Slide1FIFRAScientificAdvisoryPanelMeetingNewHighThroughputMethodstoEstimateChemicalExposureFIFRAScientificAdvisoryPanelMeetingNewHighThroughputMethodstoEstimateChemicalExposureArlington,VAJuly29‐August1,2014Arlington,VAJuly29‐August1,2014Charge QuestionsJuly29‐August1,2014FIFRAScientificAdvisoryPanelMeeting:NewHighThroughputMethodstoEstimateChemicalExposureChargeQuestions1. TheSystematicEmpiricalEvaluationofModels(SEEM)FrameworkforExposurePrioritizationThesechargequestionsaddressthesciencedescribedintheSectionentitled“ExposurePrioritizationwithExpoCast Research.”TheSEEMframeworkforevaluatinghigh‐throughputexposure(HTE)information(includingdescriptors,exposurefactors,mechanisticmodels,andheuristicsforthousandsofchemicals)extrapolatesfromchemicalswithmonitoringdatatothosewithnomonitoringdata.Bycomparingforwardmodelpredictionstoexposure/dosesinferredforthesubsetofchemicalswithmonitoringdata,weareabletoempiricallycalibrateourmeta‐modelandprovideanestimateofuncertaintyinexposurepredictions.1.1) IntheabsenceofsufficientexposureinformationtoestimateexposureforthemajorityofthechemicalsofinterestintheEDSPusingEPA'shistoricallow‐throughputmethods,pleasecommentonwhethertheSEEMapproachisscientificallysoundandsuitableforusingHTEmethodstoestimaterelativelevelsofchemicalexposuresandtheassociateduncertaintyoftheseestimatesforconsiderationinaprioritizationapproach.July29‐August1,2014FIFRAScientificAdvisoryPanelMeeting:NewHighThroughputMethodstoEstimateChemicalExposureChargeQuestions1. TheSystematicEmpiricalEvaluationofModels(SEEM)FrameworkforExposurePrioritization(continued)1.2) PleasesuggestthemostimportantstepsforEPAthatcoulddecreaseuncertaintiesandincreaseconfidenceinusingtheHTEapproachtopredictexposuresinvariousdemographicgroups(e.g.,youngchildren,womenofchildbearingage)forlargenumbersofchemicals.July29‐August1,2014FIFRAScientificAdvisoryPanelMeeting:NewHighThroughputMethodstoEstimateChemicalExposureChargeQuestions2. HighThroughputToxicokinetics(HTTK)andReverseToxicokinetics(RTK)ThesechargequestionsaddressthesciencedescribedintheSectionwiththesamename.TKcanbeusedtoprovideanadministereddosecontexttotheconcentrationsshowingbioactivityintheendocrine‐relatedHTSassays.AlackofdataontheTKofchemicalsinorganismsisasubstantialimpedimenttoprovidingthiscontext.TherecentdevelopmentofHTTKmethodsprovidesasolutiontothisproblembymeasuringkeyTKparametersforeachchemical.Todate,HTTKdatahavebeengatheredonroughly500chemicalsaspartoftheExpoCast project.TheHTTKassayscanbeincorporatedintorelativelysimpleinvitro‐to‐invivoextrapolation(IVIVE)computationalmodelstopredictsteady‐statebloodconcentrations.HTTKassayscombinedwithphysiologicalinformationandquantitativestructureactivityrelationships(QSAR)thatpredicttissuepartitioningcanbeutilizedinmorecomplex,high‐throughputphysiologically‐basedTK(HTPBTK)modelstopredictrelevantTKparameterssuchasareaunderthecurve(AUC),maximumbloodconcentration(Cmax),andtissueandbloodconcentrationsundernon‐steady‐stateconditions.Forinvitrotoinvivoextrapolation(IVIVE),reversetoxicokinetics(RTK)canbeperformedusingeithersimpleormorecomplexHTPBPKmodelstopredicttheadministereddose(mg/kgBW/day)requiredtoproducehumantissueconcentrations(μM)equaltoconcentrationsthatactivateendocrine‐relatedinvitroassays(e.g.,ToxCast,Tox21).AlthoughcurrentmodelsbasedonHTTKdataallowforasignificantlyhigherthroughputthantraditionalinvivostudies,aswithExpoCast