activity, lead can enter the environment at any stage from
its mining to its final use, including during recycling, and it contaminates crops, soil, water,
food, air and dust. Once lead is introduced, it persists. The important routes of human expo-
sure from these sources are inhalation or ingestion. The dispersion of lead throughout the
global environment and consequent human exposure has arisen predominantly from the
widespread use of leaded gasoline. Some geographic areas, for instance near lead mines and
smelters, have high environmental concentrations of lead. The past and present use of lead-
based paints can result in substantial risk for localized exposure to lead-contaminated dust.
Small industries (e.g. jewellery-making, ceramics, soldering, leaded glass) and individual
activities (smoking, home renovations, use of herbal remedies and cosmetics, certain crafts
and hobbies, and unregulated recycling) can lead to high exposure. Occupations in which
the highest potential exposure exists include mining, primary and secondary smelting, pro-
duction of lead–acid batteries, pigment production, construction and demolition.
Efforts to reduce environmental concentrations of lead, predominantly through the
decreased use of leaded gasoline, have resulted in substantial decreases in the introduction
of lead into the environment. In contaminated environments, dust control and hygienic
measures can considerably decrease exposure. In spite of the persistence of lead in the
environment, human exposure has decreased substantially in countries where control
measures have been implemented over the past 10–30 years.
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5.2 Human carcinogenicity data

Occupational studies
For lung cancer, six occupational cohort studies of highly exposed workers are parti-
cularly informative (battery workers in the USA, battery workers in the United Kingdom,
primary smelter workers in Italy, Sweden and the USA (two studies)). Potentially con-
founding exposures to other known occupational lung carcinogens were largely absent in
the battery workers. Several of the cohorts of smelter workers had low documented expo-
sures to arsenic, the principal occupational potential confounder of interest; the smelter
workers in Sweden had potentially high exposures to arsenic. Overall, with the exception
of the smelter workers in Sweden, these studies were consistent in showing no or a slight
excess of lung cancer compared with external reference populations. Observed excesses
were quite small and well within the range that might be explained by chance or confoun-
ding by smoking. Few or no data for dose–response analyses and no smoking data were
available for these cohorts. The Swedish study of smelter workers showed a statistically
significant twofold excess of lung cancer but this excess may well have been caused by
exposure to arsenic. A Finnish study of workers across many industries, whose blood lead
concentrations were sampled as part of a surveillance programme, was judged to be
moderately informative. Exposure to lead in this study was lower than in the six cohorts
of highly exposed workers but higher than in the general population. There was a modest
trend of increasing lung cancer with increasing levels of exposure in the Finnish cohort;
this trend was not statistically significant.
For stomach cancer, five (battery workers in the UK and the USA, primary smelter
workers in Italy and the USA (two studies)) of the six occupational cohort studies used
for the evaluation of lung cancer were judged to be particularly informative. In four of
these five studies, there was a fairly consistent excess of 30–50% of stomach cancer com-
pared with external reference populations. Exposure to arsenic is not considered to be a
cause of stomach cancer and any potential confounding by smoking is likely to be small.
Some analyses of limited exposure surrogates were carried out, but these did not implicate
lead exposure as the cause of the stomach cancer excess. However, little or no data for
quantitative dose–response analysis were available in these cohorts. It is possible that
ethnicity, dietary habits, prevalence of Helicobacter pylori infections or socioeconomic
status played a role in the stomach cancer excesses.
Five of the six cohort studies of highly exposed workers reported findings for kidney
cancer. In one study, there was a twofold statistically significant excess of kidney cancer,
based on comparison with an external reference population. In the remaining four studies,
mortality was either close to, or below, expected values. All five studies were based on
small numbers of deaths.
Four of the six cohort studies of highly exposed workers reported findings for
tumours of the brain and nervous system. On the basis of comparisons with external refe-
rence populations, mortality showed no consistent pattern. In addition, in a nested case–
control study, the cohort of workers from Finland showed a statistically significant posi-
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tive dose–response relationship between blood lead concentrations and the risk for
glioma. The cohort in the Finnish study had lower exposures to lead than the other occu-
pational cohorts; all studies were based on small numbers of deaths.
Environmental studies
Among the general population studies, the most informative are the two follow-up
studies on the US NHANES II population. A limitation of these two studies is the reliance
on one blood lead measurement per subject to define exposure. Both studies, analysing
essentially the same population, found a positive dose–response relationship between
blood lead concentrations and lung cancer, which approached or attained statistical signi-
ficance. However, these results within a low-dose population are not consistent with those
for lung cancer in more highly exposed occupational populations, for whom no consistent
lung cancer excess is apparent. At least some of the reported dose–response relationships
for lung cancer in these two studies may be due to residual confounding from smoking,
which was correlated with blood lead concentrations. Higher concentrations of blood lead
were apparent in those with lower income, so it is also possible that residual confounding
from occupational exposure to lung carcinogens may have contributed to positive dose–
response trends.
5.3 Animal carcinogenicity data

Lead acetate
Oral exposure to lead acetate has been shown to be carcinogenic in the rat kidney in
seven separate studies, producing adenomas and adenocarcinomas after chronic exposure
in males and/or females. Both of the studies that allowed assessment of a dose–response
relationship showed that such a relationship existed. In another experiment the offspring
of female mice exposed to oral lead acetate during pregnancy and lactation showed dose-
related increases in renal tumours as adults in the absence of chronic lead-induced
nephropathy.
Brain gliomas were observed after oral exposure to lead acetate in rats in two separate
studies.
One study in rats indicated that oral exposure to lead acetate was associated with
tumours of the adrenal gland, testes and prostate in males and adrenal gland in females.
In a study of a mixed population of male and female rats, oral exposure to lead acetate
was associated with tumours of the lung, pituitary, prostate, mammary gland and adrenal
gland.
Lead subacetate
One experiment in male and female mice and six experiments in male and/or female
rats showed that oral exposure to lead subacetate induced renal cancer. One of these
studies showed a dose–response relationship. Brain gliomas were observed in rats after
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oral administration of lead subacetate in one study. Three studies show that repeated
intraperitoneal injections of lead subacetate increased lung tumour multiplicity in strain
A mice. One study of oral exposure to lead subacetate in strain A mice was negative for
lung tumours. In one study, hamsters exposed orally to lead subacetate did not develop
tumours.
Lead powder
Two studies in rats exposed to lead powder orally or by intramuscular injection and
one study on intrarenal injection of lead powder in rats did not produce tumours.
Lead oxide
In one experiment, inhalation of lead oxide did not produce tumours in male rats.
Lead chromate
One study showed that injection-site sarcomas were induced by a single subcutaneous
injection of lead chromate in rats. One study of intramuscular injection of lead chromate
in rats produced renal tumours. One study of intramuscular injection of lead chromate in
mice and one study of intrabronchiolar implantation of different lead chromates in rats
were negative. The role of chromium in the carcinogenic response of lead chromate in
these studies cannot be excluded.
Lead phosphate
In four separate studies, injection of lead phosphate subcutaneously, or combined sub-
cutaneously and intraperitoneally, was shown to produce renal cancers in rats.
Lead arsenate
One study of oral administration of lead arsenate in male and female rats was negative.
Tetraethyl lead
One experiment with repeated subcutaneous injections of tetraethyl lead was found to
be inadequate for evaluation.
Administration of lead compounds with known carcinogens or modifiers

Three experiments showed that oral exposure to lead subacetate enhanced N-ethyl-N-
hydroxyethylnitrosamine-induced renal carcinogenesis in male rats. One study showed
that oral lead subacetate-induced renal tumours in rats were increased by concomitant oral
administration of calcium acetate. One study in strain A mice showed that calcium acetate
and magnesium acetate inhibited lung adenomas induced by intraperitoneal injection of
lead subacetate. Intratracheal instillations of combinations of lead oxide and benzo[a]-
pyrene in hamsters produced lung tumours not observed with either agent alone. Oral
exposure to lead nitrate increased the incidence of N-nitrosodimethylamine-induced renal
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tumours in male rats while intraperitoneal injections of lead subacetate enhanced N-nitro-
sodimethylamine-induced lung tumour multiplicity in mice.
Overall, extensive experimental evidence shows that various water-soluble and -inso-
luble lead compounds can induce kidney tumours in rodents. In addition, one study
showed that renal tumours can occur in the absence of lead-induced nephropathy. It is also
noteworthy that the induction of brain gliomas, which are rarely spontaneous, occurred
after oral exposure to lead in rats. Lead proved to be an effective renal tumour carcino-
gen/promoter in rats and mice exposed to various organic renal carcinogens.
5.4 Other relevant data

Toxicokinetics and metabolism of lead
Inorganic lead
Lead absorption from the gastrointestinal tract in both humans and experimental ani-
mals is strongly influenced by age (neonates and the young absorb a larger fraction than
adults), fasting/fed status (fasting humans and experimental animals absorb much larger
fractions than their fed counterparts), nutrition (fat and caloric intakes; phosphorus,
copper, zinc and especially iron and calcium status, all affect lead absorption), solubility
(soluble lead compounds are better absorbed) and particle size (in controlled studies in
rats, lead absorption from ingested mining wastes was shown to be inversely proportional
to particle size). There are no data indicating that the fraction of lead absorbed from an
inhalation exposure is dependent on the amount of lead in the lung. Patterns and rates of
particle deposition are highly dependent on particle size and ventilation rate, but all lead
deposited deep in the lung is eventually absorbed. Limited studies indicate that dermal
absorption of inorganic lead is negligible, although slightly increased by high perspiration
rates in humans.
In both humans and experimental animals, absorbed lead is rapidly distributed from
blood plasma simultaneously into erythrocytes, soft tissues, and bone. The half-life of lead
in blood and soft tissues is 20–30 days in adult humans and 3–5 days in adult rats. In both
humans and rats, the soft-tissue concentrations of lead are highest in liver and kidney and
much lower in brain. Plasma, rather than whole blood, is generally accepted as the source
of lead available for distribution and excretion, although plasma lead comprises only
0.2–0.3% of whole blood lead concentrations when these are < 6 µg/dL. The fraction of
whole blood lead in plasma is substantially larger at high blood lead concentrations than
at low blood lead concentrations.
The majority of lead is stored in bone (in adults > 90%) and is partitioned mainly into
trabecular and cortical bone. The higher rate of remodelling in trabecular bone is reflected
in a shorter half-life of lead in trabecular bone (2–8 years) compared with that in cortical
bone (> 20 years). Bone can be a significant source of endogenous lead, in particular when
the bone resorption rate is increased, such as during pregnancy, lactation, the period just
after menopause, and during weightlessness.
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After oral ingestion, inorganic lead that has not been absorbed in the gastrointestinal
tract is excreted in the faeces. Absorbed lead is excreted in the urine and, via the bile, in
the faeces. Excretion of lead through sweat is of minor importance.
Organic lead
Organic lead compounds, such as tetraethyl lead and tetramethyl lead, behave as
gases in the respiratory tract and are absorbed to a greater extent than are inorganic lead
particles. Organic lead compounds are also absorbed through the skin of both humans and
experimental animals.
Tetraethyl lead and tetramethyl lead are oxidatively dealkylated in the body. Any
inorganic lead produced from these reactions is distributed in the same way as adminis-
tered inorganic lead. In humans and rats exposed to alkyl lead, concentrations of lead are
highest in the liver and kidneys followed by the brain and heart. The rates of metabolite
production are not known in detail for either humans or experimental animals.
In humans, tetraethyl lead is excreted in the urine as diethyl lead, ethyl lead, and
inorganic lead. In rats and rabbits, dialkyl lead is the major metabolite found in urine. One
of the end-products of metabolism of tetraalkyl leads is inorganic lead, which is also
excreted in the faeces.
In humans, exhalation of unmetabolized tetraethyl lead and tetramethyl lead from the
lung is a major route of excretion.
Toxic effects of inorganic lead

Typical clinical manifestations of lead poisoning include weakness, irritability,
asthenia, nausea, abdominal pain with constipation, and anaemia.
Lead interferes with numerous physiological processes. In the haeme biosynthetic
pathway, it inhibits δ-aminolevulinic acid dehydratase (also known as porphobilinogen
synthase), probably through its high affinity for the zinc-binding site in the enzyme.
Although lead displaces zinc more readily in one of the alloenzymes of the protein, the
relationship between δ-aminolevulinic acid dehydratase genotype and sensitivity to lead
at different blood lead concentrations is at present unclear. Lead also causes an increase
in zinc protoporphyrin, by a mechanism which is not fully established. Lead inhibits pyri-
midine-5′-nucleotidase, resulting in accumulation of nucleotides, and subsequent haemo-
lysis and anaemia.
Renal manifestations of acute lead poisoning include glycosuria, aminoaciduria and
phosphaturia. Chronic exposure to low concentrations of lead is associated with increased
urinary excretion of low-molecular-weight proteins and lysosomal enzymes. Chronic
exposure to high concentrations of lead results in interstitial fibrosis, glomerular sclerosis,
tubular dysfunction and, ultimately, in chronic renal failure. Lead has also been impli-
cated in the development of hypertension secondary to nephropathy.
A considerable body of evidence suggests that children are more sensitive than adults
to the neurotoxic properties of lead. Although clinical symptoms of toxicity generally
become apparent at blood lead concentrations of 70 µg/dL, many important disturbances
P 337-378 DEF.qxp 09/08/2006 13:47 Page 376
occur at much lower concentrations. These include electrophysiological anomalies of

evoked brain potential in response to auditory stimuli and reduced peripheral nerve con-
duction. Both cross-sectional and prospective studies of children have found impairments
in cognition, attention, and language function at concentrations of lead previously thought
to be harmless. In studies with larger samples, better measures of lead burden and neuro-
behavioural function, and more advanced statistical techniques, effects are detectable at
blood lead concentrations below 10 µg/dL. The relative effect is greater below 10 µg/dL
than above this level. Recently, attention has shifted from the impact of lead on cognition
to its effects on behaviour. Exposure to lead has been found to be associated with atten-
tional dysfunction, aggression and delinquency.
Exposure to lead is associated with cardiovascular effects and with changes in endo-
crine and immune functions.
Many of the effects of lead exposure in humans have been confirmed in experimental
systems. At the cellular level, lead has mitogenic properties; it affects various regulatory
proteins, including those that depend on the presence of zinc.
Studies on the reproductive and developmental toxicity of lead did not show consistent
effects, morphologically or quantitatively, on markers of male fertility. It is not clear
whether the effects are caused by a direct interaction of lead with the reproductive organs,
or by modulation of the endocrine control of reproduction, or both.
There is consistent evidence in humans, in the form of case series and epidemiological
studies, that the risk for spontaneous abortion (pregnancy loss before the 20th week of
gestation, but after the stage of unrecognized, sub-clinical loss) is increased by maternal
exposure to high concentrations of lead.
In humans, prenatal lead exposure is associated with an increased risk for minor mal-
formations, low birth weight and reduced postnatal growth rate. The effect on postnatal
growth rate is apparent only in those children with continuing postnatal lead exposure.
Differences in reproductive end-points between species make it unlikely that useful
conclusions can be extrapolated from animals to humans.
Genotoxicity of inorganic lead compounds

Human studies
Humans occupationally exposed to lead show evidence of genotoxicity as measured in
a variety of assays. In some studies, these effects were correlated with blood lead concen-
trations. However, all the human genotoxicity studies involved co-exposure to lead and
other compounds, making it difficult to attribute genetic and other effects to lead alone.
In a limited number of studies on non-occupationally exposed individuals, no geno-
toxic effects were found that were correlated with blood lead concentrations.
Studies in experimental systems
Mutations were not induced in bacteria by either lead acetate or lead chloride, but
were induced by both lead chromate and lead bromide. In these last two cases, however,
the activity appeared to be due to the anions. In cultures of various mammalian cells, lead
P 337-378 DEF.qxp 09/08/2006 13:47 Page 377
acetate, lead chromate and lead nitrate induced DNA strand breaks. Furthermore, most
studies revealed positive mutagenic responses even though the extent of mutagenicity and
the lead concentrations at which the responses were observed varied considerably, depen-
ding on cell type and experimental conditions. Tests for sister chromatid exchange and
chromosomal aberrations showed variable responses. Micronucleus formation has been
shown to occur at low concentrations of lead. In a single study, lead sulfide induced
micronuclei, gene mutations and sister chromatid exchanges. Organo-lead compounds do
not appear to have been tested in vitro.
Studies of genetic toxicity in animals have been conducted by the oral, inhalation,
subcutaneous, intraperitoneal and intravenous routes. It should be noted that blood lead
concentrations were not available in these studies, except in a single study in cynomolgus
monkeys, and that the exposure concentrations were generally far higher than those
reported in human occupational studies. DNA strand breakage has been demonstrated in
lead-exposed animals, and variable results have been found in tests for induction of sister
chromatid exchange. Micronucleus induction in bone-marrow cells of lead-exposed ani-
mals has been demonstrated in some studies. Most studies of chromosomal aberrations
have demonstrated increased frequencies in mice, rats and in the one study in cynomolgus
monkeys reported. Aneuploidy has been demonstrated in lead-exposed rats and mice.
Increases in the proportion of morphologically abnormal sperm have also been found in
mice and cynomolgus monkeys, but not in rabbits. Dominant lethal effects were not
observed in male mice exposed to lead in a single study.
In conclusion, lead is a toxic metal and one expression of this property is genetic toxi-
city. There is, however, little evidence that it interacts directly with DNA at normally
encountered blood lead concentrations. The genetic toxicity of lead appears to be mediated
in part by increases in, and modulation of, reactive oxygen species. In addition, lead inter-
acts with proteins, including those involved in DNA repair. This latter mechanism might
be responsible for enhancing the genotoxicity of other agents. These properties could result
in mutation, changes in gene expression and cell proliferation, all of which would contri-
bute to a carcinogenic response if exposure is sustained.
5.5 Evaluation
There is limited evidence in humans for the carcinogenicity of inorganic lead
compounds.
There is inadequate evidence in humans for the carcinogenicity of organic lead
compounds.
There is sufficient evidence in experimental animals for the carcinogenicity of
inorganic lead compounds.
There is sufficient evidence in experimental animals for the carcinogenicity of lead
acetate, lead subacetate, lead chromate, and lead phosphate.
There is inadequate evidence in experimental animals for the carcinogenicity of lead
oxide and lead arsenate.
P 337-378 DEF.qxp 09/08/2006 13:47 Page 378
There is inadequate evidence in experimental animals for the carcinogenicity of

organic lead compounds.
There is inadequate evidence in experimental animals for the carcinogenicity of tetra-
ethyl lead.
There is inadequate evidence in experimental animals for the carcinogenicity of lead
powder.
Overall evaluation
Inorganic lead compounds are probably carcinogenic to humans (Group 2A).
Organic lead compounds are not classifiable as to their carcinogenicity to humans
(Group 3).
The Working Group noted that organic lead compounds are metabolized, at least in
part, to ionic lead both in humans and animals. To the extent that ionic lead, generated
from organic lead, is present in the body, it will be expected to exert the toxicities asso-
ciated with inorganic lead.
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LIST OF ABBREVIATIONS USED IN THIS VOLUME
1,25-(OH)2D: 1,25-dihydroxycholecalciferol
2-AAF: 2-acetylaminofluorene
βOHF: 6β-hydroxycortisol
6β
8-OH-dG: 8-OH-deoxyguanosine
AAS: atomic absorption spectrometry
ABEP: auditory brainstem evoked potential
ACGIH: American Conference of Governmental Industrial Hygienists
ALA: ∂-aminolevulinic acid
ALAD: ∂-aminolevulinate dehydratase
ALT: alanine aminotransferase
AOAC: Association of Official Analytical Chemists
AST: aspartate aminotransferase
ASTM: American Society for Testing and Materials
ASV: anode-stripping voltammetry
ATP: Adenosine triphosphate
AUC: area-under-the-curve
BEI: biological exposure index
bw: body weight
CaBP: calcium-binding proteins
CAT: computerized axial tomography
CBLI: cumulative blood lead index
CDC: US Centers for Disease Control and Prevention
CI: confidence interval
CNS: central nervous system
CRP: C-reactive protein
DMSA: dimercaptosuccinic acid
DMT: divalent cation metal transporter
DNA: deoxyribonucleic acid
DTH: delayed-type hypersensitivity
EDTA: ethylenediaminetetracetic acid
EHEN: N-ethyl-N-hydroxyethylnitrosamine
EP: erythrocyte protoporphyrin
EPA: Environmental Protection Agency (USA)
FBPA: N-(4′-fluoro-4-biphenyl) acetamide
Fpg: formamidopyrimidine-DNA glycosylase
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FSH: follicle-stimulating hormone

