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# Summary of External Peer Review and

Public Comments and Disposition

This document summarizes the public and external peer review comments that the EPA’s Office of

Pollution Prevention and Toxics (OPPT) received for the draft work plan risk assessment for

trichloroethylene (TCE). It also provides EPA/OPPT’s response to the comments received from the

public and the peer review panel.

EPA/OPPT appreciates the valuable input provided by the public and peer review panel. The input

resulted in substantial revisions to the risk assessment.

Peer review charge questions 1 

# are used to categorize the peer review and public comments into specific

issues related to five main themes.

 General Issues on the Risk Assessment Document

 Occupational Exposure Assessment

 Consumer Exposure Assessment

 Hazard and Dose

‐ Response Assessments

 Risk Characterization

A separate section called Other Public Comments organizes the response to those public comments that

are unrelated to the main themes listed above.

1 

# These are the questions that EPA/OPPT submitted to the panel to guide the peer review process.Version6/24/142|PageGeneralIssuesontheRiskAssessmentDocumentChargequestion1‐1:PleasecommentonwhetherthecharacterizationprovidesaclearandlogicalsummaryofEPA’sanalysis.Pleaseprovidespecificsuggestionsforimprovingthedocument.Chargequestion1‐2:Pleasecommentonwhetherappropriatebackgroundinformationisprovidedandaccuratelycharacterized.Pleaseprovideanyothersignificantliterature,reports,ordatathatwouldbeusefultocompletethischaracterization.#SummaryofPeerReviewandPublicCommentsforSpecificIssuesRelatedtoChargeQuestions1‐1and1‐2EPA/OPPTResponse1Documentisnotclearaboutthepurposeoftheriskassessment.Thedocumentwouldbesubstantiallyimprovedifaclearstatementwasmaderegardingtheaudienceandutilityofthereport.EPA/OPPThasmadesignificantrevisionstotheTCEriskassessmenttoimprovetheclarityoftheassessment.Inaddition,thepurposeandaudiencehavebeendescribedinsection1.1ofthefinalTCEOPPTriskassessment.2EPA/OPPTdidnotassessdermalexposuretoTCEforoccupationalandresidentialscenarios;whyisdermalexposureconsideredlesssignificantthaninhalationexposure?Bynotincludingdermalexposureintheexposureassessment,exposureislikelytobeunderestimated.EPA/OPPTrecognizesthatdermalexposuretohighlyvolatilematerialssuchasTCEcanoccur.However,basedonthephysical‐chemicalpropertiesofTCEandthescenariosdescribedinthisassessment,EPA/OPPTbelievesthatinhalationisthemainexposurepathwayforthisriskassessment.ThisassessmentmayunderestimatetotalexposuresresultingfromtheusesofTCEduetothisassumption.Thus,weagreethisassessmentlikelyunderestimatesrisksresultingfromtheusesofTCEbeingassessed.AsstatedinSection1.3.2ofthefinalriskassessment,recentmodeledandexperimentalworksupportstheassumptionthatinhalationisthepredominantexposurepathway.ThedermalmodeldescribedbyTibaldietal.(2014)estimatesthatabout1%ofTCEontheskinwillbeabsorbedintotheepidermiswiththeother99%evaporating.Also,anexperimentalcomparisonofdermaltovaporexposurefoundthatTCEandhexanehadtheleastdermalabsorptionamongstasetofvolatilesolvents.Theratioofdermaltorespiratoryintakewasfoundtobe0.1%forTCE(Kezicetal.,2000).Citations:Kezic,S.,A.C.Monster,J.Kruse,andM.M.Verberk.2000.SkinAbsorptionofSomeVaporousSolventsinVolunteers.InternationalArchivesofOccupationalandEnvironmentalHealth,73(6),415‐422.Tibaldi,R.,W.tenBerge,andD.Drolet.2014.DermalAbsorptionofChemicals:EstimationbyIhSkinperm.JOccupEnvironHyg,11(1),19‐31.Version6/24/143|Page3CanEPA/OPPTclarifywhyitdidnotincludetheuseofTCEasaspottingagentinitsassessment?Basedonadditionalinformationprovidedduringpeerreview,EPA/OPPThasreviseditsoriginalassessmenttoincludetheuseofTCEasaspottingagentatdrycleaningfacilities.Theexposureassessmentforthespottingusecanbefoundintheoccupationalsection2.4ofthefinalTCEOPPTriskassessmentandinAppendixH.EPA/OPPTdidnotidentifyTCE‐basedspotcleanersusedinconsumerproducts(Section2.5.1).Itispossiblethatmembersofthegeneralpubliccouldobtainproductsintendedforcommercialuse,buttheseactivitiesarenotincludedinthefinalTCEriskassessment.4Forthecommercialdegreasingscenario,EPA’sdiscussionregardingcomparisonofNationalEmissionsInventory(NEI)andToxicsReleaseInventory(TRI)datawassomewhatconfusing.Canthisbefurtherclarified?EPA/OPPThasfurtherclarifieditscomparisonofNEIandTRIdata.Inparticular,thefinalriskassessmentincludesillustrationsthatprovideanoverviewofEPA/OPPT’sassessmentforthecommercialdegreasingscenario.Theserevisionsandillustrationscanbefoundinsection2.3,Figure2‐1,andAppendicesEandFofthefinalTCEOPPTriskassessment.5EPAdidnotcitethecorrectpublicationforthetwo‐zonemassbalancemodel.Inaddition,EPAdidnotreferencethepublicationprovidedbyDr.Jayjockregardingthevalidityofthetwo‐zonemassbalancemodel.Thispublicationaddsstrongsupportforusingthetwo‐zonemodeltoestimateoccupationalexposuresfromcommercialdegreasing.IncludingthisreferencewillstronglystrengthenEPA’scaseforusingsuchamodeltoinferexposures.Also,thisreferencesupportsthatEPA/OPPT’sassessmentismorethanascreeninglevelassessment.Theriskassessmenthasbeenupdatedtocitethecorrectpublication(Keil,C.B.etal.,2009)forthetwo‐zonemassbalancemodel.Inaddition,EPA/OPPTupdateditsriskassessmenttoreferencethepublicationprovidedbyDr.Jayjockduringpeerreview.Citation:Keil,C.B.,C.E.Simmons,andA.T.Renee.2009.MathematicalModelsforEstimatingOccupationalExposuretoChemicals(2nded.)AmericanIndustrialHygieneAssociation(AIHA).6InAppendixD,aparagraphhadamissingnotationfortheFreeSurfaceArea(FSA),thuscausingconfusionforreaders.TheriskassessmenthasbeenupdatedtoaddresstheissuewiththemissingnotationfortheFreeSurfaceArea(FSA).PleasenotethatAppendixDinthedraftriskassessmentcorrespondstoAppendixGinthefinalriskassessment.7EPA/OPPTdidnotreferencemonitoringdatatovalidateitsexposureestimatesresultingfromtheuseofTCEincommercialdegreasingprocesses.HowcanonehaveconfidenceinEPA/OPPT’sestimatesforoccupationalexposures?IncollaborationwiththeOccupationalSafetyandHealthAdministration(OSHA),relevantmonitoringdataspecifictoTCEfromsitesurveyswereidentifiedandincorporatedintothefinalriskassessmentinsection2.3.3andFigure2.2.OSHA’sdataandEPA’sassessmentofitisincludedinthesupplementaryfile:“OSHAIMISTCESAMPLES_062314v1.xlsx”.Version6/24/144|Page8EPA/OPPTusedasteady‐stateassumptioninestimatingairborneexposureconcentrationsresultingfromcommercialdegreasingoperations.Thisisproblematicandperhapssimplisticforthesescenarios.Intherevisedriskassessment,EPA/OPPTusedatransient(non‐steadystate)massbalancemodeltoestimateairborneexposureconcentrationsthatresultfromcommercialdegreasingprocesses.9Theredoesnotseemtobeanexhaustiveeffortmadetofindallexistingappropriateliteratureforthevarioussectionsoftheriskassessment.AdditionalreferencessubmittedtoEPA/OPPTaspartofthepeerreviewprocesswereincorporatediftheywererelevanttotheassessment.Additionalreferenceswereincludedrelevanttotheweight‐of‐evidence(WOE)analysissupportingthehazard/dose‐responseassessment(Section2.6)andtheWOEanalysisforfetalcardiacmalformations(AppendixN).PleaseseetheReferencesectionforthecompletelistofreferencesusedinthefinalriskassessment.10EPA/OPPTshouldimprovethetransparencyandreadabilityofTableF‐1andTable3‐19.TableF‐1listedthehazardvaluesasreportedintheIRISassessment.Table3‐19listedthehazardvaluesusedintheOPPTriskassessment.EPA/OPPThasmadesignificantchangestothehazardinformationpresentedinTableF‐1andTable3‐19ofthedraftTCEOPPTriskassessment.Inthefinalassessment,theinformationcanbefoundinTable2‐18andAppendixL.Table2‐19liststhelowesthazardvaluesfordifferenteffectsdomainsthattheOPPTassessmentusedtoestimaterisks.Table2‐19containsthefollowinginformation:exposuredurationforriskanalysis(acutevs.chronic),targetorgan/system,species,routeofexposure,rangeofdosesorconcentrations,duration,pointofdeparture(POD),effect,humanequivalentconcentrations(HEC)atthe50th,95thand99thpercentiles,uncertaintyfactorsusedasthebenchmarkmarginofexposureandthereferencecitation.AppendixLcontainsthecompletelistoforalandinhalationstudiesthattheU.S.EPA’sIntegratedRiskInformationSystem(IRIS)programdeemedsuitablefornon‐cancerdose‐responseanalysis.11PeerreviewcommentssuggestedthattheEPA’sOfficeofPesticides(OPP)mayhaveempiricaldatathatcouldimprovetheTCEworkplanriskassessment.Particularly,indoormonitoringdataforinertchemicalsinconsumerpesticidesmightprovideusefulinformationfortheTCEriskassessment,providedthatthemonitoringdatawereforchemicalsubstanceswithsimilarphysical‐chemicalproperties.EPA/OPPTincollaborationwiththeOfficeofPesticideprograms(OPP)searchedOPP’sPesticideInertdatabase.NoexposuredatathatwouldberelevantorindoormonitoringdataonTCEorsurrogatechemicalwerefound.OPPconfirmedourlackofresultsandtheimprobabilityoffindingthetypeofinformationthatwassuggestedtousbythepeerreviewers.EvenifdatawerefoundwithinEPA/OPP,itishighlylikelythatitisconfidentialbusinessinformationifitwassubmittedbyacompanyaspartofapesticideregistrationunderthepesticidelaws,andthereforenotusableinapublicriskassessment.Giventhesecircumstances,EPA/OPPTbelievesthatthiseffortwouldnotprovideusefulsurrogatedataforrefiningtheOPPTriskassessment.Version6/24/145|Page12OneofthepeerreviewersstatedthatwhileSectionA.PhysicalandChemicalPropertiesofTCEandSectionC.ProductionVolumeandGeneralInformationonUsesseemedappropriate,SectionB.EnvironmentalFatedidnotseemtobenecessaryorrelevanttoanassessmentfocusedoninhalationofTCEfromindustrialorconsumerproducts?Theenvironmentalfateofasubstance(i.e.,itstransportandtransformationintheenvironment)canmitigateorenhanceitsexposuretohumansortheenvironment.Intheinitialstepsofassessingthepotentialriskofasubstance,itsenvironmentalfateisconsideredinconjunctionwithitsreleasepatternsanditsphysical‐chemicalpropertiestoprovideanunderstandingofhowitsbehaviorafterreleasemayimpactexposure.ThediscussionoftheenvironmentalfateofTCEwasusedtohelpfocustheassessmentontheappropriateexposureroutes(inhalation)andpathways(volatilizationtoair).However,EPA/OPPTagreeswiththepeerreviewerthatthefulldiscussionoftheenvironmentalfateofTCEisnotnecessarytoincludeinthemaindocument.ThefulldiscussionoftheenvironmentalfateofTCEhasbeenmovedtoAppendixC.13Oneofthepeerreviewersrequestedclarificationoftheterms“low”and“moderate”intheconclusionofthefatediscussionbelowtomakeitlessopentointerpretation:“Basedontheexperimentalevidenceandenvironmentalfatedataavailable,TCEisexpectedtohavelowbioaccumulationpotentialandmoderatepersistence.”IntheEnvironmentalFateSection,EPA/OPPTaddressedonlybioaccumulation/bioconcentrationinaquaticorganismsandenvironmentalpersistence.Thepeerreviewerappearedtointerpretbioaccumulationpotentialandpersistencetorefertohumanbioaccumulationandhalf‐lifeinhumansratherthanbioaccumulationinaquaticorganismsandenvironmentalpersistenceasitwasintended.EPA/OPPTagreesthatthelanguageusedintheconcludingstatementneedsfurtherclarificationandmadethefollowingchange:“Basedontheexperimentalevidenceandenvironmentalfatedataavailable,TCEisexpectedtohavelowbioaccumulationpotentialinaquaticorganisms(bioconcentration/bioaccumulationfactorlessthan1000)andmoderatepersistenceintheenvironment(environmentalhalf‐lifeofgreaterthantwomonthsbutlessthansixmonths).”TherevisedtextisfoundinAppendixC.Version6/24/146|PageOccupationalExposureAssessmentChargequestion2‐1:Pleasecommentontheapproachused,andprovideanyspecificsuggestionsorrecommendationsforalternativeapproaches,modelsorinformationthatshouldbeconsideredbytheAgencyforimprovingtheworkplaceexposureassessment,includingestimationsforbystander/non‐users(e.g.,womenofchildbearingage).#SummaryofPeerReviewandPublicCommentsforSpecificIssuesRelatedtoChargeQuestion2‐1EPA/OPPTResponse14EPA/OPPTdidnotreferencemonitoringdatatovalidateitsexposureestimatesresultingfromtheuseofTCEincommercialdegreasingprocesses.EPA’sriskassessmentcontainslittleactualdataonexposureatsmallcommercialshopsonwhichtobasearobustanalysis.IfEPA/OPPTisgoingtodistinguishfacilitiesbasedontheirsize,thenmorerepresentativedataneedstobeobtainedbeforefinalizedtheriskassessment.EPA/OPPTseemstoindicatethatitsexposureestimatesforworkersatcommercialdegreasingfacilitiesaresimilartomeasuredvalues;butEPAdoesnotprovideanymonitoringdatainitsriskassessment.ItisimportanttoknowwhatTCEworkplaceexposuredataareavailable;EPA/OPPTshouldincludethisdataintheriskassessment.EPA/OPPTshouldgatheroridentifymonitoringdataforTCEexposuresresultingfromactivitiesthatareofconcern;exposureassumptionsandmodelsarenosubstituteforexposuredata.Ataminimum,EPAshouldsolicitandwelcomepeerreviewoftheTCEriskassessmentfromtheConsumerProductSafetyCommission(CPSC)andtheNationalInstituteforOccupationalSafetyandHealth(NIOSH).EPA/OPPTdidnotusemonitoringdatatoestimateworkplaceexposuresforthecommercialdegreasingscenario.Instead,EPAchosetoestimateworkplaceexposuresbasedoncalculatinganemissionratefromdegreasingoperations.Further,EPAcitesWaldenetal.(1989)andincorrectlystatesIncollaborationwithOSHA,relevantmonitoringdataspecifictoTCEwasidentified.Thisadditionalinformationhasbeenincorporatedintotheriskassessmentinsection2.3.3andFigure2.2.OSHA’sdataandEPA’sassessmentofitisincludedinthesupplementaryfile:“OSHAIMISTCESAMPLES_062314v1.xlsx”.TheNationalEmissionsInventory(NEI)containsdatafornonpointsources.Traditionally,smallcommercialfacilitieshavebeenrepresentedasnonpointsources;EPA/OPPThasuseddatafornonpointsourcestorepresentsmallcommercialfacilities.ThepublicationfromWaddenetal.(1989)reportedatotalemissionof27.29gramsofTCEperminutefromanopentopdegreaser.Sincelocalexhaustventilation(LEV)wasused,only2.57gramsofTCEperminute(or9.5%ofthetotalemission)werereportedasescapingintotheworkplace.Basedonthesedata,EPA/OPPTassumedthatifnoLEVwereused,thenthetotalemissionof27.29gramsofTCEperminutecouldpotentiallybereleasedintotheworkplace.Citation:Wadden,R.A.,P.A.Scheff,andJ.E.Franke.1989.EmissionFactorsforTrichloroethyleneVaporDegreasers.AmericanIndustrialHygieneAssociationJournal,50(9),496‐500.Version6/24/147|Pagethattheemissionraterangedfrom2.57to27.29gramsofTCEperminute.ThedatafromWaldenetal.