Atrazine Science Reevaluation: Potential Health Impacts

October 7, 2009

I.  Background

Atrazine is currently one of the most widely used agricultural
herbicides in the United States, with approximately 70 million pounds of
active ingredient applied domestically per year. First registered for
use in December 1958, atrazine may be applied both before and after
planting to control broadleaf and grassy weeds.  Its primary uses are on
corn, sorghum, sugarcane and to a lesser extent on residential lawns in
the Southeast. Currently, the heaviest uses of atrazine are found in the
Midwest. 

The Interim Reregistration Eligibility Decision (IRED) was finalized in
January 2003 with an addendum added in October 2003 (US EPA 2003).  The
Agency completed the reregistration eligibility process for atrazine in
April 2006.  

Recently, articles in the media and a report by the Natural Resources
Defense Council (NRDC) have raised human health concerns for atrazine
and have been critical of EPA’s regulatory oversight of this
herbicide.  Specifically, these publications have claimed that EPA is
not taking into account emerging scientific evidence in animal
toxicology and human epidemiology studies in determining the Agency’s
levels of concern for atrazine concentrations in drinking water sources.
 The publications claim that the Agency is failing to inform the public
in a timely fashion about atrazine spikes in drinking water when they
occur.  In addition, the publications encourage EPA to expand its public
notification mandates/efforts and make the data available sooner,
suggesting that the public has a right to know about atrazine levels in
drinking water regardless of whether the detections violate any
regulatory standards.

EPA is launching a comprehensive re-evaluation of the science associated
with the atrazine human health and ecological risk assessments.  The
initial effort will consider human health issues, including cancer and
non-cancer effects observed in animals tested in controlled laboratory
studies and from human epidemiology studies.  To ensure that the best
science possible is used to inform the atrazine human health risk
assessment, and to ensure transparency in regulatory decision making,
EPA is seeking advice from the Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP or Panel) on a
variety of challenging scientific issues.  As described in detail below,
the Agency is planning to hold three meetings of the SAP in 2010 in
addition to an informational presentation to the Panel in November 2009.
 At the end of this peer review process, the Agency will determine if
the current human health risk assessment should be revised and whether
any further risk mitigation is warranted.

The following text provides the SAP and the public with a summary of the
regulatory history of atrazine and the most recent human health risk
assessment, and an overview of the science peer review plan, that will
be discussed at the November, 2009 presentation.  The purpose and scope
of subsequent SAP meetings planned for February, April, and September
2010 are also described here.

II.  Previous Scientific Advisory Panel Reviews of Atrazine

The human health and ecological risk assessments for atrazine are
complex and have a long history of data development, regulatory
evaluation, and FIFRA SAP review.  The Agency has sought advice from the
SAP on human health issues during three review meetings (FIFRA SAP,
1988, 2000a, 2003a) and it has sought advice on ecological risk
assessment issues during four review meetings (FIFRA SAP 2003b, 2007a,
2007b, 2009).  

Atrazine was first taken to the SAP for evaluation of rat mammary gland
tumor response in 1988 (FIFRA SAP, 1988).  At that time, the SAP noted
that a “hormonal influence” might be an important consideration in
the development of these mammary gland tumors.  Subsequent to this
meeting, substantial research was conducted on atrazine's hormonal or
neuroendocrine mode of action (MOA).  The Agency returned to the SAP in
2000 (FIFRA SAP, 2000a) for advice on atrazine’s MOA leading to
mammary gland tumors, reproductive and developmental effects in rats, as
well as the human relevance of these findings.  The SAP agreed with the
Agency’s proposal for atrazine’s neuroendocrine mode of action, and
they further concluded that it is unlikely that the mechanism by which
atrazine induces mammary tumors in female Sprague Dawley rats could be
operational in humans. Nevertheless, the SAP further concluded that it
is not unreasonable to expect that atrazine might cause adverse effects
on hypothalamic-pituitary function in humans if exposures were
sufficiently high (p. 14, FIFRA SAP, 2000a).  At the 2000 SAP, the Panel
further advised the Agency to evaluate cancer epidemiology research in
more depth as more information became available, particularly for
prostate cancer and Non-Hodgkin’s lymphoma.  Based on the 2000 SAP
guidance, EPA changed its position on atrazine and reclassified it from
a “possible carcinogen” to “not likely to be carcinogenic in
humans”. 

