Document MGDoDQnM13qN1jn1pYMjvddpV

AR RAG IHU3 B i 1 Distribution List 11 EPPECOTNOTPHEFLLUICVREORCSAROBFONRADTISSPAENRDSIDNOGGSAGENTS 1 Medical Research ProRjepeocrttNoNso.. M1R2-36-3695, 10-B, 10-C and 10-D I 1, 2 J. A. Zapp, Jr. 1 3, 4 J. W. Clayton, Jr. 5 J.B. Barnes i 6 0.3. some I 7 P. E. Smith, Jr. 8 EP. stula I 9 J. PF. Morgan [| 10 Haskell Laboratory Pile 11 A. J. Fleming, M.D. I 12 0. 0. Mitchell 1 13, 14D. B. Hood 1 165 Hn.sS.hevremrasnes 1 17-19 . J. Brenn 20-21 C. S. Cope ) 5 Bruin PaduslrLEtTETEE i| 236Boned) Ploa x3 3-31-72 1I : _ 1 } z 11 ; g 000056 USEPA 16941 1 EFFEC`TONOTFHEFLLUIOVREORCSARBOOFNRDAITSSPEARNSDINDGOOSAGENTS i! Medical Research Project Nos. MR-639, 10-B, 10-C and 10-D i Report No. 123-65 i Amontus pesfiucrocaprylate (CAPRC), w-hydrohexadecafluoro- nuonndaencoaaftleuor(oChaornea)noaatned a(mANoTn)iuamre3p,o6w-&eir0fxual-2s,u5r-fda1c(ttarnitfsl.uorIonmeatchuytle) k osrbarlorataolxiitcyityin'sstnuidsiaelsswistuhrvtihveisneg caomspionugnldes,ubtlheethmaolstdossterixkaisnggross 1 5Zen5n-l6ra1arbgbeaminetdnst7t0h-oa6ft1)t.hheadlAaibvsseiormribl(eaEdrasAkbeNultTlt1Lehasrbsoourgmahatroktreheyd Reefpfoerctt sicin. Nwoass. ob5s4-e6r1v,ed Although liver i edtonhsleearegforffaeec1nt2t no1fgs/kAngTotthweaasnluirnvecemoarmrwkmaaobsnlefapiipnnrdoixntihgamtiatne5lc6hyedmatyihscraeleaftitenirtmoexsaicslaiatnriggoleners, than normal. I desigTnheed etxopedretiemremnitnseTmeoproerteddethaeirles wceornecerpnrienlgi:minary studies I (1) tpheerihoidsstoolfogtiicmea,l cihnantghees,litvhearts oofccurartswitahfteirncareassiingnlge I oral dose of AH; (2) the biochemical changes during the period of rapid 1 gWriotwhtAhMTa;nd recovery in the livers of rats treated I (3) tehtehancoolmbianndedAeMfTfeicntstheofraotr;al administration of 1 (4) ttihmeeefifnecttheofratA;MTaundpon the pentobarbital sleeping 1 (5) iAthcrea,lef"iGffRebAcoPtrFaCtoanonrdyliCveOrAGfpuroincencdutreoirtodhnaetrintmdoiogghfstindbteresusosmteeefduclwliinti-hn 1 dfeltueocrtoicnugrbolnivedrispienrjsuirnyginagepnetrss.onnel exposed to 1 1. HISTOLOGICALCHANGESDURINGTHE TIME OP RAPIDGROWTH 1 surA.u_cProtofcietdhruerse:TimIenfoorldleorwitnog 4stusdiyngtlheeoral osees"inorsAiMzTe,an16d male * 1 orCfaotnsttrhweoelrseaanmeeimaacalhgegwiaevrneednkwiealilgdehoddteastoefrivnetd12emargsv/aklcgos.ntorvoeAlrss.