Glyphosate en Agua
Glyphosate en Agua
Glyphosate en Agua
Prepared by
June 2007
TABLE OF CONTENTS
INTRODUCTION .......................................................................................................... 1
INTRODUCTION
The following are the combined responses to major comments received by the Office of
Environmental Health Hazard Assessment (OEHHA) on the proposed public health goal
(PHG) technical support document for Glyphosate, based on the pre-release review draft.
Changes have already been made in response to these comments, and have been
incorporated into the draft. For the sake of brevity, we have selected the more important
or representative comments for responses. Comments that are direct quotations appear
within quotation marks and paraphrased comments are in italics.
These comments and responses are provided in the spirit of the open dialogue among
scientists that is part of the process under Health and Safety Code Section 57003. For
further information about the PHG process or to obtain copies of PHG documents, please
visit the OEHHA Web site at www.oehha.ca.gov. OEHHA may also be contacted at:
Comment 1: “We do not believe that published epidemiology studies are relevant to the
safety assessment of exposure to glyphosate residues in drinking water. By nature and
design, epidemiology is focused on exposures, usually occupational, arising through uses
of pesticides, and not to oral exposure via food or water residues.”
“We do not believe that exposure or potential effects arising through environmental
contact are relevant to the safety assessment of human exposure to glyphosate residues in
drinking water.”
Response 1: OEHHA considers toxicity studies of all kinds in its review. OEHHA is
aware of the limitations of the ecological and epidemiological studies described in the
glyphosate PHG document. The lack of reliable exposure information, the potential for
recall bias, and the presence of confounding factors were all mentioned regarding the
interpretation of these studies. No change to the PHG document was made in response to
this comment.
Comment 2: The commenter criticized a report by Garry et al. (2002) who found an
association between attention-deficit disorder (ADD) and use of glyphosate on three
points, (a) reliability of ADD self-reports, (b) reliability of self-reports of exposure, and
(c) lack of biological plausibility.
Response 2: OEHHA is aware of the limitations of this study. As was stated in the
glyphosate PHG document, a small number of subjects, exposures to multiple chemicals,
and the possibility of recall bias limit the usefulness of this study.
However, OEHHA has a different view on the biological plausibility. The commenter
suggested that because glyphosate has not been found to be teratogenic, neurotoxic, or a
reproductive toxin, and that the systemic doses in the applicators are likely to be very
low, glyphosate could not be the cause of ADD. There have been difficulties and
uncertainties in extrapolating animal neurotoxicity study results to humans. Studies in
laboratory animals may not be as sensitive as evaluations of results in humans. The
effect of lead exposure on the intelligence of small children is an example. Negative
results in several toxicological studies do not necessarily mean the association reported
by Garry et al. must be wrong.
“Difficulties in diagnosis” has been added to the list of concerns of this study in the PHG
document.
Comment 3: The commenter faulted the methodology and findings of a study reported by
Hardell et al. (2002) who found an association between glyphosate exposure and non-
Hodgkin’s lymphoma or hairy cell leukemia.
Comment 4: “We do not believe that direct ingestion of formulated products, whether
intentional or accidental, is relevant to the safety assessment of glyphosate residues in
drinking water.”
Response 4: OEHHA believes these types of studies are relevant to the discussion of the
toxic effects of glyphosate and should be included in the toxicological profile. Whether
this type of information should be used in the development of a health-based drinking
water level depends on the breadth of the toxicity database and the availability of a more
suitable toxicity study. In this case, more appropriate animal data are available. No
change to the PHG document was made in response to this comment.
Comment 5: “We do not believe that sporadic findings from non-standard, non-validated
studies such as Daruich et al., 2001, Nakashima et al., 2002 and Walsh et al., 2000 which
are not conducted according to international guidelines or in Good Laboratory Practices-
compliant testing facilities represent any credible hazard to human health or the
environment.”
Response 5: The study by Nakashima et al. (2002) was not cited in the PHG document.
OEHHA agrees with the commenter that the other two studies have their limitations in
terms of design and reporting. Nevertheless, these two studies were published in peer
reviewed scientific journals and should be included in the toxicological review. No
change to the PHG document was made in response to this comment.
Comment 1: “What are the criteria OEHHA is using for selecting studies to be included
for its reviews and how is the quality and value of the data in these studies being assessed
in evaluations of chemicals and the setting of the PHG?”
