Document pp8nq7xzbGNa4X1k95vwVv1DB

February 11,2005 Dr. Sue Shallal DU.eSs.igEnnavtierdonFemdeenrtaallOPfrfoitceecrtion Agency, Science Advisory Board (1400F) 1200 Pennsylvania Avenue, NW `Washington, D.C. 20460 Submitted via hand delivery and e-mail Re: Docket OPPT docket 2002-0001 Dear Dr. Shallal: TAhdvainskoryyouBofoarrdthCeoompmpiortttueneitcyontsoipdreorviindgeEtPhAe'ssedcroamftmernistksafsosrersesvmieenwt fboyrtPhFeOEAP.A S1cwioeunlced appreciate your circulating this letter to SAB member as soon as possible. TPhFeOseAcdoatmamseetntasndresfulbecmtitmytheoswenccoomnmcelunstisonbse,cabuutseI Inohtaevfeorbteheen ernecgoargdedthfator|aanmufmabmeilrioafryewiatrhstthoe rfiennddienrgsi.nd1epaemndaencot-aaduvtihcoer toofa3MpeeCro-mrpevaineywerde,gpaurbdlinigshietsd frlisukoraoscsheesmsimceanltrfeosreaPrFchOpAr(oBgurtaemnhaonfdf, etal, "CharacterizationofRisk for General Population Exposure to Perfluorooctanoate," Regulatory Toxicology and Pharmacology 39: 363-380, 2004)." Iwould like to comment on three topics posed for consideration by the SAB panel: 1. MOE Approach and Useof Internal Dose Comparison bEyPAdivhiadsinugsetdhethseermuamrgPinFoOfAexlpevoesluirnee(xMpeOrEi)meanptaplroaancihmatloschaatrtahceteNrOizAeEthLe oportLenOtiAaEl Lhebalythther.isk cwohrertehseproonrdinnogtPadFvOerAseleevfeflecstesenarienlhiukemlaynst.o ocTchuermianghnuimtaundes o--tfhtehelMarOgeEr tghieveMsOaEn,intdhieclaetsisonthoef piostkenatsisalesrsimskeonft (adUvSeErsPeAe2f0fe0t3s).anTdheisMapOpEroparpipartoeafcohriasscsoensssiisntgentthewriitshkscoufrrPenFtOAE.PA guidance on `The draft assessment uses serum PFOA level as the measureof dose for interspecies comparison rather than the traditional administered dose. As is widely recognized, use of an internal dose measure eliminates oneof the major uncertainties in interspecies comparisons andL1amhavecoo-vFeorun3d0eyr ofeEoNfaeVxIpeRrrOiNesncIneteirnnattoixoincaollCoogrypaonrdatriiosnk,anahleysailst.h aPnrdioertnvoirmoynmceonntsaulltsicnigenccaerseecro,n1supletritng1f5im, `Syceiaernscwei.th thhaeveFosoedrvaenddoDnrouvgerAdtmwiennitsytrBaotairodn,s faonrdtChoemlmasittttheeeesoyfeatrhseaNsatDieopnuatlyAAcsasodceimaytoefCSocmimeinscseisonaenrd ftohre Insitute of Medicine, and serve as Visiting Professor at Johns Hopkins Universit School ofPublic Health. 4350 NothFanfxDrive Sic 300 - Aingionr , Virgi-- nia 222-- 03 USA Tl (703)316-2300 Fax (703) 316.2345 Dr. Sue Shallal Page2o0f4 February 11,2005 Designated Federal Officer Trihsek aussseoesfsmseuncth,abnotihntfeorrnaclardcoisneomgeenassu(rUeSiEsPenAd2o0r0s3e)d,bayndthfeorAgneonnc-yc'asrcoiwnongleantses(tUgSuiEdPaAnc2e0f0o2r) : `eWnhviilreoncmoemnptaarliscohnesmoicfablls,oobdeclaeuveslesobfetthweereanrihtuy moafnssucahnddaatnaifmoarltshiensethtiyspwesaoyfcihs enmoitctaylpisc,alitfiosr `focrocmamrocninfoogrenpihcairtmyacsetuutdiiceaslosf.phFaorrmeaxceaumtpilcea,ltsh(eFpDroAce1d9u9r5)e.is