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REVIEW OF PROLIFERATIVE LESIONS OF THE EXOCRINE PANCREAS IN "TWO CHRONIC FEEDING STUDIES IN RATS WITH AMMONIUM PERFLUOROOCTANOATE
Authors Steven R. Frame, D.VM, Pa.D,DACVP `Emest B. McConnell, D.V.M., M.S. (Pathology), DACVP, DABT
Coc Date. 16208
Laboratory Location ELLDuPont do Nemours and Company Haskell LaborfaotrHoearltyh andEnvironmental Sciences Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050
LaboratoryProject Identification DuPont-13788
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`SIGNATURE PAGE
DuPont-13788
AuthorSignatures
Author Name: AuthorPosition: Author Address:
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Author Name:
AuthorPoston:
Author Address:
PFE ossT e oiin vate JoO03
StevenR. Frame, D.V.M,,Ph.D, DACVP
`Principal ResearchPathologist andResearch Manager
HaskellLaboratoryforHealthandEavironmSecnietnacels Elkton Road, P.0. Box 50 Newark, Delaware 19714-0050
SoneCael pe 12 OF 03
`Bmest E. McConnell, D.V.M., M.S. (Pathology), DACVP, DABT
PresiTdoexnPatt,h nc,
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Duont13768
TABLE OF CONTENTS a SIGS 0.3 TableOFCOMER evennessd
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Duan 13788
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TRWEOVCIHEROOWFNPIRCOFLEIEFDERIANTGISVTEULDEISEISOINNSRAOFTSTWHIETEHXOACMRMIONNEIPUAMNCREAS IN PERFLUOROOGTANOATE
1.0 INTRODUCTIAONDN MeTHoDS
As part ofstudy investigating the relationship between peroxisome-proliferating `compoundsandtumorigenesisintherodent liver,testis,andpancreas,maleCD
Tcaotnscweentrreaetixopnossoefd3t0o0apmpmmon(iBuigmaplerefalu,or2o0o0c1t)n.oTahtiss(sAtPuFdOy)Wfaosr2c-oyneadruscattdeaitd.stary stDuuPdoynwte'rseHaisnkcreelalseLd ia cidbeao edsurorifnpgaa19st 9e1saondr 1ae9tn9ya2.ceA ll bym ptehpelo fainidian nngdsiadng tehnaotma cihnrAoPnFofOe-etdrinegasrttaeatdsd.ywTihtehseArPeFsOultisnwwehriecihntaoppsaroentacotnstaraisntwtoasaperxepvoisoeuds o he ss`tesuaadmtyedwdiapesrtoalrsiyfcerapotivneobcyitnohenesoo3nsffM3ttc0hoo0r cpmoppcaarmcn(ity3aeMaip,d1aw9cdoa8rs7en)sc,soIwnendrtsohcatitodsdetbnutedityfwi,eendeo,nTch1oi9m5sp1oaauinndrd. 1583.
Inaneffortto addresstheapparentdiscrepanciesbetweenthe twostudies,the
followingactivities wereupdertakensequentially:
;
SFlirdaens,ofavtehteeprainnacrryepaastfhroolmogtihset3atMDsutaundywe(trheersteuvdiyepwaetdhoblyogDirs.tSftorethveeRn.
DuPont Study). This review focused on slidesfrom male ratsinthe control 2nd300ppm(highdose) grofotheu3Mp stus dy.
= Athroquestof3M,paces lide (sontolsndtes)froutheDuPont pathologist. `studywerervi byDer.wEme estdE. McCoacronsm ulte ingl vetel zin, ary
+ Dr.McConnellthenreviewedallpancreasslidesfromthe 3Mstudy,
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* Dbrast.hFtrsam3eMaannddMDcuCPoomnetlslijosin,tlyTrheivsirevweidesweilneccltueddepdanpcarnecaresasslsidiedsefsrormom tohreeDausPeodncetlsltpudryofstfarianieodnw,ith 5-bromo-2"-deo(xByrduUr) ifoddeitnecet
r"eATlPhaFetiOsv.ieTtdoorepesavnieeerwvesiaaeitowisacwceiezdraaocbneoolvl,elvbiroonssconwntdheiecttvewotceohharse,openxohdlaafureseiettdivyistenhgpoisgtfhaicdnliadooisgnwegyisptdeh r diecheevmtiweewods.sntTcahelsse,s.znTyohtteolrlievseliisedwetisfnngdopcaohaorllpggsriotausypweweereleetiexosapnmrioonseeedmxeounctrtiornneleygpartrhroiefsnaeegs sence] conclusion of hese eviews(seeReslsaadDiscussionbelow).