GABA: γ-aminobutyric acid
GC: gas chromatography
GF–AAS: graphite furnace–atomic absorption spectrometry
GFR: glomerular filtration rate
GSH: reduced glutathione
GST: glutathione S-transferase
HOME: home observation for measurement of the environment
HP2: human protamine 2
HPG: hypothalamic–pituitary–gonadal
HPLC: high-performance liquid chromatography
Hsp: heat-shock protein
ICD-8: international classification of diseases 8th revision
ICD-9: international classification of diseases 9th revision
ICP-AES: inductively coupled plasma–atomic emission spectrometry
ICP-MS: inductively coupled plasma–mass spectrometry
IFN: interferon
IL: interleukin
IQ: intelligence quotient
IUGR: intrauterine growth retardation
IUPAC: International Union of Pure and Applied Chemistry
JECFA: Joint FAO/WHO Expert Committee on Food Additives
KααXRF: X-ray fluorescence, using K-alpha line excitation
LH: luteinizing hormone
MAPK: mitogen-activated protein kinase
MEK: MAP kinase kinase
MMAD: mass median aerodynamic diameter
MMD: mass median diameter
MNNG: N-methyl-N-nitro-N-nitrosoguanidine
NAG: N-acetyl-β-D-glucosaminidase
NBBN: N-butyl-N(4-hydroxybutyl) nitrosamine
NDEA: N-nitrosodiethylamine
NDMA: N-nitrosodimethylamine
NHANES II: National Health and Nutrition Examination Survey II
NIOSH: National Institute for Occupational Safety and Health (USA)
NK: natural killer
NO: nitric oxide
NOAA: National Oceanic and Atmospheric Administration
OECD: Organisation for Economic Co-operation and Development
OR: odds ratio
OSHA: Occupational Safety and Health Administration (USA)
P5′′N: pyrimidine 5′-nucleotidase
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LIST OF ABBREVIATIONS 471
PbBP: lead-binding protein

PBGS: porphobilinogen synthase
PBMC: peripheral blood mononuclear cell
PBPK: physiologically based pharmacokinetic model
PBZ: personal breathing zone
PHA: phytohaemagglutinin
PID: photoionization detection
PKC: protein kinase C
PMOR: proportional mortality odds ratio
PVC: polyvinyl chloride
ROS: reactive oxygen species
SBG: steroid binding globulin
SBIS: Stanford-Binet Intelligence Scale
SCGE: single-cell gel electophoresis
SIR: standardized incidence ratio
SMR: standardized mortality ratio
SOD: superoxide dismutase
SPMR: standardized proportional mortality rate
T3: triiodothyronine
T4: thyroxine
TFIIIA: transcription factor IIIA
TH: tyrosine hydrolase
TIMS: thermal ionization–mass spectrometry
TNF: tumor necrosis factor
TPA: 12-O-tetradecanoyl phorbol-13-acetate
TSH: thyroid-stimulating hormone
US DHUD: United States Department of Housing and Urban Development
US EPA: United States Environmental Protection Agency
US FDA: United States Food and Drug Administration
UV: ultraviolet
VDR: vitamin D receptor
VEP: visual-evoked potential
WISC-R: Wechsler revised intelligence scale for children
XRF: X-ray fluorescence
ZPP: zinc protoporphyrin
βNF: 5,6-benzoflavone
γGT: γ-glutamyl transpeptidase
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CUMULATIVE CROSS INDEX TO IARC MONOGRAPHS ON

THE EVALUATION OF CARCINOGENIC RISKS TO HUMANS
The volume, page and year of publication are given. References to corrigenda are given
in parentheses.
A-α-C 40, 245 (1986); Suppl. 7, 56 (1987)

Acetaldehyde 36, 101 (1985) (corr. 42, 263);
Suppl. 7, 77 (1987); 71, 319 (1999)
Acetaldehyde formylmethylhydrazone (see Gyromitrin)
Acetamide 7, 197 (1974); Suppl. 7, 56, 389
(1987); 71, 1211 (1999)
Acetaminophen (see Paracetamol)
Aciclovir 76, 47 (2000)
Acid mists (see Sulfuric acid and other strong inorganic acids,
occupational exposures to mists and vapours from)
Acridine orange 16, 145 (1978); Suppl. 7, 56 (1987)
Acriflavinium chloride 13, 31 (1977); Suppl. 7, 56 (1987)
Acrolein 19, 479 (1979); 36, 133 (1985);
Suppl. 7, 78 (1987); 63, 337 (1995)
(corr. 65, 549)
Acrylamide 39, 41 (1986); Suppl. 7, 56 (1987);
60, 389 (1994)
Acrylic acid 19, 47 (1979); Suppl. 7, 56 (1987);
71, 1223 (1999)
Acrylic fibres 19, 86 (1979); Suppl. 7, 56 (1987)
Acrylonitrile 19, 73 (1979); Suppl. 7, 79 (1987);
71, 43 (1999)
Acrylonitrile-butadiene-styrene copolymers 19, 91 (1979); Suppl. 7, 56 (1987)
Actinolite (see Asbestos)
Actinomycin D (see also Actinomycins) Suppl. 7, 80 (1987)
Actinomycins 10, 29 (1976) (corr. 42, 255)
Adriamycin 10, 43 (1976); Suppl. 7, 82 (1987)
AF-2 31, 47 (1983); Suppl. 7, 56 (1987)
Aflatoxins 1, 145 (1972) (corr. 42, 251);
10, 51 (1976); Suppl. 7, 83 (1987);
56, 245 (1993); 82, 171 (2002)
Aflatoxin B1 (see Aflatoxins)
Aflatoxin B2 (see Aflatoxins)
Aflatoxin G1 (see Aflatoxins)
Aflatoxin G2 (see Aflatoxins)
Aflatoxin M1 (see Aflatoxins)
Agaritine 31, 63 (1983); Suppl. 7, 56 (1987)
Alcohol drinking 44 (1988)
Aldicarb 53, 93 (1991)
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Aldrin 5, 25 (1974); Suppl. 7, 88 (1987)

Allyl chloride 36, 39 (1985); Suppl. 7, 56 (1987);
71, 1231 (1999)
Allyl isothiocyanate 36, 55 (1985); Suppl. 7, 56 (1987);
73, 37 (1999)
Allyl isovalerate 36, 69 (1985); Suppl. 7, 56 (1987);
71, 1241 (1999)
Aluminium production 34, 37 (1984); Suppl. 7, 89 (1987)
Amaranth 8, 41 (1975); Suppl. 7, 56 (1987)
5-Aminoacenaphthene 16, 243 (1978); Suppl. 7, 56 (1987)
2-Aminoanthraquinone 27, 191 (1982); Suppl. 7, 56 (1987)
para-Aminoazobenzene 8, 53 (1975); Suppl. 7, 56, 390
(1987)
ortho-Aminoazotoluene 8, 61 (1975) (corr. 42, 254);
Suppl. 7, 56 (1987)
para-Aminobenzoic acid 16, 249 (1978); Suppl. 7, 56 (1987)
4-Aminobiphenyl 1, 74 (1972) (corr. 42, 251);
Suppl. 7, 91 (1987)
2-Amino-3,4-dimethylimidazo[4,5-f]quinoline (see MeIQ)
2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (see MeIQx)
3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (see Trp-P-1)
2-Aminodipyrido[1,2-a:3′,2′-d]imidazole (see Glu-P-2)
1-Amino-2-methylanthraquinone 27, 199 (1982); Suppl. 7, 57 (1987)
2-Amino-3-methylimidazo[4,5-f]quinoline (see IQ)
2-Amino-6-methyldipyrido[1,2-a:3′,2′-d]imidazole (see Glu-P-1)
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (see PhIP)
2-Amino-3-methyl-9H-pyrido[2,3-b]indole (see MeA-α-C)
3-Amino-1-methyl-5H-pyrido[4,3-b]indole (see Trp-P-2)
2-Amino-5-(5-nitro-2-furyl)-1,3,4-thiadiazole 7, 143 (1974); Suppl. 7, 57 (1987)
2-Amino-4-nitrophenol 57, 167 (1993)
2-Amino-5-nitrophenol 57, 177 (1993)
4-Amino-2-nitrophenol 16, 43 (1978); Suppl. 7, 57 (1987)
2-Amino-5-nitrothiazole 31, 71 (1983); Suppl. 7, 57 (1987)
2-Amino-9H-pyrido[2,3-b]indole (see A-α-C)
11-Aminoundecanoic acid 39, 239 (1986); Suppl. 7, 57 (1987)
Amitrole 7, 31 (1974); 41, 293 (1986) (corr.
52, 513; Suppl. 7, 92 (1987);
79, 381 (2001)
Ammonium potassium selenide (see Selenium and selenium compounds)
Amorphous silica (see also Silica) 42, 39 (1987); Suppl. 7, 341 (1987);
68, 41 (1997) (corr. 81, 383)
Amosite (see Asbestos)
Ampicillin 50, 153 (1990)
Amsacrine 76, 317 (2000)
Anabolic steroids (see Androgenic (anabolic) steroids)
Anaesthetics, volatile 11, 285 (1976); Suppl. 7, 93 (1987)
Analgesic mixtures containing phenacetin (see also Phenacetin) Suppl. 7, 310 (1987)
Androgenic (anabolic) steroids Suppl. 7, 96 (1987)
Angelicin and some synthetic derivatives (see also Angelicins) 40, 291 (1986)
Angelicin plus ultraviolet radiation (see also Angelicin and some Suppl. 7, 57 (1987)
synthetic derivatives)
Angelicins Suppl. 7, 57 (1987)
Aniline 4, 27 (1974) (corr. 42, 252);
27, 39 (1982); Suppl. 7, 99 (1987)
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CUMULATIVE INDEX 475
ortho-Anisidine 27, 63 (1982); Suppl. 7, 57 (1987);

73, 49 (1999)
para-Anisidine 27, 65 (1982); Suppl. 7, 57 (1987)
Anthanthrene 32, 95 (1983); Suppl. 7, 57 (1987)
Anthophyllite (see Asbestos)
Anthracene 32, 105 (1983); Suppl. 7, 57 (1987)
Anthranilic acid 16, 265 (1978); Suppl. 7, 57 (1987)
Anthraquinones 82, 129 (2002)
Antimony trioxide 47, 291 (1989)
Antimony trisulfide 47, 291 (1989)
ANTU (see 1-Naphthylthiourea)
Apholate 9, 31 (1975); Suppl. 7, 57 (1987)
para-Aramid fibrils 68, 409 (1997)
Aramite® 5, 39 (1974); Suppl. 7, 57 (1987)
Areca nut (see also Betel quid) 85, 39 (2004)
Aristolochia species (see also Traditional herbal medicines) 82, 69 (2002)
Aristolochic acids 82, 69 (2002)
Arsanilic acid (see Arsenic and arsenic compounds)
Arsenic and arsenic compounds 1, 41 (1972); 2, 48 (1973);
23, 39 (1980); Suppl. 7, 100 (1987)
Arsenic in drinking-water 84, 39 (2004)
Arsenic pentoxide (see Arsenic and arsenic compounds)
Arsenic trioxide (see Arsenic in drinking-water)
Arsenic trisulfide (see Arsenic in drinking-water)
Arsine (see Arsenic and arsenic compounds)
Asbestos 2, 17 (1973) (corr. 42, 252);
14 (1977) (corr. 42, 256); Suppl. 7,
106 (1987) (corr. 45, 283)
Atrazine 53, 441 (1991); 73, 59 (1999)
Attapulgite (see Palygorskite)
Auramine (technical-grade) 1, 69 (1972) (corr. 42, 251);
Suppl. 7, 118 (1987)
Auramine, manufacture of (see also Auramine, technical-grade) Suppl. 7, 118 (1987)
Aurothioglucose 13, 39 (1977); Suppl. 7, 57 (1987)
Azacitidine 26, 37 (1981); Suppl. 7, 57 (1987);
50, 47 (1990)
5-Azacytidine (see Azacitidine)
Azaserine 10, 73 (1976) (corr. 42, 255);
Suppl. 7, 57 (1987)
Azathioprine 26, 47 (1981); Suppl. 7, 119 (1987)
Aziridine 9, 37 (1975); Suppl. 7, 58 (1987);
71, 337 (1999)
2-(1-Aziridinyl)ethanol 9, 47 (1975); Suppl. 7, 58 (1987)
Aziridyl benzoquinone 9, 51 (1975); Suppl. 7, 58 (1987)
Azobenzene 8, 75 (1975); Suppl. 7, 58 (1987)
AZT (see Zidovudine)
Barium chromate (see Chromium and chromium compounds)

Basic chromic sulfate (see Chromium and chromium compounds)
BCNU (see Bischloroethyl nitrosourea)
Benz[a]acridine 32, 123 (1983); Suppl. 7, 58 (1987)
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Benz[c]acridine 3, 241 (1973); 32, 129 (1983);

Suppl. 7, 58 (1987)
Benzal chloride (see also α-Chlorinated toluenes and benzoyl chloride) 29, 65 (1982); Suppl. 7, 148 (1987);
71, 453 (1999)
Benz[a]anthracene 3, 45 (1973); 32, 135 (1983);
Suppl. 7, 58 (1987)
Benzene 7, 203 (1974) (corr. 42, 254); 29,
93, 391 (1982); Suppl. 7, 120
(1987)
Benzidine 1, 80 (1972); 29, 149, 391 (1982);
Suppl. 7, 123 (1987)
Benzidine-based dyes Suppl. 7, 125 (1987)
Benzo[b]fluoranthene 3, 69 (1973); 32, 147 (1983);
Suppl. 7, 58 (1987)
Benzo[j]fluoranthene 3, 82 (1973); 32, 155 (1983);
Suppl. 7, 58 (1987)
Benzo[k]fluoranthene 32, 163 (1983); Suppl. 7, 58 (1987)
Benzo[ghi]fluoranthene 32, 171 (1983); Suppl. 7, 58 (1987)
Benzo[a]fluorene 32, 177 (1983); Suppl. 7, 58 (1987)
Benzo[b]fluorene 32, 183 (1983); Suppl. 7, 58 (1987)
Benzo[c]fluorene 32, 189 (1983); Suppl. 7, 58 (1987)
Benzofuran 63, 431 (1995)
Benzo[ghi]perylene 32, 195 (1983); Suppl. 7, 58 (1987)
Benzo[c]phenanthrene 32, 205 (1983); Suppl. 7, 58 (1987)
Benzo[a]pyrene 3, 91 (1973); 32, 211 (1983)
(corr. 68, 477); Suppl. 7, 58 (1987)
Benzo[e]pyrene 3, 137 (1973); 32, 225 (1983);
Suppl. 7, 58 (1987)
1,4-Benzoquinone (see para-Quinone)
1,4-Benzoquinone dioxime 29, 185 (1982); Suppl. 7, 58 (1987);
71, 1251 (1999)
Benzotrichloride (see also α-Chlorinated toluenes and benzoyl chloride) 29, 73 (1982); Suppl. 7, 148 (1987);
71, 453 (1999)
Benzoyl chloride (see also α-Chlorinated toluenes and benzoyl chloride) 29, 83 (1982) (corr. 42, 261);
Suppl. 7, 126 (1987); 71, 453 (1999)
Benzoyl peroxide 36, 267 (1985); Suppl. 7, 58 (1987);
71, 345 (1999)
Benzyl acetate 40, 109 (1986); Suppl. 7, 58 (1987);
71, 1255 (1999)
Benzyl chloride (see also α-Chlorinated toluenes and benzoyl chloride) 11, 217 (1976) (corr. 42, 256); 29,
49 (1982); Suppl. 7, 148 (1987);
71, 453 (1999)
Benzyl violet 4B 16, 153 (1978); Suppl. 7, 58 (1987)
Bertrandite (see Beryllium and beryllium compounds)
Beryllium and beryllium compounds 1, 17 (1972); 23, 143 (1980)
(corr. 42, 260); Suppl. 7, 127
(1987); 58, 41 (1993)
Beryllium acetate (see Beryllium and beryllium compounds)
Beryllium acetate, basic (see Beryllium and beryllium compounds)
Beryllium-aluminium alloy (see Beryllium and beryllium compounds)
Beryllium carbonate (see Beryllium and beryllium compounds)
Beryllium chloride (see Beryllium and beryllium compounds)
Beryllium-copper alloy (see Beryllium and beryllium compounds)
Beryllium-copper-cobalt alloy (see Beryllium and beryllium compounds)
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Beryllium fluoride (see Beryllium and beryllium compounds)