cWohmemnonblloyodusleedveflosrasreettaivnagildaobsleesin hmeutmaabnosliasnmdoafnitmhaelcsh,eemsipceacli,alilnytewmhaelndothseerecoamrepanroiscoonmsplairceatthieonpsredfueerrteodsmpeetciheosdodilfofgeyrebnecceasuisne they reduce uncertainty in the overall risk assessment. BreeacsaounsaeblPyFwOelAl duonedsernsottooudn,desregroummePtFabOoAlipsrmo,vaindedsotthheermoassptecatpsproofprtisatpehamremaascuorkeinoeftidcossearfeor interspecies comparisons. | urge the SAB to fully support EPA's approach. 2. Uncertainty Factor for Interspecies Extrapolation AStamta,jiosrtahdatvaitntraegdueocfetshoreeulsiemoinfaatnesitnhteerunnalcemretaaisnutryeoasfsodcoisaet,edsuwcihthasthseeproutmenPtiFaOl Atoxaticsotkeiandeytic differences between species, which comprise a portionof the interspecies uncertainty factor normally used in risk assessment. "pTohretidoenfsa:ulotneinatdedrsrpeescsiiensgutnocxeirctoakiinnteytifcasc,toarndofon10e iasdcdornessisdiengretdotxoicboedcyonmapmriicsse(dRoefnwtiwcokeaqunadl-sized Lazarus 1998). Several for toxicokinetic aspect considerations of interspecies elxetardatpooltahteiocnonccalnusjuisotniftihaabtlythbeesrteandduacredd uncertainty for PFOA. factor It ndootesneneotd utondbeeragcocmoeutnatbeodlifocr.coAnvdeerqsuiaotne, dsaotdaiefxfiesrtentcoepsraomviodnegasrpeeacsioensaibnlemeutnadbeorlsitcanhdainndglionfg do aabnsiomrapltsi.onS,ubdsisttarnitbiuatlidoan,taseerxiusmtprreoltaetiinngbsitnedaidnyg-,staantde esleirmuimnaPtiFoOnAinlhevuemlasnisn saenvdereaxlpesrpiemcieenstaolf `laenviemlsa.lstTohuvsa,ruisoeuosfensdeprouinmtsP,FaOnAd tlheevseelsefffoercetsstoicmcautiroinnodfifMfeOrEenst srpeedcuiceessatthesiumniclearrtsaeinrtuymiPnhFeOreAnt ianccinotmemrsopdeactieesdiconmtphaeriMsoOnsE. apBpercoaaucshe, taonxiocvoekrianleltuinccdeirftfaeirnetnycfeascatporpeoafr3tofobreinctoemrpslpeetcieelsy extrapolation would be appropriate. `ESPuAc'hsapnraacptpircoalacahppilsiccoantsiiosnotefntthweisteh fcaucrtroernstiEnPdAerigvuiindganRcCesfoarndderRiiviDnsgfRoirCcsheamnidcaRlDssf,orawnhdicwihth the toxicokinetics are understood. Thdaetraewhaereresetvheerailnteexrsapmepclieess uonfccehrteamiinctaylsfafcotrorwhisicseht EatPlAeshsatshadner1i0v.edThReisDesifnrcolmudaenaitmalelast two examples where toxicokinetics were explicitly considered in the RID derivation: Vinyl chloride, for which a developed (httpi/wvwiv.epa physiologically based pharmacokinetic gov/irs/subst/1001. him), and model was DDre.siSguneatSehdalFleadleral Officer Pag3e of4 February 11,2005 o SApceectioense,tofjourstwihfiycehlitmhientaotxiincgotkhieneutniccesrwtaeirnetycofnasctiodrered sufficiently similar among (http://www .epa.govliris/subst/0h1t2m8).. All forty to `animal data fifty chemicals in EPA's incorporate a procedure IRIS database for which for physiological scaling RCs are to derive derived from a human ienqtueirvsapleecnitesdosscaeli(nHgE.D). The Agency then applies an uncertainty factor of 3.0 for 3. Use