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DuPon-13788
20 RESULTS AND DISCUSSION
cBoansfeidromnetdh.Seperceivfiiecwalolfy,Dcrh.rMocnCiocnenxeploslu,rteh 0c.o3o0o0lpuspiomnsAoPfFtOeaDsuPsoonctiasatdeydweirtea in`crpeaaseadiicnnmoriadleeenacaossso.fDrpa.cMreeCatoincneeclaacroneflclmhedyalpl feourarncedplallldseinaoonmssadoiifagtaohoesed. ainscaicdiennacrecoeflhnyepoeplpalsaisai(aiandeAnPcmFOo-recaxrcpionosameaissd).. Healsoconfimnzinmcreeasded `3B0a0spedpomntAhPeFOiinattrhevei3eMwbsytDardsyw.MacsCsosnonceilslteadnwdiFtrhaamsel,igehxtpionscurzesaosfeimnealceirnasr to ctelluhymperopilnarstihaibeu3gtM nseottuadndy.enomaofowriaoma.Thus, APFOwasnotapancreatic s"tTuhderieevsiaerwosmoofrbsostihztlhase 3thMaandnidssDiumPiolanrtwshtuedniceosnisnididoearteodtihnattbehceornetesxutsoofftthhetwo peaxtohcorgienneeasniosraenadsodifatghaoestaitc.crPiterriaesotabllliesshiieodnfsofofptraoloiafaecriaotativrepalinecsirvoenassoefrtohe Hoowuegvhetrt,oGexeilstkaellonogoadcoofnptriognrueassoifobnyoprerrepglraessisai,oandaelnoonmgatahntdccoanrtciinomai.s wdiasktuinogwuaisfhabmyopesrtpclaasesss,fraodm atydpeiacaolcloy at(hHearneaseen2o0tacly,to1l9o9gi5c;aElvsattiusrteasl,ha1t9c9l0e)a.ly hIynpdeerepdl,assoimateoaduetshcorrisbehapvoeunmealditgearannst csiuucaharsoheylpeesripolnass(iGaareoadvaedseannodmaFtaocuse, r1i9t92r)i.Thoavacekbioocvaesesotmabeluinshiefdotromdiitfyfienreintsigaotesaecsiancarrcoeslsllyapbeosrpatloarsiieas,fdraogmaostic faedaetnuormaeso,ftandwthocri-terdionimiozsmtocfeomhuenmlaenssliyoein(mpnolsonyeedaestlah.es1o9m5e;wBhuasttasrabiotdrary h`BeocGriraagauno,s1e9s9o0f).bTyhpuersp,laosrima aondyadaceinuoamacserelflpercotlsifaiadtiiffoenrse,ntceeidaiftfhrtenwcoe~between diifmfernesniocneaslinsbiieoolfogaircaalnpdotoemntsieaclt,iontrough. theIsic rathetthankno: wn. stBuadsieedsoanrtohqeusaelciotnasiivdeelrysatiimoinlsa,tai5sApPpFarOeparttohdautctehedrienscurletsasoefditcheiDduePaocnestoafnd 3M porbosliefrevreadtwiveeraceiqnuaeratcietlailvees,ionastofist,hmeoprroacnzdetlsairngeboftohcsatlupdrioleisf.eTrahteivdeiafcfrucaarcceesll fsoirotnisswqeuranotpirtoatdiuvceeddiiscnotrdeaDncuePdoenstpisttsuudsyecoofmptharseadztorthtes3iMsatauudyd.dTihetearryosson {`hceonrceenatrreatiuonmobfeArPoFfvOar(ia3b0l0epsptma)tfnotuhledtcoonsttfubduiteesitostnhoetdkinfoesreaa,ceHsowoebvseerrv,ed. IaTbhoerssstosrtiuedsi.eJswtereexcpoencdtuecdthedaaptphreosexitmeamtpeolrya1l0aynedalroscaatpiaorntaal dviarnidaiblfefsrweenrt.o `aspsooctiaetegdewnictthisGoimfesdwiifftehreantcheseirantasniimaa.lObFusablalndpsosys,ibalcefhciinogrsd,ic,diasfwfeelrlenacsien thedits ithemos Mkelyfiotorinfluencingthe diffrent incidencesof