&ecpoenOrndiegodrtoeosutfp oa5fn6dadoannyiesmals 1 . eLaxinavdmeirtnswaotwiteorenes.treamnodvetdw,o cwoenitgrhoeld aannidmaalsseactti7o5n atnadken128fordamysi.crosTchoepic zzg 1 KS 000057 i USEPA 16942 ] 1 1 1 1 1 1 I I I 1 1 [] 1 1 1 i1 1 '1 1 -2 iwncereaBi.sendgiRnesphueslritztsec:enwtasThoefmoswrthaoplimeadrkbgeordodwydtuhmrasiosnf,g tt1h8heelSfihvioerwrsn,t iintnePnicgGeuaryrmses, o1.freabTcohhteehd 2Sizmea,xMiomarulpnthhooblueogthgwiecesanolme40cehanainnadgregs6e0miendraiytsh,ewaaslnidvsetritlhlweenreevbegianedveindtetnaotfcdee2rc4re1ha2os6uersdaiyansf.ter the single dose. enhanced mitosis The initial change of the hepatocytes. was characterized by markedly This was less evident by the Asfetceorndthdeay;56tbhy dtahye,nmionstth doafy,thethefemaittuorteiscwhAiccthivicthyarhaacdtedreiczreedastehde. response were less intense. microTshcoepisctreuxcatmuirnalaticohnanagneds ianppethaerecdetlolsrewseurletqpuritienceivpiadlelnytfurpoomnan enlargenent of the individual cells. II. ETOCHEMICAL AND METABOLIC CHANGES IN RAT LIVER 1. Changes in the Liver of Intact Animals of AAH. TPar'oScieTndguErlee: orTahlirdotsye.malTewoChRto-CtDhrreaecswawsekrse gliavteern, 12eignhgt/kgof tshiegnreadt,s awnedreansaalcyrziefdi.cedAnbyedqeucaalpimtuamtbieorn,Sftuhnetrleiavetresd rceomnotvreodl,l werc examined to establish''the normal range of values that mignt be evxopecctoentdroilnsrawtesreofalstohissaacgreifiacndedstfroarinm.icrTowscoopAiHcT-etxraemaitnedatiraotnsofand the tissue. Eight to ten weeks after the ingle oral dose of AHT, aTatssecotnhdreegrmoounpthosf t1aetnerr.ateTiwsassuesasclriicfeiscewderaendprteheparreemdaifnroimngaten pmeoarstuiroenmeonftstheinmaedWiaarnbulrogberefsoprirroemseptierra.tionOneanpdorcthioolnineofoxtihedasleeft lateral lobe was homogenized for measurement of alkaline phospAinhngaottathsieesrsupaeocrttiwiavsointuyswea(dsAPtuaossee)md,eafsoeursrtegelrwyaacstoeegrea,nctpidrveoivtteeyri,mni,naantdfiaottn,h.easnhTu,hcelecirhoeclm-aaicni-ds. ecsatlecruolla,tedph"osaprheolaicphidGsr,oupanodfpoatnaismsailusm.andAncoamvpearraegdeWivtalhuethewascontrols. D"itfefesrten.ces vetween groups were tested for significance with the ivenB.im EReBssults:l, TTwhoe wreeseuklstAsrovefrtthhee.bsitoecehleemicdaolvemeoafsuArReFmentthse are livers of the treated rats were quite large in size, more' than btowdiycewetihgahtt.of Athneincconrteraosles,inanthdecaolmkparliisneed pahpopsrpohxaitmaasteelayc9ti%voiftytahend cPhhaonsgpehso.lipiSdasallandbuta dsetcarteiassteicianllgylyscioggneifniwcaenrte t(hpeZ0m.o0s5t)imipnocrrteaanstes ianndoxdyegcerneasceosnsuimnpttihoen,rensopni-rpatroortyeiqnuontiiternotg,en,shoVlAiCneer aoxniddapsreo,teiRnNA and INA occurred. no! loTnwgoermognrtohwsingafatteratnheaccseilngelreateordalratdeo,sefoorf AtFhTe,retwheaslnioverfsurwtehreer =z 2 increase in the abaclUSe size of the livir and ite portion relative S s 