Document 1Q7jL6jyL6jVOoEzV06k2VX8X

sfweyrresss ros ron ro, ran ACRRb=1812 ERo.cTheecshtneirc,al Report: Liver Fluorocarbon Metabolites -- University of Tide: `SummaryofQuantitative Analysis of Fluorocarbon Metabolites in Rat Liver Samples. Lin Xu and MW. Andes TFhenpenvB t nid mtbE it ofi esweoedocms mmeton ms o-- m -- re-- cM(oTn5otbo6el 1ac)Tr,hT aeo.e gTtrkhoeo euphcsovoofeevmnhemt40esPmaEnEmOpRSlEe4ws0nsw0rteeFtrOppSloeymna:tlolsbyThonendtiestognoedmps(SsGeroeuhnp s1) cmoonnnsnied ocfOrnSstAom oFcROhOaSeALrNe.34ngn0d7uF8ROomOAiiTAniA(wt)Mns3eo3di0t7iehEeedOdUSSaansdnmeFiOnoRorfsAsmoh4eeaancnov.enevsTooosomrFeekpctasemwosr mete Tfo eps Conon FOS nfromocroTnhteease5.cdonFdT goroeup (vGe eronup4d02ogan rss wasPrNReOsStEeodOrinlNovo embetrE ,sm1998. r Gg ro2ncy omand vers CvnPRSeoOTnNmOEcpSAoAsFmAaOa(nSMdEispstdyktaTlcheoecmompiionunm ntedmdeFesObsa:stheOosmSwweAsrneweFT.OsaSahA,sTohFoOTmSmaErsa hamenbm0 aastareowPmsE eons, CAFoOFlSOaAStssghocmatoricsda.envGPiReeOSKtwaaasnoalmotraammeosefroseopcriomoponaesseee Co rrialnt,ydGiTochToehscecehnioirdnaigsorAnoemuorf(aCFofrOhoSueAps3wc)PewEmaOseSlriesatnlseddeimnwmMdeerort,srsh1n9oe99,meoeGsrwgoe0n3vBcnroas.reei rpa ep snome econolhF5CS tBNhEemFciOnoS.rEdmeotSahbio,ltiEcoIKFeOroSnuAiA1,.wrcFoeOntSPo,lOaaAmaFFsOOShSEAeAa(ts1oo58EwnirOSmeEmetinroceorSsroiesrsassntedFSO m. SCIDiocsncouonsnieor,n:kyTbHhoteeshnteidsontsuahssel.ooolbwhoconslaclitusniAPontRtsOboSo1,tsvaohkeehoerrvedeErCmpo Sptwavbr tWchoefi tnhe eurnreoctaboofnfhs sodimd5Gc ROSA wa mettle 10 FON gobmenit, acNrEihsIelOrSomEEhhseeOcbdSooSnsucs yrhooelnd.gsio.fvNCeshFEirOeoSSi1Ad0ERaatcntoognhuoaorbflebmfenadopmaeNrdaneOdEmAtihRneoAo Or mSceatslc iesm, OFsSErOt ahnroe lofdebee ieoedmSiuorsmeoontfhiFOouSnEsooitshrtloorsbho. FFOOS sSoosmheetnbyPs OON gm r a sta "croovz SoRrPITSTH-62958, T-6316.4, 68682, T-10711, T7132] E. Technical Report: Liver Fluorocarbon Metabolites ~ University of Rochester. Tite: `Summaryof Quaniitative Analysisof Fluorocarbon Metabolites in Rat Liver Samples Lin Xu and M.W. Anders "The paren"tThaisndismebtraibeoflsituemsmoafrtyhoefltohreocaanarlbyosniss owferiveedrestaemrpmliensedfnrovm rratsagmipvlenesarbayngLeCo-fMlSuMoSro.carTbhoers. results ar presented below. control ra"tTs,heferogmarisogoiufvlepvnes40smagm/pklge/sdwaeyrFeOaSnaAlyozreadl:ly,Thaendfifsrtogmrroausp (gGivreonup161)0cmogn/skigs/teddaoyfFvOeSrAsArom ((MTiaSb5l6e)1r) aTlh.e dTahtea csohnocwentthrattiPoFnOsSofpwrasenthtecmoamjoproumnedtsabaonldicthfeorunmdetianbotlhietlevseirnsovferrasswegriveenmeFaOsSurAe:d rFiOsSgAivNe-nglFuOcSurAoAni(dMSwSs6):idPenFtOifSieadnad.FOmSiAn.orImteitsabnooltietweo.rtThwyothmtettahbeoclointteolwearneimiadlesnt(ifIiReOd0i74h2,e vrs of FTiRs0c0h7e4r33,44anrdat1sRm0a0i7n4ta3i)nceodntianitnheedUsniigvneirfsiictayntofcRoonccehnetsrtaetironVsivoafrFiOuSmAd.idAnotpasrahlolewldaentaelcytsaibsleof livers rom concentrationsof FOSA- from con"tTohlesreatcs,onfdrogmroautps(gGirveonup402)mogfragt/sdwaaysrPFaOtSedorailnlyN,ovfermobmerra,s1g9i9v8e.n 4G0 mrg/2kogc/odnuaayiNnp-eEdIlFiOveSrEs Caolmkophooulnodraslalyn,daniddefntriofmierdatmsetgaibveonli4t0eamrges/hdoawyn Nin-TEaGbFlOeS2.A oTrhalelyd.atTahsehocownctheanttrvatrisonsforfopmarraetnstgiven PgiFvOenS Nco-nEt(aFiOneSdEpaalrceonhtoclocmopntoauinndedPsReOveSr;alFmOeStaAbowliatesa.lsoThfeoumnadjiortmheetsaebsoalmiptleess.werTehNe-lEivIeFrsOSfAroAm, rPatFsOS, anndd FFOOSSAAAN-(gMlu5c6u)r.oniTdhee. mPiFnOoSr mweatsabholeitmeasjworermeetFaObSolAi,teFiOnSlEivearlscofhroolm, r-aEtsWgFiOveSnENa-lEcIoFhoOlSAgh;iaFrOoSniAdea,nd FraOtsSdAidN-nogtluccounrtoaniinddeetweecrteabildeenctoinfcieendtrasatmiionnsorofmpetaarbeonltitceso.mpInocuonntdroarsstme0tabGorloitueps.I th livers from control fom at"gTihveetnhi4rd0 gmrgo/ukpg/(dGaryouPpF3O)Swoarsaltlrye,aatneddifnoMmarrcaht,s g1i9v99e.n 1G6r0omuep3kgc/odnatyaiNn-eEd(lFivOeSrsEraolmcochooorroala.s, "oTwhe ccoonncceennttrraattiionosn oofftFhOecShAemwiecraelsidaenntdifmieedtiabliovelrsairrceosmhrotwsn giinvTeanbPleOS3.. AsInwtihteh iGvreoruopf2,rtPs ROgiSveanndNmEiAnFoOrSmEetaalbcoolhoilt,esXi-dEenFtOifSieAdAw,erPeFOFSO,SAa.ndFFOOSSEAaAlco(hMal5,6-)EweWrFeOSiEdenatlicfoiheodlagslmuacujroornmiedtea,bonlidteFsO,aSnAdNh-e lucuronide. Similar to Group 1, control animals showed detccale hepatic concentrations ofFOSA. SDicshceumsei)o,n:butThdeosneodtaalaloawllionwfceornecncleussiaobnosubtotuhetetxhaecotvrrouatlesomeftmabeoalbiacltiee offohrmeatilono.rocFaOrSbAonwsasstudied (see cWohnastisetveenrtliytsirdoeunttiefoifedfoarsmaatmieotna,bFolOiScAofwaPsFOmSe,tabbuotlithzeedsfoouFrcOeoSfAthN-galmuicnuorognriodu.p snot readily apparent. aris fioNm-tEheIFNO-dSeEctahylctoolniovfeNiAsFeO1SEraanlgcoeohofl,maanjdorNa-nEdUFmiOnSoArAmecioaublodlatrsi.se bFyOtShEoaxlicdoahtoilocnooufltdhe EcoIhFoOlStoEtahleccoahroblogxlyulciucroancidd.es.GluFcOuSroAnAdactouolndobfethfeorpmareedntby-Eth(eFNO-dSeEchayllcaothioolnwooful-dEg(iFveOhSeAAobosrerbvyedthe orxeimdoavtailonooffthFeOcSaErbaolxcyomheotl,hyolr gbortohu.p FofOFSOAScAouAldasbeglfyooxrymleatde.byFtOhSNA-deNc-tghlyolcautrioonniodfe mNa-yEIbFeOfSoArmoerdbybythtehe locuronidation ofFOSA. Revisedpage $9 0073 DSRTPITST-E6295.8, T-6316.4, T-6868.2, T-1071.1, T-7132.1 give FOS"ATheorflioessooffFtOheSAglAycaipnpeemaoriserteylawtoivuelldy sgtirvaeigPhFtfOoSrwadrirde.ctlLy.oss ofthe carboxymethyl group would & cova g i 4 z $ k 3 i) po 8 zZ SEE T2 o8e = age58 : g 244 E iig P| _i@i= Bz itzi EH] Baa8addae gRa53g8aJ888i28e8; ed | leEsdEd RReeeee | E3 B n0075 SSE ECCoTiiiiilii HE ini 2 258 CsES ey 5 . 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SRihas2.38s 2.882 31.883 TRIP2s 8 2.88: zit fRtses.ass s.38s 252 cbs Bz:e 33. 5:2 3.853 zgiE iLE y H te Bo dBe c2e .5302%s eaa 8P5a 3S ok [zzRRRE2EL E3 retgzirsl: sSo B8s e z 58z1 A 8 Se EL iE z fk n0079 Eee. fizize oza oz Fz az os.Bs * cf%.2z 8z % 2o 5.8g 3: 3.28 ezz.fzlzaz ose sasi. n 2B kes fziiozg 5.2y 532s 3s Bes doiz fae zoe s Bz ozos Bs Brg E3EZBEfg2 f Ford 7 HE Ref Ezsa 33n 55g .di. ve 5.38 FEE dAse 3:x 3sn .is cE 3 FE Bes. Biz 3% s soa s Bz z: 2 33 Bez.dz Beop. oz BE 5 Eg Egg dar ize or2 z Faz e. 33 kez. 2fa 58 c 23 2.8g 8: 2.3% czgg. 2fn 83 a 2c 2.8g %: 2.53 Rez. dfa3383. 3.382 82 3.33 Reg 2fo B0 85s 3.8g 33: 3.8% Pee. i3zdz soze ozBg er oni FE .Fra ifs ozoa s.dg va nah 2R5Rg =z Ex 25 8 12580g1: 8 : : 2f. f3.s22 8 8f. oFofzi gp At E 9080 23%2 8% rose. Za 2.32 5.85 9 5 2523.33 so. 8s s.33y gore og sE2z8.5c serfs giz srr oe sng IE mmm fe 538s zogro oo zzz. dg Z 2g E .R.Z. fe ndr es fe 35 szrr dz $553.38 es ge. 22 cers. 3E 22g. 8% sees des BRIR.E.I 2 senr.f 3s s383.3 3s sams die sme dig e2z2.f0: mueeilc ma.882 sissy 22.3% RE 3r s.frs adi: sia 2 fnoa nl Bir 5.53% sogrn og gory i A 5.8% 4 2.3%: i osisa og sexy og goE%a og ogosro of ggg noo segz 33 zo.iio s.Bf: osx og sess 3% Ezz iio 28s8 sss3 frgg.iz sass doz 288s sasx2 og @ x fad f $2353 Pils. sras.d ua $538 Hil, 3 i 8.3 TE 3 5s Lisf 82 8 gg Lhd g& i A.B 2 ` 60082 RIFE RE EP SE . WE 8 soz EE g2nzlIEor 2. EEr onl E og hEzessfr sei oz o2fiz oz: "iE moags EE naes.3 os 2.353 3.3% Eeresr dy sees oz hBon 8 PEE.Bof. BE3E.3.9. 2 WE Rs REEF 2 mesza 2 oa WE Yom 225.3 5 =erf.d 2 [Ee roesnda ame di oz (Eiasssda send os ozdse BER sad Tz 3. 23 adorn sige udgg E.Ao ff sai nog g. nog edgy 1.34 WE 3s A282 8 WE 8 roar El WE 2s oeer.d E =ranli coz ozzse id oz osnnalE doz sad aoe 2.82: a3 Ea aldoa of 3.3 Eg 2.3 Eo WE Ez ozElf fi REERUREE 232s in ozzzzif oc o.Bizoz.EoE og REESE FNETE 2225 28. 5s3 ss8 o i : fi WE Zo oazg.d 3 soz Lis i Bg, aess.3 2 2 83 : HHH sf raf 2s z "I Lisi 3 8 of 3 Ris g 5 C0082 ead 3 2.8% ow 398.3 7 zozz.fd sf: zesz io g 2.8% zos32.% 3 : sd: R53. " tn% 3 2.3 5 2.8= c . 8.8 3 22a 2.28 35 i. 2.2 2 sf sessdal B 5 s3s.5.5 I - 5 8 32%.% & = rafal 3 | g ~ > gers. Ea EF o 8 3% 28g.% 3 8 aoasgad | 3B aes) 2 3338.3sal8 82 2325.2 2 g tamin| sRfE: nRuasmitlz 2g 2.3 3 2 seg.loz| zLe. 17 283% s. 22 - 5 i l S Er 2 25 = 2 . C0083 ) C9084 0ors1m A. Statistics on Clinical Chemistries for rats, male and female values combined. CHOL mg/dL. By Dose Group (mg/Kg/day) Rone OSneovayyAroora arom RRHooaosnvorelenRnedSspaoansse Ere SEOanrEiasn Ctevatont to Sum ie 5 TsFoatre oF% sesSsmooiGvaStoaarmrceees MenMsUuNaEEn GFrhac 0 pr] Ta Per aR Sas Gs owe Lovnetr Me forOnn eNoArs reo"Traunween REFossonts Gwe Seisremr PNNrEEorrsooissceiomms HLTI oOmRoN oSmS Lovet S10Err te esap[oalna es>dSsautiDmean tveoonfsere variance KNEEFNroossatoanmka NErosEioms Da 1o SGhoeme Tseamm; hime2 LORR wes ss Frosioma Lon ae am Ooocoesnaimaa ccoont Mea"nNsECoRmSpSaSraiosmonss S08 26a nerosETSaoomoieoa Pro"0sOi%Toem NeroSEsSsoomsiea n cno08s To0r7s01 FR PNFEOFSOASOEm4kodmkd 3"1417.7875500 NEFOSEi60md "48750 3089.0000000 1.0000 220.09000000 230000 Apha= Comp0a0rissons for each par using Student t AbsO-LSD 2.10! 080 CONT N.EWOSADmMKd NEFOSEAOmkd NECFONOTSAWOmKS 1"1s2a2r5a6 NEFOSE4omka 1873 1"958877356 78755 Teemsss 158755 PFNOESFAOS0EmIiGdOmks 2111.9076158 1S58038927 271803123 Posie values show paiCoofmmpeaarinssotnhsawiaheasicgonnitrfoilcaunstindgifDeurennntets Method 273]189 ACbOSNOTA-LSD NEFOSAOMKA 14C5O8N8T8 Rered NPFEOFSO4S0EmdkOdmkd 15819461225 NEFOSETB0mK 35275 20200000000 0.1000 PFO2S1A0O7M5K8 s78m39e2 2144149004 `Cholesterol nats male and female combsiPinoteesrdievnftoe.rvDaTl1u5e.s sShgorwedpauicrtsioonfbmyea4n0smtkhdatPaFeIOsSigannidfi1c6a0nt md NEFOSE 280..01000000 00000 N-EIFOSE1116008m1k8d 251.001837 234147050029 n C792086 Torsor Camy 5, Dosree wd A A LNA - EY we A HE i" ERVA7 N hd con eros bro re or ov rsriNEFOSEAOmKG. Sutyf ne | nn0087 TbiIsO OSunmemwaaryaynoofvFai ReRqSquuaarree Ad RMoeoatnMoefaRnesSpqounasree. Error Observations (or Sum Wats) 0012081155672 041T81692785 is Source OF Analys'iSsuomfoVfaSrieaunrcees MeanSquare F Ratio MErordosr! 