Integration of Epidemiology andToxicity Data into Health RiskAssessmentPresentation toScientific AdvisoryPanelPresentationtoScientificAdvisoryJuly 26-29, 2011Elizabeth Méndez, Ph.D.Health Effects DivisionUSEPA Office of Pesticide ProgramsDraft Framework for IntegratingEpidemiology and Toxicity DataEpidemiologyandToxicityDataEpidemiologyToxicity•Concepts in the Draft 2010 Framework are based onpeer-reviewed, robust principles & tools• Standard practice in epidemiology, toxicology & riskassessment• Integrating new approaches based on recommendationsfrom• NRC 2007: ToxicityTestingin the 21st Centuryg y• NRC 2009: Science & Decisions: Advancing Risk Assessment• Flexibility to incorporate information from different sources•Transparent tool for organizing, reviewing & interpretingTransparenttoolfororganizing,reviewing&interpretingcomplex information•February 2010 SAP reviewed Agency’s proposedDraft FrameworkDraftFramework2

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o nCharacterizationCompoundsAssessBiologicalPerturbationAffectedPathwayDose ResponseAnalysis forPerturbationsof ToxicityPathwaysCalibratingin vitro and humanDosimetryExposureGuidelinePerturbationMeasures ofdose in vitroHuman ExposureDataMetabolite(s)Hazard CharacterizationExposure AssessmentRisk Characterization3ToxicityTestingin the 21stCenturyToxicityTestingin the 21stCenturyy g•National Research Council: “Toxicity Testing intheTwentyFirstCentury: A Vision and a-Century:AVisionandaStrategy”.• The report states that “the committee’s vision[...]is a[]shift away from traditional toxicity testing that focuseson demonstrating adverse health effects inexperimental animals toward a deeper understandingpgof biologic perturbations inkey toxicity pathways thatlead to adverse health outcomes.”• However,thecommitteecautionsthat “virtuallyalle e , e co ee cau o s a ua yenvironmental agents will perturb signaling pathwaysto some degree, a key challenge will be to determinewhen suchperturbations are likelyto lead to toxiceffects and when they are not.”4ExposureUtkD litT tTiAdverse Outcome Pathways – Definition andExample“Normal”Uptake‐DeliverytoTargetTissuesPerturbationCellularresponsepathwayBiologicinputsNormalBiologicalFunctionAdverseCellinury,InabilitytolAdaptiveResponsesEarlycellularchangesOutcomes(e.g.,mortality,ReproductiveImpairment)regulateMolecularinitiatingeventPerturbedcellularresponsepathwayAdverseoutcomerelevanttoriskassessmentToxicityPathwayAdverseOutcomePathway5Mode of Action FrameworkModeofActionFrameworkFrameworkModified Bradford Hill Criteria•Postulated mode of action• Identify sequence of key events on the path toh lth thealthoutcome•Experimental support• Concordance of dose-response for keyeventsy• Temporal relationships for key events•Biological plausibility & coherenceSt th i t & ifi it•Strength, consistency&specificity•Other modes of action•Identify uncertainties6Identifyuncertainties•ConclusionOrganization of the Draft Framework forIntegrating Epidemiology and Toxicity DataIntegratingEpidemiologyandToxicityDataIntegratingEpidemiologyToxicity•Reviewing Epidemiology Studies for Use inPesticide Risk Assessment• Types of studies• Scientific factors to consider in reviewing• Benefits & uses of epidemiology in riskassessment•Proposed Weight of the Evidence (WOE)Analysis• Consider mode of action information•Consider experimental toxicity dataConsiderexperimentaltoxicitydata• Consider epidemiology data7WOE analysis: Non-cancer EffectsWOEanalysis:NoncancerEffectsanalysis:Effects•MOA: Neuroendocrine perturbation of theHPG axisHPGaxis• Ovarian cyclicity disruption• Reproductive senescence• Other reproductive effects•General toxicity: low birth weight or smallfor gestational ageforgestationalage•September 2010 SAP concurred with theAgency’s conclusions:y• Epidemiology data useful for hazardidentification but not robust for dose-responseor risk characterization8WOE Analysis: Cancer Effects•Experimental toxicitydata•EpidemiologyDatay• Mammary gland tumors in rats dueto HPG axis disruption• MOA not operative in humansp gy• Varying degrees of study quality• Limitations ranging frominconsistency in findings toth d f• No other tumors identifiedin experimental toxicitydatamethodofexposureassessment and small numberof exposed cases•The weight of evidencedata• April 2010 SAP reaffirmedconclusions of previousTheweightofevidencedoes not supportassociation betweenti dSAPs regarding cancerclassification for atrazineas“not likely to beatrazine exposure andcancerasnotlikelytobecarcinogenic to humans.”9Conclusion•Non-cancer effects• Based on experimental toxicity data, LHsuppression (BMDL = 2.56 mg/kg/day) in ratsprotective of other effectsprotectiveofothereffects• Epidemiology data useful for hazardidentification but not robust for dose-responseor risk characterization (Presented to the SAPin September 2010)C ff t•ancer effects• Available data do not support associationbetween atrazine exposure and cancerbetweenatrazineexposureandcancer1011Ovarian Cyclicity Disruption•MOA: HPG axis disruptionleading to altered reproductive•Reproductive senescence• Experimental toxicity data:Early reproductivefunction• Experimental toxicity data:Estrous cyclicitydisruption in ratsEarlyreproductivesenescence• Epidemiology data :Menopause delayed•Women ever usingatrazineyy p• Epidemiology data: Menstrualcycle disruption• Women reportingever using•Womeneverusingatrazinenot possible to correlate thetiming and/or extent ofatrazine exposure with themenopause delayli it d f i ipg gatrazine or lindane during theirlifetime.not possible to estimate thetiming of pesticide exposure inlimitedfrequencyin assessingmenopausal status of thewomenpesticide exposureassessment do not allowtimingofpesticideexposureinrelation to changes in themenstrual cycleexposure-responseassessment• Different biological processesleading to reproductivesenescence12Male reproductive Effects•Decreases in LH lead to decreases in testosteronepotentiallyaffectingandrologyparameters(i.e.,spermyg(quality)• Experimental toxicity data•Rats: Decreased testosterone levels in at high doses (≥50Rats:Decreasedtestosteronelevelsinathighdoses(mg/kg/day)• Pigs:in vitrostudies suggest effect on sperm motility and/orviabilityHumans:in vitrostudy suggests effect on sperm motility and/or•nvitrostudysuggestseffectonspermmotilityand/orviability but no evidence of correlation with impaired reproductiveperformance• Epidemiologystudygy y• Increase in odds of poor semen quality in association with atrazineexposure.Small sample size with low precisionExposureto more than one pesticide was more frequent among men withtomorethanonepesticidewasmorefrequentamongmenwithpoor semen parameters13Small for Gestational Age (SGA)Low Birth WeightorLowBirthWeightor•Likely due to generalized toxicity and noti t d ith t id iMOAassociatedwithatrazine neuroenocrne• Experimental Toxicity Data•Decreases in fetal/offspring weights at high experimentalDecreasesinfetal/offspringweightsathighexperimentaldoses (≥50 mg/kg/day)• Epidemiologydatagy• Increase in prevalence of SGAPossible misclassification of outcome or exposure due to use ofbirth registries or maternal self-report of birth weight orbirthregistriesormaternalselfreportofbirthweightorgestational age• Low birth weight not statistically significantSmall sample size measure overalltriazineexposureSmallsamplesize,measureoveralltriazineexposure,measurements of atrazineexposure during pregnancy notavailable14