Mono 87
Mono 87
Mono 87
VOLUME 87
Inorganic and Organic
Lead Compounds
LYON, FRANCE
2006
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VOLUME 87
2006
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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.
The lists of IARC evaluations are regularly updated and are available on Internet: http://monographs.
iarc.fr/
This programme has been supported by Cooperative Agreement 5 UO1 CA33193 awarded since 1982 by the
United States National Cancer Institute, Department of Health and Human Services. Additional support has been
provided since 1986 by the European Commission, Directorate-General EMPL (Employment, and Social Affairs),
Health, Safety and Hygiene at Work Unit, and since 1992 by the United States National Institute of Environmental
Health Sciences.
This publication was made possible, in part, by a Cooperative Agreement between the United States Environ-
mental Protection Agency, Office of Research and Development (USEPA-ORD) and the International Agency for
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.:
+41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected]).
Publications of the World Health Organization enjoy copyright protection in accordance with the provisions
of Protocol 2 of the Universal Copyright Convention. All rights reserved.
The designations employed and the presentation of the material in this publication do not imply
the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization
concerning the legal status of any country, territory, city, or area or of its authorities,
or concerning the delimitation of its frontiers or boundaries.
The mention of specific companies or of certain manufacturers’ products does not imply that
they are endorsed or recommended by the World Health Organization in preference to others of a similar nature
that are not mentioned. Errors and omissions excepted, the names of proprietary products
are distinguished by initial capital letters.
The IARC Monographs Working Group alone is responsible for the views expressed in this publication.
The International Agency for Research on Cancer welcomes requests for permission to reproduce or
translate its publications, in part or in full. Requests for permission to reproduce or translate IARC publications −
whether for sale or for noncommercial distribution − should be addressed to WHO Press, at the above address
(fax: +41 22 791 4806; email: [email protected]).
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
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1 2 5
3 6
CONTENTS
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
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CONTENTS vii
CONTENTS ix
3.8.3Guinea-pig ....................................................................................245
Intratracheal administration ..........................................................245
3.8.4 Rabbit ............................................................................................246
Intratracheal administration ..........................................................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
(a) Oral administration ..............................................................247
(b) Administration of lead with known carcinogens or
modifiers ..............................................................................248
3.11 Tetraethyl lead............................................................................................248
3.11.1 Mouse ............................................................................................248
Subcutaneous administration ........................................................248
CONTENTS xi
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
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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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)
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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
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
PREAMBLE
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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).
–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.
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.
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.
PREAMBLE 15
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).
PREAMBLE 17
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.
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.
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
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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.
(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.
PREAMBLE 23
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.
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.
(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.
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.
13. REFERENCES
Breslow, N.E. & Day, N.E. (1980) Statistical Methods in Cancer Research, Vol. 1, The Analysis
of Case–Control Studies (IARC Scientific Publications No. 32), Lyon, IARCPress
Breslow, N.E. & Day, N.E. (1987) Statistical Methods in Cancer Research, Vol. 2, The Design and
Analysis of Cohort Studies (IARC Scientific Publications No. 82), Lyon, IARCPress
Cohen, S.M. & Ellwein, L.B. (1990) Cell proliferation in carcinogenesis. Science, 249,
1007–1011
Gart, J.J., Krewski, D., Lee, P.N., Tarone, R.E. & Wahrendorf, J. (1986) Statistical Methods in
Cancer Research, Vol. 3, The Design and Analysis of Long-term Animal Experiments (IARC
Scientific Publications No. 79), Lyon, IARCPress
Hoel, D.G., Kaplan, N.L. & Anderson, M.W. (1983) Implication of nonlinear kinetics on risk
estimation in carcinogenesis. Science, 219, 1032–1037
Huff, J.E., Eustis, S.L. & Haseman, J.K. (1989) Occurrence and relevance of chemically induced
benign neoplasms in long-term carcinogenicity studies. Cancer Metastasis Rev., 8, 1–21
IARC (1973–1996) Information Bulletin on the Survey of Chemicals Being Tested for Carcino-
genicity/Directory of Agents Being Tested for Carcinogenicity, Numbers 1–17, Lyon,
IARCPress
IARC (1976–1996), Lyon, IARCPress
Directory of On-going Research in Cancer Epidemiology 1976. Edited by C.S. Muir &
G. Wagner
Directory of On-going Research in Cancer Epidemiology 1977 (IARC Scientific Publications
No. 17). Edited by C.S. Muir & G. Wagner
Directory of On-going Research in Cancer Epidemiology 1978 (IARC Scientific Publications
No. 26). Edited by C.S. Muir & G. Wagner
Directory of On-going Research in Cancer Epidemiology 1979 (IARC Scientific Publications
No. 28). Edited by C.S. Muir & G. Wagner
Directory of On-going Research in Cancer Epidemiology 1980 (IARC Scientific Publications
No. 35). Edited by C.S. Muir & G. Wagner
Directory of On-going Research in Cancer Epidemiology 1981 (IARC Scientific Publications
No. 38). Edited by C.S. Muir & G. Wagner
P 007-032 DEF.qxp 09/08/2006 10:46 Page 29
PREAMBLE 29
Vol. 7. Some Volatile Halogenated Hydrocarbons (IARC Scientific Publications No. 68).
Edited by L. Fishbein & I.K. O’Neill (1985)
Vol. 8. Some Metals: As, Be, Cd, Cr, Ni, Pb, Se, Zn (IARC Scientific Publications No. 71).
Edited by I.K. O’Neill, P. Schuller & L. Fishbein (1986)
Vol. 9. Passive Smoking (IARC Scientific Publications No. 81). Edited by I.K. O’Neill, K.D.
Brunnemann, B. Dodet & D. Hoffmann (1987)
Vol. 10. Benzene and Alkylated Benzenes (IARC Scientific Publications No. 85). Edited by L.
Fishbein & I.K. O’Neill (1988)
Vol. 11. Polychlorinated Dioxins and Dibenzofurans (IARC Scientific Publications No. 108).
Edited by C. Rappe, H.R. Buser, B. Dodet & I.K. O’Neill (1991)
Vol. 12. Indoor Air (IARC Scientific Publications No. 109). Edited by B. Seifert, H. van de
Wiel, B. Dodet & I.K. O’Neill (1993)
IARC (1979) Criteria to Select Chemicals for IARC Monographs (IARC intern. tech. Rep.
No. 79/003)
IARC (1982) IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to
Humans, Supplement 4, Chemicals, Industrial Processes and Industries Associated with
Cancer in Humans (IARC Monographs, Volumes 1 to 29), Lyon, IARCPress
IARC (1983) Approaches to Classifying Chemical Carcinogens According to Mechanism of
Action (IARC intern. tech. Rep. No. 83/001)
IARC (1984) Chemicals and Exposures to Complex Mixtures Recommended for Evaluation in
IARC Monographs and Chemicals and Complex Mixtures Recommended for Long-term
Carcinogenicity Testing (IARC intern. tech. Rep. No. 84/002)
IARC (1987a) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Supple-
ment 6, Genetic and Related Effects: An Updating of Selected IARC Monographs from
Volumes 1 to 42, Lyon, IARCPress
IARC (1987b) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Supple-
ment 7, Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes
1 to 42, Lyon, IARCPress
IARC (1988) Report of an IARC Working Group to Review the Approaches and Processes Used
to Evaluate the Carcinogenicity of Mixtures and Groups of Chemicals (IARC intern. tech.
Rep. No. 88/002)
IARC (1989) Chemicals, Groups of Chemicals, Mixtures and Exposure Circumstances to be
Evaluated in Future IARC Monographs, Report of an ad hoc Working Group (IARC intern.
tech. Rep. No. 89/004)
IARC (1991a) A Consensus Report of an IARC Monographs Working Group on the Use of Me-
chanisms of Carcinogenesis in Risk Identification (IARC intern. tech. Rep. No. 91/002)
IARC (1991b) Report of an ad-hoc IARC Monographs Advisory Group on Viruses and Other
Biological Agents Such as Parasites (IARC intern. tech. Rep. No. 91/001)
IARC (1993) Chemicals, Groups of Chemicals, Complex Mixtures, Physical and Biological
Agents and Exposure Circumstances to be Evaluated in Future IARC Monographs, Report of
an ad-hoc Working Group (IARC intern. Rep. No. 93/005)
IARC (1998a) Report of an ad-hoc IARC Monographs Advisory Group on Physical Agents
(IARC Internal Report No. 98/002)
IARC (1998b) Report of an ad-hoc IARC Monographs Advisory Group on Priorities for Future
Evaluations (IARC Internal Report No. 98/004)
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PREAMBLE 31
McGregor, D.B., Rice, J.M. & Venitt, S., eds (1999) The Use of Short and Medium-term Tests for
Carcinogens and Data on Genetic Effects in Carcinogenic Hazard Evaluation (IARC
Scientific Publications No. 146), Lyon, IARCPress
Montesano, R., Bartsch, H., Vainio, H., Wilbourn, J. & Yamasaki, H., eds (1986) Long-term and
Short-term Assays for Carcinogenesis — A Critical Appraisal (IARC Scientific Publications
No. 83), Lyon, IARCPress
Peto, R., Pike, M.C., Day, N.E., Gray, R.G., Lee, P.N., Parish, S., Peto, J., Richards, S. &
Wahrendorf, J. (1980) Guidelines for simple, sensitive significance tests for carcinogenic
effects in long-term animal experiments. In: IARC Monographs on the Evaluation of the
Carcinogenic Risk of Chemicals to Humans, Supplement 2, Long-term and Short-term
Screening Assays for Carcinogens: A Critical Appraisal, Lyon, IARCPress, pp. 311–426
Tomatis, L., Aitio, A., Wilbourn, J. & Shuker, L. (1989) Human carcinogens so far identified. Jpn.
J. Cancer Res., 80, 795–807
Vainio, H., Magee, P.N., McGregor, D.B. & McMichael, A.J., eds (1992) Mechanisms of Carci-
nogenesis in Risk Identification (IARC Scientific Publications No. 116), Lyon, IARCPress
Vainio, H., Wilbourn, J.D., Sasco, A.J., Partensky, C., Gaudin, N., Heseltine, E. & Eragne, I.
(1995) Identification of human carcinogenic risk in IARC Monographs. Bull. Cancer, 82,
339–348 (in French)
Waters, M.D., Stack, H.F., Brady, A.L., Lohman, P.H.M., Haroun, L. & Vainio, H. (1987)
Appendix 1. Activity profiles for genetic and related tests. In: IARC Monographs on the
Evaluation of Carcinogenic Risks to Humans, Suppl. 6, Genetic and Related Effects: An
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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–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.
P 033-038 DEF.qxp 09/08/2006 10:50 Page 35
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
IARC (1973) IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man,
Vol 2, Some Inorganic and Organometallic Compounds, Lyon
IARC (1980) IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to
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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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
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
11:04
Pb-S 100; SSO 1
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
Chemical name Synonyms and trade names (Chemical Abstracts Service name in italics) CAS registry Molecular formula Molecular
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)
Chemical name Synonyms and trade names (Chemical Abstracts Service name in italics) CAS registry Molecular formula Molecular
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
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
Chemical name Synonyms and trade names (Chemical Abstracts Service name in italics) CAS registry Molecular formula Molecular
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
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.
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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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
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
47
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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.
1.2.2 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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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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Ab B C Db E Fb Total
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).
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).
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.
Ab B C Db E Fb Total
A B C D E Total
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
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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).
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 (contd)
Table 9 (contd)
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).
Ab B C Db E Fb Total
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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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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(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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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).
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).
Table 20. Countries or regions that had phased out the use of
lead in gasolinea by the end of 1999
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).
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).
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
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Table 22. Lead concentrations in ambient air in central and eastern Europe
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
Table 23 (contd)
Table 24. Lead concentration in indoor dust in Latin America and the
Caribbean
Table 26 (contd)
09/08/2006
Table 27. Lead concentrations in outdoor air in Japan, 1996–97, as monitored in 16 monitoring stations
11:15
parameter
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
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).
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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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INORGANIC AND ORGANIC LEAD COMPOUNDS
11:15
Table 28. Lead concentrations in water in Latin America and the Caribbean
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)
85
P 075-140 DEF.qxp 09/08/2006 11:15 Page 86
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
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
P 075-140 DEF.qxp
09/08/2006
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
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
P 075-140 DEF.qxp
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)
11:15
Nainital Lake water 150–480 Ali et al. (1999)
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
Unless specified otherwise
b
Year of sample collection
P 075-140 DEF.qxp 09/08/2006 11:15 Page 89
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
(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,
P 075-140 DEF.qxp 09/08/2006 11:15 Page 91
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).
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)
11:15
Mexico N and NE Mexico city 1980–81 Traffic fallout 5.3 ± 1.5 Albert & Badillo
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
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
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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
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
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).
09/08/2006
of study
Gasoline Aira Blooda
(g/L) (µg/m3) (µg/dL)
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)
09/08/2006
Gasoline Aira Blooda
(g/L) (µg/m3) (µg/dL)
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)
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
Country Location Population Year(s) Lead concentration in Reference
of study
Gasoline Aira Blooda
(g/L) (µg/m3) (µg/dL)
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
101
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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.
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
P 075-140 DEF.qxp 09/08/2006 11:15 Page 104
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
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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
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)
11:15
Laguna de Terminos Oyster March–May 2.4 (0.7–4.1)a mg/kg 1985–86
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)
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
N GM GSD
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.
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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
Table 51. Estimated respiratory and dietary intakes of lead in various cities
in Asia
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).
P 075-140 DEF.qxp 09/08/2006 11:15 Page 118
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).
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)
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
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.
( 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
P 075-140 DEF.qxp 09/08/2006 11:15 Page 122
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).
P 075-140 DEF.qxp 09/08/2006 11:15 Page 123
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).
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)
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)
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
(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
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
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.
P 075-140 DEF.qxp 09/08/2006 11:15 Page 130
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)
11:15
arithmetic meana
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
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
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
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
135
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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
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
137
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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
(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.
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.
P 141-164 DEF.qxp
09/08/2006
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
P 141-164 DEF.qxp
146
Table 66 (contd)
Country or Year(s) Job/task Study No. of Age Job history Smoking Blood lead (µg/dL) Lead in air (µg/m3) Reference
09/08/2006
area of survey popu- subjects (years) (years) status
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
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)
P 141-164 DEF.qxp
09/08/2006
Table 66 (contd)
11:26
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
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)
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
11:26
Italy 1977–78 Primary smelter M 1388 NR >1 NR NR 47.6 1–1650 Cocco et al.
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)
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
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
IARC MONOGRAPHS VOLUME 87
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
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
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
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
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
11:26
March (late) 44.6 27.1–62.3 1231
May 39.8 23.1–51.2
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
Arithmetic mean, unless stated otherwise
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)
Country Year(s) Job/task Sex No. of Age Years of Smoking Blood lead (µg/dL) Lead in air (µg/m3) Reference
09/08/2006
of survey subjects (years) employ- status
mean ment AMa Range/SD AMa Range
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)
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
INORGANIC AND ORGANIC LEAD COMPOUNDS
11:26
Table 73 (contd)
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
Page 157
mean ment AMa Range/SD AMa Range
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
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
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)
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Table 74 (contd)
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
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
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160
Table 74 (contd)
09/08/2006
No. of AMa Range No. of Type of AMa Range
workers samples sampling
tested taken
11:26
Non-assay laboratory personnel 5 18 7–36 6 GA NA ND–110
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)
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Table 74 (contd)
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
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
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162
Table 74 (contd)
09/08/2006
No. of AMa Range No. of Type of AMa Range
workers samples sampling
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
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
No. of AMa Range No. of Type of AMa Range
workers samples sampling
tested taken
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)
11:26
workers samples sampling
tested taken
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
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).
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).
Table 75 (contd)
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
P 165-200 DEF.qxp 09/08/2006 11:30 Page 170
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).
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).
P 165-200 DEF.qxp 09/08/2006 11:30 Page 174
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
P 165-200 DEF.qxp 09/08/2006 11:30 Page 176
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).
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
P 165-200 DEF.qxp 09/08/2006 11:30 Page 179
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)
Country/Agency Exposure limit (mg/m3) Interpretationa
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
ACGIH 0.15 TWA (TLV)
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
China, Hong Kong SAR 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)
Country/Agency Exposure limit (mg/m3) Interpretationa
USA
ACGIH 0.012 TWA (TLV)
OSHA 0.001 TWA (REL)
Lead chromate (as Pb)
Belgium 0.05 TWA
Canada
British Columbia 0.012 TWA
China, Hong Kong SAR 0.05 TWA
Malaysia 0.05 TWA
Spain 0.05 TWA
USA
ACGIH 0.05 TWA (TLV)
Lead (II) oxide
Finland 0.1 TWA
Lead phosphate (as Pb)
Norway 0.05 TWA
USA
ACGIH 0.05 TWA (TLV)
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)
Country/Agency Exposure limit (mg/m3) Interpretationa
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
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
P 165-200 DEF.qxp
186
Table 79 (contd)
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
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
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
P 165-200 DEF.qxp
09/08/2006
Table 79 (contd)
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
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
Central nervous 4 160 40–420
system
Gastrointestinal 15 80 50–130
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
Gastrointestinal 6 50 20–110
Kidney 0 0 0–150
187
P 165-200 DEF.qxp
188
Table 79 (contd)
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
09/08/2006
Lundström Highest (n = 163)
et al. (1997) All sites exposed 19 120 80–200
(contd) Lung subgroup 7 510 200–1050
Central nervous 1 190 10–1050
system
Gastrointestinal 2 50 10–190
11:30
Kidney 0 0 0–500
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
Central nervous 1 75 2–420
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
P 165-200 DEF.qxp
09/08/2006
Table 79 (contd)
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
Cocco et al. 1388 male lead smelter Lead concentration SMR National reference (1950–92)
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
P 165-200 DEF.qxp
190
Table 79 (contd)
Reference, Cohort description Assessment or indices Cancer site Exposure No of cases Relative 95% CI Comments
09/08/2006
location of exposure to lead categories or deaths risks
11:30
pigment plant 1940–69; Stomach 5 2.0
followed until 1979 Large intestine 2 0.5
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
P 165-200 DEF.qxp
Table 79 (contd)
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
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]
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
P 165-200 DEF.qxp
192
09/08/2006
Table 79 (contd)
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
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
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)
P 165-200 DEF.qxp
09/08/2006
Table 79 (contd)
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
Organic lead
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
P 165-200 DEF.qxp
194
Table 79 (contd)
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
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]
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
P 165-200 DEF.qxp
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]
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
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
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
Substantial 6 0.8 0.4–1.7
Lead dust:
Any Stomach 5 4.7 1.9–11.7
Substantial 3 21.6 3.2–99.9
Lead oxides:
Any Lung 22 1.9 1.1–3.4
Substantial 8 2.2 0.8–5.7
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
P 165-200 DEF.qxp
Table 80 (contd)
09/08/2006
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
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
P 165-200 DEF.qxp
198
Table 80 (contd)
Reference, Characteristics of cases and controls Assessment or indices of Cancer site No. of Odds 95% CI Comments
09/08/2006
location and exposure to lead cases ratio
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:
Page 198
High 71 1.2 0.9–1.6
Medium 84 1.2 1.0–1.6
Women
Substantial 11 2.6 1.2–5.5
High 14 1.0 0.6–1.9
Medium 8 0.7 0.4–1.6
Job–exposure matrix 2d:
Men
Substantial 30 1.3 0.9–2.0
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
P 165-200 DEF.qxp
09/08/2006
Table 80 (contd)
Reference, Characteristics of cases and controls Assessment or indices of Cancer site No. of Odds 95% CI Comments
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
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
P 201-252 DEF.qxp 09/08/2006 11:36 Page 205
(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.]
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.]
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.
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.
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.]
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
P 201-252 DEF.qxp 09/08/2006 11:36 Page 211
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.]
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-
P 201-252 DEF.qxp 09/08/2006 11:36 Page 213
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).
(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
P 201-252 DEF.qxp 09/08/2006 11:36 Page 215
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.]
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.]
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.]
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.]
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.]
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.]
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.]
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.
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.
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.]
3.1.2 Rat
(a) Oral administration
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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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.
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.
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.]
3.2.2 Rat
(a) Oral administration
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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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.]
3.4.2 Rat
(a) Oral administration
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.]
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.]
3.8.1 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).
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.]
3.8.3 Guinea-pig
Intratracheal administration
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
Intratracheal administration
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.]
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.]
3.10.1 Rat
(a) Oral administration
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.
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.]
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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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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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
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).
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
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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(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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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
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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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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(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.
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%.
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).
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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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
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
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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
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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).
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).
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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Pb
Reduction of
haeme body pool
Disturbed immuno-
regulatory role
of calcium
Disturbed role in
tumorigenesis
control
Impaired detoxification
of xenobiotics
Impaired metabolism
of endogenous
agonists
Figure 6 (contd)
Effects on neurons,
axons, and
Schwann cells
Impaired development
of nervous system
Impaired calcium
Disturbed calcium
role as second
metabolism
messenger
Impaired detoxification
of environmental
toxins
Impaired detoxification
of xenobiotics
Impaired detoxification
of drugs
296
Lead
09/08/2006
Chronic Acute
Distal RAS
Glomeruli Proximal tubule
tubule Ca++ signaling
12:30
IARC MONOGRAPHS VOLUME 87
Intranuclear
Normal inclusions
Page 296
histology Mitochondrial
swelling
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.
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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
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(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]
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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).
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.
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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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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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
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).
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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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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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).
(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.
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.
(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).
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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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.
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.
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).
4.3.1 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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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.
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
P 337-378 DEF.qxp 09/08/2006 13:47 Page 344
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.
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).
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
P 337-378 DEF.qxp 09/08/2006 13:47 Page 347
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.
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).
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
P 337-378 DEF.qxp
350
Table 91 (contd)
09/08/2006
Subjects No. of exposed/controls End-point Air lead Mean blood lead Reference
Resulta concentration concentration
(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
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
Subjects No. of exposed/controls End-point Air lead Mean blood lead Reference
Resulta concentration concentration
(µg/m3) (µg/dL)
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)
Subjects No. of exposed/controls End-point Air lead Mean blood lead Reference
09/08/2006
Resulta concentration concentration
(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
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).
09/08/2006
Test system Result Dosea Reference
(LED or HID)
Lead acetate
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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Table 92 (contd)
13:47
(LED or HID)
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
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
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360
Table 93 (contd)
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)
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
Test system Result Dosea Reference
(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
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362
09/08/2006
Table 93 (contd)
13:47
metabolic metabolic
system system
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)
expression resulting from low-level exposure to lead (Bouton et al., 2001; Li & Rossman,
2001).
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.
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.
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.
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).
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.
mutation, changes in gene expression and cell proliferation, all of which would contribute
to a carcinogenic response if exposure is sustained.
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.
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.
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.
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.
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.
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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.
6. References
Abdel-Moati, A.R. & Atta, M.M. (1991) Patella vulgata, Mytilus minimus and Hyale prevosti as
bioindicators for Pb and Se enrichment in Alexandria coastal waters. Marine Pollut. Bull., 22,
148–150
Abu Melha, A., Ahmed, N.A.M. & El Hassan, A.Y. (1987) Traditional remedies and lead intoxi-
cation. Trop. geogr. Med., 39, 100–103
ACGIH (2001) Lead, Elemental and Inorganic (BEI), Cincinnati, OH
ACGIH® Worldwide (2003) Documentation of the TLVs® and BEIs® with Other Worldwide Occu-
pational Exposure Values — 2003 CD-ROM, Cincinnati, OH
Adams, R.D. & Victor, M. (1993) Principles of Neurology, 5th Ed., New York, McGraw-Hill
Adeniyi, F.A.A. & Anetor, J.I. (1999) Lead-poisoning in two distant states of Nigeria: An indica-
tion of the real size of the problem. Afr. J. Med. med. Sci., 28, 107–112
Ades, A.E. & Kazantzis, G. (1988) Lung cancer in a non-ferrous smelter: The role of cadmium. Br.
J. ind. Med., 45, 435–442
Agarwal, V., Nath, S.P. & Bhavyesh, G. (2002) Chronic low level lead exposure vis-a-vis some bio-
physiological variants. Indian J. occup. environ. Med., 6, 183–185
Ahlgren, L., Lidén, K., Mattsson, L.S. & Tejning, S. (1976) X-ray fluorescence analysis of lead in
human skeleton in vivo. Scand. J. Work Environ. Health, 2, 82–86
Ahmed, N.S., El-Gendy, K.S., El-Refaie, A.K., Marzouk, S.A., Bakry, N.S., El-Sebae, A.H. &
Solimar, S.A. (1987) Assessment of lead toxicity in traffic controllers of Alexandria, Egypt,
road intersections. Arch. environ. Health, 42, 92–95
Ahner, B.A., Price, N.M. & Morel, F.M.M. (1994) Phytochelatin production by marine phyto-
plankton at low free metal ion concentrations: Laboratory studies and field data from
Massachussets Bay. Proc. natl Acad. Sci. USA, 91, 8433–8436
P 379-468 DEF.qxp 09/08/2006 13:53 Page 379
Al-Saleh, I., Khalil, M.A. & Taylor, A. (1995) Lead, erythrocyte protoporphyrin, and hemato-
logical parameters in normal maternal and umbilical cord blood from subjects of the Riyadh
region, Saudi Arabia. Arch. environ. Health, 50, 66–73
Al-Saleh, I., Nester, M., DeVol, E., Shinwari, N., Munchari, L. & Al-Shahria, S. (2001) Relation-
ships between blood lead concentrations, intelligence, and academic achievement of Saudi
Arabian schoolgirls. Int. J. Hyg. environ. Health, 204,165–174
Altmann, L., Lohmann, H. & Wiegand, H. (1988) Acute lead exposure transiently inhibits hippo-
campal neuronal activities in vitro. Brain Res., 455, 254–261
Altmann, L., Weinsberg, F., Sveinsson, K., Lilienthal, H., Wiegand, H. & Winneke, G. (1993)
Impairment of long-term potentiation and learning following chronic lead exposure. Toxicol.
Lett., 66, 105–112
Altmann, L., Sveinsson, K., Krämer, U., Weishoff-Houben, M., Turfeld, M., Winneke, G. &
Wiegand, H. (1998) Visual functions in 6-year-old children in relation to lead and mercury
levels. Neurotoxicol. Teratol., 20, 9–17
Alvares, A.P., Kapelner, S., Sassa, S. & Kappas, A. (1975) Drug metabolism in normal children,
lead-poisoned children, and normal adults. Clin. Pharmacol. Ther., 17, 179–183
American Academy of Pediatrics (1998) Screening for elevated blood lead levels. Policy statement.
Committee on Environmental Health. Pediatrics, 101, 1072–1078
Amici, A., Emanuelli, M., Raffaelli, N., Ruggieri, S., Saccucci, F. & Magni, G. (2000) Human ery-
throcyte pyrimidine 5′-nucleotidase, PN-I, is identical to p36, a protein associated to lupus
inclusion formation in response to alpha-interferon. Blood, 96, 1596–1598
Angle, C.R. & McIntire, M.S. (1978) Low level lead inhibition of erythrocyte pyrimidine nucleo-
tidase. Environ. Res., 17, 296–302
Ankrah, N.A., Kamiya, Y., Appiah-Opong, R., Akyeampon, Y.A. & Addae, M.M. (1996) Lead
levels and related biochemical findings occurring in Ghanaian subjects occupationally
exposed to lead. East Afr. med. J., 73, 375–379
Annest, J.L., Pirkle, J.L., Makuc, D., Neese, J.W., Bayse, D.D. & Kovar, M.G. (1983) Chrono-
logical trend in blood lead levels between 1976 and 1980. New Engl. J. Med., 308, 1373–1377
Antonio, M.T. & Leret, M.L. (2000) Study of the neurochemical alterations produced in discrete
brain areas by perinatal low-level lead exposure. Life Sci., 67, 635–642
Anttila, A. (1994) Occupational exposure to lead and risk of cancer. Acta Universitatis Tamperensis
(Tampere, Finland, University of Tampere), A417, 1–86
Anttila, A., Heikkilä, P., Pukkala, E., Nykyri, E., Kauppinen, T., Hernberg, S. & Hemminki, K.
(1995) Excess lung cancer among workers exposed to lead. Scand. J. Work Environ. Health,
21, 460–469
Anttila, A., Heikkilä, P., Nykyri, E., Kauppinen, T., Pukkala, E., Hernberg, S. & Hemminki, K.
(1996) Risk of nervous system cancer among workers exposed to lead. J. occup. environ.
Med., 38, 131–136
APEC (1997) Urbanization and Environment in Malaysia: Managing the Impact, Institute of Deve-
loping Economics, APEC Study Center, Report of Commissioned Studies No. 1, pp. 74–90
Apol, A.G. (1981) Health Hazard Evaluation Report, HETA 81-0036-1023, Alaska Smelting &
Refining Co., Wisilla, AK, USA, NIOSH
Apostoli, P. & Maranelli, G. (1986) The erythrocyte zinc protoporphyrin test in biological moni-
toring of workers exposed to lead. Med. Lav., 77, 529–537 (in Italian)
P 379-468 DEF.qxp 09/08/2006 13:53 Page 381
Apostoli, P., Kiss, P., Porru, S., Bonde, J.P., Vanhoorne, M. & the ASCLEPIOS Study Group
(1998) Male reproductive toxicity of lead in animals and humans. Occup. environ. Med., 55,
364–374
Apostoli, P., Porru, S. & Bisanti, L. (1999) Critical aspects of male fertility in the assessment of
exposure lo lead. Scand. J. Work Environ. Health, 25 (Suppl. 1), 40–43
Apostoli, P., Bellini, A., Porru, S. & Bisanti, L. (2000) The effect of lead on male fertility: A time
to pregnancy (TTP) study. Am. J. ind. Med., 38, 310–315
Arai, F. & Yamamura, Y. (1990) Excretion of tetramethyllead, trimethyllead, dimethyllead and
inorganic lead after injection of tetramethyllead to rabbits. Ind. Health, 28, 63–76
Arai, F., Yamamura, Y., Yoshida, M. & Kishimoto, T. (1994) Blood and urinary levels of metals
(Pb, Cr, Cd, Mn, Sb, Co and Cu) in cloisonne workers. Ind. Health, 32, 67–78
Arai, F., Yamauchi, H., Chiba, K. & Yoshida, K. (1998) Excretion of triethyllead, diethyllead and
inorganic lead in rabbits after injection of triethyl neopentoxy lead. Ind. Health, 36, 331–336
Araki, S., Murata, K. & Aono, H. (1987) Central and peripheral nervous system dysfunction in
workers exposed to lead, zinc and copper: A follow-up study of visual and somatosensory
evoked potentials. Int. Arch. occup. environ. Health, 59, 177–187
Aravindan, G.R., Bjordahl, J., Jost, L.K. & Evenson, D.P. (1997) Susceptibility of human sperm to
in situ DNA denaturation is strongly correlated with DNA strand breaks identified by single-
cell electrophoresis. Exper. Cell Res., 236, 231–237
Aribarg, A. & Sukcharoen, N. (1996) Effects of occupational lead exposure on spermatogenesis.
J. med. Assoc. Thai., 79, 91–97
Ariza, M.E. & Williams, M.V. (1996) Mutagenesis of AS52 cells by low concentrations of lead(II)
and mercury(II). Environ. mol. Mutag., 27, 30–33
Ariza, M.E. & Williams, M.V. (1999) Lead and mercury mutagenesis: Type of mutation dependent
upon metal concentration. J. Biochem. mol. Toxicol., 13, 107–112
Ariza, M.E., Bijur, G.N. & Williams, M.V. (1998) Lead and mercury mutagenesis: Role of H2O2,
superoxide dismutase, and xanthine oxidase. Environ. mol. Mutag., 31, 352–361
Artaxo, P., Maenhaut, W., Storms, H. & Van Grieken, R. (1990) Aerosol characteristics and sources
for the Amazon basin during the wet season. J. geophys. Res., 95, 16971–16985
Aschengrau, A., Beiser, A., Bellinger, D., Copenhafer, D. & Weitzman, M. (1994) The impact of
soil lead abatement on urban children’s blood lead levels: Phase II results from the Boston
lead-in-soil demonstration project. Environ. Res., 67, 125–148
Asmuss, M., Mullenders, L.H.F., Eker, A. & Hartwig, A. (2000) Differential effects of toxic metal
compounds on the activities of Fpg and XPA, two zinc finger proteins involved in DNA repair.
Carcinogenesis, 21, 2097–2104
Assennato, G., Paci, C., Baser, M.E., Molinini, R., Candela, R.G., Altamura, B.M. & Giorgino, R.
(1987) Sperm count suppression without endocrine dysfunction in lead-exposed men. Arch.
environ. Health, 42, 124–127
Association of Official Analytical Chemists (1994) AOAC official method 994.02, lead in edible
oils and fats — Direct graphite furnace — Atomic absorption spectrophotometric method.
J. AOAC Int.
Association of Official Analytical Chemists (2000a) AOAC official method 999.10, lead, cadmium,
zinc, copper, and iron in foods. Atomic absorption spectrophotometry after microwave digestion.
J. AOAC Int.
P 379-468 DEF.qxp 09/08/2006 13:53 Page 382
Association of Official Analytical Chemists (2000b) AOAC official method 972.25, lead in foods.
Atomic absorption spectrophotometric method. J. AOAC Int.
Association of Official Analytical Chemists (2000c) AOAC official method 979.17, lead in evapo-
rated milk and fruit juice. Anodic stripping voltammetric method. J. AOAC Int.
Association of Official Analytical Chemists (2000d) AOAC official method 997.15, lead in sugars
and syrups. Graphite furnace atomic absorption method. J. AOAC Int.
ASTM (1999) Standard Test Method for Determination of Lead by Inductively Coupled Plasma
Atomic Emission Spectrometry (ICP-AES), Flame Atomic Absorption Spectrometry (FAAS), or
Graphite Furnace Atomic Absorption Spectrometry (GFAAS) Techniques, Designation: E1613-
99, West Conshohocken, PA, USA, ASTM International
ASTM (2002) Standard Test Method for Elements in Water by Inductively-Coupled Argon Plasma
Atomic Emission Spectroscopy, Designation: D1976-02, West Conshohocken, PA, USA, ASTM
International
ASTM (2003a) Standard Test Method for Elements in Water by Inductively-Coupled Plasma — Mass
Spectrometry, Designation: D5673-03, West Conshohocken, PA, USA, ASTM International
ASTM (2003b) Standard Test Method for On-Line Measurement of Low Level Particulate and
Dissolved Metals in Water by X-Ray Fluorescence (XRF), Designation D6502-99 (Reapproved
2003), West Conshohocken, PA, USA, ASTM International
ATSDR (1999) Toxicological Profile for Lead, Washington DC, US Department of Health and
Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry
Aufderheide, A.C. & Wittmers, L.E., Jr (1992) Selected aspects of the spatial distribution of lead
in bone. Neurotoxicology, 13, 809–819
Aungst, B.J. & Fung, H.-L. (1981) Intestinal lead absorption in rats: Effects of circadian rhythm,
food, undernourishment, and drugs which alter gastric emptying and GI motility. Res. Commun.
chem. Pathol. Pharmacol., 34, 515–530
Aungst, B.J. & Fung, H.-L. (1985) The effects of dietary calcium on lead absorption, distribution,
and elimination kinetics in rats. J. Toxicol. environ. Health, 16, 147–159
Aungst, B.J., Dolce, J.A. & Fung, H.-L. (1981) The effect of dose on the disposition of lead in rats
after intravenous and oral administration. Toxicol. appl. Pharmacol., 61, 48–57
Awad el Karim, M.A., Hamed, A.S., Elhaimi, Y.A. & Osman, Y. (1986) Effects of exposure to lead
among lead–acid battery factory workers in Sudan. Arch. environ. Health, 41, 261–265
Awasthi, S., Awasthi, R., Pande, V.K., Srivastav, R.C. & Frumkin, H. (1996) Blood lead in pregnant
women in the urban slums of Lucknow, India. Occup. environ. Med., 53, 836–840
Awasthi, S., Awasthi, R. & Srivastav, R.C. (2002) Maternal blood lead level and outcomes of
pregnancy in Lucknow, North India. Indian Pediatr., 39, 855–860
Azar, A., Trochimowicz, H.J. & Maxfield, M.E. (1973) Review of lead studies in animals carried out
at Haskell Laboratory: Two-year feeding study and response to hemorrhage study. In: Environ-
mental health aspects of lead. In: Proceedings of an International Symposium, October 2–6 1972
Amsterdam, pp. 199–210
Baer, R.D., Garcia de Alba, J., Cueto, L.M., Ackerman, A. & Davison, S. (1989) Lead based
remedies for empacho: Patterns and consequences. Soc. Sci. Med., 29, 1373–1379
Baker, E.L., Folland, D., Taylor, T.A., Frank, M., Peterson, W., Lovejoy, G., Cox, D., Housworth,
J. & Landrigan, P.J. (1977) Lead poisoning in children of lead workers. Home contamination
with industrial dust. New Engl. J. Med., 296, 260–261
P 379-468 DEF.qxp 09/08/2006 13:53 Page 383
Baker, E.L., Jr, Landrigan, P.J., Barbour, A.G., Cox, D.H., Folland, D.S., Ligo, R.N. & Throckmorton,
J. (1979) Occupational lead poisoning in the United States: Clinical and biochemical findings
related to blood lead levels. Br. J. ind. Med., 36, 314–322
Balachandran, S., Meena, B.R. & Khillare, P.S. (2000) Particle size distribution and its elemental
composition in the ambient air of Delhi. Environ. int., 26, 49–54
Baldwin, R.W., Cunningham, G.J. & Pratt, D. (1964) Carcinogenic action of motor engine oil addi-
tives. Br. J. Cancer, 18, 503–507
Baló, J., Bajtai, A. & Szende, B. (1965) [Experimental afenoms of the kidney produced by chronic
administration of lead phosphate.] Skagyar Onkol., 9, 144–151 (in Hungarian)
Baloh, R., Sturm, R., Green, B. & Gleser, G. ( 1975) Neuropsychological effects of chronic asymp-
tomatic increased lead absorption. A controlled study. Arch. Neurol., 32, 326–330
Bannon, D.I., Portnoy, M.E., Olivi, L., Lees, P.S.J., Culotta, V.C. & Bressler, J.P. (2002) Uptake of
lead and iron by divalent metal transporter 1 in yeast and mammalian cells. Biochem. biophys.
Res. Commun., 295, 978–984
Barltrop, D. (1969) Transfer of lead to the human foetus. In: Barltrop, D. & Burland, W.L., eds,
Mineral Metabolism in Pediatrics, Blackwell Scientific Publications, Oxford, pp. 135–151
Barltrop, D. & Khoo, H.E. (1976) The influence of dietary minerals and fat on the absorption of
lead. Sci. total Environ., 6, 265–273
Barltrop, D. & Meek, F. (1975) Absorption of different lead compounds. Postgrad. med. J., 51,
805–809
Barltrop, D. & Meek, F. (1979) Effect of particle size on lead absorption from the gut. Arch. environ.
Health, 34, 280–285
Barltrop, D. & Strehlow, C.D. (1978) The absorption of lead by children. In: Kirchgessner, M., ed.,
Trace Element Metabolism in Man and Animals III, Technische Universität Munchen, Germany,
Freising-Weihenstephan, pp. 332–334
Barratt, C.L.R., Davies, A.G., Bansal, M.R. & Williams, M.E. (1989) The effects of lead on the
male rat reproductive system. Andrologia, 21, 161–166
Barregård, L., Svalander, C., Schütz, A., Westberg, G., Sallsten, G., Blohmé, I., Mölne, J., Attman, P.-
O. & Haglind, P. (1999) Cadmium, mercury, and lead in kidney cortex of the general Swedish
population: A study of biopsies from living kidney donors. Environ. Health Perspect., 107,
867–871
Barry, P.S.I. (1975) A comparison of concentrations of lead in human tissues. Br. J. ind. Med., 32,
119–139
Barsan, M.E. & Miller, A. (1996) Health Hazard Evaluation Report, HETA 91-0346-2572, FBI
Academy, Quantico, VA, USA, NIOSH
Barton, J.C. & Conrad, M.E. (1981) Effect of phosphate on the absorption and retention of lead in
the rat. Am. J. clin. Nutr., 34, 2192–2198
Barton, J.C., Conrad, M.E., Harrison, L. & Nuby, S. (1978a) Effects of calcium on the absorption
and retention of lead. J. Lab. clin. Med., 91, 366–376
Barton, J.C., Conrad, M.E., Nuby, S. & Harrison, L. (1978b) Effects of iron on the absorption and
retention of lead. J. Lab. clin. Med., 92, 536–547
Barton, J.C., Conrad, M.E., Harrison, L. & Nuby, S. (1980) Effects of vitamin D on the absorption
and retention of lead. Am. J. Physiol., 238, G124–130
P 379-468 DEF.qxp 09/08/2006 13:53 Page 384
Barton, J.C., Patton, M.A., Edwards, C.Q., Griffen, L.M., Kushner, J.P., Meeks, R.G. & Leggett,
R.W. (1994) Blood lead concentrations in hereditary hemochromatosis. J. lab. clin. Med., 124,
193–198
Battistuzzi, G., Petrucci, R., Silvagni, L., Urbani, F.R. & Caiola, S. (1981) δ-Aminolevulinate
dehydrase: A new genetic polymorphism in man. Ann. hum. Genet., 45, 223–229
Batuman, V., Maesaka, J.K., Haddad, B., Tepper, E., Landy, E. & Wedeen, R.P. (1981) The role of
lead in gout nephropathy. New Engl. J. Med., 304, 520–523
Batuman, V., Landy, E., Maesaka, J.K. & Wedeen, R.P. (1983) Contribution of lead to hypertension
with renal impairment. New Engl. J. Med., 309, 17–21
Bauchinger, M. & Schmid, E. (1972) [Chromosome analysis of cultures of Chinese hamster cells
after treatment with lead acetate.] Mutat. Res., 14, 95–100 (in German)
Bauchinger, M., Dresp, J., Schmid, E., Englert, N. & Krause, C. (1977) Chromosome analyses of
children after ecological lead exposure. Mutat. Res., 56, 75–80
Baum, C.R. & Shannon, M.W. (1997) The lead concentration of reconstituted infant formula. Clin.
Toxicol., 35, 371–375
Bearer, C.F., O’Riordan, M.A. & Powers, R. (2000) Lead exposure from blood transfusion to pre-
mature infants. J. Pediatr., 137, 549–554
Bearer, C.F., Linsalata, N., Yomtovian, R., Walsh, M. & Singer, L. (2003) Blood transfusions:
A hidden source of lead exposure. Lancet, 362, 332
Beckett, P.H., Davis, R.D. & Brindley, P. (1979) The disposal of sewage sludge onto farmland: The
scope of the problem of toxic elements. Water Pollut. Control, 78, 419–436
Beek, B. & Obe, G. (1974) Effect of lead acetate on human leukocyte chromosomes in vitro.
Experientia, 30, 1006–1007
Beek, B. & Obe, G. (1975) The human leukocyte test system. VI. The use of sister chromatid
exchanges as possible indicators for mutagenic activities. Humangenetik, 29, 127–134
Behari, J.R., Singh, S. & Tandon, S.K. (1983) Lead poisoning among Indian silver jewellery
makers. Ann. occup. Hyg., 27, 107–109
Bell, C.E., Baldwin, L.A., Kostecki, P.T. & Calabrese, E.J. (1993) Comparative response of rain-
bow trout and rat to the liver mitogen, lead. Ecotoxicol. environ. Saf., 26, 280–284
Bellinger, D.C., Needleman, H.L., Leviton, A., Waternaux, C., Rabinowitz, M.R. & Nichols, M.L.
(1984) Early sensory-motor development and prenatal exposure to lead. Neurobehav. Toxicol.
Teratol., 6, 387–402
Bellinger, D., Leviton, A., Rabinowitz, M., Allred, E., Needleman, H. & Schoenbaum, S. (1991)
Weight gain and maturity in fetuses exposed to low levels of lead. Environ. Res., 54, 151–158
Bellinger, D.C., Stiles, K.M. & Needleman, H.L. (1992) Low-level lead exposure, intelligence and
academic achievement: A long-term follow-up study. Pediatrics, 90, 855–861
Bener, A., Almehdi, AM., Alwash, R. & Al-Neamy, F.R.M. (2001) A pilot survey of blood lead
levels in various types of workers in the United Arab Emirates. Environ. int., 27, 311–314
Benkmann, H.-G., Bogdanski, P. & Goedde, H.W. (1983) Polymorphism of delta-aminolevulinic
acid dehydratase in various populations. Hum. Hered., 33, 62–64
Benoff, S., Cooper, G.W., Centola, G.M., Jacob, A., Hershlag, A. & Hurley, I.R. (2000) Metal ions
and human sperm mannose receptors. Andrologia, 32, 317–319
Benoff, S., Centola, G.M., Millan, C., Napolitano, B., Marmar, J.L. & Hurley, I.R. (2003) Increased
seminal plasma lead levels adversely affect the fertility potential of sperm in IVF. Hum.
Reprod., 18, 374–383
P 379-468 DEF.qxp 09/08/2006 13:53 Page 385
Benson, G.I., George, W.H.S., Litchfield, M.H. & Seaborn, D.J. (1976) Biochemical changes
during the initial stages of industrial lead exposure. Br. J. ind. Med., 33, 29–35
Berg, J.W. & Burbank, F. (1972) Correlations between carcinogenic trace metals in water supplies
and cancer mortality. Ann. N. Y. Acad. Sci., 199, 249–264
Bergdahl, I.A. & Skerfving, S. (1997) Partition of circulating lead between plasma and red cells
does not seem to be different for internal and external sources of lead. Am. J. ind. Med., 32,
317–318
Bergdahl, I.A., Schütz, A., Gerhardsson, L., Jensen, A. & Skerfving, S. (1997a) Lead concentrations
in human plasma, urine and whole blood. Scand. J. Work Environ. Health, 23, 359–363
Bergdahl, I.A., Grubb, A., Schütz, A., Desnick, R.J., Wetmur, J.G., Sassa, S. & Skerfving, S.
(1997b) Lead binding to δ-aminolevulinic acid dehydratase (ALAD) in human erythrocytes.
Pharmacol. Toxicol., 81, 153–158
Bergdahl, I.A., Gerhardsson, L., Schütz, A., Desnick, R.J., Wetmur, J.G. & Skerfving, S. (1997c)
delta-Aminolevulinic acid dehydratase polymorphism: Influence on lead levels and kidney
function in humans. Arch. environ. Health, 52, 91–96
Bergdahl, I.A., Sheveleva, M., Schütz, A., Artamonova, V.G. & Skerfving, S. (1998a) Plasma and
blood lead in humans: Capacity-limited binding to δ-aminolevulinic acid dehydratase and
other lead-binding components. Toxicol. Sci., 46, 247–253
Bergdahl, I.A., Strömberg, U., Gerhardsson, L., Schütz, A., Chettle, D.R. & Skerfving, S. (1998b)
Lead concentrations in tibial and calcaneal bone in relation to the history of occupational lead
exposure. Scand. J. Work environ. Health, 24, 38–45
Bergdahl, I.A., Vahter, M., Counter, S.A., Schutz, A., Buchanan, L.H., Ortega, F., Laurell, G. &
Skerfving, S. (1999) Lead in plasma and whole blood from lead-exposed children. Environ.
Res., 80, 25–33
Berglund, M., Åkesson, A., Bjellerup, P. & Vahter, M. (2000) Metal-bone interactions. Toxicol.
Lett., 112–113, 219–225
Berlin, A. & Schaller, K.H. (1974) European standardized method for the determination of δ-
aminolevulinic acid dehydratase activity in blood. Z. klin. Chem. klin. Biochem., 12, 389–390
Bernard, S.M. (2003) Should the Centers for Disease Control and Prevention’s childhood lead
poisoning intervention level be lowered? Am. J. publ. Health, 93, 1253–1260
Bertazzi, P.A. & Zocchetti, C. (1980) A mortality study of newspaper printing workers. Am. J. ind.