23 0281205500000000 00217758040107 P1r56o7b7 Cowl is 26300000 195333 0248s Level Means for OnewNaoymbAenrova Mean SigEmor GNOENFTOSAdOmKd 44 2i1s0s 002200004811 PFNOESF4OOSmEKddomka 44 e122s00 002200004 51d Eror usMeesanspoaonldedStedstDiemvaitaetoifonesro variance. LeCvoenlt Number4 12M1e5a0n osSaueDe7v NNEEFFOOSSAEddOommKkdd 44 rvieess oosee7rs PFOSAOmid 4 2200 0216025 Sud0E2m7M2e3s4n 002088349855 0.10801 PFDOiMSe4aOnmlKiMdeanl] CNOENFTOSAdOmKd NEFOSEdOmkd PFOMSeAaOnMsKSComparisoCnOsN. T 0000"000005 00..005000000000 E02C7s 025 N.EIFO0S2A7O5M0K0S0 0002020500"000003 N-EIFO0S5E7A5O0m0K0d 00350205000000 0000000 Alphas `Comparisonsfo00esach pai using Students 217t882 PAFDOSSOAOLmSKDA PFOS0I6O4M5K2d7 05C9O5N2T7 NEFO"S0A3M7O0M2K7I cNNoEEnFFtOOSSEAddoOmmkKd olosseer o4e2i0s2277 `oomzr oa0er "oas2i0s277 "oss2r N.EFOS"E0d0O7m0K2d7 ""o0s2u0s027r "osesr Positive values `sChoomwpapraisionosf wmietahnsctohnatoaleussiinggniDficuantmdffMeertehntod 26d8l20 PFAObsS(ADOimLcSdD "0C74O4N5T7 CNEOFNOTSAdOMKS `005765845577 NEFOSEdOmkS 026987 aPofseirtoinvetvalues show pairs of means that ae significant PHOS mal By Dose Group (mo/Kday) C0088 Torsom Eves > ; wol/2= wlflt/ A. Co ~~ wl TT Nd 0 Awad 7 oo N % VN wo TsO econiiam ion e roam ESohwEr Rsare OSneivayoanoava aaron RRoeaateeaRndeSsoares Err SGars3ene0ss Orseneton or Sum te HHsocsree or5 AinimsofvyCaSroasrsscas Meimomn ESreniee Sires arses mews low 5 aman Sms oem Stovr Meansfor OnAe errcina ar-- ] FHNrEEorFsooasstmaaaoonmsa iIPtohnE ee ] Suule Lovet 54ErocueesinpsNoiamnotdnSresstDiomavtieg"orlfsarnrvariSncoe e So wm ome aErboeaen FKNrEEarFsoosscaioonmaa DL{oSdmiie cSEaammeeew Soohmwee DKoeinFaosnesoeniaan oCoeoonsto"sCom"parNsonEs1R2S] NerFosm Moma T PrOSionka ars 200000 loom rose FNrEoisrioosmhisoma Sirtiiaon EDrede SSoooooo booonna Apres Comapfoos aach\prisusinogStnentss saesnon so Br cont 2"1NemFo"sSseimonekna NeFosoMtomsa PRoOsSm " 70089 TTIIOSLI FR NNEEFFOOSSEAOOmMKKSG 00..6345459010 1".03366600011 0G3301 013300009911 PFOSOMKA 038500 "03gee1 Tee t3seet Male and fPeomsailleveravtaslcuoemsbsihneodw pCaaiasnodfPmheoasncsirtihcaalarcehesmiigsntirfiiesc.anNtodiifgercenhtange rom contro 13 702090 Tbr2s07P1R a TEL miloyDose Group (mga . ee 5.0 6 [0 - AA Ewl TLAaTvAa eVvS =. oon gn CONT NEFOSMOTNEIFOSEAmka NEFOSErComEDSs veE00Po SMITTSt VorSertol iowery "tnooot TTi0s7.01 FR OSnuemwamyaAronyfovFat RRSsqquuarree Ad) 0o3a7g7s2s0i1e RMoeoa!nMoefaRnesSpqounasree Error 00.308680343913 Observations (or Sum Wets) 2% Source OF AnalSysuismooffVaSrqiuaanrcees MeanSquare Ratio MErordoerl 14 `000089s15785303030 00000281662496 P4r4o8v2o8 Cal 2 017833333 oo0mrss 0oi02 Level Means for OnewNaoymAbnecrva. Mean SudEnor NCoEnFtOSAdOmK 84 o02r00o0 0o0o3a7ssy NNEEFFOOSSEEdIo6mOkmdk PFOSAOmKd 34 002410500000 0000470152 5 0420000 003108 51dEroruseMesaanpsooalneddSetd sDevtiatoiifonesmroravartianece. LeCvOeNlT Nomber8 038M7e5a0n0 003S6tD3e5v5 NNEEFFOOSSEATdBOOmmKKSd 43 0042070500000 00000500000000 PFNEOFSOASOEmdGomks 45 0o422m0s0o000 010008s574453 Sid0E0r1r2e5a0n 000002050000 0o00a4r9e0r Df-Mean(jMear(] ~ PFOSAOmAdMeansNCEoFmOpSaErIisEoOnMsKS CONT NPEFFOOSSAOEMIKSdOmA CONT. 00"00000020 "00325 00000200000000 00..001322550000 20125 0000000 NNEEFFOOSSEA4OommhKS 01n4a5s o01n2s5 o011s25 Apna= Compar0is0osnsforeach pir using Students AbsO-LSD 2093t 01 PFOSAOMKS NEFOSEIGOmkd CONT PNFEOFSOSOEmT6d0mKd 0"o009s16z928 o001s1e8z725 00.0085s97 CNOENFTOSAOmK "000407044323 0o001s3s9e175 00.00273241324 NEIFOSEAomhg 0047433 01st 0.023434 Posie values showpairs`ofCmeoamnsptahawtriaihreasscioognnntirfsoilcaunstindgiDereuntt. t Method 270)838 PFAbOsS(DAiOmLkSdD 00C7O4N6T4 NCEOFNOTSEIGOmKd 0"01.104037036 NNEEFFOOSSEAdOommKKGd 0"00.002028888 NEFOS0A.S14O5M0K0S0 00..111225500000 00000000000000 N.EFO0S0A4A7O4T3K3I 0002133403145 "00..1100228844 NEIFO0S.E1A4O5m0K0d0 00..112152050000 00000000000000 N-EIFO0S0E447O4m3k3d 00002133493145 ""00.1100228844 EDn0092 TTIISON FR Above i or rat TBIL. maeand femal comaPboifnseeidredavtaal.uensosihgocwhpanagresso.f means that are signifcanty Ed 0093 f5 a LA JioEo . <4 O/ \ // 3LEV>a Ef IEA RS LAN TOTO) orolemroerens TESei Wow=w es G10094 To0n7s01 ER OSnuemwmayaraonyfovFiat RRsSqquuaarree Ag) MReooatnMofeRaensSpqounasree Err Observations (or Sum Wats) 0o5s0e6s0e7r27 0373812516734 2 SoMuodrsc!e OF AnalysSiusomfoVfaSraiuanacree.s 4 26441413 MeaOneSea1u0a3r5e FeRaa3tsi2o cEroroarl 128 41a76a3m2951030 0002900160205 P0r0o0b1o8r LCoovnelt Meansfor OnewNaoymAbnecrva 5 3sM1e2a8n0 0S1u1E1r8o9r NNEEFFOOSSEATO6mOmKKGd NEFOSEAOmKd 42 3a2m00000 0021273129 4 asso ome PFOS4OmKd 5 4300 01e Std ror us`eMseaanspoaonldedStedstDiemvaitaetoifonesro variance. CLOovNelT NEFOSAdOmKd Number8 38M1e2a5n 038S7u0D6e8v SWd0E.r1M3e6a8n5 4 37000 o3texzs 018811 NNEEFFOOSSEEs1O6m0Kdmd PFOSAOmkd 24 335270500 0o10520r020103 5 e300 0288087 00.0175500000 0.12884 PFDOitSMAeOanmlKldMean(] ~~ PFOSAOMKS MeansNCEoFmpOaSrAisOoMnKsS 000000 066000 07C4O7N5T0 NEIFOS0E7A8m5k0d0 CNoEnFtOSA4OmKd NEFOSEdomkd "006784070500 "078500 000080705000 000008070500 012500 003750 000132755000 000000 N-EIFOSET60mke "111000 045000 036260 0.32500 Alphas Compar0i0sson for each pair using Students t AbSO-LSD PFOSAOMKG 2 10v001 NEFOSAOMKS CONT N-EIFOSEAOmKd PFNOESF4OOSmAKddOmK Cont 0024115913698 0360464 02"1o5d1s6g6y 0033610048684 03185 033186 03"4003146359 0.36858 NNEEIFFOOSSEEdTo6m0kmoke 00338450119658 00232483 00366187848 002.44562880 Positive values show pai`rsCoofmmpearainssontshwataheasicgonnitfriocaunstinagffDeruenntn.ett Method 2721]184 PFAODSSAOOLMSKdD 025C7o7n3t5 CoNnEtF'OSAdOmKs NEFOSEdOmK ""00..423088550 "0.48850 NEFOSEI6Omks 031668 N-EIFOSE11.6101m0k0d0 003465205000 003020500000 N-EIFOS0E5156501m9k5d 001126612784 ""0o2e4s5s2i8z 8 C0095 L ons R TooytPsBeoirsieeevlGerousp showpes ofmeans (mg rt re siricanty 2 . ESeS edWI E T L CA OA AAE G NAa. O3 OY N ~ Tf cor Werot:umrotioms ww Ed ov Gs rwoeryoscicmmss Sosw t oouwn RareOnSeonamyaynoara Rinne As oGseroizes RNGeoestmeHnooertaRonensSpouornseSsEumxte aoseur=s soEcoro oAFLo n"sSiTvmarioarecees Bo ime MooMmwEaeE pFLeaAeRor Soa 2 TEvm owe oom Loovn MeorOanenNoArrseora eWdeon SGwrer NNNEEErFFoOosSstEatAoeonamimaas Prosioma BLo aSGhamooo Gaaslrsoeess STE Qier Loovner S14Eroruse s apNaana iaSrstiDmoan vtieoaf"ngseaneveSueaoey Toes ods stgeinoon NNNEeOFESooSEsEniBooonmmaaa Frosioma FDDIo oGomwmo Gi ofhmoemn doosmems Teo owons orem NPDErioFsoeiSmsaiaeatmla] ProSSooomnMso"oNnEsFCoOmpOaArioMssIonoMsG 270000 So NEFOSoGEoAoomKsoS0 baCiOeeNnT NeCNFoEonwsOeStEeaoommsa RSTor5es8 D2Seo5sr7aas SR0i00m0E0o0 EGbao]aoanssa NEFOSEir16o0m=0isa aaGroscnooo Erooas sjiean . modosFere2pd: rprrimnnmat ffNrreoorononstitsS ma E prgooasmmeyes NERMoOEiFmeOmUasMm NorodoSneEemrooammmnss coacommonmv nB e e 8 Te sen sEerm s=m Pete vsshow ir eae TotIrSeT st acer aves J mion2. sH1d, g=conur AuArehohm ESums ir rE o LGT rae oRA sgt neossTcSiaummrmnesd uSisme ert c To oseGos momo oes a nse S--un--e RfEiit ceon--e. f hweoroa ----E--mNSea--Eomn ha 3 Emm ioov wormsiscull ty. |, Noes . oiFnrea] 2 whmengmaam nnfeoaem YE u C0097 To0i7s01 FR NNEEFFOOSSAEsTO0mmKKd NEFOSEdomke 42 2a1s000 saa4m 4 750 04m PFOS4OmKG 5 wien 272m Std ror us`eMseaanspoaonldedStedstDiemvatietoifonesro variance. LCoovenlt NEFOSAOmid Number8 23M5e0a0n GrSe6eDnesv SidEmMeoarn 4 sso ess sori NNEEFFOOSSEEd1o6m0kmeK PFOSAOmKa 42 m21r10s0 a4s8e6a8r0r 5 aren seer 233801060 12820 PFDOi-SMAeOaMnlKlAMeonl] ~~ PFOSAOMKS MeansNCEoFmpOaSrAisOoMnKsd 0000 2100 5C4O1N0T0 NEFOSE6A28m5K0d CNOENFTOSAOmK NEFOSEOmKd "5254.110000 82850 29000000 200000000 3770 8750 387775500 0000 NEFOSEIE0mKG 136.600 180 82500 73750 pha Compar0is0o5ns for each pair using Studentt Avs LSD PFOSmkd 2101081 N-EFOSAAOMK CONT N.EIFOSEAOmkd NPEFFOOSSAAOdmOdmK CONT "p81r.051 18.958 oS0e8r7 a-g1e8gnste a04mr oars 2"532181677 S727 NNEEFFOOSSEETd0ommikd 220131870 S0250167 e8782173 "0281m7 Posiive values show pairsCoofmmpeaarinssotnhstwairheasciognntirfoilcaunstindgifDeurennntetts Method 272ol184 APFbOSDAOLmSKdD 40C5O5N0T7 NCEOFNOTSAiOmIG 5T320e1n4t1 NNEEFFOOSSEEdTo6mOkks 4252.715169 dPioesrietinvte.values show pairs of means that are signicanty NEIFOSE113660.m8k0d0 18112.5500 70705000 N-EIFOSE1260OM3K0d 180851137 1328712832 w C0098 TorsLR Abmg 8 Dose Group " A ' S [ I STN IS N N=\YA N OO ) () l oonGo rRl ar = a 5 cnooa9 Tr0i7s01 FR `OSneuwmamyaAronyfovFiat RsRSqquuaarreeAg Root Mean SquareError o05s0s6e0r7r2 031563 MObesaenrvoaftiRoensspo(onrsSeum Wots) 37521724 NSooudrec!e OF AnalysSiusomfoVfaSrqiuaanrcees 4 26641413 MeoaneSeqiu0m3e FsRaetxieo ErCrootr 21 p1r.7e8s32)50 00028067205 p00r0o1b8 LeCvOeNlT Means for OnewNauymAbnecrva. Mean 8 ae250 0S1wg1E1m5o9r NNEEFFOOSSEA1t6O0mmIkGd NEFOSEdOmKd 24 3227500000 o02s23e19 4 aso orem PFOSAOmid 5 43000 Orete Std Eror usMeesaanspoaonlded$1estDiemvaitaetoifonasro variance. CLOevNelT NEFOSAdOmKd Nombe8r 4 36M1e2a5n0 03S7GD0esv 37000 o3tezzs Sid0E.m1M3e0a8n5 018811 NNEEFFOOSSEEdT06m0kmaK PROStOmK 42 33527000 0o1z5r00i020 5 43000 0208067 00.0175500000 0.12884 PFOOfeSM4eOanmlKla-Mean] NEFOSAdOmK PFOSIOmK MeansNCEoFmOpaSrMiOsomnMsK.d 000000 068000 07C4O7N5T0 NEFOSE0A7O8m5k0d0 