In 2003, the Agency presented its evaluation on prostate cancer to the
FIFRA SAP.  At that meeting, the SAP evaluated the available
epidemiology studies suggesting an association between atrazine and
prostate cancer in workers at an atrazine manufacturing plant in St.
Gabriel Louisiana.  The SAP concurred with EPA’s conclusion that the
data did not suggest an association between atrazine exposure and
prostate cancer, but that the increase in incidence of prostate cancer
in workers at the plant could likely be explained by the increase in
Prostate Serum Antigen (PSA) screening at the plant (FIFRA SAP, 2003a). 
The SAP also stated that a more thorough and systematic review of the
biologic and epidemiologic literature on the topic of the potential or
observed carcinogenic effects of atrazine exposure was required before
concluding that atrazine exposure is an unlikely explanation for at
least part of the excess of prostate cancer in the St. Gabriel
manufacturing plant. 

Since 2003, the Agency sought advice from the FIFRA SAP on issues
related to potential ecological effects of atrazine (FIFRA SAP 2003b,
2007a, 2007b, 2009).  In an evaluation of the SAP’s report of 2007
(FIFRA SAP, 2007a) EPA concluded that atrazine does not affect amphibian
gonadal development or metamorphosis across concentrations of 0.1 to 100
parts per billion (ppb) based on studies available at that time. 
Although the 2007 SAP believed that further testing with indigenous
species could provide additional data, it was acknowledged that suitable
animal husbandry and rearing protocols were not available to obtain
comparable statistical power that was applied to measuring the effects
of atrazine in Xenopus laevis.  Given these husbandry and rearing
constraints, additional testing with amphibians has not been required. 
Since that review, there have been additional publications that suggest
there may be a relationship between atrazine exposure and amphibian
immune response.  These studies do not demonstrate a consistent
relationship.  In 2007 (FIFRA SAP 2007b) and 2009 (FIFRA SAP, 2009) the
SAP also provided advice on EPA's approach to assess atrazine's effects
on aquatic plants and its associated impacts on aquatic community
structure and function.  These reviews provided advice concerning the
design and subsequent interpretation of an EPA- required monitoring
program to evaluate the extent to which watersheds in high atrazine use
areas are exposed to atrazine concentrations that could cause effects to
aquatic communities.  

Considering the SAP’s previous reviews and the body and nature of
studies available, the human health risk assessment is the focus of the
Agency's 2010 science peer-review plan. At the conclusion of this
process, EPA will ask the SAP to review atrazine’s potential effects
on amphibians and aquatic ecosystems.

III.  Human Health Risk Assessment

Mode of Action Approach

In recent years, U.S. and international efforts have advanced the
scientific basis for human health risk assessments by increasing the use
of mechanistic and kinetic data.  International organizations including
the World Health Organization’s International Programme for Chemical
Safety (IPCS) (Sonich-Mullin, 2001; Boobis et al., 2006; Boobis et al.,
2008) and the International Life Sciences Institute (ILSI) discuss the
use of mechanistic data when considering animal to human extrapolation
(Meek et al., 2003; Seed et al., 2005).  The USEPA Cancer Guidelines (US
EPA 2005) also follows a similar MOA framework to the IPCS approach
(Sonich-Muller, 2001).  In addition, the ILSI human relevance framework
provides a foundation for evaluating the qualitative and quantitative
relevance of in vitro and in vivo data derived from animal models in
human health risk assessment.  Generally, a MOA understanding improves
the foundation for establishing dose-response relationships, considering
animal to human extrapolation, and estimating human variability,
including the identification of sensitive lifestages or subpopulations. 
Similarly, the 2007 National Research Council (NRC) report “Toxicity
Testing in the 21st Century: A Vision and A Strategy” (NRC 2007)
describes the importance of basing risk assessment on toxicity pathways
and the value of using initiating events in hazard identification.  