Med., 1, 85–97
Bhattacharya, A., Shukla, R., Bornshein, R., Dietrich, K. & Kopke, J.E. (1988) Postural disequili-
brium quantification in children with chronic lead exposure: A pilot study. NeuroToxicology, 9,
327–340
Bhattacharya, A., Shukla, R. & Bornshein, R.L., Dietrich, K.N. & Keith, R. (1990) Lead effects on
postural balance of children. Environ. Health. Perspect., 89, 35–42
Bhattacharya, A., Shukla, R., Kietrich, K.N., Miller, J., Bagchee, A., Bornschein, R.L., Cox, C. &
Mitchell, T. (1993) Functional implications of postural disequilibrium due to lead exposure.
Neurotoxicology, 14, 179–189
Biagini, G., Misciattelli, M.E., Contri Baccarani, M., Vangelista, A., Raffi, G.B. & Caudarella, R.
(1977) [Electron microscopy features of renal changes in chronic lead poisoning.] Lav. Um.,
29, 179–187 (in Italian)
Bicknell, R.J. (1982) Health Hazard Evaluation Report, HETA 82-0255-1193, Firing Range —
Police Dept., Cape Girardeau, MO, USA, NIOSH
P 379-468 DEF.qxp 09/08/2006 13:53 Page 386
Bijlsma, J.B. & de France, H.F. (1976) Cytogenetic investigations in volunteers ingesting inorganic
lead. Int. Arch. occup. environ. Health, 38, 145–148
Birch, J., Harrison, R.M. & Laxen, D.P.H. (1980) A specific method for 24–48 hour analysis of
tetraalkyl lead in air. Sci. tot. Environ., 14, 31–42
Blade, L.M. & Bresler, F.T. (1994) Health Hazard Evaluation Report, HETA 91-0292-2467,
Magnetics Division of Spang & Co., Butler, PA, USA, NIOSH
Blake, K.C.H. (1976) Absorption of 203Pb from gastrointestinal tract of man. Environ. Res., 11, 1–4
Blake, K.C. & Mann, M. (1983) Effect of calcium and phosphorus on the gastrointestinal absorp-
tion of 203Pb in man. Environ. Res., 30, 188–194
Blakley, B.R. (1987) The effect of lead on chemical- and viral-induced tumor production in mice.
J. appl. Toxicol., 7, 167–172
Blank, E. & Howieson, J. (1983) Lead poisoning from a curtain weight. J. Am. med. Assoc., 249,
2176–2177
Blaylock, M.J., Salt, D.E., Dushenkov, S., Zakharova, O., Gussman, C., Kapulnik, Y., Ensley, B.D.
& Raskin, I. (1997) Enhanced accumulation of Pb in Indian mustard by soil-applied chelating
agents. Environ. Sci. Technol., 31, 860–865
Bloom, N.S. & Crecelius, E.A. (1987) Distribution of silver, mercury, lead, copper and cadmium
in Central Puget Sound sediments. Marine Chem., 21, 377–390
Bloomer, J.R., Reuter, R.J., Morton, K.O. & Wehner, J.M. (1983) Enzymatic formation of zinc-
protoporphyrin by rat liver and its potential effect on hepatic heme metabolism. Gastroentero-
logy, 85, 663–668
Boerngen, J.G. & Shacklette, H.T. (1981) Chemical Analyses of Soils and Other Surficial Materials
of the Conterminous United States, US Geological Survey, Open-File Report 81–197, Denver,
CO, US Geological Survey
Bogden, J.D., Gertner, S.B., Kemp, F.W., McLeod, R., Bruening, K.S. & Chung, H.R. (1991)
Dietary lead and calcium: Effects on blood pressure and renal neoplasia in Wistar rats. J. Nutr.,
121, 718–728
Bolanowska, W. (1968) Distribution and excretion of triethyllead in rats. Br. J. ind. Med., 25,
203–208
Bolanowska, W., Piotrowski, J. & Garczynski, H. (1967) Triethyllead in the biological material in
cases of acute tetraethyllead poisoning. Arch. Toxikol., 22, 278–282
Bolger, P.M., Carrington, C.D., Capar, S.G. & Adams, M.A. (1991) Reductions in dietary lead
exposure in the United States. Chem. Spec. Bioavail., 3, 31–36
Bonanno, J., Robson, M.G., Buckley, B. & Modica, M. (2002) Lead exposure at a covered outdoor
firing range. Bull. Environ. Contam. Toxicol., 68, 315–323
Bonde, J.P., Giwercman, A. & Ernst, E. (1996) Identifying environmental risk to male reproductive
function by occupational sperm studies: Logistics and design options. Occup. environ. Med.,
53, 511–519
Bonde, J.P., Joffe, M., Apostoli, P., Dale, A., Kiss, P., Spano, M., Caruso, F., Giwercman, A.,
Bisanti, L., Porru, S., Vanhoorne, M., Camhaire, F. & Zschiesche, W. (2002) Sperm count and
chromatin structure in men exposed to inorganic lead: Lowest adverse effect levels. Occup.
environ. Med., 59, 234–242
Bono, R., Pignata, C., Scursatone, E., Rovere, R., Natale, P. & Gilli, G. (1995) Updating about
reductions of air and blood lead concentrations in Turin, Italy, following reductions in the lead
content of gasoline. Environ. Res., 70, 30–34
P 379-468 DEF.qxp 09/08/2006 13:53 Page 387
Booze, R.M., Mactutus, C.F., Annau, Z. & Tilson, H.A. (1983) Neonatal triethyl lead neurotoxicity
in rat pups: Initial behavioral observations and quantification. Neurobehav. Toxicol. Teratol.,
5, 367–375
Börjesson, J., Mattsson, S., Strömberg, U., Gerhardsson, L., Schütz, A. & Skerfving, S. (1997) Lead
in fingerbone: A tool for retrospective exposure assessment. Arch. environ. Health, 52, 104–112
Boscolo, P. & Carmignani, M. (1988) Neurohumoral blood pressure regulation in lead exposure.
Environ. Health Perspect., 78, 101–106
Boscolo, P., Carmignani, M., Sacchettoni-Logroscino, G., Rannelletti, F.O., Artese, L. & Preziosi
P. (1988) Ultrastructure of the testis in rats with blood hypertension induced by long-term lead
exposure. Toxicol. Lett., 41, 129–137
Boudene, C., Malet, D. & Masse, R. (1977) Fate of 210Pb inhaled by rats. Toxicol. appl. Pharmacol.,
41, 271–276
Bouldin, T.W. & Krigman, M.R. (1975) Acute lead encephalopathy in the guinea pig. Acta neuro-
pathol., 33, 185–190
Boulos, B.M. & von Smolinski, A. (1988) Alert to users of calcium supplements as antihyper-
tensive agents due to trace metal contaminants. Am. J. Hypertension, 1, 137S–142S
Bourgoin, B.P., Evans, D.R., Cornett, J.R., Lingard, S.M. & Quattrone, A.J. (1993) Lead content
in 70 brands of dietary calcium supplements. Am. J. public Health, 83, 1155–1160
Bouton, C.M., Hossain, M.A., Frelin, L.P., Laterra, J. & Pevsner, J. (2001) Microarray analysis of
differential gene expression in lead-exposed astrocytes. Toxicol. appl. Pharmacol., 176, 34–53
Boyland, E., Dukes, C.E., Grover, P.L. & Mitchley, B.C.V. (1962). The induction of renal tumours
by feeding lead acetate to rats. Br. J. Cancer, 16, 283–288
Bradbury, M.W.B. & Deane, R. (1993) Permeability of the blood-brain barrier to lead. Neurotoxico-
logy, 14, 131–136
Bress, W.C. & Bidanset, J.H. (1991) Percutaneous in vivo and in vitro absorption of lead. Vet. hum.
Toxicol., 33, 212–214
Bressler, J., Kim, K., Chakraborti, T. & Goldstein, G. (1999) Molecular mechanisms of lead neuro-
toxicity. Neurochem. Res., 24, 595–600
Brito, J.A.A., McNeill, F.E., Stronach, I., Webber, C.E., Wells, S., Richard, N. & Chettle, D.R.
(2001) Longitudinal changes in bone lead concentration: Implications for modelling of human
bone lead metabolism. J. environ. Monit., 3, 343–351
Brody, D.J., Pirkle, J.L., Kramer, R.A., Flegal, K.M., Matte, T.D., Gunter, E.W. & Pashal, D.C.
(1994) Blood lead levels in the US population. Phase 1 of the Third National Health and Nutri-
tion Examination Survey (NHANES III, 1988 to 1991). J. Am. med. Assoc., 272, 277–283
Brown, J.R. (1983) A survey of the effects of lead on gunners. J. R. Army med. Corps, 129, 75–81
Brown, A. & Tompsett, S.L. (1945) Poisoning due to mobilization of lead from the skeleton by leu-
caemic hyperplasia of bone marrow. Br. med. J., 11, 764–765
Brown, M.J., Hu, H., Gonzales-Cossio, T., Peterson, K.E., Sanin, L.-H., de Luz Kageyama, M.,
Palazuelos, E., Aro, A., Schnaas, L. & Hernandez-Avila, M. (2000) Determinants of bone and
blood lead concentrations in the early postpartum period. Occup. environ. Med., 57, 535–541
Browne, D.R., Husni, A. & Risk, M.J. (1999) Airborne lead and particulate levels in Semarang,
Indonesia and potential health impacts. Sci. total Environ., 227, 145–154
Bruaux, P. & Svartengren, M., eds (1985) Assessment of Human Exposure to Lead: Comparison
between Belgium, Malta, Mexico and Sweden, National Swedish Institute of Environmental
P 379-468 DEF.qxp 09/08/2006 13:53 Page 388
Cai, M.-Y. & Arenaz, P. (1998) Antimutagenic effect of crown ethers on heavy metal-induced sister
chromatid exchanges. Mutagenesis, 13, 27–32
Cake, K.M., Bowins, R.J., Vaillancourt, C., Gordon, C.L., McNutt, R.H., Laporte, R., Webber, C.E.
& Chettle, D.R. (1996) Partition of circulating lead between serum and red cells is different
for internal and external sources of lead. Am. J. ind. Med., 29, 440–445
Calabrese, E.J. & Baldwin, L.A. (1992) Lead-induced cell proliferation and organ-specific tumori-
genicity. Drug Metab. Rev., 24, 409–416
Calabrese, E.J., Baldwin, L.A., Leonard, D.A. & Zhao, X.Q. (1995) Decrease in hepatotoxicity by
lead exposure is not explained by its mitogenic response. J. appl. Toxicol., 15, 129–132
Calder, I.C., Roder, D.M., Esterman, A.J., Lewis, M.J., Harrison, M.C. & Oldfield, R.K. (1986)
Blood lead levels in children in the north-west of Adelaide. Med. J. Aust., 144, 509–512
Campbell, B.C., Beattie, A.D., Moore, M.R., Goldberg, A. & Reid, A.G. (1977) Renal insufficiency
associated with excessive lead exposure. Br. med. J., 1, 482–485
Campbell, B.C., Meredith, P.A., Moore, M.R. & Watson, W.S. (1984) Kinetics of lead following
intravenous administration in man. Toxicol. Lett., 21, 231–235
Canfield, R.L., Henderson, C.R., Jr, Cory-Slechta, D.A., Cox, C., Jusko, T.A. & Lanphear, B.P.
(2003) Intellectual impairment in children with blood lead concentrations below 10 micro-
grams per deciliter. New Engl. J. Med., 348, 1517–1526
Capar, S.G. & Gould, J.H. (1979) Lead, fluoride, and other elements in bonemeal supplements.
J. Assoc. off. anal. Chem., 62, 1054–1061
Capar, S.G. & Rigsby, E.J. (1989) Survey of lead in canned evaporated milk. J. Assoc. off. anal.
Chem., 72, 416–417
Cárdenas, A., Roels, H., Bernard, A.M., Barbon, R., Buchet, J.P., Lauwerys, R.R., Roselló, J.,
Ramis, I., Mutti, A., Franchini, I., Fels, L.M., Stolte, H., de Broe, M.E., Nuyts, G.D., Taylor,
S.A. & Price, R.G. (1993) Markers of early renal changes induced by industrial pollutants.
II. Application to workers exposed to lead. Br. J. ind. Med., 50, 28–36
Carney, J.K. & Garbarino, K.M. (1997) Childhood lead poisoning from apple cider. Pediatrics,
100, 1048–1049
Caroli, S., Alimonti, A., Coni, E., Petrucci, F., Senofonte, O. & Violante, N. (1994). The assessment
of reference values for elements in human biological tissues and fluids: A systematic review.
Crit. Rev. anal. Chem., 24, 363–398
Carta, P., Cocco, P. & Picchiri, G. (1994) Lung cancer mortality and airways obstruction among
metal miners exposed to silica and low levels of radon daughters. Am. J. ind. Med., 25, 489–506
Carvalho, F.M., Barreto, M.L., Silvany-Neto, A.M., Waldron, H.A. & Tavares, T.M. (1984) Multiple
causes of anaemia amongst children living near a lead smelter in Brazil. Sci. total Environ., 35,
71–84
Carvalho, F.M., Silvany-Neto, A.M., Tavares, T.M., Lima, M.E.C. & Waldron, H.A. (1985a) Lead
poisoning among children from Santo Amaro, Brazil. Bull. PAHO, 19, 165–175
Carvalho, F.M., Silvany-Neto, A.M., Lima, M.E.C., Tavares, T.M. & Alt, F. (1985b) [Lead and
cadmium poisoning among workers in small establishments for repairing batteries in
Salvador, Brazil.] Rev. Saúde pública, 19, 411–420 (in Portuguese)
Carvalho, F.M., Silvany-Neto, A.M., Chaves, M.E.C., de Melo, A.M.C., Galvão, A.L. & Tavares,
T.M. (1989) [Lead and cadmium contents in hair of children from Santo Amaro da Purificação,
Bahia.] Ciê. Cultura, 41, 646–651 (in Portuguese)
P 379-468 DEF.qxp 09/08/2006 13:53 Page 390
Carvalho, F.M., Silvany-Neto, A.M., Peres, M.F.T., Gonçalves, H.R., Guimarães, G.C., de Amorin,
C.J.B., Silva, J.A.S., Jr & Tavares, T.M. (1996) [Lead poisoning: Zinc protoporphyrin in blood
of children from Santo Amaro da Purificação and Salvador, Bahia. Brazil.] J. Pediatr., 72,
295–298 (in Portuguese)
Carvalho, F.M., Neto, A.M.S., Peres, M.F.T., Gonçalves, H.R., Guimarães, G.C., de Amorin,
C.J.B., Silva, J.A.S., Jr & Tavares, T.M. (1997) Lead poisoning: Zinc protoporphyrin in blood
of children from Santo Amaro da Purificação and Salvador, Bahia, Brazil. J. pediatr., 73
(Suppl. 1), 11–14
Carvalho, F.M., Silvany Neto, A.M., Tavares, T.M., Costa, A.C.A., Chaves, C.R., Nascimento, L.D.
& Reis, M.A. (2003) [Blood lead levels in children and environmental legacy of a lead foundry
in Brazil.] Rev. panam. Salud publica, 13, 19–23 (in Portuguese)
Case, J.M., Reif, C.B. & Timko, A. (1989) Lead in the bottom sediments of Lake Nuangola and
fourteen other bodies of water in Luzerne County, Pennsylvania. J. Pennsylvania Acad. Sci.,
63, 67–72
Casteel, S.W., Cowart, R.P., Weis, C.P., Henningsen, G.M., Hoffman, E., Brattin, W.J., Guzman,
R.E., Starost, M.F., Payne, J.T., Stockham, S.L., Becker, S.V., Drexler, J.W. & Turk, J.R.
(1997) Bioavailability of lead to juvenile swine dosed with soil from the Smuggler Mountain
NPL Site of Aspen, Colorado. Fundam. appl. Toxicol., 36, 177–187
Castellino, N., Lamanna, P. & Grieco, B. (1966) Biliary excretion of lead in the rat. Br. J. ind. Med.,
23, 237–239
Cavalleri, A. & Minoia, C. (1987) Lead level of whole blood and plasma in workers exposed to
lead stearate. Scand. J. Work Environ. Health, 13, 218–220
CDC (1975) Increased Lead Absorption and Lead Poisoning in Young Children. A Statement by the
Center for Disease Control, Atlanta, GA, Centers for Disease Control, US Department of
Health, Education and Welfare
CDC (1981) Use of lead tetroxide as a folk remedy for gastrointestinal illness. Mortal. Morbid.
Wkly Rep., 30, 546–547
CDC (1983) Folk remedy-associated lead poisoning in Hmong children — Minnesota. Mortal.
Morbid. Wkly Rep., 32, 555–556
CDC (1985) Preventing Lead Poisoning in Young Children (Publication No. 99-2230), Atlanta,
GA, Centers for Disease Control
CDC (1991) Preventing Lead Poisoning in Young Children, Atlanta, GA, Centers for Disease
Control
CDC (1993) Lead poisoning associated with use of traditional ethnic remedies — California,
1991–1992. Mortal. Morbid. Wkly Rep., 42, 521–524
CDC (1997a) Children with elevated blood lead levels attributed to home renovation and remode-
ling activities — New York, 1993–1994. Mortal. Morbid. Wkly Rep., 45, 1120–1123
CDC (1997b) Update: Blood lead levels — United States, 1991–1994. Morbid. Mortal. Wkly Rep.,
46, 141–146
CDC (1998) Lead poisoning associated with imported candy and powdered food coloring — Cali-
fornia and Michigan. Mortal. Morbid. Wkly Rep., 47, 1041–1043
CDC (1999) Adult lead poisoning from an Asian remedy for menstrual cramps — Connecticut,
1997. Mortal. Morbid. Wkly Rep., 48, 27–29
CDC (2001) Public health dispatch: Potential risk for lead exposure in dental offices. Mortal.
Morbid. Wkly Rep., 50, 873–874
P 379-468 DEF.qxp 09/08/2006 13:53 Page 391
CDC (2002) Childhood lead poisoning associated with tamarind candy and folk remedies — Cali-
fornia, 1999–2000. Mortal. Morbid. Wkly Rep., 51, 684-686
CDC (2003a) Second National Report on Human Exposure to Environmental Chemicals, NCEH
Pub. No. 02-0716, Atlanta, GA, National Center for Environmental Health, pp. 9–12
CDC (2003b) Surveillance for elevated blood lead levels among children — United States,
1997–2001. Mortal. Morbid. Wkly Rep., 52, SS-10
Cedeño, A.L., Arrocha, A. & Lombardi, C. (1990) Comparative Study of the Levels of Lead in the
Air and Blood Part II (Technical Report), Los Teques, Intevep SA
Central Pollution Control Board (1998–99) Annual Report 1998–1999, New Delhi, Central Pollu-
tion Control Board
Central Pollution Control Board (2001–02) Annual Report (2001–2002), New Delhi, Central
Pollution Control Board [http://www.cpcb.delhi.nic.in/ar2002/ar1-2content.htm; accessed
31/12/2003]
Chai, S. & Webb, R.C. (1988) Effects of lead on vascular reactivity. Environ. Health Perspect., 78,
85–89
Chakraborti, D., De Jonghe, W.R.A., Van Mol, W.E., Van Cleuvenbergen, R.J.A. & Adams, F.C.
(1984) Determination of ionic alkyllead compounds in water by gas chromatography/atomic
absorption spectrometry. Anal. Chem., 56, 2692–2697
Chamberlain, A.C., Heard. M.J., Little, P., Newton, D., Wells, A.C. & Wiffen, R.D. (1978) Investi-
gations into Lead from Motor Vehicles (Rep. AERE-R9198), Harwell, United Kingdom
Atomic Energy Authority
Chandra, P., Tripathi, R.D., Rai, U.N., Sinha, S. & Garg, P. (1993) Biomonitoring and amelioration
of nonpoint source pollution in some aquatic bodies. Water Sci. Technol., 28, 323–326
Chaney, R.L., Malik, M., Li, Y.M., Brown, S.L., Brewer, E.P., Angle, J.S. & Baker, A.J.M. (1997)
Phytoremediation of soil metals. Curr. Opin. Biotechnol., 8, 279–284
Chartsias, B., Colombo, A., Hatzichristidis, D. & Leyendecker, W. (1986) The impact of gasoline
lead on man blood lead: First results of the Athens lead experiment. Sci. total Environ., 55,
275–283
Chatterjee, A. & Banerjee, R.N. (1999) Determination of lead and other metals in a residential area
of greater Calcutta. Sci. total Environ., 227, 175–185
Chau, T.T., Chen, W.Y., Hsiao, T.M. & Liu, H.W. (1995) Chronic lead intoxication at an indoor
firing range in Taiwan. Clin. Toxicol., 33, 371–372
Chemical Information Services (2003) Directory of World Chemical Producers (Online Version),
Dallas, TX [www.chemicalinfo.com; accessed 12/12/2003]
Chen, Z.-Q., Chan, Q.-I., Par, C.-C. & Qu, J.-Y. (1985) Peripheral nerve conduction velocity in
workers occupationally exposed to lead. Scand. J. Work Environ. Health., 11 (Suppl. 4), 26–28
Cheng, Y., Willett, W.C., Schwartz, J., Sparrow, D., Weiss, S. & Hu, H. (1998) Relation of nutrition
to bone lead and blood lead levels in middle-aged to elderly men. The Normative Aging Study.
Am. J. Epidemiol., 147, 1162–1174
Cheng, Y., Schwartz, J., Sparrow, D., Aro, A., Weiss, S.T. & Hu, H. (2001) Bone lead and blood
lead levels in relation to baseline blood pressure and the prospective development of hyper-
tension: The Normative Aging Study. Am. J. Epidemiol., 153, 164–171
Chettle, D.R., Fleming, D.E., McNeill, F.E. & Webber, C.E. (1997) Serum (plasma) lead, blood
lead, and bone lead. Am. J. ind. Med., 32, 319–320
P 379-468 DEF.qxp 09/08/2006 13:53 Page 392
Chia, S.E., Chia, K.S. & Ong, C.N. (1991) Ethnic differences in blood lead concentration among
workers in a battery manufacturing factory. Ann. Acad. Med. Singapore, 20, 758–761
Chia, S.E., Phoon, W.H., Lee, H.S., Tan, K.T. & Jeyaratnam, J. (1993) Exposure to neurotoxic
metals among workers in Singapore: An overview. Occup. Med., 43, 18–22
Chia, S.E., Chua, L.H., Ng, T.P., Foo, S.C. & Jeyaratnam, J. (1994) Postural stability of workers
exposed to lead. Occup. environ. Med., 51, 768–771
Chia, K.S., Jeyaratnam, J., Lee, J., Tan, C., Ong, H.Y., Ong, C.N. & Lee, E. (1995) Lead-induced
nephropathy: Relationship between various biological exposure indices and early markers of
nephrotoxicity. Am. J. ind. Med., 27, 883–895
Chia, S.E., Chia, H.P., Ong, C.N. & Jeyaratnam, J. (1996a) Cumulative blood lead levels and nerve
conduction parameters. Occup. Med., 46, 59–64
Chia, S.E., Chia, H.P., Ong, C.N. & Jeyaratnam, J. (1996b) Cumulative concentrations of blood
lead and postural stability. Occup. environ. Med., 53, 264–268
Chiaradia, M., Gulson, B.L. & MacDonald, K. (1997) Contamination of houses by workers
occupationally exposed in a lead-zinc-copper mine and impact on blood lead concentrations in
the families. Occup. environ. Med., 54, 117–124
Chiba, M. (1976) Activity of erythrocyte δ-aminolevulinic acid dehydrase and its change by heat
treatment as indices of lead exposure. Br. J. ind. Med., 33, 36–42
Chisholm, J.J., Jr (1962) Aminoaciduria as a manifestation of renal tubular injury in lead intoxication
and a comparison with patterns of aminoaciduria seen in other diseases. J. Pediatr., 60, 1–17
Chisolm, J.J., Jr (1964) Disturbances in the biosynthesis of heme in lead intoxication. J. Pediatr.,
64, 174–187
Chisolm, J.J., Jr (1986) Removal of lead paint from old housing: The need for a new approach. Am.
J. public Health, 76, 236–237
Cho, H.Y., Moon, D.H., Jun, J.H., Lee, C.U. & Kim, S.C. (1992) The level of ambient heavy metal
pollution in Pusan area. Inje Med. J., 13, 177–190
Choie, D.D. & Richter, G.W. (1972a) Cell proliferation in rat kidneys after prolonged treatment
with lead. Am. J. Pathol., 68, 359–370
Choie, D.D. & Richter, G.W. (1972b) Lead poisoning: Rapid formation of intranuclear inclusions.
Science, 177, 1194–1195
Choie, D.D. & Richter, G.W. (1972c) Cell proliferation in rat kidney induced by lead acetate and
effects of uninephrectomy on the proliferation. Am. J. Pathol., 66, 265–275
Choie, D.D. & Richter, G.W. (1974a) Cell proliferation in mouse kidney induced by lead.
I. Synthesis of deoxyribonucleic acid. Lab. Invest., 30, 647–651
Choie, D.D. & Richter, G.W. (1974b) Cell proliferation in mouse kidney induced by lead.
II. Synthesis of ribonucleic acid and protein. Lab. Invest., 30, 652–656
Choie, D.D. & Richter, G.W. (1978) G2 sub-population in mouse liver induced into mitosis by lead
acetate. Cell Tissue Kinet., 11, 235–239
Chowdhury, A.R., Dewan, A. & Gandhi, D.N. (1984) Toxic effect of lead on the testes of rat.
Biomed. biochim. Acta, 43, 95–100
Christoffersson, J.O., Ahlgren, L., Schütz, A., Skerfving, S. & Mattsson, S. (1986) Decrease of
skeletal lead levels in man after end of occupational exposure. Arch. environ. Health, 41,
312–318
Chu, N.F., Liou, S.H., Wu, T.N., Ko, K.N. & Chang, P.Y. (1998) Risk factors for high blood lead
levels among the general population in Taiwan. Eur. J. Epidemiol., 14, 775–781
P 379-468 DEF.qxp 09/08/2006 13:53 Page 393
Chuang, H.-Y., Lee, M-.L.T., Chao, K.-Y., Wang, J.-D., Hu, H. (1999) Relationship of blood lead
levels to personal hygiene habits in lead battery workers: Taiwan, 1991–1997. Am. J. ind.
Med., 35, 595–603
Cikrt, M. (1972) Biliary excretion of 203Hg, 64Cu, 52Mn, and 210Pb in the rat. Brit. J. ind. Med., 29,
74–80
Cikrt, M. & Tichy, M. (1975) Role of bile in intestinal absorption of 203Pb in rats. Experientia, 31,
1320–1321
Cikrt, M., Lepši, P. & Tichy, M. (1983) Biliary excretion of lead in rats drinking lead-containing
water. Toxicol. Lett., 16, 139–143
Cilliers, L. & Retief, F.P. (2000) Poisons, poisoning and the drug trade in ancient Rome. Akroterion,
45, 88–100
Clark, A.R.L. (1977) Placental transfer of lead and its effects on the newborn. Postgrad. med. J.,
53, 674–678
Clark, M., Royal, J. & Seeler, R. (1988) Interaction of iron deficiency and lead and hematologic
findings in children with severe lead poisining. Paediatrics, 81, 247–254
Clark, N.J., Montopoli, M., Burr, G.A. & Rubin, C. (1991) Health Hazard Evaluation Report,
HETA 91-0077-2160, Pilot Industrial Batteries, Kankakee, IL, USA, NIOSH
Clark, N.J., O’Brien, D.M., Edmonds, M.A. & Gressel, M.G. (1992) Health Hazard Evaluation
Report, HETA 91-0092-2190, William Powell, Co., Cincinnati, OH, USA, NIOSH
Clasen, R.A., Hartmann, J.F., Coogan, P.S., Pandolfi, S., Laing, I. & Becker, R.A. (1974) Experi-
mental acute lead encephalopathy in the juvenile rhesus monkey. Environ. Health Perspect.,
7, 175–185
Clausen, J. & Rastogi, S.C. (1977) Heavy metal pollution among autoworkers. I. Lead. Br. J. ind.
Med., 34, 208–215
Cocco, P.L., Carta, P., Belli, S., Picchiri, G.F. & Flore, M.V. (1994a) Mortality of Sardinian lead
and zinc miners: 1960–88. Occup. environ. Med., 51, 674–682
Cocco, P.L., Carta, P., Flore, V., Picchiri, G.F. & Zucca, C. (1994b) Lung cancer mortality among
female mine workers exposed to silica. J. occup. Med., 36, 894–898
Cocco, P., Carta, P., Flore, C., Congia, P., Manca, M.B., Saba, G. & Salis, S. (1996) Mortality of
lead smelter workers with the glucose-6-phosphate dehydrogenase-deficient phenotype.
Cancer Epidemiol. Biomarkers Prev., 5, 223–225
Cocco, P., Hua, F., Boffetta, P., Carta, P., Flore, C., Flore, V., Onnis, A., Picchiri, G.F. & Colin, D.
(1997) Mortality of Italian lead smelter workers. Scand. J. Work Environ. Health, 23, 15–23
Cocco, P., Dosemeci, M. & Heineman, E.F. (1998a) Brain cancer and occupational exposure to
lead. J. occup. environ. Med., 40, 937–942
Cocco, P., Ward, M.H. & Dosemeci, M. (1998b) Occupational risk factors for cancer of the gastric
cardia. Analysis of death certificates from 24 US states. J. occup. environ. Med., 40, 855–861
Cocco, P., Heineman, E.F. & Dosemeci, M. (1999a) Occupational risk factors for cancer of the
central nervous system (CNS) among US women. Am. J. ind. Med., 36, 70–74
Cocco, P., Ward, M.H. & Dosemeci, M. (1999b) Risk of stomach cancer associated with 12 work-
place hazards: Analysis of death certificates from 24 states of the United States with the aid of
job exposure matrices. Occup. environ. Med., 56, 781–787
Cohen, S.M. & Ellwein, L.B. (1990) Cell proliferation in carcinogenesis. Science, 249, 972–975
Cohen, A.J. & Roe, F.J.C. (1991) Review of lead toxicology relevant to the safety assessment of
lead acetate as a hair colouring. Food chem. Toxicol., 29, 485–507
P 379-468 DEF.qxp 09/08/2006 13:53 Page 394
Columbano, A., Ledda, G.M., Sirigu, P., Perra, T. & Pani, P. (1983) Liver cell proliferation induced
by a single dose of lead nitrate. Am. J. Pathol., 110, 83–88
Columbano, A., Ledda-Columbano, G.M., Coni, P.P., Vargiu, M., Faa, G. & Pani, P. (1984) Liver
hyperplasia and regression after lead nitrate administration. Toxicol. Pathol., 12, 89–95
Columbano, A., Ledda-Columbano, G.M., Coni, P.P., Faa, G., Liguori, C., Santa Cruz, G. & Pani,
P. (1985) Occurrence of cell death (apoptosis) during the involution of liver hyperplasia. Lab.
Invest., 52, 670–675
Columbano, A., Ledda-Columbano, G.M., Ennas, M.G., Curto, M., Chelo, A. & Pani, P. (1990) Cell
proliferation and promotion of rat liver carcinogenesis: Different effect of hepatic regeneration
and mitogen induced hyperplasia on the development of enzyme-altered foci. Carcinogenesis,
11, 771–776
Coni, P., Pichiri-Coni, G., Curto, M., Simbula, G., Giacomini, L., Sarma, D.S.R., Ledda-
Columbano, G.M. & Columbano, A. (1993a) Different effects of regenerative and direct mito-
genic stimuli on the growth of initiated cells in the resistant hepatocyte model. Jpn J. Cancer
Res., 84, 501–507
Coni, P., Simbula, G., Carceriri de Prati, A., Menegazzi, M., Suzuki, H., Sarma, D.S.R., Ledda-
Columbano, G.M. & Columbano, A. (1993b) Differences in the steady-state levels of c-fos, c-
jun and c-myc messenger RNA during mitogen-induced liver growth and compensatory
regeneration. Hepatology, 17, 1109–1116
Conrad, M.E. & Barton, J.C. (1978) Factors affecting the absorption and excretion of lead in the
rat. Gastroenterology, 74, 731–740
Conradi, N.G., Sjostrom, A., Gustafsson, B. & Wigstrom, H. (1990) Decreased nerve conduction
velocity in optic nerve following early post-natal low-dose lead exposure. Acta physiol.
scand., 140, 515–519
Consumer Product Safety Commission (1977) CPSC Announces Final Ban on Lead-containing
Paint, Washington DC, US Consumer Product Safety Commission
Consumer Product Safety Commission (1996) CPSC Finds Lead Poisoning Hazard for Young
Children in Imported Vinyl Miniblinds, Washington DC, US Consumer Product Safety Com-
mission [http://www.cpsc.gov/cpscpub/prerel/prhtml/96150.html; accessed 10/02/2004]
Cook, L., Schafer-Mitchell, M., Angle, C. & Stohs, S. (1985) Assay of human erythrocyte pyrimi-
dine and deoxypyrimidine 5′-nucleotidase by isocratic reversed-phase high-performance
liquid chromatography. J. Chromatogr., 339, 293–301
Cook, L.R., Angle, C.R. & Stohs, S.J. (1986) Erythrocyte arginase, pyrimidine 5′-nucleotidase
(P5N), and deoxypyrimidine 5′-nucleotidase (dP5N) as indices of lead exposure. Br. J. ind.
Med., 43, 387–390
Cook, C.K., Tubbs, R.L. & Klein, M.K. (1993) Health Hazard Evaluation Report, HETA 92-0034-
2356, Saint Bernard Police Dept., Saint Bernard, OH, USA, NIOSH
Cooper, W.C. (1976) Cancer mortality patterns in the lead industry. Ann. N.Y. Acad. Sci., 271,
250–259
Cooper, W.C. (1981) Mortality in employees of lead production facilities and lead battery plants,
1971–1975. In: Environmental Lead: Proceedings of the Second International Symposium on
Environmental Lead Research, Cincinnati, Ohio, December 1978, Academic Press, New York,
London, San Francisco, pp. 111–143
Cooper, W.C. (1988) Deaths from chronic renal disease in US battery and lead production workers.
Environ. Health Perspect., 78, 61–63
P 379-468 DEF.qxp 09/08/2006 13:53 Page 395
Cooper, W.C. & Gaffey, W.R. (1975) Mortality of lead workers. J. occup. Med., 17, 100–107
Cooper, W.C., Wong, O. & Kheifets, L. (1985) Mortality among employees of lead battery plants
and lead-producing plants, 1947–1980. Scand. J. Work Environ. Health, 11, 331–345
Cordioli, G., Cuoghi, L., Solari, P.L., Berrino, F., Crosignani, P. & Riboli, E. (1987) [Mortality
from tumors in a cohort of workers in the glass industry.] Epidemiol. Prev., 30, 16–18 (in
Italian)
Cory-Slechta, D.A. (1990) Lead exposure during advanced age: Alterations in kinetics and bio-
chemical effects. Toxicol. appl. Pharmacol., 104, 67–78
Cory-Slechta, D.A. (2003) Lead-induced impairments in complex cognitive function: Offerings
from experimental studies. Neuropsychol. Dev. Cogn. Sect. C Child Neuropsychol., 9, 54–75
Cory-Slechta, D.A., Weiss, B. & Cox, C. (1989) Tissue distribution of Pb in adult vs. old rats: A
pilot study. Toxicology, 59, 139–150
Coscia, J.M., Ris, M.D., Succop, P.A. & Dietrich, K.N. (2003) Cognitive development of lead
exposed children from ages 6 to 15 years: An application of growth curve analysis. Neuro-
psychol. Dev. Cogn. Sect. C Child Neurophsycol., 9, 10–21
Costa, L.G. (2003) Correspondence re: Navas-Acien et al., Interactive effect of chemical substances
and occupational electromagnetic field exposure on the risk of gliomas and meningiomas in
Swedish men. Cancer Epidemiol. Biomarkers Prev., 12, 950
Coste, J., Mandereau, L., Pessione, F., Bregu, M., Faye, C., Hemon, D. & Spira, A (1991) Lead-
exposed workmen and fertility: A cohort study on 354 subjects. Eur. J. Epidemiol., 7, 154–158
Counter, S.A., Vahter, M., Laurell, G., Buchanan, L.H., Ortega, F. & Skerfving, S. (1997a) High lead
exposure and auditory sensory-neural function in Andean children. Environ. Health Perspect.,
105, 522–526
Counter, S.A., Buchanan, L.H., Ortega, F. & Laurell, G. (1997b) Normal auditory brainstem and
cochlear function in extreme pediatric plumbism. J. Neurol. Sci., 152, 85–92
Counter, S.A., Buchanan, L.H., Ortega, F., Amarasiriwardena, C. & Hu, H. (2000) Environmental
lead contamination and pediatric lead intoxication in an Andean Ecuadorian village. Int. J.
occup. environ. Health, 75, 169–176
Cragg, B. & Rees, S. (1984) Increased body:brain weight ratio in developing rats after low expo-
sure to organic lead. Exp. Neurol., 86, 113–121
Cramér, K., Goyer, R.A., Jagenburg, R. & Wilson, M.H. (1974) Renal ultrastructure, renal func-
tion, and parameters of lead toxicity in workers with different periods of lead exposure. Br. J.
ind. Med., 31, 113–127
Cremin, J.D., Jr & Smith, D.R. (2002) In vitro vs in vivo Pb effects on brain protein kinase C acti-
vity. Environ. Res., 90, 191–199
Cremin, J.D., Jr, Luck, M.L., Laughlin, N.K. & Smith, D.R. (2001) Oral succimer decreases the
gastrointestinal absorption of lead in juvenile monkeys. Environ. Health Perspect., 109,
613–619
Crowe, A. & Morgan, E.H. (1996) Interactions between tissue uptake of lead and iron in normal
and iron-deficient rats during development. Biol. trace Elem. Res., 52, 249–261
Crowne, H., Lim, C.K. & Samson, D. (1981) Determination of 5-aminolaevulinic acid dehydrase
activity in erythrocytes by high-performance liquid chromatography. J. Chromatogr., 223,
421–425
Cueto, L.M., Baer, R.D. & Montano Gonzalez, E. (1989) Three cases of unusual lead poisoning.
Am. J. Gastroenterol., 84, 1460
P 379-468 DEF.qxp 09/08/2006 13:53 Page 396
Cunningham, S.D. & Ow, D.W. (1996) Promises and prospects for phytoremediation. Plant
Physiol., 110, 715–719
Dabeka, R.W. & McKenzie, A.D. (1987) Lead, cadmium, and fluoride levels in market milk and
infant formulas in Canada. J. Assoc. off. anal. Chem., 70, 754–757
Dabeka, R.W. & McKenzie, A.D. (1988) Lead and cadmium levels in commercial infant foods and
dietary intake by infants 0−1 year old. Food Addit. Contam., 5, 333–342
Dabeka, R.W., McKenzie, A.D. & Lacroix, G.M.A. (1987) Dietary intakes of lead, cadmium,
arsenic and fluoride by Canadian adults: A 24-hour duplicate diet study. Food Addit. Contam.,
4, 89–102
Dabeka, R.W., Karpinski, K.F., McKenzie, A.D. & Badjik, C.D. (1988) Survey of lead and cadmium
in human milk and correlation of levels with environmental and food factors. Sci. total Environ.,
71, 65–66
Dalpra, L., Tibiletti, M.G., Nocera, G., Giulotto, P., Auriti, L., Carnelli, V. & Simoni, G. (1983) SCE
analysis in children exposed to lead emission from a smelting plant. Mutat. Res., 120, 249–256
Dalton, C.B., McCammon, J.B., Hoffman, R.E. & Baron, R.C. (1997) Blood lead levels in radiator
repair workers in Colorado. J. occup. environ. Med., 39, 58–62
Dams, R., Vandecasteele, C., Desmet, B., Helsen, M., Nagels, M., Vermeir, G. & Yu, Z.Q. (1988)
Element concentrations in the air of an indoor shooting range. Sci. total Environ., 77, 1–13
Danadevi, K., Rozati, R., Saleha Banu, B., Hanumanth Rao, P. & Grover, P. (2003) DNA damage
in workers exposed to lead using comet assay. Toxicology, 187, 183–193
Daniels, W.J. (1988) Health Hazard Evaluation Report, HETA 88-0031-1894, Camp Bird Ventures,
Ouray, CO, USA, NIOSH
Daniels, W.J. & Hales, T.R. (1989) Health Hazard Evaluation Report, HETA 89-0136-1991, Blue
Range Mining Co., Lewistown, MT, USA, NIOSH
Daniels, W.J., Hales, T.R. & Gunter, B.J. (1989) Health Hazard Evaluation Report, HETA 89-0213-
1992, Blue Range Engineering Co., Butte, MT, USA, NIOSH
David, O.J. (1974) Association between lower level lead concentrations and hyperactivity in
children. Environ. Health Perspect., 7, 17–25
Davies, B.E. (1983) A graphical estimation of the normal lead content of some British soils. Geo-
derma, 29, 67–75
Davies, J.M. (1984a) Lung cancer mortality among workers making lead chromate and zinc chro-
mate pigments at three English factories. Br. J. ind. Med., 41, 158–169
Davies, J.M. (1984b) Long term mortality study of chromate pigment workers who suffered lead
poisoning. Br. J. ind. Med., 41, 170–178
Davies, B.E., Elwood, P.C., Gallacher, J. & Ginnever, R.C. (1985) The relationships between heavy
metals in garden soils and house dusts in an old lead mining area of North Wales, Great
Britain. Environ. Pollut., B9, 255–266
Davies, D.J.A., Watt, J.M. & Thornton, I. (1987) Air lead concentration in Birmingham, England
— A comparison between levels inside and outside inner-city homes. Environ. Geochem.
Health, 9, 3–7
Davis, A., Ruby, M.V. & Bergstrom, P.D. (1992) Bioavailability of arsenic and lead in soils from
the Butte, Montana, mining district. Environ. Sci. Technol., 26, 461–468
Davis, A., Ruby, M.V. & Bergstrom, P.D. (1994) Factors controlling lead bioavailability in the
Butte mining district, Montana, USA. Environ. Geochem. Health, 16, 147–157
P 379-468 DEF.qxp 09/08/2006 13:53 Page 397
Decker, J. & Galson, S. (1991) Health Hazard Evaluation Report, HETA 91-0073-2165, Carbonnaire
Co. Palmerton, PA, USA, NIOSH
De Jonghe, W.R.A., Chakraborti, D. & Adams, F.C. (1981) Identification and determination of
individual tetraalkyllead species in air. Env. Sci. Technol., 15, 1217–1222
Deknudt, G. & Deminatti, M. (1978) Chromosome studies in human lymphocytes after in vitro
exposure to metal salts. Toxicology, 10, 67–75
Deknudt, G. & Gerber, G.B. (1979) Chromosomal aberrations in bone-marrow cells of mice given
a normal or a calcium-deficient diet supplemented with various heavy metals. Mutat. Res., 68,
163–168
Deknudt, G., Colle, A. & Gerber, G.B. (1977) Chromosomal abnormalities in lymphocytes from
monkeys poisoned with lead. Mutat. Res., 45, 77–83
De la Burdé, B. & Choate, M.S. (1975) Early asymptomatic lead exposure and development at
school age. J. Pediatr., 87, 638–642
De la Fuente, H., Portales-Pérez, D., Baranda, L., Díaz-Barriga, F., Saavedra-Alanís, V., Layseca,
E. & González-Amaro, R. (2002) Effect of arsenic, cadmium and lead on the induction of
apoptosis of normal human mononuclear cells. Clin. exp. Immunol., 129, 69–77
De Leacy, E. (1991) Lead crystal. Lancet, 337, 858–859
Delves, H.T., Diaper, S.J., Oppert, S., Prescott-Clarke, P., Periam, J., Dong, W., Colhoun, H. &
Gompertz, D. (1996) Blood lead concentrations in United Kingdom have fallen substantially
since 1984. Br. med. J., 313, 883–884
Denno, D.W. (1990) Biology and Violence, New York, Cambridge University Press
Der, R., Fahim, Z., Yousef, M. & Fahim, M. (1976) Environmental interaction of lead and cadmium
on reproduction and metabolism of male rats. Res. Comm. chem. Pathol. Pharmacol., 14,
689–713
De Restrepo, H.G., Sicard, D. & Torres, M.M. (2000) DNA damage and repair in cells of lead
exposed people. Am. J. ind. Med., 38, 330–334
DeSilva, P.E. (1981) Determination of lead in plasma and studies on its relationship to lead in
erythrocytes. Br. J. ind. Med., 38, 209–217
Dhir, H., Roy, A.K. & Sharma, A. (1993) Relative efficiency of Phyllanthus emblica fruit extract
and ascorbic acid in modifying lead and aluminium-induced sister-chromatid exchanges in
mouse bone marrow. Environ. mol. Mutag., 21, 229–236
Díaz, C., Galindo, L., Montelongo, F.G., Lerrechi, M.S. & Rius, F.X. (1990) Metals in coastal
waters of Santa Cruz de Tenerife, Canary Islands. Marine Pollut. Bull., 21, 91–95
Dickinson, L., Reichert, E.L., Ho, R.C.S., Rivers, J.B. & Kominami, N. (1972) Lead poisoning in
a family due to cocktail glasses. Am. J. Med., 52, 391–394
Diemel, J.A.L., Brunekreef, B., Boleij, J.S.M., Biersteker, K. & Veenstra, S.J. (1981) The Arnhem
lead study. II. Indoor pollution, and indoor/outdoor relationships. Environ. Res., 25, 449–456
Dieter, M.P., Matthews, H.B., Jeffcoat, R.A. & Moseman, R.F. (1993) Comparison of lead bio-
availability in F344 rats fed lead acetate, lead oxide, lead sulfide, or lead ore concentrate from
Skagway, Alaska. J. Toxicol. environ. Health, 39, 79–93
Dietrich, K., Krafft, K., Bier, M., Succop, P., Berger, O. & Bornschein, R. (1986) Early effects of
fetal lead exposure: Neurobehavioural findings at six months. Int. J. Biosoc. Res., 8, 151–168
Dietrich, K.N., Ris, M.D., Succop, P.A., Berger, O.G. & Bornschein, R.L. (2001) Early exposure
to lead and juvenile delinquency. Neurotoxicol. Teratol., 23, 511–518
P 379-468 DEF.qxp 09/08/2006 13:53 Page 398
Dillman, R.O., Crumb, C.K. & Lidsky, M.J. (1979) Lead poisoning from a gunshot wound: Report
of a case and review of the literature. Am. J. Med., 66, 509–514
Dingwall-Fordyce, I. & Lane, R.E. (1963) A follow-up study of lead workers. Br. J. ind. Med., 20,
313–315
Djuric, D., Kerin, Z., Graovac-Leposavic, L., Novak, L. & Kop, M. (1971) Environmental conta-
mination by lead from a mine and smelter — A preliminary report. Arch. environ. Health, 23,
275–279
Donald, J.M., Cutler, M.G. & Moore, M.R. (1986) Effects of lead in the laboratory mouse.
