Document DD0wYKrK1BE3MNQDjE5aaXJ6d
StudyTide
FC-143:TWoYEARORAL TOXIITY-ONCOSGTUEDNYICNIRATTYS PEER RevoFiOveanwes
Authors Peter C. Mann, D.V.M.
Expe Patr holoi gyLamboraetorines,Itnc.a (EPl L)
POBox474 Herndon, VA 20172-0474
StevenR. Frame, D.V.MP.h,D,. E. LduPontde NemoursandCompany HaskellLaboratory forHealth andEnvironmeScnitenacle: Elkton RoP.aO.d Box, 50 Newark,DE 19714-0050
TestGuideNoltAippnliceab:le
DateComplJeunet25e,2d00:4
LabPo rojr ecta ID:t DuPo ontr -15y 261
WorkrequestNumber: 14459
ServiceCodeNumber: 1243
Submitted By:
E. LduPontdeNemours andCompany `HaskellLaboratory forHealthandEnvironmeScniteancle
ENlketwonaRroakDdE,, P1.97O1.4B-o0x05500
Authors
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PeterC. Mann, D.V.M,,DiplomA.aV.tCPe.
VeterinaryPathologist Dats 24 Tama 2004
DePoat15261
SPtreinvceipna&l RFerseaamrechDPaVthMol,oFgiDst,nDdiRgelsoemairlcehMAaVna.gCePr., Pathology
25 June 2009
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DuPeat15261 FC-143:TwoYearPOerearlRToexivoefliOtveayr-iweOsucoSgteuadyiicn iRattys `TheslidesfromtheovaricsfromFC-143:Two YearOralToxicity-OncogeSntiucdiytiyn DRiaptlsowmearteep,eAemrerreivciaenwCeodlblyegtewoofveVteetreirnianrayrpyaPtahtohloolgoigsitsst:sPeatnderSCt.evMeannRo.,FDrVamMe,, DVM. o"Prhi.gDi,nDailplyleoxmaamtei,neAdmaenrdicraenpCoorlteldebgyeoDfr.VReotbeerirntaGreylPlat(hsotludoygpiastth.oTlhogeisslti)dfeosrwReirkee:r Laboratories,Inc., 3M(ProjectNuzaber:0281CRO012). `Thepeesreviewfocusedon proliferative lesionsoftheovary. Thepeerreview pathologistsdiscussedissuesrelated todiagnosticnomenclatureandcriteriaandreachedagreementonlesiondiagnosesand grading, aswellasinterpretationofthepeer review findings.Thisagreeismreeflenctted inthefollowingreport. MatersndiMeathlodss Allsideslistedasavailablebythestudypathologistweremadeavailableforthepeer reevavliueawt.iTohn,eonvdatrhieessfersoammeaofveawriaensiwmearlsewneorteavnaoitlparbeleseonrtptetehreretviimeeow.fTthhee ionriitgiianlal diagnosesandthepeerreviewdiagnosesfortheovaries forcachanimalaregivenin ``pAaptphoelnodgiisxtA,.tIhneptheoesrercoavsieeswdwihaegrnsotshiespieselrisrteevdaisew"pAagtrheoel"o.giFsotrtaghreopeudrwpiotshetshoefsatnuadlyysis, thedataareseparatedintothoseanimalsthatdiedonofbefore53weeksonstudy, and t`hwoeseekasoninmsatlusdtyhiantcdliueddeadfttheors5e3sawcereikfiscoendstodhse.inTtheerainmsiamcarlisftihcaeatnddiceadorlnyodrebaetfhos.rSein53ce noneoftheseanimalshadanyprolifeativ lesionsintheovariesineithertheinitialor `peesroviewevaluations,theywerenotincludedinthereportingoranalysisofdata below. CriteriaforDiagnosisof Proliferative ChangesintheOvary `ITnhtihsgenonoardmaallsatgrionmgaocvahraynogfepartess,esaetnseasscsemntaclolrgploarnadlsu,tleiandeedbveylcoupbionitdoailncteerlsltsi.tIianlsgolmaned.s. `acdadsietsi,otnh,elsuetceealllcselmlasmybaeycaopmpeeamroirnotchoelouvamrniaarnsatnrdohmaav.eThaesseeto(lluitfeoarlm