Beryllium hydroxide (see Beryllium and beryllium compounds)
Beryllium-nickel alloy (see Beryllium and beryllium compounds)
Beryllium oxide (see Beryllium and beryllium compounds)
Beryllium phosphate (see Beryllium and beryllium compounds)
Beryllium silicate (see Beryllium and beryllium compounds)
Beryllium sulfate (see Beryllium and beryllium compounds)
Beryl ore (see Beryllium and beryllium compounds)
Betel quid with tobacco 37, 141 (1985); Suppl. 7, 128
(1987); 85, 39 (2004)
Betel quid without tobacco 37, 141 (1985); Suppl. 7, 128
(1987); 85, 39 (2004)
BHA (see Butylated hydroxyanisole)
BHT (see Butylated hydroxytoluene)
Bis(1-aziridinyl)morpholinophosphine sulfide 9, 55 (1975); Suppl. 7, 58 (1987)
2,2-Bis(bromomethyl)propane-1,3-diol 77, 455 (2000)
Bis(2-chloroethyl)ether 9, 117 (1975); Suppl. 7, 58 (1987);
71, 1265 (1999)
N,N-Bis(2-chloroethyl)-2-naphthylamine 4, 119 (1974) (corr. 42, 253);
Suppl. 7, 130 (1987)
Bischloroethyl nitrosourea (see also Chloroethyl nitrosoureas) 26, 79 (1981); Suppl. 7, 150 (1987)
1,2-Bis(chloromethoxy)ethane 15, 31 (1977); Suppl. 7, 58 (1987);
71, 1271 (1999)
1,4-Bis(chloromethoxymethyl)benzene 15, 37 (1977); Suppl. 7, 58 (1987);
71, 1273 (1999)
Bis(chloromethyl)ether 4, 231 (1974) (corr. 42, 253);
Suppl. 7, 131 (1987)
Bis(2-chloro-1-methylethyl)ether 41, 149 (1986); Suppl. 7, 59 (1987);
71, 1275 (1999)
Bis(2,3-epoxycyclopentyl)ether 47, 231 (1989); 71, 1281 (1999)
Bisphenol A diglycidyl ether (see also Glycidyl ethers) 71, 1285 (1999)
Bisulfites (see Sulfur dioxide and some sulfites, bisulfites and
metabisulfites)
Bitumens 35, 39 (1985); Suppl. 7, 133 (1987)
Bleomycins (see also Etoposide) 26, 97 (1981); Suppl. 7, 134 (1987)
Blue VRS 16, 163 (1978); Suppl. 7, 59 (1987)
Boot and shoe manufacture and repair 25, 249 (1981); Suppl. 7, 232
(1987)
Bracken fern 40, 47 (1986); Suppl. 7, 135 (1987)
Brilliant Blue FCF, disodium salt 16, 171 (1978) (corr. 42, 257);
Suppl. 7, 59 (1987)
Bromochloroacetonitrile (see also Halogenated acetonitriles) 71, 1291 (1999)
Bromodichloromethane 52, 179 (1991); 71, 1295 (1999)
Bromoethane 52, 299 (1991); 71, 1305 (1999)
Bromoform 52, 213 (1991); 71, 1309 (1999)
1,3-Butadiene 39, 155 (1986) (corr. 42, 264);
Suppl. 7, 136 (1987); 54, 237
(1992); 71, 109 (1999)
1,4-Butanediol dimethanesulfonate 4, 247 (1974); Suppl. 7, 137 (1987)
n-Butyl acrylate 39, 67 (1986); Suppl. 7, 59 (1987);
71, 359 (1999)
Butylated hydroxyanisole 40, 123 (1986); Suppl. 7, 59 (1987)
Butylated hydroxytoluene 40, 161 (1986); Suppl. 7, 59 (1987)
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Butyl benzyl phthalate 29, 193 (1982) (corr. 42, 261);

Suppl. 7, 59 (1987); 73, 115 (1999)
β-Butyrolactone 11, 225 (1976); Suppl. 7, 59
(1987); 71, 1317 (1999)
γ-Butyrolactone 11, 231 (1976); Suppl. 7, 59
(1987); 71, 367 (1999)
Cabinet-making (see Furniture and cabinet-making)

Cadmium acetate (see Cadmium and cadmium compounds)
Cadmium and cadmium compounds 2, 74 (1973); 11, 39 (1976)
(corr. 42, 255); Suppl. 7, 139
(1987); 58, 119 (1993)
Cadmium chloride (see Cadmium and cadmium compounds)
Cadmium oxide (see Cadmium and cadmium compounds)
Cadmium sulfate (see Cadmium and cadmium compounds)
Cadmium sulfide (see Cadmium and cadmium compounds)
Caffeic acid 56, 115 (1993)
Caffeine 51, 291 (1991)
Calcium arsenate (see Arsenic in drinking-water)
Calcium chromate (see Chromium and chromium compounds)
Calcium cyclamate (see Cyclamates)
Calcium saccharin (see Saccharin)
Cantharidin 10, 79 (1976); Suppl. 7, 59 (1987)
Caprolactam 19, 115 (1979) (corr. 42, 258);
39, 247 (1986) (corr. 42, 264);
Suppl. 7, 59, 390 (1987); 71, 383
(1999)
Captafol 53, 353 (1991)
Captan 30, 295 (1983); Suppl. 7, 59 (1987)
Carbaryl 12, 37 (1976); Suppl. 7, 59 (1987)
Carbazole 32, 239 (1983); Suppl. 7, 59
(1987); 71, 1319 (1999)
3-Carbethoxypsoralen 40, 317 (1986); Suppl. 7, 59 (1987)
Carbon black 3, 22 (1973); 33, 35 (1984);
Suppl. 7, 142 (1987); 65, 149
(1996)
Carbon tetrachloride 1, 53 (1972); 20, 371 (1979);
Suppl. 7, 143 (1987); 71, 401
(1999)
Carmoisine 8, 83 (1975); Suppl. 7, 59 (1987)
Carpentry and joinery 25, 139 (1981); Suppl. 7, 378
(1987)
Carrageenan 10, 181 (1976) (corr. 42, 255); 31,
79 (1983); Suppl. 7, 59 (1987)
Cassia occidentalis (see Traditional herbal medicines)
Catechol 15, 155 (1977); Suppl. 7, 59
(1987); 71, 433 (1999)
CCNU (see 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea)
Ceramic fibres (see Man-made vitreous fibres)
Chemotherapy, combined, including alkylating agents (see MOPP and
other combined chemotherapy including alkylating agents)
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Chloral (see also Chloral hydrate) 63, 245 (1995); 84, 317 (2004)
Chloral hydrate 63, 245 (1995); 84, 317 (2004)
Chlorambucil 9, 125 (1975); 26, 115 (1981);
Suppl. 7, 144 (1987)
Chloramine 84, 295 (2004)
Chloramphenicol 10, 85 (1976); Suppl. 7, 145
(1987); 50, 169 (1990)
Chlordane (see also Chlordane/Heptachlor) 20, 45 (1979) (corr. 42, 258)
Chlordane and Heptachlor Suppl. 7, 146 (1987); 53, 115
(1991); 79, 411 (2001)
Chlordecone 20, 67 (1979); Suppl. 7, 59 (1987)
Chlordimeform 30, 61 (1983); Suppl. 7, 59 (1987)
Chlorendic acid 48, 45 (1990)
Chlorinated dibenzodioxins (other than TCDD) (see also 15, 41 (1977); Suppl. 7, 59 (1987)
Polychlorinated dibenzo-para-dioxins)
Chlorinated drinking-water 52, 45 (1991)
Chlorinated paraffins 48, 55 (1990)
α-Chlorinated toluenes and benzoyl chloride Suppl. 7, 148 (1987); 71, 453
(1999)
Chlormadinone acetate 6, 149 (1974); 21, 365 (1979);
Suppl. 7, 291, 301 (1987);
72, 49 (1999)
Chlornaphazine (see N,N-Bis(2-chloroethyl)-2-naphthylamine)
Chloroacetonitrile (see also Halogenated acetonitriles) 71, 1325 (1999)
para-Chloroaniline 57, 305 (1993)
Chlorobenzilate 5, 75 (1974); 30, 73 (1983);
Suppl. 7, 60 (1987)
Chlorodibromomethane 52, 243 (1991); 71, 1331 (1999)
3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone 84, 441 (2004)
Chlorodifluoromethane 41, 237 (1986) (corr. 51, 483);
Suppl. 7, 149 (1987); 71, 1339
(1999)
Chloroethane 52, 315 (1991); 71, 1345 (1999)
1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea (see also Chloroethyl 26, 137 (1981) (corr. 42, 260);
nitrosoureas) Suppl. 7, 150 (1987)
1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (see also Suppl. 7, 150 (1987)
Chloroethyl nitrosoureas)
Chloroethyl nitrosoureas Suppl. 7, 150 (1987)
Chlorofluoromethane 41, 229 (1986); Suppl. 7, 60
(1987); 71, 1351 (1999)
Chloroform 1, 61 (1972); 20, 401 (1979);
Suppl. 7, 152 (1987); 73, 131
(1999)
Chloromethyl methyl ether (technical-grade) (see also 4, 239 (1974); Suppl. 7, 131 (1987)
Bis(chloromethyl)ether)
(4-Chloro-2-methylphenoxy)acetic acid (see MCPA)
1-Chloro-2-methylpropene 63, 315 (1995)
3-Chloro-2-methylpropene 63, 325 (1995)
2-Chloronitrobenzene 65, 263 (1996)
Chlorophenols (see also Polychlorophenols and their sodium salts) Suppl. 7, 154 (1987)
Chlorophenols (occupational exposures to) 41, 319 (1986)
Chlorophenoxy herbicides Suppl. 7, 156 (1987)
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Chlorophenoxy herbicides (occupational exposures to) 41, 357 (1986)

4-Chloro-ortho-phenylenediamine 27, 81 (1982); Suppl. 7, 60 (1987)
4-Chloro-meta-phenylenediamine 27, 82 (1982); Suppl. 7, 60 (1987)
Chloroprene 19, 131 (1979); Suppl. 7, 160
(1987); 71, 227 (1999)
Chloropropham 12, 55 (1976); Suppl. 7, 60 (1987)
Chloroquine 13, 47 (1977); Suppl. 7, 60 (1987)
Chlorothalonil 30, 319 (1983); Suppl. 7, 60 (1987);
73, 183 (1999)
para-Chloro-ortho-toluidine and its strong acid salts 16, 277 (1978); 30, 65 (1983);
(see also Chlordimeform) Suppl. 7, 60 (1987); 48, 123
(1990); 77, 323 (2000)
4-Chloro-ortho-toluidine (see para-chloro-ortho-toluidine)
5-Chloro-ortho-toluidine 77, 341 (2000)
Chlorotrianisene (see also Nonsteroidal oestrogens) 21, 139 (1979); Suppl. 7, 280
(1987)
2-Chloro-1,1,1-trifluoroethane 41, 253 (1986); Suppl. 7, 60
(1987); 71, 1355 (1999)
Chlorozotocin 50, 65 (1990)
Cholesterol 10, 99 (1976); 31, 95 (1983);
Suppl. 7, 161 (1987)
Chromic acetate (see Chromium and chromium compounds)
Chromic chloride (see Chromium and chromium compounds)
Chromic oxide (see Chromium and chromium compounds)
Chromic phosphate (see Chromium and chromium compounds)
Chromite ore (see Chromium and chromium compounds)
Chromium and chromium compounds (see also Implants, surgical) 2, 100 (1973); 23, 205 (1980);
Suppl. 7, 165 (1987); 49, 49 (1990)
(corr. 51, 483)
Chromium carbonyl (see Chromium and chromium compounds)
Chromium potassium sulfate (see Chromium and chromium compounds)
Chromium sulfate (see Chromium and chromium compounds)
Chromium trioxide (see Chromium and chromium compounds)
Chrysazin (see Dantron)
Chrysene 3, 159 (1973); 32, 247 (1983);
Suppl. 7, 60 (1987)
Chrysoidine 8, 91 (1975); Suppl. 7, 169 (1987)
Chrysotile (see Asbestos)
CI Acid Orange 3 57, 121 (1993)
CI Acid Red 114 57, 247 (1993)
CI Basic Red 9 (see also Magenta) 57, 215 (1993)
Ciclosporin 50, 77 (1990)
CI Direct Blue 15 57, 235 (1993)
CI Disperse Yellow 3 (see Disperse Yellow 3)
Cimetidine 50, 235 (1990)
Cinnamyl anthranilate 16, 287 (1978); 31, 133 (1983);
Suppl. 7, 60 (1987); 77, 177 (2000)
CI Pigment Red 3 57, 259 (1993)
CI Pigment Red 53:1 (see D&C Red No. 9)
Cisplatin (see also Etoposide) 26, 151 (1981); Suppl. 7, 170
(1987)
Citrinin 40, 67 (1986); Suppl. 7, 60 (1987)
Citrus Red No. 2 8, 101 (1975) (corr. 42, 254);
Suppl. 7, 60 (1987)
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Clinoptilolite (see Zeolites)

Clofibrate 24, 39 (1980); Suppl. 7, 171
(1987); 66, 391 (1996)
Clomiphene citrate 21, 551 (1979); Suppl. 7, 172
(1987)
Clonorchis sinensis (infection with) 61, 121 (1994)
Coal dust 68, 337 (1997)
Coal gasification 34, 65 (1984); Suppl. 7, 173 (1987)
Coal-tar pitches (see also Coal-tars) 35, 83 (1985); Suppl. 7, 174 (1987)
Coal-tars 35, 83 (1985); Suppl. 7, 175 (1987)
Cobalt[III] acetate (see Cobalt and cobalt compounds)
Cobalt-aluminium-chromium spinel (see Cobalt and cobalt compounds)
Cobalt and cobalt compounds (see also Implants, surgical) 52, 363 (1991)
Cobalt[II] chloride (see Cobalt and cobalt compounds)
Cobalt-chromium alloy (see Chromium and chromium compounds)
Cobalt-chromium-molybdenum alloys (see Cobalt and cobalt compounds)
Cobalt metal powder (see Cobalt and cobalt compounds)
Cobalt metal with tungsten carbide 86, 37 (2006)
Cobalt metal without tungsten carbide 86, 37 (2006)
Cobalt naphthenate (see Cobalt and cobalt compounds)
Cobalt[II] oxide (see Cobalt and cobalt compounds)
Cobalt[II,III] oxide (see Cobalt and cobalt compounds)
Cobalt sulfate and other soluble cobalt(II) salts 86, 37 (2006)
Cobalt[II] sulfide (see Cobalt and cobalt compounds)
Coffee 51, 41 (1991) (corr. 52, 513)
Coke production 34, 101 (1984); Suppl. 7, 176
(1987)
Combined oral contraceptives (see Oral contraceptives, combined)
Conjugated equine oestrogens 72, 399 (1999)
Conjugated oestrogens (see also Steroidal oestrogens) 21, 147 (1979); Suppl. 7, 283
(1987)
Continuous glass filament (see Man-made vitreous fibres)
Contraceptives, oral (see Oral contraceptives, combined;
Sequential oral contraceptives)
Copper 8-hydroxyquinoline 15, 103 (1977); Suppl. 7, 61 (1987)
Coronene 32, 263 (1983); Suppl. 7, 61 (1987)
Coumarin 10, 113 (1976); Suppl. 7, 61
(1987); 77, 193 (2000)
Creosotes (see also Coal-tars) 35, 83 (1985); Suppl. 7, 177 (1987)
meta-Cresidine 27, 91 (1982); Suppl. 7, 61 (1987)
para-Cresidine 27, 92 (1982); Suppl. 7, 61 (1987)
Cristobalite (see Crystalline silica)
Crocidolite (see Asbestos)
Crotonaldehyde 63, 373 (1995) (corr. 65, 549)
Crude oil 45, 119 (1989)
Crystalline silica (see also Silica) 42, 39 (1987); Suppl. 7, 341
(1987); 68, 41 (1997) (corr. 81,
383)
Cycasin (see also Methylazoxymethanol) 1, 157 (1972) (corr. 42, 251); 10,
121 (1976); Suppl. 7, 61 (1987)
Cyclamates 22, 55 (1980); Suppl. 7, 178 (1987);
73, 195 (1999)
Cyclamic acid (see Cyclamates)
Cyclochlorotine 10, 139 (1976); Suppl. 7, 61 (1987)
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Cyclohexanone 47, 157 (1989); 71, 1359 (1999)

