Document Vr0DDYoaNd9wxn3qzYKj6z0w

M n -IW Benchmark Doses for Liver Tumors in Sprague Dawley Rats fed Perfluorooctane Sulfonic Acid Potassium Salt (PFOS) David W. Gaylor, Ph.D. Sciences International, Inc. January 24, 2002 Introduction The carcinogen risk assessment guidelines proposed by the U.S. Environmental Protection Agency (1999) recommend the use of a benchmark dose (BMD) approach for wlohwicdhotsheeceaxncceesrsrliisfketaimsseestsummeonrt.inUcindleensscestiispu10la%te,ddoetnhoetrewdibsey, BthMe DBiMo.DAisvtahleuedoosfe1a0t% was selected as this is about the lowest incidence that can be estimated with adequate precision from typical chronic bioassays in rodents. Further, a lower 95% confidence vliamriiat tiisoncaolcfutlhaetebdiofaosrstahye. bTenhcehBmMarDkLdioosise t(hBeMn DusLeido)atsoaapcocionutn-otff-odrepthaerteuxrpeefroirmleonwtadl ose cancer risk assessment. When a nonlinear dose response curve is expected in the low dose range, a margin of exposure between the BMDLio and anticipated human exposure levels is considered. Otherwise, linear extrapolation from the BMDLio to zero is used for low dose cancer risk estimation. In either case, the BMDLio serves as the point-ofdeparture. Bioassay Data The data used for calculation of the BMDLio were collected in the 104-Week Dietary PCohtraosnsiicumToSxaicltit(yPFanOdSC; Tar-c6i2n9o5g)eninicRitaytsS.tuTdhyewBiMthDPLerfilsucoarlocouclatatende fSourlfhoenpiactoAcceildlular aexdceenpotmfaosr aonnde ccaarrcciinnoommaasincotmhebhinigedh dfoorsemfaelmesalaensd. females. All tumors were adenomas In order to calculate lifetime incidence rates for each dose group, it is necessary to calculate the number of animals at risk. Clearly, animals that were removed from the study for interim sacrifices or that died before the terminal sacrifice were not at risk for a l(iBfeatiilmerea. nTdhPeoPrtoielyr,-319a8p8p)roisacuhseddevheelroepteodcbaylctuhlaetNe athtieonefafleTctoivxeicnoulomgbyePrroofgraanmimals at rsiasckr.ifiOcebvcioouunstlsy,aasnaawnhimolael ltihfaettimsuerveixvpeossfuorret.heAllisfoe,tiamneyoanf timhealsttuhdayt iusnrteilmthoveetderfmroinmalthe study with a hepatocellular adenoma/carcinoma prior to the terminal sacrifice lived long egnivoeungha wtoedigehvteloofp(tt/hTe)3tu, wmhoerries tcoisutnhteedwaeseka tlhifaettiamneaenximpoasluwrea.s rAelml ootvheedr farnoimmathlseasrteudy without a hepatocellular adenoma/carcinoma and terminal sacrifices began at FwoerekexTam=1p0l5e,..thReealantiimveallys rlietmtleowveedigahttains ignitveernimtosaacnraifnicime ahlarlfewmaoyvtehdroeuarglhytihneastsutuddyy. <00321 i at 53 weeks receive a weight of (53/105)3= 0.13 of a lifetime, whereas an animal that dsuiemdmoendwfeoerkea9c6hrdeoceseivgersoauwp etoigohbttoaifn(9th6e3/1ef0f5e)ct=iv0e.7n6umofbaerliofeftaimniem. aTlshaetwriesikghfotrs eaarceh group. The number of animals with hepatocellular adenoma/carcinoma, effective number of adnisipmlaaylsedatirnisTka,balned1a. verage serum levels of PFOS at 14 weeks for each dose group are Table 1. Results from the 104-week carcinogenicity study in SD rats fed PFOS. Dose (ppm) 14-wk Serum (ug/ml) Nwuitmh blievrerotfuamniomrsa4ls Effective number of animals 0 0.05 0.5 4.04 2.0 17.1 5.0 43.9 20.0 148 0 2.67 0.5 6.96 2.0 27.3 5.0 64.4 20.0 223 Males 0 3 3 1 7 Females 0 1 1 1 6 33 32 37 38 38 39 35 29 37 41 aHepatocellular adenomas except one hepatocellular carcinoma in the high dose females. 000322 2 As noted before, the effective numbers of animals at risk reflect the lower survival in the hcoignhtrdoolsseanfdemloawlesd.ose males and the females fed 2 ppm and the higher survival in the Benchmark Dose Calculations nTuhme bneurmobfearnsiomfaalnsiamtarlisskwwitehrheeepnatetorceedlliunltaortahdeeUno.Sm. aE/cnavrircoinnommeantaanldPtrhoeteecftfieocntiAvegency benchmark dose software program (BMDS). Estimates of the benchmark dose were obtained using the multistage model P = 1 - exp[-( qo+qid + q2d2+ q3d3+q4d4)] where P represents the proportion of animals with tumors, d is the dietary dose or serum lGevoeold, naensds-tohfe-fqit'spa-vraeleusetsimfoartetdhefrmomulttihsteaegxepmeroimdeelnatrael daboosevere0s.p1oinnsdeicdaattian.g an adequate tfhiteomf tuhlteismtaogdeeml. oSdmela. llTph-evaglouoedsnweossu-lodf-ifnitdipc-avtaeluaesst,aBtiMstiDcaioll,yasnidgnBifMicDanLtiodienvitaenrmcesforofm dietary concentration and 14-week serum levels of PFOS for males and females are displayed in Table 2. Tobatbaliene2d. uGsionogdntheessU-oSf-EfiPt Ap-vbaelnucehsmfoarrkthdeomseuslotifsttwagareempordogelr,aBmM(BDMioD, aSn)d. BMDLio values Sex p-value BMDio BMDLio Male Female Male Female Dietarv Concentration 0.24 18.2 ppm 0.54 16.7 ppm 14-Week Serum Level 0.23 135 ug/ml 0.54 193 ug/ml 7.9 ppm 8.0 ppm 62 ug/ml 92 ug/ml 000323 3 References Bmaoirletarl,itAy.Jo.natnedstPs ofrotriecra, rCciJn.oEgeffneicctitsyoifntrsemaatmll esnatm-ipnldeus.ceBd imomorettarliictsy and tumor-induced 44:417-431 (1988). U.S. Environmental Protection Agency. Guidelinesfor Carcinogen Risk Assessment. NCEA-F-0644, Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC. July, 1999. 000324 4