1Atrazine Re-Evaluation:Charge QuestionsAtrazine Re-Evaluation:Charge QuestionsFIFRA Scientific Advisory Panel Public MeetingSeptember 14-17, 2010Question 1.1 Non-cancer EpidemiologyQuestion 1.1 Non-cancer Epidemiology•Please comment on the sufficiency ofthe Agency’s non-cancer epidemiologyreviews with respect to identifying themajor strengths and limitations of eachstudy.2Question 1.2 Non-cancer EpidemiologyQuestion 1.2 Non-cancer Epidemiologya. Please comment on the scientific information thatdoes and does not support the Agency’sconclusions (as described in Section 3.0) withrespect to the characterization of quality, andlimitations of the non-cancer epidemiologicdatabase and its utility in hazard characterization,dose response analysis, and quantitative riskassessment.b. Please comment on scientific information that doesand does not support the integrative analysis andconclusions, contained in Section 4.0, with respectto the similarities, differences, and uncertainties ofthe experimental toxicology and epidemiologicfindings.3Question 2.1 Review of Studies onMammary Gland DevelopmentQuestion 2.1 Review of Studies onMammary Gland DevelopmentPlease comment on the quality,strengths, and limitations of themammary gland development studiesby Rayner et al. (2004, 2005) andCoder (2010) studies. Please discussin your comments factors which couldlead to different findings. Pleasecomment on the Agency’s conclusionsregarding these studies on atrazine.4Question 2.2 Review of Studies onMammary Gland DevelopmentQuestion 2.2 Review of Studies onMammary Gland Development•In three of the studies considered in Question 2.1(Rayner et al., 2004 and 2005; Coder, 2010), effectshave only been observed at an atrazine dose of 100mg/kg/day. In contrast, Enochet al.(2007) reportdelays in mammary gland development as low as 0.09mg/kg/day following exposure to atrazine and a mixtureof several metabolites/degradates (DEA, DIA, DACT,hydroxy-atrazine). The Agency’s review of this mixturestudy is provided in Appendix A (Section A.10) Pleasecomment on the Enochet al.(2007) study and thedegree to which the Agency’s review accurately reflectsthe strengths and limitations of the study. Pleaseinclude in your comments a consideration of the studydesign of the mixtures experiment and how this designimpacts the interpretation of the results.5Question 2.3 Review of Studies onMammary Gland DevelopmentQuestion 2.3 Review of Studies onMammary Gland DevelopmentIn light of Panel discussion on Questions2.1 and 2.2, please comment on themanner in which the Agency hasproposed to use the mammary glanddevelopment studies in the hazardassessment for atrazine.6Question 3.0: Proposed Updates to theDose-Response AssessmentQuestion 3.0: Proposed Updates to theDose-Response Assessment•At the April, 2010 SAP, the Panel made two keyrecommendations related to dose-responseassessment: 1) consider pursuing a doseresponse analysis based on aninternaldosemetric, as an alternative to theadministereddosemetric used in the previous risk assessment; and 2)identify the sensitive endpoint associated withfunctional impairment and perform benchmarkdose (BMD) modeling. The Agency conductedboth recommended analyses (Section 5.0 of thedraft Issue Paper) in response to theserecommendations. LH attenuation, as a key eventin atrazine’s MoA, is the most sensitive internaldose metric that is associated with a number ofendocrinopathies7Question 3.1 Proposed Updates to theDose-Response AssessmentQuestion 3.1 Proposed Updates to theDose-Response Assessmenta. Please comment on the Agency’s analysis ofthe pharmacokinetic data contained in Thede(1987) to estimate internal dose reflective ofatrazine and its metabolites in rat plasma.b.Based on Figure 5.5 in the draft Issue Paper,the Agency has preliminarily concluded thatplasma levels of atrazine and its metabolitesreach (or nearly reach) pharmacokineticpseudo-steady state in the rat plasma afterapproximately four daily oral exposures overa wide range of doses. Please comment onthe extent to which the data do and do notsupport this finding.8Question 3.1 Proposed Updates to theDose-Response AssessmentQuestion 3.1 Proposed Updates to theDose-Response Assessmentc. Figure 5.8 of the draft Issue Paper shows a plot of LHattenuation data versus administered atrazine across arange of exposure durations (i.e., four days up to sixmonths). The data contained on this figure were collectedfrom several different laboratories and involved two modesof oral administration (dietary, oral gavage) and twodifferent rat strains. Attenuation of LH, as measured bypercent of control, is remarkably similar across studies,strains, laboratories, and most notably duration ofexposure. The Agency has preliminarily concluded that thefindings on Figure 5.8 stronglysupport the hypothesis thatpseudo-steady state is achieved (or nearly achieved) inadult rats after