(1989)areforenvironmentalemissionsthatarereleasedexternally;only9.5%ofthevalueisemissionescapingintotheworkplace.EPAshouldnotassumeenvironmentalemissionsthatarereleasedexternallycanbeusedtoestimateworkplaceexposures.15Forthecommercialdegreasingscenario,itisnotclearwhetherEPA/OPPTisusingthemostcurrentlyavailabledatatoestimatethenumberofworkersexposed.ItseemsEPAisusingdatafromthe1970sor1980s.ReleasesofTCEhavedecreasedsubstantiallysincethattime.Also,workplacepracticesandindustrialhygienestandardshaveimproved.Thus,itislikelythatEPAisoverestimatingthenumberofworkersandnon‐usersexposed.EPA/OPPTestimatesthenumberofworkersandnon‐usersatcommercialdegreasingfacilitiesas7,415and17,796,respectively.ButEPA/OPPTdoesnotappeartoprovideanyexplanationforhowtheseestimateswereobtained.EPA/OPPThasupdatedtheriskassessmentwithadditionalinformationtofurtherclarifyhowthenumberofworkersandnon‐userswasestimated(seesection2.3.3andAppendixFoftherevisedriskassessment).Byusingmorerecentdatafromthe2008NEIandEPA’s2006riskassessmentforthehalogenatedsolventcleaningsourcecategory(EPA,2006d)toestimatethenumberoffacilities(1,746),EPA/OPPT’sestimatelikelycapturesthedownwardtrendinthenumberoffacilitiesusingTCEfordegreasingandprovidesanadequateorderofmagnitudeestimate.Morerecentandrelevantsurveydatawerenotidentifiedforthepurposesofcomparison.EPA/OPPTestimatedthenumberofworkersandnon‐userspotentiallyexposedtoTCEbasedon:(1)aNationalOccupationalExposureSurvey(NOES)fromthe1980s;(2)EPA’sdraftgenericscenarioonvapordegreasing(EPA,2001a);and(3)thenumberofsmalldegreasingfacilitiesasdeterminedfromthe2008NationalEmissionsInventory(NEI)andEPA’s2006riskassessmentforthehalogenatedsolventcleaningsourcecategory(EPA,2006d).Citation:EPA(U.S.EnvironmentalProtectionAgency).2001a.DraftGenericScenario‐UseofVaporDegreasers.OfficeofPollutionPreventionandToxics,ChemicalEngineeringBranch,Washington,DC.EPA(U.S.EnvironmentalProtectionAgency).2006d.RiskAssessmentfortheHalogenatedSolventCleaningSourceCategoryWebSite.Washington,DC.http://yosemite.epa.gov/ee/epa/ria.nsf/vwRef/A.2006.10?OpenDocument(accessedonNovember8,2012).Version6/24/148|Page16EPA’sdraftriskassessmentdoesnotconsidertheimpactsoftheHalogenatedSolventCleaningNationalEmissionStandardforHazardousAirPollutants(NESHAP),whichEPAfinalizedin2007.Thisstandardlimitsemissionsfromopen‐topdegreasers.EPA/OPPTupdateditsriskassessmenttotakeNESHAPemissionlimitsintoaccount(seesection2.3.3,Table2‐8,andAppendixEofthefinalriskassessment).17TheoverallmethodologyEPA/OPPTusedtoestimateemissionsofTCEfromcommercialdegreasingoperationsiscomplexandconvoluted.EPA/OPPThasclarifieditscomparisonofNEIandTRIdata.Inparticular,therevisedriskassessmentincludesillustrationsthatprovideanoverviewofEPA/OPPT’sassessmentforthecommercialdegreasingscenario(seesection2.3.3,Figure2‐1,andAppendixEofthefinalriskassessment).18Wedownloadedthefile"Facility‐LevelbyPollutant"atEPA's2008NEIwebsite.ThetotalTCEemissionswere4,088,000lbacross2,378facilities,whichareclose,butslightlyless,thanthetotalprovidedbyEPA(4,340,000lb).Laterinthediscussionthereisareferencemadetoonlyincludingemissionsfromfacilitiesinoneof78NorthAmericanIndustryClassificationScheme(NAICS)codes.Whenweonlyincludethe78NAICScodes,theemissionsinthe"Facility‐LevelbyPollutant"arereducedto2,734,000lbacross373facilities.ItisnotclearwhereEPAisgettingthe186TCEpointsourcesand1,779nonpointsources.Itispossiblethatsomeofthenon‐pointsourcesarenotinthefacilityfile,butitseemsthatsomeofthemmustbesincetherearemorefacilitieswiththe78NAICScodesthanthe186quotedbyEPA.EPA/OPPThasupdateditsassessmenttofurtherclarifywhichNationalEmissionsInventory(NEI)datawereused(seesection2.3.3andAppendixEofthefinalriskassessment).Inbrief,EPA/OPPTusedpointandnonpointsourcedatafromthe2008NEI.Thesedatawerefiltered,forexample,bypollutantname,sourceclassificationcodes(SCC),etc.Afterfilteringthedata,thenumberofpointsource(large)facilitieswasestimatedtobe154.BasedonEPA’s2006riskassessmentforthehalogenatedsolventcleaningsourcecategory(EPA,2006d),thetotalnumberofdegreasingfacilitieswasexpectedtobeapproximately1,900.Thenumberofsmallcommercialdegreasingfacilitieswasestimatedtobe1,746(1,900totalfacilitiesminus154largefacilities).Citation:EPA(U.S.EnvironmentalProtectionAgency).2006d.RiskAssessmentfortheHalogenatedSolventCleaningSourceCategoryWebSite.Washington,DC.http://yosemite.epa.gov/ee/epa/ria.nsf/vwRef/A.2006.10?OpenDocument(accessedonNovember8,2012).19Forthecommercialdegreasingscenario,EPA/OPPTprovidesnoindicationontherelativeprevalenceoflocalexhaustventilation(LEV).EPA/OPPTshoulddescribehowthelocalexhaustventilation(LEV)affectsthegenerationrate.EPA/OPPThasadoptedascenario‐basedapproachforitsexposureassessment.Thus,exposurescenarioswithandwithoutLEVhavebeenassessed.However,therelativeprevalenceofLEVisnotknowntoEPA.Basedoninformationpresentedin(Waddenetal.,1989),EPA/OPPTassumedthatLEVcanhaveaneffectivenessofupto90%.ForscenariosinwhichLEVisassumedtobepresent,thegenerationrateisreducedby90%(alsoseesection2.3.3andAppendixEofthefinalriskassessment).Version6/24/149|PageCitation:Wadden,R.A.,P.A.Scheff,andJ.E.Franke.1989.EmissionFactorsforTrichloroethyleneVaporDegreasers.AmericanIndustrialHygieneAssociationJournal,50(9),496‐500.20EPA/OPPTassumedthatsmallcommercialdegreasingfacilitiesoperatefor2hours(hrs)aday.Thisisacriticalparameter;thebasisforthisshouldbefullydescribed.ThebasisforthisassumptionisinformationincludedinEPA’sdraftgenericscenarioonvapordegreasing(EPA,2001a).Thisdraftscenariocontainsgeneralfacilityestimates,suchasdaysofoperation,andhoursofoperation.Theassumptionisdescribedinsection2.3.3ofthefinalriskassessment.PleasenotethatEPA/OPPTdidnotlocatefurtherdataaboutfacilityandoperatingparameters.21Thefreesurfacearea(FSA)valueinTableD‐1islistedas180squarefeet.However,basedonequation(5)inAppendixD,theFSAshouldbe340squarefeet.ItappearsthatEPAusedthecorrectvalueof340squarefeetinitscalculations,butmistakenlylistedthevalueas180squarefeetinthedocument.ThelistedFSAvaluehasbeenupdatedto340squarefeet(seeAppendixGandTableG‐1oftherevisedriskassessment).22EPA/OPPTshouldusedifferentmethodstoassessworkplaceexposures.Forexample,Drs.JayjockandDriverbothmentionedusingtheNicasmodel.Inthefinalassessment,EPA/OPPTusedtheNicasmodel(two‐zoneNF/FFmassbalancemodel)thatDrs.JayjockandDriverreferredto;thismodelwasusedtoassessworkplaceexposures(seesections2.3.3and2.4.2,andAppendicesFandGoftherevisedriskassessment).23Anunderstandingofactualworkplacepracticesandtheproportionofworkersexperiencingnearfieldexposuresisimperative.EPA/OPPTshoulduseasensitivityanalysisofsometypetoascertaintheimportantparametersinthemodelusedforworkerexposure.IncollaborationwithOSHA,relevantmonitoringdataspecifictoTCEwasidentifiedandusedintheassessment.AcomparisonbetweentheOSHA’smonitoringdataandthemodeledresultsshowedthattheEPA’sexposureestimateswerein‐linewithdatafromOSHA.Thisadditionalinformationhasbeenincorporatedintotheriskassessment(seesection2.3.3andFigure2‐2ofthefinalriskassessment).EPA/OPPTagreesthatworkplacepracticesinformationcanfurtherrefinetheexposureassessment.However,suchinformationwasnotreadilyavailableandnosuchinformationwassubmittedtoEPA/OPPTduringthereviewandcommentperiod.EPA/OPPTagreesthatperformingasensitivityanalysiscan,insome,butnotallinstances,produceusefulandactionableinsights.Inthisinstance,EPA/OPPThasVersion6/24/1410|Pageadoptedascenario‐basedapproachforitsexposureassessment.TheestimatesfromthisapproachlikelycaptureactualexposurelevelsasevidencedbyOSHAdata.24Itisnotintuitivewhythenumberofmachinesfoundatalargefacility(whichlogicallymightbeexpectedtohavemorethanonemachine)canbetranslatedtosmallnonpointsources(whichlogicallymightbeexpectedtohaveonlyonemachine/facility).Clarificationonthispointwouldbeappreciated.Inthisassessment,EPA/OPPTassumedonedegreasingunitperfacilityforsmallcommercialoperationsbecausesmallerfacilitieswereexpectedtohavelessdegreasingunitsperfacilitythanlargerones.Largefacilitieswereestimatedtohave1.2degreasingunitsperfacility(seesection2.3.3ofthefinalriskassessment).25Forthecommercialdegreasingscenario,Ifoundtheinhalationmodelchoice,modelinputsandtreatmentoftheindustrialinhalationscenariotobewelldonewiththepossibleexceptionofthe“typicalventilation”rate.Theonlyquestionablevariableinmyopinionistheuseof3,000cubicfeetperminute(cfm)asthe“typicalvalue”forgeneralventilationinanindustrialroom.Myexperiencehasbeenthatindustrialroomswithoutspecialexhaustwillbeventilatedinarangeof2to5airchangesperhr.Basedonthisinputandadditionalpublishedsources,EPA/OPPThasadjusteditsrangefortheairexchangeparameterto2to15airexchangesperhrforitsscenario‐basedexposureassessment(seeAppendixGandTableG‐1ofthefinalriskassessment).Version6/24/1411|PageConsumerExposureAssessmentChargequestion3‐1:Pleasecommentontheapproachusedandprovideanyspecificsuggestionsorrecommendationsforalternativeapproaches,models,orinformation(e.g.,informationondurationandnumberofuserevents)thatcouldbeconsideredbytheagencyindevelopingtheexposureassumptionsandestimatesforthehobbyistdegreaserandclearprotectivecoatingsprayuses,andforthebystander/non‐users(e.g.,children,womenofchildbearingage).