Document ga5o9wxbv2B2yyemVYOYOX4KJ

CC ARL2L - 1090 `BencPhemrafrlkuoDroosoecstafnoer LSuilvfeornTicumAcoirdsPiontaSspsriaugmueSaDlatw(lPeFyORSa)ts fed DScaivenicdesWI.nteGranyaltoiro,naPlh,DI.nc. January 24, 2002 Introduction ``PTrhoetcecatricoinnAoggeennrciysk(a1s9s9e9s)srmeecntomgmuiednedlitnheesupsreopoofasedbebnycthhmeaUr.kSd.oEsnev(irBoMnDm)entaaplproach for `Twohwicdhostheeceaxncceesrsrliiskfeatsismeestsumemnotr.inUcnildeesnscestiisp1ul0a%t,eddoetnhoetrewdisbey, BtMheDiBaM,DAisvtahleuedoosfe1a0t% wpraescisseiloenctferdoamsttyhpiscails acbhoruontitchebilooawsessatysinicnirdoednecnetst.hatFucratnhebre,easltoiwmaetred95wi%thcoandfeiqdueantcee lviamriitatiisocnaolfctuhlaetebdiofaosrsatyh.e bTehnechBmMaDrLkidoosse t(hBeMnDuLs1ecd)astoaapcocionutn-toff-odretphaerteuxrpeefroirmelnotwaldose cdaonsceerrarnigsek,aassmeasrsgmiennot.feWxphoesnuraenobneltiwneeeanr tdhoeseBMreDsLpoonasencduravnetiicsipeaxtpeedctheudmainntehexplooswure levels is considered. low dose cancer risk Otherwise, estimation. linear extrapolation fromthe BMDLoto In either case, the BMDL1o serves as the zero is used point-of- for departure. Bioassay Data "CThhreodnaitcaTuosxeidciftoyracnadlcCualartciionnoogfentihceitByMSDtLu1dyowwietrhePecorlflleucotreodoicntatnhee S1u0l4f-onWieceAkcDiidetary Paodteansosmiausm aSanldtc(aPrFcOiSn;omTa-s62c9o5m)biinneRdatfso.r mTahleesBaMnDdLfemisalceasl.culAaltletdufmoorrhsepwaetroceeallduelnaormas except for one carcinoma in the high dose females. Icnaolcrudleartetothcealncuumlbateerloiffaetniimmeailnsciadternicske.raCtleesafrolry,eaacnhimdaolssethgartouwpe,reit risenmoevceedssfarortmyothe slitfuedtyimfeo.r iTnhteerPiomlys-ac3riafpipcresooarcthhdaetvdeileodpebdefboyretthheeNatteiromnianlalTsoaxcircifoilcoegwyePrreongortaamt risk for a (riBsak.ileOrbavnidouPsolryt,iera,n 1a9n8i8m)alistuhastedsuhrevrievetsofocarltchuelatleiftehteimeefoffetcthievesntuudmybeunrtoilftahneimtaerlmsinaatl sSatcurdiyfiwcietchoaunhtespaatsocaewlhluollaer laidfeetniommeae/xcpaosrucrien.omAlpsroi,oratnoytahneitmearlmithnaatl issacrreimfiocveeldivferdolmotnhge eginvoeungha wtoeidgehvteloofp(tUhTe)'t,uwmhorerisectoisutnhteewdeaeska ltihfaettainmeaenxipmoaslurwea.s Arlelmootvheedrfarnoimmatlhseasrteudy wwietehkouTt=1a05h.e.patRoeclealltuilvaerlyadlietneomwae/icgahrtciisngoimvaenantdo terminal sacrifices began at an animal removed carly ina study. For example, the animals removed at an interim sacrifice halfway through the study 00321 1 at 53 weeks receive a weight of(53/105) = 0.13ofa lifetime, whereas an animal that dsiuemdmoendwfeoerkea9c6hrdeocseievgesroauwpetiogohbttoafi(n9t6he/1e0ff5e)ct=iv0e.n76umobaferloiffeatnimiem.alTshaet wreiiskghftosr eaarech group. `aTnhiemanlusmbaterrisokf,aannidmaalvserwaigteh sheerpautmocleelvleluslaorfaPdFeOnoSmaa/t1ca4rwceineokmsa,foerfefeaccthivdeosneumgbreourpoafre displayed in Table 1. `Table 1. Results from the 104-week carcinogenicity study in SD ratsfed PFOS D(popsm)eNu l4-m (wukgmSib e)wmerwito h livef r tumoa rs* mmEfa ofefctainl viemanluss mber Males 0 005 0 3 os 404 3 32 20 171 3 37 50 439 1 38 200 148 7 38 Eemales 0 267 0 39 0s 696 1 35 20 273 1 2 50 644 1 37 200 223 6 a * Hepatocellular adenomas except one hepatocellular carcinoma in the high dose females. 000322 2 `As noted before, the effective numbersofanimals at risk reflect the lower survival in the choingthrdolosseanfdemlaloews.dose males and the females fed 2 ppm and the higher survival in the Benchmark Dose Calculations `The numbersofanimals with hepatocellular adenoma/carcinoma and the effective numberofanimals at risk were entered into the U.S. Environmental Protection Agency obbetnacihnmedaruksidnogsethseomfutlwtairsetpagreogmroadmel(BMDS). Estimatesofthe benchmark dose were P=1- exp qotqud + qad+ gad' +qid")] `lewvhele,raPendretphreesge'nstrs etheesptriompaotretdifonroofmatnhiemeaxlpserwiimtehnttaulmodross,edriesstphoensdeiedtaatar.y dose or serum `Goodness-of-fit p-values for the multistage model are above 0.1 indicating an adequate fitofthe model. Small p-values would indicate a statistically significant deviance from the multistage model. The goodness-of-fit p-values, BMD,and BMDL1gin terms of ddiisetpalrayyecdonicneTnatrbalteio2.n and 14-week serum levels of PFOS for males and females are Table 2. Goodness-of-fit p-values for the multistage model, BMDi, andBMDLovalues obtained using the US EPA benchmark dose software program (BMDS). Sex Male Female Male Female pvalue BMD ~~ BMDLy Hisar . 024 182ppm 0.54 167ppm 14:WeckSerum Level 79pm 80ppm 0.23 135 ug/ml 62 ug/ml 0.54 193 ug/ml 92 ug/ml 600323 3 References . Bailer, A.J. and Portier, C.J. Effectsoftreatment-induced mortality and tumor-induced mortality ontests for carcinogenicity in small samples. Biometrics 44:417-431 (1988), U.S. Environmental Protection Agency. Guidelinesfor CarcinogenRiskAssessment. NCEA-F-0644, Risk Assessment Forum, U.S. Environmental Protection Agency, `Washington, DC. July, 1999. 000324 4