Document LKd0K9E31b13DdyoMaKp5mXnw
AR226 1089
NB-eEntchhymlaPrekrfDlousoersoofcotraTnuemsuolrfsonianmSipdroaEgtuheanDoalwl(eNy-ERtaFtOsSfEe)d
David W. Gaylor, Ph.D. Sciences International, Inc.
January 31, 2002
Introduction
`PTrhoeteccatricoinnAoggeenncriysk(1a9s9s9e)ssrmeecnotmgmueidnedlitnheesupsreopoofasebdebnycthhmeaUr.kS.doEsnev(irBoMnDm)enataplproach for
`Twohwicdhostheeceaxncceesrsrliisfkeatsimseestsummeontr.inUcnildeesnscestiisp1ul0a%t,eddoetnhoetrewdisbey, BthMeDBo.MDAisvtahleuedoofs1e0at%
`was selected as this is about the lowest incidence thatcanbe estimated with adequate.
.
lvpiarmreiictaitsiiisoocnnoalffcrtuohlmaettebydipfoioacsrasltahcyeh.rboTenhinecchBbmiMaoDarLsksiadoyoissseint(hrBeodnMeunDtsseL.d)aFstuoratahpceocrio,nutan-tolffoo-wrdeetrpha9er5teu%xrpeceofrnoirfmieldnoetwnacldeose
cdaonsceerrarnigsek, aassmeasrsgmiennotf, eWxphoesnuraenboenltiwneeeanr tdhoesBe MreDsLpo1nasendcuravnetiicsipeaxtpeedctheudmianntheexplooswure
lTeovweldsoisseccoansnicdeerrerdis.k
Otherwise, estimation.
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pzoeirnot-isofu-sed
for
departure.
Bioassay Data
E`CtTahhreacindnoaotlagieunnsiRecadtistf.yorSTtchuaeldcyBuwlMiattDihoLnNoaifsrtrchaolewcuBRlMaatnDegLde1f(oo9rw8te.hr1yre%o)cioNdl-flEoetlchltiyecldarPinecertlfhlleuao1dr0eo4no-ocWmteaaesnkeaDsniudleftoanraymido ccaormcbiinnoemdasfocrofmebmianleesd. inAlmlalteusmoarnsdweforreheapdaetnoocemlalsuleaxrcaedpetfnoormoanseancdarccairncoimnaomiansthe
30 mg/kg group in males and one carcinomain the 100 mg/kg females.
Icanlocrudleartteothceanlcuumlbateeroliffaetniimmeailnsciatderniscke. raCtleesafrolrye,aacnhimdaolssethgartouwpe,reit risemneocveesdsafrryotmothe study for interim sacrifices or that died before the termina sacrifice were notatrisk for a l(iBfaeitliemre.anTdhPeorPtoielry,-319a8p8p)roisacuhseddevheelroepteodcbalyctuhleatNeatthieoneaflfeTcotixviecnoulomgbyerPorfogarnaimmals at saricsrki.fiOcbevcioouunstlsy,asanaawnhiomlael ltihfaettsiumreveixvpeossuforre.theAllsiof,etainmeyoafntihmealstthuadtyiusntrielmtohveetdefrrmionmatlhe sfteumdaylews)itprhaiotrutmootrhoefteirnmteirneaslts(atchryirfoiicde floilvleidculloanrgceelnloiungmhatloesdeovrehleoppattohceetlulumloarriisncounted thasataalnifeatniimmeaelxwpaossurree.moAvleldotfhreormatnhiemasltsudayrweigtihvoeuntathweeitguhmtooroff(iUnTi)e,rewshtearned tteisrmtihenawleek sacrifices began at
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ewxeaemkplTe=,10t5h.e anRielmaatlisverleymolivteledwaetiagnhtinitsegriivmesnactroiafinceanhiamlaflwaryemtohrvoeudgheatrhley sintu2dystudy. For sdatiue5md3mowenedewkfeoserrkeeac9ce6hirvdeeocseaiewvgeesriogauhwpteotfio(g5ohb3tt/oaf1i(0n95t6)h7e/=1ef0f05e.)c1t3=iovf0e.an76ulmiofbefaetirmloeif,feawtnihmieem.raelaTsshaaetn`rawinesiikgmfhaotlrs eatraheacth group. e`fTfheecntiuvmebneurmobfemraolfeanraitmsawlisthattrhiysrko,iadnfdolalviecurlaagrecselelraudmelneovemlassoofr PcFaOrScinatom1a4swceoemkbsinfeodr, each dose group are displayed in Table 1.
