Risk Assessment Approaches

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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