UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: December 17, 2013 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

SUBJECT: Atrazine. Response to Comments on the Human Health Risk Scoping Document in 

Support of Registration Review. 

PC Code: 080803 

Decision No.: 485501 

Petition No.: NA 

Risk Assessment Type: Response to 

Comments 

TXRNo.:NA 

MRIDNo.:NA 

FROM: John Liccione, PhD, Toxicologist 

William Donovan, PhD, Ris As 

Seyed Tadayon, Chemist 

Risk Assessment Branch V. B V) 

DP Barcode: D416486 

Registration No.: NA 

Regulatory Action: Registration Review 

Case No.: 0062 

Health Effects Division (HED) (7509P) 

THROUGH: Michael S. Metzger, Chief 

Risk Assessment Branch V 

Health Effects Division (7509P) 

TO: Kaitlin Keller, Chemical Review Manager 

Risk Management and Implementation Branch III (RMIB3) 

Pesticide Re-Evaluation Division (PRD) (7508P) 

This memorandum contains HED's responses to atrazine comments submitted during the public 

comment period regarding HED's "Atrazine, Propazine, and Simazine. Human Health Risk 

Scoping Document in Support of Registration Review, June 04, 2013". The responses are 

provided after giving the document number, commenter affiliation, and a brief summary of the 

comment received. 

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Document Number: EPA-HQ-OPP-2013-0266-0299 

Commenter Affiliation: Syngenta 

• Comment: "In the Human Health Risk Scoping document in support of registration 

review, the agency stated that toxicity endpoints for chlorotriazine herbicides will be reevaluated after consideration of recent studies in the published literature.'' Syngenta 

suggested a number of considerations for the agency that were discussed during the July 

2011 SAP. These considerations included the following: (1) pulsatile LH is the most 

relevant for human risk assessment; (2) brief exposures to atrazine - LH surge reduction 

and observed effects; and (3) extensive new studies on atrazine establish greater 

confidence in MOEs. 

• Response: EPA will consider, on a total weight of evidence basis, all available studies on 

atrazine and LH (pulsatile and nonpulsatile), including duration of exposures and points 

of departure to atrazine as part of the registration review process. This will also entail 

critical evaluation of the scientific quality of the studies to assess the adequacy and 

acceptability of the studies (e.g., validation of hormone assays, experimental bias, 

adequacy of sample size, sampling frequency, statistical methodology, study design, 

dose-response relationships, uncertainties, extrapolation to humans) for risk assessment 

purposes. In addition, the recommendations of the SAP on LH in the interpretation of 

atrazine health effects will be considered. 

Document Number: EPA-HQ-OPP-2013-0266-0073 

Commenter Affiliation: Beyond Pesticides 

• Comment: "As a result of its endocrine disrupting ability, studies are finding associations 

between atrazine exposure, birth defects and certain cancers. EPA's past findings for the 

carcinogenic potential of atrazine- 'not likely to cause cancer in humans'- is at odds with 

current research which finds atrazine to impact mammary glands in the breast, increasing 

the risk for mammary cancer." 

• Response: EPA has evaluated a plethora of published studies investigating a wide array 

of effects potentially relevant to human health risk assessment. These studies included 

mammary cancer in various rat strains (Long-Evans, Wistar, Fischer-344) as well as other 

species. Epidemiological data were also reviewed. As part of the weight-of-evidence 

approach, the agency also evaluated mechanistic studies to determine if a particular mode 

of action identified in an animal model is relevant to humans. This approach also 

included an evaluation of studies designed specifically to examine LH surge and atrazine. 

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The key events associated with the increased incidence of mammary tumors in rats were 

explored, and relevancy to humans addressed. To be certain that the best available 

science is used to inform its atrazine risk assessment, and to ensure transparency, the 

agency sought advice on key aspects of the science evaluation from the independent 

FIFRA Scientific Advisory Panel (SAP). Based on the review of available scientific 

studies, the agency determined in 2000 that atrazine is not likely to cause cancer in 

humans. Since 2000, there have been no new data that has changed the 2000 conclusion 

with respect to mammary tumors. The agency will continue to monitor the literature and 

evaluate any new science that may impact our conclusion. 