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DuPont 13788 Spenrdionglraisfaooyiidnaztrcsaeoltrldieiseivtosnesd.efViacrieinotuisnfcohoulsinoef, dareofakrnyomwan ntodmapoodelrasintctilhueodinng, incidencesofacioacll yperplasiaandneoplasi inthepancreasofrodents (ceLllohnygpenreplcaksnieadrauMdilaldaer,no19m9a0w;eMrceiGncurieaaseodetiasvles.fo1l9d8i0)n.TcohnetironlmcaliedF3eo4fn4gscioveiesrn comm ilbygavagecomparedtoatsnotgavaged(Bustsaod Boorman, 1985). 3aconsideringthehuman relevance ofsloarcel Eyperplasia nd neoplasiainthe driosdteinnto,ittydiisfnforteenwtofrrthoymtthuamtotrheshoifstthoeloxgioccatlitnyeppeoafsttuemsomrosesetncionmtmheonrlodyentis tohebmasjoreiitnryhovufmehuusdm.aWnphainlcreeraotdiecnntotoupmloarsszasxaerteyopfictahlledyduectrailvedftyopema(cLionnagrneoclkler, a(ndGMirllea,nad19Fv9a0c)ce.inTsir,ue19d9u2c).tuIlnearddeiotpiolna,spaasaosfstahteipcasnecirneeraosalr]ohayrpoefrnpaltassainad AaPdFenOo,mparhoadvuceebpeeernopxriosdoumceepriolnifaetrsabtyion8innutnhmbelsiovefr,Tchoemspeouncdlsuwdheich, like `cplhoafrimbarcateeu,tiTchaelrsowiidse2l0ykunsoewdnianssboucmiaaatuiso,nsbuecthwestehnteehyspsolciopmipdoemuincdasgaenndt,tumors foofrtmhaeteixoocnrtiandespigannicfriecaasncienoBfupmaancarse.aTthiucsa,cwihnialrceetlhlepprorleicfiesreamtieocnhsainiastmsaofre aot m20o0w0)n., heyprobeblydonot indicatecancrhazardfor bnauens(Greaves, 3.0 Conclusions Mticursosciopatos,lecsioonndoubcsteerdbveyd3iMtahnedxDoucPrionuetpraensipaeectaisvienlyt,wwoecrherroonviofweeeddibnyg to vdeitfefreicenaacreyspbaethtowleoeginstthse.tTwhoessteurdeiveisewlaswtievreetcoocnodmupcotuendd-orcellaatceidylsepspiaornesaotfthe elxlosctruidnyepsamniczraolssws;ahsonweovtecro,ndaufcotremda.lTpahthroelsoulgtyspoefeshreetvwieowsotufdtiheespwaenrcorseaaslfarrom idinetahartycAPoFnOcpreondutcerdoapfrt3ol0ii0foeprpnatmisv.eIfnetshieon3soMfstpasadcyr,eartei aatmaeinntbortehcslhtauadtnigeeesdsat `rinecrelaismeidtieodciodelniogehsot ifnhcyrpeearspelansiaacaiondaarcdoelnlormyapewrpelraesioab.sTernvtehde.DTuhPuosu,tsGiteusdey, sdtiufdfieersenpcreosdnuocteeddbqeuailnigtqatiuvelaysinmiltar iestpoouavseertsailailihnvecipedeeonc-creebsaos,fiwprigotlhiGhfeereatirve ilnestihoenDsuaPnodgnrtesattuedryecnodmepoaeryefdofroptohgegeIsMssitcaayof.LSeisnicoenstthoeaddifefneorcmaacewbeertewoebesnerved a`rpbanicaretaytidcisabginooasstiycpcesstpelraisai(asaizned)aadnedsinoorntsniecnetshseeialtybiioolfoigeincaarlepfolteecnttiioanl,ofthe rvesulatsorftiaiettexwaiossttbboedtiwleosearnethaesmr,easAoXnbaobluegchotnhceobradaszsoefogritvheenqtuhaenetxipaetriivmeental kdinfofowrnsntcosmoobdsuelravteedtihs nportolkiufeorwatzi,vearresupboenrsoeoffytaceibelceisn,arepsapnecciraelalsydiicta,tareendaxe lsitkuedileys pweiztahtAvPeFiOn,hDeesipfiftcsentcheesseidnifdfoegrreenscoesf, traersgpeotnosrsgaeneonfiectstotnothhheoene `pcoeumatocbotrhthee3aMbaysnfdoDc,ualPcoprnotlhisfteuardaitcisrv.eleasiocnsoifpeanccreaitooza,ewedro
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DuPont 13788
40 RerERENcEs
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