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1、RiskAssessmentApproachesPresentedtoUSEPAOfficeofWaterOctober16th,2009LarryZobel,MD;RobertRickard,Ph.D.;JohnButenhoff,Ph.D.;HarveyClewell,Ph.D.RiskAssessmentApproachesforPFOS/PFOAShouldBeBasedOn:?InternaldoseasrepresentedbyserumPFOA&PFOSconcentrations?Multiplehealthendpointsthatconside
2、rhumanrelevance?Benchmark-dosemethodologywherepossible?AppropriateUncertaintyFactorsforassessmentbasedoninternaldose?AppropriateRelativeSourceContributionbasedonavailabledataWhyUseInternalDose??Robustdatasetexistfromhumanandexperimentalstudies?Includesserumconcentrationdata?Integrates
3、allroutesofexposure?BridgesPKdifferences?NOAEL/BMDhavebeenestablishedbasedonserumconcentrationInternalDoseinRiskAssessment(Butenhoffetal.2004)Internal-DoseRiskAssessment3MEHAD(2003)ExamplesofInternal-DoseRiskAssessments?EPADraftPFOARiskAssessment?German/EU“CSR”BiologicalDNEL?Minnesota
4、HRLs?Butenhoffetal.(2004)?3MPFOS“EHAD”(2003)?Tardiffetal.(2009)?StandardapproachforpharmaceuticalsHumanExperience?Numeroushumanstudiesareavailable.?ResultscanbeassociatedwithknownserumPFOS&PFOAconcentrations.?Nocausalassociationshavebeenobserved.?Likelyhuman“no-effectlevels”basedonstu
5、diedendpointsinoccupationalcohortsare>5,000ng/mL(ppb)forbothPFOAandPFOS.HumanRelevance?Rodentdatamustbeinterpretedbasedonhumanrelevanceofmodesofaction.?Non-humanprimateisbestlaboratorymodel.BenchmarkDose?Usesallstudydata?Normalizesspeciesdifferencestoaspecific,definedlevelofresponse?R
6、ecommendedinEPA’sDraftBenchmarkDoseTechnicalGuidancedocumentBenchmarkDoseUSEPAScienceAdvisoryExpertPanelonEPAPFOADraftRiskAssessment“ThePanellikewisestressedthatbenchmarkdosemethodologieswouldbepreferabletotherelianceinthedraftdocumentonLOAEL-drivenMOEcalculations.”ConsiderationsforUn
7、certainty?Lackofmetabolism,useofinternal-dosemetric,andunderstandingofpharmacokineticsreducespharmacokineticcomponentofuncertainty.?Six-monthstudiesinanappropriatemodel(monkey)combinedwithdecadesofoccupationalstudieslessenuncertaintyrelatedtochronicexposure.?Adaptiveversusadverseeffec
8、tssho