Document Number: EPA-HQ-OPP-2013-0266-0081 

Commenter Affiliation: PANNA 

• Comment: PANNA commented that the agency should consider the SAP's 

recommendations on the following points: ( 1) brief exposures to low levels of atrazine and 

LH surge reduction and observed adverse effects; (2) relevance of one day exposure to elicit 

adverse outcome(s) and of increase vs. decrease in LH; (3) evaluation of data about atrazine 

and mammary development; (4) sufficiency of agency's cancer epidemiology reviews. 

• Response: See response to comment to document number EPA-HQ-OPP-2013-0266-0073 

for background on the agency's weight of evidence approach to the evaluation of human 

health data on atrazine. In regard to the sufficiency of the agency's cancer epidemiology 

reviews, the SAP concluded that substantive and persuasive arguments have been made to 

support the agency's conclusions. The agency will consider any new data as part of the 

registration review process for the triazines. This will also entail consideration of the SAP's 

recommendations on LH surge, relevance of one day exposures and adverse outcomes, 

mammary tumor development, and epidemiological data as part of the registration review of 

!he triazines. 

Document Number: EPA-HQ-OPP-20 13-0266-0035 

Commenter Affiliation: Anonymous 

• Comment: Several comments were received pertaining to mammary tumors; these 

included: ( 1) please comment on the appropriateness of these other models [e.g., 

ovariectomized inbred Fischer-344 (MT-insusceptible), Long-Evans, and Wistar rat 

strains] in mechanistic explorations of MT induction by atrazine, and whether 

alternatives to the LH-dependent/hypothalamic site of action have been investigated 

sufficiently in appropriate models and ruled out; (2) please explain specifically why the 

Agency and registrants have not robustly investigated the direct/LH-independent effects 

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of atrazine in aromatase-positive granulosa cells derived from SD rat and primary human 

follicles in straightforward and cost-effective cell culture studies; and (3) please also 

clarify why MT-promoting events following LH attenuation in the outbred SD rat are not 

relevant to humans. 

• Response: See response to comment to document number EPA-HQ-OPP-2013-0266-

0073 for background on the agency's weight of evidence approach to the evaluation of 

human health data on atrazine. In 2000, the SAP considered all possible alternative 

models, and concluded that increased hormone levels, and the increased hormone levels 

alone, can account for the increased incidence of mammary tumors in Sprague-Dawley 

female rats. Although atrazine has been shown to increase aromatase in granulosa-lutein 

cell cultures, the concentrations needed to induce the observed change is considered to be 

outside the range likely to be achieved in human tissues. The agency will consider any 

new data including cell culture studies as part of the registration review process for the 

triazines. 

Document Number: EPA-HQ-OPP-2013-0266-0036 

Commenter Affiliation: Anonymous 

• Comment: Several comments were received pertaining to LH and mammary tumors; 

these included: (1) please explain how the hypothesized hypothalamic/LH-dependent 

effect of anovulation and 'accelerated reproductive senescence' can be reconciled with 

elevated estrogen levels in ovariectomized and male rats exposed to atrazine (2) 

regarding mechanisms of mammary tumor induction in the ovary-intact SD rat, the 

registrants and Agency repeatedly claim atrazine merely 'accelerates reproductive 

senescence' and 'early onset of mammary tumors' (not incidence, per se ). Please explain 

to a female researcher why; and (3) please comment on whether "changes in LH secretion 

as a sentinel endpoint for HPG perturbations and the basis of the atrazine risk 

assessment" are still sufficient indicators of mammary and breast tumor hazard given 

recent Agency and external studies demonstrating atrazine has direct/LH-independent 

effects on aromatase and estradiol production in both rat and human adrenal cells at very 

low biologically relevant doses. 

• Response: See response to comment to document number EP A-HQ-OPP-20 13-0266-0073 

for background on the agency's weight of evidence approach to the evaluation of human 

health data on atrazine. Based on the available data, the SAP concluded that atrazine 

treatment is associated with an early onset of mammary tumors in female Sprague-Dawley 

rats. Although in vitro studies have demonstrated that atrazine can alter aromatase activity 

and gene transcription, the total weight of evidence of all data indicate that atrazine-related 

changes in steriodogenesis is not likely mediated by aromatase. The agency will continue to 

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monitor the literature and consider any new data as part of the registration review process for 

the triazines. 