1. Influence of pregnancy upon absorption, retention, and tissue distribution of radio-labeled
lead. Environ. Res., 41, 420–431
Donmez, H., Dursun, N., Ozkul, Y. & Demirtas, H. (1998) Increased sister chromatid exchanges in
workers exposed to occupational lead and zinc. Biol. trace Elem. Res., 61, 105–109
Donovan, B.A. (1994) Health Hazard Evaluation Report, HETA 92-0029-2392, Kessler Studios,
Loveland, OH, USA, NIOSH
Drasch, G.A. (1982) Lead burden in prehistorical, historical and modern human bone. Sci. total
Environ., 24, 199–231
Drasch, G.A., Böhm, J. & Baur, C. (1987) Lead in human bones. Investigations on an occupa-
tionally non-exposed population in southern Bavaria (F.R.G.). I. Adults. Sci. total Environ., 64,
303–315
Drasch, G.A., Wanghofer, E. & Roider, G. (1997) Are blood, urine, hair, and muscle valid biomoni-
tors for the internal burden of men with the heavy metals mercury, lead and cadmium? Trace
Elem. Electrolytes, 14, 116–123
Driscoll, R.J. & Elliott, L.J. (1990) Health Hazard Evaluation Report, HETA 87-0126-2019,
Chrysler Chemical Division, Trenton, MI, USA, NIOSH
Driscoll, W., Mushak, P., Garfias, J. & Rothenberg, S.J. (1992) Reducing lead in gasoline —
Mexico’s experience. Environ. Sci. Technol., 26, 1702–1705
Dubas, T.C., Stevenson, A., Singhal, R.L. & Hrdina, P.D. (1978) Regional alterations in brain bio-
genic amines in young rats following chronic lead exposure. Toxicology, 9, 185–190
Ducoffre, G., Claeys, F. & Bruaux, P. (1990) Lowering time trend of blood lead levels in Belgium
since 1978. Environ. Res., 51, 25–34
Dunbabin, D.W., Tallis, G.A., Popplewell, P.Y. & Lee, R.A. (1992) Lead poisoning from Indian
herbal medicine (Ayurveda). Med. J. Austr., 157, 835–836
Dunkel, V.C., Zeiger, E., Brusick, D., McCoy, E., McGregor, D., Mortelmans, K., Rosenkranz,
H.S. & Simmon, V.F. (1984) Reproducibility of microbial mutagenicity assays: I. Tests with
Salmonella typhimurium and Escherichia coli using a standardized protocol. Environ. Mutag.,
6, 1–254
Duraisamy, V.P., Subramaniam, K.S., Chitdeshwari, T. & Singh, M.V. (2003) Seasonal and temporal
changes in heavy metal pollution in sewage and their impacts on soil quality. In: Singh, V.P. &
Yadava, R.N., eds, Environmental Pollution: Proceedings of the International Conference on
Water and Environment (WE-2003), New Delhi, Allied Publishers Pvt. Ltd., pp. 108–121
Dussias, V., Stefos, T., Stefanidis, K., Paraskevaidis, E., Karabini, F. & Lolis, D. [originally cited
as Vasilios, D., Theodor, S., Konstantinos, S., Evangelos, P., Fotini, K., Dimitrios, L.] (1997)
Lead concentrations in maternal and umbilical cord blood in areas with high and low air pollu-
tion. Clin. exp. Obstet. Gynecol., 24, 187–189
P 379-468 DEF.qxp 09/08/2006 13:53 Page 399
DuVal, G. & Fowler, B.A. (1989) Preliminary purification and characterization studies of a low
molecular weight, high affinity cytosolic lead-binding protein in rat brain. Biochem. biophys.
Res. Commun., 159, 177–184
Duydu, Y. & Süzen, H. S. (2003) Influence of δ-aminolevulinic acid dehydratase (ALAD) poly-
morphism on the frequency of sister chromatid exchange (SCE) and the number of high-
frequency cells (HFCs) in lymphocytes from lead-exposed workers. Mutat. Res., 540, 79–88
Dwivedi, S.K. & Dey, S. (2002) Medicinal herbs: A potential source of toxic metal exposure for
man and animals in India. Arch. environ. Health, 57, 229–231
Dwivedi, S.K., Swarup, D., Dey, S. & Patra, R.C. (2001) Lead poisoning in cattle and buffalo near
primary lead-zinc smelter in India. Vet. hum. Toxicol., 43, 93–94
Dykeman, R., Aguilar-Madrid, G., Smith, T., Juárez-Pérez, C.A., Piacitelli, G.M., Hu, H. &
Hernandez-Avila, M. (2002) Lead exposure in Mexican radiator repair workers. Am. J. ind.
Med., 41, 179–187
Eades, L.J., Farmer, J.G., MacKenzie, A.B., Kirika, A. & Bailey-Watts, A.E. (2002) Stable lead iso-
topic characterisation of the historical record of environmental lead contamination in dated
freshwater lake sediment cores from northern and central Scotland. Sci. total Environ., 292,
55–67
Eastwell, H.D., Thomas, B.J. & Thomas, B.W. (1983) Skeletal lead burden in Aborigine petrol
sniffers. Lancet, ii, 524–525
Eaton, DL., Kalman, D., Garvey, D., Morgan, M. & Omenn, G.S. (1984) Biological availability of
lead in a paint aerosol. 2. Absorption, distribution and excretion of intratracheally instilled
lead paint particles in the rat. Toxicol. Lett., 22, 307–313
Echt, A., Klein, M. & Reh, C.M. (1992) Health Hazard Evaluation Report, HETA 91-0124-2192,
U.S. Park Police, Washington, DC, USA, NIOSH
Eckel, W.P. & Jacob, T.A. (1988) Ambient levels of 24 dissolved metals in U.S. surface and ground
waters. In: Proceedings of the 196th Meeting of the American Chemical Society, Division of
Environmental Chemistry, 28, 371–372
Edelstein, S., Fullmer, C.S. & Wasserman, R.H. (1984) Gastrointestinal absorption of lead in
chicks: Involvement of the cholecalciferol endocrine system. J. Nutr., 114, 692–700
Edminster, S.C. & Bayer, M.J. (1985) Recreational gasoline sniffing: Acute gasoline intoxication
and latent organolead poisoning. Case reports and literature review. J. Emerg. Med., 3, 365–370
Ehrlich, R., Robins, T., Jordaan, E., Miller, S., Mbuli, S., Selby, P., Wynchank, S., Cantrell, A., De
Broe, M., D’Haese, P., Todd, A. & Landrigan, P. (1998) Lead absorption and renal dysfunction
in a South African battery factory. Occup. environ. Med., 55, 453–460
Eldred, R.A. & Cahill, T.A. (1994) Trends in elemental concentrations of fine particles at remote
sites in the United States of America. Atmos. Environ., 28, 1009–1019
Elias, R.W. (1985) Lead exposures in the human environment. In: Mahaffey, K.R., ed., Dietary and
Environmental Lead: Human Health Effects, Amsterdam, Elsevier Science Publisher B.V.,
pp. 79–107
Elias, Z., Poirot, O., Pezerat, H., Suquet, H., Schneider, O., Danière, M.C., Terzetti, F., Baruthio,
F., Fournier, M. & Cavelier, C. (1989) Cytotoxic and neoplastic transforming effects of indus-
trial hexavalent chromium pigments in Syrian hamster embryo cells. Carcinogenesis, 10,
2043–2052
P 379-468 DEF.qxp 09/08/2006 13:53 Page 400
Elinder, C.-G., Friberg, L., Lind, B., Nilsson, B., Svartengren, M. & Övermark, I. (1986) Decreased
blood lead levels in residents of Stockholm for the period 1980–1984. Scand. J. Work Environ.
Health, 12, 114–120
Ellis, G.B. & Desjardins, C. (1982) Male rats secrete luteinizing hormone and testosterone episo-
dically. Endocrinology, 110, 1618–1627
Elmarsafawy, S.F., Tsaih, S.-W., Korrick, S., Dickey, J.H., Sparrow, D., Aro, A. & Hu, H. (2002)
Occupational determinants of bone and blood lead levels in middle aged and elderly men from
the general community: The Normative Aging Study. Am. J. ind. Med., 42, 38–49
Englyst, V., Lundstrom, N., Gerhardsson, L., Rylander, L. & Nordberg, G. (1999) Determinants of
lung cancer risks among lead exposed smelter workers (Abstract). In: Proceedings of the Inter-
national Conference on Lead Exposure, Reproductive Toxicity, and Carcinogenicity, June 7–9,
1999, Gargano, Italy
Englyst, V., Lundström, N.-G., Gerhardsson, L., Rylander, L. & Nordberg, G. (2001) Lung cancer
risks among lead smelter workers also exposed to arsenic. Sci. total Environ., 273, 77–82
Enterline, P.E., Marsh, G.M., Esmen, N.N., Henderson, V.L., Callahan, C.M. & Paik, M. (1987)
Some effects of cigarette smoking, arsenic, and SO2 on mortality among US copper smelter
workers. J. occup. Med., 29, 831–838
Environment Agency, Japan (1997) [Air Pollution in Japan, 1996], The Government of Japan,
Tokyo, Gyosei Publishers (in Japanese)
Environmental Management Bureau (1996) Philippine Environmental Quality Report 1990–1995,
Manila, Environmental Management Bureau, Department of Environmental and Natural
Resources, the Government of the Philippines, p. 9
Environment Protection Administration ROC (1991) [Domestic Environmental Information and
Statistics of Taiwan Area ROC, 1990], Taipei, Environmental Protection Administration Prin-
ting Office, p. 480 (in Chinese)
Epstein, S.S. & Mantel, N. (1968) Carcinogenicity of tetraethyl lead. Experientia, 24, 580–581
Epstein, H.T., Newton, J.T. & Fenton, K. (1999) Lead effects on offspring depend on when mouse
mothers were exposed to lead. Biol. Neonate, 75, 272–278
Erfurth, E.M., Gerhardsson, L., Nilsson, A., Rylander, L., Schütz, A., Skerfving, S. & Börjesson,
J. (2001) Effects of lead on the endocrine system in lead smelter workers. Arch. environ.
Health, 56, 449–455
Erkkilä, J., Armstrong, R., Riihimaki, V., Chettle, D.R., Paakkari, A., Scott, M., Somervaille, L.,
Starck, J., Kock, B. & Aitio, A. (1992) In vivo measurements of lead in bone at four anatomical
sites: Long term occupational and consequent endogenous exposure. Br. J. Ind. Med., 49,
631–644
Ernhart, C., Morrow-Tlucak, M., Wolf, A.W., Super, D. & Drotar, D. (1989) Low level lead exposure
in the prenatal and early preschool periods: Intelligence prior to school entry. Neurotoxicol.
Teratol., 11, 161–170
Esernio-Jenssen, D., Donatelli-Guagenti, A. & Mofenson, H.C. (1996) Severe lead poisoning from
an imported clothing accessory: ‘Watch’ out for lead. Clin. Toxicol., 34, 329–333
ESPI Corp. (2002) Technical Data Sheets: Lead, Ashland, OR, USA, pp. 169–174
Esswein, E.J., Boeniger, M.F., Hall, R.M. & Mead, K. (1996) Health Hazard Evaluation Report,
HETA 94-0268-2618, Standard Industries, San Antonio, TX, USA, NIOSH
European Commission (1998) Council Directive 98/24/EC of 7 April 1998 on the protection of the
health and safety of workers from the risks related to chemical agents at work (fourteenth indi-
P 379-468 DEF.qxp 09/08/2006 13:53 Page 401
vidual Directive within the meaning of Article 16(1) of Directive 89/391/EEC), Official
Journal of the European Communities, L131, 11–23
Everson, J. & Patterson, C.C. (1980) ‘Ultra-clean’ isotope dilution/mass spectrometric analyses for
lead in human blood plasma indicate that most reported values are artificially high. Clin.
Chem., 26, 1603–1607
Evis, M.J., Kane, K.A., Moore, M.R. & Parratt, J.R. (1985) The effects of chronic low lead treat-
ment and hypertension on the severity of cardiac arrhythmias induced by coronary artery liga-
tion in anesthetized rats. Toxicol. appl. Pharmacol., 80, 235–242
Evis, M.J., Dhaliwal, K., Kane, K.A., Moore, M.R. & Parratt, J.R. (1987) The effects of chronic
lead treatment and hypertension on the severity of cardiac arrhythmias induced by coronary
artery occlusion or by noradrenaline in anaesthetised rats. Arch. Toxicol., 59, 336–340
Ewers, U., Stiller-Winkler, R. & Idel. H. (1982) Serum immunoglobulin, complement C3, and sali-
vary IgA levels in lead workers. Environ. Res., 29, 351–357
Ewers, L.M., Piacitelli, G.M. & Whelan, E.A. (1995) Health Hazard Evaluation Report, HETA 93-
0502-2503, George Campbell Painting Co., Groton, CT, USA, NIOSH
Facchetti, S. (1989) Lead in petrol. The isotopic lead experiment. Acc. Chem. Res., 22, 370–374
Factor-Litvak, P., Graziano, J.H., Kline, J.K., Popovac, D., Mehmeti, A., Ahmedi, G., Shrout, P.,
Murphy, M.J., Gashi, E., Haxhiu, R., Rajovic, L., Nenezic, D.U. & Stein, Z.A. (1991) A pros-
pective study of birthweight and length of gestation in a population surrounding a lead smelter
in Kosovo, Yugoslavia. Int. J. Epidemiol., 20, 722–728
Fair, J.M. & Ricklefs, R.E. (2002) Physiological, growth, and immune responses of Japanese quail
chicks to the multiple stressors of immunological challenge and lead shot. Arch. environ.
Contam. Toxicol., 42, 77–87
Fairhall, L.T. & Miller, J.W. (1941) A study of the relative toxicity of the molecular components
of lead arsenate. Publ. Health Rep., 56, 1610–1625
Falcón, M., Viñas, P. & Luna, A. (2003) Placental lead and outcome of pregnancy. Toxicology, 185,
59–66
Fanning, D. (1988) A mortality study of lead workers, 1926–1985. Arch. environ. Health, 43,
247–251
FAO/WHO (1993) Evaluation of Certain Food Additives and Contaminants, Forty-first Report of
the Joint FAO/WHO Expert Committee on Food Additives (Technical Report Series 837),
Geneva, World Health Organization
Farias, P., Borja-Aburto, V.H., Rios, C., Hertz-Picciotto, I., Rojas-Lopez, M. & Chavez-Ayala, R.
(1996) Blood lead levels in pregnant women of high and low socioeconomic status in Mexico
City. Environ. Health Perspect., 104, 1070–1074
Farmer, A.A. & Farmer, A.M. (2000) Concentrations of cadmium, lead and zinc in livestock feed
and organs around a metal production centre in eastern Kazakhstan. Sci. total Environ., 257,
53–60
Fayerweather, W.E., Karns, M.E., Nuwayhid, I.A. & Nelson, T.J. (1997) Case–control study of
cancer risk in tetraethyl lead manufacturing. Am. J. ind. Med., 31, 28–35
Fears, T.R., Elashoff, R.M. & Schneiderman, M.A. (1989) The statistical analysis of carcinogen
mixture experiment. III Carcinogens with different target systems, aflatoxins B1, N-butyl-N-
(4-hydroxybutyl)nitrosamine, lead acetate, and thiouracil. Toxicol. ind. Health, 5, 1–23
Fergusson, D.M., Horwood, L.J. & Lynskey, M.T. (1997) Early dentine lead levels and educational
outcomes at 18 years. J. Child Psychol. Psychiat., 38, 471–478
P 379-468 DEF.qxp 09/08/2006 13:53 Page 402
Fernández, R., Morales, F. & Benzo, Z. (2003) Lead exposure in day care centres in the Caracas
Valley — Venezuela. Int. J. environ. Health Res., 13, 3–9
Fernandez-Cabezudo, M.J., Hasan, M.Y., Mustafa, N., El-Sharkawy, R.T., Fahim, M.A. & Al-
Ramadi, B.K. (2003) Alpha tocopherol protects against immunosuppressive and immunotoxic
effects of lead. Free Radic. Res., 37, 437–445
Fernando, N.P., Healy, M.A., Aslam, M., Davis, S.S. & Hussein, A. (1981) Lead poisoning and
traditional practices: The consequences for world health. A study in Kuwait. Public Health
(London), 95, 250–260
Fett, M.J., Mira, M., Smith, J., Alperstein, G., Causer, J., Brokenshire, T., Gulson, B. & Cannata,
S. (1992) Community prevalence survey of children’s blood lead levels and environmental
lead contamination in inner Sidney. Med. J. Aust., 157, 441–445
Fischbein, A., Rice, C., Sarkozi, L., Kon, S.H., Petrocci, M. & Selikoff, I.J. (1979) Exposure to
lead in firing ranges. JAMA, 241, 1141–1144
Fischbein, A., Wallace, J., Sassa, S., Kappas, A., Butts, G., Rohl, A. & Kaul, B. (1992) Lead poiso-
ning from art restoration and pottery work: Unusual exposure source and household risk.
J. environ. Pathol. Toxicol. Oncol., 11, 7–11
Fischer, A.B., Georgieva, R., Nikolova, V., Halkova, J., Bainova, A., Hristeva, V., Penkov, D. &
Alandjiisk, D. (2003) Health risk for children from lead and cadmium near a non-ferrous
smelter in Bulgaria. Int. J. Hyg. environ. Health, 206, 25–38
Fitch, A. (1998) Lead analysis: Past and present. Crit. Rev. anal. Chem., 28, 267–345
Fitchko, J. & Hutchinson, T.C. (1975) A comparative study of heavy metal concentrations in river
mouth sediments around the Great Lakes. J. Great Lakes Res., 1, 46–78
Flanagan, P.R., Hamilton, D.L., Haist, J. & Valberg, L.S. (1979) Interrelationships between iron
and lead absorption in iron-deficient mice. Gastroenterology, 77, 1074–1081
Fleming, D.E.B., Boulay, D., Richard, N.S., Robin, J.-P., Gordon, C.L., Webber, C.E. & Chettle,
D.R. (1997) Accumulated body burden and endogenous release of lead in employees of a lead
smelter. Environ. Health Perspect., 105, 224–233
Fleming, D.E.B., Chettle, D.R., Wetmur, J.G., Desnick, R.J., Robin, J.-P., Boulay, D., Richard,
N.S., Gordon, C.L. & Webber, C.E. (1998) Effect of the δ-aminolevulinate dehydratase poly-
morphism on the accumulation of lead in bone and blood in lead smelter workers. Environ.
Res., 77, 49–61
Fleming, D.E., Chettle, D.R., Webber, C.E. & O’Flaherty, E.J. (1999) The O’Flaherty model of lead
kinetics: An evaluation using data from a lead smelter population. Toxicol. appl. Pharmacol.,
161, 100–109
Flora, S.J.S. & Tandon, S.K. (1986) Preventive and therapeutic effects of thiamine, ascorbic acid
and their combination in lead intoxication. Acta pharmacol. toxicol., 58, 374–378
Flora, G.J.S., Khanna, V.K. & Seth, P.K. (1999) Changes in neurotransmitter receptors and neuro-
behavioral variables in rats co-exposed to lead and ethanol. Toxicol. Lett., 109, 43–49
Florence, T.M., Lilley, S.G. & Stauber, J.L. (1988) Skin absorption of lead. Lancet, ii, 157–158
Florence, T.M., Stauber, J.L., Dale, L.S., Henderson, D., Izard, B.E. & Belbin, K. (1998) The
absorption of ionic lead compounds through the skin of mice. J. nutr. environ. Med., 8, 19–23
Forbes, G.B. & Reina, J.C. (1972) Effect of age on gastrointestinal absorption (Fe, Sr, Pb) in the
rat. J. Nutr., 102, 647–652
P 379-468 DEF.qxp 09/08/2006 13:53 Page 403
Forni, A. & Secchi, G.C. (1972) Chromosome changes in preclinical and clinical lead poisoning and
correlation with biochemical findings. In: Proceedings of the International Symposium ‘Environ-
mental Health Aspects of Lead’, Amsterdam, Oct 2–6, pp. 473–485
Forni, A., Cambiaghi, G. & Secchi, G.C. (1976) Initial occupational exposure to lead. Chromosome
and biochemical findings. Arch. environ. Health, 31, 73–78
Foster, W.G. (1992) Reproductive toxicity of chronic lead exposure in the female cynomolgus
monkeys. J. reprod. Toxicol., 6, 123–131
Foster, W.G., McMahon, A. & Rice, D.C. (1996) Sperm chromatin structure is altered in cyno-
molgus monkeys with environmentally relevant blood lead levels. Toxicol. ind. Health, 12,
723–735
Fouassin, A. & Fondu, M. (1980) Evaluation of the daily intake of lead and cadmium from food
in Belgium. Arch. Belg. Méd. Soc. Hyg. Méd. Trav. Méd. Lég., 38, 453–467
Fowler, B.A. (1998) Roles of lead-binding proteins in mediating lead bioavailability. Environ.
Health Perspect., 106 (Suppl. 6), 1585–1587
Fowler, B.A. & DuVal, G. (1991) Effects of lead on the kidney: Roles of high-affinity lead-binding
proteins. Environ. Health Perspect., 91, 77–80
Fowler, B.A., Kimmel, C.A., Woods, J.S., McConnell, E.E. & Grant, L.D. (1980) Chronic low-
level lead toxicity in the rat. III. An integrated assessment of long-term toxicity with special
reference to the kidney. Toxicol. appl. Pharmacol., 56, 59–77
Fowler, B.A., Kahng, M.W., Smith, D.R., Conner, E.A. & Laughlin, N.K. (1993) Implications of
lead binding proteins for risk assessment of lead exposure. J. Exp. Anal. environ. Epidemiol.,
3, 441–448
Fox, D.A., He, L., Poblenz, A.T., Medrano, C.J., Blocker, Y.S. & Srivastava, D. (1998) Lead-
induced alterations in retinal cGMP phosphodiesterase trigger calcium overload, mitochon-
drial dysfunction and rod photoreceptor apoptosis. Toxicol. Lett., 102–103, 359–361
Fracasso, M.E., Perbellini, L., Solda, S., Talamini, G. & Franceschetti, P. (2002) Lead induced
DNA strand breaks in lymphocytes of exposed workers: Role of reactive oxygen species and
protein kinase C. Mutat. Res., 515, 159–169
Franco, G., Cottica, D. & Minoia, C. (1994) Chewing electric wire coatings: An unusual source of
lead poisoning. Am. J. ind. Med., 25, 291–296
Franklin, C.A., Inskip, M.J., Baccanale, C.L., Edwards, C.M., Manton, W.I., Edwards, E. &
O’Flaherty, E.J. (1997) Use of sequentially administered stable lead isotopes to investigate
changes in blood lead during pregnancy in a nonhuman primate (Macaca fascicularis).
Fundam. appl. Toxicol., 39, 109–119
Freeman, G.B., Johnson, J.D., Killinger, J.M., Liao, S.C., Feder, P.I., Davis, A.O., Ruby, M.V.,
Chaney, R.L., Lovre, S.C. & Bergstrom, P.D. (1992) Relative bioavailability of lead from
mining waste soil in rats. Fundam. appl. Toxicol., 19, 388–398
Freeman, G.B., Johnson, J.D., Liao, S.C., Feder, P.I., Davis, A.O., Ruby, M.V., Schoof, R.A.,
Chaney, R.L. & Bergstrom, P.D. (1994) Absolute bioavailability of lead acetate and mining
waste lead in rats. Toxicology, 91, 151–163
Freeman, G.B., Dill, J.A., Johnson, J.D., Kurtz, P.J., Parham, F. & Matthews, H.B. (1996) Compa-
rative absorption of lead from contaminated soil and lead salts by weanling Fischer 344 rats.
Fundam. appl. Toxicol., 33, 109–119
P 379-468 DEF.qxp 09/08/2006 13:53 Page 404
Frenz, P.Y., Vega, J.M., Marchetti, N.P., Torres, J.P., Kopplin, E.I., Delgado, I.B. & Vega, F.A.
(1997) [Chronic exposure to environmental lead in Chilean nursing infants.] Rev. méd. Chile,
125, 1137–1144 (in Spanish)
Friberg, L. & Vahter, M. (1983) Assessment of exposure to lead and cadmium through biological
monitoring: Results of UNEP/WHO global study. Environ. Res., 30, 95–128
Frisancho, A.R. & Ryan, A.S. (1991) Decreased stature associated with moderate blood lead con-
centrations in Mexican-American children. Am. J. clin. Nutr., 54, 516–519
Froom, P., Kristal-Boneh, E., Benbassat, J., Ashkanazi, R. & Ribak, J. (1998) Predective value of
determinations of zinc protoporphyrin for increased blood lead concentrations. Clim. Chem.,
44, 1283–1288
Fu, H. & Boffetta, P. (1995) Cancer and occupational exposure to inorganic lead compounds: A
meta-analysis of published data. Occup. environ. Med., 52, 73–81
Fujiwara, Y. & Kaji, T. (1999) Possible mechanism for lead inhibition of vascular endothelial cell
proliferation: A lower response to basic fibroblast growth factor through inhibition of heparan
sulfate synthesis. Toxicology, 133, 147–157
Fukui, Y., Miki, M., Ukai, H., Okamoto, S., Takada, S., Higashikawa, K. & Ikeda, M. (1999) Uri-
nary lead as a possible surrogate of blood lead among workers occupationally exposed to lead.
Int. Arch. occup. environ. Health, 72, 516–20
Fukunaga, M., Kurachi, Y. & Mizuguchi, Y. (1982) Action of some metal ions on yeast chromo-
somes. Chem. pharm. Bull., 30, 3017–3019
Fullmer, C.S. (1990) Intestinal lead and calcium absorption: Effect of 1,25-dihydroxycholecalci-
ferol and lead status. Proc. Soc. exp. Biol. Med., 194, 258–264
Fullmer, C.S. (1991) Intestinal calcium and lead absorption: Effects of dietary lead and calcium.
Environ. Res., 54, 159–169
Fullmer, C.S. (1997) Lead–calcium interactions: Involvement of 1,25-dihydroxyvitamin D.
Environ. Res., 72, 45–55
Fullmer, C.S., Edelstein, S. & Wasserman, R.H. (1985) Lead-binding properties of intestinal calcium-
binding proteins. J. biol. Chem., 260, 6816–6819
Fulton, M., Thomson, G., Hunter, R., Raab, G., Laxen, D. & Hepburn, W. (1987) Influence of blood
lead on the ability and attainment of children in Edinburgh. Lancet, i, 1221–1226
Fuortes, L. & Bauer, E. (2000) Lead contamination of imported candy wrappers. Vet. hum. Toxicol.,
42, 41–42
Furst, A., Schlauder, M. & Sasmore, D.P. (1976) Tumorigenic activity of lead chromate. Cancer
Res., 36, 1779–1783
Galal-Gorchev, H. (1991a) Dietary intake of pesticide residues, cadmium, mercury and lead. Food
addit. Contam., 8, 793–806
Galal-Gorchev, H. (1991b) Global overview of dietary lead exposure. Chem. Speciation Bio-
availab., 3, 5–11
Galke, W., Clark, S., Wilson, J., Jacobs, D., Succop, P., Dixon, S., Bornschein, B., McLaine, P. &
Chen, M. (2001) Evaluation of the HUD Lead Hazard Control grant program: Early overall
findings. Environ. Res., A86, 149–156
Gallicchio, L., Scherer, R.W. & Sexton, M. (2002) Influence of nutrient intake on blood lead levels
of young children at risk for lead poisoning. Environ. Health Perspect., 110, A767–A772
Garber, B.T. & Wei, E. (1974) Influence of dietary factors on the gastrointestinal absorption of
lead. Toxicol. appl. Pharmacol., 27, 685–691
P 379-468 DEF.qxp 09/08/2006 13:53 Page 405
Garrido Latorre, F., Hernandez-Avila, M., Tamayo Orozco, J., Albores Medina, C.A., Aro, A.,
Palazuelos, E. & Hu, H. (2003) Relationship of blood and bone lead to menopause and bone
mineral density among middle-age women in Mexico City. Environ. Health Perspect., 111,
631–636
Garner, D.L., Pinkel, D., Johnson, L.A. & Pace, M.M. (1986) Assessment of spermatozoal function
using dual fluorescent staining and flow cytometric analyses. Biol. Reprod., 34, 127–138
Gartrell, M.J., Craun, J.C., Podrebarac, D.S. & Gunderson, E.L. (1985a) Pesticides, selected ele-
ments, and other chemicals in adult total diet samples, October 1979–September 1980. J. Assoc.
Off. Anal. Chem., 68, 1184–1197
Gartrell, M.J., Craun, J.C., Podrebarac, D.S. & Gunderson, E.L. (1985b) Pesticides, selected ele-
ments, and other chemicals in infant and toddler total diet samples, October 1979–September
1980. J. Assoc. Off. Anal. Chem., 68, 1163–1183
Gasiorek, K. & Bauchinger, M. (1981) Chromosome changes in human lymphocytes after separate
and combined treatment with divalent salts of lead, cadmium, and zinc. Environ. Mutag., 3,
513–518
Gélinas, Y., Lafond, J. & Schmit, J.-P. (1998) Multielemental Analysis of Human Fetal Tissues
using Inductively Coupled Plasma-Mass Spectrometry. Biol. Trace Elem. Res., 59, 63–74
Gennart, J.P., Bernard, A. & Lauwerys, R. (1992) Assessment of thyroid, testes, kidney and auto-
nomic nervous system function in lead-exposed workers. Int. Arch. occup. environ. Health, 64,
49–57
George, P.M., Walmsley, T.A., Currie, D. & Wells, J.E. (1993) Lead exposure during recreational
use of small bore rifle ranges. N.Z. Med. J., 106, 422–424
Gerhardsson, L., Lundström, N.-G., Nordberg, G. & Wall, S. (1986) Mortality and lead exposure:
A retrospective cohort study of Swedish smelter workers. Br. J. ind. Med., 43, 707–712
Gerhardsson, L., Chettle, D.R., Englyst, V., Nordberg, G.F., Nyhlin, H., Scott, M.C., Todd, A.C. &
Vesterberg, O. (1992) Kidney effects in long term exposed lead smelter workers. Br. J. ind.
Med., 49, 186–192
Gerhardsson, L., Attewell, R., Chettle, D.R., Englyst, V., Lundström, N.G., Nordberg, G.F., Nyhlin,
H., Scott, M.C. & Todd, A.C. (1993) In vivo measurements of lead in bone in long-term
exposed lead smelter workers. Arch. environ. Health, 48, 147–156
Gerhardsson, L., Hagmar, L., Rylander, L. & Skerfving, S. (1995a) Mortality and cancer incidence
among secondary lead smelter workers. Occup. environ. Med., 52, 667–672
Gerhardsson, L., Englyst, V., Lundström, N.-G., Nordberg, G., Sandberg, S. & Steinvall, F. (1995b)
Lead in tissues of deceased lead smelter workers. J. trace Elem. Med. Biol., 9, 136–143
Gerhardt, R.E., Crecelius, E.A. & Hudson, J.B. (1980) Trace element content of moonshine. Arch.
environ. Health, 35, 332–334
Gerr, F., Letz, R., Stokes, L., Chettle, D., McNeill, F. & Kaye, W. (2002) Association between bone
lead concentration and blood pressure among young adults. Am. J. ind. Med., 42, 98–106
Gersberg, R.M., Gaynor, K., Tenczar, D., Bartzen, M., Ginsberg, M., Gresham, L.S. & Molgaard,
C. (1997) Quantitative modeling of lead exposure from glazed ceramic pottery in childhood
lead poisoning cases. Int. J. environ. Health Res., 7, 193–202
Gerson, M., Van Den Eeden, S.K. & Gahagan, P. (1996) Take-home lead poisoning in a child from
his father’s occupational exposure. Am. J. ind. Med., 29, 507–508
Gething, J. (1975) Tetramethyl lead absorption : A report of human exposure to a high level of
tetramethyl lead. Br. J. ind. Med., 32, 329–333
P 379-468 DEF.qxp 09/08/2006 13:53 Page 406
Gisbert, C., Ros, R., De Haro, A., Walker, D.J., Bernal, M.P., Serrano, R. & Navarro-Aviñó, J.
(2003) A plant genetically modified that accumulates Pb is especially promising for phyto-
remediation. Biochem. biophys. Res. Commun., 303, 440–445
Gittleman, J. Estacio, P., O’Brien, D. & Montopoli, M. (1991) Health Hazard Evaluation Report,
HETA 91-0213-2123, G.T. Jones Tire & Battery Distributing Inc., Birmingham, AL, USA,
NIOSH
Giuffré de López Camelo, L., Ratto de Miguez, S. & Marbán, L. (1997) Heavy metals input with
phosphate fertilizers used in Argentina. Sci. total Environ., 204, 245–250
Godwin, H.A. (2001) The biological chemistry of lead. Curr. Opin. chem. Biol., 5, 223–227
Goering, P.L. (1993) Lead-protein interactions as a basis for lead toxicity. Neurotoxicology, 14,
45–60
Gogte, S.T., Basu, N., Sinclair, S., Ghai, O.P. & Bhide, N.K. (1991) Blood lead levels of children
with pica and surma use. Indian J. Pediatr., 58, 513–519
Goldberg, A., Doyle, D., Yeung-Laiwah, A., Moore, M.R. & McColl, K.E.L. (1985) Relevance of
cytochrome C oxidase deficiency to pathogenesis of acute porphyria. Q. J. Med., 57, 799
(Abstract)
Goldberg, R.L., Hicks, A.M., O’Leary, L.M. & London, S. (1991) Lead exposure at uncovered out-
door firing ranges. J. occup. Med., 33, 718–719
Goldman, R.H., Baker, E.L., Hannan, M. & Kamerow, D. (1987) Lead poisoning in automobile
radiator mechanics. New Engl. J. Med., 317, 214–218
Goldstein, G.W. (1993) Evidence that lead acts as a calcium substitute in second messenger meta-
bolism. Neurotoxicology, 14, 97–101
Goldstein, D.H., Benoit, J.N. & Tyroler, H.A. (1970) An epidemiologic study of an oil mist expo-
sure. Arch. environ. Health, 21, 600–603
Golter, M. & Michaelson, I.A. (1975) Growth, behavior and brain catecholamines in lead exposed
neonatal rats: A reappraisal. Science, 187, 359–361
González-Cossio, T., Peterson, K.E., Sanín, L.-H., Fishbein, E., Palazuelos, E., Aro, A.,
Hernández-Avila, M. & Hu, H. (1997) Decrease in birth weight in relation to maternal bone-
lead burden. Pediatrics, 100, 856–862
Gordon, J.N., Taylor, A. & Bennett, P.N. (2002) Lead poisoning: Case studies. Br. J. clin. Pharma-
col., 53, 451–458
Goyer, R.A. (1989) Mechanisms of lead and cadmium nephrotoxicity. Toxicol. Lett., 46, 153–162
Goyer, R.A. (1990a) Transplacental transport of lead. Environ. Health Perspect., 89, 101–105
Goyer, R.A. (1990b) Lead toxicity: From overt to subclinical to subtle health effects. Environ.
Health Perspect., 86, 177–181
Goyer, R.A. (1993) Lead toxicity: Current concerns. Environ. Health Perspect., 100, 177–187
Goyer, R.A. & Wilson, M.H. (1975) Lead-induced inclusion bodies: Results of ethylenediamine-
tetraacetic acid treatment. Lab. Invest., 32, 149–156
Goyer, R.A., Leonard, D.L., Moore, J.F., Rhyne, B. & Krigman, M.R. (1970) Lead dosage and the
role of the intranuclear inclusion body: An experimental study. Arch. environ. Health, 20,
705–711
Grandjean, P. & Bach, E. (1986) Indirect exposures: The significance of bystanders at work and at
home. Am. ind. Hyg. Assoc. J., 47, 819–824
Grandjean, P., Wulf, H.C. & Niebuhr, E. (1983) Sister chromatid exchange in response to variations
in occupational lead exposure. Environ. Res., 32, 199–204
P 379-468 DEF.qxp 09/08/2006 13:53 Page 407
Granick, J.L., Sassa, S., Granick, S., Levere, R.D. & Kappas, A. (1973) Studies in lead poisoning.
II. Correlation between the ratio of activated to inactivated δ-aminolevulinic acid dehydratase
of whole blood and the blood lead level. Biochem. Med., 8, 149–159
Grant, L.D., Kimmel, C.A., West, G.L., Martinez-Vargas, C.M. & Howard, J.L. (1980) Chronic
low-level toxicity in the rat. II. Effects on postnatal physical and behavioral development.
Toxicol. appl. Pharmacol., 56, 42–58
Grant, S., Walmsley, T.A. & George, P.M. (1992) Industrial blood lead levels in the South Island
during 1988 and 1989: Trends and follow up patterns. N.Z. med. J., 105, 323–326
Graziano, J.H. & Blum, C. (1991) Lead exposure from lead crystal. Lancet, 337, 141–142
Graziano, J.H., Popovac, D., Factor-Litvak, P., Shrout, P., Kline, J., Murphy, M.J., Zhao, Y.H.,
Mehmeti, A., Ahmedi, X., Rajovic, B., Zvicer, Z., Nenezic, D.U., Lolacono, N.J. & Stein, Z.
(1990) Determinants of elevated blood lead during pregnancy in a population surrounding a
lead smelter in Kosovo, Yugoslavia. Environ. Health Perspect., 89, 95–100
Graziano, J.H., Slavkovic, V., Factor-Litvak, P., Popovac, D., Ahmedi, X. & Mehmeti, A. (1991)
Depressed serum erythropoietin in pregnant women with elevated blood lead. Arch. environ.
Health, 46, 347–350
Graziano, J.H., Blum, C.B., Lolacono, N.J., Slavkovich, V., Manton, W.I., Pond, S. & Moore, M.R.
(1996) A human in vivo model for the determination of lead bioavailability using stable iso-
tope dilution. Environ. Health Perspect., 104, 176–179
Greene, T. & Ernhart, C.B. (1993) Dentine lead and intelligence prior to school entry: A statistical
sensitivity analysis. J. clin. Epidemiol., 46, 323–339
Gregus, Z. & Klaassen, C.D. (1986) Disposition of metals in rats: A comparative study of fecal, uri-
nary, and biliary excretion and tissue distribution of eighteen metals. Toxicol. appl. Pharmacol.,
85, 24–38
Griffin, T.B., Coulston, F., Wills, H., Russel, J.C. & Knelson, J.H. (1975a) Clinical studies on men
continuously exposed to airborne particulate lead. Environ. Qual. Saf., Suppl. 2, 221–240
Griffin, T.B., Coulston, F., Wills, H. & Russell, J.C. (1975b) Biologic effects of airborne particulate
lead on continuously exposed rats and rhesus monkeys. Environ. Qual. Saf., Suppl. 2, 202–220
Grill, E., Winnacker, E.-L. & Zenk, M.H. (1985) Phytochelatins: The principal heavy-metal com-
plexing peptides of higher plants. Science, 230, 674–676
Grill, E., Gekeler, W., Winnacker, E.-L. & Zenk, H.H. (1986) Homo-phytochelatins are heavy
metal-binding peptides of homo-glutathione containing Fabales. FEBS Letters, 205, 47–50
Grill, E., Winnacker, E.-L. & Zenk, M.H. (1987) Phytochelatins, a class of heavy-metal-binding
peptides from plants, are functionally analogous to metallothioneins. Proc. natl Acad. Sci.
USA, 84, 439–443
Grill, E., Löffler, S., Winnacker, E.-L. & Zenk, M.H. (1989) Phytochelatins, the heavy-metal-
binding peptides of plants, are synthesized from glutathione by a specific γ-glutamylcysteine
dipeptidyl transpeptidase (phytochelatin synthetase). Proc. natl Acad. Sci. USA, 86, 6838–6842
Grill, E., Winnacker, E.L. & Zenk, M.H. (1991) Phytochelatins. Meth. Enzymol., 205, 333–341
Grobler, S.R., Rossouw, R.J. & Maresky, L.S. (1985) Blood lead levels in a remote, unpolluted rural
area in South Africa. S. Afr. Med. J., 68, 323–324
Grobler, S.R., Rossouw, R.J. & Kotze, D. (1988) Effect of airborne lead on the blood lead levels
of rats. S. Afr. J. Sci., 84, 260–262
Grobler, S.R., Rossouw, R.J., Kotze, T.J.V.W. & Stander, I.A. (1991) The effect of airborne lead
on lead levels of blood, incisors and alveolar bone of rats. Arch. oral Biol., 36, 357–360
P 379-468 DEF.qxp 09/08/2006 13:53 Page 408
Gross, S.B., Pfitzer, E.A., Yeager, D.W. & Kehoe, R.A. (1975) Lead in human tissues. Toxicol.
appl. Pharmacol., 32, 638–651
Guilarte, T.R., Miceli, R.C. & Jett, D.A. (1995) Biochemical evidence of an interaction of lead at
the zinc allosteric sites of the NMDA receptor complex: Effects of neuronal development.
Neurotoxicology, 16, 63–71
Gulson, B.L. (1986) Lead Isotopes in Mineral Exploration. Developments in Economic Geology,
Vol. 23, Amsterdam, Elsevier
Gulson, B.L. (1996a) Tooth analyses of sources and intensity of lead exposure in children. Environ.
Health Perspect., 104, 306–312
Gulson, B.L. (1996b) Nails: Concern over their use in lead exposure assessment. Sci. total Environ.,
177, 323–327
Gulson, B.L., Mizon, K.J., Law, A.J., Korsch, M.J. & Davis, J.J. (1994) Source and pathways of
lead in humans from the Broken Hill mining community — An alternative use of exploration
methods. Econom. Geol., 89, 889–908
Gulson, B.L., Mahaffey, K.R., Mizon, K.J., Korsch, M.J., Cameron, M.A. & Vimpani, G. (1995)
Contribution of tissue lead to blood lead in adult female subjects based on stable lead isotope
methods. J. Lab. clin. Med., 125, 703–712
Gulson, B.L., James, M., Giblin, A.M., Sheehan, A. & Mitchell, P. (1997a) Maintenance of ele-
vated lead levels in drinking water from occasional use and potential impact on blood leads in
children. Sci. total Environ., 205, 271–275
Gulson, B.L., Mahaffey, K.R., Vidal, M., Jameson, C.W., Vidal, M., Law, A.J., Mizon, K.J., Smith,
A.J.M. & Korsch, M.J. (1997b) Dietary lead intakes for mother/child pairs and relevance to
pharmacokinetic models. Environ Health Perspect., 105, 1334–1342
Gulson, B.L., Jameson, C.W., Mahaffey, K.R., Mizon, K.J., Korsch, M.J. & Vimpani, G. (1997c)
Pregnancy increases mobilization of lead from maternal skeleton. J. Lab. Clin. Med., 130,
51–62
Gulson, B.L., Jameson, C.W., Mahaffey, K.R., Mizon, K.J., Patison, N., Law, A.J., Korsch, M.J. &
Salter, M.A. (1998a) Relationships of lead in breast milk to lead in blood, urine, and diet of
the infant and mother. Environ. Health Perspect., 106, 667–674
Gulson, B.L., Cameron, M.A., Smith, A.J., Mizon, K.J., Korsch, M.J., Vimpani, G., McMichael,
A.J., Pisaniello, D., Jameson, C.W. & Mahaffey, K.R. (1998b) Blood lead-urine lead relation-
ships in adults and children. Environ. Res., 78, 152–160
Gulson, B.L., Stockley, C.S., Lee T.H., Gray, B., Mizon, K.J. & Patison, N. (1998c) Contribution
of lead in wine to the total dietary intake of lead in humans with and without a meal: A pilot
study. J. Wine Res., 9, 5–14
Gulson, B.L., Mahaffey, K.R., Jameson, C.W., Mizon, K.J., Korsch, M.J., Cameron, M.A. &
Eisman, J.A. (1998d) Mobilization of lead from the skeleton during the postnatal period is
larger than during pregnancy. J. Lab. clin. Med., 131, 324–329
Gulson, B.L., Gray, B., Mahaffey, K.R., Jameson, C.W., Mizon, K.J., Patison, N. & Korsch, M.J.
(1999) Comparison of the rates of exchange of lead in the blood of newly born infants and
their mothers with lead from their current environment. J. Lab. clin. Med., 133, 171–178
Gulson, B.L., Mizon, K.J., Palmer, J.M., Korsch, M.J., Patison, N., Jameson, C.W. & Donnelly,
J.B. (2000) Urinary lead isotopes during pregnancy and postpartum indicate no preferential
partitioning of endogenous lead into plasma. J. Lab. clin. Med., 136, 236–242
P 379-468 DEF.qxp 09/08/2006 13:53 Page 409
Gulson, B.L., Mizon, K.J., Palmer, J.M., Patison, N., Law, A.J., Korsch, M.J., Mahaffey, K.R. &
Donnelly, J.B. (2001a) Longitudinal study of daily intake and excretion of lead in newly born
infants. Environ. Res., 85, 232–245
Gulson, B.L., Mizon, K.J., Palmer, J.M., Korsch, M.J. & Taylor, A.J. (2001b) Contribution of lead
from calcium supplements to blood lead. Environ. Health Perspect., 109, 283–288
Gulson, B., Mizon, K., Smith, H., Eisman, J., Palmer, J., Korsch, M., Donnelly, J. & Waite, K.
(2002) Skeletal lead release during bone resorption: Effect of bisphosphonate treatment in a
pilot study. Environ. Health Perspect., 110, 1017–1023
Gulson, B.L., Mizon, K.J., Korsch, M.J., Palmer, J.M. & Donnelly, J.B. (2003) Mobilization of
lead from human bone tissue during pregnancy and lactation — A summary of long-term
research. Sci. total Environ., 303, 79–104
Gulson, B.L., Mizon, K.J., Palmer, J.M., Korsch, M.J., Taylor, A.J. & Mahaffey, K.R. (2004)
Blood lead changes during pregnancy and postpartum with calcium supplementation. Environ.
Health Perspect., 112, 1499–1507
Gunshin, H., Mackenzie, B., Berger, U.V., Gunshin, Y., Romero, M.F., Boron, W.F., Nussberger,
S., Gollan, J.L. & Hediger, M.A. (1997) Cloning and characterization of a mammalian proton-
coupled metal-ion transporter. Nature, 388, 482–488
Gunter, B.J. (1985) Health Hazard Evaluation Report, HETA 85-0170-1643, C.F. & I. Steel,
Pueblo, CO, USA, NIOSH
Gunter, B.J. (1987) Health Hazard Evaluation Report, HETA 86-0070-1774, Silver Deer Spectrum,
Boulder, CO, USA, NIOSH
Gunter, B.J. & Daniels, W. (1990) Health Hazard Evaluation Report, HETA 89-0295-2007, Peerless
Alloy Inc., Denver, CO, USA, NIOSH
Gunter, B.J. & Hales, T.R. (1990a) Health Hazard Evaluation Report, HETA 89-0231-2016, Sims
Radiator Shop, Decatur, GA, USA, NIOSH
Gunter, B.J. & Hales, T.R. (1990b) Health Hazard Evaluation Report, HETA 89-0234-2014, Sims
Radiator Shop, Decatur, GA, USA, NIOSH
Gunter, B.J. & Hales, T.R. (1990c) Health Hazard Evaluation Report, HETA 89-0232-2015, Sims
Radiator Shop, Chamblee, GA, USA, NIOSH
Gunter, B.J. & Hales, T.R. (1990d) Health Hazard Evaluation Report, HETA 89-0233-2013, Sims
Radiator Shop, Lawrenceville, GA, USA, NIOSH
Gunter, B.J. & Hammel, R. (1989) Health Hazard Evaluation Report, HETA 88-0354-1955, Lake-
wood Radiator Shop, Denver, CO, USA, NIOSH
Gunter, B.J. & Seligman, P.J. (1984) Health Hazard Evaluation Report, HETA 84-0038-1513,
Kennecott Smelter, Hurley, NM, USA, NIOSH
Gunter, B.J. & Thoburn, T.W. (1984) Health Hazard Evaluation Report, HETA 84-0099-1514, C.F.
