Atrazine Re-Evaluation:

Charge Questions

Atrazine Re-Evaluation:

Charge Questions

FIFRA Scientific Advisory Panel Public Meet

September 14-17, 2010
Question 1.1 Non-cancer Epide

Question 1.1 Non-cancer Epide

• Please comment on the sufficiency 

the Agency’s non-cancer epidemioreviews with respect to identifying tmajor strengths and limitations of estudy.
Question 1.2 Non-cancer Epide

Question 1.2 Non-cancer Epide

a. Please comment on the scientific information 

does and does not support the Agency’s conclusions (as described in Section 3.0) witrespect to the characterization of quality, and limitations of the non-cancer epidemiologic database and its utility in hazard characterizadose response analysis, and quantitative risk assessment. 

b. Please comment on scientific information tha

and does not support the integrative analysis conclusions, contained in Section 4.0, with reto the similarities, differences, and uncertainthe experimental toxicology and epidemiologfindings. 
Question 2.1 Review of Stud

Mammary Gland Developm

Question 2.1 Review of Studi

Mammary Gland Developm

Please comment on the quality, strengths, and limitations of the mammary gland development studby Rayner et al. (2004, 2005) and Coder (2010) studies. Please discin your comments factors which colead to different findings. Please comment on the Agency’s conclusiregarding these studies on atrazine
Question 2.2 Review of Stud

Mammary Gland Developm

Question 2.2 Review of Studi

Mammary Gland Developm

• In three of the studies considered in Question 2.

(Rayner et al., 2004 and 2005; Coder, 2010), effhave only been observed at an atrazine dose of mg/kg/day. In contrast, Enoch et al. (2007) repo

delays in mammary gland development as low amg/kg/day following exposure to atrazine and a mof several metabolites/degradates (DEA, DIA, DAhydroxy-atrazine). The Agency’s review of this study is provided in Appendix A (Section A.10) comment on the Enoch et al. (2007) study and th

degree to which the Agency’s review accurately the strengths and limitations of the study. Pleasinclude in your comments a consideration of the design of the mixtures experiment and how this dimpacts the interpretation of the results. 
Question 2.3 Review of Stud

Mammary Gland Developm

Question 2.3 Review of Studi

Mammary Gland Developm

In light of Panel discussion on Ques2.1 and 2.2, please comment on the manner in which the Agency has proposed to use the mammary glandevelopment studies in the hazard assessment for atrazine.
Question 3.0: Proposed Updat

Dose-Response Assessm

Question 3.0: Proposed Update

Dose-Response Assessm

• At the April, 2010 SAP, the Panel made two 

recommendations related to dose-response assessment: 1) consider pursuing a doseresponse analysis based on an internal dose 

metric, as an alternative to the administered 

metric used in the previous risk assessment; identify the sensitive endpoint associated witfunctional impairment and perform benchmadose (BMD) modeling. The Agency conductboth recommended analyses (Section 5.0 of draft Issue Paper) in response to these recommendations. LH attenuation, as a key in atrazine’s MoA, is the most sensitive interdose metric that is associated with a number endocrinopathies
Question 3.1 Proposed Update

Dose-Response Assessm

Question 3.1 Proposed Update

Dose-Response Assessm

a. Please comment on the Agency’s analy

the pharmacokinetic data contained in T(1987) to estimate internal dose reflectivatrazine and its metabolites in rat plasm

b.Based on Figure 5.5 in the draft Issue P

the Agency has preliminarily concluded plasma levels of atrazine and its metaboreach (or nearly reach) pharmacokinetic pseudo-steady state in the rat plasma aapproximately four daily oral exposures a wide range of doses. Please commethe extent to which the data do and do nsupport this finding.
Question 3.1 Proposed Update