In 2000, EPA presented a proposed MOA for atrazine to the FIFRA SAP
which supported the Agency’s approach.  EPA described this MOA and the
relevant cancer and reproductive toxicity data in the “Atrazine:
Hazard and Dose-Response Assessment and Characterization” (FIFRA SAP,
2000a).  In brief, upon high levels of exposure to atrazine, the release
of gonadotropin releasing hormone (GnRH) from the hypothalamus is
reduced, thereby lessening the afternoon pituitary luteinizing hormone
surge in female Sprague Dawley rats.  As a result, the estrus cycle
lengthens.  This, in turn, leads to increased estrogen levels and an
increased incidence of mammary tumors in female Sprague Dawley rats.

The Agency incorporated the understanding of atrazine's neuroendocrine
mode of action in developing its risk assessment.  As noted below, for
several exposure scenarios, the Agency used an early key event (i.e.,
attenuation of preovulatory luteinizing hormone surge) from atrazine’s
toxicity pathway as the basis for interspecies extrapolation.  Although
EPA has determined that atrazine’s cancer mode of action (i.e.,
attenuation of the luteinizing hormone surge) in the Sprague-Dawley rat
is not likely to be operative in humans, which is consistent with the
SAP recommendation (FIFRA SAP, 2000a), it is not unreasonable to assume
that atrazine might cause adverse effects on hypothalamic-pituitary
function in humans.  Thus, the same endocrine perturbations that induce
tumors in rats may play a role in at least some developmental effects
(not associated with reproductive aging) that may be relevant to humans.
 

Hazard Identification

1.  Non-cancer:  

Summary of 2003 Human Health Risk Assessment

The 2003 EPA human health risk assessment identified non-cancer effects
of atrazine following acute and chronic dietary exposures, short- and
intermediate incidental oral exposures, and short-, intermediate-, and
long-term dermal and inhalation exposures.  Effects observed in
developmental toxicity studies (i.e., delayed ossification of certain
cranial bones in fetuses, and decreased body weight gain in adults that
are not likely due to atrazine’s MOA but rather to general toxicity)
were selected as the endpoint of concern for acute dietary exposure. 
Delayed preputial separation in male rats (which is associated with
atrazine’s neuroendocrine MOA) was the basis for assessing the
short-term oral, dermal and inhalation exposures.  Effects indicative of
disruption of hypothalamic function (i.e., attenuation of pre-ovulatory
luteinizing hormone surge) were determined to be appropriate toxicity
endpoints of concern for chronic dietary, intermediate incidental oral,
and intermediate- and long-term dermal and inhalation exposures.  For
oral to dermal route-to-route extrapolation, a dermal absorption factor
of 6% was applied.  A 100% absorption factor for oral to inhalation
route-to-route extrapolation was assumed.  Table 1 below summarizes the
toxicological endpoints and uncertainty factors from the atrazine
dietary and drinking water risk assessment.



TABLE 1.  Summary of Toxicological Endpoints and Other Factors Used in
the Dietary Risk Assessment of Atrazine and Its Chlorinated Metabolites

The 2003 atrazine human health risk assessment identified a 90-day
average concentration of 37.5 ppb for atrazine and its chlorinated
metabolites in raw water as the level of concern, providing availability
of sufficient data to estimate water exposure. This level of concern was
based on the neuroendocrine-related effects observed in laboratory
animal studies.  An FQPA safety factor of 10X was retained for the
dietary assessment of atrazine and its chlorinated metabolites if there
were insufficient data to estimate water exposure.  The FQPA factor of
10X was based on the following residual uncertainties: (a) a 3X
hazard-driven uncertainty factor for residual uncertainty pertaining to
the neuroendocrine MOA effects that have not been fully characterized in
the toxicity database, and (b) a 3X exposure-driven safety factor for
residual uncertainties pertaining to the drinking water exposure
assessment (i.e., the magnitude and duration of atrazine exposures in
drinking water).  Water monitoring data available at the time for
atrazine and its chlorinated metabolites indicated that exposure via
drinking water sources was high in some community water systems (CWS).
 In addition, widespread low levels of atrazine were commonly detected.
 Limitations in the extent and frequency of sampling for atrazine and
its chlorinated metabolites raised uncertainties regarding the level of
exposure to atrazine and its metabolites.  