Cyclohexylamine (see Cyclamates)
Cyclopenta[cd]pyrene 32, 269 (1983); Suppl. 7, 61 (1987)
Cyclopropane (see Anaesthetics, volatile)
Cyclophosphamide 9, 135 (1975); 26, 165 (1981);
Suppl. 7, 182 (1987)
Cyproterone acetate 72, 49 (1999)
2,4-D (see also Chlorophenoxy herbicides; Chlorophenoxy 15, 111 (1977)

herbicides, occupational exposures to)
Dacarbazine 26, 203 (1981); Suppl. 7, 184
(1987)
Dantron 50, 265 (1990) (corr. 59, 257)
D&C Red No. 9 8, 107 (1975); Suppl. 7, 61 (1987);
57, 203 (1993)
Dapsone 24, 59 (1980); Suppl. 7, 185 (1987)
Daunomycin 10, 145 (1976); Suppl. 7, 61 (1987)
DDD (see DDT)
DDE (see DDT)
DDT 5, 83 (1974) (corr. 42, 253);
Suppl. 7, 186 (1987); 53, 179
(1991)
Decabromodiphenyl oxide 48, 73 (1990); 71, 1365 (1999)
Deltamethrin 53, 251 (1991)
Deoxynivalenol (see Toxins derived from Fusarium graminearum,
F. culmorum and F. crookwellense)
Diacetylaminoazotoluene 8, 113 (1975); Suppl. 7, 61 (1987)
N,N′-Diacetylbenzidine 16, 293 (1978); Suppl. 7, 61 (1987)
Diallate 12, 69 (1976); 30, 235 (1983);
Suppl. 7, 61 (1987)
2,4-Diaminoanisole and its salts 16, 51 (1978); 27, 103 (1982);
Suppl. 7, 61 (1987); 79, 619 (2001)
4,4′-Diaminodiphenyl ether 16, 301 (1978); 29, 203 (1982);
Suppl. 7, 61 (1987)
1,2-Diamino-4-nitrobenzene 16, 63 (1978); Suppl. 7, 61 (1987)
1,4-Diamino-2-nitrobenzene 16, 73 (1978); Suppl. 7, 61 (1987);
57, 185 (1993)
2,6-Diamino-3-(phenylazo)pyridine (see Phenazopyridine hydrochloride)
2,4-Diaminotoluene (see also Toluene diisocyanates) 16, 83 (1978); Suppl. 7, 61 (1987)
2,5-Diaminotoluene (see also Toluene diisocyanates) 16, 97 (1978); Suppl. 7, 61 (1987)
ortho-Dianisidine (see 3,3′-Dimethoxybenzidine)
Diatomaceous earth, uncalcined (see Amorphous silica)
Diazepam 13, 57 (1977); Suppl. 7, 189
(1987); 66, 37 (1996)
Diazomethane 7, 223 (1974); Suppl. 7, 61 (1987)
Dibenz[a,h]acridine 3, 247 (1973); 32, 277 (1983);
Suppl. 7, 61 (1987)
Dibenz[a,j]acridine 3, 254 (1973); 32, 283 (1983);
Suppl. 7, 61 (1987)
Dibenz[a,c]anthracene 32, 289 (1983) (corr. 42, 262);
Suppl. 7, 61 (1987)
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Dibenz[a,h]anthracene 3, 178 (1973) (corr. 43, 261);

32, 299 (1983); Suppl. 7, 61 (1987)
Dibenz[a,j]anthracene 32, 309 (1983); Suppl. 7, 61 (1987)
7H-Dibenzo[c,g]carbazole 3, 260 (1973); 32, 315 (1983);
Suppl. 7, 61 (1987)
Dibenzodioxins, chlorinated (other than TCDD)
(see Chlorinated dibenzodioxins (other than TCDD))
Dibenzo[a,e]fluoranthene 32, 321 (1983); Suppl. 7, 61 (1987)
Dibenzo[h,rst]pentaphene 3, 197 (1973); Suppl. 7, 62 (1987)
Dibenzo[a,e]pyrene 3, 201 (1973); 32, 327 (1983);
Suppl. 7, 62 (1987)
Dibenzo[a,h]pyrene 3, 207 (1973); 32, 331 (1983);
Suppl. 7, 62 (1987)
Dibenzo[a,i]pyrene 3, 215 (1973); 32, 337 (1983);
Suppl. 7, 62 (1987)
Dibenzo[a,l]pyrene 3, 224 (1973); 32, 343 (1983);
Suppl. 7, 62 (1987)
Dibenzo-para-dioxin 69, 33 (1997)
Dibromoacetonitrile (see also Halogenated acetonitriles) 71, 1369 (1999)
1,2-Dibromo-3-chloropropane 15, 139 (1977); 20, 83 (1979);
Suppl. 7, 191 (1987); 71, 479
(1999)
1,2-Dibromoethane (see Ethylene dibromide)
2,3-Dibromopropan-1-ol 77, 439 (2000)
Dichloroacetic acid 63, 271 (1995); 84, 359 (2004)
Dichloroacetonitrile (see also Halogenated acetonitriles) 71, 1375 (1999)
Dichloroacetylene 39, 369 (1986); Suppl. 7, 62
(1987); 71, 1381 (1999)
ortho-Dichlorobenzene 7, 231 (1974); 29, 213 (1982);
Suppl. 7, 192 (1987); 73, 223 (1999)
meta-Dichlorobenzene 73, 223 (1999)
para-Dichlorobenzene 7, 231 (1974); 29, 215 (1982);
Suppl. 7, 192 (1987); 73, 223 (1999)
3,3′-Dichlorobenzidine 4, 49 (1974); 29, 239 (1982);
Suppl. 7, 193 (1987)
trans-1,4-Dichlorobutene 15, 149 (1977); Suppl. 7, 62
(1987); 71, 1389 (1999)
3,3′-Dichloro-4,4′-diaminodiphenyl ether 16, 309 (1978); Suppl. 7, 62 (1987)
1,2-Dichloroethane 20, 429 (1979); Suppl. 7, 62
(1987); 71, 501 (1999)
Dichloromethane 20, 449 (1979); 41, 43 (1986);
Suppl. 7, 194 (1987); 71, 251
(1999)
2,4-Dichlorophenol (see Chlorophenols; Chlorophenols,
occupational exposures to; Polychlorophenols and their sodium salts)
(2,4-Dichlorophenoxy)acetic acid (see 2,4-D)
2,6-Dichloro-para-phenylenediamine 39, 325 (1986); Suppl. 7, 62 (1987)
1,2-Dichloropropane 41, 131 (1986); Suppl. 7, 62
(1987); 71, 1393 (1999)
1,3-Dichloropropene (technical-grade) 41, 113 (1986); Suppl. 7, 195
(1987); 71, 933 (1999)
Dichlorvos 20, 97 (1979); Suppl. 7, 62 (1987);
53, 267 (1991)
Dicofol 30, 87 (1983); Suppl. 7, 62 (1987)
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Dicyclohexylamine (see Cyclamates)

Didanosine 76, 153 (2000)
Dieldrin 5, 125 (1974); Suppl. 7, 196 (1987)
Dienoestrol (see also Nonsteroidal oestrogens) 21, 161 (1979); Suppl. 7, 278
(1987)
Diepoxybutane (see also 1,3-Butadiene) 11, 115 (1976) (corr. 42, 255);
Suppl. 7, 62 (1987); 71, 109 (1999)
Diesel and gasoline engine exhausts 46, 41 (1989)
Diesel fuels 45, 219 (1989) (corr. 47, 505)
Diethanolamine 77, 349 (2000)
Diethyl ether (see Anaesthetics, volatile)
Di(2-ethylhexyl) adipate 29, 257 (1982); Suppl. 7, 62
(1987); 77, 149 (2000)
Di(2-ethylhexyl) phthalate 29, 269 (1982) (corr. 42, 261);
Suppl. 7, 62 (1987); 77, 41 (2000)
1,2-Diethylhydrazine 4, 153 (1974); Suppl. 7, 62 (1987);
71, 1401 (1999)
Diethylstilboestrol 6, 55 (1974); 21, 173 (1979)
(corr. 42, 259); Suppl. 7, 273
(1987)
Diethylstilboestrol dipropionate (see Diethylstilboestrol)
Diethyl sulfate 4, 277 (1974); Suppl. 7, 198
(1987); 54, 213 (1992); 71, 1405
(1999)
N,N′-Diethylthiourea 79, 649 (2001)
Diglycidyl resorcinol ether 11, 125 (1976); 36, 181 (1985);
Suppl. 7, 62 (1987); 71, 1417
(1999)
Dihydrosafrole 1, 170 (1972); 10, 233 (1976)
Suppl. 7, 62 (1987)
1,8-Dihydroxyanthraquinone (see Dantron)
Dihydroxybenzenes (see Catechol; Hydroquinone; Resorcinol)
1,3-Dihydroxy-2-hydroxymethylanthraquinone 82, 129 (2002)
Dihydroxymethylfuratrizine 24, 77 (1980); Suppl. 7, 62 (1987)
Diisopropyl sulfate 54, 229 (1992); 71, 1421 (1999)
Dimethisterone (see also Progestins; Sequential oral contraceptives) 6, 167 (1974); 21, 377 (1979))
Dimethoxane 15, 177 (1977); Suppl. 7, 62 (1987)
3,3′-Dimethoxybenzidine 4, 41 (1974); Suppl. 7, 198 (1987)
3,3′-Dimethoxybenzidine-4,4′-diisocyanate 39, 279 (1986); Suppl. 7, 62 (1987)
para-Dimethylaminoazobenzene 8, 125 (1975); Suppl. 7, 62 (1987)
para-Dimethylaminoazobenzenediazo sodium sulfonate 8, 147 (1975); Suppl. 7, 62 (1987)
trans-2-[(Dimethylamino)methylimino]-5-[2-(5-nitro-2-furyl)- 7, 147 (1974) (corr. 42, 253);
vinyl]-1,3,4-oxadiazole Suppl. 7, 62 (1987)
4,4′-Dimethylangelicin plus ultraviolet radiation (see also Suppl. 7, 57 (1987)
Angelicin and some synthetic derivatives)
4,5′-Dimethylangelicin plus ultraviolet radiation (see also Suppl. 7, 57 (1987)
2,6-Dimethylaniline 57, 323 (1993)
N,N-Dimethylaniline 57, 337 (1993)
Dimethylarsinic acid (see Arsenic and arsenic compounds)
3,3′-Dimethylbenzidine 1, 87 (1972); Suppl. 7, 62 (1987)
Dimethylcarbamoyl chloride 12, 77 (1976); Suppl. 7, 199
(1987); 71, 531 (1999)
Dimethylformamide 47, 171 (1989); 71, 545 (1999)
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1,1-Dimethylhydrazine 4, 137 (1974); Suppl. 7, 62 (1987);

71, 1425 (1999)
1,2-Dimethylhydrazine 4, 145 (1974) (corr. 42, 253);
Suppl. 7, 62 (1987); 71, 947 (1999)
Dimethyl hydrogen phosphite 48, 85 (1990); 71, 1437 (1999)
1,4-Dimethylphenanthrene 32, 349 (1983); Suppl. 7, 62 (1987)
Dimethyl sulfate 4, 271 (1974); Suppl. 7, 200
(1987); 71, 575 (1999)
3,7-Dinitrofluoranthene 46, 189 (1989); 65, 297 (1996)
3,9-Dinitrofluoranthene 46, 195 (1989); 65, 297 (1996)
1,3-Dinitropyrene 46, 201 (1989)
1,6-Dinitropyrene 46, 215 (1989)
1,8-Dinitropyrene 33, 171 (1984); Suppl. 7, 63
(1987); 46, 231 (1989)
Dinitrosopentamethylenetetramine 11, 241 (1976); Suppl. 7, 63 (1987)
2,4-Dinitrotoluene 65, 309 (1996) (corr. 66, 485)
2,6-Dinitrotoluene 65, 309 (1996) (corr. 66, 485)
3,5-Dinitrotoluene 65, 309 (1996)
1,4-Dioxane 11, 247 (1976); Suppl. 7, 201
(1987); 71, 589 (1999)
2,4′-Diphenyldiamine 16, 313 (1978); Suppl. 7, 63 (1987)
Direct Black 38 (see also Benzidine-based dyes) 29, 295 (1982) (corr. 42, 261)
Direct Blue 6 (see also Benzidine-based dyes) 29, 311 (1982)
Direct Brown 95 (see also Benzidine-based dyes) 29, 321 (1982)
Disperse Blue 1 48, 139 (1990)
Disperse Yellow 3 8, 97 (1975); Suppl. 7, 60 (1987);
48, 149 (1990)
Disulfiram 12, 85 (1976); Suppl. 7, 63 (1987)
Dithranol 13, 75 (1977); Suppl. 7, 63 (1987)
Divinyl ether (see Anaesthetics, volatile)
Doxefazepam 66, 97 (1996)
Doxylamine succinate 79, 145 (2001)
Droloxifene 66, 241 (1996)
Dry cleaning 63, 33 (1995)
Dulcin 12, 97 (1976); Suppl. 7, 63 (1987)
Endrin 5, 157 (1974); Suppl. 7, 63 (1987)

Enflurane (see Anaesthetics, volatile)
Eosin 15, 183 (1977); Suppl. 7, 63 (1987)
Epichlorohydrin 11, 131 (1976) (corr. 42, 256);
Suppl. 7, 202 (1987); 71, 603
(1999)
1,2-Epoxybutane 47, 217 (1989); 71, 629 (1999)
1-Epoxyethyl-3,4-epoxycyclohexane (see 4-Vinylcyclohexene diepoxide)
3,4-Epoxy-6-methylcyclohexylmethyl 3,4-epoxy-6-methyl- 11, 147 (1976); Suppl. 7, 63
cyclohexane carboxylate (1987); 71, 1441 (1999)
cis-9,10-Epoxystearic acid 11, 153 (1976); Suppl. 7, 63
(1987); 71, 1443 (1999)
Epstein-Barr virus 70, 47 (1997)
d-Equilenin 72, 399 (1999)
Equilin 72, 399 (1999)
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Erionite 42, 225 (1987); Suppl. 7, 203

(1987)
Estazolam 66, 105 (1996)
Ethinyloestradiol 6, 77 (1974); 21, 233 (1979);
Suppl. 7, 286 (1987); 72, 49 (1999)
Ethionamide 13, 83 (1977); Suppl. 7, 63 (1987)
Ethyl acrylate 19, 57 (1979); 39, 81 (1986);
Suppl. 7, 63 (1987); 71, 1447
(1999)
Ethylbenzene 77, 227 (2000)
Ethylene 19, 157 (1979); Suppl. 7, 63
(1987); 60, 45 (1994); 71, 1447
(1999)
Ethylene dibromide 15, 195 (1977); Suppl. 7, 204
(1987); 71, 641 (1999)
Ethylene oxide 11, 157 (1976); 36, 189 (1985)
(corr. 42, 263); Suppl. 7, 205
(1987); 60, 73 (1994)
Ethylene sulfide 11, 257 (1976); Suppl. 7, 63 (1987)
Ethylenethiourea 7, 45 (1974); Suppl. 7, 207 (1987);
79, 659 (2001)
2-Ethylhexyl acrylate 60, 475 (1994)
Ethyl methanesulfonate 7, 245 (1974); Suppl. 7, 63 (1987)
N-Ethyl-N-nitrosourea 1, 135 (1972); 17, 191 (1978);
Suppl. 7, 63 (1987)
Ethyl selenac (see also Selenium and selenium compounds) 12, 107 (1976); Suppl. 7, 63 (1987)
Ethyl tellurac 12, 115 (1976); Suppl. 7, 63 (1987)
Ethynodiol diacetate 6, 173 (1974); 21, 387 (1979);
Suppl. 7, 292 (1987); 72, 49
(1999)
Etoposide 76, 177 (2000)
Eugenol 36, 75 (1985); Suppl. 7, 63 (1987)
Evans blue 8, 151 (1975); Suppl. 7, 63 (1987)
Extremely low-frequency electric fields 80 (2002)
Extremely low-frequency magnetic fields 80 (2002)
Fast Green FCF 16, 187 (1978); Suppl. 7, 63 (1987)

Fenvalerate 53, 309 (1991)
Ferbam 12, 121 (1976) (corr. 42, 256);
Suppl. 7, 63 (1987)
Ferric oxide 1, 29 (1972); Suppl. 7, 216 (1987)
Ferrochromium (see Chromium and chromium compounds)
Fluometuron 30, 245 (1983); Suppl. 7, 63 (1987)
Fluoranthene 32, 355 (1983); Suppl. 7, 63 (1987)
Fluorene 32, 365 (1983); Suppl. 7, 63 (1987)
Fluorescent lighting (exposure to) (see Ultraviolet radiation)
Fluorides (inorganic, used in drinking-water) 27, 237 (1982); Suppl. 7, 208
(1987)
5-Fluorouracil 26, 217 (1981); Suppl. 7, 210
(1987)
Fluorspar (see Fluorides)
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Fluosilicic acid (see Fluorides)

Fluroxene (see Anaesthetics, volatile)
Foreign bodies 74 (1999)
Formaldehyde 29, 345 (1982); Suppl. 7, 211
(1987); 62, 217 (1995) (corr. 65,
549; corr. 66, 485)
2-(2-Formylhydrazino)-4-(5-nitro-2-furyl)thiazole 7, 151 (1974) (corr. 42, 253);
Suppl. 7, 63 (1987)
Frusemide (see Furosemide)
Fuel oils (heating oils) 45, 239 (1989) (corr. 47, 505)
Fumonisin B1 (see also Toxins derived from Fusarium moniliforme) 82, 301 (2002)
Fumonisin B2 (see Toxins derived from Fusarium moniliforme)
Furan 63, 393 (1995)
Furazolidone 31, 141 (1983); Suppl. 7, 63 (1987)
Furfural 63, 409 (1995)
Furniture and cabinet-making 25, 99 (1981); Suppl. 7, 380 (1987)
Furosemide 50, 277 (1990)
2-(2-Furyl)-3-(5-nitro-2-furyl)acrylamide (see AF-2)
Fusarenon-X (see Toxins derived from Fusarium graminearum,
Fusarenone-X (see Toxins derived from Fusarium graminearum,
Fusarin C (see Toxins derived from Fusarium moniliforme)
Gallium arsenide 86, 163 (2006)

Gamma (γ)-radiation 75, 121 (2000)
Gasoline 45, 159 (1989) (corr. 47, 505)
Gasoline engine exhaust (see Diesel and gasoline engine exhausts)
Gemfibrozil 66, 427 (1996)
Glass fibres (see Man-made mineral fibres)
Glass manufacturing industry, occupational exposures in 58, 347 (1993)
Glass wool (see Man-made vitreous fibres)
Glass filaments (see Man-made mineral fibres)
Glu-P-1 40, 223 (1986); Suppl. 7, 64 (1987)
Glu-P-2 40, 235 (1986); Suppl. 7, 64 (1987)
L-Glutamic acid, 5-[2-(4-hydroxymethyl)phenylhydrazide]
(see Agaritine)
Glycidaldehyde 11, 175 (1976); Suppl. 7, 64
(1987); 71, 1459 (1999)
Glycidol 77, 469 (2000)
Glycidyl ethers 47, 237 (1989); 71, 1285, 1417,
1525, 1539 (1999)
Glycidyl oleate 11, 183 (1976); Suppl. 7, 64 (1987)
Glycidyl stearate 11, 187 (1976); Suppl. 7, 64 (1987)
Griseofulvin 10, 153 (1976); Suppl. 7, 64, 391
(1987); 79, 289 (2001)
Guinea Green B 16, 199 (1978); Suppl. 7, 64 (1987)
Gyromitrin 31, 163 (1983); Suppl. 7, 64, 391
(1987)
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Haematite 1, 29 (1972); Suppl. 7, 216 (1987)