000058 g USEPA 16943 ------------------------------------------ "3 1 1 tootethienwhaonldenobno-dyprohtaedindencirteraosgeedn., Pespiratory quotient, RNA and DNA Tahned dienccrreeaassee iinn gphloyscpohgoelnipids, &gAin vas observed. the tFrievaetedandratosnew-ehraelfsmtoilnlthsslaifgthetrlythleardgoesretohfanANnTo,rmatlh,e lbiuvtertsheof ences in the biochemical measurements were no longer | I 1 csmiaglnlifdiciafnfte.r SclhieambteTcrhaelosfeastrhweeesstleuhllettcsiahcsanimgnfeodusrinpcchapttooielionontgtsihacottafoltAdhNcieThsatpnulrgrioevbedsarun.ccieenssTthhiseeniglnltiihofevwieecnrraoenrodtsfaclrboaintocms-ee.tna-- A 1 CPoalttieonandofsmyuncleic Eitotic activity. Tahceisdes Ti oapialy increasing in 1esfsifzeec.cotnssLiasatrteeern,tmowswithtehnevittdhheeentoabcwscheeerlvneerdathtaeerdrlegisrvtoeewrdth 1 $hAapapsahreseatnrotiw.yednFodiromvwaenl oorirnsceisaxistemed,o,ntthahse raerfvetecerosrvaetlrhy'eofodfobsiteohcehoeofmriAgcNaTan,l iscwhhaevnnigrettshueailslliyver 1 complete. 2. Biochemical Changes and Liver Enlargement in Hepatectomized Rate I 1 aflartesadwA.yrTerPrsgoucbsejtdeauctrteee:doftToorpaapsrittduidyaglrtohwheetpheafotfreecctrtoegmoeyfnebrAyaNtTrieoomnno,vliinsvgiexr6m0atlitesosuC7eh0R%.oCfD gTihevenorg&ans.inglFeortoyr-aeligdhostehooufrsARaTftoefr12themg/oKpge.ratiTohne, extpheerirmaetsntwewraes I A8v71n0i8i%o0moauflcssolntdyhseue.crtvleeiddSvheararsemov-feocrpoesrnarittarnsotglesdtw.hheiacnohiFrmohdauealrrstdeoedbfneoesnedtadryetswaritemtaaehtfnettdeAMrbwTyitrtaheehnsdAsohRiveTnigpnla8geteh6co0otruaorltmsoized 1 d4onsaelyzoefdAfUTo,r gthleycolgievne,rsPohfospthhoelirpaitdss,weDrNeA,remRoNvAeda,ndweailgkahleidneandphos- 1 phatase activity. B. Results: The results of these experiments are shown in 1 T pPaArTt:aiao5lfb .lyInl ihseTpwoe aagwteee,ecktsosenxia,tfteaedrndctohnsettrraooilpne,raantibimuotanl,sthetwehreaelklnaiolvriemnraeslpohfionstphsehiazteasfeor 1 aPPiceptpiiadvtlieytc;yiomatinwzdoedDweNTeAakwtsesrAewfethreierghtterrreeaatttemhdeannt'wiiwntihntoAhNrTmt,ahlethtleriivmelerirsv,.erstWhhgeernelwipvaevrretsryiawlelrye 1 DiPnohirolelei'tphithaden'cgotlnwyticecenotgetanhnosdceoanltokefnattlhiendeehcerpaphsaostsepedhc.atto|amTsioezeeadIcNctoAinvtviratosylswR.eernsnThiednecpcrhreoaessa-esded 1 3AI8nGcrreieenansetenhdte.wiTiEtvxhecretsphteofpfironertvatichotiussAmHieTna-csrteurareseaemteeindntrsaRtNosAn,, lbtihuveterrtsheesfurRloNtmAsAhRwaIed-retreianted 1 | TDoaectncsturwrsiehtdohwnwhAiNeDnt,hTeaarbllpteahrot1u.igahlTthhheeepbaeitfoefccethcoetmmsyiwceaprlreeccehsdaoenmdgeewshoartinfloeltshlesowwelihdveentrreat- = 1 hepatectomy