Dose-Response Assessm

Question 3.1 Proposed Update

Dose-Response Assessm

c. Figure 5.8 of the draft Issue Paper shows a plot of 

attenuation data versus administered atrazine acrorange of exposure durations (i.e., four days up to smonths). The data contained on this figure were cfrom several different laboratories and involved two of oral administration (dietary, oral gavage) and twdifferent rat strains. Attenuation of LH, as measurepercent of control, is remarkably similar across stustrains, laboratories, and most notably duration of exposure. The Agency has preliminarily concluded findings on Figure 5.8 strongly support the hypothepseudo-steady state is achieved (or nearly achieve

adult rats after four daily consecutive oral exposureAgency also believes that pseudo-steady state is s

associated with the attenuation of the LH surge folatrazine exposure in rats. Please comment on the shown in Figure 5.8 and the Agency’s preliminary conclusions related to these findings in rats. 
Question 3.2 Question 3.2

a.Please comment on the BMD analy

summarized in Section 5.3 of the dIssue Paper with details provided in Appendix C. 
Question 3.2 Question 3.2

b. The selection of a suitable benchmark response (BMR) is an imp

component of conducting a BMD analysis. As described in Sectiocontinuous endpoints, like LH attenuation, the BMR most often reX% change from background levels (or untreated controls). TypBMR is selected on the basis of a combination of biological (modquantitative link between key events and adverse outcomes, historical/concurrent controls) and statistical considerations (samvariability, etc). LH attenuation may be potentially associated with adverse outcomes and the level of attenuation of the LH surge co

be adverse is a function of several factors including the functiona

and the life-stage. There is an absence of information concerning 

of response (or % change) associated with the various functionalimpairments. Also, the differences in reproductive cycles/aging brodents and humans add an additional level of complexity to estaspecific BMR value. When an X% change can not be defined, the draft BMD guidance suggests that the BMD and BMDL corresponchange in the mean response equal to one standard deviation frocontrol mean be used as the BMR. This approach was applied to 

Please comment on the scientific factors important for establishinLH attenuation as part of the BMD analysis for atrazine. 
Question 4.0: Approaches To Evaluatin

Sampling Strategies And Frequency Of M

Question 4.0: Approaches To Evaluatin

Sampling Strategies And Frequency Of M

• The ultimate utility of pesticide monito

data for drinking water exposure estimations in human health risk assessments depends on how well thmonitoring data characterize the spatand temporal variability of pesticide concentrations in drinking water, with emphasis on the upper end of the exposure distribution. In addition, the method used to estimate concentratiofrom monitoring data depends on the duration of concern and how critical it estimate peak concentrations. 
Question 4.1 Approaches To Evaluatin

Sampling Strategies And Frequency Of M

Question 4.1 Approaches To Evaluatin

Sampling Strategies And Frequency Of M

• A well-designed drinking water monit

study takes into account both spatial temporal patterns of exposure. Pleascomment on the USEPA’s recommenframework for designing a monitoring study by targeting the most vulnerablareas, targeting seasonal times for mintensive sampling, basing sampling frequency on the toxicological exposuduration of concern, and using autosamplers to supplement monitoridata (see Section 7.2 of the draft IssuPaper).
Question 4.2 Question 4.2

a. Please comment on the Agency’s proposal t

chemograph shapes (number, duration, and magnitude of peaks) to match CWS with mointensively monitored datasets. In particularAgency is interested in recommendations on approaches for matching chemograph shapegiven the loss of short-duration peaks that ocwith less frequent sampling.

b. Please comment on the strengths and weak

of using more intensively sampled datasets fHeidelberg and AEEMP for analysis of flowinwater and PRZM/EXAMS for lakes and rese
Question 4.3 Question 4.3

• Please comment on the strengths a

weaknesses of these proposed approaches and provide any recommendations for improving the model applications. 
Question 5.0: Scientific Considera

Potential Sensitivity of Infants & C

Question 5.0: Scientific Considera

Potential Sensitivity of Infants & C

• The Agency requests the Panel to 

comment on important scientific factothe Agency to consider in its analysisPlease include in your comments speconsideration of uncertainties in estimdrinking water exposures and remainuncertainties in atrazine’s toxicologicaprofile across life stages, particularly they pertain to assessing risk to infanand children.
Question 6.0: Implications of 

Toxicity Profile on Water Mon

Question 6.0: Implications of 

Toxicity Profile on Water Mon

• Please comment on the Agency’s 

analysis and preliminary conclusioncontained in Section 8.0 of the drafIssue Paper as it relates to the potecritical windows of exposure. Pleainclude in your comments additionaalternative approaches or data that inform this issue.