& I. Steel, Pueblo, CO, USA, NIOSH
Gunter, B.J. & Thoburn, T.W. (1985) Health Hazard Evaluation Report, HETA 84-0384-1580,
Crystal Zoo, Boulder, CO, USA, NIOSH
Gunter, B.J. & Thoburn, T.W. (1986a) Health Hazard Evaluation Report, HETA 86-0348-1756,
J’Leen Ltd., Boulder, CO, USA, NIOSH
Gunter, B.J. & Thoburn, T.W. (1986b) Health Hazard Evaluation Report, HETA 86-0087-1686,
TAC Radiator, Minot, ND, USA, NIOSH
Gunter, B.J., Richardson, F. & Anderson, K.E. (1986) Health Hazard Evaluation Report, HETA 86-
0438,0534-1795, Bondar-Clegg, Lakewood, CO & Sparks, NV, USA, NIOSH
P 379-468 DEF.qxp 09/08/2006 13:53 Page 410
Guo, H.R., Ballard, T.J., Madar, S., Piacitelli, G.M. & Seligman, P.J. (1994) Health Hazard Evalua-
tion Report, HETA 93-0955-2390, United Seal Co., Columbus, OH, USA, NIOSH
Gupta, S. & Dogra, T.D. (2002) Air pollution and human health hazards. Indian J. occup. environ.
Med., 6, 89–93
Gustafson, A., Hedner, P., Schütz, A. & Skjerfving, S. (1989) Occupational lead exposure and pitui-
tary function. Int. Arch. occup. environ. Health, 61, 277–281
Hackett, P.L., Hess, J.O. & Sikov, M.R. (1982a) Effect of dose level and pregnancy on the distri-
bution and toxicity of intravenous lead in rats. J. Toxicol. environ. Health, 9, 1007–1020
Hackett, P.L., Hess, J.O. & Sikov, M.R. (1982b) Distribution and effects of intravenous lead in the
fetoplacental unit of the rat. J. Toxicol. environ. Health, 9, 1021–1032
Hadi, D.A., Chowdhury, A.H. & Akhter, S. (1996) Status of lead and cadmium in poly(vinyl chlo-
ride) pipes. Bangladesh J. sci. ind. Res., 31, 39–42
Haeger-Aronsen, B., Abdulla, M. & Fristedt, B.I. (1974) Effect of lead on δ-aminolevulinic acid
dehydratase activity in red blood cells. Arch. environ. Health, 29, 150–153
Hales, T.R. & Gunter, B.J. (1990) Health Hazard Evaluation Report, HETA 89-0196-2023, Hazen
Research Inc., Golden, CO, USA, NIOSH
Hales, T.R., Kiefer, M., Mitchell, C. & Salisbury, S. (1991) Health Hazard Evaluation Report,
HETA 91-0393-2171, Georgia Metals, Inc., Powder Springs, GA, USA, NIOSH
Hall, R.M., Page, E., Mattorano, D. & Roegner, K. (1998) Health Hazard Evaluation Report, HETA
97-0292-2678, General Electric — Bridgeville Glass Plant, Bridgeville, PA, USA, NIOSH
Hamilton, J.W., Bement, W.J., Sinclair, P.R., Sinclair, J.F., Alcedo, J.A. & Wetterhahn, K.E. (1991)
Heme regulates hepatic 5-aminolevulinate synthase mRNA expression by decreasing mRNA
half-life and not by altering its rate of transcription. Arch. Biochem. Biophys., 289, 387–392
Hammad, T.A., Sexton, M. & Langenberg, P. (1996) Relationship between blood lead and dietary
iron intake in preschool children. A cross-sectional study. Ann. Epidemiol., 6, 30–33
Hamurcu, Z., Donmez, H., Saraymen, R. & Demirtas, H. (2001) Micronucleus frequencies in
workers exposed to lead, zinc, and cadmium. Biol. trace Elem. Res., 83, 97–102
Hanas, J.S., Rodgers, J.S., Bantle, J.A. & Cheng, Y.-G. (1999) Lead inhibition of DNA-binding
mechanism of Cys2His2 zinc finger proteins. Mol. Pharmacol., 56, 982–988
Hansen, O.N., Trillingsgaard, A., Beese, I., Lyngbye, T. & Grandjean, P. (1989) A neuropsycho-
logical study of children with elevated dentine lead level: Assessment of the effect of lead in
different socio-economic groups. Neurotoxicol. Teratol., 11, 205–213
Harney, J.M. & Barsan, M.E. (1999) Health Hazard Evaluation Report, HETA 97-0255-2735,
Forest Park Police Department, Forest Park, OH, USA, NIOSH
Harper, C.C., Mathee, A., von Schirnding, Y., De Rosa, C.T. & Falk, H. (2003) The health impact
of environmental pollutants: A special focus on lead exposure in South Africa. Int. J. Hyg.
environ. Health, 206, 315–322
Hart, C. (1987) Art hazards: An overview for sanitarians and hygienists. J. environ. Health, 49,
282–287
Hart, M.H. & Smith, J.L. (1981) Effect of vitamin D and low dietary calcium on lead uptake and
retention in rats. J. Nutr., 111, 694–698
Hartwig, A. (1994) Role of DNA repair inhibition in lead- and cadmium-induced genotoxicity:
A review. Environ. Health Perspect., 102 (Suppl. 3), 45–50
Hartwig, A., Schlepegrell, R. & Beyersmann, D. (1990) Indirect mechanism of lead-induced geno-
toxicity in cultured mammalian cells. Mutat. Res., 241, 75–82
P 379-468 DEF.qxp 09/08/2006 13:53 Page 411
Hashim, J.H., Hashim, Z., Omar, A. & Shamsudin, S.B. (2000) Blood lead levels of urban and rural
Malaysian primary school children. Asia Pac. J. public Health, 12, 65–70
Hass, G.M., Brown, D.V.L., Eisenstein, R. & Hemmens, A. (1964) Relations between lead poiso-
ning in rabbit and man. Am. J. Pathol., 45, 691–727
Hass, G.M., McDonald, J.H., Oyasu, R., Battifora, H.A. & Paloucek, J.T. (1967) Renal neoplasia
induced by combinations of dietary lead subacetate and N-2-fluorenylacetamide. In: Renal
Neoplasia, pp. 377–412
Hayakawa, K. (1972) Microdetermination and dynamic aspects of in vivo alkyl lead compounds.
II. Studies on the dynamic aspects of alkyl lead compounds in vivo. Nippon Eiseigaku Zasshi,
26, 526–535
He, L., Poblenz, A.T., Medrano, C.J. & Fox, D.A. (2000) Lead and calcium produce rod photo-
receptor cell apoptosis by opening the mitochondrial permeability transition pore. J. biol.
Chem., 275, 12175–12184
Healy, M.A., Harrison, P.G., Aslam, M., Davis, S.S. & Wilson, C.G. (1982) Lead sulphide and
traditional preparations: Routes for ingestion, and solubility and reactions in gastric fluid. J.
clin. Hosp. Pharm., 7, 169–173
Heard, M.J. & Chamberlain, A.C. (1982) Effect of minerals and food on uptake of lead from the
gastrointestinal tract in humans. Hum. Toxicol., 1, 411–415
Heard, M.J. & Chamberlain, A.C. (1984) Uptake of Pb by human skeleton and comparative meta-
bolism of Pb and alkaline earth elements. Health Phys., 47, 857–865
Heard, M.J., Wells, A.C., Newton, D. & Chamberlain, A.C. (1979) Human uptake and metabolism
of tetra ethyl and tetramethyl lead vapour labelled with 203Pb. In: Proceedings of an Inter-
national Conference on Management and Control of Heavy Metals in the Environment,
London, England, September, Edinburgh, CEP Consultants, pp. 103–108
Heard, M.J., Chamberlain, A.C. & Sherlock, J.C. (1983) Uptake of lead by humans and effect of
minerals and food. Sci. total Environ., 30, 245–253
Hengstler, J.G., Bolm-Audorff, U., Faldum, A., Janssen, K., Reifenrath, M., Gotte, W., Jung, D.,
Mayer-Popken, O., Fuchs, J., Gebhard, S., Bienfait, H.G., Schlink, K., Dietrich, C., Faust, D.,
Epe, B. & Oesch, F. (2003) Occupational exposure to heavy metals: DNA damage induction
and DNA repair inhibition prove co-exposures to cadmium, cobalt and lead as more dangerous
than hitherto expected. Carcinogenesis, 24 , 63–73
Henning, S.J. & Leeper, L.L. (1984) Duodenal uptake of lead by suckling and weanling rats. Biol.
Neonate, 46, 27–35
Hernández, E., Gutiérrez-Ruiz, M.C. & García Vargas, G. (1998) Effect of acute lead treatment on
coproporphyrinogen oxidase activity in HepG2 cells. Toxicology, 126, 163–171
Hernandez-Avila, M., Gonzalez-Cossio, T., Palazuelos, E., Romieu, I., Aro, A., Fishbein, E.,
Peterson, K.E. & Hu, H. (1996) Dietary and environmental determinants of blood and bone
lead levels in lactating postpartum women living in Mexico City. Environ. Health Perspect.,
104, 1076–1082
Hernandez-Avila, M., Smith, D., Meneses, F., Sanin, L.H. & Hu, H. (1998) The influence of bone
and blood lead on plasma lead levels in environmentally exposed adults. Environ. Health
Perspect., 106, 473–477
Hernandez-Avila, M., Villalpando, C.G., Palazuelos, E., Hu, H., Villalpando, M.E. & Martinez,
D.R. (2000) Determinants of blood lead levels across the menopausal transition. Arch.
environ. Health, 55, 355–360
P 379-468 DEF.qxp 09/08/2006 13:53 Page 412
Hernandez-Avila, M., Peterson, K.E., Gonzalez-Cossio, T., Sanin, L.H., Aro, A., Schnaas, L. & Hu,
H. (2002) Effect of maternal bone lead on length and head circumference of newborns and
1-month-old infants. Arch. environ. Health, 57, 482–488
Hernandez-Avila, M., Gonzalez-Cossio, T., Hernandez-Avila, J.E., Romieu, I., Peterson, K.E., Aro,
A., Palazuelos, E. & Hu, H. (2003) Dietary calcium supplements to lower blood lead levels in
lactating women: A randomized placebo-controlled trial. Epidemiology, 14, 206–212
Hernberg, S. (2000) Lead poisoning in a historical perspective. Am. J. ind. Med., 38, 244–254
Hershko, C., Eisenberg, A., Avni, A., Grauer, F., Acker, C., Hamdallah, M., Shahin, S., Moreb, J.,
Richter, E. & Weissenberg, E. (1989) Lead poisoning by contaminated flour. Rev. environ.
Health, 8, 17–23
Hertz-Picciotto, I. (2000) The evidence that lead increases the risk for spontaneous abortion. Am.
J. ind. Med., 38, 300–309
Hertz-Picciotto, I. & Croft, J. (1993) Review of the relation between blood lead and blood pressure.
Epidemiol. Rev., 15, 352–373
Hertz-Picciotto, I., Schramm, M., Watt-Morse, M., Chantala, K., Anderson, J. & Osterloh, J. (2000)
Patterns and determinants of blood lead during pregnancy. Am. J. Epidemiol., 152, 829–837
Heywood, R. & James, R.W. (1985) Current laboratory approaches for assessing male reproductive
toxicity: Testicular toxicity in laboratory animals. In: Dixon, R.L., ed., Reproductive Toxi-
cology (Target Organ Toxicology Series), New York, Raven Press, pp. 147–160
Hiasa, Y., Ohshima, M., Kitahori, Y., Fujita, T., Yuasa, T. & Miyashiro, A. (1983) Basic lead
acetate: Promoting effect on the development of renal tubular cell tumors in rats treated with
N-ethyl-N-hydroxyethylnitrosamine. J. natl Cancer Inst., 70, 761–765
Hiasa, Y., Konishi, N., Nakaoka, S., Nakamura, M., Nishii, S., Kitahori, Y. & Ohshima, M. (1991)
Possible application to medium-term organ bioassays for renal carcinogenesis modifiers in rats
treated with N-ethyl-N-hydroxyethylnitrosamine and unilateral nephrectomy. Jpn. J. Cancer
Res., 82, 1385–1390
Hilderbrand, D.C., Der, R., Griffin, W.T. & Fahim, M.S. (1973) Effect of lead acetate on repro-
duction. Am. J. Obstet. Gynecol., 115, 1058–1065
Hill, G.J. & Hill, S. (1995) Lead poisoning due to hai ge fen. J. Am. med. Assoc., 273, 24–25
Hills, B. & Savery, H. (1988) Health Hazard Evaluation Report, HETA 87-0410-1868, Klotz
Brothers, Inc., Staunton, VA, USA, NIOSH
Hindy, K.T., Farag, S.A., El-Taieb, N.M., Rizk, H.F. & Ibrahim, J.M. (1987) Spectrographic study
of heavy metals in an industrial area in North Cairo. In: Proceedings, International Conference
on Heavy Metals in the Environment, New Orleans, Vol. 1, pp. 134–136
Hinton, D.E., Lipsky, M.M., Heatfield, B.M. & Trump, B.F. (1979) Opposite effects of lead on
chemical carcinogenesis in kidney and liver of rats. Bull. environ. Contam. Toxicol., 23, 464–469
Hinton, D., Coope, P.A., Malpress, W.A. & Janus, E.D. (1986) Trends in blood lead levels in
Christchurch (NZ) and environs 1978–85. J. Epidemiol. Community Health, 40, 244–248
Hirata, M., Yoshida, T., Miyajima, K., Kosaka, H. & Tabuchi, T. (1995) Correlation between lead
in plasma and other indicators of lead exposure among lead-exposed workers. Int. Arch. occup.
environ. Health, 68, 58–63
Hisham, J. & Pertanika, Z.H. (1995) Lead and cadmium content of total suspended particulates in
the atmosphere over the Klang valley. J. Sci. Technol., 3, 57–65
Ho, S.F., Sam, C,T. & Embi, G.B. (1998) Lead exposure in the lead–acid storage battery manu-
facturing and PVC compounding industries. Occup. Med., 48, 369–373
P 379-468 DEF.qxp 09/08/2006 13:53 Page 413
Hoar, S.K., Morrison, A.S., Cole, P. & Silverman, D.T. (1980) An occupation and exposure linkage
system for the study of occupational carcinogenesis. J. occup. Med., 22, 722–726
Hodgkins, D.G., Robins, T.G., Hinkamp, D.L., Schork, M.A., Levine, S.P. & Krebs, W.H. (1991)
The effect of airborne lead particle size on worker blood-lead levels: An empirical study of
battery workers. J. occup. Med., 33, 1265–1273
Holdstein, Y., Pratt, H., Goldsher, M., Rosen, G., Shenhav, R., Linn, S., Mor, A. & Barkai, A. (1986)
Auditory brainstem evoked potentials in asymptomatic lead-exposed subjects. J. Laryngol.
Otol., 100, 1031–1036
Hollett, B. & Moody, P.L. (1984) Health Hazard Evaluation Report, HETA 80-0115-1401, U.S.
Steel, Lorain-Cayahoga Works, Lorain, OH, USA, NIOSH
Hopkins, A.P. & Dayan, A.D. (1974) The pathology of experimental lead encephalopathy in the
baboon (Papio anubis). Br. J. ind. Med., 31, 128–133
Hoppin, J.A., Aro, A., Hu, H. & Ryan, P.B. (1997) In vivo bone lead measurement in suburban
teenagers. Pediatrics, 100, 365–370
Hoppin, J.A., Aro, A., Hu, H. & Ryan, P.B. (2000) Measurement variability associated with KXRF
bone lead measurement in young adults. Environ. Health Perspect., 108, 239–242
Horiguchi, S., Teramoto, K., Kiyota, I., Shinagawa, K., Nakano, H., Karai, I. & Matsuda, F. (1981)
Relationships among the parameters of lead absorption and lead effects especially on the
hematopoietic system. Osaka City med. J., 27, 35–45
Houston, D.K. & Johnson, M.A. (2000) Does vitamin C intake protect against lead toxicity? Nutr.
Rev., 58, 73–75
Hrdina, P.D., Peters, D.A.V. & Singhal, R.L. (1976) Effects of chronic exposure to cadmium, lead
and mercury on brain biogenic amines in the rat. Res. Commun. chem. Pathol. Pharmacol.,
15, 483–493
Hryhorczuk, D.O., Rabinowitz, M.B., Hessl, S.M., Hoffman, D., Hogan, M.M., Mallin, K., Finch,
H., Orris, P. & Berman, E. (1985) Elimination kinetics of blood lead in workers with chronic
lead intoxication. Am. J. ind. Med., 8, 33–42
Hsiao, C.Y., Wu, H.D.I., Lai, J.S. & Kuo, H.W. (2001) A longitudinal study of the effects of long-
term exposure to lead among lead battery factory workers in Taiwan (1989–1999). Sci. total
Environ., 279, 151–158
Hu, H. (1991) Knowledge of diagnosis and reproductive history among survivors of childhood
plumbism. Am. J. pub. Health, 81, 1070–1072
Hu, H., Pepper, L & Goldman, R. (1991) Effect of repeated occupational exposure to lead, cessa-
tion of exposure, and chelation on levels of lead in bone. Am. J. ind. Med., 20, 723−735
Hu, H., Aro, A. & Rotnitzky, A. (1995) Bone lead measured by X-ray fluorescence: Epidemiologic
methods. Environ. Health Perspect., 103 (Suppl. 1), 105–110
Hu, H., Hashimoto, D. & Besser, M. (1996a) Levels of lead in blood and bone of women giving
birth in a Boston hospital. Arch. environ. Health, 51, 52–58
Hu, H., Aro, A., Payton, M., Korrick, S., Sparrow, D., Weiss, S.T. & Rotnitzky, A. (1996b) The
relationship of bone and blood lead to hypertension. The Normative Aging Study. J. Am. med.
Assoc., 275, 1171–1176
Hu, H., Payton, M., Korrick, S., Aro, A., Sparrow, D., Weiss, S.T. & Rotnitzky, A. (1996c) Deter-
minants of bone and blood lead levels among community-exposed middle-aged to elderly
men. The Normative Aging Study. Am. J. Epidemiol., 144, 749–759
P 379-468 DEF.qxp 09/08/2006 13:53 Page 414
Hu, H., Rabinowitz, M. & Smith, D. (1998) Bone lead as a biological marker in epidemiologic
studies of chronic toxicity: Conceptual paradigms. Environ. Health Perspect., 106, 1–8
Hu, H., Wu, M.-T., Cheng, Y., Sparrow, D., Weiss, S. & Kelsey, K. (2001) The δ-aminolevulinic
acid dehydratase (ALAD) polymorphism and bone and blood lead levels in community-
exposed men: The Normative Aging Study. Environ. Health Perspect., 109, 827–832
Hu, J., Johnson, K.C., Mao, Y., Guo, L., Zhao, X., Jia, X., Bi, D., Huang, G. & Liu, R. (1998) Risk
factors for glioma in adults: A case–control study in northeast China. Cancer Detect. Prev., 22,
100–108
Hu, J., Little, J., Xu, T., Zhao, X., Guo, L., Jia, X., Huang, G., Bi, D. & Liu, R. (1999) Risk factors
for meningioma in adults: A case–control study in northeast China. Int. J. Cancer, 83, 299–304
Huang, J.W. & Cunningham, S.D. (1996) Lead phytoextraction: Species variation in lead uptake
and translocation. New Phytol., 134, 75–84
Huang, J.X., He, F.S., Wu, Y.G. & Zhang, S.C. (1988) Observations on renal function in workers
exposed to lead. Sci. total Environ., 71, 535–537
Huang, X.-P., Feng, Z.-Y., Zhai, W.-L. & Xu, J.-H. (1988) Chromosomal aberrations and sister
chromatid exchanges in workers exposed to lead. Biomed. environ. Sci., 1, 382–387
Huang, J.W., Chen, J., Berti, W.R. & Cunningham, S.D. (1997) Phytoremediation of lead-conta-
minated soils: Role of synthetic chelates in lead phytoextraction. Environ. Sci. Technol., 31,
800–805
Hueper, W.C. (1961) Environmental carcinogenesis and cancers. Cancer Res., 21, 842–857
Huguet, J.M., Braun, J.P., Burgat-Sacaze, V., Bernard, P. & Rico, A.G. (1982) Acute kidney distur-
bances by lead acetate in the rat. Toxicol. Lett., 10, 395–398
Hunaiti, A., Soud, M. & Khalil, A. (1995) Lead concentration and the level of glutathione, gluta-
thione S-transferase, reductase and peroxidase in the blood of some occupational workers from
Irbid City, Jordan. Sci. total Environ., 170, 95–100
Hunter, D. (1978) The ancient metals. In: The Diseases of Occupations, 6th Ed., London, Hodder
& Stroughton
Hursh, J.B. (1973) Retention of 210Pb in beagle dogs. Health Phys., 25, 29–35
Hursh, J.B. & Suomela, J. (1968) Absorption of 212Pb from the gastrointestinal tract of man. Acta
radiol. ther. phys. biol., 7, 108–120
Huseman, C.A., Varma, M.M. & Angle, C.R. (1992) Neuroendocrine effects of toxic and low blood
lead levels in children. Pediatrics, 90, 186–189
Hussain, T., Khan, I.H. & Ali Khan, M. (1990) Study of environmental pollutants in and around
the city of Lahore. I. Determination of lead in blood of various population groups. Sci. total
Environ., 99, 137–143
Hwang, Y.-H., Chao, K.-Y., Chang, C.-W., Hsiao, F.-T., Chang, H.-L. & Han, H.-Z. (2000) Lip lead
as an alternative measure for lead exposure assessment of lead battery assembly workers. Am.
ind. Hyg. Assoc. J., 61, 825–831
Hwang, K.-Y., Schwartz, B.-S., Lee, B.-K., Strickland, P.T., Todd, A.C. & Bressler, J.P. (2001) Asso-
ciations of lead exposure and dose measures with erythrocyte protein kinase C activity in 212
current Korean lead workers. Toxicol. Sci., 62, 280–288
Hwua, Y.-S. & Yang, J.-L. (1998) Effect of 3-aminotriazole on anchorage independence and muta-
genicity in cadmium- and lead-treated diploid human fibroblasts. Carcinogenesis, 19, 881–888
Hytten, F. (1985) Blood volume changes in normal pregnancy. Clin. Haematol., 14, 601–612
P 379-468 DEF.qxp 09/08/2006 13:53 Page 415
IAEA (1987) Co-ordinated research programme on human daily dietary intakes of nutritionally
important trace elements as measured by nuclear and other techniques. IAEA Newl., 2, 6–15
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
IARC (1973) IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man,
Vol. 2, Some Inorganic and Organometallic Compounds, Lyon
IARC (1976) IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man,
Vol. 12, Some Carbamates, Thiocarbamates and Carbazides, Lyon
IARC (1980) IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to
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 (1989) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 46,
Diesel and Gasoline Engine Exhausts and Some Nitroarenes, Lyon, pp. 153
IARC (1990) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 49,
Chromium, Nickel and Welding, Lyon
IARC (1994) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 58,
Beryllium, Cadmium, Mercury, and Exposures in the Glass Manufacturing Industry, Lyon,
pp. 371
IARC (1999) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 74,
Surgical Implants and Other Foreign Bodies, Lyon
IARC (2004a) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 83,
Tobacco Smoke and Involuntary Smoking, Lyon
IARC (2004b) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 84,
Some Drinking-water Disinfectants and Contaminants, including Arsenic, Lyon
Iavicoli, I., Sgambato, A., Carelli, G., Ardito, R., Cittadini, A. & Castellino, N. (2001) Lead-related
effects on rat fibroblasts. Mol. cell. Biochem., 222, 35–40
Iavicoli, I., Carelli, G., Stanek, E.J. III, Castellino, N. & Calabrese, E.J. (2003) Effects of low doses
of dietary lead on red blood cell production in male and female mice. Toxicol. Lett., 137,
193–199
Ikeda, M., Zhang, Z.W., Shimbo, S., Watanabe, T., Nakatsuka, H., Moon, C.-S., Matsuda-Inoguchi,
N. & Higashikawa, K. (2000a) Exposure of women in general populations to lead via food and
air in East and Southeast Asia. Am. J. intern. Med., 38, 271–280
Ikeda, M., Zhang, Z.-W., Shimbo, S., Watanabe, T., Nakatsuka, H., Moon, C.-S., Matsuda-
Inoguchi, N. & Higashikawa, K. (2000b) Urban population exposure to lead and cadmium in
East and South-East Asia. Sci. total Environ., 249, 373–384
Industrias Deriplom SA (2003) Our Products: Pure Lead and Alloys; Lead Oxides; Lead Shot
Pellets; Lead Sheets, Buenos Aires
Inskip, M.J., Franklin, C.A., Baccanale, C.L., Manton, W.I., O’Flaherty, E.J., Edwards, C.M.H.,
Blenkinsop, J.B. & Edwards, E.B. (1996) Measurement of the flux of lead from bone to blood
in a nonhuman primate (Macaca fascicularis) by sequential administration of stable lead iso-
topes. Fundam. appl. Toxicol., 33, 235–245
P 379-468 DEF.qxp 09/08/2006 13:53 Page 416
International Lead and Zinc Study Group (1990) Lead and Zinc Statistics — 1960–1988, London,
pp. 9–56
International Lead and Zinc Study Group (1992) Principal Uses of Lead and Zinc, 1960–1990,
London, pp. 32–51, 63–86
International Lead and Zinc Study Group (2000) Environmental and Health Controls on Lead,
London
International Lead and Zinc Study Group (2003) Principal Uses of Lead and Zinc, London, pp. 5, 7
International Lead and Zinc Study Group (2004) Interactive Statistical Database, London
[http://www.ilzsg.org; accessed 03/02/2004]
International Lead Management Center (ILMC) (1999) Lead in Gasoline Phase-Out Report Card,
Washington DC [http://www.ilmc.org; accessed 10/02/2004]
IOMC (1998) Lead exposure and human health. In: Global Opportunities for Reducing the Use of
Leaded Gasoline, United Nations, Inter-organization Programme for the sound Management
of Chemicals, pp. 7–16
Ishida, M., Ishizaki, M. & Yamada, Y. (1996) Decreases in postural change of finger blood flow in
ceramic painters chronically exposed to low level lead. Am. J. ind. Med., 29, 547–553
Israili, A.W. (1991) Occurrence of heavy metals in Ganga river water and sediments of western
Uttar Pradesh. Pollut. Res., 10, 103–109
Israili, A.W. & Khurshid, S. (1991) Distribution of heavy metals in Yamuna river water and sedi-
ments from Delhi to Allahabad. Poll. Res., 10, 215–222
Ito, N. (1973) Experimental studies on tumors of the urinary system of rats induced by chemical
carcinogens. Acta pathol. Jpn, 23, 87–109
Ito, N., Hiasa, Y., Kamamoto, Y., Makiura, S., Sugihara, S. & Marugami, M. (1971) Histopatho-
logical analysis of kidney tumors in rats induced by chemical carcinogens. Gann, 62, 435–444
Ivanova-Cemišanska, L., Antov, G., Hinkova, L., Valceva, V. & Hristeva, V. (1980) Lead acetate
effect upon reproduction in male Albino rats. Hig. Zdraveopazvane, 23, 304–308
Jacobson, J.L. & Snowdon, C.T. (1976) Increased lead ingestion in calcium-deficient monkeys.
Nature, 262, 51–52
Jacquet, P. & Tachon, P. (1981) Effects of long-term lead exposure on monkey leucocyte chromo-
somes. Toxicol. Lett., 8, 165–169
Jacquet, P., Léonard, A. & Gerber, G.B. (1977) Cytogenetic investigations on mice treated with
lead. J. Toxicol. Environ. Health, 2, 619–624
Jaffe, E.K., Bagla, S. & Michini, P.A. (1991) Reevaluation of a sensitive indicator of early lead expo-
sure. Measurement of porphobilinogen synthase in blood. Biol. trace Elem. Res., 28, 223–231
Jaffe, E.K., Volin, M., Bronson-Mullins, C.R., Dunbrack, R.L., Jr, Kervinen, J., Martins, J.,
Quinlan, J.F., Jr, Sazinsky, M.H., Steinhouse, E.M. & Yeung, A.T. (2000) An artificial gene for
human porphobilinogen synthetase allows comparison of an allelic variation implicated in
susceptibility to lead poisoning. J. biol. Chem., 275, 2619–2626
Jaffe, E.K., Martins, J., Li, J., Kervinen, J. & Dunbrack, R.L., Jr (2001) The molecular mechanism
of lead inhibition of human porphobilinogen synthase. J. biol. Chem., 276, 1531–1537
Jagetia, G.C. & Aruna, R. (1998) Effect of various concentrations of lead nitrate on the induction
of micronuclei in mouse bone marrow. Mutat. Res., 415, 131–137
James, H.M., Hilburn, M.E. & Blair, J.A. (1985) Effects of meals and meal times on uptake of lead
from the gastrointestinal tract in humans. Hum. Toxicol., 4, 401–407
P 379-468 DEF.qxp 09/08/2006 13:53 Page 417
Janakiraman, V., Ettinger, A., Mercado-Garcia, A., Hu, H. & Hernandez-Avila, M. (2003) Calcium
supplements and bone resorption in pregnancy. A randomized crossover trial. Am. J. prev.
Med., 24, 260–264
Janin, Y., Couinaud, C., Stone, A. & Wise, L. (1985) The ‘lead-induced colic’ syndrome in lead
intoxication. Surg. Annu., 17, 287–307
Jaremin, B. (1990) Immunological humoral responsiveness in men occupationally exposed to lead.
Bull. Inst. marit. trop. Med. Gdynia, 41, 27–36
Jasmin, G. & Riopelle, J.L. (1976) Renal carcinomas and erythrocytosis in rats following intrarenal
injection of nickel subsulfide. Lab. Invest., 35, 71–78
Jason, K.M. & Kellog, C.K. (1981) Neonatal lead exposure: Effects of development of behavior
and striatal dopamine neurons. Pharmacol. Biochem. Behav., 15, 641–649
JECFA (2002) Summary of Evaluations Performed by the Joint FAO/WHO Expert Committee on
Food Additives, Geneva, International Programme on Chemical Safety, World Health
Organization
Jemal, A., Graubard, B.I., Devesa, S.S. & Flegal, KM. (2002) The association of blood lead level and
cancer mortality among whites in the United States. Environ. Health Perspect., 110, 325–329
Jeyaratnam, J., Devathasan, G., Ong, C.N., Phoon, W.O. & Wong, P.K. (1985) Neurophysiological
studies on workers exposed to lead. Br. J. ind. Med., 42, 173–177
Jiang, X., Liang, Y. & Wang, Y. (1992) Studies of lead exposure on reproductive system: A review
of work in China. Biomed. environ. Sci., 5, 266–275
Jin, Y.-P., Kobayashi, E., Okubo, Y., Suwazono, Y., Nogawa, K. & Nakagawa, H. (2000) Changes
of lead levels in 24-h urine from 1985 to 1998 in Japanese adults. Toxicol. Lett., 114, 91–99
Johansson, L. (1989) Premature acrosome reaction in spermatozoa from lead-exposed mice. Toxi-
cology, 54, 151–162
Joffe, M., Bisanti, L., Apostoli, P., Kiss, P., Dale, A., Roeleveld, N., Lindbohm, M.-L., Sallmén,
M., Vanhoorne, M. & Bonde, J.P. & the ASCLEPIOS Study Group (2003) Time to pregnancy
and occupational lead exposure. Occup. environ. Med., 60, 752–758
Jorhem, L., Mattsson, P. & Slorach, S. (1988) Lead in table wines on the Swedish market. Food
addit. Contam., 5, 645–649
Jowsey, J., Kelly, P.J., Riggs, B.L., Bianco, A.J., Jr, Scholz, D.A. & Gershon-Cohen, J. (1965)
Quantitative microradiographic studies of normal and osteoporotic bone. J. Bone Joint Surg.,
47A, 785–806
Kachru, D.N., Tandon, S.K., Misra, U.K. & Nag, D. (1989) Occupational lead poisoning among
silver jewellery workers. Indian J. med. Sci., 43, 89–91
Kaiser, R., Henderson, H.A.K., Daley, W.R., Naughton, M., Khan, M.H., Rahman, M., Kieszak, S.
& Rubin, C.H. (2001) Blood lead levels of primary school children in Dhaka, Bangladesh.
Environ. Health Perspect., 109, 563–566
Kákosy, T., Hudák, A. & Náray, M. (1996) Lead intoxication epidemic caused by ingestion of
contaminated ground paprika. Clin. Toxicol., 34, 507–511
Kalra, V., Chitralekha, K.T., Dua, T., Pandey, R.M. & Gupta, Y. (2003) Blood lead levels and risk
factors for lead toxicity in children from schools and an urban slum in Delhi. J. trop. Pediatr.,
49, 121–123
Kamal, A.-A., Eldamaty, S.E. & Faris, R. (1991) Blood lead level of Cairo traffic policemen. Sci.
tot. Environ., 105, 165–170
P 379-468 DEF.qxp 09/08/2006 13:53 Page 418
Kamaraj, S., Muthuvel, P., Dhakshinamoorthy, M. & Singh, M.V. (2003) Heavy metal accumu-
lation in a swell-shrink soil environment as influenced by long term fertilization. In: Singh,
V.P. & Yadava, R.N., eds, Environmental Pollution: Water and Environment, New Delhi,
Allied Publishers, pp. 236–242
Kampe, W. (1983) [Lead and cadmium in food — A current danger?] Forum Städte-Hyg., 34,
236–241 (in German)
Kandiloros, D.C., Goletsos, G.A., Nikolopoulos, T.P., Ferekidis, E.A., Tsomis, A.S. & Adamopoulos,
G.K. (1997) Effect of subclinical lead intoxication on laryngeal cancer. Br. J. clin. Pract., 51,
69–70
Kang, H.K., Infante, P.F. & Carra, J.S. (1980) Occupational lead exposure and cancer. Science, 207,
935–936
Kanisawa, M. & Schroeder, H. A. (1969) Life term studies on the effect of trace elements on
spontaneous tumors in mice and rats. Cancer Res., 29, 892–895
Kantor, A.F., Curnen, M.G., Meigs, J.W. & Flannery J.T. (1979) Occupations of fathers of patients
with Wilms’s tumour. J. Epidemiol. Community Health, 33, 253–256
Kapaki, E.N., Varelas, P.N., Syrigou, A.I., Spanaki, M.V., Andreadou, E., Kakami, A.E. &
Papageorgiou, C.T. (1998) Blood lead levels of traffic- and gasoline-exposed professionals in
the city of Athens. Arch. environ. Health, 53, 287–291
Kaphalia, B.S., Chandra, H., Bhargava, S.K., Seth, T.D. & Gupta, B.N. (1981) Lead in drinking
water. Indian J. environ. Prot., 1, 92–96
Karita, K., Shinozaki, T., Yano, E. & Amari, N. (2000) Blood lead levels in copper smelter workers
in Japan. Ind. Health, 38, 57–61
Kasprzak, K.S., Hoover, K.L. & Poirier, L.A. (1985) Effects of dietary calcium acetate on lead sub-
acetate carcinogenicity in kidneys of male Sprague-Dawley rats. Carcinogenesis, 6, 279–282
Kastori, R., Plesnicar, M., Sakac, Z., Pankovic, D. & Arsenijevic-Maksimovic, I. (1998) Effect of
excess lead on sunflower growth and photosynthesis. J. Plant Nutr., 21, 75–85
Kaul, B. (1999) Lead exposure and iron deficiency among Jammu and New Delhi children. Indian
J. Pediatr., 66, 27–35
Kaul, P.S. & Kaul, B. (1986) Blood lead and erythrocyte protoporphyrin levels among papier-
mâché workers in Kashmir. Mount Sinai J. Med., 53, 145–148
Kaul, B., Rasmuson, J.O., Olsen, R.L., Chanda, C.R., Slazhneva, T.I., Granovsky, E.L. &
Korchevsky, A.A. (2000) Blood lead and erythrocyte protoporphyrin levels in Kazakhstan.
Indian J. Pediatr., 67, 87–91
Kauppinen, T., Riala, R., Seitsamo, J. & Hernberg, S. (1992) Primary liver cancer and occupational
exposure. Scand. J. Work Environ. Health, 18, 18–25
Kaye, W.E., Novotny, T.E. & Tucker, M. (1987) New ceramics-related industry implicated in ele-
vated blood lead levels in children. Arch. environ. Health, 42, 161–164
KCM SA (2003) Product Data Sheet: Lead, Plovdiv
Kehoe, R.A. (1987) Studies of lead administration and elimination in adult volunteers under natural
and experimentally induced conditions over extended periods of time. Food chem. Toxicol., 25,
421–493
Kelada, S.N., Shelton, E., Kaufmann, R.B. & Khoury, M.J. (2001) δ-aminolevulinic acid dehydra-
tase genotype and lead toxicity: A HuGE review. Am. J. Epidemiol., 154, 1–13
Keller, C.A. & Doherty, R.A. (1980a) Lead and calcium distributions in blood, plasma and milk of
the lactating mouse. J. Lab. clin. Med., 95, 81–89
P 379-468 DEF.qxp 09/08/2006 13:53 Page 419
Keller, C.A. & Doherty, R.A. (1980b) Distribution and excretion of lead in young and adult female
mice. Environ. Res., 21, 217–228
Kello, D. & Kostial, K. (1973) The effect of milk diet on lead metabolism in rats. Environ. Res.,
6, 355–360
Kemper, A.R., Bordley, W.C. & Downs, S.M. (1998) Cost-effectiveness analysis of lead poisoning
screening strategies following the 1997 guidelines of the Centers for Disease Control and Pre-
vention. Arch. pediatr. adoles. Med., 152, 1202–1208
Kerr, M.A., Nasca, P.C., Mundt, K.A., Michalek, A.M., Baptiste, M.S. & Mahoney, M.C. (2000)
Parental occupational exposures and risk of neuroblastoma: A case–control study (United
States). Cancer Causes Control, 11, 635–643
Kessler, M., Durand, P.Y., Huu, T.C., Royer-Morot, M.J., Chanliau, J., Netter, P. and Duc, M.
(1999) Mobilization of lead from bone in end-stage renal failure patients with secondary
hyperparathyroidism. Nephrol. Dial. Transplant., 14, 2731–2733
Khalil-Manesh, F., Gonick, H.C., Cohen, A.H., Alinovi, R., Bergamaschi, E., Mutti, A. & Rosen,
V.J. (1992a) Experimental model of lead nephropathy. I. Continuous high-dose lead adminis-
tration. Kidney int., 41, 1192–1203
Khalil-Manesh, F., Gonick, H.C., Cohen, A., Bergamaschi, E. & Mutti, A. (1992b) Experimental
model of lead nephropathy. II. Effect of removal from lead exposure and chelation treatment
with dimercaptosuccinic acid (DMSA). Environ. Res., 58, 35–54
Khalil-Manesh, F., Tartaglia-Erler, J. & Gonick, H.C. (1994) Experimental model of lead nephro-
pathy. IV. Correlation between renal functional changes and hematological indices of lead
toxicity. J. trace Elem. Electrolytes Health Dis., 8, 13–19
Khan, M.H., Khan, I., Shah, S.H. & Rashid, Q. (1995) Lead poisoning — A hazard of traffic and
industries in Pakistan. J. environ. Pathol. Toxicol. Oncol., 14, 117–120
Khandekar, R.N., Mishra, U.C. & Vohra, K.G. (1984) Environmental lead exposure of an urban
Indian population. Sci. total Environ., 40, 269–278
Kharab, P. & Singh, I. (1985) Genotoxic effects of potassium dichromate, sodium arsenite, cobalt
chloride and lead nitrate in diploid yeast. Mutat. Res., 155, 117–120
Kiefer, M., Trout, D. & Wallace, M.E. (1998) Health Hazard Evaluation Report, HETA 97-0260-
2716, Avondale Shipyards, Avondale, LA, USA, NIOSH
Kies, C & Ip, S.W. (1991) Lead bioavailability to humans from diets containing constant amounts
of lead: Impact of supplemental copper, zinc and iron. In: Hemphill, D.H.C. & Cothern, C.R.,
eds, Trace Substances in Environmental Health, Vol. XXIV, University of Missouri, Columbia,
pp. 177–184
Kim, Y., Harada, K., Ohmori, S., Lee, B.K., Miura, H. & Ueda, A. (1995a) Evaluation of lead expo-
sure in workers at a lead-acid battery factory in Korea: With focus on activity of erythrocyte
pyrimidine 5′-nucleotidase (P5N). Occup. environ. Med., 52, 484–488
Kim, R., Aro, A., Rotnitzky, A., Amarasiriwardena, C. & Hu, H. (1995b) K X-ray fluorescence
measurements of bone lead concentration: The analysis of low-level data. Phys. med. Biol., 40,
1475–1485
Kim, R., Hu, H., Rotnitzky, A., Bellinger, D. & Needleman, H. (1996a) Longitudinal relationship
between dentin lead levels in childhood and bone lead levels in young adulthood. Arch.
environ. Health, 51, 375–382
P 379-468 DEF.qxp 09/08/2006 13:53 Page 420
Kim, R., Rotnitsky, A., Sparrow, D., Weiss, S.T., Wager, C. & Hu, H. (1996b) A longitudinal study
of low-level lead exposure and impairment of renal function. The Normative Aging Study. J.
Am. med. Assoc., 275, 1177–1181
Kim, Y., Lee, H., Lee, C.R., Park, D.U., Yang, J.S., Park, I.J., Lee, K.Y., Lee, M.Y., Kim, T.-K.,
Sohn, N.-S., Cho, Y.S., Lee, N.R. & Chung, H.K. (2002) Evaluation of lead exposure in
workers at secondary lead smelters in South Korea: With focus on activity of erythrocyte pyri-
midine 5′-nucleotidase (P5N). Sci. total Environ., 286, 181–189
Kimmel, E.C., Fish, R.H., & Casida, J.E. (1977) Bioorganotin chemistry: Metabolism of organotin
compounds in microsomal monoxygenase systems and in mammals. J. agric. Food Chem., 25,
1–9
Kinnes, G.M. & Hammel, R.R. (1990) Health Hazard Evaluation Report, HETA 88-0357-2042,
A.W. Cash Valve Manufacturing Corp., Decatur, IL, USA, NIOSH
Kirkby, H. & Gyntelberg, F. (1985) Blood pressure and other cardiovascular risk factors of long-
term exposure to lead. Scand. J. Work Environ. Health, 11, 15–19
Klaassen, C.D. & Shoeman, D.W. (1974) Biliary excretion of lead in rats, rabbits, and dogs.
Toxicol. appl. Pharmacol., 29, 434–446
Klein, M., Namer, R., Harpur, E. & Corbin, R. (1970) Earthenware containers as a source of fatal
lead poisoning. New Engl. J. Med., 283, 669–672
Knowles, S.O. & Donaldson, W.E. (1997) Lead disrupts eicosanoid metabolism, macrophage
function, and disease resistance in birds. Biol. trace Elem. Res., 60, 13–26
Kobayashi, N. & Okamoto, T. (1974) Effects of lead oxide on the induction of lung tumors in
Syrian hamsters. J. natl Cancer Inst., 52, 1605–1610
Koh, D., Ng, V., Chua, L.H., Yang, Y., Ong, H.Y. & Chia, S.E. (2003) Can salivary lead be used
for biological monitoring of lead exposed individuals? Occup. environ. Med., 60, 696–698
Kohler, K., Lilienthal, H., Guenther, E., Winneke, G. & Zrenner, E. (1997) Persistent decrease of
the dopamine-synthesizing enzyme tyrosine hydroxylase in the rhesus monkey retina after
chronic lead exposure. NeuroToxicology, 18, 623–632
Koller, L.D. & Brauner, J.A. (1977) Decreased B-lymphocyte response after exposure to lead and
cadmium. Toxicol. appl. Pharmacol., 42, 621–624
Koller, L.D. & Kovacic, S. (1974) Decreased antibody formation in mice exposed to lead. Nature,
250, 148–150
Koller, L.D., Roan, J.G. & Isaacson Kerkvliet, N. (1979) Mitogen stimulation of lymphocytes in
CBA mice exposed to lead and cadmium. Environ. Res., 19, 177–188
Koller, L.D., Kerkvliet, N.I. & Exon, J.H. (1985) Neoplasia induced in male rats fed lead acetate,
ethyl urea, and sodium nitrite. Toxicol. Pathol., 13, 50–57
Kopito, L., Byers, R.K. & Shwachman, H. (1967) Lead in hair of children with chronic lead poiso-
ning. New Engl. J. Med., 276, 949–953
Korea Zinc Co. (2003) Product Data Sheet: Lead, Seoul
Korrick, S.A., Hunter, D.J., Rotniszky, A., Hu, H. & Speizer, F.E. (1999) Lead and hypertension in
a sample of middle-aged women. Am. J. pub. Health, 89, 330–335
Korrick, S.A., Schwartz, J., Tsaih, S.-W., Hunter, D.J., Aro, A., Rosner, B., Speizer, F.E. & Hu, H.
(2002) Correlates of bone and blood lead levels among middle-aged and elderly women. Am.
J. Epidemiol., 156, 335–343
P 379-468 DEF.qxp 09/08/2006 13:53 Page 421
Kosnett, M.J., Becker, C.E., Osterloh, J.D., Kelly, T.J. & Pasta, D.J. (1994) Factors influencing
bone lead concentration in a suburban community assessed by noninvasive K X-ray fluores-
cence. J. Am. med. Assoc., 271, 197–203
Kostial, K. & Kello, D. (1979) Bioavailability of lead in rats fed ‘human’ diets. Bull. environ.
Contam. Toxicol., 21, 312–314
Kostial, K. & Momcilovic, B. (1972) The effect of lactation on the absorption of 203Pb and 47Ca in
rats. Health Phys., 23, 383
Kostial, K. & Momcilovic, B. (1974) Transport of lead 203 and calcium 47 from mother to off-
spring. Arch. environ. Health, 29, 28–30
Kostial, K., Kello, D., Jugo, S., Rabar, I. & Maljkovic, T. (1978) Influence of age on metal meta-
bolism and toxicity. Environ. Health Perspect., 25, 81–86
Kotok, D. (1972) Development of children with elevated blood lead levels: A controlled study.
J. Pediatr., 80, 57–61
Kovar, I.Z., Strehlow, C.D., Richmond, J. & Thompson, M.G. (1984) Perinatal lead and cadmium
burden in a British urban population. Arch. Dis. Child, 59, 36–39
Kozarzewska, Z. & Chmielnicka, J. (1987) Dynamics of diethyllead excretion in the urine of
rabbits after tetraethyllead administration. Br. J. ind. Med., 44, 417–421
Kristensen, P. & Andersen, A. (1992) A cohort study on cancer incidence in offspring of male
printing workers. Epidemiology, 3, 6–10
Kristensen, P., Eilertsen, E., Einarsdóttir, E., Øvrebø, S. & Haugen, A. (1993) Effect modification
by inorganic lead in the dominant lethal assay. Mutat. Res., 302, 33–38
Kroes, R., van Logten, M.J., Berkvens, J.M., de Vries, T. & van Esch, G.J. (1974) Study on the
carcinogenicity of lead arsenate and sodium arsenate and on the possible synergistic effect of
diethylnitrosamine. Food Cosmet. Toxicol., 12, 671–679
Krueger, J.A. & Duguay, K.M. (1989) Comparative analysis of lead in Maine urban soils. Bull.
environ. Contam. Toxicol., 42, 574–581
Krugner-Higby, L.A., Gendron, A., Laughlin, N.K., Luck, M., Scheffler, J. & Phillips, B. (2001)
Chronic myelocytic leukemia in a juvenile rhesus macaque (Macaca mulatta). Contemp. top.
Lab. Anim. Sci., 40, 44–48
Ku, Y., Alvarez, G.H. & Mahaffey, K.R. (1978) Comparative effects of feeding lead acetate and
phospholipid-bound lead on blood and tissue lead concentrations in young and adult rats. Bull.
environ. Contam. Toxicol., 20, 561–567
Kumar, B.D. & Krishnaswamy, K. (1995a) Detection of sub-clinical lead toxicity in monocasters.