followed the treatment with ANT. . g 1 0000S9 i Jr USEPA 16944, 11 , . " |; . Effect of Chemical Injury on AMP-treated Rat Livers | 1 A, Procedure: Six male CHR-CD rats were given a single oral 1 1ldo0es0tehaglm mofod1g of2seb/ odoyfkwceaog irfgbhotnA,HTtientatrnradacphtelhroeirnti,odne8,salehloqyuu.risvalAleanntitemra,flosa0w.hs1iicnAghllerpeecsruebi-ved only carbon tetrachloride served as controls. 1 | idnle7d eB4.ign75tR.esd1uaOlynts5se:loatfeTrht,ehebruestsiuxlarltlastssofidxotrshaiestdsweixttprheeraitcmeaedrnbtwointarhteetANarTlascophrloisrohirodwetno :i tthhee cliavrebronwatsecproascshilbolrei,defoared11wiotfhintheASahnoiumrasl.s wNeoreanfaoluynsdisdeoafd and 1 ilpniovsetcro-slmoorwr,etreepmrmocabhsaasbniglveyesfihrnaodmsaibcteusg,tuen.ipfpaWrthotexyniimenexftiaelmltiyrnae3td0ioTgnro.osAsOlTyhg,en,rhoeawpneidvdelyrye,llothwe 1 1e8nl`asrogriengsulsicveeprt,iblWeitthoatghreeattoxeirc.tehfafnecntormoaflCClli,pidtihgalnyncoorgmeanlraltiivoe,r. 1 rats Bsihoocwheednincoalappmreeacsiuarbelmeentdsifofnertehnecessurfvriovmicnogntcraorlbsontwtoetrwaecekhsloride after the treatment. 1 III. SNEED EFFECTS OP ORAL ADMINISERATION ----OFETHYL ALCOHOL AMD ABT INTHE RAT 1 eaBA.ESTFPrOohcedeuRre:KrrTahctessotFudcyomwbaisnidnegsihgenpeadtoatsoxaincadadgienttiso.nalToe Wohbejtehcetriverewpaesatteod dseutbelremtihnael,'dbosyesoroafl ethyl asltcroahtoilonwotuoldraetsn,hance I tthhee setfufdeyc,t ionf taabsuilngalrefohremp,atiostopxriecsednotseedofinATRaT.bleTh3.e outline of 1 the sMtuadlye,ChTRh-eCyD wreartse,'ofwefiegrheidnwgabteetrweaennd P3u0r0i-n4a00Lgaub,orawteoreryuCshedowin on an ad iibitun basis and were weighed daily. 1 subjecAttedthetotgirmeossOfpatthheolPorgeisccarlibeevdalsuaactriiofni.ies,Thethelivaenrimwaalss rweemroeved, Weighed, and preserved in appropriate fizatives. 1 variSOBiE. RRTeRosdle: aAtospuemimeasrytoofftrheenLiinveTrabwleeigh4.ts Toobetapirneedlimatinatrhey 1 sriensgulletsdoosfetohfis1n2stiudys, ,whesriemiintAaRneTouwsalsyawdimtihn,istoerraefdtetro,Tatthseiirn a exposure to ethyl alcohol, indicate that the increase in liver 1 yeignta observed in this experiment was not any greater than that produced by AHT alone at a dose of 12 mg/kg. Be SRESL tanoder ein 2 1 1V. THEEFFECTOFANTUPONPENTOMREITALSLEKPINGTIMEINTHERAT : A s S in liver function or liver morphology z | recently, a quick and simple pharmacologic test hae been developed z 1 000060 = USEPA 16945 "5 11 SwlheiecphinhgasTibmeeen(uPsSTe)d. to determine liver damage - Pentobarcital i particPuelnatrobalribvietralenz1ysmemsetiasbolriezfleedctiendtbhye alivperro;jonagacthiaonng,e ionr 1 SpsohTuonrhdta'esnsinbngoe,remnaolcforatnrheeesltashtleeetdeipcwiintgahcttiicomhnea.ngienTsdhueicrneedfloiirnvee,arnaiflmutanelcrstaitobinyonathnidisnlitcvhoeme-r i I Nmaavoerprpeahngoteloobgsaylr.ebeiptiWanhlgenitinysoeuanngwaaqsaudeuflootuusndmsaolteloutCbieHoRn5-8CiD+ntrra1at9psemriainrtueotnegesiavle(lnfyo,r30m1t1hg0eiKrg rate). 