Slide1IntegratedActivityandExposureBasedPrioritizationandScreeningIntegratedActivityandExposureBasedPrioritizationandScreeningPresentedbyStevenKnottEndocrineDisruptorScreeningProgramOfficeofScienceCoordination&PolicyOfficeofChemicalSafetyandPollutionPreventionPresentedbyStevenKnottEndocrineDisruptorScreeningProgramOfficeofScienceCoordination&PolicyOfficeofChemicalSafetyandPollutionPreventionPresentationRoadmapFutureApplicationsExposureEstimationwithExpoCast ResearchHighThroughputToxicokinetics(HTTK)andReverseToxicokinetics(RTK)OngoingResearchIntroductionWhyanIntegratedActivity–ExposureApproachforEDSPSlide3EDSTACrecommendation(August1998)“DataresultingfromHTPSwillbecombinedwithexposure‐relatedinformation,andwithanyothereffects‐relatedinformationthatisavailable,foreachchemicalforthepurposeofsettingprioritiesforT1S”Lists1and2•Basedprimarilyonexposureconsiderations•NotpresumedtointerferewiththeendocrinesystemsofhumansorotherspeciesOtherchemicalscouldhavehigherpriorityforEDSPscreeningandtestingifbioactivityconsiderationsarejoinedwithexposureconsiderationsinanintegratedapproach1000067109176EDSPUniverseList1List2WhyanIntegratedActivity–ExposureApproachforTSCASlide4MandatetoaddressbothexistingandnewchemicalsLimitedexistingandavailabledata(nexttonilfornewsubstances)•Historically,havereliedonanalogandread‐acrossanalysis,categoryapproaches,andpredictivemodeling(e.g.,QSAR)Couldserveinevaluatingnewchemicalsandinprioritizingassessmentfocusforexistingchemicals>84,0001,000ExistingChemicalsApproximate#ofNewChemicals/YearCapturingCriticalPointsAlongtheSourcetoOutcomePathwaySlide5PhysicochemicalPropertiesHighThroughPutExposureHTSandQSARActivityBroaderUniverseEDSPUniverseEDSPList2•HigherPriority•LowerPriority•HigherPriority•LowerPriority•HigherPriority•LowerPriorityIntegratingActivityandExposureSlide6invitrochemicaldose‐responseHTSbioactivitydataareusedtoidentifypotentialbiologicaltargetsHTTKmethodsarethenemployedtodeterminethehumandoseneededforeachchemicaltoactivatethesetargetsinvivoputativebioactivedosesarethendirectlycomparedtoHTEpredictionstoestimatelikelihoodofexposuresthatcausebioactivedosesChemicalswheretheputativehumanbioactivedoseiscomparabletoHTEpredictionsbecometargetsforfurtherinvestigationOverallapproachwillbethesubjectofafutureFIFRASAPreviewPotentialExposurefromExpoCastmg/kgBW/dayInvitroBioactivityfromToxCastwithReverseToxicokineticsLowPriorityMedPriorityHigherPriorityHighThroughputExposureMethodsandReverseToxicokineticsforScreeningandPrioritizationHTEMethodsandRTK•Rapidexposureestimationbasedonreadilyavailablechemicaluseandproductiondata•Usetoxicokinetics tobridgeinvitro,concentration‐basedToxCast datatoinvivo,dose‐basedExposuresfromExpoCastHighThroughputPrioritizationRTKToxCastHTEMethodsToxCast•ExpandinguseofCompTox(Phys‐chem properties,QSARS,etc.)tosupportscreeningandprioritization•TransparentandcollaborativeThisSAPFitforPurposeHighThroughputExposure(HTE)IS•HTEestimationis“fit”tobeusedinanintegratedactivity‐exposureapproachtorankchemicals.•Thatis,HTEexposureestimatesare“fit”todiscernchemicalswithhigherpotentialexposurefromchemicalswithlowerpotentialexposure.•Thisinturnwillbeconsideredalongwithbioactivitytoprioritizeandscreenchemicalsfortraditionallow‐throughputassessmentmethods.