To address uncertainty regarding exposures to atrazine and its
chlorinated metabolites in drinking water, a monitoring program was
implemented as a condition of atrazine’s re-registration under FIFRA,
for CWS identified as being of potential concern.  In this program, CWS
are sampled weekly prior to and during the growing season and biweekly
during the remainder of the year in order to capture 90-day
“rolling” average concentrations during the year.  All compliance
monitoring data required under the Safe Drinking Water Act are reviewed
to determine whether the CWS exceed a yearly average concentration of
1.6 ppb atrazine or 2.6 ppb Total Chloro-Triazine (TCT). These triggers
are used as indicators to identify potentially vulnerable CWS for
inclusion in the weekly to biweekly monitoring program.  (Note that the
maximum contaminant level (MCL) derived through the SDWA is a yearly
average of 3 ppb.)  For those CWS in the monitoring program, the 3X
exposure-driven portion of the FQPA safety factor was not considered
necessary and, therefore, it was removed.  However, the hazard-driven
3X FQPA safety factor was retained for all drinking water risk
assessments. 

As part of the year-long review of the health effects associated with
exposure to atrazine, the Agency will be evaluating the results of
laboratory animal and human epidemiology studies published since the
Agency’s last evaluation of atrazine’s non-cancer effects.  Included
in this review will be the most recent “ecological epidemiology”
studies dealing with atrazine and its potential association with birth
defects, low birth weight, and premature births.  

“Ecological epidemiology studies” are based on a human population
rather than an individual unit of analysis.  Ecological studies are
normally regarded as inferior to non-ecological designs, such as  
HYPERLINK "http://en.wikipedia.org/wiki/Cohort_study" \o "Cohort study" 
cohort  and   HYPERLINK
"http://en.wikipedia.org/wiki/Case-control_study" \o "Case-control
study"  case-control  studies, because they are susceptible to the “ 
HYPERLINK "http://en.wikipedia.org/wiki/Ecological_fallacy" \o
"Ecological fallacy"  ecological fallacy ” (i.e., assuming that the
average value of the characteristic being studied and the average
incidence/prevalence of a disease or condition applies to all the
individuals in a human population).  Thus, ecological epidemiology
studies are viewed as being hypothesis-generating, in that they provide
useful guidance to help in the design of additional studies, but they
are not viewed as being conclusive by themselves.

The Agency will conduct a robust literature review to identify
peer-reviewed scientific papers published since 2003 to ensure that all
available studies are evaluated in a weight of the evidence analysis
that includes new epidemiology studies, new studies in laboratory
animals, and new information about potential MOAs that might have been
identified since EPA’s 2003 assessment.

2.  Cancer:  

In the 2003 IRED, EPA concluded that, considering human epidemiology and
laboratory animal data, atrazine is “not likely to be carcinogenic to
humans.”  Consistent with the advice of the SAP (FIFRA SAP 2000a), EPA
determined that atrazine’s cancer MOA for the formation of mammary
tumors in the Sprague-Dawley rat is not likely operative in humans. 
Although hypothalamic disruption of pituitary function (i.e.,
attenuation of the luteinizing hormone surge) and resulting estrus cycle
disruption may be occurring in humans following atrazine exposure, the
hormonal environment resulting from these events would be expected to be
much different from the hormonal environment seen in the rat because of
its reproductive aging process for which there is no human counterpart. 
Specifically, the prolonged/increased exposure to estrogen and
prolactin, which is associated with early onset of prolonged estrus that
provides the basis for early-onset and increased mammary tumors in
susceptible strains of rats, is not expected to occur in humans.