Response 1: In the development of PHGs, OEHHA considers toxicity information of all
kinds but generally puts more weight on studies published in peer reviewed scientific
journals or conducted by reputable institutions, such as the National Toxicology Program
(NTP), funded by the federal government. Indeed, one of the critical tasks of developing
PHGs is to recognize the strengths and weaknesses of the studies being reviewed and
choose the most relevant and appropriate studies for human health risk assessment. No
change to the PHG document was made in response to this comment.
Comment 3: Referring to the Summary Section, page 1, the commenter stated, “„The
proposed value is judged to be protective of potential sensitive populations, including
pregnant women and their fetuses, infants and children and the elderly.‟ As no
susceptible subgroups have been identified we request the removal of the phrase
„potential sensitive subpopulations such as pregnant women and their fetuses and
children and, the elderly.‟ from the sentence on pages 1 and 23 or provide a basis for
including these statements that are at odds with the conclusion on subgroups as stated on
page 24.”
Response 3: The California Safe Drinking Water Act (HSC 116365) requires OEHHA to
consider sensitive subgroups in deriving PHGs, and OEHHA considers it to be
appropriate to note that such groups have been considered in the risk assessment.
Because no potentially sensitive subgroups were identified, OEHHA considered the PHG
value derived by using adult exposure assumptions as sufficiently protective of other age
groups as well. If a sensitive subgroup were identified in the evaluation, a lower PHG
value would have been developed due to the use of exposure parameters specific to
infants or children and/or the use of an additional uncertainty factor. No change to the
PHG document was made in response to this comment.
Comment 5: Referring the Introduction Section, to page 2, the commenter stated, “Please
delete the IRIS paragraph. The toxicology data on glyphosate in the IRIS database is
significantly out of date. The Oral reference dose was calculated in 1990 using the
original studies conducted with glyphosate (see section on Revision History below). The
chronic rat and rat multigenerational reproduction toxicology studies were repeated at
much higher doses and supersede the earlier studies.”
Comment 6: Referring to the Introduction Section, page 3, the commenter stated, “If this
document is to provide a brief summary of relevant oral and dermal toxicity studies in the
context of the updated review of chemical contaminants why are studies with
intraperitoneal routes of exposure, in vitro studies, reports on effects following
intentional suicides and epidemiology studies included in this review? What is the
relevancy of these to oral or dermal exposures to drinking water?”
Response 6: In the evaluation of toxicological properties of a chemical, OEHHA
generally reviews all routes of exposure. This is particularly relevant when the chemical
is a systemic toxicant and the target organs are not dependent on the route of exposure. It
is important to note that while OEHHA included intraperitoneal injection studies in the
review, these studies were not selected for dose-response characterization.
The last paragraph of the Introduction Section has been changed to reflect that not only
oral and dermal toxicity studies were included in the review.
Comment 7: Referring to the Chemical Profile Section, to page 2, the commenter stated,
“It should be noted that there is no commercial product called “Roundup ” in the US
markets today. Roundup represents a group of branded products.”
Response 7: We note that several registered glyphosate products use the term “Roundup”
in their names. The term “Roundup ” has been changed to “Roundup branded
herbicides,” “Roundup products,” or similar wording.
Comment 8: Referring to the Chemical Profile Section, page 3, the commenter stated, “It
is correct that glyphosate is usually formulated as a salt (isoproplyamine, potassium,
ammonium) however not all salts are the same. The trimethylsulfonium salt of
glyphosate (sulfosate) is very different and in fact has a different toxicity profile, it has an
acute RfD while glyphosate does not, it has a different chronic RfD and is registered
separately in the US and Europe. Therefore, it is inappropriate to include it in an
evaluation of “glyphosate”.”
Response 8: Glyphosate and sulfosate contain the same active moiety of N-
(phosphonomethyl)glycine. Roundup is the isopropylamine salt of the parent acid.
Sulfosate is the trimethylsulfonium salt of the same acid; it is sold under the trade name
of Touchdown®. We acknowledge their difference as formulated products. In biological
systems, these two salts disassociate and give the same anion. Both products would also
be expected to be dissociated if found in drinking water.
The difference in acute toxicity of various formulations of glyphosate may be attributed
to the difference in absorption rate or the use of different surfactants. Perspectives on the
toxicity of the N-(phosphonomethyl)glycine moiety can potentially be obtained from
Comment 10: Referring to the Environmental Occurrence and Human Exposure Section,
Water, page 5, the commenter stated, “Please provide the literature reference for this
statement; “Inhalation of spray droplets by agricultural workers and residents living near
agricultural fields can be an important exposure pathway”. There is absolutely no
scientific evidence to indicate that inhalation of spray droplets are an important route of
exposure to glyphosate for applicators and especially not for people living near
agricultural fields. To control spray drift spray droplets must be 100 microns or more in
diameter and these are physically too large to enter the lungs. Particles having an
aerodynamic diameter of 5 to 30 microns also would not enter the lungs and would be
deposited in the nasopharyngeal region.”