068000 000000 00a7S0 0.12500 N-CEOFNOTSEdomkd NEFOSE 60m 007748755000 1.11000 001028570500 000030705000 "045000 03250 000003070500 032500 pha Compar0is0osns for each pair using Students t PFAObSs(ADOimfKLaSD PFO0S4A1OM9K3S 210!081 NEFOS0A2A1O5M1K6S8 036C0O4N8T4 N.EIF0O3S4E0A1O6K6d NCEoFnOtSAdOmKd, NEFOSEdOmk 0023165418648 0340168 0"3o146s5s8 003331185868 0339 03%a88 0.0336483598 0.488 NEFOSE 60m 0385195 012428 036174 "024528 Positive values show pai`rsCoofmmpaeriasotnnhasswiaheasicgonirfoicaunstindgieDreunt.tt Method 272f1l84 APDFSOSOALOmSKDd NEFOSAtOmKY 025c7o7n3t5 "0.43850 CNOENFTO.SEdomkd NEFOSEISmks 04s2s0a8s50 031688 N-EIFOSE1f161o0m0k0d 003465205000 00.3020500000 N-EIFOS0E5i5So8m1k5d 0.1162107248 o"0e2s435i2z8 5% "2200 TotAi0s7L1R 17 P8otDsoiotsrievoevGarlouuepssho(wmpgasirs of means thataresignificantly 0 A2 hd end COA A: Aa Ne- L 0. < vYv AANE con Werommaroseioms wr re oveGo rawheroscremmass aSoes t Duavsets Rsquare OSnievmaymAorrioFryaa osmaszz RReoaeontaoMrfeaARnegsSpqounasree Era 0s0a532r5se0 Ohsarvatons or SumWits) = Socdso OFs ArSiimofoVGisaSraiaaasnbrees MeaEnSNwaEw SFRaeio ESneora 2 J Tae me oowms moooro coLouver MeansforOnvaoymAevra eWsesm Sowwneenr NeNNFEEoFFsoOaSSsEEoAmoDkmmaaa 2i oSeimxtooo ooOrizaosseee Prosdomea 5 feo overer Lowe S16ErruseesarpsoNaolnmeabdetersatiDmoavteaaoMfnaesonr variaSncee v SiEnMesn cNNoEeIErFrOoSsEaoomkmaa T2 eGooxstoo ooozwrmesma oo0i2me0 PrNoEsFtOoSmeEdoma i5 GTemco 0oavsoo4 oDiosemss PrOfoesMetsaritjateani] PRO5S0I0Om0k0d0MeansNCoEmFpOarSi0As7Oo5nT0sK0S0 NEFOSoEAmOem 15C2O7N5T0 CNNEoEInFFoOsShEaddmmiaa 2S270o06050000 20003070950%0000 000020055000000 000203602105%00 Neroseseomka 4d000 285000 D5 03% N-EFOSEpa16raOemnKdd 0S08o37%15020050 w nnsoL Tbar0s7L1ER Aonas Co00ms fpo saeh|prauasinogSunest [ArseoveL50 POFSyING NEF2O10So02M0r1OiaMtGo NEFOSDEAiOmoD oCsONeT CNNEEorwroossntiiaanmkksd dGGiosrsaeasssests0 aSptsreeiin SuDsiemnr ooosrzms Neroseieoma osoores Sodese Qamssa ozaams Positive valuesshow pasCofmeoanmhtviapesSnafrcarritnygaaiufroemn snMetshod AsO27L5aS1D04 cont ENNREeorrSootssotdniasommad osooessssosss CoVuEfroseisoma Soi4ssmes% LUmPloCsiiaBtriyvaDenovsaeluGersousphowpa(inrrsgof meansthataresignificantly NEFOSEIG"aGDoiomnmmeissde SDDo2imaasmascse = A /2\ , 3 t1l 4a 0 2 A ANTN AL N cT o erov Bercsoctmeesn a ~We~e oc Ronny aw nse OSroemvaaynnoorvfa ognazr RRoeooaanuM!emaFenegSssaornsse Ere GGSoseoavaaeeetr0 Crenatons orSumWei) 2 Sooswes OF svimoofavSlaSlntmcmses MemmSwsaw Foamo ETrra i2" GTaeriasns uomuess moewnet SLoo Means or GnoNonvweacrT"ryaamMeman Shuereo uscno102 T0711 FR oTIS NN-EEIIFFOOSSEA1d6O0mmIkId PFN-OESIF4OOSEKAAOmKd 24 2312120500 83014539 54 w2847e50 230742579 1d ror usMeesaanspoaonldedStesdtDiemvaitaeotifonesrror variance LCeOveNlT Numbe8r 20M3e5a0n 7S.i8d8D7e8v NN--EEWIFFOOSSEA1O6m0Kmdkd 42 321215000 416969461960 PFNOESF4OS0EmAKOamKd 45 u278T7e500 248568637117 SIE Mean 319.907713 233801060 12820 PDFiOtS=M4e0amnK{-dMean(] CNOENIFTOSALOMKd NNEEIIFFOOSSEAEO1m0KmdK PFOSAOTKY MeansNC-oEmIpFaOrSiAs4oOnMsKd 205.100000 20100000 6524.815000 2797.08000 136.600 A150 5C4O1N0T0 N-EFOSE4Omkd 62850 200.000000 37.750 8750 682755000 730705000 Alphas PAFBSO(SD4I0-mLKSdD CNO-NEITFOSA4OmKd NN-EEIIFFOOSSEE146O0mmKKdd `Compar0i0s5ons fo each pair using Student'ts 2.10t091 PFOS8A1O.M0K51S N-EIFOS6A0O8M6K7S 1C8O9N8T 8180.896578 49004617 449047787 221031870 28os6t77 98782173 NEIFOSE2A1Om1k7d "6502782677 9307621373 Positive values show pairs`oCfommpeaarnissotnhsatwiateh asicgonnitfircoalnutlsyindgifeDruennnte.tt's Method 272fo1l84 PAFBOSS(4D0-MLKSdD. 40C5O5N0T7 CNO-NEITFOSALOmKd T8320617411 NN-EEFIOFSOESETAEOOmMKKdd 9482.87251619 fPoesriteinvte values show pais of means tha are significantly N-EIFOSE160mkd 113161650000 8732.570500 0.000 N-EIFOSE126003m8K0d 180851137 "13278..213632 8 r9103 To0r7s11 FR BUN mad By Dose Group (moldy) & A P a] y AN aTWT A oa L | i 9 LE VIN " con Re:roharierozon: = or wSea ogn i 0% wo 0 n2104 TpImOs7LI ER OSnuemwmaayryAnofcvFal RsRqSuauaarree Ady RMoeoalnMoefaRneSsqpuoanrseeError `Observations (or Sum Wats) 00216140600224 33108131765 2% Source OF Analys'iSsuomfoVfaSrqiuaancrees MeanSquare FRatio MoEndmeorl 194 270475.70580000 160489%7 P1r7o1b0o8F Com Ed 28162500 22148 01862 Level Means for OnewNaoymAbneorva. Mean SugEror NCoENFTOSAOmK 45 1i07000 t16i5e0r8 NNEEIFFOOSSEEd1O6m0mkKdd 3i 2ter000 1196055098 PFOSAOmkd 5 ies 1476s Std Error usMeesaanspoaonldedSetdsDetviiatmoifaonatsreo variance. LCeOveNlT Numbe5r 18M7e5a0n0 S4tddoDee0v NNEEFFOOSSEAIO6m0mKKdd 43 2160000000 226444807450 PFNOESFOASDEmdKOdmKG 45 liesrsoo 22126177985 Sid Er1m.M5e0a0n6 1125224178 01.91609857 NDEiFfMOeSaEn(T-6M0eamn() PFCOOSN4T0mkd NNEEFFOOSSEAdOOmmKKGd NEFOSEIGMOeaMnKs CompPaFrOiSsioOnsmkd CONT NEFOSEAmkd 302000000000 302000000000 302058000000 522055000000 352255000000 02005000000 200000000000 02.0000000000 500000 28000 275000 075000 Alphas NAbEsF(OOISELTS6D0mKd PFCOONST4.0mkd NNEEFFOOSSEAdOommKkGs Comparisofn0o0sr5each pair using Students t 208'301 NEFOSEIsGeOaMtKsde PFOtSeAaOsMeKrS 14C2O7N6T0 J1a42s78e0 34s3e0a0s 33848s8a8E93 o07o2227006s suseeass 212438110044 NEFO"S0E.A0O2m7k0d4 "225283418084 "p8r85e5y0 Posie values show pits`oCfommpeaarnissotnhswaiaheasicgonnitfriocaunstindigfDeruenntn.ett Method 270ol838 ANbEsF(OOSLEStDGOmS 27c6o3n0t2 PFCOONSTA.0mkd "L5a0s3a0r4s4 NNEEFFOOSSEA4doOmmkK a271e69s3 N-EIFOS6A0O0m0K0S0 228705000000 007050000000 N.EIFO0SA7O2m2K6S 1".r8a3g418084 p48e85c5t0 9 rnnio5 ToTiOsI FR = ALKPULGPeorBsyeiBneo.vsaeluGerossupho(wpmigsrofmeansthatare significantly = gawd >0 " o . C lolP o=l .- 2 NOO ET Ti ( Na )J Ouse no monn 00s oot Rquare OSnuemvmaaryyAvoovFa osxe2 RRaoMuoeaatnrMoeefaARnedSsjapuoenrsee Ercr oesse0sss7s 243875 Obsanatons (or Sum te) i NSowdee DF" AnaSulomfyovSalsr3Siwia0nrsc5ees MemSaquarse Rseatro TEnoerw 2 25T5on2es25z7s5 w1o3m693 Poooo0fs Lcooverr MeansforOnewNaoymAbneTcraomeMesan SueErser NENNEEFFFOOOSSEStAEemO0imKkaa 43i aatmeaoonwo 2eeww1ss PrOS4OmG 5 teiso ier Lovet 510 ErrusVes peoNoaolnmeabadSeerasDinmeavteosonfMaseonc variance SWDev SWENMean NECoFnOtSAOkS NEFOSETEDmks T43 ammdeeaso w9Bia9s0 221535002801880 PrNOESFAOOSmEaOms +5 aiememe awie s 17az5801 NEDiFcOMeSmAfiOMmeanl] NEFOSA0MMe0Oa0Gns Compa2rC6iOs2NosTns NEFOSEA1O0m0K0S MEFOSETI0S0O2m0i NcEoNFEnOFtSOESdE06m0Kms oB2d8oz0o08 2mse00r0s0 35023000s0 BT0e0a0s0 PrOSOmd Giges tos ss650 12400 PRO1SI1O6m6Asd oararsaoe0 2000 %0206 ro secrorosmoar ahee nesses evosmss moses fEeEeEmn,ssA thrsEooTsEtma2emms 3RE Jih Gree EE 4Gm8 i4nB r mE ses srt : FH] Toe <i" Aa - 1 Q- L) eo: =; No 7 = CONT NEIFOSAMOMMIEFOSEdomas | E70PO oL r BeeTe etpShEo.E--e m--RTe nEwOSEIEOmDSS SUE! "WR Dat Suree 5a% we 5re comBmEPmwe ouvme )Chae? TT0s701 FR NNEEFFOOSSETA6O0mmKkd PFNOESIFHOOSmEI4A0mKd 43 srseaemr0 6s9e1sss 45 e7i2a0s00 s5e3e6s Std Eton usMeesaanspoaonldedSiedstDiemvatietioofenrsrorvariance CLOevNelT Number8 sMieasn 7S7W0D7e4v NNEEFFOOSSEA1O60mmEK 43 e73ssae0y Taeorutms PFNOESF4OS0EmdkOdmkd 54 eT2i0m0o ssooums SidE6m2M6e0sn5 3235383730 320517526 DCiOfNeTM,ean{-Mean(] NNEEIFFOOSSAEddO0mmKkdd PFNOESFAOOSmEKTd0mKG Aphas CAbOsN(TDiLSD NNEEFFOOSSEA4dOOmmiid NPEFFOOSSAEO1m6dOmd CONT MeNanEsFOCoSmApaWrOisMoKnIs. 13080705000 10308070500 "21972875500 "45..00600000 25.4583 11.6833 NEFOSEAeIsMKoS 0400000000 E5r0500 `Com0pa0rsisonsfo each pai using Students t 208t301 "1C2O5N47T N-EFOSA"A1O.M47K6I8 NEFOSE2A5M2K%S "215427326 "1173.77226688 a13r7e26s8 Bsaeesz T"7s767e1 CGauesne PFO22S0M25m0 9500550000 205003030 PFOS8A6m3k3d2 a7i776e7n iisss7rsase Positive values show pairs`CoofmmpeaarinssotnhsawliaheasicgoniifrilcaunstindgifeDruennnte.tt's Method 270I]438 ACOBNSTOLSD 16.c1o9n8t1 NNEEFFOOSSAEd4OommKkdd "59e6e1n1 PFNOEFSO{SOEmTY0mKd 4345528870 ePorseitnitv.e values show air of means thal ae significantly ALT UL By Dose Group (mg/Kgiday) N-EFOSE215G405m8K3S 17155883333 020503030 N-EIFOSEB146806m2K 171.5568338 C"i2s074784981 % n231.08 s=ana A Yo i. ro oe) 5 - oteGun (romp oss. 00s. aorsl[Li on ofaers TS e EEE t D cn e Ssio3 Hurw 7--G-- ETeHaEEn niwTegEemEp inSaEm - NeyeTEoro em em [ NH3eNao--s, PH iopEmmaxIaaee fner S pTe r loyk on seen eCOrosom , Pi oagpgeEgWuee =Twoaw 5ine3pnEptiory eroscima aon nermm[ ome -- TEPTroUs,ioonme sdcoonw FBnarem gggeam asmme comocsrpno" neriess werosni2ewmm0n ofmA verfrnooiem 1sa ws "2109 b0rs.1 ER sPersooOnsieasona NEFOSTEIomma 2O000MT1 uTm Ser sem icCOomNmT NEFOfpSEirAeeOdtm NJKEasRoeSseioma gStoeEs nhhaidmm osoama p3eu3n% Poste vive show prCeofmaorreor scanty arnt a abot JNoEe2 fRsIeo! nO Scoont PJ orraia 2 iw NEROSoma home TR PmJoptutueoetkeussGrohup owmsiofgmans hav scanty NEFOSMSrOmaeksd 2pS%oo WALA AO Belfh = 71 7yaAy / A2\| e= rr ( SE\ J N-EFOSEI6ORROSS `DoseGroup (mo/Kpiday) = o%5 y Roe OSneaors Reng oSsesanes RrCoostetmalaniSaruEmvr3) Reones% prHsoaoaurce oAFna hiomfvoSatraCrrcesss MemSSqEme 8 lemma aEernaeteo eB MEE BD em Looeu Moors RFossioma or nevi a ArTcaouetn {pum Sur aes NEEFrSoSErioomnas F io%Ea NE chasse Tpiamm prosiomks 5 amo ome Lovet Sor seapNon olmeaderstGimoarteeoMfraonr vinScWeDev Siem SNKoEFrnoosseaosmomses NEFoSEioms DSo oneReumym sthohemene oSpoira 1k wes eee Frosonss Pas ue HA OfoKtFreoasnet oemaar Scooont [ "NERGS-- Eainonta NeFosr aomaRPr] OSiom 59% Sisco rie Seek PNNrEeorrsooissstieoammas aLrreierse SS2a7ac5a0 hSI omoo . EouRn Aas C0o0smpforoach\prisusinogSndns RNaoossesma PCrONT NerFO2S0r5Es0M0eM1ta 3151 Fr) NEFOr eSAtOoTiPRe OoSKnM FNNreeorrsoiosotsniosemomaa zT1uaarem% STsaoonrn ESTierms NseEm soevales showpoeCofmeoansnmtviprne oaiciannviigiSfoonmensMetshod Aco0n 12755Idkize Pceonit FNNreiorrsooissoaemiwsommaa 3AS9ams%sy NerSsema ia Comsine otdotfor males adfemalePsGosesnvales showpasofmeans ht ars sigcanty SGcocuaies I ALKP, AST andTAG5340 hd PEOS ad 160 mkd NEFOSE rts NEFOSEIpSSooeTmoksdas "pSo=oso]so NEFOSEaSiomesid PaTooireo] o croasz pat mgeetcp gr "1.