Bull. environ. Contam. Toxicol., 54, 863–869
Kumar, B.D. & Krishnaswamy, K. (1995b) Detection of occupational lead nephropathy using early
renal markers. Clin. Toxicol., 33, 331–335
Kumar, R.K. & Kesaree, N. (1999) Blood lead levels in urban and rural Indian children. Indian
Pediatr., 36, 303–306
Kurasaki, M., Hartoto, D.I., Saito. T., Suzuki-Kurasaki, M. & Iwakuma, T. (2000) Metals in water
in the central Kalimantan, Indonesia. Bull. environ. Contam. Toxicol., 65, 591–597
Labbé, R.F., Vreman, H.J. & Stevenson, D.K. (1999) Zinc protoporphyrin: A metabolite with a
mission. Clin. Chem., 45, 2060–2072
Lagerkvist, B.J., Sandberg, S., Frech, W., Jin, T. & Nordberg, G.F. (1996a) Is placenta a good indi-
cator of cadmium and lead exposure? Arch. environ. Health, 51, 389–394
P 379-468 DEF.qxp 09/08/2006 13:53 Page 422
Lagerkvist, B.J., Ekesrydh, S., Englyst, V., Nordberg, G.F., Söderberg, H.-A. & Wiklund, D.-E.
(1996b) Increased blood lead and decreased calcium levels during pregnancy: A prospective
study of Swedish women living near a smelter. Am. J. public Health, 86, 1247–1252
LaGoy, P.K. (1987) Estimated soil ingestion rates for use in risk assessment. Risk Anal., 7, 355–359
Lai, C.S. (1972) Lead poisoning as an occupational hazard in Chinese opera actors — A case
report. Singap. Med. J., 13, 115–117
Lai, J.S., Wu, T.N., Liou, S.H., Shen, C.Y., Guu, C.F., Ko, K.N., Chi, H.Y. & Chang, P.Y. (1997)
A study of the relationship between ambient lead and blood lead among lead battery workers.
Int. Arch. occup. environ. Health, 69, 295–300
Lal, B., Murthy, R.C., Anand, M., Chandra, S.V., Kumar, R., Tripathi, O. & Srimal, R.C. (1991)
Cardiotoxicity and hypertension in rats after oral lead exposure. Drug chem. Toxicol., 14,
305–318
Lalor, G., Rattray, R., Vutchkov, M., Campbell, B. & Lewis-Bell, K. (2001) Blood lead levels in
Jamaican school children. Sci. total Environ., 269, 171–181
Lamola, A.A. & Yamane, T. (1974) Zinc protoporphyrin in the erythrocytes of patients with lead
intoxication and iron deficiency anemia. Science, 186, 936–938
Lancranjan, I., Popescu, H.I., Gavanescu, O., Klepsch, I. & Serbanescu, M. (1975) Reproductive
ability of workmen occupationally exposed lo lead. Arch. environ. Health, 30, 396–401
Landrigan, P.J. & Straub, W.E. (1985) Health Hazard Evaluation Report, HETA 85-0132-1598,
Mystic Seaport, Mystic, CT, USA, NIOSH
Landrigan, P.J., Gehlbach, S.H., Rosenblum, B.F., Shoults, J.M., Candelaria, R.M., Barthel, W.F.,
Liddle, J.A., Smrek, A.L., Staehling, N.W. & Sanders, J.F. (1975a) Epidemic lead absorption
near an ore smelter — The role of particulate lead. N. Engl. J. Med., 292, 123–129
Landrigan, P.J., McKinney, A.S., Hopkins, L.C., Rhodes, W.W., Jr, Price, W.A. & Cox, D.H.
(1975b) Chronic lead absorption: Result of poor ventilation in an indoor pistol range. JAMA,
234, 394–397
Landrigan, P.J., Baloh, R.W., Barthel, W.F., Whitworth, R.H., Staehling, N.W. & Rosenblum, B.F.
(1975c) Neuropsychological dysfunction in children with chronic low-level lead absorption.
Lancet, i, 708–712
Landrigan, P.J., Straub, W., McManus, K., Stein, G.F., Baker, E.L. & Himmelstein, J.S. (1980)
Technical Assistance Report, TA 80-099-859, Tobin-Mystic River Bridge, Boston, MA, USA,
NIOSH
Landrigan, P.J., Albrecht, W.N., Watanabe, A. & Lee, S. (1982) Health Hazard Evaluation Report,
HETA 80-0116-1034, Ferro Corp., Cleveland, OH, USA, NIOSH
Lang, D.S., Meier, K.L. & Luster, M.I. (1993) Comparative effects of immunotoxic chemicals on
in vitro proliferative responses of human and rodent lymphocytes. Fundam. appl. Toxicol., 21,
535–545
Langlois, P., Smith, L., Fleming, S., Gould, R., Goel, V. & Gibson, B. (1996) Blood lead levels in
Toronto children and abatement of lead-contaminated soil and house dust. Arch. environ. Health,
51, 59–67
Lanphear, B.P., Matte, T.D., Rogers, J., Clickner, R.P., Dietz, B., Bornschein, R.L., Succop, P.,
Mahaffey, K.R., Dixon, S., Galke, W., Rabinowitz, M., Farfel, M., Rohde, C., Schwartz, J.,
Ashley, P. & Jacobs, D.E. (1998) The contribution of lead-contaminated house dust and resi-
dential soil to children’s blood lead levels — A pooled analysis of 12 epidemiologic studies.
Environ. Res., 79, 51–68
P 379-468 DEF.qxp 09/08/2006 13:53 Page 423
Lanphear, B.P., Eberly, S. & Howard, C.R. (2000a) Long-term effect of dust control on blood lead
concentrations. Pediatrics, 106, 48–51
Lanphear, B.P., Dietrich, K., Auinger, P. & Cox, C. (2000b) Cognitive deficits associated with
blood lead concentrations < 10 microg/dL in US children and adolescents. Public Health Rep.,
115, 521–529
Lanphear, B.P., Hornung, R., Ho, M., Howard, C.R., Eberle, S. & Knauf, K. (2002) Environmental
lead exposure during early childhood. J. Pediatr., 140, 40–47
Lansdown, R.G., Sheperd, J., Clayton, B.E., Delves, H.T., Graham P.J. & Turner, W.C. (1974)
Blood lead levels, behaviour and intelligence: A population study. Lancet, i, 538–541
Lansdown, R., Yule, W., Urbanowicz, M.-A. & Hunter, J. (1986) The relationship between blood-
lead concentrations, intelligence, attainment and behaviour in a school population: The second
London study. Int. Arch. occup. environ. Health, 57, 225–235
Larsen, S.B., Abell, A. & Bonde, J.P. (1998) Selection bias in occupational sperm studies. Am. J.
Epidemiol., 147, 681–685
Larson, J.K., Buchan, R.M., Blehm, K.D. & Smith, C.W. (1989) Characterization of lead fume
exposure during gas metal arc welding on carbon steel. Appl. ind. Hyg., 4, 330–333
Larsson, B., Slorach, S.A., Hagman, U. & Hofvander, Y. (1981) WHO collaborative breast feeding
study. II. Levels of lead and cadmium in Swedish human milk, 1978–1979. Acta paediatr.
scand., 70, 281–284
Lasheen, M.R. (1987) The distribution of trace metals in Aswan High Dam Reservoir and River
Nile ecosystems. In: Hutchinson, T.C. & Meema, K.M., eds, Lead, Mercury, Cadmium and
Arsenic in the Environment, New York, Wiley, pp. 235–253
Laurier, C., Tatematsu, M., Rao, P.M., Rajalakshmi, S. & Sarma, D.S.R. (1984) Promotion by
orotic acid of liver carcinogenesis in rats initiated by 1,2-dimethylhydrazine. Cancer Res., 44,
2186–2191
Lauwerys, R.R., Buchet, J.-P. & Roels, H.A. (1973) Comparative study of effect of inorganic lead
and cadmium on blood δ-aminolevulinate dehydratase in man. Br. J. ind. Med., 30, 359–364
Lauwerys, R.R., Bernard, A., Roels, H. & Buchet, J.P. (1995) Health risk assessment of long-term
exposure to non-genotoxic chemicals: Application of biological indices. Toxicol. Lett., 77, 39–44
Lead Development Association International (2003a) Technical Note: Primary Extraction of Lead,
London [www.ldaint.org/default.htm; accessed 01/02/2004]
Lead Development Association International (2003b) Lead Information, London
[www.ldaint.org/default.htm; accessed 01/02/2004]
Lead Development Association International (2003c) Technical Note: Primary Lead Refining,
London [www.ldaint.org/default.htm; accessed 01/02/2004]
Lead Development Association International (2003d) Technical Note: Secondary lead production,
London [www.ldaint.org/default.htm; accessed 01/02/2004]
Lead Development Association International (2003e) Technical Note: Lead Products and Their
Uses, London [www.ldaint.org/default.htm; accessed 01/02/2004]
Leal, R.B., Cordova, F.M., Herd, L., Bobrovskaya, L. & Dunkley, P.R. (2002) Lead-stimulated
p38MAPK-dependent Hsp27 phosphorylation. Toxicol. appl. Pharmacol., 178, 44–51
Leal-Garza, C., Montes de Oca, R., Cerda-Flores, R.M., Garcia-Martinez, E. & Garza-Chapa, R.
(1986) Frequency of sister chromatid exchange (SCE) in lead exposed workers. Arch. invest.
Med., 17, 267–276
P 379-468 DEF.qxp 09/08/2006 13:53 Page 424
Ledda-Columbano, G.M., Coni, P., Curto, M., Giacomini, L., Faa, G., Sarma, D.S.R. & Columbano,
A. (1992) Mitogen-induced liver hyperplasia does not substitute for compensatory regeneration
during promotion of chemical hepatocarcinogenesis. Carcinogenesis, 13, 379–383
Lee, S.A. (1987) Health Hazard Evaluation Report, HETA 87-0262-1852, Artistic Awards, Colorado
Springs, CO, USA, NIOSH
Lee, S.A. (1991) Health Hazard Evaluation Report, HETA 91-0076-2164, Silver Deer, Boulder,
CO, USA, NIOSH
Lee, B.K. (1999) The role of biological monitoring in the health management of lead-exposed
workers. Toxicol. Lett., 108, 149–160
Lee, S.A. & McCammon, C.S. (1992) Health Hazard Evaluation Report, HETA 91-0161-2225,
Denver Police Dept., Denver, CO, USA, NIOSH
Lee, V.W.K., De Kretser, D.M., Hudson, B. & Wang, C. (1975) Variations in serum FSH, LH, and
testosterone levels in male rats from birth to sexual maturity. J. Reprod. Fertil., 42, 121–126
Lee, R.G., Becker, W.C. & Collins, D.W. (1989) Lead at the tap: Sources and control. J. Am. Water
Works Assoc., 81, 52–62
Lee, S.A., Goldfield, J., Hales, T.R. & Gunter, B.J. (1990a) Health Hazard Evaluation Report,
HETA 89-0052-2006, Alma American Labs, Fairplay, CO, USA, NIOSH
Lee, S.A., Hales, T.R. & Daniels, W.J. (1990b) Health Hazard Evaluation Report, HETA 89-0139-
2025, Tamco, Etiwanda, CA, USA, NIOSH
Lee, D.-S., Lee, Y.-K., Huh, J.-W., Lee, S.-I., Sohn, D.-H. & Kim, M.-G. (1994) [Annual variation
of atmospheric lead concentration in Seoul (1984–1993).] J. Kor. Air Pollut. Res. Assoc., 10,
170–174 (in Korean with English Abstract)
Lee, J.-E., Chen, S., Golemboski, K.A., Parsons, P.J. & Dietert, R.R. (2001) Developmental
windows of differential lead-induced immunotoxicity in chickens. Toxicology, 156, 161–170
Lee, S.-S., Lee, B.-K., Lee, G.-S., Stewart, W.F., Simon, D., Kelsey, K., Todd, A.C. & Schwartz,
B.S. (2001) Associations of lead biomarkers and delta-aminolevulinic acid dehydratase and
vitamin D receptor genotypes with hematopoietic outcomes in Korean lead workers. Scand. J.
Work Environ. Health, 27, 402–411
Lee, C.R., Lee, J.H., Yoo, C.I. & Kim, S.-R. (2002) Trend of blood lead levels in children in an
industrial complex and its suburban area in Ulsan, Korea. Int. Arch. occup. environ. Health,
75, 507–510
Leggett, R.W. (1993) An age-specific kinetic model of lead metabolism in humans. Environ.
Health Perspect., 101, 598–616
Leighton, J., Klitzman, S., Sedlar, S., Matte, T. & Cohen, N.L. (2003) The effect of lead-based
paint hazard remediation on blood lead levels of lead poisoned children in New York City.
Environ. Res., 92, 182–190
Lerda, D. (1992) Study of sperm characteristics in persons occupationally exposed lo lead. Am. J.
ind. Med., 22, 567–571
Leroyer, A., Hemon, D., Nisse, C., Bazerques, J., Salomez, J.L. & Haguenoer, J.M. (2001) Envi-
ronmental exposure to lead in a population of adults living in northern France: Lead burden
levels and their determinants. Sci. total Environ., 267, 87–99
Leung, F.Y., Bradley, C. & Pellar, T.G. (1993) Reference intervals for blood lead and evaluation of
zinc protoporphyrin as a screening test for lead toxicity. Clin. Biochem., 26, 491–496
Levin, L., Zheng, W., Blot, W.J., Yu-tang, G. & Fraumeni, J.F., Jr (1988) Occupation and lung
cancer in Shanghai: A case–control study. Br. J. ind. Med., 45, 450–458
P 379-468 DEF.qxp 09/08/2006 13:53 Page 425
Levy, L.S. & Venitt, S. (1986) Carcinogenicity and mutagenicity of chromium compounds: The
association between bronchial metaplasia and neoplasia. Carcinogenesis, 7, 831–836
Levy, L.S., Martin, P.A. & Bidstrup, P.L. (1986) Investigation of the potential carcinogenicity of a
range of chromium containing materials on rat lung. Br. J. ind. Med., 43, 243–256
Li, P. & Rossman, T.G. (2001) Genes upregulated in lead-resistant glioma cells reveal possible
targets for lead-induced developmental neurotoxicity. Toxicol. Sci., 64, 90–99
Li, W., Han, S., Gregg, T.R., Kemp, F.W., Davidow, A.L., Louria, D.B., Siegel, A. & Bogden, J.D.
(2003) Lead exposure potentiates predatory attack behavior in the cat. Environ. Res., 92,
197–206
Lide, D.R., ed. (2003) CRC Handbook of Chemistry and Physics on CD-ROM, Version 2004, 84th
Ed., Boca Raton, FL, pp. 4-17–4-18; 4-64–4-65
Lidsky, T.I. & Schneider, J.S. (2003) Lead neurotoxicity in children: Basic mechanisms and
clinical correlates. Brain, 126, 5–19
Lilley, S.G., Florence, T.M. & Stauber, J.L. (1988) The use of sweat to monitor lead absorption
through the skin. Sci. total Environ., 76, 267–278
Lin, R.H., Lee, C.H., Chen, W.K. & Lin-Shiau, S.Y. (1994) Studies on cytotoxic and genotoxic
effects of cadmium nitrate and lead nitrate in Chinese hamster ovary cells. Environ. mol.
Mutag., 23, 143–149
Lin, S., Hwang, S.-A., Marshall, E.G. & Marion, D. (1998) Does paternal occupational lead expo-
sure increase the risks of low birth weight or prematurity? Am. J. Epidemiol., 148, 173–181
Lindblad, B., Lindstedt, S. & Steen, G. (1977) On the enzymic defects in hereditary tyrosinemia.
Proc. natl Acad. Sci. USA, 74, 4641–4645
Lindbohm, M.L., Sallmén, M., Anttila, A., Taskinen, H. & Hemminki, K. (1991) Paternal occupa-
tional lead exposure and spontaneous abortion. Scand. J. Work Environ. Health, 17, 95–103
Linden, M.A., Manton, W.I., Stewart, R.M., Thal, E.R. & Feit, H. (1982) Lead poisoning from
retained bullets: Pathogenesis, diagnosis, and management. Ann. Surg., 195, 305–313
Lin-Fu, J.S. (1992) Modern history of lead poisoning: A century of discovery and rediscovery. In:
Needleman, H.L., ed., Human Lead Exposure, Boca Raton, FL, CFRC Press, pp. 23–43
Liou, S.H., Wu, T.N., Chiang, H.C., Yang, T., Yang, G.Y., Wu, Y.Q., Lai, J.S., Ho, S.T., Guo, Y.L.,
Ko, Y.C., Ko, K.N. & Chang, P.Y. (1996) Three-year survey of blood lead levels in 8828
Taiwanese adults. Int. arch. Occup. Environ. Health, 68, 80–87
Little, P., Fleming, R.G. & Heard, M.J. (1981) Uptake of lead by vegetable foodstuffs during
cooking. Sci. total Environ., 17, 111–131
Litvinov, N.N., Voronin, V.M. & Kazachkov, V.I. (1982) [Experimental study of aniline, lead
nitrate and sodium alkylsulfate as modifiers of chemical blastomogenesis] Vopr. Onkol., 28,
56–59 (in Russian)
Litvinov, N.N., Voronin, V.M. & Kazachkov, V.I. (1984) [Characteristics of aniline, lead nitrate,
carbon tetrachloride and formaldehyde as modifiers of chemical carcinogenesis] Vopr. Onkol.,
30, 56–60 (in Russian)
Lloyd, R.D., Mays, C.W., Atherton, D.R. & Bruenger, F.W. (1975) 210Pb studies in beagles. Health
Phys., 28, 575–583
Lockhart Gibson, J., Love, W., Hardie, D., Bancroft, P. & Jefferis Turner, A. (1892) Notes on lead-
poisoning as observed among children in Brisbane. In: Transactions of the Intercolonial
Medical Congress of Australia, Sydney, pp. 78–83
P 379-468 DEF.qxp 09/08/2006 13:53 Page 426
Lockitch, G., Berry, B., Roland, E., Wadsworth, L., Kaikov, Y. & Mirhady, F. (1991) Seizures in a
10-week-old infant: Lead poisoning from an unexpected source. Can. med. Assoc. J., 145,
1465–1468
Löfstedt, H., Seldén, A., Storéus, L. & Bodin, L. (1999) Blood lead in Swedish police officers. Am.
J. Ind. Med., 35, 519–522
Loghman-Adham, M. (1997) Renal effects of environmental and occupational lead exposure: A
review. Environ. Health Perspect., 105, 928–938
Loikkanen, J., Chvalova, K., Naarala, J., Vähäkangas, K.H. & Savolainen, K.M. (2003) Pb2+-
induced toxicity is associated with p53-independent apoptosis and enhanced by glutamate in
GT1-7 neurons. Toxicol. Lett., 144, 235–246
Lokhande, R.S. & Kelkar, N. (1999) Studies on heavy metals in water of Vasai Creek, Maharashtra.
Indian J. environ. Prot., 19, 664–668
Loranger, S. & Zayed, J. (1994) Manganese and lead concentrations in ambient air and emission
rates from unleaded and leaded gasoline between 1981 and 1992 in Canada: A comparative
study. Atmos. Environ., 28, 1645–1651
Lu, H., Guizzetti, M. & Costa, L.G. (2001) Inorganic lead stimulates DNA synthesis in human
astrocytoma cells: Role of protein kinase C alpha. J. Neurochem., 78, 590–599
Lu, H., Guizzetti, M. & Costa, L.G. (2002) Inorganic lead activates the mitogen-activated protein
kinase kinase-mitogen-activated protein kinase-p90(RSK) signaling pathway in human astro-
cytoma cells via a protein kinase C-dependent mechanism. J. Pharmacol. exp. Ther., 300,
818–823
Lubin, J.H., Pottern, L.M., Stone, B.J. & Fraumeni, J.F., Jr (2000) Respiratory cancer in a cohort
of copper smelter workers: Results from more than 50 years of follow-up. Am. J. Epidemiol.,
151, 554–565
Lucas, S.R., Sexton, M. & Langenberg, P. (1996) Relationship between blood lead and nutritional
factors in preschool children: A cross-sectional study. Pediatrics, 97, 74–78
Lundström, N.-G., Nordberg, G., Englyst, V., Gerhardsson, L., Hagmar, L., Jin, T., Rylander, L. &
Wall, S. (1997) Cumulative lead exposure in relation to mortality and lung cancer morbidity
in a cohort of primary smelter workers. Scand. J. Work Environ. Health, 23, 24–30
Luo, W., Zhang, Y. & Li, H. (2003) Children’s blood lead levels after the phasing out of leaded
gasoline in Shantou, China. Arch. environ. Health, 58, 184–187
Lussenhop, D.H., Parker, D.L., Barklind, A. & McJilton, C. (1989) Lead exposure and radiator
repair work. Am. J. public Health, 79, 1558–1560
Lustberg, M. & Silbergeld, E. (2002) Blood lead levels and mortality. Arch. intern. Med., 162,
2443–2449
Luster, M.I., Faith, R.E. & Kimmel, C.A. (1978) Depression of humoral immunity in rats following
chronic developmental lead exposure. J. environ. Pathol. Toxicol., 1, 397–402
Lynge, E., Kurppa, K., Kristofersen, L., Malker, H. & Sauli, H. (1986) Silica dust and lung cancer:
Results from the Nordic occupational mortality and cancer incidence registers. J. natl Cancer
Inst., 77, 883–889
Lyon, T.D.B., Patriarca, M., Howatson, A.G., Fleming, P.J., Blair, P.S. & Fell, G.S. (2002) Age depen-
dence of potentially toxic elements (Sb, Cd, Pb, Ag) in human liver tissue from paediatric
subjects. J. environ. Monit., 4, 1034–1039
P 379-468 DEF.qxp 09/08/2006 13:53 Page 427
Maddaloni, M., Lolacono, N., Manton, W., Blum, C., Drexler, J. & Graziano, J. (1998) Bioavaila-
bility of soilborne lead in adults, by stable isotope dilution. Environ. Health Perspect., 106
(Suppl. 6), 1589–1594
Maenhaut, W., Zoller, W.H., Duce, R.A. & Hoffman, G.L. (1979) Concentration and size distribution
of particulate trace elements in the south polar atmosphere. J. geophys. Res., 84, 2421–2431
Mahaffey, K.R. & Annest, J.L. (1986) Association of erythrocyte protoporphyrin with blood lead
level and iron status in the second National Health and Nutrition Examination Survey,
1976–1980. Environ. Res., 41, 327–338
Maja, M., Penazzi, N., Baudino, M. & Ginatta, M.V. (1989) Recycling of Lead-acid Batteries. The
Ginatta Process. Proceedings of the International Conference on Lead/Acid Batteries (LABAT
‘89), Drujba, Varna, Bulgaria
Makino, S., Matsuno, K., Hisanaga, N., Seki, Y., Ortega, V.S.D., Villanueva, M.B., Cucueco, M.T.,
Yu-Sison, S. & Castro, F.T., II (1994) [Medical examination of workers exposed to lead in the
Philippines.] Jpn. J. ind. Health, 36, 114–123 (in Japanese)
Mäki-Paakkanen, J., Sorsa, M. & Vainio, H. (1981) Chromosome aberrations and sister chromatid
exchanges in lead-exposed workers. Hereditas, 94, 269–275
Malcolm, D. & Barnett, H.A.R. (1982) A mortality study of lead workers 1925–1976. Br. J. ind.
Med., 39, 404–410
Maldonado-Vega, M., Cerbón-Solórzano, J., Albores-Medina, A., Hernández-Luna, C. &
Calderon-Salinas, J.V. (1996) Lead: Intestinal absorption and bone mobilization during lacta-
tion. Hum. exp. Toxicol., 15, 872–877
Maldonado-Vega, M., Solórzano, J.C. & Salinas, J.V. (2002) The effects of dietary calcium during
lactation on lead in bone mobilization: Implications for toxicology. Hum. exp. Toxicol., 21,
409–414
Malkin, R. (1993) Health Hazard Evaluation Report, HETA 93-0739-2364, Curcio Scrap Metal
and Cirello Iron and Steel, Saddle Brook, NJ, USA, NIOSH
Mallin, K., Rubin, M. & Joo, E. (1989) Occupational cancer mortality in Illinois white and black
males, 1979–1984, for seven cancer sites. Am. J. ind. Med., 15, 699–717
Maltoni, C. (1976) Predictive value of carcinogenesis bioassays. Ann. N.Y. Acad. Sci., 271, 431–443
Maltoni, C., Morisi, L. & Chieco, P. (1982) Experimental approach to the assessment of the carci-
nogenic risk of industrial inorganic pigments. Adv. mod. environ. Toxicol., 2, 77–92
Mameli, O., Caria, M.A., Melis, F., Solinas, A., Tavera, C., Ibba, A., Tocco, M., Flore, C. & Sanna
Randaccio, F. (2001) Neurotoxic effect of lead at low concentrations. Brain Res. Bull., 55,
269–275
Manton, W.I. (1985) Total contribution of airborne lead to blood lead. Br. J. ind. Med., 42, 168–172
Manton, W.I. (1994) Lead poisoning from gunshots — A five century heritage. Clin. Toxicol., 32,
387–389
Manton, W.I. & Cook, J.D. (1984) High accuracy (stable isotope dilution) measurements of lead
in serum and cerebrospinal fluid. Br. J. ind. Med., 41, 313–319
Manton, W.I., Angle, C.R., Stanek, K.L., Reese, Y.R. & Kuehnemann, T.J. (2000) Acquisition and
retention of lead by young children. Environ. Res., 82, 60–80
Manton, W.I., Rothenberg, S.J. & Manalo, M. (2001) The lead content of blood serum. Environ.
Res., 86, 263–273
Mao, P. & Molnar, J.J. (1967) The fine structure and histochemistry of lead-induced renal tumors
in rats. Am. J. Pathol., 50, 571–603
P 379-468 DEF.qxp 09/08/2006 13:53 Page 428
Maranelli, G. & Apostoli, P. (1987) Assessment of renal function in lead-poisoned workers. In: Foà,
V., Emmet, E.A., Maroni, M., Colombi, A., eds, Occupational and Environmental Chemical
Hazards: Cellular and Biochemical Indices for Monitoring Toxicity, Chichester, Ellis Horwood
Ltd, pp. 344–348
Marcus, A.H. (1985) Multicompartment kinetic model for lead III. Lead in blood plasma and
erythrocytes. Environ. Res., 36, 473–489
Marcus, A.H. & Schwartz, J. (1987) Dose–response curves for erythrocyte protoporphyrin vs blood
lead: Effects of iron status. Environ. Res., 44, 221–227
Maresky, L.S. & Grobler, S.R. (1993) Effect of the reduction of petrol lead on the blood lead levels
of South Africans. Sci. total Environ., 136, 43–48
Markowitz, M.E. & Shen, X.M. (2001) Assessment of bone lead during pregnancy: A pilot study.
Environ. Res., A85, 83–89
Markowitz, M.E. & Weinberger, H.L. (1990) Immobilization-related lead toxicity in previously
lead-poisoned children. Pediatrics, 86, 455–457
Markowitz, S.B., Nunez, C.M., Klitzman, S., Munshi, A.A., Kim, W.S., Eisinger, J. & Landrigan,
P.J. (1994) Lead poisoning due to hai ge fen: The porphyrin content of individual erythrocytes.
J. Am. med. Assoc., 271, 932–934
Marshall, J.H. & Onkelinx, C. (1968) Radial diffusion and power function retention of alkaline
earth radioisotopes in adult bone. Nature, 217, 742–743
Maslat, A.O. & Haas, H.J. (1989) Mutagenic effects of lead (II) bromide. J. trace Elem. Electro-
lytes Health Dis., 3, 187–191
Mathee, A., von Schirnding, Y.E.R., Levin, J., Ismail, A., Huntley, R. & Cantrell, A. (2002) A survey
of blood lead levels among young Johannesburg school children. Environ. Res., 90, 181–184
Matte, T.D. (2003) [Effects of lead exposure on children’s health]. Salud Publica Mex., 45
(Suppl. 2), 220–224 (in Spanish)
Matte, T.D. & Burr, G.A. (1989a) Health Hazard Evaluation Report, HETA 87-0371-1986,
Technical Assistance to the Jamaican Ministry of Health, Kingston, Jamaica, NIOSH
Matte, T.D. & Burr, G.A. (1989b) Health Hazard Evaluation Report, HETA 87-0371-1989,
Technical Assistance to the Jamaican Ministry of Health, Kingston, Jamaica, NIOSH
Mattorano, D.A. (1996) Health Hazard Evaluation Report, HETA 94-0273-2556, Bruce Mansfield
Power Station, Shippingport, PA, USA, NIOSH
Maynard, E., Thomas, R., Simon, D., Phipps, C., Ward, C. & Calder, I. (2003) An evaluation of
recent blood lead levels in Port Pirie, South Australia. Sci. total Environ., 303, 25–33
Mazess, R.B. (1982) On aging bone loss. Clin. Orthoped. rel. Res., 165, 239–252
Mazess, R.B., Barden, H.S., Ettinger, M., Johnston, C., Dawson-Hughes, B., Baran, D., Powell, M.
& Notelovitz, M. (1987) Spine and femur density using dual-photon absorptiometry in US
white women. Bone Miner., 2, 211–219
McCammon, C.S., Daniels, W.J., Hales, T.R. & Lee, S.A. (1991) Health Hazard Evaluation Report,
HETA 91-0290-2131, New England Lead Burning Co. (NELCO), Eaton Metals, Salt Lake City,
UT, USA, NIOSH
McCammon, C.S., Hales, T.R., Daniels, W.J. & Lee, S.A. (1992) Health Hazard Evaluation Report,
HETA 91-0391-2174, New England Lead Burning Co. (NELCO), Eaton Metals, Salt Lake
City, UT, USA, NIOSH
McClain, R.M. & Siekierka, J.J. (1975) The placental transfer of lead-chelate complexes in the rat.
Toxicol. appl. Pharmacol., 31, 443–451
P 379-468 DEF.qxp 09/08/2006 13:53 Page 429
McDonald, J.A. & Potter, N.U. (1996) Lead’s legacy? Early and late mortality of 454 lead-
poisoned children. Arch. environ. Health, 51, 116–121
McGivern, R.F., Sokol, R.Z. & Berman, N.G. (1991) Prenatal lead exposure in the rat during the
third week of gestation: Long-term behavioral, physiological, and anatomical effects asso-
ciated with reproduction. Toxicol. appl. Pharmacol., 110, 206–215
McGlothlin, J., Mattorano, D.A., Harney, J.M., Habes, D., Cook, C. & Roegner, K. (1999) Health
Hazard Evaluation Report, HETA 97-0196-2755, Astoria Metal Corp., Hunters Point Naval
Shipyard, San Francisco, CA, USA, NIOSH
McGregor, A.J. & Mason, H.J. (1990) Chronic occupational lead exposure and testicular endocrine
function. Hum. exp. Toxicol., 9, 371–376
McIntosh, J.F., Möller, E. & Van Slyke, D.D. (1928) Studies of urea excretion III. The influence
of body size on urea output. J. clin. Invest., 6, 467–483
McLaughlin, J.K., Thomas, T.L., Stone, B.J., Blot, W.J., Malker, H.S., Wiener, J.A., Ericsson, J.L.
& Malker, B.K. (1987) Occupational risks for meningiomas of the CNS in Sweden. J. occup.
Med., 29, 66–68
McManus, K.P. (1991) Health Hazard Evaluation Report, HETA 91-0376-2154, U.S. Customs
Service, World Trade Center New York, NY, USA, NIOSH
McMichael, A.J. & Johnson, H.M. (1982) Long-term mortality profile of heavily-exposed lead
smelter workers. J. occup. Med., 24, 375–378
McMichael, A.J., Baghurst, P.A., Robertson, E.F., Vimpani, G.V. & Wigg, N.R. (1985) The Port
Pirie cohort study. Blood lead concentrations in early childhood. Med. J. Aust., 143, 499–503
McMichael, A.J., Vimpani, G.V., Robertson, E.F., Baghurst, P.A. & Clark, P.D. (1986) The Port
Pirie cohort study: Maternal blood lead and pregnancy outcome. J. Epidemiol. Community
Health, 40, 18–25
McMichael, A.J., Baghurst, P.A., Wigg, N.R., Vimpani, G.V., Robertson, E.F. & Roberts, R.J.
(1988) Port Pirie cohort study: Environmental exposure to lead and children’s abilities at the
age of four years. N. Engl. J. Med., 319, 468–475
McNeill, F.E., Laughlin, N.K., Todd, A.C., Sonawane, B.R., Van de Wal, K.M. & Fowler, B.A.
(1997) Geriatric bone lead metabolism in a female nonhuman primate population. Environ.
Res., 72, 131–139
McNutt, T.K., Chambers-Emerson, J., Dethlefsen, M. & Shah, R. (2001) Bite the bullet: Lead
poisoning after ingestion of 206 lead bullets. Vet. hum. Toxicol., 43, 288–289
Mehdi, J.K., Al-Imarah, F.J.M. & Al-Suhail, A.A. (2000) Levels of some trace metals and related
enzymes in workers at storage-battery factories in Iraq. East mediterr. Health J., 6, 66–82
Mehra, R.K. & Tripathi, R.D. (2000) Phytochelatins and metal tolerance. In: Agarwal, S.B. &
Agarwal, M., eds, Environmental Pollution and Plant Responses, Boca Raton, FL, Lewis
Publishers, pp. 367–382
Mencel, S.J. & Thorp, R.H. (1976) A study of blood lead levels in residents of the Sydney area.
Med. J. Aust., 1, 423–426
Meredith, P.A., Moore, M.R. & Goldberg, A. (1977) The effect of calcium on lead absorption in
rats. Biochem. J., 166, 531–537
Merzenich, H., Hartwig, A., Ahrens, W., Beyersmann, D., Schlepegrell, R., Scholze, M., Timm, J.
& Jöckel, K.-H. (2001) Biomonitoring on carcinogenic metals and oxidative DNA damage in
a cross-sectional study. Cancer Epidemiol. Biomarkers Prev., 10, 515–522
P 379-468 DEF.qxp 09/08/2006 13:53 Page 430
Mexico City Commission for Prevention and Control of Pollution (1993) [Program to Control
Atmospheric Pollution in Mexico City], Mexico City (in Spanish)
Meyer, B.R., Fischbein, A., Rosenman, K., Lerman, Y., Drayer, D.E. & Reidenberg, M.M. (1984)
Increased urinary enzyme excretion in workers exposed to nephrotoxic chemicals. Am. J.
Med., 76, 989–998
Michaels, D., Zoloth, S.R. & Stern, F.B. (1991) Does low-level lead exposure increase risk of
death? A mortality study of newspaper printers. Int. J. Epidemiol., 20, 978–983
Mielke, H.W. (1991) Lead in residential soils: Background and preliminary results of New Orleans.
Water Air Soil Pollut., 57–58, 111–119
Mielke, H.W., Anderson, J.C., Berry, K.J., Mielke, P.W., Chaney, R.L. & Leech, M. (1983) Lead
concentrations in inner-city soils as a factor in the child lead problem. Am. J. public Health,
73, 1366–1369
Mielke, H.W., Adams, J.L., Reagan, P.L. & Mielke, P.W., Jr (1989) Soil-dust lead and childhood
lead exposure as a function of city size and community traffic flow: The case for lead abate-
ment in Minnesota. Environ. Chem. Health, 9 (Suppl.), 253–271
Mielke, H.W., Dugas, D., Mielke, P.W., Jr, Smith, K.S., Smith, S.L. & Gonzales, C.R. (1997a)
Associations between soil lead and childhood blood lead in urban New Orleans and rural
Lafourche Parish of Louisiana. Environ. Health Perspect., 105, 950–954
Mielke, H.W., Taylor, M.D., Gonzales, C.R., Smith, M.K., Daniels, P.V. & Buckner, A.V. (1997b)
Lead-based hair coloring products: Too hazardous for household use. J. Am. pharm. Assoc.,
NS37, 85–89
Miller, G.D., Massaro, T.F., Granlund, R.W. & Massaro, E.J. (1983) Tissue distribution of lead in
the neonatal rat exposed to multiple doses of lead acetate. J. Toxicol. environ. Health, 11,
121–128
Miller, M.B., Curry, S.C., Kunkel, D.B., Arreola, P., Arvizu, E., Schaller, K. & Salmen, D. (1996)
Pool cue chalk: A source of environmental lead. Pediatrics, 97, 916–917
Miller, T.E., Golemboski, K.A., Ha, R.S., Bunn, T., Sanders, F.S. & Dietert, R.R. (1998) Develop-
mental exposure to lead causes persistent immunotoxicity in Fischer 344 rats. Toxicol. Sci., 42,
129–135
Milne, K.L., Sandler, D.P., Everson, R.B. & Brown, S.M. (1983) Lung cancer and occupation in
Alameda county: A death certificate case–control study. Am. J. ind. Med., 4, 565–575
Ministry of Health, Brazil (2004) Portaria No. 518, de 25 de março de 2004
[http://www.sabesp.com/legislacao/Pdf/518_04.pdf; assessed 01/02/2005] (in Portugese)
Ministry of Health, Labour and Welfare (2001) [Database for quality of water supply] (in Japanese)
[http://www.jwwa.or.jp/mizu/bunpu/bunpu1_D.asp; accessed 26/01/2004]
Ministry of Health, Labour and Welfare (2002) The National Nutrition Survey in Japan, 2001,
Tokyo, Dai-ichi Shuppan Publishers (in Japanese)
Ministry of Health, Labour and Welfare (2003) Journal of Health and Welfare Statistics, Health
and Welfare Statistics Association, p. 269
Minnesota Pollution Control Agency (1987) Soil Lead Report to the Minnesota State Legislature,
Minneapolis, Minnesota, Minnesota Pollution Control Agency & Minnesota Department of
Health
Mira, M., Bawden-Smith, J., Causer, J., Alperstein, G., Karr, M., Snitch, P., Waller, G. & Fett, M.J.
(1996) Blood lead concentrations of preschool children in Central and Southern Sydney. Med.
J. Australia, 164, 399–402
P 379-468 DEF.qxp 09/08/2006 13:53 Page 431
Mishra, K.P., Singh, V.K., Rani, R., Yadav, V.S., Chandran, V., Srivastava, S.P. & Seth, P.K. (2003)
Effect of lead exposure on the immune response of some occupationally exposed individuals.
Toxicology, 188, 251–259
Mistry, P., Lucier, G.W. & Fowler, B.A. (1985) High-affinity lead binding proteins in rat kidney
cytosol mediate cell-free nuclear translocation of lead. J. Pharmacol. exp. Ther., 232, 462–469
Mistry, P., Mastri, C. & Fowler, B.A. (1986) Influence of metal ions on renal cytosolic lead-
binding proteins and nuclear uptake of lead in the kidney. Biochem. Pharmacol., 35, 711–713
Modak, A.T., Weintraub, S.T. & Stavincha, W.B. (1975) Effect of chronic ingestion of lead on the
central cholinergic system in rat brain regions. Toxicol. appl. Pharmacol., 34, 340–347
Modak, A.T., Purdy, R.H. & Stavinoha, W.B. (1978) Changes in acetylcholine concentration in
mouse brain following ingestion of lead acetate in drinking water. Drug chem. Toxicol., 1,
373–389
Mokhtar, M.B., Awaluddin, A.B., Yusof, A.B.B.M. & Bakar, B.B. (2002) Lead in blood and hair
of shipyard workers, Sabah, Malaysia. Bull. environ. Contam. Toxicol., 69, 8–14
Mombeshora, C., Osibanjo, O. & Ajayi, S.O. (1983) Pollution studies on Nigerian rivers: The
onset of lead pollution of surface waters in Ibadan. Environ. Int., 9, 81–84
Momcilovic, B. (1978) The effect of maternal dose on lead retention in suckling rats. Arch.
environ. Health, 33, 115–117
Momcilovic, B. (1979) Lead metabolism in lactation. Experientia, 35, 517–518
Momcilovic, B. & Kostial, K. (1974) Kinetics of lead retention and distribution in suckling and
adult rats. Environ. Res., 8, 214–220
Monchaux, G., Morin, M., Morlier, J.P. & Olivier, M.F. (1997) Long-term effects of combined
exposure to fission neutrons and inhaled lead oxide particles in rats. Ann. occup. Hyg., 41
(Suppl. 1), 630–635
Montopoli, M., Seligman, P., O’Brien, D. & Zaebst, D. (1989) Health Hazard Evaluation Report,
HETA 88-0244-1951, Orrville Bronze and Aluminum Co., Orrville, OH, USA, NIOSH
Moon, C.-S. & Ikeda, M. (1996) Pollutant levels in ambient air and blood in Korea. Environ.
Health prev. Med., 1, 33–38
Moon, D.-H. & Lee, C.-U. (1992) [A study on the ambient air pollution by heavy metals in Pusan
area.] Inje. Med. J., 13, 61–91 (in Korean with English abstract)
Moon, C.-S., Zhang, Z.-W., Shimbo, S., Watanabe, T., Moon, D.-H., Lee, C.-U., Lee, B.-K., Ahn,
K.-D., Lee, S.-H. & Ikeda, M. (1995) Dietary intake of cadmium and lead among the general
population in Korea. Environ. Res., 71, 46–54
Moore, M.R. (1988) Haematological effects of lead. Sci. tot. Envir., 71, 419–431
Moore, J.F. & Goyer, R.A. (1974) Lead-induced inclusion bodies: Composition and probable role
in lead metabolism. Environ. Health Perspect., 7, 121–127
Moore, M.R., Beattie, A.D., Thompson, G.G. & Goldberg, A. (1971) Depression of δ-aminolaevu-
linic acid dehydrase activity by ethanol in man and rat. Clin. Sci., 40, 81–88
Moore, P.J., Pridmore, S.A. & Gill, G.F. (1976) Total blood lead levels in petrol vendors. Med. J.
Aust., 1, 438–440
Moore, M.R., Meredith, P.A., Campbell, B.C. & Watson, W.S. (1979) The gastrointestinal absorp-
tion of lead 203 chloride in man. In: Hemphill, D.D., ed., Trace Substances in Environmental
Health, Vol. XIII, Columbia, MO, University of Missouri, pp. 368–373
Moore, M.R., Meredith, P.A., Watson, W.S., Sumner, D.J., Taylor, M.K. & Goldberg, A. (1980a)
The percutaneous absorption of lead-203 in humans from cosmetic preparations containing
P 379-468 DEF.qxp 09/08/2006 13:53 Page 432
lead acetate, as assessed by whole-body counting and other techniques. Food Cosmet. Toxicol.,
18, 399–405
Moore, M.R., Meredith, P.A. & Goldberg A. (1980b) Lead and heme biosynthesis. In: Singhal,
R.L. & Thomas, J.A., eds, Lead Toxicity, Baltimore, Urban and Schwarzenberg, pp. 79–117
Moore, M.R., Goldberg, A., Pocock, S.J., Meredith, A., Stewart, I.M., MacAnespie, H., Lees, R. &
Low, A. (1982) Some studies of maternal and infant lead exposure in Glasgow. Scot. med. J.,
27, 113–121
Moorman, W.J., Skaggs, S.R., Clark, J.C., Turner, T.W., Sharpnack, D.D., Murrell, J.A., Simon,
S.D., Chapin, R.E. & Schrader, S.M. (1998) Male reproductive effects of lead, including
species extrapolation for the rabbit model. Reprod. Toxicol., 12, 333–346
Moreira, E.G., de Magalhaes Rosa, G.J., Barros, S.B.M., Vassilieff, V.S. & Vassillieff, I. (2001) Anti-
oxidant defense in rat brain regions after developmental lead exposure. Toxicology, 169, 145–151
Morgan, A. & Holmes, A. (1978) The fate of lead in petrol-engine exhaust particulates inhaled by
the rat. Environ. Res., 15, 44–56
Morgan, A., Holmes, A. & Evans, J.C. (1977) Retention, distribution, and excretion of lead by the
rat after intravenous injection. Br. J. ind. Med., 34, 37–42
Morgan, B.W., Todd, K.H. & Moore, B. (2001) Elevated blood lead levels in urban moonshine
drinkers. Ann. emerg. Med., 37, 51–54
Morrison, J.N. & Quarterman, J. (1987) The relationship between iron status and lead absorption
in rats. Biol. trace Elem. Res., 14, 115–126
Morrow, P.E., Beiter, H., Amato, F. & Gibb, F.R. (1980) Pulmonary retention of lead: An experi-
mental study in man. Environ. Res., 21, 373–384
Moser, R., Oberley, T.D., Daggett, D.A., Friedman, A.L., Johnson, J.A. & Siegel, F.L. (1995)
Effects of lead administration on developing rat kidney. I. Glutathione S-transferase iso-
enzymes. Toxicol. appl. Pharmacol., 131, 85–93
Mouradian, R.F. & Kinnes, G.M. (1991) Health Hazard Evaluation Report, HETA 90-0348-2135,
Grosse Pointes-Clinton Refuse Disposal Authority, Mount Clemens, MI, USA, NIOSH
Muldoon, S.B., Cauley, J.A., Kuller, L.H., Scott, J. & Rohay, J. (1994) Lifestyle and sociodemo-
graphic factors as determinants of blood lead levels in elderly women. Am. J. Epidemiol., 139,
599–608
Mulligan, C.N., Yong, R.N. & Gibbs, B.F. (2001) Remediation technologies for metal-conta-
minated soils and groundwater: An evaluation. Eng. Geol., 60, 193–207
Murata, K., Araki, S. & Aono, H. (1987) Effects of lead, zinc, and coper absorption on peripheral
nerve conduction in metal workers. Int. Arch. occup. environ. Health, 59, 11–20
Murata, K., Araki, S., Yokoyama, K., Nomiyama, K., Nomiyama, H., Tao, Y.-X. & Liu, S.-J. (1995)
Autonomic and central nervous system effects of lead in female glass workers in China. Am.
J. ind. Med., 28, 233–244
Muro, L.A. & Goyer, R.A. (1969) Chromosome damage in experimental lead poisoning. Arch.
Path., 87, 660–663
Murphy, M.J., Graziano, J.H., Popovac, D., Kline, J.K., Mehmeti, A., Factor-Litvak, P., Ahmedi,
G., Shrout, P., Rajovic, B., Nenezic, D.U. & Stein, Z.A. (1990) Past pregnancy outcomes
among women living in the vicinity of a lead smelter in Kosovo, Yugoslavia. Am. J. pub.
Health, 80, 33–35
Mushak, P. (1991) Gastro-intestinal absorption of lead in children and adults: Overview of bio-
logical and biophysico-chemical aspects. Chem. Spec. Bioavail., 3, 87–104
P 379-468 DEF.qxp 09/08/2006 13:53 Page 433
Muskett, C.J. & Caswell, R. (1980) An investigation into lead in two indoor small-bore rifle
ranges. Ann. occup. Hyg., 23, 283–294
Mykkänen, H.M. & Wasserman, R.H. (1982) Effect of vitamin D on the intestinal absorption of
203Pb and 47Ca in chicks. J. Nutr., 112, 520–527
Mykkänen, H.M., Lancaster, M.C. & Dickerson, J.W.T. (1982) Concentrations of lead in the soft
tissues of male rats during a long-term dietary exposure. Environ. Res., 28, 147–153
Mykkänen, H.M., Fullmer, C.S. & Wasserman, R.H. (1984) Effect of phosphate on the intestinal
absorption of lead (203Pb) in chicks. J. Nutr., 114, 68–74
Mylius, E.A. & Ophus, E.M. (1977) Pulmonary distributions of lead in human subjects. Bull
environ. Contam. Toxicol., 17, 302–310
Nakaji, S., Fukuda, S., Sakamoto, J., Sugawara, K., Shimoyama, T., Umeda, T. & Baxter, D.
(2001) Relationship between mineral and trace element concentrations in drinking water and
gastric cancer mortality in Japan. Nutr. Cancer, 40, 99–102
Nambi, K.S.V., Raghunath, R., Tripathi, R.M. & Khandekar, R.N. (1997) Scenario of ‘Pb pollution
and children’ in Mumbai: Current air quality standard vindicated. Energy Environ. Monitor.,
13, 53–60
Namihira, D., Saldivar, L., Pustilnik, N., Carreón, G.J. & Salinas, M.E. (1993) Lead in human
blood and milk from nursing women living near a smelter in Mexico City. J. Toxicol. environ.