“Furthermore, investigators in a biomonitoring study (Acquavella et al. 2004) with a limit
of detection of 1 ppb found that 40% of the farmers who applied glyphosate had no
detectable levels of glyphosate in their urine. This biomonitoring study reflects all routes
of exposure.”
Response 10: The monitoring data reported by Acquavella et al. (2004) showed a
majority (60%) of the farmers who participated in the study had detectable levels of
glyphosate in their urine on the day of application. Farmers who did not use rubber
gloves had higher geometric mean urinary concentrations than did other farmers (10 ppb
vs. 2 ppb). This result shows that while the dermal route is important, other exposure
routes, such as inhalation and oral, should not be overlooked. In the WHO report (2004),
it was stated, “In operators applying glyphosate products, cases of eye, skin, and/or
respiratory tract irritation have been reported.” This information supports the statement
that inhalation of spray droplets may be an important worker exposure pathway.
Drift of pesticides to residents living near agricultural fields during and after a spraying
operation generally poses an inhalation exposure risk. The significance of this pathway
depends on weather condition, method of spraying, and the distance between the field
and the residents. The study of Acquavella et al. (2004) found 12% of the children had
detectable glyphosate in their urine on the day of application. All but one of the children
with detectable concentration had helped with the application or were present during
herbicide mixing, loading, or application. While there is no evidence that all the
exposure took place when the children were close to the mixing, loading, or application
of glyphosate, there is at least one child whose exposure cannot be easily explained. It is
possible that the child was exposed because of the drift of glyphosate sprays.
Comment 11: Referring to the Environmental Occurrence and Human Exposure Section,
Water, page 5, the commenter stated, “The section on water degradation is not entirely
correct suggest the following paragraph as a replacement and reference the Geisy et al.
2000 review….”
Response 11: The commenter did not specify what was wrong with the text regarding
degradation of glyphosate in water, and it was not clear with reference to the suggested
paragraph. As a result, no change to the PHG document was made in response to this
comment.
Comment 12: Referring to the Environmental Occurrence and Human Exposure Section,
Food, page 6, the commenter stated, “As residues of glyphosate at tolerance are legally
allowed to be there, have never been found to exceed the tolerances and no risk to human
health has been identified why is the potential exposure to glyphosate residues implied to
be from contaminated vegetation? This is misleading and appears to give the impression
of some risk or harm. Please delete this sentence “Ingestion of sprayed food material or
products from animals fed contaminated vegetation may lead to glyphosate exposure.”
Response 12: The word “contaminated” has been changed to “treated.”
Comment 14: Referring to the Toxicological Effects in Animals Section, Dermal and
Ocular Effects, page 9, the commenter stated, “Please indicate the test material used in
these studies? Is it glyphosate or a formulated product? Please include the references for
these studies.”
Response 14: This paragraph has been revised along the lines suggested.
Incidence and severity score for cytoplasmic alteration of the parotid salivary gland
in B6C3F1 mice in the 13-week glyphosate-dosed feed study (from NTP, 1992).
Thus these results are completely out of the range of effects induced by bulk changes in
the diets. No change to the PHG document was made in response to this comment.
Comment 17: Referring to the Toxicological Effects in Animals Section, Chronic Effects
and Carcinogenicity Studies, page 10, the commenter stated, “As there is no evidence to
indicate that glyphosate is carcinogenic nor genotoxic and regulators and scientific bodies
around the world have concluded that to be the case why is this not clearly indicated in
the discussion on pages 10-15? What is the purpose of discussing in great detail findings
that were not considered to be related to treatment? For example, no tumors have ever
been concluded to be related to treatment in any glyphosate study yet tumor after tumor is
discussed in great detail.”
Response 17: In this section, tumor data were presented and their biological significance
discussed. The determination of the carcinogenic potential of glyphosate was presented
in the Dose-Response Assessment Section. No change to the PHG document was made
in response to this comment.
Comment 18: Referring to the Toxicological Effects in Animals Section, Genetic Toxicity,
page 13, the commenter stated, “Why are only the studies indicating positive results for
genotoxicity discussed in detail in section of the PHG while those showing negative
results are not discussed or not even identified? We request these detailed discussions be
deleted or this bias be corrected by a weight of evidence analysis and discussion.”