of NOAELs and LOAELS or Benchmark Dose The draft assessment uses NOAELs and LOAELS for a varietyofendpoints to assess the MOEs afosrsehsusmmeannt,exEpoPsAurhe.as While there increasingly imsoavleodngtohitshteouryseofofusbienngcNhmOaArEkLdsosaensdasLOpoAiEntLsSoffodrepraisrkture t(hPeObDeSn)cfhomratrhiksdpousrepopsreo.ceAdusreE:P"Athneotbeesncinhmitasrdkradfotsteec(hBniMcDal) gaupipdraonaccehdporcouvmiedenst on the a more use of quantitative altemative to the first step i the dose-response assessment than the current 'PNOODApErLo/pLosOeAdEfLorpcraoncecsesr efonrdpnooinnctasn"ce(rUSheEaPltAh effects, 2000). Tahnedyisgosiominltaor ntootteh,at"(fiorhededteevremlionpimnegnttheof this approach has been pursued because of recognized limitations in the NOAEL/LOAEL dapopsreosaeclhec"t(ioUn,SEanPdAm2a00y0)n.ot NrOepArEeLsesnatancdonLsiOsAteEnLtSleavreelohfirgehslypodnespeenidnednitffoenresnatmsptludeiessi.ze Baencdause ofthese limitations, EPA has increasingly adopted the benchmark dose procedure for many ofits `most recent assessments. The benchmark dose procedure systematically accounts for differences in study design, and provides a means to normalize such differences across studies that may affect identification of NOAELSs and LOAELS. "That the PFOA data are amenable tothebenchmark dose procedure is illustrated by the use of the procedure in the recently published risk assessment of|PFOA by Butenhoff, et al. (2004). Turge the Agencytomake useofbenchmark dose `methodology where feasible. Thank you for your consideration of these comments. Respectfully submitted, PorC Sa Lek s Joseph V. Rodricks, Ph.D. cc: Dr. Jennifer Seed, USEPA Dr. Sue Shallal Designated Federal Officer Page dof4 February 11,2005 References: BZoubteeln.hof2f0,04J..L.C,hDa.raWc.teGraiyzlaotri,onJ.oAf. rMisokorfoer,gGe.neWr.alOlpsoepnu,laJt.iRoondreixcpkoss,urJeH.toMpaenrfdleulo,roaoncdtaLnoRa.te. Regul. Toxicol. Pharmacol. 39:363-380. FGuoioddelainndeDornuDgoAsdemiSneilsetcrtaitoinofnor(FCDaAr)c.inog1e99n5i.citIyntSetrundaitieosonafl PChoanrfmearceenucteicoanlsH;aArvmaoinliasbailtiitoyn.; Fed Reg 60:11278-11281 Renwick, A.G. analysisofthe and N.R. Lazarus. default uncertainty 1998. factor. Human variability and noncancer risk Regul. Toxicol. Pharmacol. 27:3-20. assessment--an UD.oSc.umEenvnitr.onEmPeAn/t6a3l0/PrRo-t0e0c/t0i0on1,AgExetnecryna(lURSeEvPiAe)w.Dr2a0f0t0.. ABveainlcahbmlaerakt Dose Technical Guidance hitpi/cfpub.cpa govincea/cfin/recordisplay.cfin?deid=20871 UR.eSf.erEennvcierCoonnmceennttarlaPtriootnecPrtoicoensAsegse.ncRyep(oUrStEpPrAe)p.are2d00f2o.r tAheRReivsikeAwsosfetshsemeRnetfeFroernucme.Dose and EPA/630/P-02/002F. Available at http:/cfpub.cpa gov/ncea/rafirecordisplay.cfim?deid=55365 UA.sSs.esEsnmveintr.onmReinstkalAsPsreostescmteinotn Agency Forum. E(UPSAE/P6A3)0./P-20030/3.001DAr.aftNCFiEnAa-lFG-u0i6d4el4iAn.es for Cancer Risk Available at hitp://www.epa.govincea/raf/cancer2h0t0m3