Health, 38, 225–232
Nathan, E., Huang, H.F.S., Pogach, L., Giglio, W., Bogden, J.D. & Seebode, J. (1992) Lead acetate
does not impair secretion of Sertoli cell function marker proteins in the adult Sprague Dawley
rat. Arch. environ. Health, 47, 370–375
National Food Processors Association (1992) Public Comment on the Toxicological Profile for
Lead. Submitted to the Academy for Toxic Substances and Disease Registry. Washington, DC,
February 4, 1992
National Institute for Occupational Safety and Health (1994a) Lead by GFAAS, Method 7105,
Issue 2, In: NIOSH Manual of Analytical Methods (NMAM), 4th Ed.
National Institute for Occupational Safety and Health (1994b) Lead by Flame AAS, Method 7082,
Issue 2, In: NIOSH Manual of Analytical Methods (NMAM), 4th Ed.
National Institute for Occupational Safety and Health (1994c) Tetraethyl Lead (as Pb), Method
2533, Issue 2, In: NIOSH Manual of Analytical Methods (NMAM), 4th Ed.
National Institute for Occupational Safety and Health (1994d) Tetramethyl Lead (as Pb), Method
2534, Issue 2, In: NIOSH Manual of Analytical Methods (NMAM), 4th Ed.
National Institute for Occupational Safety and Health (1995) Report to Congress on Workers’
Home Contamination Study Conducted Under the Workers’ Family Protection, Cincinnati,
OH, National Institute for Occupational Safety and Health
National Institute for Occupational Safety and Health (1998) Lead by Field Portable XRF, Method
7702, Issue 1, In: NIOSH Manual of Analytical Methods (NMAM), 4th Ed.
National Institute for Occupational Safety and Health (2001) Health Hazard Evaluations: Occupa-
tional Exposure to Lead 1994 to 1999, Research Triangle Park, NC, Centers for Disease
Control and Prevention
National Institute for Occupational Safety and Health (2003a) Elements by ICP (Nitric/Perchloric
Acid Ashing), Method 7300, Issue 3. In: NIOSH Manual of Analytical Methods (NMAM),
4th Ed.
P 379-468 DEF.qxp 09/08/2006 13:53 Page 434
National Institute for Occupational Safety and Health (2003b) Lead by Portable Ultrasonic Extrac-
tion/ASV, Method 7701, Issue 2. In: NIOSH Manual of Analytical Methods (NMAM), 4th Ed.
National Institute of Health Sciences, Japan (2000) [Total Diet Survey in Japan (Estimation of Daily
Dietary Intake of Food Contaminants), 1977–1999], National Institute of Health Sciences,
Tokyo (in Japanese)
National Institute of Nutrition (1995–96) Annual Report, Hyderabad, National Institute of Nutri-
tion, pp. 43–44
National Library of Medicine (2003) [http://chem.sis.nlm.nih.gov/chemidplus/chemidlite, jsp;
accessed 01/02/2004]
National Oceanic and Atmospheric Administration (1998a) Sampling and analytical methods of the
national status and trends program: 1993–1996 update. Method 140.0. In: National Environ-
mental Methods Index
National Oceanic and Atmospheric Administration (1998b) Sampling and analytical methods of the
national status and trends program: 1993–1996 update. Method 172.0. In: National Environ-
mental Methods Index
National Oceanic and Atmospheric Administration (1998c) Sampling and analytical methods of the
national status and trends program: 1993–1996 update. Method 160.0. In: National Environ-
mental Methods Index
National Research Council (1993) Measuring Lead Exposure in Infants, Children, and Other
Sensitive Populations (ISBN 030904927X), Committee on Measuring Lead in Critical Popu-
lations, NRC, Washington DC, National Academies Press
Navas-Acién, A., Pollán, M., Gustavsson, P. & Plato, N. (2002) Occupation, exposure to chemicals
and risk of gliomas and meningiomas in Sweden. Am. J. ind. Med., 42, 214–227
Nawrot, T.S., Thijs, L., Den Hond, E.M., Roels, H.A. & Staessen, J.A. (2002) An epidemiological
re-appraisal of the association between blood pressure and blood lead: A meta-analysis. J.
Human Hypert., 16, 123–131
Nayak, B.N., Ray, M., Persaud, T.V.N. & Nigli, M. (1989) Relationship of embryotoxicity to geno-
toxicity of lead nitrate in mice. Exp. Pathol., 36, 65–73
Needleman, H.L., Gunnoe, C., Leviton, A., Reed, R., Peresie, H., Maher, C. & Barret, P. (1979)
Deficits in psychologic and classroom performance of children with elevated dentine lead
levels. New Engl. J. Med., 300, 689–695
Needleman, H.L., Leviton, A. & Bellinger, D. (1982) Lead-associated intellectual deficit. New
Engl. J. Med., 306, 367
Needleman, H.L., Rabinowitz, M., Leviton, A., Linn, S. & Schoenbaum, S. (1984) The relation-
ship between prenatal exposure to lead and congenital anomalies. J. Am. med. Assoc., 251,
2956–2959
Needleman, H.L., Schell, A., Bellinger, D., Leviton, A. & Allred, E.N. (1990) The long-term
effects of exposure to low doses of lead in childhood. An 11-year follow-up report. New Engl.
J. Med., 322, 83–88
Needleman, H.L., Riess, J.A., Tobin, M.J., Biesecker, G.E. & Greenhouse, J.B. (1996) Bone lead
levels and delinquent behavior. J. Am. med. Assoc., 275, 363–369
Needleman, H.L., McFarland, C., Ness, R.B., Fienberg, S.E. & Tobin, M.J. (2002) Bone lead levels
in adjudicated delinquents. A case control study. Neurotoxicol. Teratol., 24, 711–717
P 379-468 DEF.qxp 09/08/2006 13:53 Page 435
Nehéz, M., Lorencz, R. & Dési, I. (2000) Simultaneous action of cypermethrin and two environ-
mental pollutant metals, cadmium and lead, on bone marrow cell chromosomes of rats in sub-
chronic administration. Ecotoxicol. environ. Safety, 45, 55–60
Neri, L.C., Hewitt, D. & Orser, B. (1988) Blood lead and blood pressure: Analysis of cross-
sectional and longitudinal data from Canada. Environ. Health Perspect., 78, 123–126
Nestmann, E.R., Matula, T.I., Douglas, G.R., Bora, K.C. & Kowbel, D.J. (1979) Detection of the
mutagenic activity of lead chromate using a battery of microbial tests. Mutat. Res., 66, 357–365
Neuberger, J.S. & Hollowell, J.G. (1982) Lung cancer excess in an abandoned lead-zinc mining
and smelting area. Sci. total Environ., 25, 287–294
Neuman, D.R. & Dollhopf, D.J. (1992) Lead levels in blood from cattle residing near a lead
smelter. J. environ. Qual., 21, 181–184
Nevin, R. (2000) How lead exposure relates to temporal changes in IQ, violent crime, and unwed
pregnancy. Environ. Res., 83, 1–22
Newton, D., Pickford, C.J., Chamberlain, A.C., Sherlock, J.C. & Hislop, J.S. (1992) Elevation of
lead in human blood from its controlled ingestion in beer. Hum. exp. Toxicol., 11, 3–9
Ng, R. & Martin, D.J. (1977) Lead poisoning from lead-soldered electric kettles. Can. med. Assoc.
J., 116, 508–509, 512
Ng, T.P., Goh, H.H., Ng, Y.L., Ong, H.Y., Ong, C.N., Chia, K.S., Chia, S.E. & Jeyaratnam, J.
(1991) Male endocrine functions in workers with moderate exposure to lead. Br. J. ind. Med.,
48, 485–491
Nielsen, T., Jensen, K.A. & Grandjean, P. (1978) Organic lead in normal human brains. Nature,
274, 602–603
Nielsen, C.J., Nielsen, V.K., Kirkby, H. & Gyntelberg, F. (1982) Absence of peripheral neuropathy
in long-term lead-exposed subjects. Acta. neurol. scand., 65, 241–247
NIH (1994) Optimal calcium intake. Consensus development panel on optimal calcium uptake.
J. Am. med. Assoc., 272, 1942–1948
Nilas, L. & Christiansen, C. (1988) Rates of bone loss in normal women: Evidence of accelerated
trabecular bone loss after the menopause. Eur. J. clin. Invest., 18, 529–534
Nilsson, U., Attewell, R., Christoffersson, J.O., Schutz, A., Ahlgren, L., Skerfving, S. & Mattsson,
S. (1991) Kinetics of lead in bone and blood after end of occupational exposure. Pharmacol.
Toxicol., 69, 477–84
Nishii, K. (1993) A study of modulation by phosphate salts and potassium citrate on rat renal tumo-
rigenesis. J. Nara Med. Ass., 44, 156–167
Nishioka, H. (1975) Mutagenic activities of metal compounds in bacteria. Mutat. Res., 31, 185–189
Nogueira, E. (1987) Rat renal carcinogenesis after chronic simultaneous exposure to lead acetate
and N-nitrosodiethylamine. Virchows Arch., B53, 365–374
Nolan, C.V. & Shaikh, Z.A. (1992) Lead nephrotoxicity and associated disorders: Biochemical
mechanisms. Toxicology, 73, 127–146
Nomiyama, K., Nomiyama, H., Liu, S.-J., Tao, Y-X., Nomiyama, T. & Omae, K. (2002) Lead
induced increase of blood pressure in female lead workers. Occup. environ. Med., 59, 734–739
Noranda (2003) Product Data Sheet: Lead, Belledune, New Brunswick
Nordenson, I., Beckman, G., Beckman, L. & Nordström, S. (1978) Occupational and environ-
mental risks in and around a smelter in northern Sweden. IV. Chromosomal aberrations in
workers exposed to lead. Hereditas, 88, 263–267
P 379-468 DEF.qxp 09/08/2006 13:53 Page 436
Nordström, S., Beckman, L. & Nordenson, I. (1978) Occupational and environmental risks in and
around a smelter in northern Sweden. III. Frequencies of spontaneous abortion. Hereditas, 88,
51–54
Nordström, S., Beckman, L. & Nordenson, L. (1979a) Occupational and environmental risks in and
around a smelter in northern Sweden. VI. Congenital malformations. Hereditas, 90, 297–302
Nordström, S., Beckman, L. & Nordenson, I. (1979b) Occupational and environmental risks in and
around a smelter in northern Sweden. V. Spontaneous abortion among female employees and
decreased birth weight in their offspring. Hereditas, 90, 291–296
Norman, E.H., Hertz-Picciotto, I., Salmen, D.A. & Ward, T.H. (1997) Childhood lead poisoning
and vinyl miniblind exposure. Arch. pediatr. adoles. Med., 151, 1033–1037
Novotny, T., Cook, M., Hughes, J. & Lee, S.A. (1987) Lead exposure in a firing range. Am. J.
Public Health, 77, 1225–1226
Nriagu, J.O. (1978) Lead in soils, sediments and major rock types. In: Nriagu, J.O., ed., The Bio-
geochemistry of Lead in the Environment. Part A. Ecological Cycles, New York, Elsevier/
North-Holland Biomedical Press, pp. 15–72
Nriagu, J.O. (1992) Toxic metal pollution in Africa. Science tot. Environ., 121, 1–37
Nriagu, J.O. & Pacyna, J.M. (1988) Quantitative assessment of worldwide contamination of air,
water and soils by trace metals. Nature, 333, 134–139
Nriagu, J., Jinabhai, C., Naidoo, R. & Coutsoudis, A. (1996a) Atmospheric lead pollution in
KwaZulu/Natal, South Africa. Sci. total Environ., 191, 69–76
Nriagu, J.O., Blankson, M.L. & Ocran, K. (1996b) Childhood lead poisoning in Africa: A growing
public health problem. Sci. total Environ., 181, 93–100
Nriagu, J., Jinabhai, C.C., Naidoo, R. & Coutsoudis, A. (1997a) Lead poisoning of children in
Africa, II. Kwazulu/Natal, South Africa. Sci. total Environ., 197, 1–11
Nriagu, J., Oleru, N.T., Cudjoe, C. & Chine, A. (1997b) Lead poisoning of children in Africa, III.
Kaduna, Nigeria. Sci. total Environ., 197, 13–19
Nwankwo, J.N. & Elinder, C.G. (1979) Cadmium, lead and zinc concentrations in soils and in food
grown near a zinc and lead smelter in Zambia. Bull. environ. contam. Toxicol., 22, 625–631
Oberto, A., Marks, N., Evans, H.L. & Guidotti, A. (1996) Lead (Pb2+) promotes apoptosis in new-
born rat cerebellar neurons: Pathological implications. J. Pharmacol. exp. Ther., 279, 435–442
Occupational Safety and Health Administration (2002a) Metal and Metalloid Particulates in Work-
place Atmospheres (Atomic Absorption), Method No. ID-121, US Department of Labor, Divi-
sion of Physical Measurements and Inorganic Analyses, Sandy, UT, USA
Occupational Safety and Health Administration (2002b) Metal and Metalloid Particulates in Work-
place Atmospheres (ICP Analysis), Method No. ID-125G, US Department of Labor, Division
of Physical Measurements and Inorganic Analyses, Sandy, UT, USA
Occupational Safety and Health Administration (2002c) ICP Analysis of Metal/Metalloid Particu-
lates from Solder Operations, US Department of Labor, Division of Physical Measurements
and Inorganic Analyses, Sandy, UT, USA
Occupational Safety and Health Administration (2003) Lead (Pb) on Surfaces by a Portable X-Ray
Fluorescence (XRF) Analyzer, Method No. OSS1, US Department of Labor, Division of Phy-
sical Measurements and Inorganic Analyses, Sandy, UT, USA
Octel Ltd (1982) World Wide Survey of Motor Gasoline Quality, London
Octel Ltd (1988) World Wide Survey of Motor Gasoline Quality 1987, London
Octel Ltd (1990) World Wide Survey of Motor Gasoline Quality, London
P 379-468 DEF.qxp 09/08/2006 13:53 Page 437
OECD (1993) Lead — Background And National Experience With Reducing Risk (Risk Reduction
Monograph No. 1; OCDE/GD(93)67), Paris, Organization for Economic Co-operation and
Development
O’Flaherty, E.J. (1991a) Physiologically based lead kinetics. Trace Subst. environ. Health, 24,
44–54
O’Flaherty, E.J. (1991b) Physiologically based models for bone-seeking elements. I. Rat skeletal
and bone growth. Toxicol. appl. Pharmacol., 111, 299–312
O’Flaherty, E.J. (1991c) Physiologically based models for bone-seeking elements. II. Kinetics of
lead disposition in rats. Toxicol. appl. Pharmacol., 111, 313–331
O’Flaherty, E.J. (1992) Modeling bone mineral metabolism, with special reference to calcium and
lead. Neurotoxicology, 13, 789–798
O’Flaherty, E.J. (1993) Physiologically based models for bone-seeking elements. IV. Kinetics of
lead disposition in humans. Toxicol. appl. Pharmacol., 118, 16–29
O’Flaherty, E.J. (1995) Physiologically based models for bone-seeking elements. V. Lead absorp-
tion and disposition in childhood. Toxicol. appl. Pharmacol., 131, 297–308
O’Flaherty, E.J. (1998) A physiologically based kinetic model for lead in children and adults.
Environ. Health Perspect., 106 (Suppl. 6), 1495–1503
O’Flaherty, E.J. (2000) Modeling normal aging bone loss, with consideration of bone loss in osteo-
porosis. Toxicol. Sci., 55, 171–188
O’Flaherty, E.J., Hammond, P.B. & Lerner, S.I. (1982) Dependence of apparent blood lead half-
life on the length of previous lead exposure in humans. Fundam. appl. Toxicol., 2, 49–54
O’Flaherty, E.J., Inskip, M.J., Yagminas, A.P. & Franklin, C.A. (1996) Plasma and blood lead con-
centrations, lead absorption, and lead excretion in nonhuman primates. Toxicol. appl. Pharma-
col., 138, 121–130
O’Flaherty, E.J., Inskip, M.J., Franklin, C.A., Durbin, P.W., Manton, W.I. & Baccanale, C.L. (1998)
Evaluation and modification of a physiologically based model of lead kinetics using data from
a sequential isotope study in cynomolgus monkeys. Toxicol. appl. Pharmacol., 149, 1–16
Ogunsola, O.J., Oluwole, A.F., Asubiojo, O.I., Olaniyi, H.B., Akeredolu, F.A., Akanle, O.A.,
Spyrou, N.M., Ward, N.I. & Ruck, W. (1994a) Traffic pollution: Preliminary elemental charac-
terisation of roadside dust in Lagos, Nigeria. Sci. total Environ., 146/147, 175–184
Ogunsola, O.J., Oluwole, A.F., Asubiojo, O.I., Durosinmi, M.A., Fatusi, A.O. & Ruck, W. (1994b)
Environmental impact of vehicular traffic in Nigeria: Health aspects. Sci. total Environ.,
146–147, 111–116
Oishi, H., Nomiyama, H., Nomiyama, K. & Tomokuni, K. (1996a) Comparison between males and
females with respect to the porphyrin metabolic disorders found in workers occupationally
exposed to lead. Int. Arch. occup. environ. Health, 68, 298–304
Oishi, H., Nomiyama, H., Nomiyama, K. & Tomokuni, K. (1996b) Fluorometric HPLC determi-
nation of ∆-aminolevulinic acid (ALA) in the plasma and urine of lead workers: Biological
indicators of lead exposure. J. anal. Toxicol., 20, 106–110
Okada, I.A., Sakuma, A.M., Maio, F.D., Dovidauskas, S. & Zenebon, O. (1997) [Evaluation of
lead and cadmium levels in milk due to environmental contamination in the Paraiba Valley
Region of southeastern Brazil.] Rev. Saúde pública, 31, 140–143 (in Portuguese)
Okayama, A., Fujii, S. & Miura, R. (1990) Optimized fluorometric determination of urinary delta-
aminolevulinic acid by using pre-column derivatization, and identification of the derivative.
Clin. Chem., 36, 1494–1497
P 379-468 DEF.qxp 09/08/2006 13:53 Page 438
Olaiz, G., Fortoul, T.I., Rojas, R., Doyer, M., Palazuelos, E. & Tapia, C.R. (1996) Risk factors for high
levels of lead in blood of schoolchildren in Mexico City. Arch. environ. Health, 51, 122–126
Olejnik, D., Walkowska, A., Wisniewska, J. & Ziembinski, R. (1985) [Evaluation of the daily
intake of mercury, lead and cadmium in the meals of some population groups.] Roczn. Pzh.,
XXXVI, 9–21 (in Polish, with English abstract)
Olguín, A., Jauge, P. & Cebrián, M.E. (1982) Determinación del plomo en leches industrializadas.
Resúmenes. II. Congreso sobre Problemas Ambientales de México, ENCB-IPN, México, p. 60
Oliveira, S., Aro, A., Sparrow, D. & Hu, H. (2002) Season modifies the relationship between bone
and blood lead levels: The Normative Aging Study. Arch. environ. Health, 57, 466–472
Olshan, A.F., Breslow, N.E., Daling, J.R., Falletta, J.M., Grufferman, S., Robison, L.L.,
Waskerwitz, M. & Hammond, G.D. (1990) Wilms’ tumor and paternal occupation. Cancer
Res., 50, 3212–3217
Omokhodion, F.O. (1994) Blood lead and tap water lead levels in Ibadan, Nigeria. Sci. total
Environ., 151, 187–190
Omokhodion, F.O. & Crockford, G.W. (1991a) Sweat lead levels in persons with high blood lead
levels: Experimental elevation of blood lead by ingestion of lead chloride. Sci. total Environ.,
108, 235–242
Omokhodion, F.O. & Crockford, G.W. (1991b) Lead in sweat and its relationship to salivary and
urinary levels in normal healthy subjects. Sci. total Environ., 103, 113–122
Omokhodion, F.O. & Howard, J.M. (1991) Sweat lead levels in persons with high blood lead
levels: Lead in sweat of lead workers in the tropics. Sci. total Environ., 103, 123–128
Onalaja, A.O. & Claudio, L. (2000) Genetic susceptibility to lead poisoning. Environ. Health
Perspect., 108, 23–28
O’Neil, M.J., ed. (2003) The Merck Index, 15th Ed., Whitehouse Station, NJ, Merck & Co.,
available on CD-Rom
Ong, C.N., Phoon, W.O., Law, H.Y., Tye, C.Y. & Lim, H.H. (1985) Concentrations of lead in
maternal blood, cord blood, and breast milk. Arch. Dis. Child., 60, 756–759
Ong, C.N., Endo, G., Chia, K.S., Phoon, W.O. & Ong, H.Y. (1987) Evaluation of renal function in
workers with low blood lead levels. In: Foà, V., Emmet, E.A., Maroni, M. & Colombi, A., eds,
Occupational and Environmental Chemical Hazards: Cellular and Biochemical Indices for
Monitoring Toxicity, Chichester, Ellis Horwood Ltd, pp. 327–333
Ong, C.N., Kong, Y.M., Ong, H.Y. & Teramoto, K. (1990) The in vitro and in vivo effects of lead on
δ-aminolevulinic acid dehydratase and pyrimidine 5′-nucleotidase. Pharmacol. Toxicol., 66,
23–26
Onyari, J.M., Wandiga, S.O., Njenga, G.K. & Nyatebe, J.O. (1991) Lead contamination in street
soils of Nairobi City and Mombasa Island, Kenya. Bull. environ. Contam. Toxicol., 46, 782–789
Ordóñez, B.R., Ruíz Romero, L. & Mora, R. (2003) [Epidemiological investigations on the lead
levels of a childhood population and the home environment of Juarez City, Chihuahua, in
relation to a smelter from El Paso, Texas.] Salud pub. Mex., 45 (Suppl. 2), 281–295 (in Spanish)
O’Riordan, M.L. & Evans, H.J. (1974) Absence of significant chromosome damage in males occu-
pationally exposed to lead. Nature, 247, 50–53
Oskarsson, A., Squibb, K.S. & Fowler, B.A. (1982) Intracellular binding of lead in the kidney: The
partial isolation and characterization of postmichondrial lead binding components. Biochem.
biophys. Res. Commun., 104, 290–298
P 379-468 DEF.qxp 09/08/2006 13:53 Page 439
Oskarsson, A., Jorhem, L., Sundberg, J., Nilsson, N.G. & Albanus, L. (1992) Lead poisoning in
cattle — Transfer of lead to milk. Sci. total Environ., 111, 83–94
Otto, D.A. & Fox, D.A. (1993) Auditory and visual dysfunction following lead exposure. Neuro-
toxicology, 142, 191–203
Otto, D., Robinson, G., Baumann, S., Schroeder, S., Mushak, P., Kleinbaum, D. & Boone, L.
(1985) 5-Year follow-up study of children with low to-moderate lead absorption: Electro-
physiological evaluation. Environ. Res., 38, 168–186
Overmann, S.R. (1977) Behavioral effects of asymptomatic lead exposure during neonatal deve-
lopment in rats. Toxicol. appl. Pharmacol., 41, 459–471
Oyasu, R., Battifora, H.A., Clasen, R.A., McDonald, J.H. & Hass, G.M. (1970) Induction of cere-
bral gliomas in rats with dietary lead subacetate and 2-acetylaminofluorene. Cancer Res., 30,
1248–1261
Paglia, D.E. & Valentine, W.N. (1975) Characteristics of a pyrimidine-specific 5′-nucleotidase in
human erythrocytes. J. biol. Chem., 250, 7973–7979
Paglia, D.E., Valentine, W.N. & Dahlgren, J.G. (1975) Effects of low-level lead exposure on pyri-
midine 5′-nucleotidase and other erythrocyte enzymes: Possible role of pyrimidine 5′-nucleo-
tidase in the pathogenesis of lead-induced anaemia. J. clin. Invest., 56, 1164–1169
Pagliuca, A., Mufti, G.J., Baldwin, D., Lestas, A.N., Wallis, R.M. & Bellingham, A.J. (1990) Lead
poisoning: Clinical, biochemical, and haematological aspects of a recent outbreak. Clin.
Pathol., 43, 277–281
Palminger Hallén, I. & Oskarsson, A. (1993) Dose dependent transfer of 203lead to milk and tissue
uptake in suckling offspring studied in rats and mice. Pharmacol. Toxicol., 73, 174–179
Palminger Hallén, I. & Oskarsson, A. (1995) Bioavailability of lead from various milk diets
studied in a suckling rat model. Biometals, 8, 231–236
Palminger Hallén, I., Jorhem, L., Lagerkvist, B.J. & Oskarsson, A. (1995a) Lead and cadmium
levels in human milk and blood. Sci. tot. Environ., 166, 149–155
Palminger Hallén, I., Jorhem, L. & Oskarsson, A. (1995b) Placental and lactational transfer of lead
in rats: A study on the lactational process and effects on offspring. Arch. Toxicol., 69, 596–602
Palminger Hallén, I., Jonsson, S., Karlsson, M.O. & Oskarsson, A. (1996a) Kinetic observations
in neonatal mice exposed to lead via milk. Toxicol. appl. Pharmacol., 140, 13–18
Palminger Hallén, I., Jonsson, S., Karlsson, M.O. & Oskarsson, A. (1996b) Toxicokinetics of lead
in lactating and nonlactating mice. Toxicol. appl. Pharmacol., 136, 342–347
Palus, J., Rydzynski, K., Dziubaltowska, E., Wyszynska, K., Natarajan, A.T. & Nilsson, R. (2003)
Genotoxic effects of occupational exposure to lead and cadmium. Mutat. Res., 540, 19–28
P’an, A.Y.S. & Kennedy, C. (1989) Lead distribution in rats repeatedly treated with low doses of
lead acetate. Environ. Res., 48, 238–247
Pan American Health Organization (1997) Eliminating Lead in Gasoline in Latin America and the
Caribbean. Report — 1996, Epidemiol. Bulletin, 18, 9–10
Parikh, D., Pandya, C.B. & Kashyap, S.K. (1999) Investigating environmental lead sources and path-
ways. In: Lead Poisoning Prevention and Treatment: Implementing a National Programme in
Developing Countries, February 8–10, Bangalore, India, pp. 205–208 [http:/www.leadpoison.
net/environment/investigating.htm; accessed 09/02/2004]
Parkinson, D.K., Hodgson, M.J., Bromet, E.J., Dew, M.A. & Connell, M.M. (1987) Occupational
lead exposure and blood pressure. Br. J. ind. Med., 44, 744–748
P 379-468 DEF.qxp 09/08/2006 13:53 Page 440
Parkpian, P., Leong, S.T., Laortanakul, P. & Thunthaisong, N. (2003) Regional monitoring of lead
and cadmium contamination in a tropical grazing land site, Thailand. Environ. Monitor.
Assess., 85, 157–173
Parry, C. & Eaton, J. (1991) Kohl: A lead-hazardous eye makeup from the Third World to the First
World. Environ. Health Perspect., 94, 121–123
Parsons, P.J., Reilly, A.A. & Esernio-Jenssen, D. (1997) Screening children exposed to lead: An
assessment of the capillary blood lead fingerstick test. Clin. Chem., 43, 302–311
Parsons, P.J., Reilly, A.A., Esernio-Jenssen, D., Werk, L.N., Mofenson, H.C., Stanton, N.V. &
Matte, T.D. (2001) Evaluation of blood lead proficiency testing: Comparison of open and blind
paradigms. Clin. Chem., 47, 322–330
Partanen, T., Heikkila, P., Hernberg, S., Kauppinen, T., Moneta, G. & Ojajarvi, A. (1991) Renal cell
cancer and occupational exposure to chemical agents. Scand. J. Work. environ. Health, 17,
231–239
Pasminco Metals (1998) Product Specification Sheet: 99.97% & 99.99% Lead Product, Melbourne
Pasminco Metals (2000) Product Specification Sheet: Pasminco Preferred Products (PPP): Oxide
Lead, Melbourne
Pasternack, B. & Ehrlich, L. (1972) Occupational exposure to an oil mist atmosphere. A 12-year
mortality study. Arch. environ. Health, 25, 286–294
Patel, A.B., Williams, S.V., Frumkin, H., Kondawar, V.K., Glick, H. & Ganju, A.K. (2001) Blood
lead in children and its determinants in Nagpur, India. Int. J. occup. environ. Health, 7, 119–126
Patierno, S.R. & Landolph, J.R. (1989) Soluble vs insoluble hexavalent chromate. Relationship of
mutation to in vitro transformation and particle uptake. Biol. trace Elem. Res., 21, 469–474
Patierno, S.R., Banh, D. & Landolph, J.R. (1988) Transformation of C3H/10T1/2 mouse embryo
cells to focus formation and anchorage independence by insoluble lead chromate but not
soluble calcium chromate: Relationship to mutagenesis and internalization of lead chromate
particles. Cancer Res., 48, 5280–5288
Patriarca, M., Menditto, A., Rossi, B., Lyon, T.D.B. & Fell, G.S. (2000) Environmental exposure
to metals of newborns, infants and young children. Microchem. J., 67, 351–361
Patterson, C., Ericson, J., Manea-Krichten, M. & Shirahata, H. (1991) Natural skeletal levels of
lead in Homo sapiens sapiens uncontaminated by technological lead. Sci. total Environ., 107,
205–236
Paul, R., White, F. & Luby, S. (2003) Trends in lead content of petrol in Pakinstan. Bull. World
Health Org., 81, 468
Pawlik-Skowronska, B. (2001) Phytochelatin production in freshwater algae Stigeoclonium in
response to heavy metals contained in mining water; effects of some environmental factors.
Aquat. Toxicol., 52, 241–249
Pawlik-Skowronska, B., Sanità di Toppi, L., Favali, M.A., Fossati, F., Pirszel, J. & Skowronski, T.
(2002) Lichens respond to heavy metals by phytochelatin synthesis. New Phytol., 156, 95–102
Penoles (2003) Product Data Sheet: Lead, Torreon, Coah
Peraino, C., Fry, R.J.M. & Staffeldt, E. (1971) Reduction and enhancement by phenobarbital of
hepatocarcinogenesis induced in the rat by 2-acetylaminofluorene. Cancer Res., 31, 1506–1512
Pereira, L., Mañay, N., Cousillas, Z.A., Barregård, L., Sällsten, G. & Schütz, A. (1996) Occupa-
tional lead exposure in Montevideo, Uruguay. Int. J. occup. environ. Health, 2, 328–330
Perino, J. & Ernhart, C.B. (1974) The relation of subclinical lead level to cognitive and sensori-
motor impairment in black preschoolers. J. learning Disord., 7, 26–30
P 379-468 DEF.qxp 09/08/2006 13:53 Page 441
Perkins, K.C. & Oski, F.A. (1976) Elevated blood lead in a 6-month-old breast-fed infant: The role
of newsprint logs. Pediatrics, 57, 426–427
Pesch, B., Haerting, J., Ranft, U., Klimpel, A., Oelschlagel, B. & Schill, W. & the MURC Study
Group (2000) Occupational risk factors for renal cell carcinoma: Agent-specific results from
a case−control study in Germany. Int. J. Epidemiol., 29, 1014–1024
Petering, D.H., Huang, M., Moteki, S. & Shaw, C.F., III (2000) Cadmium and lead interactions
with transcription factor IIIA from Xenopus laevis: A model for zinc finger protein reactions
with toxic metal ions and metallothionein. Mar. environ. Res., 50, 89–92
Petrucci, R., Leonardi, A. & Battistuzzi, G. (1982) The genetic polymorphism of δ-aminolevulinate
dehydrase in Italy. Hum. Genet., 60, 289–290
Phuapradit, W., Jetsawangsri, T., Chaturachinda, K. & Noinongyao, N. (1994) Maternal and umbi-
lical cord blood lead levels in Ramathibodi Hospital, 1993. J. med. Assoc. Thai., 77, 368–372
Physical and Theoretical Chemistry Laboratory (2004) Chemistry resoures [http://physchem.ox.
ac.uk/resources.html; accessed 01/02/2004]
Pickston, L., Brewerton, H.V., Drysdale, J.M., Hughes, J.T., Smith, J.M., Love, J.L., Sutcliffe, E.R.
& Davidson, F. (1985) The New Zealand diet: A survey of elements, pesticides, colours, and
preservatives. N.Z. J. Technol., 1, 81–89
Piechalak, A., Tomaszewska, B., Baralkiewicz, D. & Malecka, A. (2002) Accumulation and
detoxification of lead ions in legumes. Phytochemistry, 60, 153–162
Pinkerton, L.E., Biagini, R.E., Ward, E.M., Hull, R.D., Deddens, J.A., Boeniger, M.F., Schnorr,
T.M., MacKenzie, B.A. & Luster, M.I. (1998) Immunologic findings among lead-exposed
workers. Am. J. ind. Med., 33, 400–408
Pinon-Lataillade, G., Thoreux-Manlay, A., Coffigny, H., Monchaux, G., Masse, R. & Soufir, J.-C.
(1993) Effect of ingestion and inhalation of lead on the reproductive system and fertility of
adult male rats and their progeny. Hum. exp. Toxicol., 12, 165–172
Piomelli, S., Corash, L., Corash, M.B., Seaman, C., Mushak, P., Glover, B. & Padgett, R. (1980)
Blood lead concentrations in a remote Himalayan population. Science, 210, 1135–1137
Pirkle, J.L., Brody, D.J., Gunter, E.W., Kramer, R.A., Paschal, D.C., Flegal, K.M. & Matte, T.D.
(1994) The decline in blood lead levels in the United States — The National Health and Nutri-
tion Examination Surveys (NHANES). J. Am. med. Assoc., 272, 284–291
Pirkle, J.L., Kaufmann, R.B., Brody, D.J., Hickman, T., Gunter, E.W. & Paschal, D.C. (1998)
Exposure of the US population to lead, 1991–1994. Environ. Health Perspect., 106, 745–750
Poirier, L.A., Theiss, J.C., Arnold, L.J. & Shimkin, M.B. (1984) Inhibition by magnesium and
calcium acetates of lead subacetate- and nickel acetate-induced lung tumors in strain A mice.
Cancer Res., 44, 1520–1522
Polák, J., O’Flaherty, E.J., Freeman, G.B., Johnson, J.D., Liao, S.C. & Bergstrom, P.D. (1996) Eva-
luating lead bioavailability data by means of a physiologically based lead kinetic model.
Fundam. appl. Toxicol., 29, 63–70
Pollock, C.A. & Ibels, L.S. (1988) Lead nephropathy — A preventable cause of renal failure. Int.
J. artif. Organs, 11, 75–78
Pollution Control Department (1996) Pollution Thailand, 1995, Bangkok, Ministry of Science,
Technology and Environment, the Government of Thailand, pp. 8–9
Pönkä, A. (1998) Lead in the ambient air and blood of children in Helsinki. Sci. total Environ., 219,
1–5
P 379-468 DEF.qxp 09/08/2006 13:53 Page 442
Pönkä, A., Salminen, E. & Ahonen, S. (1993) Lead in the ambient air and blood specimens of
children in Helsinki. Sci. total Environ., 138, 301–308
Pontifex, A.H. & Garg, A.K. (1985) Lead poisoning from an Asian Indian folk remedy. Can. med.
Assoc. J., 133, 1227–1228
Potula, V.L. & Hu, H. (1996a) Occupational and lifestyle determinants of blood lead levels among
men in Madras, India. Int. J. occup. environ. Health, 2, 1–4
Potula, V.L. & Hu, H. (1996b) Relationship of hemoglobin to occupational exposure to motor
vehicle exhaust. Toxicol. ind. Health, 12, 629–637
Pounds, J.G. & Leggett, R.W. (1998) The ICRP age-specific biokinetic model for lead: Validations,
empirical comparisons, and explorations. Environ. Health Perspect., 106 (Suppl. 6), 1505–1511
Pounds, J.G. & Rosen, J.F. (1986) Cellular metabolism of lead: A kinetic analysis in cultured osteo-
clastic bone cells. Toxicol. appl. Pharmacol., 83, 531–545
Pounds, J.G., Marlar, R.J. & Allen, J.R. (1978) Metabolism of lead-210 in juvenile and adult rhesus
monkeys (Macaca mulatta). Bull. environ. Contam. Toxicol., 19, 684–691
Pounds, J.G., Wright, R. & Kodell, R.L. (1982) Cellular metabolism of lead: A kinetic analysis in
the isolated rat hepatocyte. Toxicol. appl. Pharmacol., 66, 88–101
Prince, T.S. & Horstman, S.W. (1993) Case study at a college rifle range: The effect of a new venti-
lation system on air and blood lead levels. Appl. Occup. Environ. Hyg., 8, 909–911
Prpic-Majic, D., Pizent, A., Jurasovic, J., Pongracic, J. & Restek-Samarzija, N. (1996) Lead poiso-
ning associated with the use of Ayurvedic metal-mineral tonics. Clin. Toxicol., 34, 417–423
Pulido, M.D. & Parrish, A.R. (2003) Metal-induced apoptosis: Mechanisms. Mutat. Res., 533,
227–241
Purser, D.A., Berrill, K.R. & Majeed, S.K. (1983) Effects of lead exposure on peripheral nerve in
the cynomolgus monkey. Br. J. ind. Med., 40, 402–412
Quarterman, J. & Morrison, J.N. (1975) The effects of dietary calcium and phosphorus on the
retention and excretion of lead in rats. Br. J. Nutr., 34, 351–362
Quarterman, J., Morrison, J.N. & Humphries, W.R. (1977) The role of phospholipids and bile in
lead absorption. Proc. Nutr. Soc., 36, 103A
Quarterman, J., Morrison, J.N. & Humphries, W.R. (1978) The influence of high dietary calcium
and phosphate on lead uptake and release. Environ. Res., 17, 60–67
Quarterman, J., Humphries, W.R., Morrison, J.N. & Morrison, E. (1980) The influence of dietary
amino acids on lead absorption. Environ. Res., 23, 54–67
Queirolo, F., Stegen, S., Restovic, M., Paz, M., Ostapczuk, P., Schwuger, M.J. & Muñoz, L. (2000)
Total arsenic, lead, and cadmium levels in vegetables cultivated at the Andean villages of
northern Chile. Sci. total Environ., 255, 75–84
Queiroz, M.L., Perlingeiro, R.C., Bincoletto, C.,. Almeida, M., Cardoso, M.P. & Dantas, D.C.
(1994a) Immunoglobulin levels and cellular immune function in lead exposed workers.
Immunopharmacol. Immunotoxicol., 16, 115–128
Queiroz, M.L.S., Costa, F.F., Bincoletto, C., Perlingeiro, R.C.R., Dantas, D.C.M., Cardoso, M.P. &
Almeida, M. (1994b) Engulfment and killing capabilities of neutrophils and phagocytic splenic
function in persons occupationally exposed to lead. Int. J. Immunopharmacol., 16, 239–244
Quinn, M.J. (1985) Factors affecting blood lead concentrations in the UK: Results of the EEC
blood lead surveys, 1979–1981. Int. J. Epidemiol., 14, 420–431
Quinn, M.J. & Delves, H.T. (1987) UK blood lead monitoring programme 1984–1987: Protocol
and results for 1984. Human Toxicol., 6, 459–474
P 379-468 DEF.qxp 09/08/2006 13:53 Page 443
Quinn, M.J. & Delves, H.T. (1988) UK blood lead monitoring programme 1984–1987: Results for
1985. Human Toxicol., 7, 105–123
Quinn, M.J. & Delves, H.T. (1989) The UK blood lead monitoring programme 1984–1987: Results
for 1986. Human Toxicol., 8, 205–220
Quintanilla-Vega, B., Hoover, D.J., Bal, W., Silbergeld, E.K., Waalkes, M.P. & Anderson, L.D.
(2000) Lead interaction with human protamine (HP2) as a mechanism of male reproductive
toxicity. Chem. Res. Toxicol., 13, 594–600
Rabinowitz, M.B. (1991) Toxicokinetics of bone lead. Environ. Health Perspect., 91, 33–37
Rabinowitz, M.B. (1995) Relating tooth and blood lead levels in children. Bull. environ. Contam.
Toxicol., 55, 853–857
Rabinowitz, M. & Needleman, H.L. (1982) Temporal trends in the lead concentrations of umbilical
cord blood. Science, 216, 1429–1431
Rabinowitz, M.B., Wetherill, G.W. & Kopple, J.D. (1976) Kinetic analysis of lead metabolism in
healthy humans. J. clin. Invest., 58, 260–270
Rabinowitz, M.B., Wetherill, G.W. & Kopple, J.D. (1977) Magnitude of lead intake from respi-
ration by normal man. J. Lab. clin. Med., 90, 238–248
Rabinowitz, M.B., Kopple, J.D. & Wetherill, G.W. (1980) Effect of food intake and fasting on
gastrointestinal lead absorption in humans. Am. J. clin. Nutr., 33, 1784–1788
Rabinowitz, M.B., Needleman, H., Burley, M., Finch, H. & Rees, J. (1984) Lead in umbilical
blood, indoor air, tap water, and gasoline in Boston. Arch. environ. Health, 39, 299–301
Rabinowitz, M., Leviton, A. & Needleman, H. (1985) Lead in milk and infant blood: A dose–
response model. Arch. environ. Health, 40, 283–286
Rader, J.I., Peeler, J.T. & Mahaffey, K.R. (1981) Comparative toxicity and tissue distribution of
lead acetate in weanling and adult rats. Environ. Health Perspect., 42, 187–195
Ragan, H.A. (1977) Effects of iron deficiency on the absorption and distribution of lead and
cadmium in rats. J. Lab. clin. Med., 90, 700–706
Raghavan, S.R.V., Culver, B.D. & Gonick, H.C. (1980) Erythrocyte lead-binding protein after
occupational exposure. I. Relationship to lead toxicity. Environ. Res., 22, 264–270
Raghunath, R. & Nambi, K.S.V. (1998) Lead leaching from pressure cookers. Sci. total Environ.,
224, 143–148
Raghunath, R., Tripathi, R.M., Khandekar, R.N. & Nambi, K.S.V. (1997) Retention time of Pb, Cd,
Cu and Zn in children’s blood. Sci. total Environ., 207, 133–139
Raghunath, R., Tripathi, R.M., Kumar, A.V., Sathe, A.P., Khandekar, R.N. & Nambi, K.S. (1999)
Assessment of Pb, Cd, Cu and Zn exposures of 6 to 10 year old children in Mumbai. Environ.
Res., 80, 215–221
Raghunath, R., Tripathi, R.M., Sastry, V.N. & Krishnamoorthy, T.M. (2000) Heavy metals in
maternal and cord blood. Sci. total Environ., 250, 135–141
Rahbar, M.H., White, F., Agboatwalla, M., Hozhabri, S. & Luby, S. (2002) Factors associated with
elevated blood lead concentrations in children in Karachi, Pakistan. Bull. World Health Org.,
80, 769–775
Rahman, H., Al Khayat, A. & Menon, N. (1986) Lead poisoning in infancy — Unusual causes in
the UAE. Ann. trop. Paediatr., 6, 213–217
Rahman, A., Maqbool, E. & Zuberi, H.S. (2002) Lead-associated deficits in stature, mental ability
and behaviour in children in Karachi. Ann. trop. Paediatr., 22, 301–311
P 379-468 DEF.qxp 09/08/2006 13:53 Page 444
Rai, U.N. & Sinha, S. (2001) Distribution of metals in aquatic edible plants: Trapa natans (Roxb.)
Makino and Ipomoea aquatica Forsk. Environ. Monitor. Assess., 70, 241–252
Rai, U.N., Sinha, S. & Chandra, P. (1996) Metal biomonitoring in water resources of Eastern
Ghats, Koraput (Orissa), India by aquatic plants. Environ. Monitor. Assess., 43, 125–137
Rai, U.N., Tripathi, R.D., Vajpayee, P., Jha, V. & Ali, M.B. (2002) Bioaccumulation of toxic metals
(Cr, Cd, Pb and Cu) by seeds of Euryale ferox Salisb. (Makhana). Chemosphere, 46, 267–272
Rajah, T. & Ahuja, Y.R. (1995) In vivo genotoxic effects of smoking and occupational lead expo-
sure in printing press workers. Toxicol. Lett., 76, 71–75
Ramel, C. & Magnusson, J. (1979) Chemical induction of nondisjunction in Drosophila. Environ.
Health Perspect., 31, 59–66
Ramesh, G.T., Manna, S.K., Aggarwal, B.B. & Jadhav, A.L. (2001) Lead exposure activates
nuclear factor kappa B, activator protein-1, c-Jun N-terminal kinase and caspases in the rat
brain. Toxicol. Lett., 123, 195–207
Razmiafshari, M., Kao, J., d’Avignon, A. & Zawia, N.H. (2001) NMR identification of heavy
metal-binding sites in a synthetic zinc finger peptide: Toxicological implications for the inter-
actions of xenobiotic metals with zinc finger proteins. Toxicol. appl. Pharmacol., 172, 1–10
Rees, D.C., Duley, J.A. & Marinaki, A.M. (2003) Pyrimidine 5′ nucleotidase deficiency. Br. J.
Haematol., 120, 375–383
Regional Environmental Center for Central and Eastern Europe (1998) Sofia Initiative on Local Air
Quality: Phase-out of Leaded Gasoline — Synthesis Report, Szentendre, Hungary
Reh, C.M. & Klein, M.K. (1990) Health Hazard Evaluation Report, HETA 87-0376-2018, U.S.
Dept. of Justice, U.S. Marshals Service, Washington, DC, USA, NIOSH
Rencher, A.C., Carter, M.W. & McKee, D.W. (1977) A retrospective epidemiological study of
mortality at a large western copper smelter. J. occup. Med., 19, 754–758
Rendall, R.E.G., Baily, P. & Soskolne, C.L. (1975) The effect of particle size on absorption of
inhaled lead. Am. ind. Hyg. Assoc. J., 36, 207–213
Revich, B.A., Bykov, A.A., Liapunov, S.M., Prikhozhan, A.M., Seregina, I.F. & Sobolev, M.B.
(1998) [Experience in the study of the effects of lead on the health status of children in
Belovo.] Med. Tr. Prom. Ekol., 12, 25–32 (in Russian)
Reynolds, S.J., Seem, R., Fourtes, L.J., Sprince, N.L., Johnson, J., Walkner, L., Clarke, W. &
Whitten, P. (1999) Prevalence of elevated blood leads and exposure to lead in construction
trades in Iowa and Illinois. Am. J. ind. Med., 36, 307–316
Rice, D.C. (1997) Effects of lifetime lead exposure in monkeys on detection of pure tones. Fundam.
appl. Toxicol., 36, 112–118
Rice, D.C. & Hayward, S. (1999) Comparison of visual function at adulthood and during aging in
monkeys exposed to lead or methylmercury. NeuroToxicology, 20, 767–784
Richter, E.D., Yaffe, Y. & Gruener, N. (1979) Air and blood lead levels in a battery factory.
Environ. Res., 20, 87–98
Richter, J., Hájek, Z., Pfeifer, I. & Šubrt, P. (1999) Relation between concentration of lead, zinc
and lysozyme in placentas of women with intrauterine foetal growth retardation. Cent. Eur. J.
public Health, 7, 40–42
Rinehart, R. & Almaguer, D. (1992) Health Hazard Evaluation Report, HETA 90-084-2219,
Kansas City Kansas Police Dept., Kansas City, KS, USA, NIOSH
Risch, H.A., Burch, J.D., Miller, A.B., Hill, G.B., Steele, R. & Howe, G.R. (1988) Occupational
factors and the incidence of cancer of the bladder in Canada. Br. J. ind. Med., 45, 361–367
P 379-468 DEF.qxp 09/08/2006 13:53 Page 445
Robbiano, L., Carrozzino, R., Puglia, C.P., Corbu, C. & Brambilla, G. (1999) Correlation between
induction of DNA fragmentation and micronuclei formation in kidney cells from rats and
humans and tissue-specific carcinogenic activity. Toxicol. appl. Pharmacol., 161, 153–159
Robbins, S.K., Blehm, K.D. & Buchan, R.M. (1990) Controlling airborne lead in indoor firing
ranges. Appl. Occup. Environ. Hyg., 5, 435–439
Roberts, H.J. (1983) Potential toxicity due to dolomite and bonemeal. South. med. J., 76, 556–559
Robertson, I.K. & Worwood, M. (1978) Lead and iron absorption from rat small intestine: The
effect of dietary Fe deficiency. Br. J. Nutr., 40, 253–260
Robins, T.G., Bornman, M.S., Ehrlich, R.I., Cantrell, A.C., Pienaar, E., Vallabh, J. & Miller, S.
