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oruns tr REVIEWOF PROLIFERATIVE LESIONSOFTHE EXOCRINE PANCREASIN "TWO CHRONIC FEEDING STUDIES IN RATSWITHAMMONIUM [PERFLUOROOCTANOATE Steven R. Frame, D.V.M,FD, DACVP EmmesEt.McConnell, D.V.M, M.S. (Pathology), DACVE, DABT Dass October 16,2003 Laboratory Location Bel, EX DuPontdeNemours and Company Newark, Delaware 19714-0050 S LabsoPrroeactHtdenoefricayon Page lof 8 | DuPout 13788 PAGERESERVED `STATEMENOFT CONFIDENTIALITY `cTohnitsadioncgcumeontnithfepsrioodpedardtyeeosfenEcLt.tdinnfioPromnaattdislonN.eBwxmcouerpsteesnedCqoumpanbyyalnadw,tis do0cummoeunstidsehpoaurltdypwoittbhoopuatrhaepliocrefwurliltyi)ncpohnosteoncotopifeEd.o,rdruelPeoansetddienNaecmyofurosra : `rnegdisCtoramtpioannyoarnyitostahfeFlripartosd,uocrtw(i1t)huosuetdtboyprairoergiwsrtriatteionncsounsbeonrtitoyftBosLu,pdpuoPrtonthte dsNemours10dCompra or itsaffiistes. . -- --2. -_-- SIGNATURE PAGE DDuuPMoonmt1u3m78s8 AutorSnares Author Nome: Author Posision: AuthorAddress: F pfttussnTE l ver E 14 03 SevenR Frame,DVM, PD, DACVP PrincipalResearch Pathologist andResearch Manager EHlakstkoenllRLoaabdo,raPt.oOr.yBfooxrH5e0althsad Baviroameatal Sciences Newark, Delaware 19714-0050 AuthorSignature:Eteloll paw 1H O03 AuthorNemar ErestB. MoCouull, D.V.M, M.. (Pailogy), DACVE, DABT AuthorPostion: PresiTdoexPnatth,, Ino, : Author Address: TRoalxePiught,,NToor.thCarolia -- = _-- DuDuePmonit1y3m78s8 `TABLEOF CONTENTS TS H PAGE ess Y es | TSobUleOIFCPOBAGc O. s ee ss s se ed d 10 T0000808MeOcrosses 20 RESUS820 DIACUION everson 6. a 40 REFEIED00S corse _-- -_-- uDuPom nt-13m788 T"RWEOVICEHWROOFNIPRCOFLEIEFDEIRNAGTSITVUEDLIEESSIIONNSROAFTSTHWEITEHXAOMCRMIONNEIPUAMNCREAS IN .t PERFLUOROOCTANOATE 1.0 INTRODAUNCDMTEITHOODNS AcFsoamsppwaoeturneoefdxsspttoundsdyeitdnuvmfeoosratimigmgoaontenieinlgustmhiepterreelfaltouidoorensoaototavbeasec,tstwtsoo(seiAnspP,eFarOno)dxfpiaosnroc3mr-eeypaesra,ormlaailtferiCastDtngry DucPoont'ns cHasekoelfln3La0bt0opraprtmor(ayBdietigenligot1ao9l9,12n00ns1d)1.9T92h.ssAtudym wtahsefo cionnddin nugcstiseng dtthat ci$hntioAodnPyiRwoOfe-erteerdianitcnergdesratisutedady.iwTnichitedhseAencPseosOuolifsnpwwaehnricecrheftaGiaoopsapcaaicnmeanortcceonlstthrryiapienrwpolaasaspieraxaopvnoisdoeadasdfoetnaoema. rsetalamadtyedwdipacrttoalsipfoecncstoiorveeldnbesystahnoeo3offMc3t0hcr0ooepmxaoppcarct(iyn3eMsia,d1awo9c8ar7sno)sc.sowInendrtchetaiotddesbatetutdiyfw,eedneo.ncToh1im98spl1oazutnnteddr. 