#SummaryofPeerReviewandPublicCommentsforSpecificIssuesRelatedtoChargeQuestion3‐1EPA/OPPTResponse26PanelistsandthegeneralpubliccommentedontheuseoftheConsumerExposureModel(CEM)tocalculateexposuresfortheconsumerusescenarios.SomecommentersfeltthattheMulti‐ChamberConcentrationandExposureModel(MCCEM)orothermodels(e.g.,Nicas2)shouldbeusedaswell.Somecommentersalsosuggestedtheuseofprobabilisticmethods(e.g.MonteCarlo).Inthefinalassessment,EPA/OPPTretainedthecurrentconsumerexposuremodeltoestimateexposurelevelsfortheresidentialscenarios.TheavailabledataforTCEdidnotsupporttheuseofMCCEMorotherhighertiermodels.Thosemodelsrelyonmorecomplexinputdatatogeneratehumanexposure.Itshouldbenotedthatmanyoftheinhalationmodelsusesimilarcalculationenginestogenerateexposureconcentrations.Forexample,oneofthemainpropertiesdistinguishingMCCEMfromCEMistheabilitytoenterdatafromchamberstudiesintoMCCEMtoreplacetheempiricalmodelusedtogenerateevaporationratesinCEM.Runningadditionalmodelswithoutthesatisfactoryinputdata,whenmanyusesimilar2boxmodelsforthecalculationengines,willnotyieldsignificantimprovementstotheconsumerexposureassessment.ModelslikeNicas2thatincludepersonalbreathingzonecalculationwouldlikelyincreasetheexposuretoconsumersbyaccountingforthehigherairconcentrationsnearusersofaerosolproducts.Thisaddedlevelofdetailmaybeimportantforassessmentswherefurtherrefinementofexposureisneeded,butinthisassessmentriskexistswithoutthemorerefinedNicasmodelforconsumers.Giventhecurrentuncertaintyintheinputparametersandhowcloselytheymaycorrespondtorealuserbehavior,appropriateinputdistributionsarenotavailableforprobabilisticexposuremodeling.Version6/24/1412|Page27Panelistsandthegeneralpubliccommentedontheabsenceofindoormonitoringdatawithintheconsumerexposureassessment.EPA/OPPTdidnotfindmonitoringstudiesrelatedtotheuseofconsumerproductscontainingTCE.Indoorairconcentrationshavebeenaddedtothefinalriskassessmentinsection2.5.4.2andalistofreferencesandconcentrationsisinthesupplementalmaterialentitled“LiteratureReviewofMeasuredTCEConcentrationsinIndoorAir”.TheonlystudiesfoundwerethoserelatedtoTCEexposuresfromvaporintrusionorstudiesrelatedtogeneralhouseholdlevelsofvolatileorganiccompounds(VOCs).ThesestudiesarenotexpectedtorepresenttheconcentrationsthatmayresultduetotheuseofproductscontainingTCEunderthescopeofthisassessment.28Panelistsandthegeneralpublicsuggesteddescribingtheconsumerexposureassessmentasscreeninglevel.APanelistrecommendedusingtheWestatsurveydatatoprovidefurtherinformationonconsumerbehaviorpatternsandthecollectionofmassusedduringproductusedata.Theexposureassessmentisnotatheoreticalboundingassessmentoraworstcaseassessment.Collectionofnewdataormeasurementsisoutsidethescopeoftheworkplanassessmentprocess.TheTCEassessmentdidnotusethescreeninglevelparametersthataresetasthedefaultsintheEFAST2modelingsoftware.Ahypotheticalscenariowascreatedbasedonprofessionaljudgmentduetoalackofconsumerusedatafortheproductsintheassessment.EPA/OPPThasnotfoundaquantitativesourceofconsumeruseinformationfortheseproducts.Thevalueschosenforthehypotheticalconsumerusebehaviorpatternsweremeanttobehighend,butthehouseholdparametersusedinthemodelingweresettomeanormedianvaluese.g.airexchangerate.TheWestatsurveydatahavebeenaddedtothefinalassessmentinAppendixI.Version6/24/1413|Page29Thepubliccommentedonthebackcalculationusedtogenerate24‐hrtimeaveragedexposurenumbersfortheconsumerexposureportionoftheexposureassessment.OnereviewerseemedtothinktheassessmentwasbasedonasinglepeakvaluefromtheCEMrun.TheCEMmodulecalculatespotentialacutedoserates(ADRs)fortheoccupantsofthesimulatedhome.Thisdoserateinvolvessummingthedosesfrommultiplesmallintervalswhicharebasedontheconcentrationofthechemicalinthehomeandthebreathingrateandbodymassoftheuserorabystander.Thebackcalculationremovedtheparametersdescribingthephysicalcharacteristicsoftheusersindifferentagegroups(e.g.breathingrateandbodyweight)fromtheacutedoserateandconvertedittothemeanconcentrationexperiencedbyeithertheuserorabystanderovera24‐hrtimeperiod.TheCEMoutputalsodiscussesapeakconcentrationforthe24‐hrtimeperiod,butthisvaluewasnotusedintheriskassessmentbecauseitonlydescribesasingle10‐secondintervalwithintheentiresimulationandismainlymeantfordoingmodeldiagnostics.AdditionalinformationabouttheconversionofADRstoairconcentrations(ppm)isfoundinAppendixJ.30PeerreviewersandthepublicsubmittedcommentsexpressingconfusionregardinghowCEMcalculatedemissionratesofTCEandonhowmixturesofchemicalsmayaffecttheevaporationrates.CommentersexpressedadesireforfurthertransparencyonthemodelparameterselectionwithinEFASTinthemainbodyofthedocument.IntheabsenceofmeasureddataforemissionofTCEinresidentialsettingsorchamberstudiesfortheselectedproducts,EPA/OPPTusedanempiricalmodeltoestimatetheevaporationratesofsolventsfromasurface.Theemissionrateisbasedonanexponentialdecaymodelandisnotconstantduringtheperiodofuseorthe24‐hrperiodusedtocalculatetheairconcentrationtheoccupantsareexposedto.Furtherexplanationforthiscalculation,theeffectsofmixtures,andinformationonthemodelparametersingeneralhasbeenaddedintheexposuresection2.5andAppendixI.31Commenterswereunsureofthemeaningofsomefateparametersandtheneedforafatesection.Thepersistenceandbioaccumulationscoreswerebasedonaquaticconsiderationsandweremainlypresentaspartofthejustificationfornotperforminganecologicalassessment.AnoverviewoftheenvironmentalfateandreleasesofTCEcanbefoundinthemainbodyofthedocument,particularlysection2.2.TherestoftheinformationhasbeenmovedtoAppendixC.32PeerreviewersrequestedfurtherinformationonthepeerreviewoftheCEMmodel.EPA/OPPThaspostedthepeerreviewdocumentationfortheCEMmodelathttp://www.epa.gov/oppt/exposure/pubs/efastqa.htm.33Peerreviewersrequestedthatthetechnicalpresentationbemorecontiguouswithinthemainbodyofthedocument.Moreinformationontheexposureassessmenthasbeenmovedfromthesupplementarydocumentstothemainbodyoftheriskassessment,inparticularinsection2.5.3.Version6/24/1414|Page34Publicandpeerreviewersrequestedthecollectionofexperimentaldatatoincreasethecertaintyoftheexposureassessment.RequesteddataincludedmassofTCEemittedduringuse,chamberstudydata,personalbreathingzonemonitoring,andindoorairmeasurementstovalidateuserandbystanderexposures.DatacollectionrequestsareoutsidethescopeofOPPTWorkplanchemicalassessmentprocess,whichrelyondataandmodelsthatarecurrentlyavailable.EPA/OPPTrequestedthatoutsidepartiessubmitdatathatwouldinformworkplanchemicalriskassessmentswiththeagency,buttheagencyhasnotreceiveddatathatwouldaugmenttheTCEconsumerexposureassessment.35ApeerreviewersuggestedexpandingtheagelevelforusersoftheTCEconsumerproducts.EPA/OPPTbelievesthatusersoftheseproductswillgenerallybeadults,howeveritispossiblethatteenagersoryoungerchildrenmaybeusersorbeinthesameroomwiththeuserwhileengaginginartsandcraftsprojectsordegreasing.Thecurrentexposureassessmentcanbeexpandedtoallpotentialuseragelevelsbyusingtheindoorairconcentrationsestimatesfortheuseroftheproducts.Dataarenotavailableforanyconsumerusepatterns,sothecurrentestimatedindoorairconcentrationswouldbeappliedtoanyageuser.36PeerreviewerssuggestedthatCEMundergomodelvalidationCEMhasundergoneapeerreviewandsomelimitedvalidation.37Peerreviewersrequestedthatasensitivityanalysisbeperformedfortheexposureassessment.ThemassofproductusedpereventwouldbeahighlysensitiveparameterbasedonprofessionaljudgmentscreatedthroughrepeateduseofCEM.Howeverwhenweighingtherelativeimportanceofotherparameters,itisimportanttorememberthatalloftheconsumerbehaviorpatterninputparametersfortheconsumerbehaviorarehypothetical.Thiscouldleadafullsensitivityanalysistoincorrectlyidentifycertainparametersasbeingmoreimportantthantheywouldbeifsurveydatawereavailablefortheseuses.Forexample,thecurrentassumptionisthattheuserspends2hrsintheroomofuse(i.e.,autilityroom).ThisparameterchoiceleadstoarelativedecreaseintheimportanceoftheemissionrateofTCEtotheroomairsinceaslowerratewouldstillleadtoexposureofalloftheemittedTCE.Thus,asensitivityanalysisofthecurrentparameterswouldperhapsfalselyindicatethattheemissionratefromthesurfaceofusewasrelativelyunimportant.Furtherconsumerbehaviorpatterninformationwouldbeneededbeforeasensitivityanalysiswouldbeuseful,andsuchinformationhasnotbeenidentifiedbyEPA.Version6/24/1415|Page38Apanelmembercommentedthatthemodelrunsmayhavenotcorrectlyusedthedatafromthemostrecentexposurefactorshandbookfortheweightandbreathingratesofthemembersofdifferentagegroups.ThedefaultexposurevaluescitedintheEFAST2documentationandusedinthepublicallyavailablemodelprecededthoserecentlypublishedintheEPA’s2011ExposureFactorsHandbook(EFH).EPA/OPPTdidnotusethedefaultvaluesinEFAST2,butinsteadreliedontheexposurevaluespublishedinEPA’s2011EFH.Thishasbeenclarifiedinsection2.5.3andinAppendixI.39Apanelistcommentedthatproductcompositionswouldvaryovertimeleadingtoinaccuratechronicexposurecalculations.ThechronicexposurenumbersaregeneratedbydefaultinCEMbuttheywerenotusedintheTCEriskassessment.TheyareonlyincludedforcompletenesssincetheyaregeneratedbyCEMforallmodelruns.40Peerreviewersaskedforadeterminationoftheexposedpopulationfromtheseconsumerproducts.EPA/OPPTdidnotfindexposedpopulationdatanorreceivedataduringthepubliccommentperiodforthedraftTCEriskassessmentthatwouldhelpaddressthispoint.Theworkplanassessmentsarebasedonavailabledata.Thisinformationwouldnotaffectthecalculatedexposureconcentrationsforusersandbystanders.Version6/24/1416|PageHazardandDose‐ResponseAssessmentsChargequestion4‐1:Pleasecommentonthestrengthsandweaknessesofevaluatingdifferentendpointsbasedonexposuredurations(i.e.,acuteversuschronic).Chargequestion4‐2:Pleasecommentonthestrengthsandweaknessesofusingmultiplevaluesforeachtypeofadverseeffect.Chargequestion4‐3:PBPKmodelingwasemployedinthe2011IRISassessmentforroute‐to‐routeextrapolationtodevelopacorrespondinginhalationvaluefromoralstudies,someofwhichinvolvedendpointsnotstudiedorreportedininhalationstudies.OPPTsupportstheapproachusedintheIRISassessment.However,OPPTdidnotusePBPK‐derivedhuman‐equivalentconcentrationsfromoralstudiesinthecurrentdraftriskassessment,becauseOPPTfocusedonanarrowsetofTCEconsumeruses(e.g.,degreasingandarts/craftsuses)thataresubjecttoTSCAandtherefore,OPPT’sdraftriskassessmentreliedonlyoninhalationexposurestudiesthatdirectlymimickedinhalationexposureusescenariosforbothadultsanddevelopmentallifestages.Pleasecommentonwhetherthe2011IRISassessment'sPBPK‐derivedinhalationvaluesfromoralstudiesshouldbeusedinthefinalOPPTriskassessment.#SummaryofPeerReviewandPublicCommentsforSpecificIssuesRelatedtoChargeQuestions4‐1,4‐2and4‐3EPA/OPPTResponse41ItwassuggestedthatEPA/OPPTneededtoconductasystematicevaluationofthequalityofeachtoxicologicalstudyusedintheTCEriskassessment.ThefinalTCEOPPTriskassessmentshouldhaveadiscussionofthestudyqualitycriteriausedinthestudyevaluation,aswellasadiscussionofthestrengthsandlimitationsofthestudiesselectedasthebasisforhazardvalues.SomepeerreviewersandpubliccommenterscriticizedEPA/OPPTforusingstudiesthathaddeficienciesandwerenotusedintheIRIS’non‐cancerdose‐responseassessmentforderivingcandidateRfCs.Somepeerreviewersandpubliccommenterssuggestedthattheselectionofthehazardvalueshouldbebasedonthe“best”studythatrepresentsthehealtheffectsdomain(orendpoint)basedontheassessmentofstudyintegrity/quality.This“best”studyshouldbeselectedinsteadofusingarangeofhazardvalueswithinaspecificendpoint.ThefinalTCEriskassessmentreliesonthenon‐cancerandcancerassessmentsthatwerepublishedinthelatestToxicologicalReviewforTCEpreparedbytheU.S.EPA’sIntegratedRiskInformationSystem(IRIS)in2011[alsoreferredastheTCEIRISassessment].TheU.S.EPA’sIRISassessmentrepresentsthelatesthazard/dose‐responseanalysisforTCEthatEPAhascompletedtodate.TheTCEIRISassessmentsusedasystematicweight‐of‐evidence(WOE)approach,thelatestscientificinformationandphysiologically‐basedpharmacokineticmodeling(PBPK)todevelophazardanddose‐responseassessmentsforTCE’scarcinogenicandnon‐carcinogenichealtheffectsresultingfromlifetimeoralorinhalationexposure.Thestrengthsandlimitationsofthedatasetforcancerandnon‐cancereffectscanbefoundintheTCEIRISassessment.DevelopmentofTCE’shazardanddose‐responseassessmentsconsideredtheprinciplessetforthbythevariousriskassessmentguidelinesissuedbytheNationalResearchCouncilandtheU.S.EPA(seeAppendixKofthefinalTCEriskassessment).Primary,peer‐reviewedliteratureidentifiedthroughDecember2010wasalsoincludedwherethatliteraturewasdeterminedtobecriticaltotheassessment.Version6/24/1417|PageOnepeerreviewerrecommendedreviewingthedatasetavailableforeachendpointanddeterminingwhetherthedataareadequatetodescribethequalitativeanddose‐responseelementsoftheendpoint.TheTCEIRISassessmentidentifiedthemostsuitablenon‐cancerstudiesfordose‐responseanalysisbyhealtheffectsdomain(i.e.,livertoxicity,kidneytoxicity,neurotoxicity,immunotoxicity,reproductivetoxicity,anddevelopmentaltoxicity).AlistofthesestudiesarefoundinAppendixLofthefinalTCEOPPTriskassessment.EPA/OPPTreliedonthestudieswiththelowesthazardvalues(i.e.,humanequivalentconcentrationorHECs)toestimateacuteorchronicnon‐cancerrisksforthespecificTCEuses(seesection2.6.1.2.2andTable2‐18inthefinalTCEOPPTassessment).42ThedraftriskassessmentdidnotprovideinformationabouthowthePBPKmodelingwasusedtodevelopthenon‐cancerhazardvalues(i.e.,HECs).EPA/OPPTaddednewlanguageintheriskassessmentexplainingthePBPKmodelingapproachandHECderivation.Theinformationispresentedinsections2.6.1.2.2and2.6.1.4.AcomprehensivediscussionoftheTCEPBPKmodelcanbefoundintheTCEIRISassessment.43EPA/OPPTshouldusebothinhalationandoralstudiesthattheTCEIRISassessmentevaluatedwhenderivingtheinhalationRfC.TheTCEIRISassessmentusedphysiologically‐basedpharmacokinetic(PBPK)modelingtodoroute‐to‐routeextrapolation.ThefinalTCEOPPTriskassessmentusedtheoralandinhalationstudiesthattheTCEIRISassessmentevaluatedinthenon‐cancerdose‐responseanalysis.EPA/OPPTreliedonthepointofdepartures(PODs)thattheTCEIRISassessmentidentifiedforthemostsuitablestudiesfordose‐responseanalysis.ThePODswerecategorizedbyhealtheffectsdomains(i.e.,livertoxicity,kidneytoxicity,neurotoxicity,immunotoxicity,reproductivetoxicity,anddevelopmentaltoxicity).ThesestudiesarelistedinAppendixLofthefinalTCEOPPTriskassessment.Thestudieswiththelowesthazardvalues(i.e.,humanequivalentconcentrationorHECs)wereusedtoestimateacuteorchronicnon‐cancerrisksforthespecificTCEuses(seesection2.6.1.2.2andTable2‐18inthefinalTCEOPPTassessment).44Somepanelistsandpubliccommentersindicatedthatthedevelopmentaltoxicitystudiescannotbeusedtoderivehazardvaluesforsingleexposures.ThedevelopmentaltoxicitystudiesreportedadverseeffectsthatresultedfromrepeatedexposurestoTCEandthustheyshouldnotbeusedtoestimateacuterisks.Inaddition,therewerealsopublicandpeerreviewcommentsobjectingtotheuseofthedevelopmentaltoxicitystudiesbyJohnsonetal.