= ASA :3 I Ll = ANA mo] A\/ wo] Lv ANN W, com weroskimreeroeteioma or oseGo Ing ous Tee Lom p noaa2 TboIriOsTLIR OSnuemwamyaAronyfovFat RRSsqquuarree Ag RoMeoatnMoefanResSpqounasree Error `Observations (or Sum Wats) Source OF Analys'iSsuomfoVfaSraiuaanrcees MEondoerl " 630947044.59258 Co 2 o7370.478 Level Means for OnewNauymAbneorva CNOENFTOSAMOmK NEFOSEI60mKd 452 NPFEOFSOASOEm4iOdmKd 5 o0.a1v5z0z3a8r9 6300.106806817 2 Mean7S6a0u1m1e3 F2Ra0t2i0o a372s083 Porobmor 20Me5a0n Si2E1r5o8r8 a2e0s00 4431m33 awae75o0 0z4z 51d ror usMeesaanspoaonldedStesdtDiemvaitaetoifonesror variance. LeCvoenlt NEFOSAdOmK Numbe8r 2:Me5a0n eSreevs SidEr3r1M0e7s3n 4 320 19046 Sort NNEEIFFOOSSEEdToommKkdd PFOSAOMKE 24 2m1r0s0 4as6enmy 233801060 5 sare 286671 2820 PFOfOMSeAanOlmlk-dMeanf) PFOSAOmKd MeansNCEoFmOpSarAiMsOomnksd 0000 210 5C4O1N0T0 NEIFOSE2AO8M5K0I NCOENFTOSAdOmKd NEFOSEdomK 2554..110000 "82850 2090000 20000000 7750 8750 378775500 0000 NEIFOSET0mKd 135600 1150 82500 737% Alphas Compar0i0sosnsforeach pair using Students| AbsD-LSD PFOSAMKI 2 10t081 N-EFOSAOTKS CONT N.EFOSEAOmkd NPEFFOSOASOAmKOdmK "s801806571 CONT. "8950 0S6o1t7s a18v.a9n5t8 war 4078 C235121677 S127 NNEEIFFOOSSEEdTo0mmKKdc 2203318107 S2o0s6 eaoiraar "7028317 Positive values show pair`oCfommpeaarnissotnhstwairheasicgonnitfroilcaunstindgifDeruennnte.tts Method 272a1l84 APbFsO(SOAOLmSKdD 40C5O5N0T7 NCOENFTOSAOmA T2s63701t11 NNEEFFOOSSEEIdGOOmmKkdd 4280.2751610 N-EIFOSE1f366o.m5k0d0 18121550000 70705000 N-EFOSEf2S0O3m8k0d 108581173 13278.12832 9% n2113 5 = i fS ro ARA A 4p - i BR=K A aA) HAN 2 T A = -- ers CONT NEEOSAmMEIFOTSHE VV wrose earese SiteZ pn Sovy Demat: 7 / Sspee,A gn ERE ete S-- 3em LhintSome ee% Bpmr %J ESE eelam vgwegnen errn BF Sn i[--8 T--E"{lomnIsos= epm 1seoO m ECC LLL EE tSonia y RrrTIEo1Ss tTe4TA 2ce e W9er2e. essTg Uf Romss ew, 1PaSommEe ogRamEn ogheen iTgverpmer.s Amc4oE2m -- 2"Fgm2OmEE RerosyTty=EymRs ncroseTaegmRwys BbEeEm 2 3 32Bm 40%B &=8 werosuoms nT=7HeE "2124 we jwneiso Tew, " cour srosiabe; weroscim nesoscioms SWDEI OmEE dnaromseims aweroRscimus rete ouiStome 2 ttdytc Poem, mE seerririmmraeetop hme tom spt - A- wP i =N Aoa C fel = FL LOY OY ATT i, - OO) " T Tach NEFOSAMBFOSEsOmig En EO" PO EEVACA DoseGroup(meKaidey) ----005 00s | EffoeTntosows S=si PR BEGoF ETHEER aiEE om to eonTsE tn seer nerosmowerrossasgs on 2315 wons R NNEENrFeoSoSSEsEirceoonmssa Frosima Pmonooasmmm oosomm on Leovd EonseesroNonios rsTatoaatos"iatgrne viSScaevems sirSeNnD NFENNrFEEorosFoSioSEosEumimaiaoammmaia DPSFooodE meee Sceoewm hE dcaume im RSEDoruiSrSeinltomea) NEFOSolMaOo[ mMoeG -- s1Co6OmmNomT NEFOScTEAaEIsm PR"eOOMSeeOs PKNreEofrsooiSsEcasamnaia GSH iuoI mSiis Sa Soemme ioitaohmoe Apr Cam0fp0ossah|rpa susinogSunnts Jj[ Srr o -- nEFOfTSMornwia 2o0CmOmmNT NeFoSTa Taimma PRoOTSiOumSka SRE aes Fa omen NFerroossitonisaana [frorr iCna hrme [TT ----Cam--pari--vS i --2 Si-- hea -- g Samet Mebed pSNroeemya Nfoseuma 13F3c5oo5n5s0t FNeeorssooSnsama Soasse Ks eA Bns Grup (rol ---- NEFOSEIpSGrOim]d SSBootmm] NEFOSEp5 IaG1eraoo5m]uen5s 2 60316 on 5 Pf lh se S L]aT a N TOl T Ea N) . FA| = O =X cmsmer28 CONT NEIFOSAOMEBFOSES nErosEempass wsSupper Sues 5Sarcoma Ouwatts are pa REsseoamaemin we i foSnemums sme ET or0 rEpISmsyStmn 2 cweea sreoee gSew EpB rEmEsms oTepems oeid -oMtoyrroriWnse,strAarTooPrsooIEwmEmow sutrc = cum pLirl {Poogmmm cuumms Ein--) _--ErriTeW le tTaetO emntenrc trmfgeoamems outTSreeunmnd Leeann, heres Pogam cum Pome oom ems smn EoMgnisoreoresourmmasa ies 2a2c2eow -- "VEJTToESk oom werossMieroonSnsg oem werosFfwyeraosromuosms rroesriosoimonss 2mm Swe gam Sm ine a apr = Fr Cwroe hunngss rs ! `enna T o7is aER AcsoonLS0 05C0O1N3T WEFOS"2E100I00G8D10T%G NEFOS5E0AaOM NEFOSTMeOmMeK NNNEEEfFrooossseEaiiosoommmaaa 101051000%%9 oSi172s0e0ae0e2s Ao20s500s2% SEomwcse Prosdmia Zadna 0505s Q5eu7 Dies Posievaluesshow pairs oCfmeoans mrtwaiprneasiGagonnfcoarlnvtiy idgiDurnontett'nsMetshod coABuSrOI27L5JS1)D64 dcoonmt NNNeEerRvooossstiaieooommmaaa~ 005oi2see5eo8nr32s Postma 20s GrmolPtGo.setBryveBeonsvaelvGersosuhpo(wpnagsaof)meansthatare sgrifcanty PFOzoSKsIamskd ArOismreea wo wonl =. 1=1= 4 j \ Uo 7 Aa N \il | LN x wl o VY S TT or awenrodteasRmoaSsreoitocmimounsaa | BS=PeEt Oe= umaer Rsare SOnoemvaayAorionFaa RRMooeoaatnrMoofaARnegSsapuoanrseeErr Onsenatons (om vii) oSodurece OFL AnSuaomfoviiaSrSiahasnwceses ECrloon "2 sStieecss0 Lcoovnen MeansforOneaNyoAenrx7 a NNNEEEFFFOooSSsEAE10o6m0mwmaa 2Io a22ot5zo5en1ae0r?6e Sovean=s MeaosnoSuawaisw Rpeawotnre seas 026 immMeeeswn SuotEriromnr jmon iisme Tot cn0118 TorIiOIFR PFOSAOmKa 5 102000 1000 1d Error usMeesaanspoaonldedSiedstDiemvaitaetiofonesnor variance CLOevNelT Number8 10M0e6a2n5 2SW8Dme7v NENFEOFOSSEA1t6O0mmKkSd 42 11004005000 1000900s0 NPFEOFSO4SDEmdkOamKd 45 1021020500 21682101846 SWE 0M9e4a3n7 o0g0s07040 o13o18m0 ONiEteFMOeSanEiI-6Me0amndt] PFNOESFOOSmAktdOmK NCOENFTO'SE4Omkd Alphas ANbEsFOO-SLESIOS0mK PFNEOFSOASOAKddOmKd NCEoFnO'SEdomka NEFOSEIMGeOanMs C~o~mpNaEriFsOonSsMOMKS PFOSAOMKS NEIFOSEAOkd 005000000000 005000000000 210500000000 + 222755000000 227050000000 2520500000 007050000000 007050000000 337500 2870 137500 062500 `Comparis0foo0nr5eachpair using Studentts 210!001 NEFOSEI"S47O3m9k0d0 NEFOS3AA6O0Mkid PFO1S.A0O6M7K6S NEFOS1E3A5O4m0k6i 316.906455766 Gesroesss 2ee0m7mss rZiazoetss ""1033s7i2c9e Coootzeess 2ta4z2r0a6r8 S2s2e8 Posie values show pairs`oCfommpeaarnissotnhsatwiarteasicgonnitrfoilcaunstindgifDeruenetts Method 27211]84 ANbESIOFNOSLEStDSOmka 1.c4o79n8t2 PFNOESFO{SOAmdKOdmKd, "2o.s1s2s5e826 NCEoFnOSE4Omkd "330173055426 iPorsiettiv.e values show pais of means thal ae significantly CREA mga. By Dose Group (mgkolcay) 33C7O5N0T0. 218377550000 006020500000 03C7O2N2T9 032277261s 2223107060 10s n2119 n5im or tel est R tP . ee AA7) N .( A N Ia ) ~~|9]9] E omer e= = fgr--.PnRr osases SLemEinSymiees ssreg3e pameeroo poR Sinmenm suwiemasemw orcoene EEA -Haim[Ie TE7Doosopaomw sEsemea iRi rIosons, 3PDooopgpsgm nsaooomm pa-h oarsWsiT oLdTTan nIrcv GdoEo osSgmn i Sreeg, ens 3P1 oi ooamm ssoomme osBemEme BSfrorseriniirWreEs cEomTaaERrIsN eoepnm rewsemRp 2 ome BeRFsseen: 32288 ss=amz go=mm omm=se sew jut Conn00s xn3 sets 0 noAR0 TotisauER fNAresrOeosLtiSDomd P"F5OD0S0oK0sm3s3K NEF2O1S0pA00Mr1OeTNdS Dios NEFOS"E0fG0Go0O3ms0ktd4 NEFO0"SEo0AwM0sS 000oC0sOoNsrTs NNpEEsFFOOSSEEidcomoma GoQ30000e0e0s00sre8ss o200ou50u0rs1 DSDiioaoso0rmr 2DDi0oze3no%sr dSooooonrarss Posive valuesshowparCofmooanstmhtwaiprnssinagiofclarnitygefrDounonntttns etshos A0sOi2L55aDh cont PNNPEeOrrsoossenioonmaa ooo0g1oa0n2or6s8 . SoNEurrostoma caosssiss Circa chifotr sts (es andPGeforsaeines:vacloumebsisnheodwipaDrT1sGoSf.moSahnoswtshstigaiecsoingtnificant chraaornagereesadoscmcuphreoint4g0aimnskhbeyP44F00SkaPPFFnO40SSm,doeNsaEeIgLrFoOEuSpGE ACanddoLrseEWge(OeCSR:AaEAwTiiwhasnsratnnsineaort 0 cn0122 Tbrsie B. Statistics on Clinical ChemistrceosmfboirGnuedi.nea Pig, male and female values CHOL mgt. by Des Ga ino E2 1 A+ A (/\0 oa / Ann E/ \ SZ > Rw J cont" rn.erosand7 Prroosssis &Sah a Par TrWPits Yenoaoz TomIisOLIR OSunmemwaaryAynoofvFia. ReRqSquuiarree Ag RMoooatnMoefaRnesSpqounasree Error Observations (or Sum Wets) 00310634758825 0.2434373675 Source OF AnalysSiusmooffVSaariuaenrcees MeanSquare Fal NoEndoen! 13s 3166783..81405 T5910028 P2r1ow0o1F Cow 18 11761047 esses 01327 LCoOveNlT Means for OnewNauymbAencrva. Mean 6 wos StoEsromr NNEEFFOOSSEAddoOmmkKad PFOS4OmKd 44 mTasmo rtieemm 5 54000 04k 51d rorusMeesaanpsooalneddSeisdtiDmevaitaetoiofnse.rovariance. Lecvoenlt Numbe5r s0Memann wSWeDreev NEFOSEdaom]Kd +4 m7m70s 3270540304 PFOSAOmKd 5 ses0 20787 SidEm8M.e1s5n6 115827157 9280 DiNfEeFMOeaSnAi4iOMmeKaGn) PCFOONSTOmKd NEFOSE4omAd NEFMOeSanAsSOCoMmKpGarisonPsFOSAOMKS CONT 106.08050000 10608050000 311468816677 STasse 0e5m2e0r 507000080 Alphas Comparisons for eac0h0psair using Student{s 213t104 NAbEsF(OOSiA-LdSODmKd NEFOSBA2O1T4S7 PFOeSsIOsmKed 0C4O7N9T8 PFCOONSTA.OmKY NEFOSEdomK e0s47s9e8 351347%0 125837952974 2160 zee 26432 Positive values`sChomopwapraiissonosfwmiethanasctohnattoalreussiinggniDfuicmalntt sdifMeeretnhto.d 262o8l08 NAEbsF(OOSiAndLSODmId 7c5o8n3t8 PFCOONST40md 2f37r87 NEFOSEdOmk 339421 N.EIFOS3E7A.O3m7K5d0 25075028530 00000 N-EFOSE2d.1O6m0K8 128248368226 382147 Paofsfietrievnetvalues show parsofmeatnhas ae significant Cholesterol, Male and female guinea pig combined 109 72423 TT0I7S11 FR "gna 0 oris 1 Cagoy oseGp ggg 20 : wl A - N A CI AA / AL NC X ; o 2N 7 TYH A wil/ 7 i | ne con iT ece] r NEFOSMOTKI PFC f aowwi ry f Dooweinec neneaRs TIOLIFR bTIS OSnuemwmaayryAnofovFiat RRsSqquuaarree Ad) MRoeoatnMoefaRnesSpqounasree Error Observations (or Sum Wots) 000719520819 060122.412785 16 SoNuodrec!e OF Analys'iSsuomfoViaSrqiuaanrcees MeanSquare F Ratio 3 03750000 0125000 03444 CErroorw 125 4437535000000000 0033662383137 P0r7o9t%o CLOeNveTl Means for OnewNauymbAenrcva Mean 4 mgs oSugaErnmor NENFEFOOSSEAddoOmmkKd 44 11222e000000 003300172211 PFOS40mkd 4 is osm 1d Error uMseeasnspoaonldedSdestDiemvaitaetoiofnasro variance