acpelplesamraanycea.lIsno `awphpiecharitsonfootrmrgesleanntdisn,bouttetrhsetyiihlagvleanadcsha,raalcttheoriusgthitchfilnaetgerarcneulllasr,mfaoymhayvaepapearance `smhacoruolvdensoitcbuleadrivaagcnuoosleadracsytporploalsim.fTehrecsahbatonivgevecseh.angesarenormalforaging rats,and Pclraoslsiiffeireadtaisveelietshieornesp(ihtyhepleirapll,agsoinaaodranlesotplraosmiaal) i(nsterxcinosridc-tsotrtohmeoalv)aorrygaerremgecneelrlailnlyorigin (oDbisxerovneeditan,th1e9o9v9a;PrieelsufsrooamntdhGeocrurdroenn,ts1t9u9d2;ywAelirsooanleltgaoln,a1d9a9l0s)t.rPormoalliifniaotriigvienl.esTihoinss categoryincludeslesionscomposedofgranulosa,thecal,lutealorsetoli-likecels, or
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DuPont15261 ``hmaisxbeodpconpruelcaotmiomnesnodfetdhtehsaetceflolrttyhpeepsu(rDpioxsoensoeftaln,al1y9s9i9s;PanedleuvsaolauantdioGnorodfocna,rc1i9n9o2)g.enIitc s"iThku,s,tufomotrhsidsepreievrerdofvrioemw,ghoynpaedrapllasstiraomaanldcnaelolpslbaesicaowmebriendeid(aPgenlousseodaasngdoGnoarddaolns,t1r9o9m2a)l. hyperplasiaandgonadalstromaadeaomms,respectively(PelusoandGordon,1992). `Gonadalstromal hyperplasiaispreseatwhe th interstitialand/or sertoliformcels(but `toubtutlhaerpnroorfmiallelsoutfesatrcoemlall)cfelolrsmwiditshcorertweiotrhdoiuftfausneianrceraesacsoenitnainbirnoguesncloanrngeecdtcilvuesttiesrssou.r `H(ypeirplnasigcarwaardsegwreiatdheaidnfcsrreoamis1i-n4gns,idzegep)e.ndingontherelativesizeof theproliferation ``Typihcallyy, tphreoresmagroernnaodpallesaltrcryoatmoallsoagdiecinaolmafae.atuTrheesrtehfaotrdei,sttoinaglulioswhgfoonrasdoamlesctoronmsailstenicyn d`isaogmneowsihsa,ttahrbeictirtarryifeeasttuarbeloifsthwedof-odrgiomneandsalisotsnriozaeml.alGaodneandoamlasitsrobmaasleaddperinmoamrailsyaornethe dcairargensopsoenddisfttohaedboiuatmetesirnogfltefhieelledsuisoinsnigstghree1a0texrmtihcarnos3cmompe(oDbijxeoctnievtea.l1,f1a99n9a)n. iThmihasald `bothadenomaandhyperplasiapresent,ool the adenomawasrecorded.Sincesizei the `fporritmhaersyeclreistieorinosnidnicflfuerdeendtaianteivnaglhuyapteiropnlbaassiaefdroonmtthumotro,altihneciadsesnecsesomefaptroofliifnecriadteiavceedata `gonadalstroma lesions (combinedhyperplasiaandadenoma). Manyoftheovariesdiagnosedwithgonadal stromalhyperplasiaduringthepeerreview odfiatghnisossteudddyucroinntgaairnoeudtvieneryevsamlaulaltairoena(sDoifzpornoelitfaelr,a1t9io9n9w;hPieclhuwsooaunlddGproorbdaobl,y1n9o92t)b.e Hcohwaenvgeersw,etroeednisaugrneotsheadtnduorsiunbtgltehdeorseev-ieefwf.ectwasoverlooked,al possibleprolifeative: Incidence ofproliferativelesions(gonadalstromalhyperplasia, adenoma,or `hyperplasia/adenomacombined)weroevaluatedbytheCochran-Armitage trendtestand
the Fisher'sexact test. Statisticalsigniwafsjuidgcedaat Pnc0.0e5.