1983, nanefforttoaddressth spacesisrepenciesbotwesafh twostudies, the eTrr FSlriadmees,oaf.thepancrea`sfaobm othlea3oMDgusPtiuodnsytw(etrheosrteuvdiyepwaetdhoblogiystfoar th.e 524300pp (ighdos)groupeofth 3M std. sAtutdyhwreerquesvtioefw3eMd,bpyaDnrcr.eEaxsnselitdeEs.MceonCtormolmenld,frceonasdul)tirnogmvehteeDiuzParoynt * Dr.MoComellthenrevivedallpancreas idesfom tho 3Mstudy, + Doonh.Frhdsand dmMeo de cevi iewedselected prices e sidesn froma tihenDuoPourteslotlupradoylsistfaerieanteiddown.ith-bromo-2'decx(yBwedr)ifoddiontet "rTelhaetsilvietdorpoavnicerwesatoiuctaiosnadscheolvelweseiorncsionndhuecttewdocohbreotnocfleaecidtiynhgostSuiddiiesnwgsih dePreeRvriOmeew,sd.TnTehcheeusssos,ranreyvotiteoawlslmiwcedsreos1n2ooac,ohamolprltweegsvreo,tudphseewoseifrgenceedxoaansmetixhnbeeaeduxbtoictrviaennpeiytphtahoncolrsoeegayspiect eatewosctoundcileuss.iTohnseorefvtiheewsienrgepvaitehwosl(osgciosRtessweurlst ianaadgDriesecmuessnitornobgealoiwn)g.fo TTT -_ 20 Rssuurusp Discussion DvuPeonmt13788 g{Boaefndimoeendt.hSrcpiredeceeviiecwlalooyff,sDpcra.oenrMitedCcioexnpncoasiluortechee1cl3oyo0c0hpupspimoneAsoPafFrntOhdwopDadusePslovonoctincsaottafeadhdywweeitrhe pacciidaennaocreicocenflmlrEnayslpoeepulrsaspsa.isDysr(i.ndMeAenCPooFnnOnoer-lcxacprocuoifnsaiomcesamsde.)d. aHl easlcsaorcceolnerfionimsariacmrgeaeaosdesdd 3oB0oa0slepEdoyopmuoArtPlhaeFifOaoibnautttrhneevo3iteMawdbesyntDoordmysaw.oaMfescCaxosonoiconieoslmtaea.dwdTihFtsrha,msAeiP,gFehxOtpwosraueraassooe ffpaalnocnrasstas.ttioo tumoinrhei3Mgsenday. `"sPTtahutdehiroegesevanieeeswrissooarfnsbdsoditimaitglhnaerost3thiMacsncdrdiitseiDrziuaaePlsoatraatwbtlhiiesheeodsfuisoniddieecoaltftehicnaathitevhceeorenostunelstsoooffftihhoeet {Hehxooowncgorhwitsntp,oaeehosrHetaksllooonfogthdeocrofantpt.oigPresroiofnyooprerrlepelglsriaeossnisisi,ooanfdsehalnoooancmgthaaahtaaitdiccnoacnrvrtceiiansoemaar.ois Idudinssikooguwoinhmhmyoepsterhtpolcraasssiheasaf,vraeovdmetayepdictcaaeolmlsyast(huEecrishsaernyoo2pte0apcl,yalls1oi9g9si5ae;nEaldvaisdearzosamlatho1an9cs9l)e.aly `y1p8e9r2p)l.Tasoiaactkoidoewsecrsiobmeanwonnimfnolmiigtuaynitn cdiisagaooroelsscoconssssb(oGrrmesaoverseasn,ddiFaagcnoonsii,s adternioma,avuedbothrencxraibvlriisohnmios1tcGoimffmiernnttaecacpilneeyecdelsbyapesroplmaeswihafartombitcy 1f`sBooeotGrugmrasonoo,fmt1ws9o9o-0df)i.mTpehnuessir,osnfaiolrKsmoanxndoyfaatdceotnasioolnf(lproaolnifieraitiofoancsl,,oh1se9i9d5in;fBltuehsentross-abnedtween J iffsimnizeeloogfniacraaclnpdoaotemnstseicatli.on roughthelesion atesthen