four daily consecutive oral exposures. TheAgency also believes thatpseudo-steady state is stronglyassociated with the attenuation of the LH surge followingatrazine exposure in rats. Please comment on the analysisshown in Figure 5.8 and the Agency’s preliminaryconclusions related to these findings in rats.9Question 3.2Question 3.2a.Please comment on the BMD analysissummarized in Section 5.3 of the draftIssue Paper with details provided inAppendix C.10Question 3.2Question 3.2b.The selection of a suitable benchmark response(BMR) is an importantcomponent of conducting a BMD analysis. As described inSection 5.3, forcontinuous endpoints, like LH attenuation, the BMR most often represents anX% change from background levels (or untreated controls). Typically, theBMR is selected on the basis of a combination of biological (mode of action,quantitative link between key events and adverse outcomes,historical/concurrent controls) and statistical considerations (sample size,variability, etc). LH attenuation may bepotentially associated with severaladverse outcomes and the level of attenuation of the LH surge considered tobe adverse is a function of several factors including thefunctional outcomeand the life-stage. There is an absenceof information concerning the levelof response (or % change) associated with the various functionalimpairments. Also, thedifferences in reproductive cycles/aging betweenrodents and humans add an additional level of complexity to establishing aspecific BMR value. When an X% change can not be defined, the Agency’sdraft BMD guidance suggests thatthe BMD and BMDL corresponding to achange in the mean response equal toone standard deviation from thecontrol mean be used as the BMR. Thisapproach was appliedto atrazine.Please comment on the scientific factors important for establishing a BMR forLH attenuation as part of the BMD analysis for atrazine.11Question 4.0: Approaches To Evaluating WaterSampling Strategies And Frequency Of MonitoringQuestion 4.0: Approaches To Evaluating WaterSampling Strategies And Frequency Of Monitoring•The ultimate utility of pesticide monitoringdata for drinking water exposureestimations in human health riskassessments depends on how well themonitoring data characterize the spatialand temporal variability of pesticideconcentrations in drinking water, with anemphasis on the upper end of theexposure distribution. In addition, themethod used to estimate concentrationsfrom monitoring data depends on theduration of concern and how critical it is toestimate peak concentrations.12Question 4.1 Approaches To Evaluating WaterSampling Strategies And Frequency Of MonitoringQuestion 4.1 Approaches To Evaluating WaterSampling Strategies And Frequency Of Monitoring•A well-designed drinking water monitoringstudy takes into account both spatial andtemporal patterns of exposure. Pleasecomment on the USEPA’s recommendedframework for designing a monitoringstudy by targeting the most vulnerableareas, targeting seasonal times for moreintensive sampling, basing samplingfrequency on the toxicological exposureduration of concern, and usingautosamplers to supplement monitoringdata (see Section 7.2 of the draft IssuePaper).13Question 4.2Question 4.2a. Please comment on the Agency’s proposal to usechemograph shapes (number, duration, andmagnitude of peaks) to match CWS with moreintensively monitored datasets. In particular, theAgency is interested in recommendations onapproaches for matching chemograph shapesgiven the loss of short-duration peaks that occurswith less frequent sampling.b. Please comment on the strengths and weaknessesof using more intensively sampled datasets fromHeidelberg and AEEMP for analysis of flowingwater and PRZM/EXAMS for lakes and reservoirs.14Question 4.3Question 4.3•Please comment on the strengths andweaknesses of these proposedapproaches and provide anyrecommendations for improving themodel applications.15Question 5.0: Scientific Considerations inPotential Sensitivity of Infants & ChildrenQuestion 5.0: Scientific Considerations inPotential Sensitivity of Infants & Children•The Agency requests the Panel tocomment on important scientific factors forthe Agency to consider in its analysis.Please include in your comments specificconsideration of uncertainties in estimatingdrinking water exposures and remaininguncertainties in atrazine’s toxicologicalprofile across life stages, particularly asthey pertain to assessing risk to infantsand children.16Question 6.0: Implications of MOA &Toxicity Profile on Water MonitoringQuestion 6.0: Implications of MOA &Toxicity Profile on Water Monitoring•Please comment on the Agency’sanalysis and preliminary conclusionscontained in Section 8.0 of the draftIssue Paper as it relates to the potentialcritical windows of exposure. Pleaseinclude in your comments additional oralternative approaches or data that mayinform this issue.17