Lecvoenlt NEFOSAsOmKd Number4 nMoeaon 080Sst1D0e8v Su E0m.M40e2a8n5 4 12200 oseazes 028439 PFNOESFAOOSEmdKoSmkd 44 i124s000 oOassessss 002224886373 DiNfEzFMOeSaEnAiOMmeKaGn) N.PFEOISFAO0OSmAdOmA cont Aipha= ANbEsI(FOOSLESdDomke PFNOESF4OOSmKAdOmK CONT NEFMOeSanEsOCMoAmpGarisons.NEFOSAMOmK 000000020 00020000000000 o0a2z1s5 "02027s5 Comparisons for eac0h0psir using Student'ts 217t882 NEFOS"E0O92T8K1S3 N-EFO0S7M2O8m1K3S "07825831133 0o8w3e1s3 "050813 070313 Posiive values`sChomopwaprairssonosfwmietahnasctohraoaeussiinggniDcuannnteytdtifMeertehntod 268ol204 ANbEs(FDOiSELdSoDmks 07c1o7n8t8 PFNOESF#O0SmAkOdTKS 0"09910728888 cont 1.14288 PF0O2S7A5O0mk0d0 00007080000000 015 PF0O6S5A3O1k3S 0o@sB1s3 oes 042C5O0N0T0 00.212550000000 0.000000 05C0O3N1T3 0077708133 ower fPeorseiinvte,values show pair of means tha ae significant PHOS mgidL. By Dose Group (mg/Kpiday) nn0I26 Tbr0ie71F1R o SAAN S/AL=\ 4 wl NET A FN i vo VED \ v { Y -- re -- ww Te oocmnngrgeny om ou Rsqure OSnoevmaayAorcrursa orarase RRMoetaavneataenRaeSqsqpuoanrsee Er d"(rorefeszisr Chsanatons orSum We) Nsooduec:e oF5 AnSiaomfTVoiarrieSasnscses Me"mGsiwtwese Roowtno Toeaw 6 iTasro oomseanmsa Boeonmt wCootn Means orOneNowraaTvyaoMoaan Soisnm NPNrEeowFsoosssotaniaaoommsa 11 1S% Sum SOoulmeeennn Lovet S10 rorusWesapeNioamenosdaeSriasinDmoavtiettao"fnasemrrvariaSnicaeDov sdEntiean NNSenFoorssaeammiaa BmoogSmio0mm ooomskmemn ooozrsmeoesn Prosims LoSm me oem ONiEewMoosatii}oomosl) NEJ FOSpEI-- MrAG CONT NEFOaSAaOTnKS PF0O7S5O0n0K0S0 oNPreuoFrsoiosnaisaoms 0S33e% co00 nc%n 20007050E00r00 brarasdooon Aras Comfporeaae0|p0rsa isinsgSuodns sNsERnOsiEssama NEFOSTEAiO2eMrnGesz oCsONoT NEFOSDMOomwknd PFOCSoKsImaKsS mn cnoaR? TIO7LI FR ori cNoEnFtOSAOmKd PFOS<OmKd s08e2e10s8 11.1129160088 Dae 072108 1110260088 007702610088 o7o608 1.19608 Posiive values`sChomopwapraiisrosonsfwmiehanasctohnrtooallreussiinggniDfuicnannet rdffMeertehntod AbSO2-6L8S2D04 cont NCoEnFTOSEdOmkd 1a.1m97e82 PFNOESFHOOSmAKOdmKd "1o.s3e9r7e822 he two analysesdirect Above arefor Paoseitrivoe values show pars of means tha are significantly guinea pig Ca and PHOS, male and female combined. No sig changes occured -- i -------- a n2Ar8 feBhs Ke nal. DoseGrup (ps W ESA a 1. i 2 5: he -- a con aroamrcrsosar GSoere oteGp (rama) oss O Wbeoese 00s "noane ToiIsLL OSnuemwamyaAronyfovFai RRsSqquuaarree Ag RMoooatnMeofaRnesSpqounasree Error `Observations or Sum Wats) ooss20ss678678 18.21345012098 fl SMooudrsc!e E3 rror OF AnalySsuismooffVaSrqiuaanrcees Mean Square Ratio 33 213156809285000 71192097858 sParorveo 16 23043089 wast <0007 Level Means for OnewNauymAbneorva Mean Su Emor NECOFNOTSAOmKG 44 1628s0s000 005577000055 PNFEOFSO4S0Em4domk 45 1a22s0o0 o05s70e05 19 Error usMeesanaspoanldedSiedstDiemvaitaetioofnesnorvariance CLeOvNelT Numbe4r 28Me0a0n 1S0W6Desv NNEEFFOOSSAEtOOmmKKG 44 e2s0o0 ooseszses PFOSAOmkd 5 asa0 15461 Sid0E5r0M8e2s7n 00384173621 osotes CDOiNfeTb"ean(-Mean] NNEEFFOOSSAEOOmmKK PFOS4Omkd CMOeNaTns~ComNpEaFriOsSoEnsAOmkd 008000000000 00.6000000000 581.512000000 575825000000 N-EFOS6M1O5m0k0d0 5050500000 497000 Apra= Comparisons0f0osr each pair using Student{s 216087 ACbONsTO. LSD NEFOSEdOmKd 17C4O1N6T4 NEFOSTETdtO6mdk 114164 "r7at64 N-EFOS4A4O0m8k3d e086 PFNOESF#OOSmAKddOMKS 46.440678733 3e86078338 Ao7m4e6 PFO5S.A1O2m0K0S0 17.9572000000 0.00000 PFO6S4A6O7m7K3S 0s3s1e7r7r3s vss Positive values `sChoomwpparlissoonfs wmiehanasctohnatloaloussiinggniDfuicnanetsdifMeertehntod 264a3l45 ACosnOTLSD 21c3o5n0t3 NNEEFFOOSSEMAOOmmKKGS 14.0513450073 PFOSAomKd 6088 Piofseirteinvte.values show pais of means that are significantly `N-AFOibSAoorogtvu4i0neemoaKpgiigacaoym.binedmale and femal poasium levels. Sig reduced by PFOS and ne 12430 aa AA I MEASYO = hud EachPar. VonConra 043s ToiAsLI OSnuemwmayarAonyfovFiat RRsSqauuaarree Ag) MRoeoatneofaRnesSpqounasree Error Observations (or Sum Wots) 00.0152808419 00..110761705883 10 MSooduercle OF AnalysSiusmooffVSaariuaanrcees 3 001062081 MeOanoSqouroe F0R3a1t0i8o CErroor 1iss 001178010578889353 0o0o1l1o3o9e7s P0r8o1b7osr Love! Means for OnewNauymbAenrava Mean Sig Eror CNoEnFtOSAdOmK NEFOSEdomks 45 oo1sm00e0 0o0oa5s3e3 4 otes0 005i PFOSAOmKA 5 0210000 004774 S10 ror uMseesanaspoaonldedSiedstDiemvatietoofnsero variance. LeCvOeNlT NEFOSAOmK Nombe6r 015M6e3a3n3 00S9d1D7e4v2 4 0180000 0087735 PFNEOFSO4SOEm4dOmKd 45 o02l10e0s0 00111403816788 Sid0E0r3M7e4a5n 000052584637 006603 DPiFtOMSeAaOnmlKld-Mean] NCOENFTO.SE4OmK NEFOSAdOmKS PFOMSeAaOnmsdComparNiEsFonOsSEAOmkd 0000.00407050 00000407050000 005010687 00000142157 0.0C5O16N6T7 00..000004010607 000833 Alphas Comparisonsfor0e0asch pair using Students{ 213t 14 PAFbOSS4OOLmkSdO NEFOSEdomKa PFO"0S.I1O4m3K91S 010514 NEFOS0E1A0O8m1K4d 00C8O8N12T "i609 0271 CNoEnFtOSAOmKd "0o0s0e28142 oottes 0o13u8r85 Positive values s`Choomwpapraiirssonosf mwietahnasctohnatlorleussiinggniDfuninceatntt'difMeeretnhto.d 2621)808 PAFbOsS(ADIOfmLkSdD 11c8o2n8t NCOENFTOSEOmK "0"60210747 NEFOSAdOmKS 0.17283 N-EIFO0S0A6L0O0m0k0d 00000182353030 0000000 N-EFO"S0A0O0m2E6S4 00..113488845 0.1609 Pafofseirievnetvalues show pairs of means that ae signicanty Alb mg/d. By Dose Group (my/Kgiday) ns C2432 ToTios m = IwolZA:RPED RA E7 Av fa A A[NS aN| 2 7 7I 1 - . * -- wer--oNe:rosttumrao EachPor Souwsest owsr "WithControl fare OSneovmeyanoorvraa ozisezs RRMoeadarnaetaanasSgsaumrees ror SSGoisroSernsst Otevatons orSumWe) % Sosoee OAFLoes SiomfoTViaSroimamnecees MeUmwees F(aooe THoew B3 Deimme Ooilse poeemr oowrt Me forOnenyNeoyAosrno|ra zMeman SGirreew FNrEorsooissaemaisommaa 1odGummm ooGmmE Lovet 18Eror aees iapNconmieegurtabmoanvtseiaaocwnrnorvariSaincoeey SwEnesn SNKoeEurFroossstuioonmtas Prosioms SaGGxSiaeoo oGammieemnse bbGraoemss Does ie Shon PNOriEeorMsSasishoriimioaemaensl] NEeFnOSsSoMoCoOoomMspGoars|aPnsRasOsoSs0 NEFOSSEiAmKoA 0aCoOeNnT Sos ooo Gisooe0 033% CNoinostianka ola5s osFrs Geoosoosoo G0oreosssaes Apa Comfor sapca\opsiauirSodean NAEuRsSosinhLasnDka NEFOpSM2rIdmee PROSMINTK NEFOSTEoAOmmsS oCoONmT no70133 TotisLR CpNorenortsossmEisaoma aDDaoeoer Duolssreeeesr oaa5sstsss oooszeesr PosiivevaluessChoomwppanaisonosfmweiahnstcohnttoalreisnggicDuannmteyrfs rMeethod Abson2d1bo5hDce cont NPNrEEoFFSOOdSSmEAiADcOnnKGS D001oi6oe0aa4ss8 cont om TeBPyoGDseosireemGvraoluupes h(omwaprgaersofmeansthat aesincanty = L . o ve wvD XY ] :- 9oO CONT NEFOSAtoma PFOSIR ChPM DoseGroup(naNaEmF)OSEOm Soasts e Yroabel Sowuse RquareSOonevmayaAnooFvaa 0360 RoReatan MorafaRnAesgSpconasreeEror ofosrsezo0tse]s Observations or SumWats) fi} MSoosc OF5 AnSusomfovZafyraSiwiasnwrcmees MeomSmwaee FfeRasieo ECroow 5 SDorwos oomwincs mooeosr Loovnet Means orOnewNaoybAenrova GS asMeeamn Soignzor PNNrEEoFFsoodssmEaiioaonmia i45 5SS7io%dm Ooorsmeees Love 510 Ero usMes peo2l0edaSdedstDniomvaitaesioofnasorvariance Nomber Mem SigDey SUE Mean Sr Tamim osm oaies 2134 a piioo . rPeEE EE BaEGTEI Weomm weroMEmR wcoan pl rorSsosEyEs Ru I BfEeRRl. EodmtE OrEoEmme wHB ovEen Eouomn mme ----h--eg ----t--es piel, . si pA o wl SN * A S\N : weSee ] =o3e ] CONT NEFOSAWOmks PFOSA0s ENP di C2435 TT0s701 FR OSunmemwaaryAynoofvFai RRsSqquuaarree Ad RMoeoatnoMfeRaensSpqounasree Error `Observations or Sum Wats) 0001178748827 213a0522364322 3 SMooudrecle OF AnalysSiusmooffvSaqriuaanrcees 3 1603509 MesnoSsquusaoe FR0a0teiaoz ErCoorl 118s 8865713363834323 a56s7t5e5r6 Porosvoer Level Meansfor OnewNaoymbAenrova. Mean SudEnor cNo-nEtIFOSAOmK 46 t1aasg0s0 o19g2 PNFEOFSOOSEmdAomkd 45 11ea0s000 t10i8e8r4 1d Error uMseesanaspoanodediedstDiemvaitaetioofnesror variance LCoOveNlT NEFOSAOmKG Numbe6r taMseearn 1S2t1D1e0v SidE0m.M4e9s4n4 4 1as00 238048 11902 PFNOESF4O0SmEKddOmKd 54 114e8c0000 32767242889 1152861110 PROOfeSMAeOamn(KiAMean(] ~~ PFOSMAeOaMnKsGComparisoCnOsN.T 0000000 0.133333 N.EIFO0S3A0O0m0k0d0 N-EIFO0S8E040O0m0k0d CNOENFTOSAOmKS NEFOSEcomka 01330333 00.10600006070 08 0sess7 00..010608066070 05 00.858080608070 0000000 Alphas Comparison fo0r0esach par using Studentts ADSOILSD PFOSAOMKS213:144CONT NEFOSAMOmkS N-EFOSE4omkd PFcOoSn4TOmKd NEFOSAOmK 2312141s0 229934116484 Frost 311108 3"31110180351 50058 "226610180381 "308086 NEFOSEdomKe Zeoext 2610 "300056 "350056 Posiive values `sChoomwpaariisoonfs mwietahnasctohnartorleussiinggniDiucnannteytdteMreetnh,od 262o8l08 APvFsO(SD4iOmLcSdD 36c5o0n1t0 CNOENFTOSAdOmkS S3s817660127 NEFOSEdOmKS 3.37817 Paofseire values show pai of means tha ae signicanty GLU mgd By Dose Group (moiday) im "2136 Torsan -0 C~o 400. : A A go=l1 NALC SN NL T AN N def = TN) LN LS ) " on TeemosaNiemrsostroonsae|s | SEAPTS oseGrup aay 005 DCuraasr { 005 | RsqureOnS ewayo Arora ReqvareAg oposseizs RWCreotaesnrsieoRndeeosrrssSEumrrte nfieefdi] isToyut or5 Anesofivyasnanscese 3 mong ensrSueheeds erGaaameoe a Teams Ss ome LoSvoet MesosforOneyNeoyoArr"Tosameman REFosasomis Dae Sii sgErwor PNrEorsoistioma iioEEem aBma Loovuerr aErrssosmapNoaonlmdoeed5re4sbtaotveoe"fNnargorvariSanoceey Toms we 0EmUhetaen FKNroEisriooosmsesiskomsa IDPOooammmsR umeemms 9 aunme NDNiEEctOkoessnhiooomld) NEFeoOnSsEGCAooGnmMoparsonsNEFOSa MOmiS 575000 Goooo PFOoCSAiOmmTInS sHCoeONwwT CPoronsiomes SSaostiiere Tdeeews aovme Hdoeme j- Conpforeaa 0p0rsirsusinagSdnentss ANEMRDSILSDna NEFOESE2SAiGdee| NEFOStMonwes PROTSGem sCeONmT `eroaa7 ooear whieetrroosnsisons Bmwzyn TEwaeme ommemmms mmneeees Porte ves sEhoep ofan ot resStere Scta.s sR NnEorbdoy so1aonma iacoe5ur oMoosameTM adaea Ae u eTtoSany vGkrsshowprarnear nt rest 3 AN -- SamI y iSA NETAAALN