(2003,2005)forestimatingacuteorchronicnon‐cancerrisksduetomethodologicalandreplicabilityissues.EPA/OPPTuseddevelopmentaltoxicitydatatoevaluatethenon‐cancerrisksofacuteexposuresbasedonEPA’slongstandingpolicythatasingleexposurewithinacriticalwindowofdevelopmentmayinducedevelopmentaleffects,asdiscussedintheEPA’sGuidelinesforDevelopmentalToxicityRiskAssessment(http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=23162).EPA/OPPTacknowledgesthatthisisahealth‐protectivepolicythatmayoverestimatetheacuterisks.Developmentaleffects,includingfetalcardiacdefects,mayoccurfollowingmaternalexposuretoTCE.Chickembryoandoraldevelopmentalstudies,includingthosereportedbytheJohnsonetal.studies(seelistofreferencesbelow),havereportedcardiacmalformationsafterexposuretoTCE.TheVersion6/24/1418|PageincidenceofcongenitalcardiacmalformationhasbeenreplicatedinseveralstudiesfromthesamelaboratorygroupandhasbeenshowntobeTCE‐related.Moreover,studieswithTCEmetaboliteshavealsoinducedcardiacdefectsindevelopmentaloraltoxicitystudies.Arecenterratum(Johnson,2014)andsubsequentevaluationofthedevelopmentaltoxicitydatareaffirmedthattheJohnsonetal.studiesareadequatetouseinhazardidentificationanddose‐responseassessment(AppendixN).AsexplainedintheTCEIRISassessment,whiletheJohnsonetal.studieshavelimitations,thereisinsufficientreasontodismisstheirfindings,especiallywhenthefindingsareanalyzedincombinationwithhuman,animalandmechanisticevidence.AsummaryoftheweightofevidencesupportingTCE‐relatedfetalcardiacdefectsisprovidedinsection2.6.2.3.6andAppendixNofthefinalTCEOPPTriskassessment.ThecomprehensiveWOEevaluationofthedevelopmentaltoxicitydata,includingfetalcardiacteratogenesis,isdiscussedintheTCEIRISassessmentandexpandedinthisassessment(AppendixN).Thus,EPA/OPPThasincorporatedtheJohnsonetal.studiesinthefinalriskassessment(seeTables2‐18,2‐31to2‐35;sections2.7.2and2.7.3.2).Citations:Dawson,B.,P.Johnson,S.Goldberg,andJ.Ulreich.1990.CardiacTeratogenesisofTrichloroethyleneandDichloroethyleneinaMammalianModel.JournaloftheAmericanCollegeofCardiology,16(5),1304‐1309.(ascitedinEPA,2011e).Dawson,B.,P.Johnson,S.Goldberg,andJ.Ulreich.1993.CardiacTeratogenesisofHalogenatedHydrocarbon‐ContaminatedDrinkingWater.JournaloftheAmericanCollegeofCardiology,21(6),1466‐1472.(ascitedinEPA,2011e).Johnson,P.,S.Goldberg,S.Mays,andB.Dawson.2005.Correction:ThresholdofTrichloroethyleneContaminationinMaternalDrinkingWatersAffectingFetalHeartDevelopmentintheRat.EnvironmentalHealthPerspectives,113,A18.(ascitedinEPA,2011e).Johnson,P.D.2014.Erratum:ErratumforJohnsonEtAl.[EnvironHealthPerspect113:A18(2005)].EnvironmentalHealthPerspectives,10.1289/ehp.122‐A94.Version6/24/1419|PageJohnson,P.D.,S.J.Goldberg,M.Z.Mays,andB.V.Dawson.2003.ThresholdofTrichloroethyleneContaminationinMaternalDrinkingWatersAffectingFetalHeartDevelopmentintheRat.EnvironmentalHealthPerspectives,111(3),289‐292.(ascitedinEPA,2011e).45PBPK‐derivedHECsfromdevelopmentaltoxicitystudiesshouldnotbeusedintheOPPT’sriskassessmentofTCE.TheTCEPBPKmodeldoesnotmodelpregnancyorgestationandassuchtheinternaldosesarebasedondose‐metricsthatarenotconsideringdevelopmentaleffectsinthefetus.Typicallytheplacentaisexpectedtolowerexposuretothefetusby2to10‐fold.Sinceakeyconcernisdevelopmentaltoxicity,thatshouldbeconsidered.Comparisonofbenchmarksderivedfromoralandinhalationroutescanprovideusefulinsight.TheTCEPBPKmodeldidnotincorporateapregnancycompartmentinthemodeltoestimatetheinternaldoseofTCEinthedevelopingfetus.Thematernaldosemetricwasusedassurrogateforthefetalinternaldose.Thisassumptionhasbeennotedinsection2.6.1.4andTable2‐23ofthefinalTCEOPPTriskassessment.Also,theuncertaintiesrelatedtousingmaternaldose‐metricsforthedevelopingfetushavebeendiscussedinsection2.8.2.2oftheTCEOPPTriskassessment.46EPA/OPPTinappropriatelyusestheHealyetal.(1982)studyfortheacuteinhalationexposures,astheHealyetalstudydoesnotreportdose‐responsedata.TheTCEIRISassessmentidentifiedHealyetal.(1987)asoneofthecriticaldevelopmentaltoxicitystudies(seeAppendixLofthefinalTCEOPPTriskassessment).AmongallofthedevelopmentaltoxicitystudieslistedinAppendixL,EPA/OPPTselectedthestudyreportingthelowesthazardvalue(i.e.,HEC),whichinthiscasewastheJohnsonetal.(2003)studyandnotHealyetal.1982.47PeerreviewersnotedthattheForandetal.(2012)studywascitedintheEPA’spresentationtotheTCEpeerreviewpanelasasupportingstudyfortheassociationbetweenTCEexposureandfetalcardiacmalformationsinhumans.Twopanelistsrequestedtoreviewthestudy.Oneofthereviewersrequestedtodoareviewbyanindependentscientist.TheForandetal.,(2012)isasmallretrospectivecohortstudyof1,440livebirthsamongNewYorkresidentsinaTCEcontaminatedareaviavaporintrusion.ThestudyprovidesevidenceforanassociationbetweenmaternalexposuretoTCEandcardiacdefects.Thestudyobservedanelevatedriskestimateforcardiacdefects(adjustedrateratiosof2.15;95%confidenceinterval:1.27‐3.62)andconotruncaldefectscomparedtonoexposure(adjustedraterationof4.91;95%confidenceinternal:1.58‐15.24).EPAconductedaninternalreviewoftheForandetal.studyandconcludedthatthestudyfindingswereconsistentwithotherhumanepidemiologicaldatathathaveobservedcardiacmalformationsinchildrenexposedprenatallytoTCE.EPA/OPPTincorporatedabriefsummaryofthestudyanditsfindingsinsection2.6.2.3.6ofthefinalTCEOPPTriskassessment.Section2.6.2.3.6alsoprovidesasummaryofthehumandatasupportingtheeffectsintheheartfollowingprenatalexposuretoTCEaswellasasummaryoftheweight‐of‐evidenceanalysissupportingtheassociationbetweenTCEexposureandfetalcardiacVersion6/24/1420|Pageteratogenesis.AppendixNcontainstheweight‐of‐evidenceanalysisforfetalcardiacmalformationsfollowingTCEexposure.Citation:Forand,SP;Lewis‐Michl,EL;Gomez,MI.(2012).AdversebirthoutcomesandmaternalexposuretotrichloroethyleneandtetrachloroethylenethroughsoilvaporintrusioninNewYorkState.EnvironHealthPerspect120:616‐621.48TheselectionoftheHEC99forthedose‐responseassessmentisoverlyconservative.EPA/OPPTshouldexploreusinganotherHECatadifferentpercentile.SeveralpanelistsindicatedthatthedocumentdidnotarticulatewhytheHEC99wasthebestchoicecomparedtoothervaluesatdifferentpercentiles.ThepanelistsalsocouldnotunderstandtheuncertaintyaroundthechosenHECandtheappropriatenessofthelowerbound99thpercentileacrossthevariousdose‐responserelationshipsconsidered.EPA/OPPTusedtheHEC50,HEC95orHEC99estimatesreportedintheTCEIRISassessment,whichrepresentthe50th,95thor95thpercentileofthecombineduncertaintyandvariabilitydistributionofhumaninternaldoses,respectively.TheHEC50wasinterpretedasbeingtheconcentrationofTCEinairforwhichthereis50%likelihoodthatarandomlyselectedindividualwillhaveaninternaldoselessthanorequaltotheinternaldosePOD(idPOD)fromtherodentstudy.TheHEC95andHEC99wereinterpretedasbeingtheconcentrationsofTCEinairforwhichthereis95%and99%likelihood,respectively,thatarandomlyselectedindividualwillhaveaninternaldoselessthanorequaltotheidPODderivedfromtherodentstudy.TheTCEIRISassessmentpreferredtheHEC99forthenon‐cancerdose‐responseanalysisbecausetheHEC99wasinterpretedtobeprotectiveforasensitiveindividual.EPA/OPPTsupportedtheinterpretationoftheHEC99asexpressedintheTCEIRISassessment.Hence,HEC99‐basedriskestimatesarefavoredinthisassessmentoverthoseestimatedfromtheHEC50andHEC95values.Despitethispreference,theOPPT’sriskassessmentalsoincludesriskestimatesbasedontheHEC50andHEC95valuestoprovideasenseofthedifferencebetweenthemedian,the95%and99%confidenceboundforthecombineduncertaintyandvariability.CalculationsofHEC50/95andHEC50/99ratiosgenerallyshoweda2‐3folddifferenceforthevariousstudiesidentifiedinTable2‐18.Theexceptionwasthestudyreportingkidneyeffects(NTP,1998)thatshowedhigherHEC50/95andHEC50/99ratios(i.e.,5‐9‐fold)duetouncertaintiesintherodentinternaldoseestimates.Incontrast,HEC95valuesweresimilartoHEC99valueswithHEC95/99ratiosshowinga1.3‐1.5folddifference.Section2.6.1.4describestherangeofHECpercentilesusedintheTCEOPPTriskassessmentaswellastheratiocomparisonamongtheHECsatspecificpercentilevalues.Sections2.7.2and2.7.3.2presenttheacuteandchronicnon‐cancerriskestimates,respectively,fortherangeofHECpercentiles.Version6/24/1421|PageCitation:NTP(NationalToxicologyProgram).1988.ToxicologyandCarcinogenesisStudiesofTrichloroethylene(CASNo.79‐01‐6)inFourStrainsofRats(ACI,August,Marshall,Osborne‐Mendel‐‐GavageStudies).U.S.DepartmentofHealthandHumanServices,PublicHealthService,NationalInstitutesofHealth,ResearchTrianglePark,NC.(ascitedinEPA,2011e).49HEC99valuesarequestionablesincetheyare2to10,000‐foldlowerthanthecorrespondingPODvalue.WhenthedifferencebetweenthebenchmarkfromananimalstudyandtheHEC99is>100itsuggeststhatadditionalUFsarenotnecessary.Moreover,differencesof1000‐foldormorecallintoquestiontheunderlyingassumptionsthatproducedthesehypotheticaldifferences.Forexample,whenendpointsaresimilar(neurotoxicityorreproductivetoxicity)foranimalsandhumans,theratioofPODtoHECare<100‐foldbetweenspecies.SowhatunderlyingassumptionsmaketheratioofBMDLtoHEC99>10,000forkidneyeffects?EPA/OPPTdisagreeswiththewaytheHEC99valueswerecomparedwiththeanimalPODvalues.TheTCEPBPKmodelpredictedhumanequivalentconcentration(HEC)thatwouldbeexpectedtoinducethesamemagnitudeoftoxiceffectastheexperimentalanimalspeciesconcentrationbasedoninternaldosemetricsatthetargettissue.Ontheotherhand,theanimalPODistheexternalairconcentrationofTCEobtainedfromtheanimalstudythatmarksthebeginningofalow‐doseextrapolationinthenon‐cancerdose‐responseanalysis.Thus,itisnotappropriatetocomparetheanimalPODwiththeHECsatdifferentpercentilesbecausetheHECsarebasedonmeasuresofinternaldoseextrapolatedfromrodenttohumans,whereastheanimalPODisonlybasedontheexternalairconcentration.50EPA/OPPTinappropriatelyusedtheHEC99tosupportexcludingdermalexposures.SeveralpanelistscriticizedthattheHEC“canprovideacounterweighttonotconsideringdermalexposure.”EPA/OPPTdeletedthisargumentfromthefinalriskassessment.Also,notethatthePBPKmodelforTCElacksadermalcompartmentthatwouldfacilitatedermalriskestimationviaroute‐to‐routeextrapolationoraggregateriskofdermalandinhalationexposures.51Neurotoxicendpointsshouldbeusedwhenevaluatingthechronicrisksattheworkplacesetting.Theoccupationalriskswereassessedusingrenal,immuneandreproductiveendpoints.Neurotoxicitywasnotincluded.EPA/OPPTagreeswiththiscomment.Inclusionoftheneurotoxicityendpointforchronicnon‐cancerriskestimationispresentedinsection2.7.3.2.EPA/OPPTalsoconsideredotherendpoints(i.e.,developmentaltoxicity,kidney,immunotoxicity,reproductivetoxicity,livertoxicity)whenassessingtheoccupationalnon‐cancerrisksofTCEexposures.52EPA/OPPTincorrectlydescribedTCEasa“probablehumancarcinogen”.EPA/OPPTagreeswiththiscomment.TheU.S.EPA’sIRISprogramhasclassifiedTCEasahumancarcinogenbyallroutes.Thecorrectclassificationappearsinsections1.3.4and2.6.1.2.1ofthefinalTCEOPPTriskassessment.53EPA/OPPTdidnotprovideempiricaldatasupportingtheassumptionthatminimalbuildupofTCEwouldbeexpectedThisassumptionwassupportedbyPBPKsimulationspresentedinTables2‐24and2‐25.Inthesesimulations,theTCEPBPKmodelwasusedtoestimateHECsatthe50thand99thpercentileforthecardiacmalformationendpointunderVersion6/24/1422|PageinhumansexposedtoTCEinanintermittentbasisbasedonproductusageassumptions.chronic(steady‐state)orintermittent(occupational)exposuretoTCEunderdifferentexposuredurations(i.e.,1day,3weeks,9months,chronic).The1‐dayHECatthe50thand99thpercentiledidnotshowsignificantvariationwhencomparedtotheHECsfortheotherexposuredurations(i.e.,3weeksand9months)undercontinuousandintermittedexposurestoTCE.Thus,theresultsfromthePBPKsimulationsshowedthattheassumption(i.e.,nosubstantialbuildupofTCEinthebodybetweenexposureevents)isreasonabletouseinthefinalTCEOPPTriskassessment.Thisexplanationhasbeenincorporatedinsection2.6.1.4ofthefinalriskassessment.54EPA/OPPTdidnotdiscussthephysiologicalTCElevelsassociatedwiththeacuteexposuresassessedinthedocument.TheTCEPBPKmodelcanbeusedtoestimatetheinternaldosesofTCE(“physiologicalTCElevels)associatedwiththeacuteexposuresofTCEuseswithinthescopeoftheOPPTriskassessment.Themodelalreadyintegratedtheinternaldoseswhencalculatingthe24‐hrhumanequivalentconcentrations(HECs)forspecifichealtheffectsdomains.EPA/OPPTusedthe24hr‐HECs(HEC50,HEC95,orHEC99)fordevelopmentaleffectstoestimateacuterisksbycomparingtheHECswiththeacuteexposureconcentrationsestimatedintheconsumerexposureassessment(i.e.,24‐hrexposurelevels).55EPA/OPPTincorrectlyadjustedtheexposuredurationandfrequencyforthehazardvalues.Thisresultedinhazardvaluesthatdidnotmatchtheexposureofthepersonsforwhomtheassessmentwasbeingconducted.Selectionoftheappropriatetime‐averagingperiod,relevanttoeachendpointselectedfromreliablestudiesiscriticallyimportantfordecidingwhatexposure(absorbeddose)metricshouldbeusedforriskestimatederivation.Forexample,thePODhazardvalueswereadjustedintheIRISprogramtocontinuousexposure(i.e.,24‐hrHECs).Thus,workerexposureestimatesneedtobeadjustedfrom8‐hrto24‐hrestimates.Forchronicrisks,thedailyexposureshouldbeputintoanannual(chronic)averageexposureandcomparedtothechronichazardbenchmark.Also,neurotoxicityanddevelopmentaltoxicityendpointsmay,ormaynotbeappropriateforcomparisontoacute/EPA/OPPTused24‐hrexposureestimatestoestimateacuteorchronicrisksandmadetimeadjustmentstotheexposureestimates,whennecessary,tomatchthemwiththe24‐hrHECs.Forinstance,the8‐hrworkerexposureestimateswereadjustedto24hrsforacuteexposures.Averagedailyconcentrations(ADCs)orlifetimeaveragedailyconcentrations(LADCs)wereestimatedandusedforthenon‐cancerorcancerchronicriskcalculations,respectively.NotethattheconsumerexposureestimatesforTCEwerenotadjustedbecausetheywereexpressedas24‐hrtimeaveragedindoorairconcentrations.Sections2.3.3and2.4.2ofthefinalTCEOPPTriskassessmentpresenttheequationsthatwereusedtoadjusttheworkerestimatesto24‐hrs.ThefinalTCEOPPTriskassessmentconsideredthebodyofdevelopmentaltoxicitydata,includingtherecentdevelopmentalneurotoxicitystudies(Blossometal.2012and2013),butonlyestimatedacuterisksfordevelopmentaleffectsbasedonthecardiacdefectfindingsreportedbytheJohnsonstudies(seecomment#44).AcuterisksforneurotoxiceffectsasreportedbyAritoetal.(1994)weredroppedinthefinalassessmentbecausetheneurotoxicityinhalationstudydidnotinvolveanacute/short‐termexposuretoTCE.Forinstance,Aritoetal.(1994)exposedratstoTCEfor8hrs/day,5daysperweekfor6weeks.Version6/24/1423|Pagepeakpotentialinhalationexposure/doseestimates,dependingonthetimetoeffect.Althoughdevelopmentaltoxicitystudiesareofarepeat‐dosenature,EPA’spolicyisthatasingleexposurewithinacriticalwindowofdevelopmentmayinducedevelopmentaleffects.EPA/OPPTacknowledgesthatthisisahealth‐protectivepolicythatmayoverestimatetheacuterisks.Seecomment#44forfurtherinformationabouttheselectionoffetalcardiacdefectsasthepreferredendpointfortheacuteriskestimates.Citations:Arito,H.,M.Takahashi,andT.Ishikawa.1994.EffectofSubchronicInhalationExposuretoLow‐LevelTrichloroethyleneonHeartRateandWakefulness‐SleepinFreelyMovingRats.SangyoIgaku/JapaneseJournalofIndustrialHealth(Japan),36(1),1‐8.