In July 2003, EPA convened a meeting of the FIFRA SAP that addressed
human epidemiology data on atrazine and its potential to cause prostate
cancer.  EPA concluded that the epidemiology data do not support a
positive cancer finding for atrazine.  EPA’s conclusion is based on an
assessment that the increase in prostate cancer incidence at the St.
Gabriel plant in Louisiana was not a true increase of cancer incidence
but rather an increase in cancer detection due to the intensive PSA
screening at this plant.  This conclusion was reached because prostate
cancer was found primarily in active employees who received intensive
PSA screening; there was no increase in advanced tumors or mortality due
to prostate cancer in this cohort; and the proximity to atrazine
manufacturing did not appear to be correlated with a worker’s risk of
prostate cancer detection.

The FIFRA SAP (FIFRA SAP, 2003a) concurred with EPA’s conclusion on
these epidemiology studies stating “the increase in prostate specific
antigen (PSA) screening at the St. Gabriel plant likely led to an
increase in the detection of cases of prostate cancer.”  Further, the
Panel noted that “substantive and persuasive arguments have been made
to support the EPA’s conclusion that PSA screening could explain the
observed increase in prostate cancer incidence in the workers”.  In
addition, the Panel further states that “A more thorough and
systematic review of the biologic and epidemiologic literature on the
topic of the potential or observed carcinogenic effects of atrazine
exposure is required before concluding that atrazine exposure is an
unlikely explanation for at least part of the excess of prostate cancer
in the St. Gabriel workers.”

Since the 2003 SAP meeting on the cancer epidemiology of atrazine, EPA
has continued to follow additional work including the National Cancer
Institute’s Agricultural Health Study (AHS), which is the largest
study to date on pesticides.  Rusiecki et al. (2004) did not find clear
associations between atrazine exposure and any cancer site available for
analysis in the AHS.  The authors did point out further studies are
warranted for tumor types in which there was a suggestion of trend
(lung, bladder, non-Hodgkin lymphoma, and multiple myeloma).  However,
the numbers of cases for these tumor types were small and the lower
bound confidence intervals were below 1.0.  Consequently, it is unclear
whether these findings could be due to a chance association.  In
addition, Alavanja et al. (2003) did not observe an association between
atrazine use and prostate cancer in an AHS study comparing those with
prostate cancer to those not diagnosed with the disease.  Outside of the
AHS cohort, in a pooled analysis of non-Hodgkin lymphoma (NHL) cases
identified through a series of case-control studies in Midwestern
states, De Roos (2003) observed increased risk for NHL among men who
report use of atrazine (1.5 (1.0 to 2.2)) (adjusting for the influence
of the use of other pesticides); researchers also observed evidence of a
joint effect of increased risk of NHL among men who used atrazine in
combination with carbofuran, diazinon or alachlor, with an odds ratio
1.5 (0.9 to 2.7), 2.3 (1.2 to 4.2), 1.6 (1.0 to 2.7), respectively.  EPA
is waiting for the follow-up AHS studies to confirm the initial findings
of no-association with prostate cancer and to clarify the other
suggested findings with a larger sample size.  It is anticipated that
these results will be available in 2010.

Drinking Water Monitoring

As a condition of reregistration of atrazine, EPA required the
registrants to implement a monitoring program in selected CWS.  The
inclusion of a CWS into the atrazine monitoring program is based on
Total Chloro-Triazine (TCT) concentration that includes atrazine and its
metabolites. If the annual TCT average exceeds 2.6 ppb in finished
water, the registrant must comply with atrazine monitoring program
requirements specified in the IRED. The atrazine monitoring program
requires the registrant to sample raw and finished water weekly during
the use season when atrazine is applied to cropland, and biweekly during
all other months.

The Agency and other researchers have studied the issue of sample
frequency to characterize pesticide exposure for drinking water.  For
example, in 2000, the Agency held a consultation with the SAP on
national drinking water survey designs (FIFRA SAP, 2000b).  Generally,
longer durations of concern (e.g., annual average concentration for a
long-term chronic effect) require a less frequent sampling design to
approximate longer term exposures.  However, as the duration of the
exposure of concern shortens, the frequency and timing of sampling
become more important in determining the confidence in how well the
sample data capture these short-duration exposures.  This is most
critical when the Agency is concerned about acute effects resulting from
peak, or single day, exposures.  Depending on the aquatic resource being
sampled, the likelihood increases that a peak exposure is being missed
by less frequent sampling.  