1 of tenInrasttsudwyeirneg etmhpeloeyfefde.ct oAfcoAnRtMroaldmivanliusstrfaotrioPnSTupwoansPSoTb,taignreodups for each group of ten rats, usually 2% hours before the test began. 1 TATwaMteTant&f%yo-futhoreuhroruahrtoseu,rosf2l4a1th2eorunr,gs/,ktgh,e8rPhaoStuTsrsww,earseandgdeitveaetrnmoitanheedsrionngtilseeeacohirnaltgerroduvospaelsooff 1 saifmtielrartlhey of two of toerhxaealsmeinateddemsitfnsiosrtaPrraSetTisoauntmaocrfhieztehsdeameiANnTtT.iambelCeoinntt5.reorvlalgsr.oupTshewerreesults 1 proBl.o_fneIgsuteldts;:then TbheecamPeSTsohforrtaetrsantdhatshroercteeirvuendtiAlN,T Awtasapfpirrosxti- 1 mAbpayptraeolxydiomsseaitxeolfdyaNyassepvaeefnntteorwbeaedokrssbiintlgaa,tlertn,ohnaettheosftPiSltTlheoaffTfaeAtcHstDe-cdtorueulandtterbdeeaartanetedssrtahctoesut.lidzed 1 otahgbeasiennrevxebted itdnweotecrwoemneitknrseo,dl,aatnbiutmtahleist.ewnadTshoefstiswluhlmiechmoutbcihsmeersvhatothrietoenersxptweherarinseetnmhtaadtewasfor 1 terminated. I VY. E4F_FE_CpTroOcFetFuLrUeG:ROCaARcEeOsN mSaUlReFACbTeAaNgTleSsOfNroLnIVEthReFUsNoCTkIOcNolIoNnyDOGwSere 1 Sgampi leas v woifne gblloeoon drawleredosteakoefn 30d then veeldy thereafter. aAtMT,freeqquueinvtaleinnttertvoal4,s 6f,ororthr9eeBE/wKese.ks The dog chac received guy ves 1 lgai5t0veer0ng&g/ikgvseiannngddloeaseosrsailomfidloa26sreasnoerdfiee6si0tomhgfe/rkmgeC.iosAuPPrCoesueornrtoCsthAmeFarCd,em.aleeqSuiinvcabeelaeglnbetosthtwoere i: i r42e6pseatreedcewiivtihngtwtoheotCGhAePrRCdogdsiewdhiwcihthwienre36gihvouerns,a the 200 experinent mg/kg dose was of | 1 tthheisCOdAiRsCperwserienggiagveennt.an ag/kg] at this time. aTdhdeittiwoonadlogosratlhatdosseu,rveiqvueidvatlheentexptoos6u7r0e to | | |] tne bTlohoed:fo|llsouwgeirn,g ubrieoachenmiitcraolgenm,eaisourraelmencthsolweesrteeromladeanrdoaultkianleilnyeon 1 x pChGoAsaEpcRhtCaitvoairsteyt.heof6W7hl0eancmtietc/heKEde6h0dyodnrsogeonfadCedooAsReG(iowf4e)rA;eHT,aidamoAieTniOiesrmtigec/rksdgde,fdyodtsrheeogoeflneavseel =g2 1 {GfFTe) mtr`aindsoalmninnea;se"swieurceamAt1s8o0xmienacmeitrseed.