Response 18: This section has been revised. Tables 4 and 5 are deleted.
Response 24: In the Discussion Section of the paper by Dallegrave et al. (2003), it was
stated, “The developmental retardations of the skeleton reported in the present study
shows that the effect of glyphosate-Roundup® was more marked than that of technical
glyphosate (WHO, 1994). The higher maternal toxicity reported here in comparison to
that of technical glyphosate is probably related to the presence of other components in the
commercial formulation, such as the surfactant polyoxyethleneamine.” No change to the
PHG document was made in response to this comment.
Comment 27: Referring to the Toxicological Effects in Humans Section, Case Studies
and Human Clinical Studies, page 18, the commenter stated, “As a PHG is a level of
drinking water contaminant at which adverse health effects are not expected to occur
from a lifetime of exposure and glyphosate has never been detected in finished drinking
water we request that this section with discussion on reports of attempted suicides with
concentrated formulations, accidental exposures to the trimesium salt of glyphosate
which is very different than the other salts of glyphosate, and a single case report on
Parkinson that has no biological plausibility be deleted or justification for their inclusion
and relevancy to the PHG be given.”
Response 27: OEHHA considers toxicity studies of all kinds in its evaluation, generally
putting more weight on studies using a route of administration that is relevant or similar
to human exposure. Thus, evaluation of human effects of glyphosate ingestion is
considered relevant to evaluation of glyphosate toxicity for human risk assessment. The
development of PHGs is mandated by law for regulated chemicals in drinking water,
irrespective of the present frequency of detection of the contaminants in drinking water.
In this section, human cases of exposure to glyphosate-containing products (Roundup®
and Touchdown®) were discussed. Clearly, exposure situations related to suicide
attempts are different from environmental exposures. Nevertheless, OEHHA believes
these data constitute part of the toxicological profile of the chemical.
Comment 28: Referring to the Toxicological Effects in Humans Section, Case Studies
and Human Clinical Studies, page 18, the commenter stated, “Please remove the
following statement in the last sentence of the first paragraph or provide the reference
that supports this statement; “and the toxicity of glyphosate might have been increased by
the presence of surfactants.”
Response 28: Please see the discussion on studies reported by Sorensen and Gregersen
(1999) and Dallegrave et al. (2003). These two references have been added to the
sentence.
Comment 29: Referring to the Toxicological Effects in Humans Section, Case Studies
and Human Clinical Studies, page 19, the commenter stated, “Please provide the
relevancy of including dermal irritation studies in volunteers in the setting of a PHG.”
Response 29: In general, dermal irritation studies are not directly applicable in the
development of PHGs. However, this information constitutes part of the toxicological
profile of the chemical. For this reason, OEHHA prefers to keep these studies in the
document. No change to the PHG document was made in response to this comment.
Comment 30: Referring to the Toxicological Effects in Humans Section, Ecological and
Epidemiologic Studies, page 19, the commenter stated, “Regarding the study by
Goldstein et al. 2002. The limited amount of discussion is very misleading…how was
that 23 % determined and what does this really represent in the context of 15 years and
are those systemic signs directly related to glyphosate? ”
Response 30: The discussion of the paper by Goldstein et al. (2002) has been revised.
Comment 31: Referring to the Toxicological Effects in Humans Section, Ecological and
Epidemiologic Studies, page 20, the commenter submitted three unpublished papers by
Acquavella (2001 and 2003) and Adami and Trichopoulos (1999) that are critical of the
epidemiological studies discussed in the section. These unpublished papers criticize the
design, methodology, analysis, and results of the studies published by Hardell et al.
(2002), Arbuckle et al. (2001), and Savitz et al. (1997). The commenter requested the
deletion of these epidemiological studies or the justification for their inclusion and
relevancy to setting a PHG for glyphosate.
Response 31: In the description of the three epidemiological studies, their deficiencies
and weaknesses were also discussed. Many of those issues overlap with those raised by
Acquavella (2001 and 2003) and Adami and Trichopoulos (1999). Despite these
Comment 32: Referring to the Risk Characterization Section, page 24, the commenter
stated, “The Yousef et al. 1994 study is poorly conducted, has many flaws and does not
represent credible evidence of effects on the male reproductive system. It is suggested
that based on the results of the Yousef study that further study is warranted. The
definitive study has been conducted and was evaluated by the WHO in the 2004 JMPR
periodic review of glyphosate. The new multigenerational rat reproduction study
contained all male and female reproductive endpoints including sperm analysis and was
submitted by another glyphosate manufacturer. No adverse effects on the male or female
reproductive system were observed in this study. As there is no evidence of any effect on
the male reproductive system in any species in any study conducted according to
international guidelines and under GLP we request that this paragraph be deleted or
justification given for its continued reference and its relevancy to determining a PHG for
glyphosate.”