In the April and September 2010 SAP meetings the Agency will be
eliciting comments from the SAP about the scientific basis for the
drinking water sampling frequency and monitoring approach used in the
required atrazine monitoring plan.  In the event that the critical
effect and/or duration of exposure used to assess risk changes, the
Agency may need to re-consider the monitoring frequency currently
required. 

IV.  2009-2010 Science Peer Review Plan

As noted previously, EPA is launching a special comprehensive scientific
re-evaluation of the human health and ecological effects of atrazine. 
The initial effort will focus on human health issues and include four
SAP meetings.  The first to be held, in November 2009, will be a
presentation of the Agency’s approach for this re-evaluation.  

The Agency’s 2003 IRED provided a detailed evaluation of the human
health effects of atrazine.  New evidence will be analyzed in the
context of how it relates to or is different from the evidence available
for the last atrazine assessment.  The Agency evaluations presented at
these meetings will represent collaborative efforts by the Office of
Pesticide Programs (lead office), the Office of Water, and the Office of
Research and Development.  

In November 2009, EPA will present the peer review plan to the FIFRA
SAP.

At the February 2010 meeting, the Agency will present a proposed generic
approach for incorporating epidemiology and human incidence data in risk
assessment along with EPA’s preliminary evaluation of the human
ecological epidemiology studies of atrazine that have become available
since the last atrazine assessment.  These studies focus on the
potential link between atrazine and non-cancer human health effects. 
The Agency will solicit comment on how these human ecological
epidemiology studies inform the Agency’s on-going re-evaluation of
non-cancer effects.

At the April 2010 meeting the Agency will solicit comment from the SAP
on the Agency’s scientific evaluation of atrazine non-cancer effects
based on animal laboratory toxicology studies, including both those
studies used in past evaluations and those that have been published
since then (i.e. the extent to which the Agency’s IRED was
scientifically sound when released in 2003 and the extent to which new
scientific findings change the understanding and assessment of
atrazine’s risks).  The SAP also will be asked to comment on EPA’s
review of the scientific evidence relevant to setting an appropriate
FQPA Safety Factor for protection of infants and children, selecting the
point of departure, selecting an appropriate averaging time for
monitoring water and developing the sampling frequency for monitoring
CWS.

At the September 2010 meeting, the SAP will be charged with reviewing
the Agency’s scientific evaluation of atrazine cancer and non-cancer
effects based on animal laboratory toxicology studies and human
epidemiological studies, including both those studies used in past
evaluations and those that have been published since the 2003 IRED.  The
SAP will be convened at this time because it is anticipated that the
Agency will have received the new results of the AHS for atrazine
earlier in 2010.  A key focus of the September 2010 meeting will be to
receive feedback about EPA’s evaluation of the weight of the evidence
of the human health effects of atrazine using MOA information and the
findings of both the human epidemiology and animal laboratory studies in
an integrated analysis.  In the event that new, relevant information
becomes available, the SAP may again be asked to review the scientific
evidence relevant for considering the FQPA Safety Factor for atrazine. 
The Panel will also be asked to comment on the sampling frequency plan
for monitoring CWS in the context of the new integrated weight of the
evidence analysis.  

At the conclusion of this process, EPA will ask the SAP to review
atrazine’s potential effects on amphibians and aquatic ecosystems.

IV.  References

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"http://www.epa.gov/scipoly/sap/tools/atozindex/atrazine.htm" 
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http://www.epa.gov/scipoly/sap/meetings/2000/060600_mtg.htm   

FIFRA Scientific Advisory Panel (SAP).  1988. “A set of issues being
considered by the Agency in connection with the peer review
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Office of Prevention, Pesticides and Toxic Substances, U.S. 
Environmental Protection Agency.  Washington, DC.  Available:  
HYPERLINK "http://www.epa.gov/scipoly/sap/1988" 
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