Haematite and ferric oxide Suppl. 7, 216 (1987)
Haematite mining, underground, with exposure to radon 1, 29 (1972); Suppl. 7, 216 (1987)
Hairdressers and barbers (occupational exposure as) 57, 43 (1993)
Hair dyes, epidemiology of 16, 29 (1978); 27, 307 (1982);
Halogenated acetonitriles 52, 269 (1991); 71, 1325, 1369,
1375, 1533 (1999)
Halothane (see Anaesthetics, volatile)
HC Blue No. 1 57, 129 (1993)
HC Blue No. 2 57, 143 (1993)
α-HCH (see Hexachlorocyclohexanes)
β-HCH (see Hexachlorocyclohexanes)
γ-HCH (see Hexachlorocyclohexanes)
HC Red No. 3 57, 153 (1993)
HC Yellow No. 4 57, 159 (1993)
Heating oils (see Fuel oils)
Helicobacter pylori (infection with) 61, 177 (1994)
Hepatitis B virus 59, 45 (1994)
Hepatitis C virus 59, 165 (1994)
Hepatitis D virus 59, 223 (1994)
Heptachlor (see also Chlordane/Heptachlor) 5, 173 (1974); 20, 129 (1979)
Hexachlorobenzene 20, 155 (1979); Suppl. 7, 219
(1987); 79, 493 (2001)
Hexachlorobutadiene 20, 179 (1979); Suppl. 7, 64 (1987);
73, 277 (1999)
Hexachlorocyclohexanes 5, 47 (1974); 20, 195 (1979)
(corr. 42, 258); Suppl. 7, 220
(1987)
Hexachlorocyclohexane, technical-grade (see Hexachlorocyclohexanes)
Hexachloroethane 20, 467 (1979); Suppl. 7, 64 (1987);
73, 295 (1999)
Hexachlorophene 20, 241 (1979); Suppl. 7, 64 (1987)
Hexamethylphosphoramide 15, 211 (1977); Suppl. 7, 64
(1987); 71, 1465 (1999)
Hexoestrol (see also Nonsteroidal oestrogens) Suppl. 7, 279 (1987)
Hormonal contraceptives, progestogens only 72, 339 (1999)
Human herpesvirus 8 70, 375 (1997)
Human immunodeficiency viruses 67, 31 (1996)
Human papillomaviruses 64 (1995) (corr. 66, 485)
Human T-cell lymphotropic viruses 67, 261 (1996)
Hycanthone mesylate 13, 91 (1977); Suppl. 7, 64 (1987)
Hydralazine 24, 85 (1980); Suppl. 7, 222 (1987)
Hydrazine 4, 127 (1974); Suppl. 7, 223
(1987); 71, 991 (1999)
Hydrochloric acid 54, 189 (1992)
Hydrochlorothiazide 50, 293 (1990)
Hydrogen peroxide 36, 285 (1985); Suppl. 7, 64
(1987); 71, 671 (1999)
Hydroquinone 15, 155 (1977); Suppl. 7, 64
(1987); 71, 691 (1999)
1-Hydroxyanthraquinone 82, 129 (2002)
4-Hydroxyazobenzene 8, 157 (1975); Suppl. 7, 64 (1987)
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17α-Hydroxyprogesterone caproate (see also Progestins) 21, 399 (1979) (corr. 42, 259)
8-Hydroxyquinoline 13, 101 (1977); Suppl. 7, 64 (1987)
8-Hydroxysenkirkine 10, 265 (1976); Suppl. 7, 64 (1987)
Hydroxyurea 76, 347 (2000)
Hypochlorite salts 52, 159 (1991)
Implants, surgical 74, 1999

Indeno[1,2,3-cd]pyrene 3, 229 (1973); 32, 373 (1983);
Suppl. 7, 64 (1987)
Indium phosphide 86, 197 (2006)
Inorganic acids (see Sulfuric acid and other strong inorganic acids,
occupational exposures to mists and vapours from)
Inorganic lead compounds Suppl. 7, 230 (1987); 87 (2006)
Insecticides, occupational exposures in spraying and application of 53, 45 (1991)
Insulation glass wool (see Man-made vitreous fibres)
Involuntary smoking 83, 1189 (2004)
Ionizing radiation (see Neutrons, γ- and X-radiation)
IQ 40, 261 (1986); Suppl. 7, 64
(1987); 56, 165 (1993)
Iron and steel founding 34, 133 (1984); Suppl. 7, 224
(1987)
Iron-dextran complex 2, 161 (1973); Suppl. 7, 226 (1987)
Iron-dextrin complex 2, 161 (1973) (corr. 42, 252);
Suppl. 7, 64 (1987)
Iron oxide (see Ferric oxide)
Iron oxide, saccharated (see Saccharated iron oxide)
Iron sorbitol-citric acid complex 2, 161 (1973); Suppl. 7, 64 (1987)
Isatidine 10, 269 (1976); Suppl. 7, 65 (1987)
Isoflurane (see Anaesthetics, volatile)
Isoniazid (see Isonicotinic acid hydrazide)
Isonicotinic acid hydrazide 4, 159 (1974); Suppl. 7, 227 (1987)
Isophosphamide 26, 237 (1981); Suppl. 7, 65 (1987)
Isoprene 60, 215 (1994); 71, 1015 (1999)
Isopropanol 15, 223 (1977); Suppl. 7, 229
(1987); 71, 1027 (1999)
Isopropanol manufacture (strong-acid process) Suppl. 7, 229 (1987)
(see also Isopropanol; Sulfuric acid and other strong inorganic
acids, occupational exposures to mists and vapours from)
Isopropyl oils 15, 223 (1977); Suppl. 7, 229
(1987); 71, 1483 (1999)
Isosafrole 1, 169 (1972); 10, 232 (1976);
Suppl. 7, 65 (1987)
Jacobine 10, 275 (1976); Suppl. 7, 65 (1987)

Jet fuel 45, 203 (1989)
Joinery (see Carpentry and joinery)
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Kaempferol 31, 171 (1983); Suppl. 7, 65 (1987)

Kaposi’s sarcoma herpesvirus 70, 375 (1997)
Kepone (see Chlordecone)
Kojic acid 79, 605 (2001)
Lasiocarpine 10, 281 (1976); Suppl. 7, 65 (1987)

Lauroyl peroxide 36, 315 (1985); Suppl. 7, 65
(1987); 71, 1485 (1999)
Lead acetate (see Lead and lead compounds)
Lead and lead compounds (see also Foreign bodies) 1, 40 (1972) (corr. 42, 251); 2, 52,
150 (1973); 12, 131 (1976);
23, 40, 208, 209, 325 (1980);
Suppl. 7, 230 (1987); 87 (2006)
Lead arsenate (see Arsenic and arsenic compounds)
Lead carbonate (see Lead and lead compounds)
Lead chloride (see Lead and lead compounds)
Lead chromate (see Chromium and chromium compounds)
Lead chromate oxide (see Chromium and chromium compounds)
Lead compounds, inorganic and organic Suppl. 7, 230 (1987); 87 (2006)
Lead naphthenate (see Lead and lead compounds)
Lead nitrate (see Lead and lead compounds)
Lead oxide (see Lead and lead compounds)
Lead phosphate (see Lead and lead compounds)
Lead subacetate (see Lead and lead compounds)
Lead tetroxide (see Lead and lead compounds)
Leather goods manufacture 25, 279 (1981); Suppl. 7, 235
(1987)
Leather industries 25, 199 (1981); Suppl. 7, 232
(1987)
Leather tanning and processing 25, 201 (1981); Suppl. 7, 236
(1987)
Ledate (see also Lead and lead compounds) 12, 131 (1976)
Levonorgestrel 72, 49 (1999)
Light Green SF 16, 209 (1978); Suppl. 7, 65 (1987)
d-Limonene 56, 135 (1993); 73, 307 (1999)
Lindane (see Hexachlorocyclohexanes)
Liver flukes (see Clonorchis sinensis, Opisthorchis felineus and
Opisthorchis viverrini)
Lucidin (see 1,3-Dihydro-2-hydroxymethylanthraquinone)
Lumber and sawmill industries (including logging) 25, 49 (1981); Suppl. 7, 383 (1987)
Luteoskyrin 10, 163 (1976); Suppl. 7, 65 (1987)
Lynoestrenol 21, 407 (1979); Suppl. 7, 293
(1987); 72, 49 (1999)
Madder root (see also Rubia tinctorum) 82, 129 (2002)

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Magenta 4, 57 (1974) (corr. 42, 252);

Suppl. 7, 238 (1987); 57, 215
(1993)
Magenta, manufacture of (see also Magenta) Suppl. 7, 238 (1987); 57, 215
(1993)
Malathion 30, 103 (1983); Suppl. 7, 65 (1987)
Maleic hydrazide 4, 173 (1974) (corr. 42, 253);
Suppl. 7, 65 (1987)
Malonaldehyde 36, 163 (1985); Suppl. 7, 65
(1987); 71, 1037 (1999)
Malondialdehyde (see Malonaldehyde)
Maneb 12, 137 (1976); Suppl. 7, 65 (1987)
Man-made mineral fibres (see Man-made vitreous fibres)
Man-made vitreous fibres 43, 39 (1988); 81 (2002)
Mannomustine 9, 157 (1975); Suppl. 7, 65 (1987)
Mate 51, 273 (1991)
MCPA (see also Chlorophenoxy herbicides; Chlorophenoxy 30, 255 (1983)
MeA-α-C 40, 253 (1986); Suppl. 7, 65 (1987)
Medphalan 9, 168 (1975); Suppl. 7, 65 (1987)
Medroxyprogesterone acetate 6, 157 (1974); 21, 417 (1979)
(corr. 42, 259); Suppl. 7, 289
(1987); 72, 339 (1999)
Megestrol acetate Suppl. 7, 293 (1987); 72, 49 (1999)
MeIQ 40, 275 (1986); Suppl. 7, 65
(1987); 56, 197 (1993)
MeIQx 40, 283 (1986); Suppl. 7, 65 (1987)
56, 211 (1993)
Melamine 39, 333 (1986); Suppl. 7, 65
(1987); 73, 329 (1999)
Melphalan 9, 167 (1975); Suppl. 7, 239 (1987)
6-Mercaptopurine 26, 249 (1981); Suppl. 7, 240
(1987)
Mercuric chloride (see Mercury and mercury compounds)
Mercury and mercury compounds 58, 239 (1993)
Merphalan 9, 169 (1975); Suppl. 7, 65 (1987)
Mestranol 6, 87 (1974); 21, 257 (1979)
(corr. 42, 259); Suppl. 7, 288
(1987); 72, 49 (1999)
Metabisulfites (see Sulfur dioxide and some sulfites, bisulfites
and metabisulfites)
Metallic mercury (see Mercury and mercury compounds)
Methanearsonic acid, disodium salt (see Arsenic and arsenic compounds)
Methanearsonic acid, monosodium salt (see Arsenic and arsenic
compounds)
Methimazole 79, 53 (2001)
Methotrexate 26, 267 (1981); Suppl. 7, 241
(1987)
Methoxsalen (see 8-Methoxypsoralen)
Methoxychlor 5, 193 (1974); 20, 259 (1979);
Suppl. 7, 66 (1987)
Methoxyflurane (see Anaesthetics, volatile)
5-Methoxypsoralen 40, 327 (1986); Suppl. 7, 242
(1987)
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8-Methoxypsoralen (see also 8-Methoxypsoralen plus ultraviolet 24, 101 (1980)

radiation)
8-Methoxypsoralen plus ultraviolet radiation Suppl. 7, 243 (1987)
Methyl acrylate 19, 52 (1979); 39, 99 (1986);
Suppl. 7, 66 (1987); 71, 1489
(1999)
5-Methylangelicin plus ultraviolet radiation (see also Angelicin Suppl. 7, 57 (1987)
and some synthetic derivatives)
2-Methylaziridine 9, 61 (1975); Suppl. 7, 66 (1987);
71, 1497 (1999)
Methylazoxymethanol acetate (see also Cycasin) 1, 164 (1972); 10, 131 (1976);
Suppl. 7, 66 (1987)
Methyl bromide 41, 187 (1986) (corr. 45, 283);
Suppl. 7, 245 (1987); 71, 721
(1999)
Methyl tert-butyl ether 73, 339 (1999)
Methyl carbamate 12, 151 (1976); Suppl. 7, 66 (1987)
Methyl-CCNU (see 1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-
1-nitrosourea)
Methyl chloride 41, 161 (1986); Suppl. 7, 246
(1987); 71, 737 (1999)
1-, 2-, 3-, 4-, 5- and 6-Methylchrysenes 32, 379 (1983); Suppl. 7, 66 (1987)
N-Methyl-N,4-dinitrosoaniline 1, 141 (1972); Suppl. 7, 66 (1987)
4,4′-Methylene bis(2-chloroaniline) 4, 65 (1974) (corr. 42, 252);
Suppl. 7, 246 (1987); 57, 271
(1993)
4,4′-Methylene bis(N,N-dimethyl)benzenamine 27, 119 (1982); Suppl. 7, 66 (1987)
4,4′-Methylene bis(2-methylaniline) 4, 73 (1974); Suppl. 7, 248 (1987)
4,4′-Methylenedianiline 4, 79 (1974) (corr. 42, 252);
39, 347 (1986); Suppl. 7, 66 (1987)
4,4′-Methylenediphenyl diisocyanate 19, 314 (1979); Suppl. 7, 66
(1987); 71, 1049 (1999)
2-Methylfluoranthene 32, 399 (1983); Suppl. 7, 66 (1987)
3-Methylfluoranthene 32, 399 (1983); Suppl. 7, 66 (1987)
Methylglyoxal 51, 443 (1991)
Methyl iodide 15, 245 (1977); 41, 213 (1986);
Suppl. 7, 66 (1987); 71, 1503
(1999)
Methylmercury chloride (see Mercury and mercury compounds)
Methylmercury compounds (see Mercury and mercury compounds)
Methyl methacrylate 19, 187 (1979); Suppl. 7, 66
(1987); 60, 445 (1994)
Methyl methanesulfonate 7, 253 (1974); Suppl. 7, 66 (1987);
71, 1059 (1999)
2-Methyl-1-nitroanthraquinone 27, 205 (1982); Suppl. 7, 66 (1987)
N-Methyl-N′-nitro-N-nitrosoguanidine 4, 183 (1974); Suppl. 7, 248 (1987)
3-Methylnitrosaminopropionaldehyde [see 3-(N-Nitrosomethylamino)-
propionaldehyde]
3-Methylnitrosaminopropionitrile [see 3-(N-Nitrosomethylamino)-
propionitrile]
4-(Methylnitrosamino)-4-(3-pyridyl)-1-butanal [see 4-(N-Nitrosomethyl-
amino)-4-(3-pyridyl)-1-butanal]
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone [see 4-(N-Nitrosomethyl-
amino)-1-(3-pyridyl)-1-butanone]
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N-Methyl-N-nitrosourea 1, 125 (1972); 17, 227 (1978);

Suppl. 7, 66 (1987)
N-Methyl-N-nitrosourethane 4, 211 (1974); Suppl. 7, 66 (1987)
N-Methylolacrylamide 60, 435 (1994)
Methyl parathion 30, 131 (1983); Suppl. 7, 66, 392
(1987)
1-Methylphenanthrene 32, 405 (1983); Suppl. 7, 66 (1987)
7-Methylpyrido[3,4-c]psoralen 40, 349 (1986); Suppl. 7, 71 (1987)
Methyl red 8, 161 (1975); Suppl. 7, 66 (1987)
Methyl selenac (see also Selenium and selenium compounds) 12, 161 (1976); Suppl. 7, 66 (1987)
Methylthiouracil 7, 53 (1974); Suppl. 7, 66 (1987);
79, 75 (2001)
Metronidazole 13, 113 (1977); Suppl. 7, 250
(1987)
Mineral oils 3, 30 (1973); 33, 87 (1984)
(corr. 42, 262); Suppl. 7, 252
(1987)
Mirex 5, 203 (1974); 20, 283 (1979)
(corr. 42, 258); Suppl. 7, 66 (1987)
Mists and vapours from sulfuric acid and other strong inorganic acids 54, 41 (1992)
Mitomycin C 10, 171 (1976); Suppl. 7, 67 (1987)
Mitoxantrone 76, 289 (2000)
MNNG (see N-Methyl-N′-nitro-N-nitrosoguanidine)
MOCA (see 4,4′-Methylene bis(2-chloroaniline))
Modacrylic fibres 19, 86 (1979); Suppl. 7, 67 (1987)
Monochloramine (see Chloramine)
Monocrotaline 10, 291 (1976); Suppl. 7, 67 (1987)
Monuron 12, 167 (1976); Suppl. 7, 67
(1987); 53, 467 (1991)
MOPP and other combined chemotherapy including Suppl. 7, 254 (1987)
alkylating agents
Mordanite (see Zeolites)
Morinda officinalis (see also Traditional herbal medicines) 82, 129 (2002)
Morpholine 47, 199 (1989); 71, 1511 (1999)
5-(Morpholinomethyl)-3-[(5-nitrofurfurylidene)amino]-2- 7, 161 (1974); Suppl. 7, 67 (1987)
oxazolidinone
Musk ambrette 65, 477 (1996)
Musk xylene 65, 477 (1996)
Mustard gas 9, 181 (1975) (corr. 42, 254);
Suppl. 7, 259 (1987)
Myleran (see 1,4-Butanediol dimethanesulfonate)
Nafenopin 24, 125 (1980); Suppl. 7, 67 (1987)

Naphthalene 82, 367 (2002)
1,5-Naphthalenediamine 27, 127 (1982); Suppl. 7, 67 (1987)
1,5-Naphthalene diisocyanate 19, 311 (1979); Suppl. 7, 67
(1987); 71, 1515 (1999)
1-Naphthylamine 4, 87 (1974) (corr. 42, 253);
Suppl. 7, 260 (1987)
2-Naphthylamine 4, 97 (1974); Suppl. 7, 261 (1987)
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1-Naphthylthiourea 30, 347 (1983); Suppl. 7, 263