A NT J | - i TA oey"Ty re weoe Vs | ote rs opin oes aos RJengS rev mrs -- pio] Reh e eoSaoe E--re- wis% T sonegorOf sonVs tEvmSamrNemrltcIgemmm Momusweamngmmaaes pFCerowum Sha 8 mm mn nes -orruA--e--s fo CrmeTvEsT mkoEw sEhwmee SHeroges FPE oms a+n] f--e Po -- ineaTrnoottl Sgymbe SurSieenm i0" 138 Tom0is70F1R PNNreoorsoissoeamaamniaa +Simwmiommm vnnoeensse a essns OForonesisomte) cCeoOmNnoTsConFpFaOrSSsoIanOasmsd ees box NEFOSSSoAinOezm NEFOSSSrEiaAnIen JNEotosvteaimia Srere BE 8G0%0 di0o00 noha Comp00orsaacrhjpi iicussinoSunens A3 fosoi--nisD mcoent 2"1P3oCmSainmea Ln ua NeroSasoairormea NEFOSrSEoIoOnnrsa NNeErrOossMcoummaa rShoersa seeeree pr est pSetrar -- Comparsonswi-- n onia 508 Doers ess cA0osn02nc1i5sDe Pecoendr NFNFEEoFsFOiOosnMEioaikmaa dS47a3sm38e0 ASTUABpT ;oBooseGroup (mgt r ---- 3 AA ' 0 LA S AJN FA NE =N E wF e N oANT EoR o T rr sro i nProsi oSohwuat =Oonusii 12s --- 72339 T0711 FR DTS SOnuemwmaayryAnofovFiat RSRqSuquaarree Ad) RMoeoatnMoefaRnesSpqounasree Error `Observations (or Sum Wgts) 00.10083003537 2s016182442618 1 SMooudrecle ErCroort OF AnalysSiusomfoVfaSraivaanrcees MeanSquare FRatio 53 6660963.73823139 42060215027 P0r4o5b2>9E 73001053 ass 07191 Level Meansfor OneNvuamybAenorva. Mean CNOENFTOSA4OmKd 64 d44s2i5e0r0 PFNO-SEIAFOOmSEK4dOmKd 45 55575400000 S16sEeroer 11006622 oder StdErrorusMeesaanpsoaonldedSetsdtDiemvaitaetoifonesrrorvariance LCeOvNelT Numbe6r deiMeeea7n 1S0i1g4D7e2v NN--EEIIFFOOSSAEAAOOmmKKAA 44 s55250000 47172612810 PFOSA0KA 5 5.4000 150100 Sid EmM4e1a4n3 230868019 6713 DiPfF=OMSeAaOn{m}KMdean(] CNO-NEITFOSEAOmKd NEIFOSA4OmKd PFOSMAeOaMnKsGComparNiEsIonFsOSEOmkd CONT N-EFOSAOmkd 10..90000000 0109000000 19132333333 1113..21550000 "111321353030 192353030 10.09010607 01.90106070 Alphas APbRSO(SD4if0-mLkSdD CNOENIFTOSE4Omkd NEFOSAOmKd Comparisons fo0r0e5ach pair using Student'ts 213t144 PFO2S8A4O7M7K0S N-EIFO2SE843OT0K4d 16C0O3N1T3 2168..0330143 31917838028 129579300588 17.0544 205882 21.1475 NEIFOS"A147O.0M5K4S4 2270.51848725 "318382 Positive values`sChomopwapraiisrosnosfwmietahnasctohntaraoreussiignnigfDicuannettlyfd'isfeMreetnht.od 2627)808 PAFbOSS(OAI0-mLKSdD 22C3O9N5T6 CN-OENITFOSEAOmId 2326.50165430 N-EFOSAdOmKd 339319 Pafofseirteinvte. values show pairs of meansthat are significant ALT URLByDose Group (mg/day) 126 n2140 ToTOIFR " Zed a no ER $< CoOeGerrposoioLienr)soseriomsse|s | oSoeort bSoouvoeinna Rsquaro OSneuwmamyaaonrofvFyai. 047383 FRSMoqoiaunaMorefeaRnAedSs)apuoensree Encr osS3igsss0sesaa5rs1sT Observations (or Sum igs) 1 Soudcee OF3 AnaSulomfoyVfa5sSr1iai2aun0msc6ee1s Meon0S7eu%e R4aaom EnCelorw 1s 1S1623876385 s0e8s0s Pooowme cLoovent MeforaOnewNnaaymAbnesrcva aMseasn SuoEeromr NPErNOFESFO4OSOSAmEdIdmAiSd 544 ssmosawww si2eesms Lever 510 Err usMes eNpooaonmldtaeSedrdesDtniomvaitaesiMoofenasrnorvariSaingcDeev SudEmean NNcEEoFFuOOrSSEMdOonmKk +1e ommsasmwm taSineeozm pTseernmo PrOS4Om woe 4m Tess PDiRcOMSeaijMeanl] PFOMS0eA0aOn0TsA0CG0ompariNsoEnWsOSAedOTkd tCeONeT NEFOSE1d35o0m0k0 NNcEEoFFnOOtSSEAAOTTKHSS 13825176050007 awco0oo r0saa0t0se0 05T70a500s00 Aptos `Comfpo0e0aasch'rpiriusisngSotudnentss t APsROsSn4OLnsKDd PrOSsUeOmrkos21318N4EFOS2MOmsks sCiOeNnT NEFOSCpAIrmK 2 noang Torsom CnWoefrnoossemioonmiaa 24Sorm%en SsJoearsmeses sTGseraesnens F2Sre1se5st0a PosievaluesshowmpaolnseofwmietanchoamateeossiDefmtataWreand p PrSie 2bnid 1c6omnitn SNWofoormseiinomaa 3ssao0sns wonPuoyCsbhteeetneasusshowpasofmean ht ars scanty _ 3wwlo oA SAA\AANL|T | | SY 2) 721A LNT NN ! [o --Cs r-- on ne con 5 oo ons ro oe a Rquae OSroemvaayvyaa ot0m2 rRRSoGeuamenAigSs)e re e2So0me5e%s Chseatont or Sum Wot) To sosoee OF5 AnSiomfaovraorSaasgsnaceeess MemPSwraw Fao iao 85 Wsooess prisser boreorw Loovret ean for OravNeoyrAereoI rra Mem Suro SrRNoErsrooessoatmiodcmmaa DIH o lEx swmei Lovet 4EroushesesapNoncmgeeonttbimoavteioNnfeeienre varSa om $0 Mean Sor Toe wae URE 1n2142 JSyerpE {:{Eommsw gowmmmm aEumyw ppBoeyemss, oygrTaeToomIn0ees sume wUweOeeroodmmsw 0pcao0umt paE m: g=em s5m jumm iio aoe cEv oExipe!eiss innas . pn erp ren wes om a OBE mk ods Foon soCn amtp tsA=no S o I my TuiW veos howtwesoy " ~~ -|o]O] - vA [XO |w <T1 OD | = er.WohweeTee o=n Each Par w5e WnConve ~2313 Tbr0ie71F1R square SOinmewmay noouan orssane RReaoanswoerfhnAedsusoansee Ere eSWTerni Crsanatons or SumWas) ) sosoee oF5 AnSisomfovTalyriSimdasnmeceess Mem"Suwhamw rFoavie JSa 51 daersieiss dTeosms pLoenoen Lovet efoa rOnaNyyon Arroora iesne SSwreene RPNrEForososissocnoismoimaa $ 1Hon Eoo oosasmss Lovet 4 Evo ute es apNoka eoSdumtbin moaatveoifnsvor vrs soe Swern RNoEEnrroossseainotmsa D 1TS wlM aesem Tvrmaaemes Cooaorremmn Prosioms PONE mm Es Dcoines ent) oMCeoaannsCompNaEriFsOonBsTtioma NEFOSSoMamOems PRTOSaKmIsS RNFrEForososiseosdmioeommiaa SSSoeenssa SSGhaaonooon SSGho5oe0os sSsoammm Apres Com0fp0rs aach\ptisingoSunens soonurs 25c5omnt 2p"dNriasf"osSceiioma NeEFoSsMoomsa Praossuts FNKreFotsooissoenmaisoommas S2B7ai08s8 pBGieeaaesrsre Sdf messrwi. smos Posie vles Cshiowmpcooinfmiesans ornostarevirsiDaoenrsdifeeerss par2e5k 2c0osr PKNrerotosoisscnioommas J2L9oe5sn11sz3 Pastivvalues showpas ofmeans hee sigan different. a Cl- mmol ByDose Group (mg/kg/day) "Eroza To0r7s11 ER 0 toad > A- e PT NZ 3 0 LINN JES 7%LN / >=< | XX OOame St - ee a DoseGroup (maKotday) 5 Sms WhConvo os Rsquare OSroemvaaynmaorvrah assis RReoaoantcemtiRnseSaosuonrssEre GSSsoaevssaeiass Csovatont or SumWet) (i Seoauece OF5ArSiomfaoVlahrSiaasamnsceees MemUSkweew FoRano HChroa i1"8 Savsamna STeorise pooamk: SLoovet Means or OnNoevwenaroyva wMeaaen SCuomoorsr PKNrEoErsroioSoEsmiaaoommiaa Oo DONo REE SpTieeems Low 510 ror te esaNps aoosmnewd$ere1ntDnovait atoeofnisene vraSrucDeev SuEniean [NECrFooruSr-- EAdmia TLOov'weRernS sToerhmeees OoStaiums Prosiom 5 Ne lees ie OCfoeutreant eset) aCaeONaaTr"s Com"pNarEiFsoOnSsStouooemear Prsoeasmein NEOSAtoInkear NNeePrrrooosissomreiadanmaa LS26ee6me0e0sn7 GSSaaommmm 0o1280k0%0 S0530o00n000o00 Apa Compafoorsaeacrh|paii ssingoSennss paress 26c0o0nt 2*1NEsrosDceionmsa proCsioormies NEFOSsAIamnked 3 no14s5 Tb0r7s11FR NFNreeosFriooomssiemamadm aGoeoarrsieeosss ZaGohsoessne SzSihmne fS2e0re0o0]8s0e Poste aus sChoompwarpiaslosnosfwmiehaancohntarveasrypDeumdasdrMoepned Scoouucri2ci8s5e Pcornt PrNNoeesvFsooossmcmiiaownnaa 0G11o53r5e78r68s CREA PmgGoaasBiryeabovsaeluGerssovheowpa(rmsgogfemyeanstat resirfcanty MA A - 3 08: T[/NAA SN | N ji TNT YRS 03 oron rNnersorskiieorrosscpuromssu|s |oSEwRsPt Coovaenrrst Rare SPoan--o--r-- azssses RoRMoeetaanatrnFneSgssoiunseeror GGiiszeera%osse Cnsovatins orsumWot) % seaoee OFSsleimoaoofivStsaamnsisems Me"mOSowlwee FboReomiso CHloraw %Bo OOlroemomw cOocsa poavme Loovnet Means or OnNwomnaeoyra owMenan SComsi [PrNroEsrrsoos-- mitsima { 0005am%m cdcosooennmt SLoovet 1Enoute es apNa alonmedodSerurtmGaoes voa"fMnaranor varSnicdbeov Tous omen SEnTtioeean Penosae c1oi iimsmse spoetnteer EcSToifrmEooamPm,owmeoomeronsnieroeoinctosnssm ccoounr Hreaey GFEn TIE ORE oi -- rtm renoeo gs ser phpfeeeonsenede wawSTrerEotEsiRd" rorTsoeseemss wevoswSNseiroErsEttoLnss |doccoehonn eeEep relveNlrEoesemontteoeon, preeet 3c8o0n rirseteensostoes ssn go SN) | od CONT NEFOSAOmAS PFOSA0s NEFOSEAOmKG COOP Sn. WorCony' Sworn; non? ToIiOs7LIRR OSnuemwmaayryAonfoFviat ReRqsquuaarree Aq Root Mean Square Error 00.01430280035 3482088 OMbesaenrovaftRieosnpso(norsSeumWets) 123210159 NSooduerc!e OF AnalysSiusomfofVSaariuaenrcees 3 2740575 MeanS9q1ua3r%e F0R7a5t1i0o ErCoarl 11ss 201883179.6155883 T21e3l1s P0r5a3b7ssr CLoevnelt Means for OnewNauymbAenrova Mean 6 ster si1geE2rr1o0r NENEFFOOSSEA4OommKka PFOSOmkd 44 i2m2s0 ir7aattss 5 105000 1ss78 Std ror u`sMeesanspoaonldedSiedstDiemvaitsetoifonasro variance. CLOevNelT NEFOSAtOmKG Nomber 4 11Me6a7n 1850 aS2i6dDuerv Sid En17M.e4a1n0 4533 262 PFNOESFAOOSmEkddOmk 45 2130255000 214702448628 172701243 DNiEfIeFMOeSaAn]4OMmeKaGn] NEFMOeaSnAsACOomMpaKrisons. CONT 00000 103333 NEFOSE1A5O2m5K0d PFO3S3A5O0m0K0 NCOENFTO.SEomK PFOSA0mkd 80235080 a0s0t0e0r0 05000 23.1667 0as0i0e0r0 2T3275600607 18.2500 00000 Apha= `Comparisonsfo each00psai using Student|s Abs(Oin-LSD 213'144 NEFOSAOMK CONT N.EFOSEOmKd PFOSAOmKd NCOENFTOSAdOmkd NEFOSEdomkd 2ar4sess 3a7z5e0s8i7o 3723 430034 4702403%8 121673808030 s2438 315500 PROS4OmKd 183000 217863 35600 489ste Posiive values s`Choomwpapraiirssonosf wmietahnasctohnattroalreussiinggniDfuicmalnttsdifMeeretnhto.d 262a5l08 ANbEsF(ODSIALdSODMKS Cont 48c7o7n2t7 "528660 PFNOESF<OOSmEKddOmKd S54e.z18e8r3 `Above i for the male and female guinea paPiogfssieclrovem.bvianleudesclsihniocwalacihresmoisftrmyeasantsistihcsa.aresignificant 134 C238 Tor0s71m1R `Appendix 8. Hepatic Palmitoyl Co-A oxidase activity = Hr fSSoooo0irssit 135100000 uNSoeoa0se 23:.:26500 5 ed M-BtROSAtORkd 5S8Go01t4BsS :31.0000 ven 3L.0i00 \eirosEiGomks 3SG0o000o0s5s3 3:3..0000 Y=on 25.000000 Nepsrossitmkd SsScootiiesssr 22:..0000 V5en 2B.0e00 erosion SsEc0oo1ot5ss7st w25i.s00e0ing VSicoonoose de0e0r 3 pd wo com sSScoootnrssn 211..1000000 3dSecaonne 2i1..05000 = 5% Nestrosaionkd WS8eot1tdese :11.10000 J5 5000 M-strosElGORke 33H 600047 H 2i.00 M[ ean 2.000 Nertrossionka 8SS0o1t4i7s8a 11.6000 15s noaa9 TTIIOSTLIRR SPECIES SEH M SPECIES SEX DOSELGRO PrOSEOmkd cont N-ECFOSAOMKA N-ELFOSEIG0mKd N-ELFOSEAOmKd PFOS4OmKd WsSe-160mkd CoDnOStE_GRO ni Mseoan 8sG6o011e4s8s3 99660000004590 Nvean sp 8BRR0044004410 598R0000447609 Mean so BBRRO0440044S dean so 5SRR0000447712 Moan so 8BRR0044008432 d0ean 88RR0O44004467 S5R0000447743 NM0ean 118R0O00774489 n1NR00750 MseDan 1800742 11880000774443 88RROOI4003323 9800463 2FEORO_=D.