(1997) Semen quality and fertility of men employed in a South African lead acid battery plant.
Am. J. ind. Med., 32, 369–376
Robison, S.H., Cantoni, O. & Costa, M. (1984) Analysis of metal-induced DNA lesions and DNA-
repair replication in mammalian cells. Mutat. Res., 131, 173–181
Rodamilans, M., Osaba, M.J.M., To-Figueras, J., Rivera Fillat, F., Marques, J.M., Perez, P. &
Corbella, J. (1988) Lead toxicity on endocrine testicular function in an occupationally exposed
population. Hum. Toxicol., 7, 125–128
Rodamilans, M., Torra, M., To-Figueras, J., Corbella, J., López, B., Sánchez, C. & Mazzara, R.
(1996) Effect of the reduction of petrol lead on blood lead levels of the population of Barcelona
(Spain). Bull. environ. Contam. Toxicol., 56, 717–721
Roe, F.J.C., Boyland, E., Dukes, C.E. & Mitchley, B.C.V. (1965) Failure of testosterone or xanthop-
terin to influence the induction of renal neoplasms by lead in rats. Br. J. Cancer, ii, 860–866
Roels, H.A., Hoet, P. & Lison, D. (1999) Usefulness of biomarkers of exposure to inorganic
mercury, lead, or cadmium in controlling occupational and environmental risks of nephro-
toxicity. Ren. Fail., 21, 251–262
Rogalla, T., Ehrnsperger, M., Preville, X., Kotlyarov, A., Lutsch, G., Ducasse, C., Paul, C., Wieske,
M., Arrigo, A.-P., Buchner, J. & Gaestel, M. (1999) Regulation of Hsp27 oligomerization,
chaperone function, and protective activity against oxidative stress/tumor necrosis factor alpha
by phosphorylation. J. biol. Chem., 274, 18947–18956
Rogan, W.J., Ragan, N.B., Damokosh, A.L., Davoli, C., Shaffer, T.R., Jones, R.L., Wilkens, S.,
Heenehan, M.C., Ware, J.H. & Henretig, F. (1999) Recall of a lead-contaminated vitamin and
mineral supplement in a clinical trial. Pharmacoepidemiol. Drug Saf., 8, 343–350
Roh, Y.-M., Kim, K. & Kim, H. (2000) Zinc protoporphyrin IX concentrations between normal
adults and the lead-exposed workers measured by HPLC, spectrofluorometer, and hemato-
fluorometer. Ind. Health, 38, 372–379
Romero, A.J. (1996) The environmental impact of leaded gasoline in Venezuela. J. environ. Dev.,
5, 434–438
Romieu, I. & Lacasana, M. (1996) Lead in the Americas. A call for action. In: Howson, C.P.,
Hernández-Avila, M. & Rall, D.P., eds, Committee to Reduce Lead Exposure in the Americas,
Board on International Health Institute of Medicine, Washington, DC in collaboration with the
National Institute of Public Health, Cuernavaca, Morelos, Mexico
Romieu, I., Lacasana, M., McConnell, R. & the Lead Research Group of the Pan-American Health
Organization (1997) Lead exposure in Latin America and the Caribbean. Environ. Health
Perspect., 105, 398–405
P 379-468 DEF.qxp 09/08/2006 13:53 Page 446
Ronis, M.J.J., Badger, T.M., Shema, S.J., Roberson, P.K. & Shaikh, F. (1996) Reproductive toxicity
and growth effects in rats exposed to lead at different periods during development. Toxicol.
appl. Pharmacol., 136, 361–371
Rosenkranz, H.S. & Poirier, L.A. (1979) Evaluation of the mutagenicity and DNA-modifying acti-
vity of carcinogens and noncarcinogens in microbial systems. J. natl Cancer Inst., 62, 873–891
Roses, O.E., Gonzalez, D.E., López, C.M., Piñeiro, A.E. & Villaamil, E.C. (1997) Lead levels in
Argentine market wines. Bull. environ. Contam. Toxicol., 59, 210–215
Rosman, K.J.R., Chisholm, W., Boutron, C.F., Candelone, J.P. & Hong, S. (1994a) Isotopic evi-
dence to account for changes in the concentration of lead in Greenland snow between 1960
and 1988. Geochim. Cosmochim. Acta, 58, 3265–3269
Rosman, K.J.R., Chisholm, W., Boutron, C.F., Candelone, J.P. & Patterson, C.C. (1994b) Anthro-
pogenic lead isotopes in Antarctica. Geophys. Res. Lett., 21, 2669–2672
Rothenberg, S.J., Karchmer, S., Schnaas, L., Perroni, E., Zea, F. & Fernandez Alba, J. (1994)
Changes in serial blood lead levels during pregnancy. Environ. Health Perspect., 102, 876–880
Rothenberg, S.J., Schnaas, L., Perroni, E., Hernández, R.M. & Karchmer, S. (1998) Secular trend
in blood lead levels in a cohort of Mexico City children. Arch. environ. Health, 53, 231–235
Rothenberg, S.J., Manalo, M., Jiang, J., Khan, F., Cuellar, R., Reyes, S., Sanchez, M., Reynoso, B.,
Aguilar, A., Diaz, M., Acosta, S., Jauregui, M. & Johnson, C. (1999) Maternal blood lead level
during pregnancy in South Central Los Angeles. Arch. environ. Health, 54, 151–157
Rothenberg, S.J., Khan, F., Manalo, M., Jiang, J., Cuellar, R., Reyes, S., Acosta, S., Jauregui, M.,
Diaz, M., Sanchez, M., Todd, A.C. & Johnson, C. (2000) Maternal bone lead contribution to
blood lead during and after pregnancy. Environ. Res., 82, 81–90
Rothenberg, S.J., Kondrashov, V., Manalo, M., Jiang, J., Cuellar, R., Garcia, M., Reynoso, B.,
Reyes, S., Diaz, M. & Todd, A.C. (2002) Increases in hypertension and blood pressure during
pregnancy with increased bone lead levels. Am. J. Epidemiol., 156, 1079–1087
Roy, N.K. & Rossman, T.G. (1992) Mutagenesis and comutagenesis by lead compounds. Mutat.
Res., 298, 97–103
Roy, M.M., Gordon, C.L., Beaumont, L.F., Chettle, D.R. & Webber, C.E. (1997) Further experience
with bone lead content measurements in residents of southern Ontario. Appl. Radiat. Isot., 48,
391–396
Rudnick, R.L. & Fountain, D.M. (1995) Nature and composition of the continental crust: A lower
crustal perspective. Rev. Geophys., 33, 267–309
Ruhe, R.L. (1982a) Health Hazard Evaluation Report, HETA 81-0426-1062, Xomox Corp.,
Cincinnati, OH, USA, NIOSH
Ruhe, R.L (1982b) Health Hazard Evaluation Report, HETA 81-0438-1090, Matryx Corp.,
Sharonville, OH, USA, NIOSH
Ruhe, R.L. & Thoburn, T.W. (1984) Health Hazard Evaluation Report, HETA 83-0459-1465, Stuart
Manufacturing, Denver, CO, USA, NIOSH
Russell, J.C., Griffin, T.B., McChesney, E.W. & Coulston, F. (1978) Metabolism of airborne parti-
culate lead in continuously exposed rats: Effect of penicillamine on mobilization. Ecotoxicol.
Environ. Saf., 2, 49–53
Ryu, J.E., Ziegler, E.E. & Fomon, S.J. (1978) Maternal lead exposure and blood lead concentration
in infancy. J. Pediatrics, 93, 476–478
Ryu, J.E., Ziegler, E.E., Nelson, S.E. & Fomon, S.J. (1983) Dietary intake of lead and blood lead
concentration in early infancy. Am. J. Dis. Child, 137, 886–891
P 379-468 DEF.qxp 09/08/2006 13:53 Page 447
Ryu, J.E., Ziegler, E.E., Nelson, S.E. & Fomon, S.J. (1985) Dietary and environmental exposure to
lead and blood lead during early infancy. In: Mahaffey, K.R., ed., Chapter 7, Dietary and Envi-
ronmental Lead: Human Health Effects, Amsterdam, Elsevier Science Publishers, pp. 187–209
Sadasivan, S., Negi, B.S. & Mishra, U.C. (1987) Atmospheric lead levels in some cities in India.
Indian J. environ. Health, 29, 280–286
Saenger, P., Markowitz, M.E. & Rosen, J.F. (1984) Depressed excretion of 6-beta-hydroxycortisol
in lead-toxic children. J. clin. Endocrinol. Metab., 58, 363–367
Sakai, T. (2000) Biomarkers of lead exposure. Ind. Health, 38, 127–142
Sakai, T. & Ushio, K. (1986) A simplified method for determining erythrocyte pyrimidine 5′-
nucleotidase (P5N) activity by HPLC and its value in monitoring lead exposure. Br. J. ind.
Med., 43, 839–844
Sakai, T., Yanagihara, S. & Ushio, K. (1980) Restoration of lead-inhibited 5-aminolevulinate dehy-
dratase activity in whole blood by heat, zinc ion, and (or) dithiothreitol. Clin. Chem., 26,
625–628
Sakai, K., Susuki, M., Yamane, Y., Takahashi, A. & Ide, G. (1990) Promoting effect of basic lead
acetate administration on the tumorigenesis of lung in N-nitrosodimethylamine-treated mice.
Bull. environ. Contam. Toxicol., 44, 707–714
Sallmén, M., Lindbohm, M.-L., Anttila, A., Taskinen, H. & Hemminki, K. (2000) Time to pregnancy
among wives of men occupationally exposed lo lead. Epidemiology, 11, 141–147
Salt, D.E., Blaylock, M., Kumar, N.P.B.A., Dushenkov, V., Ensley, B.D., Chet, I. & Raskin, I.
(1995) Phytoremediation: A novel strategy for the removal of toxic metals from the environ-
ment using plants. Bio/Technology, 13, 468–474
Salt, D.E., Smith, R.D. & Raskin, I. (1998) Phytoremediation. Ann. Rev. Plant Physiol. Plant mol.
Biol., 49, 643–668
Sandhu, S.S., Ma, T.-H., Peng, Y. & Zhou, X.-D. (1989) Clastogenicity evaluation of seven
chemicals commonly found at hazardous industrial waste sites. Mutat. Res., 224, 437–445
Sanín, L.H., Gonzalez-Cossio, T., Romieu, I., Peterson, K.E., Ruíz, S., Palazuelos, E., Hernandez-
Avila, M. & Hu, H. (2001) Effect of maternal lead burden on infant weight and weight gain at
one month of age among breastfed infants. Pediatrics, 107, 1016–1023
Sankila, R., Karjalainen, S., Pukkala, E., Oksanen, H., Hakulinen, T., Teppo, L. & Hakama, M.
(1990) Cancer risk among glass factory workers: An excess of lung cancer? Br. J. ind. Med.,
47, 815–818
Sauerhoff, M.W. & Michaelson, I.A. (1973) Hyperactivity and brain catecholamines in lead-exposed
developing rats. Science, 182, 1022–1024
Savolainen, K.M., Loikkanen, J., Eerikainen, S. & Naarala, J. (1998) Glutamate-stimulated ROS
production in neuronal cultures: Interactions with lead and the cholinergic system. Neurotoxi-
cology, 19, 669–674
Saxena, D.K., Srivastava, R.S., Lal, B. & Chandra, S.V. (1987) The effect of lead exposure on the
testis of growing rats. Exp. Pathol., 31, 249–252
Saxena, D.K., Lal, B., Srivastava, R.S. & Chandra, S.V. (1990) Lead induced testicular hypersensi-
tivity in stressed rats. Exp. Pathol., 39, 100–109
Saxena, D.K, Singh, C., Murthy, R.C., Mathur, N. & Chandra, S.V. (1994) Blood and placental
lead levels in an Indian city: A preliminary report. Arch. environ. Health, 49, 106–110
Scarano, G. & Morelli, E. (2002) Characterization of cadmium- and lead-phytochelatin complexes
formed in a marine microalga in response to metal exposure. Biomet., 15, 145–151
P 379-468 DEF.qxp 09/08/2006 13:53 Page 448
Scelfo, G.M. & Flegal, A.R. (2000) Lead in calcium supplements. Environ. Health Perspect., 108,
309–313
Schaller, K.H., Angerer, J. & Drexler, H. (2002) Review. Quality assurance of biological monito-
ring in occupational and environmental medicine. J. Chromatogr. B., 778, 403–417
Schechtman, L.M., Hatch, G.G., Anderson, T.M., Putman, D.L., Kouri, R.E., Cameron, J.W., Nims,
R.W., Spalding, J.W., Tennant, R.W. & Lubet, R.A. (1986) Analysis of the interlaboratory and
intralaboratory reproducibility of the enhancement of simian adenovirus SA7 transformation
of Syrian hamster embryo cells by model carcinogenic and noncarcinogenic compounds. Envi-
ron. Mutag., 8, 495–514
Schmid, E., Bauchinger, M., Pietruck, S. & Hall, G. (1972) [Cytogenetic action of lead in human
peripheral lymphocytes in vitro and in vivo.] Mutat. Res., 16, 401–406 (in German)
Schmitt, C.J. & Brumbaugh, W.G. (1990) National contaminant biomonitoring program: Concen-
trations of arsenic, cadmium, cooper, lead, mercury, selenium, and zinc in U.S. freshwater fish,
1976–1984. Arch. environ. Contam. Toxicol., 19, 731–747
Schmitt, M.D.C., Trippler, D.J., Wachtler, J.N. & Lund, G.V. (1988) Soil lead concentrations in
residential Minnesota as measured by ICP-AES. Water Air Soil Pollut., 39, 157–168
Schnaas, L., Rothenberg, S.J., Perroni, E., Martínez, S., Hernández, C. & Hernández, R.M. (2000)
Temporal pattern in the effect of postnatal blood lead level on intellectual development of
young children. Neurotoxicol. Teratol., 22, 805–810
Schroeder, H.A. & Mitchener, M. (1971) Toxic effects of trace elements on the reproduction of
mice and rats. Arch. environ. Health, 23, 102–106
Schroeder, H.A., Balassa, J.J. & Vinton, W.H., Jr (1965) Chromium, cadmium and lead in rats:
Effects of life span, tumors and tissue levels. J. Nutr., 86, 51–66
Schroeder, H.A., Mitchener, M. & Nason, A.P. (1970) Zirconium, niobium, antimony, vanadium
and lead in rats: Life term studies. J. Nutr., 100, 59–68
Schuhmacher, M., Bellés, M., Rico, A., Domingo, J.L. & Corbella, J. (1996a) Impact of reduction
of lead in gasoline on the blood and hair lead levels in the population of Tarragona Province,
Spain, 1990–1995. Sci. total Environ., 184, 203–209
Schuhmacher, M., Hernández, M., Domingo, J.L., Fernández-Ballart, J.D., Llobet, J.M. &
Corbella, J. (1996b) A longitudinal study of lead mobilization during pregnancy: Concentra-
tions in maternal and umbilical cord blood. Trace Elem. Electrolytes, 13, 177–181
Schuhmacher, M., Paternain, J.L., Domingo, J.L. & Corbella, J. (1997) An assessment of some bio-
monitors indicative of occupational exposure to lead. Trace elem. Electrolytes, 14, 145–149
Schütz, A., Skerfving, S., Ranstam, J. & Christoffersson, J.-O. (1987) Kinetics of lead in blood
after the end of occupational exposure. Scand. J. Work Environ. Health, 13, 221–231
Schütz, A., Attewell, R. & Skerfving, S. (1989) Decreasing blood lead in Swedish children,
1978–1988. Arch. environ. Health, 44, 391–394
Schütz, A., Bergdahl, I.A., Ekholm, A. & Skerfving, S. (1996) Measurement by ICP-MS of lead in
plasma and whole blood of lead workers and controls. Occup. environ. Med., 53, 736–740
Schütz, A., Barregård, L., Sällsten, G., Wilske, J., Manay, N., Pereira, L. & Cousillas, Z.A. (1997)
Blood lead in Uruguayan children and possible sources of exposure. Environ. Res., 74, 17–23
Schwanitz, G., Lehnert, G. & Gebhart, E. (1970) [Chromosome damage after occupational expo-
sure to lead.] Dtsch. Med. Wochenschr., 95, 1636–1641 (in German)
P 379-468 DEF.qxp 09/08/2006 13:53 Page 449
Schwanitz, G., Gebhart, E., Rott, H.-D., Schaller, K.-H., Essing, H.-G., Lauer, O. & Prestele, H.
(1975) [Chromosome investigations in subjects with occupational lead exposure.] Dtsch. med.
Wochenschr., 100, 1007–1011 (in German)
Schwartz, J. (1994) Low-level lead exposure and children’s IQ: A meta-analysis and search for a
threshold. Environ. Res., 65, 42–55
Schwartz, J. & Otto, D. (1987) Blood lead, hearing thresholds and neurobehavioral development
in children and youth. Arch. environ. Health, 42, 153–160
Schwartz, J., Landrigan, P.J., Feldman, R.G., Silbergeld, E.K., Baker, E.L., Jr & von Lindern, I.H.
(1988) Threshold effect in lead-induced peripheral neuropathy. J. Pediatr., 112, 12–17
Schwartz, J., Landrigan, P.J., Baker, E.L., Jr, Orenstein, W.A. & von Lindern, I.H. (1990) Lead-
induced anemia: Dose–response relationships and evidence for a threshold. Am. J. pub.
Health, 80, 165–168
Schwartz, B.S., Lee, B.-K., Stewart, W., Ahn, K.-D., Springer, K. & Kelsey, K. (1995) Associations
of δ-aminolevulinic acid dehydratase genotype with plant, exposure duration, and blood lead
and zinc protoporphyrin levels in Korean lead workers. Am. J. Epidemiol., 142, 738–745
Schwartz, B.S., Stewart, W.F., Todd, A.C. & Links, J.M. (1999) Predictors of dimercaptosuccinic
acid chelatable lead and tibial lead in former organolead manufacturing workers. Occup.
environ. Med., 56, 22–29
Schwartz, B.S., Stewart, W.F., Todd, A.C., Simon, D. & Links, J.M. (2000a) Different associations
of blood lead, meso 2,3-dimercaptosuccinic acid (DMSA)-chelatable lead, and tibial lead
levels with blood pressure in 543 former organolead manufacturing workers. Arch. environ.
Health, 55, 85–92
Schwartz, B.S., Lee, B.K., Lee, G.S., Stewart, W.F., Simon, D., Kelsey, K. & Todd, A.C. (2000b)
Associations of blood lead, dimercaptosuccinic acid-chelatable lead, and tibia lead with poly-
morphisms in the vitamin D receptor and δ-aminolevulinic acid dehydratase genes. Environ.
Health Perspect., 108, 949–954
Schwartz, B.S., Lee, B.-K., Lee, G.-S., Stewart, W.F., Lee. S.-S., Hwang, K.-Y., Ahn, K.-D., Kim,
Y.-B., Bolla, K.L., Simon, D., Parsons, P.J. & Todd, A.C. (2001) Associations of blood lead,
dimercaptosuccinic acid-chelatable lead, and tibia lead with neurobehavioral test scores in
South Korean lead workers. Am. J. Epidemiol., 153, 453–464
Seidel, S., Kreutzer, R., Smith, D., McNeel, S. & Gilliss, D. (2001) Assessment of commercial labo-
ratories performing hair mineral analysis. J. Am. med. Assoc., 285, 67–72
Selevan, S.G., Landrigan, P.J., Stern, F.B. & Jones, J.H. (1985) Mortality of lead smelter workers.
Am. J. Epidemiol., 122, 673–683
Seppäläinen, A.M., Tola, S., Hernberg, S. & Kock, B. (1975) Subclinical neuropathy at ‘safe’
levels of lead exposure. Arch. environ. Health, 30, 180–183
Seppäläinen, A.M., Hernberg, S. & Kock, B. (1979) Relationship between blood lead levels and
nerve conduction velocities. Neurotoxicology, 1, 313–332
Seppäläinen, A.M., Hernberg, S., Vesanto, R . & Kock, B. (1983) Early neurotoxic effects of lead
exposure: A prospective study. Neurotoxicology, 4, 181–192
Sepúlveda, V., Vega, J. & Delgado, I. (2000) [Severe exposure to environmental lead in a child
population in Antofagasta, Chile.] Rev. méd. Chile, 128, 221–232 (in Spanish)
Shaltout, A., Yaish, S.A. & Fernando, N. (1981) Lead encephalopathy in infants in Kuwait. Ann.
trop. Paediatr. (London), 1, 209–215
P 379-468 DEF.qxp 09/08/2006 13:53 Page 450
Sharma, K. & Reutergardh, L.B. (2000) Exposure of preschoolers to lead in the Makati area of
Metro Manila, the Phillippines. Environ. Res., A83, 322–332
Sheffet, A., Thind, I., Miller, A.M. & Louria, D.B. (1982) Cancer mortality in a pigment plant
utilizing lead and zinc chromates. Arch. environ. Health, 37, 44–52
Shen, X.-M., Rosen, J.F., Guo, D. & Wu, S.-M. (1996) Childhood lead poisoning in China. Sci.
total Environ., 181, 101–109
Shen, X., Yan, C., Zhang, Y., Wu, S., Jiang, F., He, J., Yin, J., Ao, L., Zhang, Y. & Li, R. (1999)
[Comparison of children’s blood lead levels in Shanghai before and after the introduction of
lead free gasoline]. Natl med. J. China, 79, 739–741 (in Chinese)
Sherlock, J.C., Smart, G.A., Walters, B., Evans, W.H., McWeeny, D.J. & Cassidy, W. (1983)
Dietary surveys on a population at Shipham, Somerset, United Kingdom. Sci. total Environ.,
29, 121–142
Sherlock, J.C., Pickford, C.J. & White, G.F. (1986) Lead in alcoholic beverages. Food addit.
Contam., 3, 347–354
Shih, T.-M. & Hanin, I. (1978) Chronic lead exposure in immature animals: Neurochemical corre-
lates. Life Sci., 23, 877–888
Shimbo, S., Zhang, Z.-W., Moon, C.-S., Watanabe, T., Nakatsuka, H., Matsuda-Inoguchi, N.,
Higashikawa, K. & Ikeda, M. (2000) Correlation between urine and blood concentrations, and
dietary intake of cadmium and lead among women in the general population of Japan. Int.
Arch. occup. environ. Health, 73, 163–170
Shimbo, S., Zhang, Z.-W., Watanabe, T., Nakatsuka, H., Matsuda-Inoguchi, N., Higashikawa, K.
& Ikeda, M. (2001) Cadmium and lead contents in rice and other cereal products in Japan in
1998-2000. Sci. total Environ., 281, 165–175
Shimkin, M.B., Stoner, G.D. & Theiss, J.C. (1977) Lung tumor response in mice to metals and
metal salts. Adv. exp. Med. Biol., 91, 85–91
Shirai, T., Ohshima, M., Masuda, A., Tamano, S. & Ito, N. (1984) Promotion of 2-(ethylnitrosa-
mino)ethanol-induced renal carcinogenesis in rats by nephrotoxic compounds: Positive
responses with folic acid, basic lead acetate, and N-(3,5-dichlorophenyl)succinimide but not
with 2,3-dibromo-1-propanol phosphate. J. natl Cancer Inst., 72, 477–482
Shukla, R., Bornschein, R.L., Dietrich, K.N., Buncher, C.R., Berger, O.G., Hammond, P.B. &
Succop, P.A. (1989) Fetal and infant lead exposure: Effects on growth in stature. Pediatrics,
84, 604–612
Shukla, R., Dietrich, K.N., Bornschein, R.L., Berger, O. & Hammond, P.B. (1991) Lead exposure
and growth in the early preschool child: A follow-up report from the Cincinnati lead study.
Pediatrics, 88, 886–892
Shukla, V.K., Prakash, A., Tripathi, B.D., Reddy, D.C.S. & Singh, S. (1998) Biliary heavy metal con-
centrations in carcinoma of the gall bladder: Case–control study. Br. med. J., 317, 1288–1289
Siddiqui, M.K.J., Srivastava, S. & Mehrotra, P.K. (2002) Environmental exposure to lead as a risk
for prostate cancer. Biomed. environ. Sci., 15, 298–305
Sidhu, M.K., Fernandez, C., Khan, M.Y. & Kumar, S. (1991) Induction of morphological transfor-
mation, anchorage-independent growth and plasminogen activators in non-tumorigenic human
osteosarcoma cells by lead chromate. Anticancer Res., 11, 1045–1053
Siemiatycki, J. (1991) Risk Factors for Cancer in the Workplace, Boca Raton, FL, CRC Press
Silbergeld, E.K. (1991) Lead in bone: Implications for toxicology during pregnancy and lactation.
Environ. Health Perspect., 91, 63–70
P 379-468 DEF.qxp 09/08/2006 13:53 Page 451
Silbergeld, E.K. & Chisholm, J.J., Jr (1976) Lead poisoning: Altered urinary catecholamine meta-
bolites as indicators of intoxication in mice and children. Science, 192, 153–155
Silbergeld, E.K. & Goldberg, A.M. (1975) Pharmacological and neurochemical investigations of
lead-induced hyperactivity. Neuropharmacology, 14, 431–444
Silbergeld, E.K., Schwartz, J. & Mahaffey, K. (1988) Lead and osteoporosis: Mobilization of lead
from bone in postmenopausal women. Environ. Res., 47, 79–94
Silbergeld, E.K., Waalkes, M. & Rice, J.M. (2000) Lead as a carcinogen: Experimental evidence
and mechanisms of action. Am. J. ind. Med., 38, 316–323
de Silva, P.E. & Donnan, M.B. (1977) Petrol vendors, capillary blood lead levels and contami-
nation. Med. J. Aust., 1, 344–347
de Silva, P.E. & Donnan, M.B. (1980) Blood lead levels in Victorian children. Med. J. Aust., 2,
315–318
Silva, P.A., Hughes, P., Williams, S. & Faed, J.M. (1988) Blood lead, intelligence, reading attain-
ment, and behaviour in eleven year old children in Dunedin, New Zealand. J. Child Psychol.
Psychiat., 29, 43–52
Silvany Neto, A.M., Carvalho, F.M., Lima, M.E.C. & Tavares, T.M. (1985) [Social determination
of lead intoxication in children from Santo Amaro-Bahia] Ciê. Cultura, 37, 1614–1626 (in
Portuguese)
Silvany-Neto, A.M., Carvalho, F.M., Chaves, M.E.C., Brandão, A.M. & Tavares, T.M. (1989)
Repeated surveillance of lead poisoning among children. Sci. total Environ., 78, 179–186
Silvany-Neto, A.M., Carvalho, F.M., Tavares, T.M., Guimarães, G.C., Amorim, C.J.B., Peres,
M.F.T., Lopes, R.S., Rocha, C.M. & Raña, M.C. (1996) Lead poisoning among children of
Santo Amaro, Bahia, Brazil in 1980, 1985, and 1992. Bull. PAHO, 30, 51–62
Silver, W. & Rodriguez-Torres, R. (1968) Electrocardiographic studies in children with lead poiso-
ning. Pediatrics, 41, 1124–1127
Simmon, V.F. (1979) In vitro assays for recombinogenic activity of chemical carcinogens and
related compounds with Saccharomyces cerevisiae D3. J. natl Cancer Inst., 62, 901–909
Simmonds, P.L., Luckhurst, C.L. & Woods, J.S. (1995) Quantitative evaluation of heme bio-
synthetic pathway parameters as biomarkers of low-level lead exposure in rats. J. Toxicol.
environ. Health, 44, 351–367
Simon, J.A. & Hudes, E.S. (1999) Relationship of ascorbic acid to blood lead levels. J. am. med.
Assoc., 281, 2289–2293
Simons, T.J.B. (1995) The affinity of human erythrocyte porphobilinogen synthase for Zn2+ and
Pb2+. Eur. J. Biochem., 234, 178–183
Singal, M., Zey, J.N. & Arnold, S.J. (1985) Health Hazard Evaluation Report, HETA 84-0041-
1592, Johnson Controls, Inc., Owosso, MI, USA, NIOSH
Singh, K.P. (1996) Monitoring and Assessment of the Gomti River Quality (Project Report),
Lucknow, Industrial Toxicology Research Centre
Singh, R.P., Tripathi, R.D., Sinha, S.K., Maheshwari, R. & Srivastava, H.S. (1997) Response of
higher plants to lead contaminated environment. Chemosphere, 34, 2467–2493
Singh, B., Chandran, V., Bandhu, H.K., Mittal, B.R., Bhattacharya, A., Jindal, S.K. & Varma, S.
(2000) Impact of lead exposure on pituitary–thyroid axis in humans. Biometals, 13, 187–192
Singh, V.K., Mishra, K.P., Rani, R., Yadav, V.S., Awasthi, S.K. & Garg, S.K. (2003) Immunomodu-
lation by lead. Immunol. Res., 28, 151–166
P 379-468 DEF.qxp 09/08/2006 13:53 Page 452
Sithisarankul, P., Schwartz, B.S., Lee, B.-K., Kelsey, K.T. & Strickland, P.T. (1997) Aminolevu-
linic acid dehydratase genotype mediates plasma levels of the neurotoxin, 5-aminolevulinic
acid, in lead-exposed workers. Am. J. ind. Med., 32, 15–20
Six, K.M. & Goyer, R.A. (1970) Experimental enhancement of lead toxicity by low dietary
calcium. J. Lab. clin. Med., 76, 933–942
Six, K.M. & Goyer, R.A. (1972) The influence of iron deficiency on tissue content and toxicity of
ingested lead in the rat. J. Lab. clin. Med., 76, 128–136
Skerfving, S., Schütz, A. & Ranstam, J. (1986) Decreasing lead exposure in Swedish children,
1978–84. Sci. total Environ., 58, 225–229
Skreb, Y. & Habazin-Novak, V. (1977) Lead induces modifications of the response to X-rays in
human cells in culture. Stud. biophys., 63, 97–104
Slorach, S., Gustafsson, I.-B., Jorhem, L. & Mattsson, P. (1983) Intake of lead, cadmium and
certain other metals via a typical Swedish weekly diet. Vår Föda, 35 (Suppl. 1), 3–16
Slovin, D.L. & Albrecht, W.N. (1982) Health Hazard Evaluation Report, HETA 81-0356-1183,
Sherwin Williams Co., Coffeyville, KS, USA, NIOSH
Smith, D.L. (1976) Lead absorption in police small-arms instructors. J. Soc. occup. Med., 26,
139–140
Smith, G.R. (1999) Lead, Reston, VA, US Geological Survey
Smith, G.R. (2002) 2002 Minerals Yearbook: Lead, Reston, VA, US Geological Survey
Smith, C.M., DeLuca, H.F., Tanaka, Y. & Mahaffey, K.R. (1978) Stimulation of lead absorption by
vitamin D administration. J. Nutr., 108, 843–847
Smith, M., Delves, T., Lansdown, R., Clayton, B. & Graham, P. (1983) The effects of lead exposure
on urban children: The institute of child health/Southampton Study. Dev. Med. Child Neurol.,
25 (Suppl.), 1–54
Smith, D.R., Markowitz, M.E., Crick, J., Rosen, J.F. & Flegal, A.R. (1994) The effects of succimer
on the absorption of lead in adults determined by using the stable isotope 204Pb. Environ. Res.,
67, 39–53
Smith, C.M., Wang, X., Hu, H. & Kelsy, K.T. (1995) A polymorphism in the δ-aminolevulinic acid
dehydratase gene may modify the pharmacokinetics and toxicity of lead. Environ. Health
Perspect., 103, 248–253
Smith, D.R., Osterloh, J.D. & Flegal, A.R. (1996) Use of endogenous, stable lead isotopes to deter-
mine release of lead from the skeleton. Environ. Health Perspect., 104, 60–66
Smith, D.R., Ilustre, R.P. & Osterloh, J.D. (1998) Methodological considerations for the accurate
determination of lead in human plasma and serum. Am. J. ind. Med., 33, 430–438
Smith, D., Hernandez-Avila, M., Téllez-Rojo, M.M., Mercado, A. & Hu, H. (2002) The relationship
between lead in plasma and whole blood in women. Environ. Health Perspect., 110, 263–268
Smitherman, J. & Harber, P. (1991) A case of mistaken identity: Herbal medicine as a cause of lead
toxicity. Am. J. ind. Med., 20, 795–798
Smolders, A.J.P., Lock, R.A.C., Van der Velde, G., Medina Hoyos, R.I. & Roelofs, J.G.M. (2003)
Effects of mining activities on heavy metal concentrations in water, sediment, and macro-
invertebrates in different reaches of the Pilcomayo River, South America. Arch. environ.
Contam. Toxicol., 44, 314–323
Snyder, R.D., Davis, G.F. & Lachmann, P.J. (1989) Inhibition by metals of X-ray and ultraviolet-
induced DNA repair in human cells. Biol. trace Elem. Res., 21, 389–398
P 379-468 DEF.qxp 09/08/2006 13:53 Page 453
Sobel, A.E. & Burger, M. (1955) Calcification. XIII. The influence of calcium, phosphorus, and
vitamin D on the removal of lead from blood and bone. J. biol. Chem., 212, 105–110
Sobotka, T.J. & Cook, M.P. (1974) Postnatal lead acetate exposure in rats: Possible relationship to
minimal brain dysfunction. Am. J. ment. Defic., 79, 5–9
Sokol, R.Z. & Berman, N. (1991) The effect of age of exposure on lead-induced testicular toxicity.
Toxicology, 69, 269–278
Sokol, R.Z., Madding, C.E. & Swerdloff, R.S. (1985) Lead toxicity and the hypothalamic–pituitary–
testicular axis. Biol. Reprod., 33, 722–728
Solliway, B.M., Schaffer, A., Pratt, H., Mittelman, N. & Yannai, S. (1995) Visual evoked potentials
N75 and P100 latencies correlate with urinary δ-aminolevulinic acid, suggesting γ-amino-
butyric acid involvement in their generation. J. neurol. Sci., 134, 89–94
Solt, B. & Farber, E. (1976) New principle for the analysis of chemical carcinogenesis. Nature,
263, 701–703
Somervaille, L.J., Chettle, D.R., Scott, M.C., Aufderheide, A.C., Wallgren, J.E., Wittmers, L.E., Jr
& Rapp, G.R., Jr (1986) Comparison of two in vitro methods of bone lead analysis and the
implications for in vivo measurements. Phys. Med. Biol., 31, 1267–1274
Southpolymetal (2003) Product Data Sheet: Lead, Shymkent
Spanò, M., Bonde, J.P., Hjøllund, H.I., Kolstad, H.A., Cordelli, E., Leter, G. & The Danish First
Pregnancy Planner Study Team (2000) Sperm chromatin damage impairs human fertility.
Fertil. Steril., 73, 43–50
Spickett, J.T., Bell, R.R., Stawell, J. & Polan, S. (1984) The influence of dietary citrate on the
absorption and retention of orally ingested lead. Agents Actions, 15, 459–462
Spivey, G.H., Baloh, R.W., Brown, C.P., Browdy, B.L., Campion, D.S., Valentine, J.L., Morgan,
D.E. & Culver, B.D. (1980) Subclincal effects of chronic increased lead absorption — A pros-
pective study. III. Neurological findings at follow-up examination. J. occup. Med., 22, 607–612
Sprinkle, R.V. (1995) Leaded eye cosmetics: A cultural cause of elevated lead levels in children.
J. fam. Pract., 40, 358–362
Srianujata, S. (1998) Lead — The toxic metal to stay with human. J. toxicol. Sci., 23 (Suppl. 2),
237–240
Srikanth, R., Madhumohan Rao, A., Shravan Kumar, C. & Khanum, A. (1993) Lead, cadmium,
nickel, and zinc contamination of ground water around Hussain Sagar Lake, Hyderabad, India.
Bull. environ. Contam. Toxicol., 50, 138–143
Srikanth, R., Ramana, D. & Rao, V. (1995a) Lead uptake from beer in India. Bull. environ.
Contam. Toxicol., 54, 783–786
Srikanth, R., Ramana, D. & Rao, V. (1995b) Role of rice and cereal products in dietary cadmium
and lead intake among different socio-economic groups in south India. Food Addit. Contam.,
12, 695–701
Srivastava, S., Mehrotra, P.K., Srivastava, S.P., Tandon, I. & Siddiqui, M.K.J. (2001) Blood lead
and zinc in pregnant women and their offpring in intrauterine growth retardation cases. J. anal.
Toxicol., 25, 461–465
Staessen, J., Yeoman, W.B., Fletcher, A.E., Markowe, H.L.J., Marmot, M.G., Rose, G., Semmence,
A., Shipley, M.J. & Bulpitt, C.J. (1990) Blood lead concentration, renal function, and blood
pressure in London civil servants. Br. J. ind. Med., 47, 442–447
P 379-468 DEF.qxp 09/08/2006 13:53 Page 454
Staessen, J.A., Lauwerys, R.R., Buchet, J.-P., Bulpitt, C.J., Rondia, D., Vanrenterghem, Y., Amery,
A. & the Cadmibel Study Group (1992) Impairment of renal function with increasing blood
lead concentrations in the general population. New Engl. J. Med., 327, 151–156
Staessen, J.A., Bulpitt, C.J., Fagard, R., Lauwerys, R.R., Roels, H., Thijs, L. & Amery, A. (1994)
Hypertension caused by low-level lead exposure: Myth or fact? J. cardiovasc. Risk, 1, 87–97
Staessen, J.A., Roels, H., Lauwerys, R.R. & Amery, A. (1995) Low-level lead exposure and blood
pressure. J. hum. Hypertens., 9, 303–328
Stauber, J.L. & Florence, T.M. (1988) A comparative study of copper, lead, cadmium and zinc in
human sweat and blood. Sci. total Environ., 74, 235–247
Stauber, J.L., Florence, T.M., Gulson, B.L. & Dale, L.S. (1994) Percutaneous absorption of inorganic
lead compounds. Sci. total Environ., 145, 55–70
Steenland, K. & Boffetta, P. (2000) Lead and cancer in humans: Where are we now? Am. J. ind.
Med., 38, 295–99
Steenland, K., Selevan, S. & Landrigan, P. (1992) The mortality of lead smelter workers: An up-
date. Am. J. public Health, 82, 1641–1644
Steenland, K., Loomis, D., Shy, C. & Simonsen, N. (1996) Review of occupational carcinogens.
Am. J. ind. Med., 29, 474–490
Steffee, C.H. & Baetjer, A.M. (1965) Histopathologic effects of chromate chemicals. Arch. environ.
Health, 11, 66–75
Stephenson, R.L. & Burt, S. (1992) Health Hazard Evaluation Report, HETA 89-0252,0293-2178,
Chempower Inc., Combustion Engineering Inc., Albright Power Station, Albright, WV, USA,
NIOSH
Sternowsky, H.J. & Wessolowski, R. (1985) Lead and cadmium in breast milk. Arch. Toxicol., 57,
41–45
Stevenson, A.J., Kacew, S. & Singhal, R.L. (1977) Reappraisal of the use of a single dose of lead
for the study of cell proliferation in kidney, liver and lung. J. Toxicol. environ. Health, 2,
1125–1134
Stewart, W.F., Schwartz, B.S., Simon, D., Kelsey, K. & Todd, A.C. (2002) ApoE genotype, past
adult lead exposure and neurobehavioral function. Environ. Health Perspect., 110, 501–505
STN International (2003) Registry file [http://stuweb.cas.org; latest update 25/11/2003]
Stockholm Municipal Environment and Health Administration (1983) Undersokningar av Fordon-
strafikens Luftfororeningar under 1982 [Investigations of air pollution from the traffic during
1982], Stockholm (in Swedish)
Stoner, G.D., Shimkin, M.B., Troxell, M.C., Thompson, T.L. & Terry, L.S. (1976) Test for carcino-
genicity of metallic compounds by the pulmonary tumor response in strain A mice. Cancer
Res., 36, 1744–1747
Stoner, G.D., Conran, P.B., Greisiger, E.A., Stober, J., Morgan, M. & Pereira, M.A. (1986) Com-
parison of two routes of chemical administration on the lung adenoma response in strain A/J
mice. Toxicol. appl. Pharmacol., 82, 19–31
Stowe, H.D., Goyer, R.A., Krigman, M.M., Wilson, M. & Cates, M. (1973) Experimental oral lead
toxicity in young dogs. Clinical and morphologic effects. Arch. Pathol., 95, 106–116
Stretesky, P.B. & Lynch, M.J. (2001) The relationship between lead exposure and homicide. Arch.
pediat. adol. Med., 155, 579–582
Strömberg, U., Schütz, A. & Skerfving, S. (1995) Substantial decrease of blood lead in Swedish
children, 1978–94, associated with petrol lead. Occup. environ. Med., 52, 764–769
P 379-468 DEF.qxp 09/08/2006 13:53 Page 455
Subramanian, K.S. (1989) Determination of lead in blood by graphite furnace atomic absorption
spectrometry — A critique. Sci. total Environ., 89, 237–250
Sun, C.-C., Wong, T.-T., Hwang, Y.-H., Chao, K.-Y., Jee, S.-H. & Wang, J.-D. (2002) Percutaneous
absorption of inorganic lead compounds. Am. ind. Hyg. Assoc. J., 63, 641–646
Sundström, R. & Karlsson, B. (1987) Myelin basic protein in brains of rats with low dose lead
encephalopathy. Arch. Toxicol., 59, 341–345
Suplido, M.L. & Ong, C.N. (2000) Lead exposure among small-scale battery recyclers, automobile
radiator mechanics, and their children in Manila, the Philippines. Environ. Res., 82, 231–238
Sussell, A.L. & Piacitelli, G.M. (1999) Health Hazard Evaluation Report, HETA 98-0283, Illinois
Historic Preservation Agency, Springfield, IL, USA, NIOSH
Sussell, A.L. & Piacitelli, G.M. (2001) Health Hazard Evaluation Report, HETA 99-0113-2853,
University of California-Berkeley, Berkeley, CA, USA, NIOSH
Sussell, A.L., Montopoli, M. & Tubbs, R. (1992a) Health Hazard Evaluation Report, HETA 91-
0006-2193, M & J Painting Company, Covington, KY, USA, NIOSH
Sussell, A.L., Elliott, L.J., Wild, D. & Freund, E. (1992b) Health Hazard Evaluation Report, HETA
90-0070-2181, HUD Lead-Based Paint Abatement Demonstration Project
Sussell, A.L., Mickelsen, R.L. & Rubin, C. (1992c) Health Hazard Evaluation Report, HETA 91-
0209-2249, Seaway Painting, Inc., Annapolis, MD, USA, NIOSH
Sussell, A.L., Weber, A., Wild, D., Ashley, K. & Wall, D. (1993) Health Hazard Evaluation Report,
HETA 92-0095-2317, Ohio University, Athens, OH, USA, NIOSH
Sussell, A.L., Gittleman, J. & Singal, M. (1997) Health Hazard Evaluation Report, HETA 93-0818-
2646, People Working Cooperatively, Cincinnati, OH, USA, NIOSH
Sussell, A.L., Piacitelli, G.M. & Trout, D. (2000) Health Hazard Evaluation Report, HETA 96-
0200-2799, Rhode Island Department of Health, Providence, RI, USA, NIOSH
Sussell, A.L., Piacitelli, G.M., Chaudre, Z. & Ashley, K. (2002) Health Hazard Evaluation Report,
HETA 99-0305-2878, Lead Safe Services, Inc., Neenah, WI, USA, NIOSH
Suwansaksri, J. & Wiwanitkit, V. (2001) Monitoring of lead exposure among mechanics in
Bangkok. Southeast Asian J. trop. Med. public Health, 32, 661–663
Suwansaksri, J., Teerasart, N., Wiwanitkit, V. & Chaiyaset, T. (2002) High blood lead level among
garage workers in Bangkok, public concern is necessary. Biometals, 15, 367–370
Süzen, H.S., Duydu, Y., Aydin, A., Isimer, A. & Vural, N. (2003) Influence of the delta-amino-
levulinic acid dehydratase (ALAD) polymorphism on biomarkers of lead exposure in Turkish
storage battery manufacturing workers. Am. J. ind. Med., 43, 165–171
Suzuki, S. (1990) Health effects of lead pollution due to automobile exhaust: Findings from field
surveys in Japan and Indonesia. J. hum. Ergol., 19, 113–122
Svensson, B.G., Schütz, A., Nilsson, A. & Skerfving, S. (1992) Lead exposure in indoor firing
ranges. Int. Arch. Occup. Environ. Health, 64, 219–221
Sweeney, M.H., Beaumont, J.J., Waxweiler, R.J. & Halperin, W.E. (1986) An investigation of
mortality from cancer and other causes of death among workers employed at an east Texas
chemical plant. Arch. environ. Health, 41, 23–28
Sylvain, D.C. (1996) Health Hazard Evaluation Report, HETA 94-0122-2578, Bath Iron Works
Corp., Bath, ME, USA, NIOSH
Symanski, E. & Hertz-Picciotto, I. (1995) Blood lead levels in relation to menopause, smoking,
and pregnancy history. Am. J. Epidemiol., 141, 1047–1058
P 379-468 DEF.qxp 09/08/2006 13:53 Page 456
Tabuchi, T., Okayama, A., Ogawa, Y., Miyajima, K., Hirata, M., Yoshida, T., Sugimoto, K. &
Morimoto, K. (1989) A new HPLC fluorimetric method to monitor urinary delta-amino-
levulinic acid (ALA-U) levels in workers exposed to lead. Int. Arch. occup. environ. Health,
61, 297–302
Tachi, K., Nishimae, S. & Saito, K.(1985) Cytogenetic effects of lead acetate on rat bone marrow
cells. Arch. environ. Health, 40, 144–147
Tait, P.A., Vora, A., James, S., Fitzgerald, D.J. & Pester, B.A. (2002) Severe congenital lead poiso-
ning in a preterm infant due to a herbal remedy. Med. J. Aust., 177, 193–195
Tamayo, L., Liceaga, C., Sánchez, P. & Herce, J.L. (1984) Estudio comparativo de envases de
frutas y jugos. Rev. Soc. Quím. Méx., 28, 359–362
Tanner, D.C. & Lipsky, M.M. (1984) Effect of lead acetate on N-(4′-fluoro-4-biphenyl)acetamide-
induced renal carcinogenesis in the rat. Carcinogenesis, 5, 1109–1113
Tantanasrikul, S., Chaivisuth, B., Siriratanapreuk, S., Padungtod, C., Pleubreukan, R., Boonnark,
T., Worahan, S., Bhumiratanarak, P. & Chomchai, C. (2002) The management of environ-
mental lead exposure in the pediatric population: Lessons from Clitty Creek, Thailand. J. med.