own Btausteidoonanethqeuseacoinvsildeyrastiimoinlse,ias3sApPpaFrOeparohdaatctehdrnclrosaseodftihoeciDduePnocenstofod3M lpoebsrtieoocnlvseiwsfewerearrcoioqnudaeiractetedaltliiveteo,hentDhsautofot,meotpraaoadecynrcdeoamspgieesrbteoftohsattlhuperdoi3li,MfTsztahtueidvdyei.faTfcehhreoenrcscesesloln thfcoeoxrnteoieasnrqotuiainutomintboatfeiAvrePodfFivOasrc(io3ar0bd0lepecsmtcd)aoiscapottuhsloutdscwooonosrfldtbieectsseafoenh1oe3tkinfofoarwec,tcedHsodwocebnvsreerycv,ed. TIhaobosrasttourdiinesIwteireexcpoencdtuecdtteadspthpersoeztiezcezpsolryal10aynedlaoscsaptaisonsaldasiabilefswrero `apsostoecnitiaatlepdwnitth sdoimefdwiiftcieaafceosiantasniimaa.l OBufsoblelnpdeoysenssufdciknorgds,icai,fasfweenlcle13 thedietsisthomostlikelyfactorinfluencingthedifferentincidencesof - = _-- DDuupoentm1u378m8 ipnccriifnlogonlcremsiosffsoaoyceiindnamairrcatceelotllrlliedhsyiivposenresep,lVfaasziiaiatonudnsnfeohocpullsa,soifairenottKahroeypwraanacrs0emiaospdoufelrroadiecnncitlsoudnin,g cc(oeLlomlnoghyalpeebcrkypelgarasgviuaaadgoMeicdloalmdamrep,nao1rm9e9a0tW;oeMarcteGsuncoirtneoagesaevsdaogieavde,(fBou1l9sd8ti0s)na.coTodhnBetoooalcraimdalsnae,cFe13s9o48f549sg,ciivnesnc eies tio pes s nc Iacousideingthebucaanrelevanceofsinacellhyperplasia nd neoplnastihae tdhoisetbminacsjtolreyiditirnyfhofvufrneeahnnutdsmf.arnWophmatinulcmeroreroasdtoelnfnttethouepmeloxarosscmarsiaenteepyoapnifcctrahelealsydudmcetocaislvaterdctoyrmpomemo(anLcloiynngaarsceeklelrs, `a(anddeGMniorlmlaeerhu,aadv1e9Fbv9ae0)eec.neTspr,ruoo1d9du9t2c)ae.ldIaaraandtdeisotbpiloyna,smpsaaonmfcbtreehrtoeipfescnoicmrnepsaosouanlrdleshwayhpeieicrhpnl,aastkiassand ApcFhlaForfOmfa,bcapetru,otTidchuaeclrssopweiirdnseoilksyunosmoeewdnipranoslbsioufcmeiaraaottsii,oornn nbcehhtsewseltnhveteh,beyTspheoeclsoiempiipndoceulmunidcdaesagned,huzors ofonfutomhawetei,xoonthcseroyipdnrseoibgaanbiclfriyedcsaoninoaotohfiunpmdeaiarcsae.taTethuccsaac,niwcnheairrhleaezhlalorppdrrfoelociirfsueeremeteaicoshnsan(iGiarsemavoaefsr,s ot 2000). 30 Conclusions Mstiacdriocsacoipiaosl,scioannduocbtseedrbveyd3iMtahnedxDoucrPioncetpraessipzeecatsivienlyt,wwoecbronvdisefwaeddibnygtwo dvieftfeetrnenacreyspbatehtolwoeginstths.etTwhoesteurdoiveisewlsawtievreetcoocnodmupcotuendtd-nrceleatceidylaepspiaornesaotftho `eelxosctruidnyeparnacirolssw;haoswneovtecro,ndufcotremda.lTphaethroeloaglyspoefctGevtioewsotufdtihesepwaenrcreseismfirlaorm idinettaartycAPoRnOcpreondutcerdoapfrt3ol0ii0foeprpnatmis.veInstihoen3sMofstpuedoye,reraetactamcent