(ascitedin2011TCEIRISassessment).Blossom,S.J.,S.Melnyk,C.A.Cooney,K.M.Gilbert,andS.J.James.2012.PostnatalExposuretoTrichloroethyleneAltersGlutathioneRedoxHomeostasis,MethylationPotential,andNeurotrophinExpressionintheMouseHippocampus.Neurotoxicology,33(6),1518‐1527.Blossom,S.J.,C.A.Cooney,S.B.Melnyk,J.L.Rau,C.J.Swearingen,andW.D.Wessinger.2013.MetabolicChangesandDNAHypomethylationinCerebellumAreAssociatedwithBehavioralAlterationsinMiceExposedtoTrichloroethylenePostnatally.ToxicologyandAppliedPharmacology,269(3),263‐269.Johnson,P.D.,S.J.Goldberg,M.Z.Mays,andB.V.Dawson.2003.ThresholdofTrichloroethyleneContaminationinMaternalDrinkingWatersAffectingFetalHeartDevelopmentintheRat.EnvironmentalHealthPerspectives,111(3),289‐292.(ascitedin2011TCEIRISassessment).Version6/24/1424|PageRiskCharacterizationChargequestion5‐1:PleasecommentonthestrengthsandweaknessesoftheMOEapproachusedtoestimatethechronic,non‐cancerriskfortheworkplaceexposures;includingnon‐users.Chargequestion5‐2:PleasecommentonthestrengthsandweaknessesoftheMOEapproachusedtoestimatetheacuterisktoconsumers;includingnon‐users(e.g.,children,womenofchildbearingage).Specifically,pleasecommentonthedecisiontolimittheanalysistoacuteexposureswithoutresidualconcernbetweenevents(i.e.,once/weekforusersoftheclearprotectivecoatingspray,andtwice/monthfordegreaserusers).Chargequestion5‐3:PleasecommentontheuseofauniformbenchmarkMOEof30ratherthanabenchmarkMOEequaltothecompositeUncertaintyFactorsforeachstudyasidentifiedinthe2011USEPAIRISassessmentforTCE.#SummaryofPeerReviewandPublicCommentsforSpecificIssuesRelatedtoChargeQuestions5‐1,5‐2,and5‐3EPA/OPPTResponse56Somepeerreviewersandpubliccommenterssuggestedusingtheendpoint/study‐specificuncertaintyfactors(UFs)reportedintheTCEIRISassessmentasthebenchmarkMOE.SomepeerreviewandpubliccommentsnotedthattheUFsassociatedwiththePBPK‐derivedHEC99werenotappropriate.OnereviewersaidthattheUFsassociatedwiththePBPK‐derivedHEC99mustberevisedforacuteexposures.EPA/OPPTrevisedthebenchmarkMOEstoreflecttheendpoint/study‐specificUFsidentifiedintheIRISassessmentforthePBPK‐derivedhazardvaluesassociatedwithspecificnon‐cancereffectsdomains.Table2‐18showstheendpoint/study‐specificUFsbystudy/effectsdomainthatEPA/OPPTusedasbenchmarkMOEsfortheacuteandchronicnon‐cancerriskcalculations.57EPA/OPPTprovidedaninadequateexplanationfornotusingtheRfCvaluesandhazardquotients(HQ)calculationsintheEPA/OPPTdraftriskassessmentforTCE.EPA/OPPTusedmarginofexposures(MOEs)topresentarangeofriskestimatesfordifferentadverseendpointsidentifiedtoberelevantfordifferentexposurescenarios.Forthisreason,MOEswereselectedoverasingleHQriskestimatebasedontheinhalationRfC.TheIRISRfCisgenerallyapplicableforchronicexposures,althoughcanbeusedforless‐than‐chronicexposureundercertaincircumstances.Thisissuewasdiscussedinsection2.6.1.2.2oftheTCEOPPTriskassessment.58EPA/OPPTusedariskmetric(i.e.,MOEs)thatdidnotaccountfordifferencesthatoccurinsusceptibilitybetweenhumansandanimalsnorwithinanimalsorhumans.ThedifferencesbetweenhumanandanimalsorwithinanimalorhumanswerecapturedintheUFsthatwereusedasthebenchmarkMOE.Dependingonthestudy/endpoint,avarietyofUFswereused(Section2.7.1):InterspeciesUFIntraspeciesUFVersion6/24/1425|PageSubchronictochronicUFLOAELtoNOAELUF;59Peerreviewandpubliccommentscriticizedthecancerrisklevelof1x10‐5thattheassessmentusedtointerpretthecancerrisksandsuggestedtouse1x10‐4.EPA/OPPTreportedtheoccupationalcancerrisksforthreebenchmarklevelsfordifferentscenariosanduses:1x10‐4,1x10‐5,and1x10‐6(seesection2.7.3.1andFigures2‐6and2‐7).60TheMOEapproachdoesnotquantitativelycharacterizetheuncertaintyintheestimatedrisk.ThefactthattheMOEisreducedtotheuseoftwonumbers,thehazardvalueandtheexposurevalue,regardlessofhowtheywereobtained,doesnotprovideaquantitativeassessmentofhowmuchwecanrelyonthatestimatedrisk.Thisissuecouldbeaddressed,byincorporatingintheMOEametrictocharacterizetheuncertaintyinthehazardvalueand/ortheexposurevalue,forinstancecalculatingtheMOEwithdifferentpossiblevaluesofboth,thehazardandtheexposure,underdifferentscenariostounderstandtheimpactintheobtainedMOE.AnempiricalvarianceoftheMOEwouldexplainhowvariabletheMOEwouldbe,andsensitivityanalysiswouldexplainhowsensitivetheMOEistohowtheexposureandthehazardareobtainedunderdifferentscenariosofinterest.ComparingtheMOEtojustabenchmarknumber,30inthiscase,isquestionable,inparticularwhenthereisnoassessmentofthevariabilityanduncertaintyintheMOE.ThecommentisimplyingthatEPA/OPPTshouldconductaprobabilisticriskassessment.EPA/OPPTfocusedonfeasiblerefinementstotheexposureandhazard/dose‐responseassessmentbasedontheavailabledataandresources.Thus,aprobabilisticriskassessmentwasnotdeveloped.Thefinalriskassessmentestimatesnon‐cancerrisksforvarioushealtheffectsendpointsbasedonthePBPK‐derivedhazardvalues(HEC50,HEC95,HEC99).TheseHECscapturedthe50th,95thor95thpercentileofthecombineduncertaintyandvariabilitydistributionofhumaninternaldoses,respectively.Seecomment#48Chargequestion5‐4:PleasecommentonwhetherthedocumenthasadequatelydescribedtheuncertaintiesanddatalimitationsinthemethodologyusedtoassessriskstoallowtheEPAtoreduceriskstohumanhealthfromTCE.Pleasecommentonwhetherthisinformationispresentedinatransparentmanner.#SummaryofPeerReviewandPublicCommentsforSpecificIssuesRelatedtoChargeQuestion5‐4EPA/OPPTResponse61HowcanonehaveconfidenceinEPA’sestimatesforoccupationalexposures?EPAdidnotreferencemonitoringdatatovalidateitsexposureestimatesresultingfromtheuseofTCEincommercialdegreasingprocesses.IncollaborationwithOSHA,relevantmonitoringdataspecifictoTCEwasidentified.EPA/OPPTincorporatedthisadditionalinformationinsection2.3.3ofthefinalriskassessment.62EPA/OPPThasnotadequatelydescribeddatalimitationsanduncertaintiesassociatedtotheexposure,hazard/doseresponse,andriskcharacterizationassessments.InEPA/OPPThasexpandeduponandfurtherrefinedtheUncertaintyandDataLimitationssection.Seesection2.8ofthefinalTCEOPPTriskassessment.Version6/24/1426|Pageaddition,variabilityanduncertaintyweretreatedthesameinsomeofthediscussionintheUncertaintysection.Version6/24/1427|PageOtherPublicComments#SummaryofOtherPublicCommentsEPA/OPPTResponse63PubliccommentersindicatedthatEPAisadequatelyregulatingTCEundertheCleanAirAct(CAA).Doesthatpertaintotheexposurescenariosdescribedintheassessment?AppendixBofthefinalriskassessmentprovidesasummaryoftheregulatoryhistoryofTCEintheU.S.EPA,includingregulationsunderCAA.TheNationalEmissionStandardsforHazardousAirPollutants(NESHAP)areanexampleofsuchregulationunderCAA.OPPT’sriskassessmenttookNESHAPemissionlimitsintoaccountandcharacterizedhumanhealthrisksforspecificTCEusescoveredundertheToxicSubstancesControlAct(TSCA).64Itwasstatedthattheassessmentwasbasedonexposuredatathatpredatedregulationsonvapordegreasing.Isthistrue?Ifso,howwouldmorerecentvaluesaffecttheriskassessment?EPA/OPPT’sexposureassessmentforvapordegreasingwasbasedonrecentdatafromthe2008NationalEmissionsInventory(NEI)andthe2012ToxicsReleaseInventory(TRI).Further,EPA/OPPTupdateditsriskassessmenttotakeNESHAPemissionlimitsintoaccount.65SomepubliccommentscriticizedEPA/OPPTforusingmodeledratherthanmeasuredexposuredata.EPA/OPPTacknowledgesthatitisnotalwayspossibletouseonlymeasureddataforthepurposesofriskassessmentandthatvalidatedmodelscanalsobeusedforthepurposesofestimatingpotentialexposures.