(1987)
Neutrons 75, 361 (2000)
Nickel acetate (see Nickel and nickel compounds)
Nickel ammonium sulfate (see Nickel and nickel compounds)
Nickel and nickel compounds (see also Implants, surgical) 2, 126 (1973) (corr. 42, 252); 11,
75 (1976); Suppl. 7, 264 (1987)
(corr. 45, 283); 49, 257 (1990)
(corr. 67, 395)
Nickel carbonate (see Nickel and nickel compounds)
Nickel carbonyl (see Nickel and nickel compounds)
Nickel chloride (see Nickel and nickel compounds)
Nickel-gallium alloy (see Nickel and nickel compounds)
Nickel hydroxide (see Nickel and nickel compounds)
Nickelocene (see Nickel and nickel compounds)
Nickel oxide (see Nickel and nickel compounds)
Nickel subsulfide (see Nickel and nickel compounds)
Nickel sulfate (see Nickel and nickel compounds)
Niridazole 13, 123 (1977); Suppl. 7, 67 (1987)
Nithiazide 31, 179 (1983); Suppl. 7, 67 (1987)
Nitrilotriacetic acid and its salts 48, 181 (1990); 73, 385 (1999)
5-Nitroacenaphthene 16, 319 (1978); Suppl. 7, 67 (1987)
5-Nitro-ortho-anisidine 27, 133 (1982); Suppl. 7, 67 (1987)
2-Nitroanisole 65, 369 (1996)
9-Nitroanthracene 33, 179 (1984); Suppl. 7, 67 (1987)
7-Nitrobenz[a]anthracene 46, 247 (1989)
Nitrobenzene 65, 381 (1996)
6-Nitrobenzo[a]pyrene 33, 187 (1984); Suppl. 7, 67
(1987); 46, 255 (1989)
4-Nitrobiphenyl 4, 113 (1974); Suppl. 7, 67 (1987)
6-Nitrochrysene 33, 195 (1984); Suppl. 7, 67
(1987); 46, 267 (1989)
Nitrofen (technical-grade) 30, 271 (1983); Suppl. 7, 67 (1987)
3-Nitrofluoranthene 33, 201 (1984); Suppl. 7, 67 (1987)
2-Nitrofluorene 46, 277 (1989)
Nitrofural 7, 171 (1974); Suppl. 7, 67 (1987);
50, 195 (1990)
5-Nitro-2-furaldehyde semicarbazone (see Nitrofural)
Nitrofurantoin 50, 211 (1990)
Nitrofurazone (see Nitrofural)
1-[(5-Nitrofurfurylidene)amino]-2-imidazolidinone 7, 181 (1974); Suppl. 7, 67 (1987)
N-[4-(5-Nitro-2-furyl)-2-thiazolyl]acetamide 1, 181 (1972); 7, 185 (1974);
Suppl. 7, 67 (1987)
Nitrogen mustard 9, 193 (1975); Suppl. 7, 269 (1987)
Nitrogen mustard N-oxide 9, 209 (1975); Suppl. 7, 67 (1987)
Nitromethane 77, 487 (2000)
1-Nitronaphthalene 46, 291 (1989)
2-Nitronaphthalene 46, 303 (1989)
3-Nitroperylene 46, 313 (1989)
2-Nitro-para-phenylenediamine (see 1,4-Diamino-2-nitrobenzene)
2-Nitropropane 29, 331 (1982); Suppl. 7, 67
(1987); 71, 1079 (1999)
1-Nitropyrene 33, 209 (1984); Suppl. 7, 67
(1987); 46, 321 (1989)
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2-Nitropyrene 46, 359 (1989)

4-Nitropyrene 46, 367 (1989)
N-Nitrosatable drugs 24, 297 (1980) (corr. 42, 260)
N-Nitrosatable pesticides 30, 359 (1983)
N′-Nitrosoanabasine 37, 225 (1985); Suppl. 7, 67 (1987)
N′-Nitrosoanatabine 37, 233 (1985); Suppl. 7, 67 (1987)
N-Nitrosodi-n-butylamine 4, 197 (1974); 17, 51 (1978);
Suppl. 7, 67 (1987)
N-Nitrosodiethanolamine 17, 77 (1978); Suppl. 7, 67 (1987);
77, 403 (2000)
N-Nitrosodiethylamine 1, 107 (1972) (corr. 42, 251);
17, 83 (1978) (corr. 42, 257);
Suppl. 7, 67 (1987)
N-Nitrosodimethylamine 1, 95 (1972); 17, 125 (1978)
(corr. 42, 257); Suppl. 7, 67 (1987)
N-Nitrosodiphenylamine 27, 213 (1982); Suppl. 7, 67 (1987)
para-Nitrosodiphenylamine 27, 227 (1982) (corr. 42, 261);
Suppl. 7, 68 (1987)
N-Nitrosodi-n-propylamine 17, 177 (1978); Suppl. 7, 68 (1987)
N-Nitroso-N-ethylurea (see N-Ethyl-N-nitrosourea)
N-Nitrosofolic acid 17, 217 (1978); Suppl. 7, 68 (1987)
N-Nitrosoguvacine 37, 263 (1985); Suppl. 7, 68
(1987); 85, 281 (2004)
N-Nitrosoguvacoline 37, 263 (1985); Suppl. 7, 68
(1987); 85, 281 (2004)
N-Nitrosohydroxyproline 17, 304 (1978); Suppl. 7, 68 (1987)
3-(N-Nitrosomethylamino)propionaldehyde 37, 263 (1985); Suppl. 7, 68
(1987); 85, 281 (2004)
3-(N-Nitrosomethylamino)propionitrile 37, 263 (1985); Suppl. 7, 68
(1987); 85, 281 (2004)
4-(N-Nitrosomethylamino)-4-(3-pyridyl)-1-butanal 37, 205 (1985); Suppl. 7, 68 (1987)
4-(N-Nitrosomethylamino)-1-(3-pyridyl)-1-butanone 37, 209 (1985); Suppl. 7, 68 (1987)
N-Nitrosomethylethylamine 17, 221 (1978); Suppl. 7, 68 (1987)
N-Nitroso-N-methylurea (see N-Methyl-N-nitrosourea)
N-Nitroso-N-methylurethane (see N-Methyl-N-nitrosourethane)
N-Nitrosomethylvinylamine 17, 257 (1978); Suppl. 7, 68 (1987)
N-Nitrosomorpholine 17, 263 (1978); Suppl. 7, 68 (1987)
N′-Nitrosonornicotine 17, 281 (1978); 37, 241 (1985);
Suppl. 7, 68 (1987)
N-Nitrosopiperidine 17, 287 (1978); Suppl. 7, 68 (1987)
N-Nitrosoproline 17, 303 (1978); Suppl. 7, 68 (1987)
N-Nitrosopyrrolidine 17, 313 (1978); Suppl. 7, 68 (1987)
N-Nitrososarcosine 17, 327 (1978); Suppl. 7, 68 (1987)
Nitrosoureas, chloroethyl (see Chloroethyl nitrosoureas)
5-Nitro-ortho-toluidine 48, 169 (1990)
2-Nitrotoluene 65, 409 (1996)
Nitrous oxide (see Anaesthetics, volatile)
Nitrovin 31, 185 (1983); Suppl. 7, 68 (1987)
Nivalenol (see Toxins derived from Fusarium graminearum,
NNA (see 4-(N-Nitrosomethylamino)-4-(3-pyridyl)-1-butanal)
NNK (see 4-(N-Nitrosomethylamino)-1-(3-pyridyl)-1-butanone)
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Nonsteroidal oestrogens Suppl. 7, 273 (1987)

Norethisterone 6, 179 (1974); 21, 461 (1979);
Suppl. 7, 294 (1987); 72, 49
(1999)
Norethisterone acetate 72, 49 (1999)
Norethynodrel 6, 191 (1974); 21, 461 (1979)
(corr. 42, 259); Suppl. 7, 295
(1987); 72, 49 (1999)
Norgestrel 6, 201 (1974); 21, 479 (1979);
Suppl. 7, 295 (1987); 72, 49 (1999)
Nylon 6 19, 120 (1979); Suppl. 7, 68 (1987)
Ochratoxin A 10, 191 (1976); 31, 191 (1983)

(corr. 42, 262); Suppl. 7, 271
(1987); 56, 489 (1993)
Oestradiol 6, 99 (1974); 21, 279 (1979);
Suppl. 7, 284 (1987); 72, 399
(1999)
Oestradiol-17β (see Oestradiol)
Oestradiol 3-benzoate (see Oestradiol)
Oestradiol dipropionate (see Oestradiol)
Oestradiol mustard 9, 217 (1975); Suppl. 7, 68 (1987)
Oestradiol valerate (see Oestradiol)
Oestriol 6, 117 (1974); 21, 327 (1979);
Suppl. 7, 285 (1987); 72, 399
(1999)
Oestrogen-progestin combinations (see Oestrogens,
progestins (progestogens) and combinations)
Oestrogen-progestin replacement therapy (see Post-menopausal
oestrogen-progestogen therapy)
Oestrogen replacement therapy (see Post-menopausal oestrogen
therapy)
Oestrogens (see Oestrogens, progestins and combinations)
Oestrogens, conjugated (see Conjugated oestrogens)
Oestrogens, nonsteroidal (see Nonsteroidal oestrogens)
Oestrogens, progestins (progestogens) and combinations 6 (1974); 21 (1979); Suppl. 7, 272
(1987); 72, 49, 339, 399, 531
(1999)
Oestrogens, steroidal (see Steroidal oestrogens)
Oestrone 6, 123 (1974); 21, 343 (1979)
(corr. 42, 259); Suppl. 7, 286
(1987); 72, 399 (1999)
Oestrone benzoate (see Oestrone)
Oil Orange SS 8, 165 (1975); Suppl. 7, 69 (1987)
Opisthorchis felineus (infection with) 61, 121 (1994)
Opisthorchis viverrini (infection with) 61, 121 (1994)
Oral contraceptives, combined Suppl. 7, 297 (1987); 72, 49 (1999)
Oral contraceptives, sequential (see Sequential oral contraceptives)
Orange I 8, 173 (1975); Suppl. 7, 69 (1987)
Orange G 8, 181 (1975); Suppl. 7, 69 (1987)
Organic lead compounds Suppl. 7, 230 (1987); 87 (2006)
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Organolead compounds (see Organic lead compounds)

Oxazepam 13, 58 (1977); Suppl. 7, 69 (1987);
66, 115 (1996)
Oxymetholone (see also Androgenic (anabolic) steroids) 13, 131 (1977)
Oxyphenbutazone 13, 185 (1977); Suppl. 7, 69 (1987)
Paint manufacture and painting (occupational exposures in) 47, 329 (1989)
Palygorskite 42, 159 (1987); Suppl. 7, 117
(1987); 68, 245 (1997)
Panfuran S (see also Dihydroxymethylfuratrizine) 24, 77 (1980); Suppl. 7, 69 (1987)
Paper manufacture (see Pulp and paper manufacture)
Paracetamol 50, 307 (1990); 73, 401 (1999)
Parasorbic acid 10, 199 (1976) (corr. 42, 255);
Suppl. 7, 69 (1987)
Parathion 30, 153 (1983); Suppl. 7, 69 (1987)
Patulin 10, 205 (1976); 40, 83 (1986);
Suppl. 7, 69 (1987)
Penicillic acid 10, 211 (1976); Suppl. 7, 69 (1987)
Pentachloroethane 41, 99 (1986); Suppl. 7, 69 (1987);
71, 1519 (1999)
Pentachloronitrobenzene (see Quintozene)
Pentachlorophenol (see also Chlorophenols; Chlorophenols, 20, 303 (1979); 53, 371 (1991)
Permethrin 53, 329 (1991)
Perylene 32, 411 (1983); Suppl. 7, 69 (1987)
Petasitenine 31, 207 (1983); Suppl. 7, 69 (1987)
Petasites japonicus (see also Pyrrolizidine alkaloids) 10, 333 (1976)
Petroleum refining (occupational exposures in) 45, 39 (1989)
Petroleum solvents 47, 43 (1989)
Phenacetin 13, 141 (1977); 24, 135 (1980);
Suppl. 7, 310 (1987)
Phenanthrene 32, 419 (1983); Suppl. 7, 69 (1987)
Phenazopyridine hydrochloride 8, 117 (1975); 24, 163 (1980)
(corr. 42, 260); Suppl. 7, 312
(1987)
Phenelzine sulfate 24, 175 (1980); Suppl. 7, 312
(1987)
Phenicarbazide 12, 177 (1976); Suppl. 7, 70 (1987)
Phenobarbital and its sodium salt 13, 157 (1977); Suppl. 7, 313
(1987); 79, 161 (2001)
Phenol 47, 263 (1989) (corr. 50, 385); 71,
749 (1999)
Phenolphthalein 76, 387 (2000)
Phenoxyacetic acid herbicides (see Chlorophenoxy herbicides)
Phenoxybenzamine hydrochloride 9, 223 (1975); 24, 185 (1980);
Suppl. 7, 70 (1987)
Phenylbutazone 13, 183 (1977); Suppl. 7, 316
(1987)
meta-Phenylenediamine 16, 111 (1978); Suppl. 7, 70 (1987)
para-Phenylenediamine 16, 125 (1978); Suppl. 7, 70 (1987)
Phenyl glycidyl ether (see also Glycidyl ethers) 71, 1525 (1999)
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N-Phenyl-2-naphthylamine 16, 325 (1978) (corr. 42, 257);

Suppl. 7, 318 (1987)
ortho-Phenylphenol 30, 329 (1983); Suppl. 7, 70
(1987); 73, 451 (1999)
Phenytoin 13, 201 (1977); Suppl. 7, 319
(1987); 66, 175 (1996)
Phillipsite (see Zeolites)
PhIP 56, 229 (1993)
Pickled vegetables 56, 83 (1993)
Picloram 53, 481 (1991)
Piperazine oestrone sulfate (see Conjugated oestrogens)
Piperonyl butoxide 30, 183 (1983); Suppl. 7, 70 (1987)
Pitches, coal-tar (see Coal-tar pitches)
Polyacrylic acid 19, 62 (1979); Suppl. 7, 70 (1987)
Polybrominated biphenyls 18, 107 (1978); 41, 261 (1986);
Suppl. 7, 321 (1987)
Polychlorinated biphenyls 7, 261 (1974); 18, 43 (1978)
(corr. 42, 258); Suppl. 7, 322
(1987)
Polychlorinated camphenes (see Toxaphene)
Polychlorinated dibenzo-para-dioxins (other than 69, 33 (1997)
2,3,7,8-tetrachlorodibenzodioxin)
Polychlorinated dibenzofurans 69, 345 (1997)
Polychlorophenols and their sodium salts 71, 769 (1999)
Polychloroprene 19, 141 (1979); Suppl. 7, 70 (1987)
Polyethylene (see also Implants, surgical) 19, 164 (1979); Suppl. 7, 70 (1987)
Poly(glycolic acid) (see Implants, surgical)
Polymethylene polyphenyl isocyanate (see also 4,4′-Methylenediphenyl 19, 314 (1979); Suppl. 7, 70 (1987)
diisocyanate)
Polymethyl methacrylate (see also Implants, surgical) 19, 195 (1979); Suppl. 7, 70 (1987)
Polyoestradiol phosphate (see Oestradiol-17β)
Polypropylene (see also Implants, surgical) 19, 218 (1979); Suppl. 7, 70 (1987)
Polystyrene (see also Implants, surgical) 19, 245 (1979); Suppl. 7, 70 (1987)
Polytetrafluoroethylene (see also Implants, surgical) 19, 288 (1979); Suppl. 7, 70 (1987)
Polyurethane foams (see also Implants, surgical) 19, 320 (1979); Suppl. 7, 70 (1987)
Polyvinyl acetate (see also Implants, surgical) 19, 346 (1979); Suppl. 7, 70 (1987)
Polyvinyl alcohol (see also Implants, surgical) 19, 351 (1979); Suppl. 7, 70 (1987)
Polyvinyl chloride (see also Implants, surgical) 7, 306 (1974); 19, 402 (1979);
Suppl. 7, 70 (1987)
Polyvinyl pyrrolidone 19, 463 (1979); Suppl. 7, 70
(1987); 71, 1181 (1999)
Ponceau MX 8, 189 (1975); Suppl. 7, 70 (1987)
Ponceau 3R 8, 199 (1975); Suppl. 7, 70 (1987)
Ponceau SX 8, 207 (1975); Suppl. 7, 70 (1987)
Post-menopausal oestrogen therapy Suppl. 7, 280 (1987); 72, 399
(1999)
Post-menopausal oestrogen-progestogen therapy Suppl. 7, 308 (1987); 72, 531
(1999)
Potassium arsenate (see Arsenic and arsenic compounds)
Potassium arsenite (see Arsenic and arsenic compounds)
Potassium bis(2-hydroxyethyl)dithiocarbamate 12, 183 (1976); Suppl. 7, 70 (1987)
Potassium bromate 40, 207 (1986); Suppl. 7, 70 (1987);
73, 481 (1999)
Potassium chromate (see Chromium and chromium compounds)
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Potassium dichromate (see Chromium and chromium compounds)