(ooAf)fouatnignegluhteammaitcolopgyirciavlie g 1 000061 E--e ---------------------------------------------------- {SEA 16946 1i eatxaimnntaetrivoanlsaonnd tanhesaenaalnyismiaslso.f a 24-hour urine specimen vere mde 1 i eathaveesruadrgToeehsneeevnloatfelvueemflaldoueboosfraeotrctvaheterdhbeov[narsriadimoioerusspetorcsotimhnpegoneaexgnpetonsstusorfewatsahnedcobwmlipotaohdredsfolsslitoowne:s:loeS dogs. tise on Specidens from stock sojeny 1 dfoarssoendaPlbwsoeioratshmuterhaeetsnhueeernnedtzdaiysoepmateadraceslteiianovsgntitaaigoeenrsncut,ess,b.eaprrniooorfrmaslttoocrktarndegoaegtsmw.eanst,TehsetoanbAlothitesihvdeiedcgys 1 i findinB.gs Raerseulstusm:oarTihzeedsbirgineifflicyanitn Tbaibolcehe6m.ical and clinical The principal finding indieative of some inury or dysrunceion 1 Tgiicnsgttuietrvrhieoetslyd.2aongdasTnhdtaenh3a.teifnfcrTerehcecetaesssieevoenbdiengcAaUhbnTorlotewmosastsueclrhafoaalndleeacinrndearAsePetaesnietniaotrnhee (spBhlSoPa)wsnmsainndchAoPia.se 1 ddLoeasvbeinaotwriaaosanl"sa,dmfiiino.iems.t,tehreeexdpc.rees-dTeehxdepoasinunrcaerrebamisetearnaigrnewyiBtlwSihiPmitinhtrienttoherfoennetetiwoowwneeeesckktosacnauadnrafdrrtseebdrectahmee addneudprriebnsegsgaitnohentofofirrpsetltausrtnmesntocdahnyooslremsaatnledrostlohoeinnnerbetghaallanntthtroheeeredrtiousgresn ctoocunrorrmeadl.earTlhieer in plasma Abase 1 1 GaSgacrcttetoiairvtvsieitstytyo,focflhTiahvaneegrneudisionbngjeuprtrlhyaaotfswmaearsnezAcymPemeaieasvsseeudrcfeortdnhoesmiinhdtiehegrthheepedrspettl-oaedsxbosepsaoesswuoehrfneesniAtmHaiTavnes.hionwdTeihd.ethe 1 medoeasasesuurroeefdmeAnwTtesrewaaesrleeavpdarmetinseiedsnttweeirdtehdii.nn TTahbleere7.sultAsllofthethpelseasmbaioecnhzeGy0nmteonssetck the first three days after the dose 1 iOnF th0enGgP/Tkganodf AAPNaTgsw.as the norsal range. The Wdaidetmphirnieinssstioeonrenedow.feekt,TheheAplllgarsebmauattesctthhoelsieensctwreeerraeesleswitwherien 1 n9oocrmcneua/rklrge.dafmtoerrethsrleowelyw,aekBsutasthoecrceurwraesd nionevtihdeendcoegs orfecaeirvetiunrgn6 toor 1 glevaWtietdhitnhebo2t0h0dmogg/skgwidtohsieno3f8ChGoAuPrsR.C',tOhneeGwPeTekanldatGeOrT, wtehreey were 1 i3isn8t.ehtroheuedr,snoalralmtlaelro.frantTghhee.eegnWrzehyaemteness4tM3e0acmshugarn/egkdeg Both animals expired Within M8 hours owoecfrceutrhirmseadrkcieondmlpytohueenldGePvwTaatsaendaddmoIiiCnO.iNo. after dosing. ;A1 dhthoeegsseeeTnhxzwepeyormsee5es0dw.imtemha8isO/nnuKrEtethhddeeowtitnstoerhnOmitFanhlC8OdAaryaPnChgaoefuc.rtaseursTiehtndeheeoonlteedhovesa(retNoe.wdasl2)eavgeomlfisnttoheeftetanulcsld = effect fron the treatment. At the 670 mg/kg dosdeogofshothwiesd cnoompound, 3g 1 ta 000062 USEPA 16947 1 Dog No. 2 showed a rise in Te GOT, OPT, and APase during the first 1 2l8i%ghhotursr,iseandin4trheetuArPanset,o nGPoTrmaalndwGiOtThiinntDwoogweNeok.s.i. There was & 1 STRURY Single oral doses of 12 mg/kgSf ART, sdministered to rats, 1 