Response 32: OEHHA agrees with the commenter that the reproductive study reported
by Yousef et al. (1995) has its limitations. There were only 4 rabbits in each dose group
and the dosage information was not clearly reported. Nonetheless, we do not feel we can
ignore this study. It is not clear what is the “multigen rat study” mentioned by the
commenter. It is also not clear if this study investigated the same biological endpoints as
those in the study reported by Yousef. A negative study in rats cannot preclude the
possibility of a positive finding in another species, rabbit. Further, similar findings
(reduction of sperm concentrations) have been reported in rats (NTP, 1992).
Comment 1: “Syngenta is of the view that Public Health Goals (PHG) developed for
chemical containments should be based on the best available toxicological data, derived
from the best available studies that conform to good laboratory and scientific practices.
Some of the studies discussed in PHG for glyphosate were not conducted according to
internationally accepted GLP practices and some followed scenarios that did not
correspond to valid physiological systems. All these questionable studies were accorded
equal weight with valid GLP compliant studies. This practice should be corrected.”
Response 1: Many toxicological investigations, outside the arenas of drug development
and pesticide regulation, do not follow the good laboratory practices (GLP) regulations,
nor the international guidelines developed for submission of foreign studies in support of
American marketing of pesticides and drugs. In the development of PHGs, OEHHA
considers toxicity information of all kinds but generally puts more weight on studies
published in peer reviewed scientific journals or conducted by reputable institutions, such
as the National Toxicology Program (NTP), funded by the federal government. Indeed,
one of the jobs of developing PHGs is to recognize the strengths and weaknesses of the
Comment 2: “The document reviewed various mutagenicity studies, some of which had
procedural flaws, and accorded the same weight of relevance to all the reviewed studies.
The document, after reviewing these studies failed to explicitly provide the weight of
evidence conclusion from scientists and regulatory agencies worldwide – which is that
glyphosate is not mutagenic.”
Response 2: The section on genetic toxicity has been revised. The first paragraph now
states, “Glyphosate was mostly negative in in vivo and in vitro test systems evaluating
gene mutation, chromosomal aberration and DNA damage. Using the weight-of-
evidence approach, glyphosate is considered to be neither genotoxic nor clastogenic.”
Comment 3: “The document summarizes the conduct and results from rabbit
teratogenicity study. In this study, no adverse effects were observed in pups in the
absence of severe maternal toxicity. However, this review has not made this distinction,
contary to the position of other regulatory agencies word wide, including US EPA. In the
absence of any teratogenic or reproductive effects, it is not clear why OEHHA needs an
additional 10X uncertainty factor in setting the PHG for glyphosate.”
Response 3: As stated in the dose-response assessment section, the no-observed-adverse-
effect-level of 175 mg/kg-day used for the risk assessment was based on maternal
toxicity, not adverse effects observed in pups. The combined uncertainty factor of 1,000
includes 10-fold for inter-species variation, 10-fold for human variability and 10-fold for
the severity of the endpoint (early mortality was observed in the next higher dose group)
and the short exposure duration. No change to the PHG document was made in response
to this comment.
Comment 1. “…US Environmental Protection Agency has reviewed the draft document
for Glyphosate (May 2006 draft…) and found it to be scientifically sound. We generally
agree with your assessment of the chronic RfD with respect to the choice of study (rabbit
developmental study), the end point (mortality, diarrhea/nasal discharge), and the
NOAEL (175 mg/kg/d) used in the RfD assessment. However, we would like to
emphasize here that OPP used an Uncertainty Factor of 100 which is 10-fold less than
what you have used. We do realize that different concerns and different policies might
exist dictating this variation in the use of uncertainty factor among different agencies.
For your information, OPP decided not to add the otherwise appropriate 10X to account
for severity of effect/duration of exposure because the weight-of-evidence shows toxicity
at much higher doses in other species (NOAELs of 500, 750, 400, and 500 mg/kg/d for
the one-year dog, chronic mouse, chronic rat, and two-generation reproductive toxicity
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