Assoc. Thai., 85 (Suppl. 2), S762–S768
Taskinen, H., Nordman, H., Hernberg, S. & Engström, K. (1981) Blood lead levels in Finnish pre-
school children. Sci. total Environ., 20, 117–129
Taupeau, C., Poupon, J., Treton, D., Brosse, A., Richard, Y. & Machelon, V. (2003) Lead reduces
messenger RNA and protein levels of cytochrome p450 aromatase and estrogen receptor beta
in human ovarian granulosa cells. Biol. Reprod., 68, 1982–1988
Tavares, T.M. (1990) Avaliação de Efeitos das Emissões de Cádmio e Chumbo em Santo Amaro,
Bahia, PhD Thesis, São Paulo, University of São Paulo
Tavares, T.M. (1991) Ecological studies of the Recôncavo, Bahia, Brazil (1976 until 1990). Rev.
int. Contam. ambient., 7, 33–50
Tavares, T.M. (1992) The role of lead and cadium reference samples in an epidemiological case
study at Santo Amaro, Bahia, Brazil. In: Rossbach, M., Schladot, J.D. & Ostapczuk, P., eds,
Specimen Banking: Environmental Monitoring and Modern Analytical Approaches, Berlin,
Springer Verlag, pp. 89–98
Tavares, T.M. (1996a) Distribuição Espacial de Poluentes Atmosféricos no entorno da RLAM in
Programa de Monitoramento dos Ecossistemas ao Norte da Baía de Todos os Santos,
1994–1995, Tomo 8, Vol. II, Salvador, Bahia, Petrobrás
Tavares, T.M. (1996b) Distribuição Espacial de Metais Pesados e Hidrocarbonetos ao Norte da
Baía de Todos os Santos em Programa de Monitoramento dos Ecossistemas ao Norte da Baía
de Todos os Santos, 1994–1995, Tomo 8, Vol. I, Salvador, Bahia, Petrobrás
Taylor, S.R. & McLennan, S.M. (1995) The geochemical evolution of the continental crust. Rev.
Geophys., 33, 241–265
Taylor, R., Bazelmans, J., Golec, R. & Oakes, S. (1995) Declining blood lead levels in Victorian
children. Aust. J. public Health, 19, 455–459
Teck Cominco (2003) Product Data Sheet: Lead, Vancouver, BC
Telisman, S., Cvitkovic, P., Jurasovic, J., Pizent, A., Gavella, M. & Rocic, B. (2000) Semen quality
and reproductive endocrine function in relation to biomarkers of lead, cadmium, zinc, and
copper in men. Environ. Health Perspect., 108, 45–53
P 379-468 DEF.qxp 09/08/2006 13:53 Page 457
Téllez-Rojo, M.M., Hernández-Avila, M., González-Cossio, T., Romieu, I., Aro, A., Palazuelos, E.,
Schwartz, J. & Hu, H. (2002) Impact of breastfeeding on the mobilization of lead from bone.
Am. J. Epidemiol., 155, 420–428
Teraki, Y. & Uchiumi, A. (1990) Inorganic elements in the tooth and bone tissues of rats bearing
nickel acetate- and lead acetate-induced tumors. Shigaku, 78, 269–273
Tharr, D. (1993) Lead contamination in radiator repair shops. Appl. occup. environ. Hyg., 8,
434–438
Tharr, D. (1997) Lead exposure during custodial activities. Appl. occup. environ. Hyg., 12,
395–399
Thier, R., Bonacker, D., Stoiber, T., Bohm, K.J., Wang, M., Unger, E., Bolt, H.M. & Degen, G. (2003)
Interaction of metal salts with cytoskeletal motor protein systems. Toxicol. Lett., 140–141, 75–81
Thomas, V.M., Socolow, R.H., Fanelli, J.J. & Spiro, T.G. (1999) Effects of reducing lead in gaso-
line: An analysis of the international experience. Environ. Sci. Technol., 33, 3942–3948
Thoreux-Manlay, A., Vélez de la Calle, J.F., Olivier, M.F., Soufir, J.C., Masse, R. & Pinon-
Lataillade, G. (1995) Impairment of testicular endocrine function after lead intoxication in the
adult rat. Toxicology, 100, 101–109
Threlfall, T., Kent, N., Garcia-Webb, P., Byrnes, E. & Psaila-Savona, P. (1993) Blood lead levels
in children in Perth, Western Australia. Aust. J. public Health, 17, 379–381
Todd, A.C. & Chettle, D.R. (1994) In vivo X-ray fluorescence of lead in bone: Review and current
issues. Environ. Health Perspect., 102, 172–177
Todd, A.C., Carroll, S., Godbold, J.H., Moshier, E.L. & Khan, F.A. (2000a) Variability in XRF-
measured tibia lead levels. Phys. Med. Biol., 45, 3737–3748
Todd, A.C., Ehrlich, R.I., Selby, P. & Jordaan, E. (2000b) Repeatability of tibia lead measurement
by X-Ray fluorescence in a battery-making workforce. Environ. Res., 84, 282–289
Todd, A.C., Lee, B.-K., Lee, G.-S., Ahn, K.-D., Moshier, E. & Schwartz, B.S. (2001a) Predictors
of DMSA chelatable lead, tibial lead, and blood lead in 802 Korean lead workers. Occup.
environ. Med., 58, 73–80
Todd, A.C., Buchanan, R., Carroll, S., Moshier, E.L., Popovac, D., Slavkovich, V. & Graziano, J.H.
(2001b) Tibia lead levels and methodological uncertainty in 12-year-old children. Environ.
Res., A86, 60–65
Todd, A.C., Carroll, S., Godbold, J.H., Moshier, E.L. & Khan, F.A. (2001c) The effect of measure-
ment location on tibia lead XRF measurement results and uncertainty. Phys. Med. Biol., 46,
29–40
Todd, A.C., Parsons, P.J., Tang, S. & Moshier, E.L. (2001d) Individual variability in human tibia
lead concentration. Environ. Health Perspect., 109, 1139–1143
Todd, A.C., Parsons, P.J., Carroll, S., Geraghty, C., Khan, F.A., Tang, S. & Moshier, E.L. (2002)
Measurements of lead in human tibiae. A comparison between K-shell x-ray fluorescence and
electrothermal atomic absorption spectrometry. Phys. Med. Biol., 47, 673–687
Toews, A.D., Kolber, A., Hayward, J., Krigman, M.R. & Morell, P. (1978) Experimental lead
encephalopathy in the suckling rat: Concentration of lead in cellular fractions enriched in brain
capillaries. Brain Res., 147, 131–138
Toffaletti, J. & Savory, J. (1976) An overview of the laboratory diagnosis of lead poisoning. Ann.
clin. Lab. Sci., 6, 529–536
Tola, S., Hernberg, S., Asp, S. & Nikkanen, J. (1973) Parameters indicative of absorption and bio-
logical effect in new lead exposure: A prospective study. Br. J. ind. Med., 30, 134–141
P 379-468 DEF.qxp 09/08/2006 13:53 Page 458
Tomokuni, K. & Ichiba, M. (1988a) A simple method for colorimetric determination of urinary
delta-aminolevulinic acid in workers exposed to lead. Jpn J. ind. Health, 30, 52–53
Tomokuni, K. & Ichiba, M. (1988b) Comparison of inhibition of erythrocyte pyrimidine 5′-nucleo-
tidase and delta-aminolevulinic acid dehydratase by lead. Toxicol. Lett., 40, 159–163
Tomokuni, K. & Ogata, M. (1976) Relationship between lead concentration in blood and biological
response for porphyrin metabolism in workers occupationally exposed to lead. Arch. Toxicol.,
35, 239–246
Tomokuni, K., Ichiba, M., Hirai, Y., Sugimoto, K., Yoshida, T. & Hirata, M. (1988) Comparison
between the fluorimetric HPLC method and the conventional method for determining urinary
δ-aminolevulinic acid and coproporphyrin as indices of lead exposure. Int. Arch. occup.
environ. Health, 61, 153–156
Tomokuni, K., Ichiba, M. & Mori, K. (1992) Relation between urinary β-aminoisobutyric acid
excretion and concentration of lead in the blood of workers occupationally exposed to lead. Br.
J. ind. Med., 49, 365–368
Tomsig, J.L. & Suszkiw, J.B. (1996) Metal selectivity of exocytosis in alpha-toxin-permeabilized
bovine chromaffin cells. J. Neurochem., 66, 644–650
Tong, S., Baghurst, P., McMichael, A., Sawyer, M. & Mudge, J. (1996) Lifetime exposure to
environmental lead and children’s intelligence at 11–13 years: The Port Pirie cohort study. Br.
med. J., 312, 1569–1575
Tönz, O. (1957) [Changes in the kidney of rats after chronic experimental exposure to lead.] Z. ges.
exp. Med., 128, 361–377 (in German)
Torelli, G. (1930) L’influenza dell’avvelenamento cronico da piombo (saturnismo) sulla discen-
denza. La Medicina del Lavoro, 3, 110–121
Torrance, J.D., Mills, W., Kilroe-Smith, T.A. & Smith, A.N. (1985) Erythrocyte pyrimidine-5′-
nucleotidase activity as a sensitive indicator of lead exposure. S. Afr. med. J., 67, 850–852
Torvik, E., Pfitzer, E., Kereiakes, J.G. & Blanchard, R. (1974) Long term effective half-lives for
lead-210 and polonium-210 in selected organs of the male rat. Health Phys., 26, 81–87
Treble, R.G. & Thompson, T.S. (1997) Preliminary results of a survey of lead levels in human liver
tissue. Bull. environ. Contam. Toxicol., 59, 688–695
Treble, R.G. & Thompson, T.S. (2002) Elevated blood lead levels resulting from the ingestion of
air rifle pellets. J. anal. Toxicol., 26, 370–373
Triebig, G., Weltle, D. & Valentin, H. (1984) Investigations on neurotoxicity of chemical subs-
tances at the workplace. V. Determination of the motor and sensory nerve conduction velocity
in persons occupationally exposed to lead. Int. Arch. occup. environ. Health, 53, 189–203
Tripathi, R.K., Sherertz, P.C., Llewellyn, G.C., Armstrong, C.W. & Ramsey, S.L. (1989) Over-
exposures to lead at a covered outdoor firing range. J. Am. College Toxicol., 8, 1189–1195
Tripathi, R.K., Sherertz, P.C., Llewellyn, G.C., Armstrong, C.W. & Ramsey, S.L. (1990) Reducing
exposures to airborne lead in a covered, outdoor firing range by using totally copper-jacketed
bullets. Am. Ind. Hyg. Assoc. J., 51, 28–31
Tripathi, R.K., Sherertz, P.C., Llewellyn, G.C. & Armstrong, C.W. (1991) Lead exposure in out-
door firearm instructors. Am. J. publ. Health, 81, 753–755
Tripathi, R.M., Raghunath, R., Kumar, A.V., Sastry, V.N. & Sadasivan, S. (2001) Atmospheric and
children’s blood lead as indicators of vehicular traffic and other emission sources in Mumbai,
India. Sci. total Environ., 267, 101–108
P 379-468 DEF.qxp 09/08/2006 13:53 Page 459
Trotter, R.T. (1990) The cultural parameters of lead poisoning: A medical anthropologist’s view of
intervention in environmental lead exposure. Environ. Health Perspect., 89, 79–84
Tsaih, S.W., Schwartz, J., Lee, M.-L., Amarasiriwardena, C., Aro, A., Sparrow, D. & Hu, H. (1999)
The independent contribution of bone and erythrocyte lead to urinary lead among middle-aged
and elderly men: The Normative Aging Study. Environ. Health Perspect., 107, 391–396
Tubbs, R.L., Moss, C.E. & Fleeger, A. (1992) Health Hazard Evaluation Report, HETA 89-0364-
2202, ARMCO Advanced Materials Corp., Butler, PA, USA, NIOSH
Turlakiewicz, Z. & Chmielnicka, J. (1985) Diethyllead as a specific indicator of occupational
exposure to tetraethyllead. Br. J. ind. Med., 42, 682–685
Tuthill, R.W. (1996) Hair lead levels related to children’s classroom attention-deficit behavior.
Arch. environ. Health, 51, 214–220
Ukhun, M.E., Nwazota, J. & Nkwocha, F.O. (1990) Levels of toxic mineral elements in selected
foods marketed in Nigeria. Bull. environ. contam. Toxicol., 44, 325–330
Umicore Precious Metals (2002) Technical Data Sheet: Lead, Hoboken
Ündeger, Ü., Basaran, N., Canpinar, H. & Kansu, E. (1996) Immune alterations in lead-exposed
workers. Toxicology, 109, 167–172
US Department of Housing and Urban Development (US DHUD) (1987) Code Fed. Regul., 24
CFR 35, 510, 511, 570, 590
US Department of the Treasury (1991) Report of Analyses of Wines and Related Products to Deter-
mine Lead Content, Washington, DC, US Department of the Treasury, Bureau of Alcohol,
Tobacco and Firearms
US Environmental Protection Agency (US EPA) (1978) Lead (AA, Direct Aspiration), Method
No. 239.1
US Environmental Protection Agency (1982) An Exposure and Risk Assessment for Lead
(EPA/440/4-85/010, NTIS PB85-220606), Washington DC, Office of Water Regulations and
Standards, Monitoring and Data Support Division
US Environmental Protection Agency (1985) National Air Quality and Emissions Trends Report
1983 (EPA-450/4-84-029), Bethesda, MD
US Environmental Protection Agency (1986a) Air Quality Criteria for Lead (EPA 600/8-83-028F),
Research Triangle Park, NC, Office of Research and Development, Office of Health and Envi-
ronmental Assessment, Environmental Criteria and Assessment Office
US Environmental Protection Agency (1986b) Lead (AA, Direct Aspiration), Method No. 7420
US Environmental Protection Agency (1986c) Lead (AA, Furnace Technique), Method No. 7421
US Environmental Protection Agency (1989) Evaluation of the Potential Carcinogenicity of Lead
and Lead Compounds (EPA/600/8-89/045A), Washington, DC, US Environmental Protection
Agency, Office of Health and Environmental Assessment
US Environmental Protection Agency (1991) Maximum contaminant level goals and national
primary drinking water regulations for lead and copper. Fed. Reg., 56, 26461–26564
US Environmental Protection Agency (1992) National Air Quality and Emissions Trends Report
1991 (EPA 450-R-92-001), Bethesda, MD
US Environmental Protection Agency (1994) Guidance Manual for the Integrated Exposure
Uptake Biokinetic Model for Lead in Children (EPA/540/R-93/081; PB93-963510), Research
Triangle Park, NC, US Environmental Protection Agency, DC 20460
US Environmental Protection Agency (1996a) National Air Quality and Emissions Trends Report
1995, Washington DC, Office of Air Quality Planning and Standards
P 379-468 DEF.qxp 09/08/2006 13:53 Page 460
US Environmental Protection Agency (1996b) Urban Soil Lead Abatement Demonstration Project
(EPA/600/P-93/001aF), Washington DC, Office of Research and Development
US Environmental Protection Agency (1996c) Determination of Trace Elements in Ambient Waters
by Off-Line Chelation, Preconcentration and Stabilized Temperature Graphite Furnace Atomic
Absorption, Method 1637, Washington, DC, Office of Water
US Environmental Protection Agency (1996d) Determination of Trace Elements in Ambient Waters
by Inductively Coupled Plasma–Mass Spectrometry, Method 1638, Washington, DC, Office of
Water
US Environmental Protection Agency (1997a) Determination of Trace Elements in Water by Pre-
concentration and Inductively Coupled Plasma–Mass Spectrometry, Method 1640,
Washington, DC, Office of Water
US Environmental Protection Agency (1997b) Determination of Trace Elements in Marine Waters
by Stabilized Temperature Graphite Furnace Atomic Absorption, Method 200.12, Cincinnati,
OH, National Exposure Research Laboratory, Office of Research and Development
US Environmental Protection Agency (1997c) Determination of Trace Elements in Marine Waters
by On-Line Chelation Preconcentration and Inductively Coupled Plasma–Mass Spectrometry,
Method 200.10, Cincinnati, OH, National Exposure Research Laboratory, Office of Research
and Development
US Environmental Protection Agency (2000) Inductively Coupled Plasma–Atomic Emission Spectro-
metry, Method 6010C
US Food and Drug Administration (1994) Action Levels for Poisonous or Deleterious Substances
in Human Food and Animal Feed, Department of Health and Human Services, Public Health
Service
US Food and Drug Administration (2000a) Flame atomic absorption spectrometric determination
of lead and cadmium extracted from ceramic foodware. In: FDA Elemental Analysis Manual
For Food and Related Products
US Food and Drug Administration (2000b) Graphite furnace atomic absorption spectrometric
determination of lead and cadmium extracted from ceramic foodware. In: FDA Elemental
Analysis Manual For Food and Related Products
Vaglenov, A.K., Laltchev, S.G., Nosko, M.S. & Pavlova, S.P. (1997) Cytogenetic monitoring of
workers exposed to lead. Cent. Eur. J. occup. environ. Med., 3, 298–308
Vaglenov, A., Carbonell, E. & Marcos, R. (1998) Biomonitoring of workers exposed to lead. Geno-
toxic effects, its modulation by polyvitamin treatment and evaluation of the induced radio-
resistance. Mutat. Res., 418, 79–92
Vaglenov, A., Creus, A., Laltchev, S., Petkova, V., Pavlova, S. & Marcos, R. (2001) Occupational
exposure to lead and induction of genetic damage. Environ. Health Perspect., 109, 295–298
Vahter, M., Berglund, M., Slorach, S., Friberg, L., Šaric, M., Xingquan, Z. & Fujita, M. (1991a)
Methods for integrated exposure monitoring of lead and cadmium. Environ. Res., 56, 78–89
Vahter, M., Berglund, M., Lind, B., Jorhem, L., Slorach, S. & Friberg, L. (1991b) Personal moni-
toring of lead and cadmium exposure — A Swedish study with special reference to methodo-
logical aspects. Scand. J. Work environ. Health, 17, 65–74
Vahter, M., Counter, S.A., Laurell, G., Buchanan, L.H., Ortega, F., Schütz, A. & Skerfving, S.
(1997) Extensive lead exposure in children living in an area with production of lead-glazed
tiles in the Ecuadorian Andes. Int. Arch. occup. environ. Health, 70, 282–286
P 379-468 DEF.qxp 09/08/2006 13:53 Page 461
Valverde, M., Fortoul, T.I., Díaz-Barriga, F., Mejía, J. & Rojas del Castillo, E. (2002) Genotoxicity
induced in CD-1 mice by inhaled lead: Differential organ response. Mutagenesis, 17, 55–61
Valway, S.E., Martyny, J.W., Miller, J.R., Cook, M. & Mangione, E.J. (1989) Lead absorption in
indoor firing range users. Am. J. Public Health, 79, 1029–1032
Van Barneveld, A.A. & Van den Hamer, C.J.A. (1985) Influence of Ca and Mg on the uptake and
deposition of Pb and Cd in mice. Toxicol. appl Pharmacol., 79, 1–10
Vander, A.J., Taylor, D.L., Kalitis, K., Mouw, D.R. & Victery, W. (1977) Renal handling of lead in
dogs: Clearance studies. Am. J. Physiol., 233, F532–F538
Van Esch, G.J. & Kroes, R. (1969) The induction of renal tumours by feeding basic lead acetate to
mice and hamsters. Br. J. Cancer, 23, 765–771
Van Esch, G.J., Van Genderen, H. & Vink, H.H. (1962) The induction of renal tumours by feeding
of basic lead acetate to rats. Cancer, 16, 289–297
Varnai, V.M., Piasek, M., Blanuša, M., Saric, M.M., Šimic, D. & Kostial, K. (2001) Calcium
supplementation efficiently reduces lead absorption in suckling rats. Pharmacol. Toxicol., 89,
326–330
Varo, P. & Koivistoinen, P. (1983) Mineral element composition of Finnish foods. XII. General
discussion and nutritional evaluation. Acta agric. Scand., 22, 165–171
Vassil, A.D., Kapulnik, Y., Raskin, I. & Salt, D.E. (1998) The role of EDTA in lead transport and
accumulation by Indian mustard. Plant Physiol., 117, 447–453
Vatsala, S. & Ramakrishna, T. (1985) ‘Tinning’ of brass ustensils: Possibility of lead poisoning.
Indian J. environ. Health, 27, 140–141
Vena, J.E. (1983) Lung cancer incidence and air pollution in Erie County, New York. Arch. environ.
Health, 38, 229–236
Venable, H.L., Moss, C.E., Connon, C.L., Kinnes, G.M., Freund, E., Seitz, T.A. & Kaiser, E.A.
(1993) Health Hazard Evaluation Report, HETA 90-0075-2298, Boston Edison Co., Boston,
MA, USA, NIOSH
Verberk, M.M., Willems, T.E.P., Verplanke, A.J.W. & De Wolff, F.A. (1996) Environmental lead
and renal effects in children. Arch. environ. Health, 51, 83–87
Verity, M.A. (1990) Comparative observations on inorganic and organic lead neurotoxicity.
Environ. Health Perspect., 89, 43–48
Verrengia Guerrero, N.R. & Kesten, E.M. (1994) Levels of heavy metals in waters from the La
Plata River, Argentina: An approach to assess bioavailability. Bull. environ. Contam. Toxicol.,
52, 254–260
Verschoor, M., Wibowo, A., Herber, R., van Hemmen, J. & Zielhuis, R. (1987) Influence of occu-
pational low-level lead exposure on renal parameters. Am. J. ind. Med., 12, 341–351
Victery, W. (1988) Evidence for effects of chronic lead exposure on blood pressure in experimental
animals: An overview. Environ. Health Perspect., 78, 71–76
Victery, W., Vander, A.J., Shulak, J.M., Schoeps, P. & Julius, S. (1982) Lead, hypertension, and the
renin-angiotensin system in rats. J. Lab. clin. Med., 99, 354–362
Vig, E.K. & Hu, H. (2000) Lead toxicity in older adults. J. Am. Geriatr. Soc., 48, 1501–1506
Viskum, S., Rabjerg, L., Jørgensen, P.J. & Grandjean, P. (1999) Improvement in semen quality
associated with decreasing occupational lead exposure. Am. J. ind. Med., 35, 257–263
Von Schirnding, Y.E.R. & Fuggle, R.F. (1984) A study of the relationship between low level lead
exposure and classroom performance in South African children. Int. J. Biol. Sci., 6, 97–106
P 379-468 DEF.qxp 09/08/2006 13:53 Page 462
Von Schirnding, Y., Bradshaw, D., Fuggle, R. & Stokol, M. (1991a) Blood lead levels in South
African inner-city children. Environ. Health Perspect., 94, 125–130
Von Schirnding, Y.E.R., Fuggle, R.F. & Bradshaw, D. (1991b) Factors associated with elevated
blood lead levels in inner city Cape Town children. S. Afr. Med. J., 79, 454–456
Vural, N. & Duydu, Y. (1995) Biological monitoring of lead in workers exposed to tetraethyllead.
Sci. total Environ., 171, 183–187
Waalkes, M.P., Diwan, B.A., Ward, J.M., Devor, D.E. & Goyer, R.A. (1995) Renal tubular tumors
and atypical hyperplasias in B6C3F1 mice exposed to lead acetate during gestation and lacta-
tion occur with minimal chronic nephropathy. Cancer Res., 55, 5265–5271
Waalkes, M.P., Fox, D.A., States, J.C., Patierno, S.R. & McCabe, M.J., Jr (2000) Metals and
disorders of cell accumulation: Modulation of apoptosis and cell proliferation. Toxicol. Sci.,
56, 255–261
Wadge, A. & Hutton, M. (1987) The leachability and chemical speciation of selected trace ele-
ments in fly ash from coal combustion and refuse incineration. Environ. Pollut., 48, 85–99
Wahid, A., Koul, P.A., Shah, S.U., Khan, A.R., Bhat, M.S. & Malik, M.A. (1997) Lead exposure
in papier mâché workers. Hum. exp. Toxicol., 16, 281–283
Wai, C.M., Knowles, C.R. & Keely, J.F. (1979) Lead caps on wine bottles and their potential
problems. Bull. environ. Contam. Toxicol., 21, 4–6
Wallace, D.M., Kalman, D.A. & Bird, T.D. (1985) Hazardous lead release from glazed dinnerware:
A cautionary note. Sci. total Environ., 44, 289–292
Walmsley, T.A., Sise, J.A. & Hinton, D. (1988) Blood Lead Levels — Population Data Base. Trace
Elements in New Zealand: Environmental, Human and Animal. Proceedings of the New
Zealand Trace Elements Group Conference, 30 November to 2 December 1988, Canterbury,
Lincoln College, pp. 125–131
Walmsley, T., Grant, S. & George, P. (1995) Trends in adult blood lead levels in New Zealand,
1974–1994. N.Z. public Health Rep., 2, 81–82
Walsh, C.T. & Ryden, E.B. (1984) The effect of chronic ingestion of lead on gastrointestinal transit
in rats. Toxicol. appl. Pharmacol., 75, 485–495
Walsh, T.J. & Tilson, H.A. (1984) Neurobehavioral toxicology of the organoleads. Neurotoxico-
logy, 5, 67–86
Wananukul, W., Sirivarasai, J., Sriapha, C., Chanatara, V., Chunvimaluang, N., Keanpoompuang,
A., Boriboon, W., Pumala, K. & Kaojarern, S. (1998) Lead exposure and accumulation in
healthy Thais: Assessed by lead levels, EDTA mobilization and heme synthesis-related para-
meters. J. med. Assoc. Thai., 81, 110–116
Wang, Y.-L. (1984) Industrial lead poisoning in China over the past 33 years. Ecotoxicol. environ.
Saf., 8, 526–530
Wang, L. (1988) Blood lead levels of children with different degree of lead exposures. Environ.
Health, 5, 1–4
Wang, L., Xu, S., Zhang, G.-D. & Wang, W.-Y. (1989) Study of lead absorption and its effect on
children’s development. Biomed. environ. Sci., 2, 325–330
Wang, J.-D., Soong, W.-T., Chao, K.-Y., Hwang, Y.-H. & Jang, C.-S. (1998) Occupational and
environmental lead poisoning: Case study of a battery recycling smelter in Taiwan. J. toxicol.
Sci., 23 (Suppl. 2), 241–245
Wang, C., Huang, L., Xu, G. & Xin, Y. (2000) [Dynamic study on blood and milk lead levels of
pregnant women in three districts of Hubei.] J. Hyg. Res., 29, 149–150, 153 (in Chinese)
P 379-468 DEF.qxp 09/08/2006 13:53 Page 463
Wang, C.-L., Chuang, H.-Y., Ho, C.-K., Yang, C.-Y., Tsai, J.-L., Wu, T.-S. & Wu, T.N. (2002a)
Relationship between blood lead concentrations and learning achievement among primary
school children in Taiwan. Environ. Res., 89, 12–18
Wang, V.-S., Lee, M.-T., Chiou, J.-Y., Guu, C.-F., Wu, C.-C., Wu, T.-N. & Lai, J.-X. (2002b)
Relationship between blood lead levels and renal function in lead battery workers. Int. Arch.
occup. environ. Health, 75, 569–575
Wasserman, G.A., Liu, X., Popovac, D., Factor-Litvak, P., Kline, J., Waternaux, C., LoIacono, N.
& Graziano, J.H. (2000) The Yugoslavia prospective lead study: Contributions of prenatal and
postnatal lead exposure to early intelligence. Neurotoxicol. Teratol., 22, 811–818
Waszynski, E. (1977) Nonneoplastic and neoplastic changes in the kidneys and other organs in
rodents fed lead acetate and sulfathiazole chronically. Pathol. pol., 28, 101–111
Watanabe, T., Fujita, H., Koizumi, A., Chiba, K., Miyasaka, M. & Ikeda, M. (1985) Baseline level
of blood lead concentration among Japanese farmers. Arch. environ. Health, 40, 170–176
Watanabe, T., Nakatsuka, H. & Ikeda, M. (1989) Cadmium and lead contents in rice available in
various areas of Asia. Sci. total Environ., 80, 175–184
Watanabe, T., Nakatsuka, H., Shimbo, S., Iwami, O., Imai, Y., Moon, C.-S., Zhang, Z.-W., Iguchi,
H. & Ikeda, M. (1996) Reduced cadmium and lead burden in Japan in the past 10 years. Int.
Arch. occup. environ. Health, 68, 305–314
Watanabe, T., Zhang, Z.-W., Qu, J.-B., Gao, W.-P., Jian, Z.-K., Shimbo, S., Nakatsuka, H.,
Matsuda-Inoguchi, N., Higashikawa, K. & Ikeda, M. (2000) Background lead and cadmium
exposure of adult women in Xian city and two farming villages in Shaanxi Province, China.
Sci. total Environ., 247, 1–13
Watson, D.S. (1985) The use of ultrasound scanning by Aboriginal health workers in antenatal care
in a remote area of Australia. Med. J. Austr., 143, S61–S62
Watson, W.S., Hume, R. & Moore, M.R. (1980) Oral absorption of lead and iron. Lancet, ii, 236–237
Watson, W.S., Morrison, J., Bethel, M.I.F., Baldwin, N.M., Lyon, D.T.B., Dobson, H., Moore,
M.R. & Hume, R. (1986) Food iron and lead absorption in humans. Am. J. clin. Nutr., 44,
248–256
Weaver, V.M., Schwartz, B.S., Ahn, K.-D., Stewart, W.F., Kelsey, K.T., Todd, A.C., Wen, J.,
Simon, D.J., Lustberg, M.E., Parsons, P.J., Silbergeld, E.K. & Lee, B.-K. (2003) Associations
of renal function with polymorphisms in the δ-aminolevulinic acid dehydratase, vitamin D
receptor, and nitric oxide synthase genes in Korean lead workers. Environ. Health Perspect.,
111, 1613–1619
Webber, C.E., Chettle, D.R., Bowins, R.J., Beaumont, L.F., Gordon, C.L., Song, X., Blake, J.M. &
McNutt, R.H. (1995) Hormone replacement therapy may reduce the return of endogenous lead
from bone to the circulation. Environ. Health Perspect., 103, 1150–1153
Wedeen, R.P., Mallik, D.K. & Batuman, V. (1979) Detection and treatment of occupational lead
nephropathy. Arch. intern. Med., 139, 53–57
Weitzman, M., Aschengrau, A., Bellinger, D., Jones, R., Hamlin, J.S. & Beiser, A. (1993) Lead-
contaminated soil abatement and urban children’s blood lead levels. J. Am. med. Assoc., 269,
1647–1654
Wesseling, C., Pukkala, E., Neuvonen, K., Kauppinen, T., Boffetta, P. & Partanen, T. (2002)
Cancer of the brain and nervous system and occupational exposures in Finnish women. J.
occup. environ. Med., 44, 663–668
P 379-468 DEF.qxp 09/08/2006 13:53 Page 464
West, R. (1998) Vinyl miniblinds and childhood lead poisoning. Arch. pediatr. adolesc. Med., 152,
512–513
West, W.L., Knight, E.M., Edwards, C.H., Manning, M., Spurlock, B., James, H., Johnson, A.A.,
Oyemade, U.J., Cole, O.J., Westney, O.E., Laryea, H., Jones, S. & Westney, L.S. (1994) Maternal
low level lead and pregnancy outcomes. J. Nutr., 124, 981S–986S
Wetmur, J.G., Kaya, A.H., Plewinska, M. & Desnick, R.J. (1991a) Molecular characterization of the
human δ-aminolevulinate dehydratase 2 (ALAD2) allele: Implications for molecular screening
of individuals for genetic susceptibility to lead poisoning. Am. J. hum. Genet., 49, 757–763
Wetmur, J.G.., Lehnert, G. & Desnick, R.J. (1991b) The δ-aminolevulinic dehydratase poly-
morphism: Higher blood lead levels in lead workers and environmentally exposed children
with the 1-2 and 2-2 isozymes. Environ. Res., 56, 109–119
Weyermann, M. & Brenner, H. (1998) Factors affecting bone demineralization and blood lead
levels of postmenopausal women — A population-based study from Germany. Environ. Res.,
76, 19–25
WHO (1977) Lead (Environmental Health Criteria 3), Geneva, World Health Organization
WHO (1980) WHO Study Group Recommended Health-based Limits in Occupational Exposure to
Heavy Metals (Tech. Rep. Ser. 647), Geneva, pp. 36–80
WHO (1985) Inorganic Lead (Environmental Health Criteria 165), Geneva, International Pro-
gramme on Chemical Safety
WHO (1989) Lead — Environmental Aspects (Environmental Health Criteria 85), Geneva, World
Health Organization
WHO (1995) Inorganic Lead (Environmental Health Criteria 165), Geneva, International Pro-
gramme on Chemical Safety, World Health Organization
WHO (1996) Biological Monitoring of Chemical Exposure in the Workplace. Guidelines, Vol. 1,
Geneva, International Programme on Chemical Safety, World Health Organization, pp. 20–51
WHO (2000a) Air Quality Guidelines for Europe (European Series, No. 91), Copenhagen, World
Health Organization, Regional Office for Europe, pp. 149–153
WHO (2000b) Safety Evaluation of Certain Food Additives and Contaminant — Lead (WHO Food
Additives Series 44), Geneva, International Programme on Chemical Safety, World Health
Organization
Wibberley, D.G., Khera, A.K., Edwards, J.H. & Rushton, D.I. (1977) Lead levels in human
placentae from normal and malformed births. J. med. Gen., 14, 339–345
Wiebe, J.P., Barr, K.J. & Buckingham, K.D. (1982) Lead administration during pregnancy and
lactation affects steroidogenesis and hormone receptors in testes of offspring. J. Toxicol.
environ. Health, 10, 653–666
Wiebe, R.A., Anderson, B.S., Lehman, C.W. & Fu, D.J. (1991) Lead poisoning in Hawaii: 1990.
Hawaiian Med. J., 50, 89–95
Wietlisbach, V., Rickenbach, M., Berode, M. & Guillemin, M. (1995) Time trend and determinants
of blood lead levels in a Swiss population over a transition period (1984–1993) from leaded to
unleaded gasoline use. Environ. Res., 68, 82–90
Wilkins, J.R., 3rd & Sinks, T.H., Jr (1984a) Occupational exposures among fathers of children with
Wilms’ tumor. J. occup. Med., 26, 427–435
Wilkins, J.R., 3rd & Sinks, T.H., Jr (1984b) Paternal occupation and Wilms’ tumour in offspring.
J. Epidemiol. Community Health, 38, 7–11
P 379-468 DEF.qxp 09/08/2006 13:53 Page 465
Willems, M.I., de Schepper, G.G., Wibowo, A.A.E., Immel, H.R., Dietrich, A.J.J. & Zielhuis, R.L.
(1982) Absence of an effect of lead acetate on sperm morphology, sister chromatid exchanges
or on micronuclei formation in rabbits. Arch. Toxicol., 50, 149–157
Willes, R.F., Lok, E., Truelove, J.F. & Sundaram, A. (1977) Retention and tissue distribution of
210Pb (NO ) administered orally to infant and adult monkeys. J. Toxicol. environ. Health, 3,
3 2
395–406
Williams, M.K., King, E. & Walford, J. (1969) An investigation of lead absorption in an electric
accumulator factory with the use of personal samplers. Br. J. ind. Med., 26, 202–216
Wilson, D., Esterman, A., Lewis, M., Roder, D. & Calder, I. (1986) Children’s blood lead levels in
the lead smelting town of Port Pirie, South Australia. Arch. environ. Health, 41, 245–250
Wingren, G. & Axelson, O. (1985) Mortality pattern in a glass producing area in SE Sweden. Br.
J. ind. Med., 42, 411–414
Wingren, G. & Axelson, O. (1987) Mortality in the Swedish glassworks industry. Scand. J. Work
Environ. Health, 13, 412–416
Wingren, G. & Axelson, O. (1993) Epidemiologic studies of occupational cancer as related to
complex mixtures of trace elements in the art glass industry. Scand. J. Work Environ. Health,
19, 95–100
Wingren, G. & Englander, V. (1990) Mortality and cancer morbidity in a cohort of Swedish glass-
workers. Int. Arch. occup. environ. Health, 62, 253–257
Winneke, G., Hrdina, K.G. & Brockhaus, A. (1982) Neuropsychological studies in children with
elevated tooth-lead concentrations. I. Pilot study. Int. Arch. occup. environ. Health, 51,
169–183
Winneke, G., Kramer, U., Brockhaus, A., Ewers, U., Kujanek, G., Lechner, H. & Janke, W. (1983)
Neuropsychological studies in children with elevated tooth-lead concentrations. II. Extended
study. Int. Arch. occup. environ. Health, 51, 231–252
Wise, J.P., Leonard, J.C. & Patierno, S.R. (1992) Clastogenicity of lead chromate particles in
hamster and human cells. Mutat. Res., 278, 69–79
Wise, J.P., Sr, Stearns, D.M., Wetterhahn, K.E. & Patierno, S.R. (1994) Cell-enhanced dissolution
of carcinogenic lead chromate particles: The role of individual dissolution products in clasto-
genesis. Carcinogenesis, 15, 2249–2254
Wittmers, L.E., Jr, Aufderheide, A.C., Wallgren, J., Rapp, G., Jr & Alich, A. (1988) Lead in bone.
IV. Distribution of lead in the human skeleton. Arch. environ. Health, 43, 381-391
Wong, O. & Harris, F. (2000) Cancer mortality study of employees at lead battery plants and lead
smelters, 1947–1995. Am. J. ind. Med., 38, 255–270
Wozniak, K. & Blasiak, J. (2003) In vitro genotoxicity of lead acetate: Induction of single and
double DNA strand breaks and DNA–protein cross-links. Mutat. Res., 535, 127–139
Wright, R.O., Tsaih, S.W., Schwartz, J., Wright, R.J. & Hu, H. (2003) Association between iron
deficiency and blood lead level in a longitudinal analysis of children followed in an urban
primary care clinic. J. Pediatr., 142, 9–14
Wu, J., Hsu, F.C. & Cunningham, S.D. (1999) Chelate-assisted Pb phytoextraction: Pb availability,
uptake, and translocation constraints. Environ. Sci. Technol., 33, 1898–1904
Wu, T.-N., Yang, K.-C., Wang, C.-M., Lai, J.S., Ko, K.N., Chang, P.Y. & Liou, S.H. (1996) Lead
poisoning caused by contaminated Cordyceps, a Chinese herbal medicine: Two case reports.
Sci. total Environ., 182, 193–195
P 379-468 DEF.qxp 09/08/2006 13:53 Page 466
Wu, F.-Y., Chang, P.-W., Wu, C.-C. & Kuo, H.-W. (2002) Correlations of blood lead with
DNA–protein cross-links and sister chromatid exchanges in lead workers. Cancer Epidemiol.
Biomarkers Prev., 11, 287–290
Wu, Y., Huang, Q., Zhou, X., Hu, G., Wang, Z., Li, H., Bao, R., Yan, H., Li, C., Wu, L. & He, F.
(2002) Study on the effects of lead from small industry of battery recycling on environment
and children’s health. Chin. J. Epidemiol., 23, 167–171
Wulff, M., Högberg, U. & Sandström, A. (1996) Cancer incidence for children born in a smelting
community. Acta Oncol., 35, 179–183
Xu, J., Wise, J.P. & Patierno, S.R. (1992) DNA damage induced by carcinogenic lead chromate
particles in cultured mammalian cells. Mutat. Res., 280, 129–136
Yamamura, K., Kishi, R., Maehara, N., Sadamoto, T. & Uchino, E. (1984) An experimental study
of the effects of lead acetate on hearing. Cochlear microphonics and action potential of the
guinea pig. Toxicol. Lett., 21, 41–47
Yáñez, L., García-Nieto, E., Rojas, E., Carrizales, L., Mejía, J., Calderón, J., Razo, I. & Díaz-
Barriga, F. (2003) DNA damage in blood cells from children exposed to arsenic and lead in a
mining area. Environ. Res., 93, 231–240
Yang, J.J. & Ma, Y.P. (1997) [The characteristics of metal elements in airborne particle in Taiyuan.]
J. Hyg. Res., 26, 87–89 (in Chinese)
Yang, J.-L., Yeh, S.-C. & Chang, C.-Y. (1996) Lead acetate mutagenicity and mutational spectrum
in the hypoxanthine guanine phosphoribosyltransferase gene of Chinese hamster ovary K1
cells. Mol. Carcinog., 17, 181–191
Yang, J.-L., Wang, L.-C., Chang, C.-Y. & Liu, T.-Y. (1999) Singlet oxygen is the major species
participating in the induction of DNA strand breakage and 8-hydroxydeoxyguanosine adduct
by lead acetate. Environ. mol. Mutag., 33, 194–201
Ye, X.-B., Fu, H., Zhu, J.-L., Ni, W.-M., Lu, Y.-W., Kuang, X.-Y., Yang, S.-L. & Shu, B.-X. (1999)
A study on oxidative stress in lead-exposed workers. J. Toxicol. environ. Health, A56, 161–172
Yokoyama, K., Araki, S., Murata, K., Morita, Y., Katsuno, N., Tanigawa, T., Mori, N., Yokota, J.,
Ito, A. & Sakata, E. (1997) Subclinical vestibulo-cerebellar, anterior cerebellar lobe and spino-
cerebellar effects in lead workers in relation to concurrent and past exposure. Neurotoxicology,
18, 371–380
Yuan, X. & Tang, C. (2001) The accumulation effect of lead on DNA damage in mice blood cells
of three generations and the protection of selenium. J. environ. Sci. Health, A36, 501–508
Yule, W., Lansdown, R., Millar, I.B. & Urbanowicz, M.A. (1981) The relationship between blood
lead concentrations, intelligence and attainment in a school population: A pilot study. Dev.
Med. Child Neurol., 23, 567–576
Yule, W., Urbanowicz, M.A., Lansdown, R. & Millar, I. (1984) Teachers ratings of children’s
behavior in relation to blood lead levels. Br. J. dev. Psychol., 2, 295–305
Yusof, M., Yildiz, D. & Ercal, N. (1999) N-Acetyl-L-cysteine protects against δ-aminolevulinic
acid-induced 8-hydroxydeoxyguanosine formation. Toxicol. Lett., 106, 41–47
Zawia, N.H., Crumpton, T., Brydie, M., Reddy, G.R. & Razmiafshari, M. (2000) Disruption of the
zinc finger domain: A common target that underlies many of the effects of lead. Neurotoxico-
logy, 21, 1069–1080
Zawirska, B. (1981) The role of the kidneys in disorders of porphyrin metabolism during carcino-
genesis induced with lead acetate. Environ. Res., 24, 391–408
P 379-468 DEF.qxp 09/08/2006 13:53 Page 467
Zawirska, B. & Medras, K. (1968) [Tumors and disorders of porphyrin metabolism in rats with
chronic experimental lead poisoning. I. Morphological studies]. Zdrav. Prac., 111, 1–12 (in
German)
Zawirska, B. & Medras, K. (1972) The role of the kidneys in disorders of porphyrin metabolism
during carcinogenesis induced with lead acetate. Arch. immunol. Ther. exp., 20, 257–272
Zejda, J.E., Sokal, A., Grabecki, J., Panasiuk, Z., Jarkowski, M. & Skiba, M. (1995) Blood lead
concentrations in school children of Upper Silesian Industrial Zone, Poland. Cent. Eur. J.
Public Health, 3, 92–96
Zelikoff, J.T., Li, J.H., Hartwig, A., Wang, X.W., Costa, M. & Rossman, T.G. (1988) Genetic toxi-
cology of lead compounds. Carcinogenesis, 9, 1727–1732
Zeng, J. & Kagi, J.H.R. (1995) Zinc fingers and metallothionein in gene expression. In: Goyer,
R.A. & Cherian, M.G., eds, Toxicology of Metals, Heidelberg, Springer Verlag, pp. 333–335
Zey, J.N. & Cone, J.E. (1982) Health Hazard Evaluation Report, HETA 81-0039-1104, Modine
Manufacturing Co., Bloomington, IL, USA, NIOSH
Zhang, J., Ichiba, M., Wang, Y., Yukitake, S. & Tomokuni K. (1998) Relation between poly-
morphism of δ-aminolevulinic acid dehydratase and some parameters in lead workers.
J. occup. Health, 40, 77–78
Zhang, Z.-W., Moon, C.-S., Watanabe, T., Shimbo, S. & Ikeda, M. (1996) Lead content of rice
collected from various areas in the world. Sci. total Environ., 191, 169–175
Zhang, Z.-W., Moon, C.-S., Watanabe, T., Shimbo, S., He, F.-S., Wu, Y.-Q., Zhou, S.-F., Su, D.-M.,
Qu, J.-B. & Ikeda, M. (1997a) Background exposure of urban populations to lead and cadmium:
Comparison between China and Japan. Int. Arch. occup. environ. Health, 69, 273–281
Zhang, Z.-W., Qu, J.-B., Xu, G.-F., Song, L.-H., Wang, J.-J., Shimbo, S., Watanabe, T., Nakatsuka,
H., Higashikawa, K. & Ikeda, M. (1997b) Maize and foxtail millet as substantial sources of
dietary lead intake. Sci. total Environ., 208, 81–88
Zhang, Z.W., Shimbo, S., Ochi, N., Eguchi, M., Watanabe, T., Moon, C.S. & Ikeda, M. (1997c)
Determination of lead and cadmium in food and blood by inductively coupled plasma mass
spectrometry: A comparison with graphite furnace atomic absorption spectrometry. Sci. total
Environ., 205, 179–187
Zhang, Z.-W., Qu, J.-B. & Ikeda, M. (1998) Lead and cadmium levels in the atmosphere in main-
land China: A review. J. occup. Health, 40, 257–263
Zhang, Z.-W., Qu, J.-B., Watanabe, T., Shimbo, S., Moon, C.-S. & Ikeda, M. (1999) Exposure of
citizens in China and in Japan to lead and cadmium: A comparative study. Toxicol. Lett., 108,
167–172
Zhang, Z.-W., Moon, C.-S., Shimbo, S., Watanabe, T., Nakatsuka, H., Matsuda-Inoguchi, N.,
Higashikawa, K. & Ikeda, M. (2000) Further reduction in lead exposure in women in general
populations in Japan in the 1990s, and comparison with levels in east and south-east Asia. Int.
Arch. occup. environ. Health., 73, 91–97
Zheng, X.Q., Liu, J.R. & Song, H.Q. (1993) Blood lead levels of children and their relationship
with blood lead levels of adults. Public Health Res., 23 (Suppl.), 29–33
Zheng, Y., Leng, S., Song, W., Wang, Y., Niu, Y., Zhang, W., Yan, H., Liu, Y., Huang, Q. & Wu, Y.
(2002) [A molecular epidemiological study of childhood lead poisoning in lead-polluted envi-
ronment.] Chin. J. Epidemiol., 23, 175–78 (in Chinese)
Zhou, W.X. & Chen, J.Z. (1988) Health effects of lead exposure in children. Environ. Health,
5,18–22
P 379-468 DEF.qxp 09/08/2006 13:53 Page 468
Zhou, W., Yuan, D., Ye, S., Qi, P., Fu, C. & Christiani, D.C. (2001) Health effects of occupational
exposures to vehicle emissions in Shanghai. Int. J. occup. environ. Health, 7, 23–30
Zhu, B.G., Su, D.Q., Qin, M. & Jian, C.P. (1984) [Study of chronic lead-poisoning from using tin-
kettles.] Chinese J. Prevent. Med., 18, 328–330 (in Chinese)
Ziegler, E.E., Edwards, B.B., Jensen, R.L., Mahaffey, K.R. & Fomon, S.J. (1978) Absorption and
retention of lead by infants. Pediatr. Res., 12, 29–34
Zollinger, H.U. (1953) [Renal adenomas and carcinomas induced in rats after chronic lead expo-
sure, and their relationship with corresponding neoplasia in humans.] Virchows Arch., 323,
697–710 (in German)
Zuckerman, M.A. (1991) Lead exposure from lead crystal. Lancet, 337, 550
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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
–469–
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The volume, page and year of publication are given. References to corrigenda are given
in parentheses.
–473–
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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)
3-Chloronitrobenzene 65, 263 (1996)
4-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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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)
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)
occupational exposures to; Polychlorophenols and their sodium salts)
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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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
Volume 17 1982; 341 pages (out-of-print)
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 18 1982; 486 pages (out-of-print)
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 19 1982; 416 pages (out-of-print)
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).
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Imprimé en France
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