wcCahouasreDaocntatehrrisazpeiadfdtbgeyrrotawhnteheontflraerattghmeeem1ne.tnv.teroMfotrhtpahtheolhceoopgnaittcioancluyletyse,.ftohreChaascnhgalenosgneginiass || nathcoecrommbapioacnmhyeetmatibhcoialslicecnolfmauprnogcsetimiteoinnotsn,aonfdentsihyenmdeoircgaaactnte.ivaiTtdhyiesatnucdrhbaarnengscepesiriianntimtohunec,leic 1 miaocnindtmhistcootnatinecdntiasctanniedviatmryol.ryphcoRoelmvopeglryestaeolfitonhfeftichveeelsletoscuhsgaignxegmseotsntabhnesg.iinnsterifnetrweonce I the 1Riavtesr t4h8athouhrasvebbeefeornesOuFbjeacftteedr t&oseixncgilseioonralofdo60setoof70128 omfg/kg 1 of AMT regenerate larger than normal livers. I givemnCtaaherbsoaincngclutemeitoirraaatclhiloondrois4ednedoifrset12meonrmteeio/nktgoxoifocfthMfeEoTr,CCrlaT,thsiistnhatmthaeyhearvneelsualbrtegienng iver which has more fat and less glycogen than normal liver. I ng/kgVhseinmuAlNtTaneisouasdlmyinwiisttherOeFdatfoterrattsheiirn eaxpsoisnugrlee tdoosereopfes1t2ed 1 aWsleuoibnglehetthaatolbtsohereravlesdadvoeissedsNooseto.faentyhyglreaaltceorhotlh,intthheatinpcrroedausceedinbylivAeMrT 1 that Pmoeltlaobwoilinfgeansoidniiutmiaplentdoebparrebsistaanlt,etfhfeercet biys AaHpTpaornenetnlzyymaens 1 1 idhnoacsterea4ls6eevecilasnn.nottheexreartte oiftsmeatneasbtohleitsimcoafctsioodniuamtpuesnutaolbalrybiatnaels:thseotic 1 vGAaetnsoLioavfnedrCOfAunTcCdtoiscoenl,apsatAucIdaTiien1se8 ianptdosgswheacveectsthhoewnLitvheart, ATO,b mat, and CoAFC lesat, lose Ltohe ii n pthreodulcievers"ievaDtoesedsplofas2s6s lmee/vieclgsofo!fAeHnPry0m9e2a0ctimvgi/tkyg ionfaCiOfAaPtRiCve of cellular damage. Only ART lowersthe cholesterol level in ! 1 dGdooPgsTes.g"arievOeftnheal4nlmogtsohtersmmeenoasrsieutriPevemereniktngsdomefatdebeco,tdiyanlwgkeaailngihneteffiepnchto&sspohnianttgahlseeeolairnvadelr in dogs from all three dispersing agents. I . 3 1 TN :g 000063 3 USEPA 16948 Ci 1 .s. 1 --B--i ONT5 HE LIVERSoF MATS ANDDood > 1 Medica) Reseeren Project Nos. MI-639, 10-8, 10: 4nd 10.0 i] Report No. 123.65 ;1 1 I I 1 1 1 be 1 8-15-65 i 1 1 i i i 1 --_--_-- ER YI 3, HASKELL LABORATORY PORTOXICOLOGY AND INDUSTRIAL MEDICINE cntac) Blocnentstry Section --Heyer Chief, Ore Toxicity Section Approved by:--H ?a rosisk viht DireSHle v . 00008% a-- = z g USEPA 16949 I a : 38of832d2 ase dds 3AT= ggeosagmnm AoREseEnR 1 I 93 can :E233 sar 53%s 2 2& = nom @ggadsiist BdAaefsES 1 1: : . 27v88 B8E8%S EEBRR gUTTRRY I5EsRe : :1 JLA=fg&|l [2T5e2o% 3% 5% 3S3an%e 2S5e8n2ca23i87 8 3 a mE we gm 1 78 es 1 i3 SAwaid Some '1 HUE| 20%a52 9H3Ia I29 2e7R58 T999E7N ' Si, Lh 1. . : i 1 $5se5 ive 91 Sgh3d Hgiads iBiea Fnw,l2 : 3 ofe 238 8 33REai3ls 3Bpfeisats!2 i 1 000065 USEPA 16950 ] 1 1 ic In 1i:ii s3z ro feeoesl :!! i5| i HE HFa az zze2z2d%: | ; $359 ef y 1 H 5 ysfPerzarneasi | | ad . 