Prazepam 66, 143 (1996)
Prednimustine 50, 115 (1990)
Prednisone 26, 293 (1981); Suppl. 7, 326
(1987)
Printing processes and printing inks 65, 33 (1996)
Procarbazine hydrochloride 26, 311 (1981); Suppl. 7, 327
(1987)
Proflavine salts 24, 195 (1980); Suppl. 7, 70 (1987)
Progesterone (see also Progestins; Combined oral contraceptives) 6, 135 (1974); 21, 491 (1979)
(corr. 42, 259)
Progestins (see Progestogens)
Progestogens Suppl. 7, 289 (1987); 72, 49, 339,
531 (1999)
Pronetalol hydrochloride 13, 227 (1977) (corr. 42, 256);
Suppl. 7, 70 (1987)
1,3-Propane sultone 4, 253 (1974) (corr. 42, 253);
Suppl. 7, 70 (1987); 71, 1095
(1999)
Propham 12, 189 (1976); Suppl. 7, 70 (1987)
β-Propiolactone 4, 259 (1974) (corr. 42, 253);
Suppl. 7, 70 (1987); 71, 1103
(1999)
n-Propyl carbamate 12, 201 (1976); Suppl. 7, 70 (1987)
Propylene 19, 213 (1979); Suppl. 7, 71
(1987); 60, 161 (1994)
Propyleneimine (see 2-Methylaziridine)
Propylene oxide 11, 191 (1976); 36, 227 (1985)
(corr. 42, 263); Suppl. 7, 328
(1987); 60, 181 (1994)
Propylthiouracil 7, 67 (1974); Suppl. 7, 329 (1987);
79, 91 (2001)
Ptaquiloside (see also Bracken fern) 40, 55 (1986); Suppl. 7, 71 (1987)
Pulp and paper manufacture 25, 157 (1981); Suppl. 7, 385
(1987)
Pyrene 32, 431 (1983); Suppl. 7, 71 (1987)
Pyridine 77, 503 (2000)
Pyrido[3,4-c]psoralen 40, 349 (1986); Suppl. 7, 71 (1987)
Pyrimethamine 13, 233 (1977); Suppl. 7, 71 (1987)
Pyrrolizidine alkaloids (see Hydroxysenkirkine; Isatidine; Jacobine;
Lasiocarpine; Monocrotaline; Retrorsine; Riddelliine; Seneciphylline;
Senkirkine)
Quartz (see Crystalline silica)

Quercetin (see also Bracken fern) 31, 213 (1983); Suppl. 7, 71
(1987); 73, 497 (1999)
para-Quinone 15, 255 (1977); Suppl. 7, 71
(1987); 71, 1245 (1999)
Quintozene 5, 211 (1974); Suppl. 7, 71 (1987)
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Radiation (see gamma-radiation, neutrons, ultraviolet radiation,

X-radiation)
Radionuclides, internally deposited 78 (2001)
Radon 43, 173 (1988) (corr. 45, 283)
Refractory ceramic fibres (see Man-made vitreous fibres)
Reserpine 10, 217 (1976); 24, 211 (1980)
(corr. 42, 260); Suppl. 7, 330
(1987)
Resorcinol 15, 155 (1977); Suppl. 7, 71
(1987); 71, 1119 (1990)
Retrorsine 10, 303 (1976); Suppl. 7, 71 (1987)
Rhodamine B 16, 221 (1978); Suppl. 7, 71 (1987)
Rhodamine 6G 16, 233 (1978); Suppl. 7, 71 (1987)
Riddelliine 10, 313 (1976); Suppl. 7, 71
(1987); 82, 153 (2002)
Rifampicin 24, 243 (1980); Suppl. 7, 71 (1987)
Ripazepam 66, 157 (1996)
Rock (stone) wool (see Man-made vitreous fibres)
Rubber industry 28 (1982) (corr. 42, 261); Suppl. 7,
332 (1987)
Rubia tinctorum (see also Madder root, Traditional herbal medicines) 82, 129 (2002)
Rugulosin 40, 99 (1986); Suppl. 7, 71 (1987)
Saccharated iron oxide 2, 161 (1973); Suppl. 7, 71 (1987)

Saccharin and its salts 22, 111 (1980) (corr. 42, 259);
Suppl. 7, 334 (1987); 73, 517 (1999)
Safrole 1, 169 (1972); 10, 231 (1976);
Suppl. 7, 71 (1987)
Salted fish 56, 41 (1993)
Sawmill industry (including logging) (see Lumber and
sawmill industry (including logging))
Scarlet Red 8, 217 (1975); Suppl. 7, 71 (1987)
Schistosoma haematobium (infection with) 61, 45 (1994)
Schistosoma japonicum (infection with) 61, 45 (1994)
Schistosoma mansoni (infection with) 61, 45 (1994)
Selenium and selenium compounds 9, 245 (1975) (corr. 42, 255);
Suppl. 7, 71 (1987)
Selenium dioxide (see Selenium and selenium compounds)
Selenium oxide (see Selenium and selenium compounds)
Semicarbazide hydrochloride 12, 209 (1976) (corr. 42, 256);
Suppl. 7, 71 (1987)
Senecio jacobaea L. (see also Pyrrolizidine alkaloids) 10, 333 (1976)
Senecio longilobus (see also Pyrrolizidine alkaloids, Traditional) 10, 334 (1976); 82, 153 (2002)
herbal medicines)
Senecio riddellii (see also Traditional herbal medicines) 82, 153 (1982)
Seneciphylline 10, 319, 335 (1976); Suppl. 7, 71
(1987)
Senkirkine 10, 327 (1976); 31, 231 (1983);
Suppl. 7, 71 (1987)
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Sepiolite 42, 175 (1987); Suppl. 7, 71

(1987); 68, 267 (1997)
Sequential oral contraceptives (see also Oestrogens, progestins Suppl. 7, 296 (1987)
and combinations)
Shale-oils 35, 161 (1985); Suppl. 7, 339
(1987)
Shikimic acid (see also Bracken fern) 40, 55 (1986); Suppl. 7, 71 (1987)
Shoe manufacture and repair (see Boot and shoe manufacture
and repair)
Silica (see also Amorphous silica; Crystalline silica) 42, 39 (1987)
Silicone (see Implants, surgical)
Simazine 53, 495 (1991); 73, 625 (1999)
Slag wool (see Man-made vitreous fibres)
Sodium arsenate (see Arsenic and arsenic compounds)
Sodium arsenite (see Arsenic and arsenic compounds)
Sodium cacodylate (see Arsenic and arsenic compounds)
Sodium chlorite 52, 145 (1991)
Sodium chromate (see Chromium and chromium compounds)
Sodium cyclamate (see Cyclamates)
Sodium dichromate (see Chromium and chromium compounds)
Sodium diethyldithiocarbamate 12, 217 (1976); Suppl. 7, 71 (1987)
Sodium equilin sulfate (see Conjugated oestrogens)
Sodium fluoride (see Fluorides)
Sodium monofluorophosphate (see Fluorides)
Sodium oestrone sulfate (see Conjugated oestrogens)
Sodium ortho-phenylphenate (see also ortho-Phenylphenol) 30, 329 (1983); Suppl. 7, 71, 392
(1987); 73, 451 (1999)
Sodium saccharin (see Saccharin)
Sodium selenate (see Selenium and selenium compounds)
Sodium selenite (see Selenium and selenium compounds)
Sodium silicofluoride (see Fluorides)
Solar radiation 55 (1992)
Soots 3, 22 (1973); 35, 219 (1985);
Suppl. 7, 343 (1987)
Special-purpose glass fibres such as E-glass and ‘475’ glass fibres
(see Man-made vitreous fibres)
Spironolactone 24, 259 (1980); Suppl. 7, 344
(1987); 79, 317 (2001)
Stannous fluoride (see Fluorides)
Static electric fields 80 (2002)
Static magnetic fields 80 (2002)
Steel founding (see Iron and steel founding)
Steel, stainless (see Implants, surgical)
Sterigmatocystin 1, 175 (1972); 10, 245 (1976);
Suppl. 7, 72 (1987)
Steroidal oestrogens Suppl. 7, 280 (1987)
Streptozotocin 4, 221 (1974); 17, 337 (1978);
Suppl. 7, 72 (1987)
Strobane® (see Terpene polychlorinates)
Strong-inorganic-acid mists containing sulfuric acid (see Mists and
vapours from sulfuric acid and other strong inorganic acids)
Strontium chromate (see Chromium and chromium compounds)
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Styrene 19, 231 (1979) (corr. 42, 258);

Suppl. 7, 345 (1987); 60, 233
(1994) (corr. 65, 549); 82, 437
(2002)
Styrene−acrylonitrile copolymers 19, 97 (1979); Suppl. 7, 72 (1987)
Styrene−butadiene copolymers 19, 252 (1979); Suppl. 7, 72 (1987)
Styrene-7,8-oxide 11, 201 (1976); 19, 275 (1979);
36, 245 (1985); Suppl. 7, 72
(1987); 60, 321 (1994)
Succinic anhydride 15, 265 (1977); Suppl. 7, 72 (1987)
Sudan I 8, 225 (1975); Suppl. 7, 72 (1987)
Sudan II 8, 233 (1975); Suppl. 7, 72 (1987)
Sudan III 8, 241 (1975); Suppl. 7, 72 (1987)
Sudan Brown RR 8, 249 (1975); Suppl. 7, 72 (1987)
Sudan Red 7B 8, 253 (1975); Suppl. 7, 72 (1987)
Sulfadimidine (see Sulfamethazine)
Sulfafurazole 24, 275 (1980); Suppl. 7, 347
(1987)
Sulfallate 30, 283 (1983); Suppl. 7, 72 (1987)
Sulfamethazine and its sodium salt 79, 341 (2001)
Sulfamethoxazole 24, 285 (1980); Suppl. 7, 348
(1987); 79, 361 (2001)
Sulfites (see Sulfur dioxide and some sulfites, bisulfites and metabisulfites)
Sulfur dioxide and some sulfites, bisulfites and metabisulfites 54, 131 (1992)
Sulfur mustard (see Mustard gas)
Sulfuric acid and other strong inorganic acids, occupational exposures 54, 41 (1992)
to mists and vapours from
Sulfur trioxide 54, 121 (1992)
Sulphisoxazole (see Sulfafurazole)
Sunset Yellow FCF 8, 257 (1975); Suppl. 7, 72 (1987)
Symphytine 31, 239 (1983); Suppl. 7, 72 (1987)
2,4,5-T (see also Chlorophenoxy herbicides; Chlorophenoxy 15, 273 (1977)

Talc 42, 185 (1987); Suppl. 7, 349
(1987)
Tamoxifen 66, 253 (1996)
Tannic acid 10, 253 (1976) (corr. 42, 255);
Suppl. 7, 72 (1987)
Tannins (see also Tannic acid) 10, 254 (1976); Suppl. 7, 72 (1987)
TCDD (see 2,3,7,8-Tetrachlorodibenzo-para-dioxin)
TDE (see DDT)
Tea 51, 207 (1991)
Temazepam 66, 161 (1996)
Teniposide 76, 259 (2000)
Terpene polychlorinates 5, 219 (1974); Suppl. 7, 72 (1987)
Testosterone (see also Androgenic (anabolic) steroids) 6, 209 (1974); 21, 519 (1979)
Testosterone oenanthate (see Testosterone)
Testosterone propionate (see Testosterone)
2,2′,5,5′-Tetrachlorobenzidine 27, 141 (1982); Suppl. 7, 72 (1987)
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2,3,7,8-Tetrachlorodibenzo-para-dioxin 15, 41 (1977); Suppl. 7, 350

(1987); 69, 33 (1997)
1,1,1,2-Tetrachloroethane 41, 87 (1986); Suppl. 7, 72 (1987);
71, 1133 (1999)
1,1,2,2-Tetrachloroethane 20, 477 (1979); Suppl. 7, 354
(1987); 71, 817 (1999)
Tetrachloroethylene 20, 491 (1979); Suppl. 7, 355
(1987); 63, 159 (1995) (corr. 65,
549)
2,3,4,6-Tetrachlorophenol (see Chlorophenols; Chlorophenols,
Tetrachlorvinphos 30, 197 (1983); Suppl. 7, 72 (1987)
Tetraethyllead (see Lead and lead compounds)
Tetrafluoroethylene 19, 285 (1979); Suppl. 7, 72
(1987); 71, 1143 (1999)
Tetrakis(hydroxymethyl)phosphonium salts 48, 95 (1990); 71, 1529 (1999)
Tetramethyllead (see Lead and lead compounds)
Tetranitromethane 65, 437 (1996)
Textile manufacturing industry, exposures in 48, 215 (1990) (corr. 51, 483)
Theobromine 51, 421 (1991)
Theophylline 51, 391 (1991)
Thioacetamide 7, 77 (1974); Suppl. 7, 72 (1987)
4,4′-Thiodianiline 16, 343 (1978); 27, 147 (1982);
Suppl. 7, 72 (1987)
Thiotepa 9, 85 (1975); Suppl. 7, 368 (1987);
50, 123 (1990)
Thiouracil 7, 85 (1974); Suppl. 7, 72 (1987);
79, 127 (2001)
Thiourea 7, 95 (1974); Suppl. 7, 72 (1987);
79, 703 (2001)
Thiram 12, 225 (1976); Suppl. 7, 72
(1987); 53, 403 (1991)
Titanium (see Implants, surgical)
Titanium dioxide 47, 307 (1989)
Tobacco habits other than smoking (see Tobacco products, smokeless)
Tobacco products, smokeless 37 (1985) (corr. 42, 263; 52, 513);
Suppl. 7, 357 (1987)
Tobacco smoke 38 (1986) (corr. 42, 263); Suppl. 7,
359 (1987); 83, 51 (2004)
Tobacco smoking (see Tobacco smoke)
ortho-Tolidine (see 3,3′-Dimethylbenzidine)
2,4-Toluene diisocyanate (see also Toluene diisocyanates) 19, 303 (1979); 39, 287 (1986)
2,6-Toluene diisocyanate (see also Toluene diisocyanates) 19, 303 (1979); 39, 289 (1986)
Toluene 47, 79 (1989); 71, 829 (1999)
Toluene diisocyanates 39, 287 (1986) (corr. 42, 264);
Suppl. 7, 72 (1987); 71, 865 (1999)
Toluenes, α-chlorinated (see α-Chlorinated toluenes and benzoyl chloride)
ortho-Toluenesulfonamide (see Saccharin)
ortho-Toluidine 16, 349 (1978); 27, 155 (1982)
(corr. 68, 477); Suppl. 7, 362
(1987); 77, 267 (2000)
Toremifene 66, 367 (1996)
Toxaphene 20, 327 (1979); Suppl. 7, 72
(1987); 79, 569 (2001)
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T-2 Toxin (see Toxins derived from Fusarium sporotrichioides)

Toxins derived from Fusarium graminearum, F. culmorum and 11, 169 (1976); 31, 153, 279
F. crookwellense (1983); Suppl. 7, 64, 74 (1987);
56, 397 (1993)
Toxins derived from Fusarium moniliforme 56, 445 (1993)
Toxins derived from Fusarium sporotrichioides 31, 265 (1983); Suppl. 7, 73
(1987); 56, 467 (1993)
Traditional herbal medicines 82, 41 (2002)
Tremolite (see Asbestos)
Treosulfan 26, 341 (1981); Suppl. 7, 363
(1987)
Triaziquone (see Tris(aziridinyl)-para-benzoquinone)
Trichlorfon 30, 207 (1983); Suppl. 7, 73 (1987)
Trichlormethine 9, 229 (1975); Suppl. 7, 73 (1987);
50, 143 (1990)
Trichloroacetic acid 63, 291 (1995) (corr. 65, 549);
84 (2004)
Trichloroacetonitrile (see also Halogenated acetonitriles) 71, 1533 (1999)
1,1,1-Trichloroethane 20, 515 (1979); Suppl. 7, 73
(1987); 71, 881 (1999)
1,1,2-Trichloroethane 20, 533 (1979); Suppl. 7, 73
(1987); 52, 337 (1991); 71, 1153
(1999)
Trichloroethylene 11, 263 (1976); 20, 545 (1979);
Suppl. 7, 364 (1987); 63, 75 (1995)
(corr. 65, 549)
2,4,5-Trichlorophenol (see also Chlorophenols; Chlorophenols, 20, 349 (1979)
2,4,6-Trichlorophenol (see also Chlorophenols; Chlorophenols, 20, 349 (1979)
(2,4,5-Trichlorophenoxy)acetic acid (see 2,4,5-T)
1,2,3-Trichloropropane 63, 223 (1995)
Trichlorotriethylamine-hydrochloride (see Trichlormethine)
T2-Trichothecene (see Toxins derived from Fusarium sporotrichioides)
Tridymite (see Crystalline silica)
Triethanolamine 77, 381 (2000)
Triethylene glycol diglycidyl ether 11, 209 (1976); Suppl. 7, 73
(1987); 71, 1539 (1999)
Trifluralin 53, 515 (1991)
4,4′,6-Trimethylangelicin plus ultraviolet radiation (see also Suppl. 7, 57 (1987)
2,4,5-Trimethylaniline 27, 177 (1982); Suppl. 7, 73 (1987)
2,4,6-Trimethylaniline 27, 178 (1982); Suppl. 7, 73 (1987)
4,5′,8-Trimethylpsoralen 40, 357 (1986); Suppl. 7, 366
(1987)
Trimustine hydrochloride (see Trichlormethine)
2,4,6-Trinitrotoluene 65, 449 (1996)
Triphenylene 32, 447 (1983); Suppl. 7, 73 (1987)
Tris(aziridinyl)-para-benzoquinone 9, 67 (1975); Suppl. 7, 367 (1987)
Tris(1-aziridinyl)phosphine-oxide 9, 75 (1975); Suppl. 7, 73 (1987)
Tris(1-aziridinyl)phosphine-sulphide (see Thiotepa)
2,4,6-Tris(1-aziridinyl)-s-triazine 9, 95 (1975); Suppl. 7, 73 (1987)
Tris(2-chloroethyl) phosphate 48, 109 (1990); 71, 1543 (1999)
P 469-506 DEF.qxp 09/08/2006 13:57 Page 505
1,2,3-Tris(chloromethoxy)propane 15, 301 (1977); Suppl. 7, 73

(1987); 71, 1549 (1999)
Tris(2,3-dibromopropyl) phosphate 20, 575 (1979); Suppl. 7, 369
(1987); 71, 905 (1999)
Tris(2-methyl-1-aziridinyl)phosphine-oxide 9, 107 (1975); Suppl. 7, 73 (1987)
Trp-P-1 31, 247 (1983); Suppl. 7, 73 (1987)
Trp-P-2 31, 255 (1983); Suppl. 7, 73 (1987)
Trypan blue 8, 267 (1975); Suppl. 7, 73 (1987)
Tussilago farfara L. (see also Pyrrolizidine alkaloids) 10, 334 (1976)
Ultraviolet radiation 40, 379 (1986); 55 (1992)

Underground haematite mining with exposure to radon 1, 29 (1972); Suppl. 7, 216 (1987)
Uracil mustard 9, 235 (1975); Suppl. 7, 370 (1987)
Uranium, depleted (see Implants, surgical)
Urethane 7, 111 (1974); Suppl. 7, 73 (1987)
Vanadium pentoxide 86, 227 (2006)