ienlbaottehdcshtaudnigeessat `cverreleimditeddtonalisghtoifncrpeaesepaeacsooarctellykypevrepriasshi.uInetdae,DTuPhontBsetusdey, dstiufdfieersenpcreosndoutceedbqueailnitgaqtivuolyasimniltarirestpoonasveetsriaalilhivnecpieedseca-rceebasso,ifwpirtgohlihfereatrive lesitohnosDaunPdoagrteastteurdytceonmdpenacryefdotroptrhoegr3esMsisotndoyf.lSeisnicoenstatoeaddifefneoremnaowsebretoowbesene.rved `aprabnictrreaartydiicnagbnioosatriBoycpeireplraas(issaen)daanddcanoortanaeicnetshsearrialtybsioofltoegnicaarlepfolteecnttiionalo,fthe ryaessiaubsleosftthhaettewxoisttbudeiets awroetthenermne,asAolnfasboluecgohnthceobradsainscfeogitvhenqtuhaenteixapteicivmeental kdioffnrentcoe omobdsselravtesdithsenporolkinfoewrast,ivaeuremsbpoenrseooffvtahceaicaibnaerspa,nccarepaesdcaieatal,atlxyetnd ace sUtkaedlicysowpietchtAiePiOn,thDdiffeerens cesidnpicfofegcireeaceosof,teasrt pgeotnosrshgsaenee mfinftssheotneotchehronic puccormemoens,tcobothhtha e3MbrsyafdocDtaulPpoenrtosltruidifesee. lesdionsof paaersieaa,wieore ---------------------------------------- 7 40 Rererences Deport 13788 BMeicheaLmiBenFsuofteMEx,FtumaetSbuRa,erOCipnodumactciieonGbynpderCoxoiskomCep2r0of1f)r.atons inmale . CDs.TortcolSct,60.4485. _ a Busts,SL zadBoormus,GA (1950).8, Exocrinepencres. In:Pahologyofthe MFaicskcehnezrRiae,te(dsG)A.BoAocramdan,SLrBsusttios,cM,RSEalnwDeilel,goCpApMo95n-t1g0o8m,ery, Jr, andWF `Buti SL.aadBoormanGA (1985).Proliferative sionsoftoexcrinepancues: T`oresltat1io5n1s0h6ip7t.o7c3.omoilgavageintheNational ToxicologyProgram. : JNatlCancer Graves, (2000).CaperVIL.Digostvosystem.1.Exocrinepancreas. os: | H`istAopamthosloptgpy.o4ef9P0rr-e5c1l,i4n.ical ToricltyStudies,SecondEdition,Rlsevies, Greaves, PandFaccizi,JM (1992).Digestivesystem.Pancreas.In:Rat. Histopathology, SecondEdition, Blscvier, Amsterdam,pp.118-126 Hansen,IF,Ross,PE, Makoves,GT,Busts, I,andSige,RE (1995). `Proliferativeandotherselectedlesionsoftheexocrine pancreasinrats.GI-6,In: GuidesforToxicologicPathology. STE/ARP/AFIP, Washington,DC. o`T Lfongooi ckeir,nDLn aSbaornadto Moirlyldairs mPMs(.15V9o0l)u.mTeuImouTrusmoofuroseopfantchreeRaest,,ISne:cPoantdhEoldoigyon (LVySonT,uprpu.s2o4v1e2n4d51. Mok,os). emational Agea=cyforResearch aCen, . `'WMoorGusilnenyesKsGE.E,(1M9o8r0)g.eTnhReGe,ffLeecvtisosofnloDngA-,tFerrmapfeeDeLdi,nBgoofpswooyoadflDo,uraonmdthe zat `paacres.Scand JGastroederol,15:497-502. `3RMat(,19R8i7c)k.TEwoYxearpOraelN(oDr.ie0t2)i81TCoaROxOiTn2c.ity/CarciSntuodgyoefnFiC-c1i43tiya. ---