Results A`pThpeepnrdesiexnAc.eTohfealilnpcriodleinfcaetoifvgeloensaidoanlssitnrtohmeaolvhayrpieersploafsiinadainvdi/douraalrdtesniosmpareisnetnhteeodvianries ``oTfaablllea1.tsRoantsstsaacdryibfeioyeodnadtthheeoonnee--yyeeaarri(n5t3e-rwiemeska)cirnitfeirciem,assawcreilflioassirsastshtohawtndiineTdperxitor to trheeflienctteerdiimnstahcerfifaictet,hwaetrtehneontucmobnesriodefraendim"aatlrsi/sgkr"ofuop,ratsugmiovredneivseTlaobplmee1n,t.isTlheisssitshan 50 o(fesdaepaptehsarisnincatchhgorroiugpitnahlarteopocrctu)rarenddbveafsoirestshiegihnttleyraimmsoancrgigfriocue.psTbhaesnedoun tmhoefbnaunmeibmearrls I`necxiadmeinnceedspoefrgovraoruipaansloesrieofnlsebcatssaendiomnatlhsefoorrgwihniaclhmniocroovsacroypwiacsevaavlauialtaibolnecfaonrrbeevfioewu.nd intheoriginalstudyreport(Sibinsd, 1987)
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IncidenceofGonadalStromalTHaybpelr1eplasiaandAdenoma in Rats"
DT ose o T 350 T 300 |]
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`Therewere0ostatistically significantincreasesinhyperplasia(totalnumber),adenomas, oervihdencyeofpincreeaserd lecpsoiomnbglirnaedsdefiortipersotlaeifdegrra/otiuvpesalcesoimdopnasrweeadsotonbcsoenro tvreodlism.nStohamee300ppm ``mgororuep.(thFaotrise,xgarmapdlee3,,in4c,iodrenacdeesnoofmpao)lwiafsea4t/i4v5e,l6e/s4i7oannsddia1g1/n4o6seadwthieth0,a3g0r,aadnedof3030oprpm groups,respectively.Theincidencesoflesionsofgrade 3andsbovewerestatistical sreisgpneicftiicvaenltya)t.3Ho0w0epvpemr(,Pr=e0st.m0e4n6taenldat0e.d0p4r8ofgorretshseiCoonochfrpraonlAifremriattaivgeelaensidoFnissthoetrh'setseiszte, ccrointterroilase.stablishedforadenomadidnotoccur,asincidencesofadenomawerehighestin DiscsandsCosncilusoionns r`Tehveiseiwdeedswoiftohveamrpiheassoifsroantsprforloimfeactawtiov-eyleeasirofneseodifntghsetoavdayrwyi.tLhesFiCo-n1s43diwaegrneospeodcbrythe `cpoerrersopvoinedwepdattohotlhoegdiisatgsn2ossgeosnoafdtaulbsutlraormhayplehrypplearspilaaosriatoubguolnaraaddaelsntormoambaylatdheenstoumday pathologist (onegranulosacllumor-atypeofgonadalstromaltumar-svasalso `pdathoiloga isbtsyg wtehren esbtauo sdeydpoastnhmole oorgiosdrte)c.eTnhtleydpiuabglniosshteidcntoemremnsculsaetdurbey,tehnedpteheermroerveigeewneric dcehsainggneastoibosneorfvgeodniandatlhseptrroomlalilfeseironlasebtseiitovnesre.reFflecutedrthetspbheacsteerduomrnocfummroreronpthdorilaoggeniocs,tic `snuormfeancceleaptiutrhee,ltiuubmurlaatrhheyrptehraplnafsioamoorvaadreinanomstarwoomuallcdeslulsg,gestan originfromovarian 1E0xtcheopstefoofrtdhiefofreriegnicneaslisntduidaygnoorstthiec3n0om0epncplmatgurroeu,pre.sMuoltrseodfthieposcrrrpeesvuailetwsrwocecrauersrtiemdfieloarr thecontroland30ppm groupswhere morehyperplasticlesions(respectiveofthe
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DuPont15261 `omenclatureused)wereobservedbythe pee reviewpathologists, Basedontheresults o`hfyptehrepplaesriar,eavdieenwo,mtah,eroerwaedreennoomsataetinsdthicyaplelrypsliagsniiafcicoamnbtiinnceredaisnestirnatgeodngardoaulpsstrreolmaatilveto `controls. Someevidenceofincreasedlesiongrade,whichwouldcorrespondtoen iandcerneoamsaeisnosciczuerorfedsitnrogmraelalteesriionncsi,dweancseosbisnetrhveedcionnttrhoelg3r0o0upppthmagnrionuept.heHorowefvtheer,treated groups. References SAlLi,sEolnwReHll,MMoRr,gMaonnKtgTo,maenrdyJMro.nCtAg,omaenrdyMJarc.kCeAnz(i1e9W90F),.O(veadrsy)P.aItnhBooloogrymoafntGhAe,FiEsuhsetris Rat. AcademicPress, SuaDiego,ppa29-442 DPrioxliofnerDa,tLieveilneisnigoenrsJoRf,tVhaelOevrairoyM,GUt,erJuosh,nsVoangiAnNa,, SCtearbviinxsainidLGOvaindudcFtriinthRaCtHs.(U1R99G9-)S.. In:GidesforToxicologicPathology.STP/ARP/AFIP, Washington,DC. `IPne:lMusooh1rUa,ndDGuonrgdwoonrtLhRDL(,19a9n2d).CaNpenoCCm(edns)aPneadthNoeoboipollaposgtyiolofCthhaaengAegssiinngttRhaeti,OvVaocrly1.. ILSIPress, WashiDnC,gppt35o1-n36,4. Sibinsk,LJ (1987).Two YearOral(Diet)Toxicity (Oncogenicitystudyof FIlnuco/r3oMcCheommipcaanlFyC.-143inRats. RikerExperimentNo,0281CRO012,RikerLaboratories,
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