Vat Yellow 4 48, 161 (1990)
Vinblastine sulfate 26, 349 (1981) (corr. 42, 261);
Suppl. 7, 371 (1987)
Vincristine sulfate 26, 365 (1981); Suppl. 7, 372
(1987)
Vinyl acetate 19, 341 (1979); 39, 113 (1986);
Suppl. 7, 73 (1987); 63, 443 (1995)
Vinyl bromide 19, 367 (1979); 39, 133 (1986);
Suppl. 7, 73 (1987); 71, 923 (1999)
Vinyl chloride 7, 291 (1974); 19, 377 (1979)
(corr. 42, 258); Suppl. 7, 373
(1987)
Vinyl chloride-vinyl acetate copolymers 7, 311 (1976); 19, 412 (1979)
(corr. 42, 258); Suppl. 7, 73 (1987)
4-Vinylcyclohexene 11, 277 (1976); 39, 181 (1986)
Suppl. 7, 73 (1987); 60, 347 (1994)
4-Vinylcyclohexene diepoxide 11, 141 (1976); Suppl. 7, 63
(1987); 60, 361 (1994)
Vinyl fluoride 39, 147 (1986); Suppl. 7, 73
(1987); 63, 467 (1995)
Vinylidene chloride 19, 439 (1979); 39, 195 (1986);
Suppl. 7, 376 (1987); 71, 1163
(1999)
Vinylidene chloride-vinyl chloride copolymers 19, 448 (1979) (corr. 42, 258);
Suppl. 7, 73 (1987)
Vinylidene fluoride 39, 227 (1986); Suppl. 7, 73
(1987); 71, 1551 (1999)
N-Vinyl-2-pyrrolidone 19, 461 (1979); Suppl. 7, 73
(1987); 71, 1181 (1999)
Vinyl toluene 60, 373 (1994)
Vitamin K substances 76, 417 (2000)
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Welding 49, 447 (1990) (corr. 52, 513)

Wollastonite 42, 145 (1987); Suppl. 7, 377
(1987); 68, 283 (1997)
Wood dust 62, 35 (1995)
Wood industries 25 (1981); Suppl. 7, 378 (1987)
X-radiation 75, 121 (2000)

Xylenes 47, 125 (1989); 71, 1189 (1999)
2,4-Xylidine 16, 367 (1978); Suppl. 7, 74 (1987)
2,5-Xylidine 16, 377 (1978); Suppl. 7, 74 (1987)
2,6-Xylidine (see 2,6-Dimethylaniline)
Yellow AB 8, 279 (1975); Suppl. 7, 74 (1987)

Yellow OB 8, 287 (1975); Suppl. 7, 74 (1987)
Zalcitabine 76, 129 (2000)

Zearalenone (see Toxins derived from Fusarium graminearum,
Zectran 12, 237 (1976); Suppl. 7, 74 (1987)
Zeolites other than erionite 68, 307 (1997)
Zidovudine 76, 73 (2000)
Zinc beryllium silicate (see Beryllium and beryllium compounds)
Zinc chromate (see Chromium and chromium compounds)
Zinc chromate hydroxide (see Chromium and chromium compounds)
Zinc potassium chromate (see Chromium and chromium compounds)
Zinc yellow (see Chromium and chromium compounds)
Zineb 12, 245 (1976); Suppl. 7, 74 (1987)
Ziram 12, 259 (1976); Suppl. 7, 74
(1987); 53, 423 (1991)
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List of IARC Monographs on the Evaluation of Carcinogenic Risks to Humans*

Volume 1 Volume 11 Volume 20
Some Inorganic Substances, Cadmium, Nickel, Some Some Halogenated Hydrocarbons
Chlorinated Hydrocarbons, Epoxides, Miscellaneous 1979; 609 pages (out-of-print)
Aromatic Amines, N-Nitroso Industrial Chemicals and General
Compounds, and Natural Considerations on Volatile Volume 21
Products Anaesthetics Sex Hormones (II)
1972; 184 pages (out-of-print) 1976; 306 pages (out-of-print) 1979; 583 pages

Some Inorganic and Organo- Some Carbamates, Thio- Some Non-Nutritive Sweetening
metallic Compounds carbamates and Carbazides Agents
1973; 181 pages (out-of-print) 1976; 282 pages (out-of-print) 1980; 208 pages
Volume 3 Volume 23
Volume 13
Certain Polycyclic Aromatic Some Metals and Metallic
Hydrocarbons and Heterocyclic Some Miscellaneous
Pharmaceutical Substances Compounds
Compounds 1980; 438 pages (out-of-print)
1973; 271 pages (out-of-print) 1977; 255 pages
Volume 14 Volume 24
Volume 4 Some Pharmaceutical Drugs
Some Aromatic Amines, Hydra- Asbestos
1977; 106 pages (out-of-print) 1980; 337 pages
zine and Related Substances,
N-Nitroso Compounds and Volume 25
Miscellaneous Alkylating Agents Volume 15
Wood, Leather and Some
1974; 286 pages (out-of-print) Some Fumigants, the Herbicides
Associated Industries
2,4-D and 2,4,5-T, Chlorinated
1981; 412 pages
Volume 5 Dibenzodioxins and Miscella-
Some Organochlorine Pesticides neous Industrial Chemicals
Volume 26
1974; 241 pages (out-of-print) 1977; 354 pages (out-of-print)
Some Antineoplastic and
Volume 6 Immunosuppressive Agents
Volume 16 1981; 411 pages (out-of-print)
Sex Hormones Some Aromatic Amines and
1974; 243 pages (out-of-print) Related Nitro Compounds—Hair Volume 27
Dyes, Colouring Agents and Some Aromatic Amines,
Volume 7 Miscellaneous Industrial
Some Anti-Thyroid and Related Anthraquinones and Nitroso
Chemicals Compounds, and Inorganic
Substances, Nitrofurans and 1978; 400 pages
Industrial Chemicals Fluorides Used in Drinking-water
1974; 326 pages (out-of-print) and Dental Preparations
Some N-Nitroso Compounds
Volume 8
Some Aromatic Azo Compounds 1978; 365 pages Volume 28
1975; 357 pages (out-of-print) The Rubber Industry
Volume 9 Polychlorinated Biphenyls and
Some Aziridines, N-, S- and Polybrominated Biphenyls Volume 29
O-Mustards and Selenium 1978; 140 pages (out-of-print) Some Industrial Chemicals and
1975; 268 pages (out-of-print) Dyestuffs
Volume 10 Some Monomers, Plastics and
Some Naturally Occurring Synthetic Elastomers, and Volume 30
Substances Acrolein Miscellaneous Pesticides
1976; 353 pages (out-of-print) 1979; 513 pages (out-of-print) 1983; 424 pages (out-of-print)
*High-quality photocopies of all out-of-print volumes may be purchased from University Microfilms International,
300 North Zeeb Road, Ann Arbor, MI 48106-1346, USA (Tel.: +1 313-761-4700, +1 800-521-0600).
P 507-514 DEF.qxp 09/08/2006 14:30 Page 2

Some Food Additives, Feed Some Naturally Occurring and Coffee, Tea, Mate, Methyl-
Additives and Naturally Synthetic Food Components, xanthines and Methylglyoxal
Occurring Substances Furocoumarins and Ultraviolet 1991; 513 pages
1983; 314 pages (out-of-print) Radiation
1986; 444 pages (out-of-print) Volume 52
Volume 32 Chlorinated Drinking-water;
Polynuclear Aromatic Volume 41 Chlorination By-products; Some
Compounds, Part 1: Chemical, Some Halogenated Hydrocarbons Other Halogenated Compounds;
Environmental and Experimental and Pesticide Exposures Cobalt and Cobalt Compounds
Data 1986; 434 pages (out-of-print) 1991; 544 pages
1983; 477 pages (out-of-print)
Volume 42 Volume 53
Silica and Some Silicates Occupational Exposures in
Volume 33
1987; 289 pages Insecticide Application, and
Polynuclear Aromatic
Some Pesticides
Compounds, Part 2: Carbon
Volume 43 1991; 612 pages
Blacks, Mineral Oils and Some Man-Made Mineral Fibres and
Nitroarenes Radon Volume 54
1984; 245 pages (out-of-print) 1988; 300 pages (out-of-print) Occupational Exposures to Mists
and Vapours from Strong
Volume 34 Volume 44 Inorganic Acids; and Other
Polynuclear Aromatic Alcohol Drinking Industrial Chemicals
Compounds, Part 3: Industrial 1988; 416 pages 1992; 336 pages
Exposures in Aluminium
Production, Coal Gasification, Volume 45 Volume 55
Coke Production, and Iron and Occupational Exposures in Solar and Ultraviolet Radiation
Steel Founding Petroleum Refining; Crude Oil 1992; 316 pages
1984; 219 pages (out-of-print) and Major Petroleum Fuels
1989; 322 pages Volume 56
Volume 35 Some Naturally Occurring
Polynuclear Aromatic Volume 46 Substances: Food Items and
Compounds, Part 4: Bitumens, Diesel and Gasoline Engine Constituents, Heterocyclic
Coal-tars and Derived Products, Exhausts and Some Nitroarenes Aromatic Amines and Mycotoxins
Shale-oils and Soots 1989; 458 pages 1993; 599 pages
1985; 271 pages
Volume 47 Volume 57
Volume 36 Some Organic Solvents, Resin Occupational Exposures of
Allyl Compounds, Aldehydes, Monomers and Related Hairdressers and Barbers and
Epoxides and Peroxides Compounds, Pigments and Personal Use of Hair Colourants;
1985; 369 pages Occupational Exposures in Some Hair Dyes, Cosmetic
Paint Manufacture and Painting Colourants, Industrial Dyestuffs
1989; 535 pages (out-of-print) and Aromatic Amines
Volume 37
1993; 428 pages
Tobacco Habits Other than
Volume 48
Smoking; Betel-Quid and Areca- Some Flame Retardants and Volume 58
Nut Chewing; and Some Related Textile Chemicals, and Exposures Beryllium, Cadmium, Mercury,
Nitrosamines in the Textile Manufacturing and Exposures in the Glass
1985; 291 pages (out-of-print) Industry Manufacturing Industry
1990; 345 pages 1993; 444 pages
Volume 38
Tobacco Smoking Volume 49 Volume 59
1986; 421 pages Chromium, Nickel and Welding Hepatitis Viruses
1990; 677 pages 1994; 286 pages
Volume 39
Some Chemicals Used in Plastics Volume 50 Volume 60
and Elastomers Pharmaceutical Drugs Some Industrial Chemicals
1986; 403 pages (out-of-print) 1990; 415 pages 1994; 560 pages
P 507-514 DEF.qxp 09/08/2006 14:30 Page 3

Schistosomes, Liver Flukes and Hormonal Contraception and Tobacco Smoke and Involuntary
Helicobacter pylori Post-menopausal Hormonal Smoking
1994; 270 pages Therapy 2004; 1452 pages
1999; 660 pages
Volume 62 Volume 84
Wood Dust and Formaldehyde Volume 73 Some Drinking-Water
1995; 405 pages Some Chemicals that Cause
Disinfectants and Contaminants,
Tumours of the Kidney or Urinary
Bladder in Rodents and Some including Arsenic
Volume 63 2004; 512 pages
Other Substances
Dry Cleaning, Some Chlorinated
1999; 674 pages
Solvents and Other Industrial Volume 85
Chemicals Volume 74 Betel-quid and Areca-nut
1995; 551 pages Surgical Implants and Other Chewing and Some Areca-nut-
Foreign Bodies derived Nitrosamines
Volume 64 1999; 409 pages 2004; 334 pages
Human Papillomaviruses
1995; 409 pages Volume 75 Volume 86
Ionizing Radiation, Part 1, Cobalt in Hard Metals and Cobalt
Volume 65 X-Radiation and γ-Radiation, Sulfate, Gallium Arsenide, Indium
Printing Processes and Printing and Neutrons
Phosphide and Vanadium
Inks, Carbon Black and Some 2000; 492 pages
Pentoxide
Nitro Compounds 2006; 330 pages
1996; 578 pages Volume 76
Some Antiviral and Anti-
neoplastic Drugs, and Other Volume 87
Volume 66
Pharmaceutical Agents Inorganic and Organic Lead
Some Pharmaceutical Drugs
2000; 522 pages Compounds
1996; 514 pages
2006; 506 pages
Volume 77
Volume 67
Some Industrial Chemicals Supplement No. 1
Human Immunodeficiency 2000; 563 pages Chemicals and Industrial
Viruses and Human T-Cell
Processes Associated with
Lymphotropic Viruses Volume 78
1996; 424 pages Cancer in Humans (IARC
Ionizing Radiation, Part 2, Monographs, Volumes 1 to 20)
Some Internally Deposited
Radionuclides
Silica, Some Silicates, Coal Dust 2001; 595 pages
and para-Aramid Fibrils Supplement No. 2
1997; 506 pages Volume 79 Long-term and Short-term Scree-
Some Thyrotropic Agents ning Assays for Carcinogens: A
Volume 69 2001; 763 pages Critical Appraisal
Polychlorinated Dibenzo-para- 1980; 426 pages (out-of-print)
Dioxins and Polychlorinated Volume 80 (updated as IARC Scientific
Dibenzofurans Non-Ionizing Radiation, Part 1: Publications No. 83, 1986)
1997; 666 pages Static and Extremely Low-
Frequency (ELF) Electric and Supplement No. 3
Magnetic Fields Cross Index of Synonyms and
Volume 70
2002; 429 pages Trade Names in Volumes 1 to 26
Epstein-Barr Virus and Kaposi’s
Sarcoma Herpesvirus/Human of the IARC Monographs
Volume 81
Herpesvirus 8 1982; 199 pages (out-of-print)
Man-made Vitreous Fibres
1997; 524 pages 2002; 418 pages
Supplement No. 4
Volume 71 Volume 82 Chemicals, Industrial Processes
Re-evaluation of Some Organic Some Traditional Herbal and Industries Associated with
Chemicals, Hydrazine and Medicines, Some Mycotoxins, Cancer in Humans (IARC
Hydrogen Peroxide Naphthalene and Styrene Monographs, Volumes 1 to 29)
1999; 1586 pages 2002; 590 pages 1982; 292 pages (out-of-print)
P 507-514 DEF.qxp 09/08/2006 14:30 Page 4
Supplement No. 5 Supplement No. 7

Cross Index of Synonyms and Overall Evaluations of Carcino-
Trade Names in Volumes 1 to 36 genicity: An Updating of
of the IARC Monographs IARC Monographs Volumes 1–42
Supplement No. 6
Genetic and Related Effects: Supplement No. 8
An Updating of Selected IARC Cross Index of Synonyms and
Monographs from Volumes 1 Trade Names in Volumes 1 to 46
to 42 of the IARC Monographs
P 507-514 DEF.qxp 09/08/2006 14:30 Page 5
Achevé d’imprimer sur rotative par l’Imprimerie Darantiere

à Dijon-Quetigny en août 2006
P 507-514 DEF.qxp 09/08/2006 14:30 Page 6
P 507-514 DEF.qxp 09/08/2006 14:30 Page 7
Dépôt légal : août 2006 - N° d’impression : 26-1273
Imprimé en France
P 507-514 DEF.qxp 09/08/2006 14:30 Page 8

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WORLD HEALTH ORGANIZATION

INTERNATIONAL AGENCY FOR RESEARCH ON CANCER

IARC Monographs on the Evaluation of

WORLD HEALTH ORGANIZATION

IARC Monographs on the Evaluation

Inorganic and Organic

This publication represents the views and expert opinions

10–17 February 2004

1 Leaded gasoline: tetraethyl lead has been used as an additive in gasoline

Cover design: Georges Mollon, IARC

NOTE TO THE READER ..................................................................................................1

LIST OF PARTICIPANTS ..................................................................................................3

GENERAL REMARKS ON THE SUBSTANCES CONSIDERED................................33

MONOGRAPH ON INORGANIC AND ORGANIC LEAD COMPOUNDS ................37

vi IARC MONOGRAPHS VOLUME 87

(iii) Removal of zinc ..........................................................53

(j) Others ..................................................................................121

viii IARC MONOGRAPHS VOLUME 87

2. Studies of Cancer in Humans ..............................................................................183

3. Studies of Cancer in Experimental Animals ......................................................225

3.2 Lead subacetate..........................................................................................232

x IARC MONOGRAPHS VOLUME 87

4. Other Data Relevant to an Evaluation of Carcinogenicity

4.2 Toxic effects ..............................................................................................285

xii IARC MONOGRAPHS VOLUME 87

Effects on neurochemical parameters........................318

LIST OF ABBREVIATIONS USED IN THIS VOLUME ............................................469

CUMULATIVE INDEX TO THE MONOGRAPHS SERIES ........................................473

NOTE TO THE READER

IARC WORKING GROUP ON THE EVALUATION

Lyon, 10–17 February 2004

4 IARC MONOGRAPHS VOLUME 87

Herbert L. Needleman, Lead Research Group, University of Pennsylvania, 310 Keystone

Observer for the Lead Development Association International 2

6 IARC MONOGRAPHS VOLUME 87

Jane Mitchell, Carcinogen Identification and Evaluation

IARC MONOGRAPHS PROGRAMME ON THE EVALUATION

2. OBJECTIVE AND SCOPE

10 IARC MONOGRAPHS VOLUME 87

3. SELECTION OF TOPICS FOR MONOGRAPHS

4. DATA FOR MONOGRAPHS

5. THE WORKING GROUP

12 IARC MONOGRAPHS VOLUME 87

14 IARC MONOGRAPHS VOLUME 87

8. STUDIES OF CANCER IN HUMANS

(b) Quality of studies considered

16 IARC MONOGRAPHS VOLUME 87

(c) Inferences about mechanism of action

(d ) Criteria for causality

risk after cessation of or reduction in exposure in individuals or in whole populations also

9. STUDIES OF CANCER IN EXPERIMENTAL ANIMALS

18 IARC MONOGRAPHS VOLUME 87

(a) Qualitative aspects

(b) Quantitative aspects

20 IARC MONOGRAPHS VOLUME 87

(c) Statistical analysis of long-term experiments in animals

10. OTHER DATA RELEVANT TO AN EVALUATION OF

22 IARC MONOGRAPHS VOLUME 87

11. SUMMARY OF DATA REPORTED