= 01..000000 21..0000 33..0000 32.250 0.957 M4i.s00sing 76..0000 35.667 Tis28 MMiissssiinngg M0issing Missing 58..0000 26.500 212 MMiissssiinngg oMissing wissing MMiissssiinngg 1108..0000 214.000 5.657 MMiissssiinngg M0issing MHiissssiinng MCiOsRsOi.ng MMiissssiinngg 04..0000 9:00 : . 136 N2150 Tbrsao rosMomk NeEtROSMORKS SegtrosEisomks W-ECROSBAORKS Prostomka YSv oenow :f.s00 wr 1ie0o0e7r4s5 MWaiinsssniineng Bean mi seiinng w8Ser8o01k03e6 Mmiesnsiinngg Mworan wHisasinng "osRo00dres 1H109:.0000 Vw ean e 59.500 8Sy8h0o40t3s4 MN3iiesssiinngg NS ea u Hissin SSSRhooRiootOseyr m1H1ii.sa0sb0ing "YRoeontes 3D0r.a60m wr iE Wenoase TTIHS OR 138 C2452 Toism Appendix. Effect of acute FC administration on catlase and cyiCoA oxidase expression sPTshFseOueSfofolrlnoowmciantegaxlpraoesspeeordatndrsuutasmcmayanlrdCiozgAeusionxtehiaedapesifegfseg,ctesanneodfexwinparsveisvpsorioeansdemaninnedidstearnaztyiompneoosafecrtNi-vaiEtttytFhiOonS2lE0iv0oe1rr wSoecrieetdyeroifveTdoxfircoomloagpyprmoexeitmiatnegly(Wa1llgacoef er al. frozen 2001). liver frToimsscuaecshoanfatlywzoedmianlethaisndsttuwdoy female rats and guinea pigs that received cither 40 mg/kg/day PFOS or 160 mg/kg/day 2- (N-ethylperfluorooetanesulfonamido)-cthyl alcohol (N-EWFOSE) orally for 4 days, or an equivalent volume of 2% tween 80 (vehicle control) from March 1, 1999 to March 4, fP1oo9o9r9t1.i0oDnsuAollfultthhaneoirmraealsspvecwyteir,vee lkiivlelresd woenreMqauricchk f5,roozenne idnalyiqaufitdernitthreogleanstancdonssheicpupteidveondodsrey. Enzyme Sample Preparation - The enzyme fraction consisted of the 6,000 g supernatant of a 10% (wt/vol) homogenate of 0.5-1.0g frozen liver tissue in 300 mM mannitol-10 mM HEPES-1 mM EGTA (pH 7.2). Protein concentration was estimated according to the method of Bradford using commercial bovine serum albumin as standard. LC Orta dvay ~ The sqpivlent of <5, 5 ugh tows homogenate, wos shyudsrpoexnydpehdeniynla6c0etamtMe (PKHHP,AP)O,4-04.u0n2its%/mlTrpietroonxiXda1s0e0, 2(0pHuM7.F4)ADc,onatnaidni6n0g u1MmlaMurypl-- (CoA (LCoA). The reactions were allowed to incubate at 37C for 30 min in ashaking c`waartbeornabtaeth(apnHd 1t0e.5r)m.inatTehde bcyonacdednitnrgati3onvoolfumHe;s0;ofge2nemraMtedKdCuNrinign t1h0e0 rmeaMctisonodwiausm estimated from the fluorescence of PHAP as measured with an excitation wavelength of 317 nm and emission at 405 nm. The fluorescence was calibrated with commercial H,0, and the results are expressed as nmol peroxide generated/min/mg mitochondrial protein (Table 1). Protein was quantitated by the Bradford method. Catalase Assay - The activityofcatalase was estimated by a modificationofthe original mwheitchhod ispubblaissehdedobny tChleaidbiorrencte amnedasFurriedmoevnitch o(fJ. HB;ioOl;. Cdihseamp.pe2a5r4a,nce424a5s-5q2u,an1t9i7f9i)e,d `spectrophotometrically at 240 nm. In this procedure, the tissue sample was diluted in 50 mM potassium phosphate (pH 7.0). The medium was warmed to 27C and the reaction initiated nm for 5 by adding 10.3 mM H;0,. min. Catalase activitywas The progress estimated from of the reaction was monitored at 240 the initial linear rate(E**=43.6 mM" `em') and expressed as units/mg protein (Table 1). One unitofactivity is defined as that amountof enzyme which catalyzes the decomposition of 1 pmoleof H;0; per min. nnasg ToAr0i7sLI FR NaonrdtchaetranlasBelowteArneapleyrsfeosrm- edQubayntNiotratthieonrnobflomtRanNaAlysfiosrofboqtuhicakcyfrloCzoeAn loixviedrassaem(plAeCsofArOo)m ntrietartoegdernatussainngd agumiornteaar/ppiegsst.leA.ppTrootxailmaRtNelAyw1agsorfefcroovzeernedliuvseirnwgatshepoPwEdRerFiEzCedTiRn NliAquTMid RisNolAatiwoanskeitleactnrdopthhoerecsoendceonntraat1i%onagquaarnotsiefigeeld, sbploetcttrroapnhsofteormreedtrtiocaalcleyllautlo2s6e0mnme.mbraTnhee aPnCdRhyabmrpliidfiizeedd ftorotmheprciomrerressp1o0ndcai.n,g3r5a0ndboamselyse[q*uPe]ncleaboelfetdheolriegsopneucctlievoetirdaetslitvheart were gene. mRNA band density was quantified autoradiographically using. phospho-imaging software. RESULTS: sRuabtssta~ntBioatlhdimfafleereanncde ifnemeanlzeyrmaetsaectxipvrietsisesLb.eCtowAeeOnatnhdecsaetxaelsa.seTahcteivsiatimees,iasntdrutehfeorre tihseno `cmoanlsetirtauttsivdeoenxoptreesxspiroenssotfhRe mNesAsafgoer fboorthPCeOnAzyOm.es, with the exception that unexposed Acute exposure to N-E-FOSE liver from both male and female causes a rats, but doubling of the catalase activity specific activity of LCoAO in is unchanged. Associated with this is a PCOAO, proportionate but no change 2-fold increase in in catalase mRNA, the concentration in livers from both of MRNA encoding sexes. Again, there is for no remarkable sex difference in response numberof animals ested (1-2). to N-Et-FOSE exposure, atleast with this limited `EaxnpdopsousrseibolyfarastlsigthotPinFcOreSaseeliicnitcsaatalsaismeilaacrtidvoituybliinnlgivoefr fLrCoom AmOaleactraitvsi.tyHefopratbiocthcasteaxleass,e aFcOtSivEi,tywihnicfhemcaalueseradtsaddooeusblniontgaopfpemaRr N10AbebaanfdfeicntteednsbiytyPfForOSpCeoxApoOs,uraec.uteUnelxipkoesuNr-eEtt-o PFOS caused expression of a 3-6 message fold was increase in PCOAO more pronounced in mRNA expression. female compared to This enhanced male rats, and in both sexes resulted in no greater LCoAQ enzyme mRNA level for rats exposed to N-Et-FOSE. activity than was observed at half the dGruaimnaetiacaPlilgysd-iffTehreentrefsrpoomnstehattoobgsueirnevaedpfiogrs rtaots.expTohseurcoensttoitNu-tEivte-aFcOtSivEitaynodfLPFCOOSAOwaisn uacnteixviptoysewdasgu1i.n5-e3a tpiimgessohfigchietrh.er Hsoewxewvaers,vethrey alcotiwvi(tnyeoafrnLeiOtDhervaelnuezsy)mewhwearseassticmautlaaltaesde following difference acute exposure to N-EG-FOSE or PFOS in between species is the fact that guinea pig vivo. Perhaps the most dramatic mRNA encoding for PCOAO was undetectable, even following for this observation may be exposure to that we were N-EG-FOSE or PFOS. Part using hybridization probes of the explanation developed against I) n2a54 TbT0I7S 1ER the sequence for rat known at this time. liver ACOAO because the It may be that the guinea sequence of the pig sequence is guinea pig enzyme is sufficiently different not that rtahte sPeCquRenpcreo.ducAtltlahcokusghcomthpilsemmeanytariintdeyedforbeadaenquaartteifahcytb,ritdhiezaatbisoennctoe tohfe cpornosbteituftoirvetlhye expressed consistent wmietshstahgeeloawndantdheuniinnadbuicliibtyleteonzstyimmeulaactteivietxyprinesgsuiionneaofpigPs.CoAO mRNA are sCtOiNmuClLatUeSbIoOtNhSt:he tranTschreispetidoantaal parnodvitrdaenssltartoinognaelviexdpernecsestihoanto: f1a)cNy-lECLo-AFOoxSiEdaasned iPnFrOatSs in vivo, and 2) vivo exposure there is to these a marked difference two fluorochemicals. in the response These results of rats and guinea pigs 10 in are very consistent with the suggestion and, much that like these what hfalsuobreoecnhedmeimcoalnstcroamtpeodunfodrstahreecl"apsesricoaxlis"opmeeropxriolsiofmeeraptroorlsi"feirnatroart"s ncohtemgiciavlesn, tghueidnaetaa pfiogrs oarrgearneswiesitagnhtts(0othinsecefrfoepcstyoffifnlduiongrsocahnedmitchaulsexcpaonsnuortesc.omWmeenwteorne awshseotchieartedexwpiotshurpeer0oxicsiothmeerparogleinfteractaiuons.ed Hhoewpeavteorm,egbaalsyedoronotohuerrdaitnad,icwaetiosnussptehcatt tahraet gthueineevaipdiegnsc,ecawiulsledrebvyeatlhetsheeaccluatsesiecxaplossuirgenss. of peroxisome proliferation in rats, but not 1 Cn2455 Tor0is71F1R ASniumaml mofaScSrrpeeeycniefoSre.HepTarteiactPmeenrtoxBiosdomyeLPirvoelrifLeriaetrion P50 LauyiCoh Sx Ww Protein content Ovidase Caactlavltayse uRgNA MpCRoNAAO mCRaNlAe (mg) (molimg) A(cotmiovlimyining) (Unisimg [CoA ntrol Control protein) yo RROOOMMSS RRaa MM VVeehh RROOMOOM RRaat FF VVeehh 320038 II12 I1SSL6S 00006876 22100 7706 118383 0010sst SROMES Ra M NFOES.E 22 13 Isis 03 ROMS Ra M NFOES.E 231 ILI 149 02% SROMTI Ra F NFoEs.E 1% 75 1658 004 SRONT Ra F FNoES.E 175 73 2158 oss 5431289S9 0922 2a04l7 Bos noms ns uel M2 me 226s0nmd 17637 32139 11000 19018ss 3s 20 26 mors 19 2 uns un m0 ws RROOOMSST RRaa MM PPRFOOS 225279 112159 1115543 0042213 RROOTTA RRwa FFPFPROOSS 1I7S5 7833 218316 00007979 BDs 2629 23098 B19 7s1ss 1%2 aamm 1is5s7 6a0 1w8n0s4 9S0G0000004456 GGppiigg MM VVeehh SS0G0O000SSI2 GGppiigg FF VVeehh 229968 111139 21227 000189 227a 114129 2182013 00.1878 96000 Gpig M NFOES.E 9G00MS Gig M NFOES.E 9000S Gpig FONFEOS.E 6000S Gpig FONFEo.sE 20 87 2127 226 85 200 0013 210 96 1764 0126 26 89 283 0195 GG0009) GGppiigg MM PPRFOOSS 22i0s 7120 2125312+ 007 G90o0s0sS GGpiigg FF PPRROOSS 222317 7844 1127768 00003l16 (5)innsutffdiectieencttasbalmeple for analysis 3L3M0T7 LLeonwd 1103 0192550a6m L2e3sma 15015 M03. ow - 07 3 unin 2 07 wes 177m 10s 1s am 12se 104 09 4a08 n1e270w4 . 