Document Number: EPA-HQ-OPP-2013-0266-0064 

Commenter Affiliation: Pesticide Action Network 

• Comment: Several comments were received pertaining to LH and mammary tumors; 

these included: (1) please describe "the particular cascade of events leading to tumor 

formation" in the SD rat, and how this differs from the cascade of events that follow LH 

attenuation in the Fisher-344 rat; (2) please also clarify why MT-promoting events 

following LH attenuation in the outbred SO rat are not relevant to humans, but 

mechanisms of toxicity via LH suppression in the inbred MT-insusceptible Fisher-344 rat 

can be relied upon to inform regulatory decisions; (3) please also comment the decision 

of the 2003 IRED to "use changes in LH secretion as a sentinel endpoint for HPG 

perturbations and the basis of the atrazine risk assessment" in the absence of robust cell 

culture studies that could easily capture the direct effects of atrazine on 

estrogen/progesterone biosynthesis in rat and human ovarian granulosa/luteal cells; ( 4) 

please explain how the hypothesized hypothalamic/LH-dependent effect of anovulation 

and 'accerated reproductive senescence' can be reconciled with elevated estrogen levels 

in ovariectomized and male rats exposed to atrazine; (5) please comment on whether 

"changes in LH secretion as a sentinel endpoint for HPG perturbations and the basis of 

the atrazine risk assessment" are still sufficient indicators of mammary and breast tumor 

hazard given recent Agency and external studies demonstrating atrazine has direct/LHindependent effects on aromatase and estradiol production in both rat and human adrenal 

cells at very low biologically relevant doses; (6) please explain how LH-independent 

effects of atrazine in the rat ovary ( aromatase) are not relevant to human breast cancer 

(aromatase misregulation in the breast). 

• Response: See response to comment to document number EPA-HQ-OPP-2013-0266-

0073 for background on the agency's weight of evidence approach to the evaluation of 

human health data on atrazine. The agency will continue to monitor the literature and 

consider any new data and the comments as part of the registration review process for the 

triazines. 

Document Number: EPA-HQ-OPP-2013-0266-0037 

Commenter Affiliation: Anonymous Public Comment 

• Comment: Several comments were received pertaining to LH and mammary tumors; 

these included: (1) please explain how LH-independent effects of atrazine in the rat 

ovary (aromatase gonadal promoter) are not relevant to human breast cancer (aromatase 

gonadal promoter misregulation in the breast); (2) please ask the Agency Lab: if one 

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transfects human breast cancer cells with a rat gonadal aromatase-reporter gene and treats 

these with atrazine, would the gene to light up? Would this indicate mechanisms are 

conserved between species?; (3) please discuss whether epigenetic background is 

considered in 'species-specific' responses to atrazine and whether the outbred SD strain 

(mammary-tumor susceptible) or inbred Fisher-344 rat strain (used by registrants and 

Agency in 'mechanistic studies') would be expected to have epigenetic variation more 

relevant to human health. 

• Response: See response to comment to document number EP A-HQ-OPP-20 13-0266-

0073 for background on the agency's weight of evidence approach to the evaluation of 

human health data on atrazine. The agency will continue to monitor the literature and 

consider any new data and comments as part of the registration review process for the 

triazines. 

Document Number: EPA-HQ-OPP-20 13-0266-0015 and EPA-HQ-OPP-20 13-0266-0305 

Commenter Affiliation: PANNA 

• Comment: PANNA commented that the agency has not responded to the SAP's 

recommendations on the cancer classification of atrazine, and comments on increased 

risks of reproductive harms and birth defects linked to low-level atrazine exposures. 

• Response: Even though the Panel agreed with EPA that the epidemiologic evidence 

does not strongly suggest a link between atrazine and cancer, the Panel noted some 

suggestive epidemiologic findings for specific tumors that warrant additional analyses 

prior to EPA's full weight-of-evidence review of the cancer classification for atrazine. 

Following the EPA's Cancer Assessment Guidelines, the Agency will weigh and integrate 

all ofthe lines of scientific evidence (e.g., toxicology, metabolism, epidemiology, mode 

of action studies). EPA plans to take the recommendations from the SAPs into account as 

it updates the state of the science on the health effects of atrazine. 

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