`Table 1.
Results from the fed N-E(FOSE.
104-week
carcinogenicity
study
in
male
SD
rats
_--
Group Dose (opm)
_--
Serum PFOS at 14 weeks (ug/ml)
Number of rats with thyroid tumors'
Effective `number of rats at risk:
1
0
0.078
0
34
2
3
614
3
35
3
30
59.1
2
36
4
100
192
6
37
8
0
0.039
1
34
-- 9 1 _ 219 -- 2 -- 37 * Thyroid follicular cell adenomas except one carcinoma in Group 3.
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`The numberoffemale rats with hepatocellular adenomas or carcinomas combined, effective numberofanimals at risk,andthe average serum levels ofPFOS at 14 weeks are shown in Table 2.
Table 2. Results from the 104-week carcinogenicity study
in female SD rats fed N-EtFOSE.
Group
Dose (ppm)
Serum PFOS at 14 weeks (ug/ml)
`Number of rats with liver tumors*
Effective number of rats at risk
1
0
0.196
0
32
2
3
122
1
32
3
30
104
3
33
4`
100
268
7
38
8
0
0.126
2
33
9
1
3.26
1
36
* Hepatocellular adenomas except one carcinoma in Group 4.
Benchmark Dose Calculations
`The numbersofanimals with hepatocellular adenoma/carcinoma and the effective `numberofanimals at risk were entered into the U.S. Environmental Protection Agency benchmark dose software program (BMDS). Estimates ofthe benchmark dose were obtained using the multistage model
P=1-expl-{ qo+aid + gud+' gud' +qud*)]
whereP represents the proportionof animals with tumors, i the dietary dose or serum Gleovoedln,easns-dotfh-efiqt'sp-avraeleusetsifmoartetdhefrmuolmttishteaegxepmeroidmeelntaarle adboosevere0.s1poinnsdeicdaattian.g an adequate
fitofthe model. Small p-values would indicatea statistically significant deviance from the multistage model. The goodness-of-fit p-values, BMD, and BMDL gin terms of
dietary concentrationof N-EtFOSE and 14-week serum levels of PFOS for males and
females are ay displayed in Table 3.
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Table 3. obtained
uGsoiondgnetshse-UofS-fEitPpA-vbaelnucehsmfaorrkthdeosmeulstoifsttwaagreempordoelg,raBmM(DBoM,DaSn)d
BMDL1ovalues
_--
Sex -_--
pale BMD BMDLi
Di
.
Male
023
89ppm 40pm
Female 099
SSppm 32ppm
14:WeekSerum Level
Male
023
17lugml 77 ug/ml
Female 098 ---
166 ug/ml 91 ug/ml
References
B`maoirltearl,itAy.Jo.natnedstPsofrtoirecra,rCc.iJn.oEgfefneicctistoyfintrsemaatlmlesnatm-pilnedsu.ceBdimoomrettarliictsy 4a4n:d41t7u-m4o3r1-i(n1d9u8c8e).d NU.CSE.AE-nFv-i0r6o4n4m,enRtiaslkPArsotseecstsimoennAtgFeonrcuy.m,GuU.iSd.elEinnveisfroonrmCeanrtcailnPorgoetnecRtiisoknAAsgseenscsyme,nt, Washington, DC. July, 1999.
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