152221%.} i:; !5F38E%zFn : H q-- ; : ; ME 1 : iSe oo . : { : 1 gq 557 fi{ed ii |! ii: AEivi.; 3 ae dl :3 i 3| 1 8 jLHi : c l i 8 vo ov 8w % 00066 i sera e951 i | 1 2.5 1 2 CY ~ 1 L|} gg; !t 2. g| gles . a 1 3{ j2=2 I 1 gas BaPHie oa I 3 4s 1 i g |, IL | IP rf | ' 1 8 it eo @ wv 1 3 - i 5g 1&55%; 88S GStEa ' y EYBhad In 2 3 #5 #5 3 11 CT8 2Ee sElnalde] dgleeds dgueels 1 i i: 000067 =- alll USEPA 16952 I | ' 1 I 1 1 1 II . ! g% R |8 8 y= Fp g E OEE] no g3q8s]lgLXfF 8 . EEEEE 8 2 8 dRTe E es8 ---- Rr R |8 ) Ra :R oz &a rd : 8 5a 0. I i. 55) 8& 8 . :: roy Cen a a | Cy : || Fi fis i 8 $ydi s Ef nny : : ; of E22 gad i wi3 l 8 BE| foa~d hofs ad| f | 52 38S%18 33x0gdf Ednxsf f3 ees |; | :Z 1 iy o } 000068 a ` USEPA 16953 . I1 op op 1 I 1 : = | ! : .Ror |[i3 I 2) "os dame med 1 -} 3 R s 3 Po Eee (2. | 1 5 2% 28 1 i gd . SRR [RR g 1 deg BAZ oo |e = 5% 1 o ? OR FR " i 2 seek |e (556 Vow. CC iE 1 sf PHS oo [00 EE 1 GTE* 8 For gE : 1 g sme |e= 2[1 HEN EE 1 AEF = R- 1D 4fe of 2 s31|B :E 1 i: 2 PE . g i Bada = 000069 5 USEPA 16954 | I ---- | =| EC] | | 2 "om i | gl i |e = | =| i Ler | 3 i | 5P| E[oEfB i| R 2 eli2 | fo gl | |r | R= EFS oder 1 Ey | HE i : IGE g |mR Lg Pogugg Eilfal 2 [oc | idor ]| =i 5a ERE 2a ! Bgl E|i ; |2e i |i 1 [el | |e Eo 1 = i ] RB R i n | o 2 1 AEE] ge I 5 i 8 + ! I --i~--eh |T o=F 5 : 1 Bl s 8 |8 "8 000070 f i * a USEPA 16955 | 1 i PTT r13o%n3 8%HLI;:(8: i 3d 0% E3F [3,8 .1 Ei qi B# aif iof soB3 SSEpEE Popgoad: pgEE pEstgosB8l (53 dsi . G :BRH EEETi |E e 5: he Bh , -- 8 |i eile ||2S8 HEpHi [S8g4t3a8sid h(31ei35ll7e5ae:l od : CI J3 o 0 0 0 0 fou oo Pl yr ;"B1R4 i 1 SF |g d88d, , op HHilEl E2.E33C. EIRI Bgr agFerad BFiiseFtlREfaEsHalEf ' 4 1 2 ~ 2g |rs [rf :1 &8 - 8 1g8 |B 8 : A. - J i 1yd3 1 8g=E | 2= 8 5gFE g 000074 _ ]. USEPA 16956 1 o vo!1 i e I o I Az 2 Fs agan $82 11 PERELEE g2 g= II Bdeegx 1 gJ &6 3 ge5ac| : 3 : 11 i E3 EE sSahaeda. g2i 1 fi * 1 HE EAR tesag| ! i 8 5f2z 1 a LE 1 fre nen|nca2.x23 t)|8s4 i i: 1 ~" | a$ 8 ciei Z USEPA 16957 1i iwl 1 5. 1. i i i gIAgRg * g |v 8 gles 8 a g 12% % 1 pla 5 1 gl.|o 3 LpIg 824 13 gSh] wganzez amazes a0gggRTe2ess megrere | |= 8g8g|A gIREe g [48R preter R22298% 290 Ag8R8E:IRE & 8RRLARR 17 |Ib3sp|3da3e33iEeRnR oGnRl e|< sReERnNiEnE sSeEaRmRaEn 1i 24Fllo veenemesns 0da|oenocnnna aaanaeaa oy , : 1 | : | 1 3 p|s o8a588 523 BE20R% REANAAR $ 1 2h ; |z sexes 2 (2 93RERS IRIRERT | 8 1 shale ~oomsan oo [3 eomrzg oeonnan| ivo (52BOFEg OF2 BoB 000073 :: 1 La USEPA 16958