57 019 S6i2e9 1i6snmd 190%3 02 Cn2156 rbiosn Appendix 10: Final Report for FOSA (T-7132.1). Title: Comparative Molecular BiologyofPerfluorooctanesulfonamide (FOSA, T- 7132) in Rats following four consecutive days of dosing. Final Report : February 18, 2004 PrS3otMtuodMyceodNliucAmabmleeDrne:dpmaertnmteNDnuTt1mS5btuedry:Nu2.mber: T1132.1 Study Director: Andrew Seacat Ph.D. Analytical laboratories: 1 Kendall B.Wallace, Ph.D. D.AB.T. Professor, Deptof Biochemistry and Molecular Biology Schoolof Medicine 10 University Drive Duluth, MN 55812-2496 2 DrXinlu 6DR0eo1cphaeErslttmmeerwn,otoNodefwAPvhYeao,rrmbkaocx1o47l61o41g2y and Physiology StudyProtocol Title: Comparative Molecular BiologyofPeroxisome Proliferation in ISnt-uLidfyeISntiaratteDda:t: November 16, 1998 Rats and Guinea Pigs In-Life End Date: December21, 1998 "troas7 Tb0i7s11 ER Purpose: "(Tvheehipculrepcoosnetorfol)tohirs 4st0udmyg/wkags/d1a0ytrpeeartftlhuroereoomcatlaenersautlftorenaatmeiddew:itCh8cFit1h7erS0no2NcHom2po(uFnOdSA, PceFrOtaSiAn ,toFxiOcSolAomgiidcael, eTf-fe7c1t3s2,)s.uTchheassthuedpyatwiac spedreosxiginseodmetopreovlailfueartateitohne,omftethaibsocliosmmpoaundnd and to compare these effects to other compounds dosed at the same concentration.. Methods Test Materials: . P1e2r0f0l6u7o-r1o0o8c,taG.nesMuolofroenam1i0d/2e8(/0F0O,STA-,71P3F2O)SwAa,sFiOnvSesAtmiigadtee,d.C8TFh1e7vSeOh2icNlHe2coNntBro#l was propylene glycol. Dose Groups: `Three male volume of 5 rats received mk body propylene weight. glycol as the vehicle control by oral gavage ata oTnheretehrmoaulgehrfaotsurroefcetihveedstauddyo,seaondfw4e0rmegeuFtOhaSnAi/zeKdgobnoddayywfeiivge.ht,Avsiausopreanlsgiaovnaogefonmgd/aymsl. o`fThiFsOdSosAinign prergoipmyelnetneacglhyiceovledwaascuprmeuplaarteidv,eadnodseaovfol1u6m0emogf/k5gmlaf/tkegr wfoausrasdumcicneissstievreedd.ays ofdosing. This of this protocol dose was the same and is comparable as t0 the dose effective of PFOS administered dose levels for hepatic under amendment peroxisome 1 bpurtoltihfeercautimounlaintirvaetsodofsePFofOSFOfSouAndadimnitnhiestleitreerdatuunred.eTrhtehisLDprSoOtofcoorlFisObSeAloiws ntohte kLnDoSw0n,for PFOS 251 mg/kg for PFOS in com oil, asa point of reference. Method of Specimen Collection: `iTnhet~oliv1ergwpaisecresemaonvdefdlaassh-rfarpoizdelny daisrepcotslsyibilnelaifqtueirdenuitthraongaesniai.nTthareedlipvoerlsypwreorpeyldeinveided (Nalgene) containers. The containers were moved to dry ice and weighed aftr all liquid nitrogen had evaporated. The tissue was stored at-70 C and shipped on dry ice. Sera: cUlpotttiong1,0tmhle oblfoboldoowdaswacsenctorlilfeucgteeddfforro1m0emaicnhutaensiamatl1i1n0to0gxlagsasts4eruC.m tthuebesse.raFowlaloswing. transferred 10 new tubes and be centrifuged again for 10 minutes at 1100 x gat 4 C. 144 n2a58 Aot0is71 FR Tanwaloysails.iquots ofthe serum sample (~ 0.75 ml) were saved for possible metabolite Specimen Handling: A 1-2 gram aliquotofthe liver samples that were flash frozen in liquid nitrogen were sihdeinptpiefdiciantidornychiacerttobetlheowantaolytical laboratories listed according to the livers sample Kendall B. Wallace, Ph.D. D.AB.T. Professor, Dept ofBiochemistry and Molecular Biology S1c0hUonoilvoefrsMietydiDcriinvee UniversityofMinnesota Duluth, MN 55812-2496 Liver samples were analyzed by previously published methods for P450 content,Lauroyl CoA oxidase activity (Poosch and Yamazaki 1986) andprotein content (Bradford 1976) in the laboratoryofKen University of MN. Wallace Dept of Biochemistry and Molecular Biology at the Another 1-2 gram aliquotofthe liver samplewas sent to: Dr. MichLaaeblorWateomrpyeof M. W. Anders Departmentof Pharmacology and Physiology 6Ro0c1heEsltmerw,ooNdewAvYeo,rbkox14761412 Dr. Lin Xu performed the analysisof these samples and provideda brief summary ofthe analysisofliver samples from rats given a rangeof metabolitesofthe fluorocarbons were determined fluorocarbons. in liver samples The parent and by LC-MS/MS using previously published methods (Hansen er al. 2001). Liver Sample Identification Chartfor T-7132.1 [Sample# Animal#[Species [Sex[DoseGroup | T TT T [7 [Ro07az| Rat [WJoontel | |Z iR00743| Rat |W Jeane | [3 [iR00744| Rat |Wfeos [4 [RO[R0at7|4Wr_5[40 mgkgiday FOSA | [5T0746 | Rat|W[40mghgidayFOSA | 1s Cn2L59 Tbrsai (oo |Tar|o Jiomgrgiay rosa us Cn2A860 Toraso ER Results and Discussion Average body control group weightsofthe FOSA on days four and five treatment (Table 1). group were significantly Liver weights were not lower than the significantly different between the treated and control groups, bu the liver weight as a percentage of body weight was significantly increased in the FOSA treatment group `The liver results of P450 content samples indicated that (Figure1)and FOSA induced Acyl CoA oxidase activity (Figure 2) for the the expressionofthese proteins and FOSA is therefore a hepatic peroxisome proliferator in rats. alow rat, but not by microsomes or cytosol `The concentrationsofthe parent compound and metabolites in livers were measured (Table 2). The data show that PFOS was the major metabolite found in the livers of rats given FOSA and FOSA N-glucuronide was identified as a minor metabolite. Approximately 0.3 percentofthe cumulative dose was present in the liasveiethr er the parent compound, FOSA,oras the metabolite PFOS, one day after the last dose (Table 3). The low percentage of FOSA in the liver and the apparent low conversion of FOSA to PFOS has also been noted in in-vitro microsomal and liver slice metabolism studies Xu et al. 2003) which observed that FOSA was converted to PFOS in-vitro by liver slices at sIitginsifnioctaentwocrotnhceyntthraatttihoenscoofntFroOlSaAn.imaFlusrt(h1eRr0m0or7e4,2,no1RP0F0O7S43o,r aFnOd S1AR0N0-7g4l4u)cucroonntiadiened were found in the control samples witah high background of FOSA. A parallel analysis of livers from Fischer 344 rats maintained in the Universityof Rochester Vivarium did nsoatmpslheoswfdorettehcitsasbtluedcyownceernetrcaotnitoanmsionaftFeOdSaAt.soTmheespeoirnetsutltismesuegxg-evsitv that o by the control liver trace quantities of FOSA, as no metabolism to PFOS or FOSA N-glucuronide had occurred in the control samples. wr Cag, 0or7s1 FR Signatures: Report prepared by, Andrew M. Seacat, PhD, DABT Date Study Director Reviewedby, DSapnoineslorC.reHparkeseesntative Date as cn2a62 TorAsLIFR References: Bradford, M. M. (1976). A rapid and sensitive method for the quantitationofmicrogram quantitiesofprotein utilizing the principleofprotein-dye binding. Anal Biochem 72, 24854. Hansen, K. J., Clemen, L. A., Ellefson, M. E., and Johnson, H. O. (2001). Compoundspecific, quantitative characterization oforganic fluorochemicals in biological matrices. Environmental Science and Technology 35, 766-770. Lazarow, P. B. (1981). Assay ofperoxisomal beta-oxidationoffatty acids. Methods Enzymol 72, 315-9. Poosch, M. S., and Yamazaki, R. K. (1986). Determination of peroxisomal fatty acyl- `CoA oxidase activity usinag lauroyl-CoA-based fluorometric assay. Biochim Biophys Acta 884, 585-93. Wallace, K. B., Luebker, D. J., Butenhoff, J. L., and Seacat, A. M. (2001). Perfluorooctane sulfonate and 2-(N-ethylperfluorooctanesulfonamido)-ethyl alcohol are `peroxisome prolifirators in rats, but not guinea pigs. Toxicologist 60, 348 Abstract ID: 1657. Xu, L., Seacat, A. M., Butenhoff, J. L., and Anders, M. W. (2003). Biotransformation of N-Ethyl-N-(2-hydroxyethyl)perfluorooctanesulfonamide (N-EtFOSE) by rat liver `microsomes, cytosol and slices. In Toxicological Sciences, Suppl., Vol. 72, p. 314. wo C0463 0 oTis m Tables foT[Cuao1rbmc5lpeoaAnr1mstBevienoedclmoMugoeilvdnceeatacylu#ls2PaorafrBaGomooestgerosfPefuaroocanes[ uionarideT (FOSA T71T 32) RatT s olowing [--DTS1BodyWeight(BW),LiverWei2g1hJ 1t90(LWS),TOTahiyroZidWeeight (oWyT2 [SomeAriDosaeGrloup [GW BW BW [ow 6 |||| | e(0T) [WE |TW| # Gay Gaz dad [aye Gays We (0) l REG carl c P ma 0 TT m osTl SER I l 3Roa coalc == cc EU ccA i ii ae| BT g[ Tw r amW wsm y itors sXeLdi] ASSRS OT[o EOomlRoo ri || 2487 pe or [Toro rope| 20 zeaaaae on To%0%] MC g 6/T 71R0074 [4E0omegR/kgida| y-- 2589 aw m ga w w aO 7 vor7 asu110.s84] PTT G21 G13 605 002 001oss ao 032 Tromscon(rnepr an ed, al vin) A Pau of 0.05wasconsidered signify dices 1% cn0184 TorAsLI FR `Table 2 Liver Fluorocarbon Concentration Hepat Concentrations oflaorocarboannsd lorocarbon Metals in LiversofRats Given FOSA (40 ple #| Anima#l iver sample pom) _| roopm)sa|| FoGorsa| giucouoronide [2 Twos[mown [oome| oo sal 00 oo [=Tow|ovorleoen s[vi|eorooma odong [Towoorss|v rosa [oor| 1633 wos] aml [5Tomoons| m rosa ["om0s| 21a a aml oad os LsTwoonr| "mTosn ["ossos| owe 160 om oad mg/kg/day) Note: nm. = not measured. 151 Cn21G5 Slows--------------] `Table 3 Percent Fluorocarbon Dose in Liver mg/kg/day) for Four Days Erre rh bien teme pfee E PercentDosenvr T_1 T 1 : fe (mg) (dose** |(ppm) |(mg) oa (ppm) (mg) ol T_T | TT 1 TT 1 ptE evT :; e OT m c e fT vog T T T T THeea er [--r afmooras rosa]essr sae] rez170] or z] 5T 7 2ar os [[--6--]l1irRo0o0r7a4e7T[FFoOsSAAl 6e1640.23] 6e164023]]22104238] 223.126]] 03s 035 1741] tol 1638] 17] 02g] 028] [vsgoT TT T TAaseseatsl o2z0s8]] o0s0zT [sT A]7t7.e9z04 oidts] 003020]] C2156 omAi0s71 FR Figures Figure 1 Cytochrome P450 content in Liver oxo Total CYTP450 Content in RaFtoLisver Following Treatment With orm eAEnrntgtaenetosresan : 00500 Control rosa 153 C2187 TorosT PR Figure 2: Lauroyl CoA oxidase activity in liver LCoA-Oxidase Activity in Rat Liver Homogenate Following Treatment With FOSA I 3Bi%n, Emolsi; * 2 he Staanordofahermeedn. iIEmm Zen Tew iHY fw "m0 contol rosa 154 "2168 EIR EEREIN C EE EEE E eT HEEEIELHIRIIRINE CA SEETEECEEIN [TE 3 RE JES Shien Ere rr So CnDAn9 TTTITTH H [HE E] mm |TT ly loli |aule g J i bit | ne Heke i * [fEEEE| s [BE Slzlz|zis|s/8)s | [rE oT] Baas4 ssa" [Tpke n2170 exegEE][1] | [esse[]1] = | EEE TIT C m CT n H al] |FRFHTIT age[1] [oes TTTT1T] nave T TT T L HH LLLT| pRrRReRsRRsA i | TTT | EE ol | | FElele a eTR Hee: a [sF? 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