predictions,thefasterandlessdataintensivepredictionsallowedbyHTTKmethodsareassociatedwithhigheruncertaintycomparedtoinvivomethods.Thishigheruncertaintyisdueinparttothelackofavailabilityofinvitromethodstocapturebiologicalprocessesimportanttotoxicokinetics(e.g.,activetransport,enterohepaticcirculation,etc.).2.1) IntheabsenceofsufficientempiricaltoxicokineticsinformationforthethousandsofEDSPrelevantchemicals,pleasecommentontheapproachofusingHTTK,HTPBTK,IVIVE,andRTKforestimatingchemicalTKtoprovideanadministereddosecontexttotheconcentrationsshowingbioactivityintheendocrine‐relatedHTSassays.July29‐August1,2014FIFRAScientificAdvisoryPanelMeeting:NewHighThroughputMethodstoEstimateChemicalExposureChargeQuestions2. HighThroughputToxicokinetics(HTTK)andReverseToxicokinetics(RTK)(continued)2.2) AcomparisonoftheHTTK‐predictedsteady‐statebloodconcentrationswithinvivovaluesfromtheliteraturesuggeststhattheoverallcorrelationislow,butthatthediscrepancybetweenthetwocanbepredictedusingacombinationofchemicalproperties,quantitativestructureactivityrelationships(QSAR),andcutoffsfromtheHTTKassays.Pleasecommenton:a)howwellthisapproachcharacterizestheuncertaintyinthesteady‐statebloodconcentrations,andb)whethertheidentificationofchemicalclassesthatneedadditionalTKinvestigationisusefulinachemicalprioritizationorinitialscreeningcontext.July29‐August1,2014FIFRAScientificAdvisoryPanelMeeting:NewHighThroughputMethodstoEstimateChemicalExposureChargeQuestions2. HighThroughputToxicokinetics(HTTK)andReverseToxicokinetics(RTK)(continued)2.3) Pleasecommentonwhethertheassumptionsmadeinthesemodelsareappropriategiventhecurrentstateofthescienceanddatalimitations.2.4) PleasesuggestthemostimportantstepsEPAshouldtaketoimprovethevariouskineticmodelstoproviderapidandcost‐effectivepredictionsforlargenumberofchemicals.2.5) PleasecommentontheapproachespresentedinthepresentWhitePaperforcomparingRTK‐derivedendocrine‐activedoserangeswithexposurepredictionsfromExpoCast.Discussthestrengthsandlimitationsofthesecomparisons,andwhetherthisorotherapproachesaresuitableforclearlydistinguishingchemicalswithhigherpredicteddosesfromchemicalswithlowerpredictedRTKadjusteddoses.July29‐August1,2014FIFRAScientificAdvisoryPanelMeeting:NewHighThroughputMethodstoEstimateChemicalExposureChargeQuestions3. FutureDirectionsThesechargequestionsaddressthesciencedescribedintheSectionwiththesamename.Scienceisproceedinginthreekeyareastosupporthighthroughputexposureprioritization:1. Near‐field(indoororconsumeruse)exposurestohumans2. Ecologicalexposures3. Refinementofhigh‐throughputtoxicokineticsForallthreeoftheseareas,ongoingsciencedevelopmenteffortsaddresstheneedforrapidprioritizationandinitialscreeningofEDSPandotherchemicals.3.1) Pleasecommentonthethreekeyareasincludingwhetherthereareotherareasthatareofequalorhigherprioritytosupportanintegratedactivity/hazardandexposurebasedprioritizationandscreeningapproachwithintheEDSPorotherchemicalprograms.July29‐August1,2014FIFRAScientificAdvisoryPanelMeeting:NewHighThroughputMethodstoEstimateChemicalExposureChargeQuestions3. FutureDirections(continued)3.2) WeproposeapplyingtheExpoCast frameworktoecologicalexposuresusingaggregatedwatermonitoringdatatoevaluatethepredictionsofenvironmentalfateandtransportmodels.Pleaseidentifyotherdata,modelsorenvironmentalmediathatmaybeofgreatervalueintheinitialmodelcalibrationanduncertaintyanalysis.3.3) Pleaseidentifyotherrelativelyhigh‐throughputsourcesofexposure‐relatedinformationthatshouldbeincludedinthesethreekeyareasandsuggesthowthisinformationwouldbeusedtohelpprioritizechemicals.3.4) FortheHTTKworkgoingforward,pleasecommentonadditionalstudiesthatcouldbeperformedorapproachesthatcouldbetakentoimproverapidandcostefficientpredictionsofTKforlargenumbersofchemicals.