Document O3DM5bpawMa3yz66B8XpVQmpM

REFERENCES (FDA Docket No. 94P-0420/CP 1) SECTION II. D thru SECTION IV. I SECTION II.D REGULATORY TOXICOLOGY AND PHARMACOLOGY 2 1 , 244-249 ( 1995) An Analysis of the National Toxicology Program's (NTP) Technical Report (NTP TR 421) on the Toxicology and Carcinogenesis Studies of Talc*1 J ay I. G o o d m a n 2 Department of PharmacologyMaincdhigTaoxnicSotlaotgey,UInnisvteirtusittey,foEraEsnt vLiarnosnimnge,nMtailcThoigxaicnol4o8g8y2,4B-440 Life Sciences Building, Received October 1, 1994 The NTP toxicology and carcinogenicity studies of pnoornta)sbweesrtiefocromn,dcuocstmedetbicy-gerxapdoestianlgc (mthaelNe TaPndTafelcmRaele F344/N rats and B6C3F1 mice to target aerosol concen trations of 0, 6, and 18 mg/m3talc for 6 hr daily, 5 days per week. Based on results of the high dose, the Report concluded that talc caused lung tumors in female rats athnedrephweaoschnrooemviodceyntocme oafs cianrmcinaloegaennidc faecmtiavlietyraintsm, aicned. A thorough evaluation of lung toxicity revealed that atanlicm-inaldsutcheadtluenxhg itbuimteodrsthoeccumrorsetdpornolfyouinndthedeggroreuep ooff chronic toxicity. However, these data were presented amimsapenlmniceparitritoihcnaastl woofboustheldrevrbaetioliaoatnsessatrhyae, tmhi.eetr.o, ttrhheaelenrviadsnikstcaudssasseteasdsmwineernaet cthoellepctheedocbhurtonmoot c"yutsoemda."s Iwn aasddiintiaodne,qtuhaeteevableucaatuiosne oitf failed to place sufficient emphasis on the spontaneous incidence of this tumor in rats. These deficiencies caused the author to vote against the conclusions pre sented in the Talc Report when it was reviewed by the NTP Board of Scientific Counselors. The appropriate cpohnecolcuhsrioomnsocayrteom(1a)sthweerdeattaredaotmneont ti-nrdeliactaetde; th(2a)t tthhee maximum tolerated dose (MTD) was exceeded in the fe emxapleecrteadts teoxpcoasuesde tolutnhge htuigmhodrsoseu;ndanerd (c3o)ndtailtcioinssnootf exposu icity. r e 1 that f 995 Aca ail dem t ic o P result rew , Inc. in m arked chronic lung to x IN T R O D U C T IO N noTnahsebeNstTifPormtox, iccooslmogeytica-ngdradcaertcailncog(tehneicNitTyPstTuadlicesReo-f eccsdawttoadctssFgoppwtoBB"mmFhr(rohroeetoTaatmynneeUnlnfeoi33auaoiaoaivveaxsnrTmentrdtehcr4t4stpdfcanpoJtansihiicomticaeofeheecw4iBeu4rri)rdhmondetvolenwoewdpadieehe/tc/n.moaneeotesBfoNshNvoenaa'xdyweseeecTrrsastgvssiteafdoivapvi,odkohdrhinpceshe2isTitltraoonoridoifndvenoerocioheeanane3(rtosvbfgeefafecooccwladenNetitre-rlenoycoan0sncbuasiltnteul2e)ddfmmuhhelvt(,gTcad,cercgni4atvaoibJradwstrencoen6eyhttdlTaPaeegnlh,.ifeiaociau,oi1cnnteloiatraomdaedc,seatIoeatosatd9ladgs6lin.niedcbahcsaiirfinv1boiwn9BupomdaassasFclGhriNnero9dieorond2ctcehepnr/tl6tni3graio9RsrbiecoofyaattTns.epsctCobitt4he3fia1asrrson1JocaaesoortnPoendco)s43o8mrlrt8haod,palpctf.nochaifeaavnFt/fhyeevmlhneommgNyhegiAttaelneBcb1evtgrtehherorbRn.lceesIhrcaashyoaitggne.ogeyiehnuitrm(dpnasliferinomsns//Gcbaeesoeoinraee)ammpt.diaBetscciRrnccy)drancnliothnocposd.xiTrpqoaisi3o3ntecneahtcsootdneceerpiT.rabumhhhvaaeyd"vttaafdrbcootvopyaseemrymfeihoeoatsaleaimagmofeoedsleoaeeeducrcsRaawaetictffaNrtstm(dadSrrnehteeegoslauaintNlceieenef,ondngpecihlvaTnriaitoaSvoggiglcnndgihoTrenawiopsdroifrPreauoonetieeaccemoncmowaPytnsrrbas6nwvatwitytatidrdserThttnios,tidcaanaf'stiuaovoionhohseofeifaiosleomlntSne1d(enngfceipifurrmlgndmf1gccpro9nucfiicsataeateocdt)ihcepohh9tmabrhtmnasmtanyoeaetsoasRhCceal3ieeachltendoveloeiieftnuacotb)osiogctocoelohedselitmntshscyelecdtprcBmfuhewdoecvilepaaa,erehseabonunosrebodg6oecodnfrremii5inrerteosrseonfegteCn.ytntoumrdcNtchireimmfenidveniolcivsdTm3wenwtltawustineniaitT(ohtenaFiaiaghdcnfhhn2eanoyetooaoatanlrsilinP1inyeeodesege)eessssftsslf: U8ircu9osa121elr5ToPsy.groaye1ns,wdae1nnh9Hdot9eme4dPa.,hlctiahnorrmpPreaeasrrcptso,polaenotcdgtteyihvn/eUecsIe.n,StsN.ehrIFonHDua,lAtdiBoeWbnteaholearSsdkdodsachr,eioesMptsyeDodon,.fJRTaFnaeaglxucu:a:lra(Cy5to1o3r7n1y)s-uTF3meo5bex3-r SYNOPSIS OF TH E CARCINOGENICITY STUDY OF TALC wtaelGcre,ro6euxhpprsoasoefdda5y0to5madaealreoyssaonplsderc4wo9neotearki,n5iu0nngfteilm0,ma6loe, rotFar3li41t8y4/mNingra/amntys3 0AC2lol7pr3yi-gr2ih3gt0hs0to/9f 5r1e$9p69r.5o0d0buycAtiocnadienmaincyPfroersms, rIensce.rved. 244 ANALYSIS--NTP TECHNICAL REPORT 421 245 TABLE 1 Summary of the Lifetime and 2-Year Carcinogenicity Studies of Talc" Male F344/N rats Female F344/N rats SEBNuxoerpdovyopivslwauaserlteiirgcalhetetevfsseflescts Lecavacertlicvoiniftoyegveidneicnce of 90AH,/di56gr0,he,on-dr1ao4l1s/8m5e0meg,drg1uo/6luml/ap53:0sbliegnhitglny lower than controls or malignant pheochromocytom a (26/49, 32/48, 37/47) Some evidence 0ACHL1,1uldip6(egn/r1,ha5heg/roe0n-5: odre,a0a1ovcl1,l3hvsi80mder/e/em4oe4ognm9d8lrgca,uo,o/9erlum1c/l/pba5y33:r0t/so5obln0imeg)cnhahitgi(lony1l3oalo/rr4wam8de, are1lnti4hgo'/an4mn7aa,nc2too3rn/ct4ra9or)lcsin m a National Toxicology Program, 1993. awenedpmmaWinlm(r1unNaxlxnoori2evia3gndotpGpe2sdceTsleengitexeooeekacrwvoPktiessosailaghwmirlnexuec.,dnuatar6ede,prieFeao1rpdtfn5ekros/n6teiu9msebgtesnmsmc9pog(ahlroeaeeeNs3fynroaadrfaxolowo)tdonllT.nprmam4aueiet1fcgTlo7cPopfr0cebcdrheeneslh,a%aaeoatimeteraotoeawrnyadoe1dvsnclalryan9.irec4atlbi5ltdceo9lenrTeo9rpoywehesv3wwdosdhhnuama)e)igaesaeyde..escdeldyliesrtaoieTeigrTew)ssnsmglonc8hnstehohihwsehp0cuicttioefmeositlhe%aredemlgacaolnyrasyorosirhracmeuldnaewffrt(taclirsstics1osocitrvoove4uinh1twaacsenain8ihtl3tevnrutyoknttoeetoycshatdmat,rrdgwaisootloipnifweehnns(mmneoosro5cnnuiaieeeerfm0agnaamoiroktrtcvrmursegeeftsoafciiioinpcdetzivalmif0cifynfeisnmenla,ctoo.ateotdoobltmih6irahnsetrnmaao,leyieetm1raiensnrofnpat0leobctdthearcBTds3rhdhloaleeosia16efaaesnocootnen8sCebnehtarnfammtdrddlmtir3afoe1igtaboaitFnnofhl0cagephleles11ndge4eessr/,. m24omntohnsthans.dTluhnegsebaiorechoeumtliisnteryd abneldocwy.tology studies after PARAMETERS ASSESSTSUEDDIEISN THE ANCILLARY pwLLPLrouppCuRkCLuuaonlhsohnnnyehetmecoegagglsasrlyitosponortnaicptseonaabnnesaoohdllniiaesjslcycomauus,lr,ezactyecrbapaaeighyatunlnsudafetec--refuodslnamtdlmt.eniacolvepo.icammtosnirixdtcttovniyemrietotaadayt.tenaretat;aiieybrtnnoimob.dotnmlrenii--ionshan--nmecyj^c:urdp-,ohrgropypoolluh--argyoclaemvtugineneoreaioocsrnsrlpn,eaehi.saradyolsaknnlesaatudevhlciaengalgseenleiausdrpt,afhallateuochnuiisiddd INTERIM EVALUATIONS IN RATS oagbrrooInpuvpue,aslmaopnofadnraaaenrlxylieamlmfausilnneserciwdteiosefrnoeorftieenxastpntesocriismlaeldaftrpeytaroths6tto,ualldoc1ig,1ey,sa,es1v8ada,delduasincatirtdoiiobnen2ad4sl LUNG TALRCESBPUIRRADTEONR,YLUFUNGNCWTIEOINGHTS, AND moTnhteh ilnuntegrimtalcsacbruifridceentimatetshwea6s-s,im11i-l,ar1i8n-,maanlde a2n4d- TABLE 2 Lung Talc Burden (Normalized to Exposure Concentration) of Rats" Male Female 6 mg/m3 18 mg/m3 6 mg/m3 18 mg/m3 2116482----MMMMoooonnnntttthhhh iiiinnnntttteeeerrrriiiimmmm 00..1174..33271924 0000....1002492108* 01..1161..06352543 0000....1010119533** 00..1174..80255628 0000....1000564332 00..1147..68364753 0000....0110843077* *"*TUSaingbinltseifaFicr3ea,npNtrlyeastdieoinfnftaeeldreTanostxm(iPcgoltoa0glc.y0/g5P)rcoforgnortmarmotlh,leu196n9gm3/.mg/gm/m1g'.roup by Dunn's or Shirley's test. 246 JAY I. GOODMAN TABLE 3 Total Lung Capacity of Rats" 0 mg/m3 6 mg/m3 18 mg/m3 sahhnigodhw,eeirdninsgttaehtneiesftrieacml,aalltlyheses.igmnaifginciatnutdeincorfeatshees iinnctrheeasfeesmawleass Male ASSESSMENT OF THE NTP TALC REPORT 2116418----MMMMoooonnnntttthhhh iiiinnnntttteeeerrrriiiimmmm 22210009....03586060 0000....438552346 111889...844748 000...434196*** 20.20 0.28 11119766....26345747 0001....54352593** 2116418----MMMMoooonnnntttthhhh iiiinnnntttteeeerrrriiiimmmm Female 11113434....92284095 0000....22326115 11112234....97651386 0000....21328747*** 11112131....04856300 0001...3.2201677*** grou*`*pTPU=amnbSielt0eas.n0Fa)11r.eX0,p1N0re0as.teionnteadl Taosxmicol;lorgaytioPriosg(rdaoms,ed19g9r3o.up mean/control Sh*i*rlSeyig'sntiefiscta. ntly different (P 0.05) from the control by Dunn's and etetcesfmiita(1(hhnmieeTTxvvan9oooamvTpnaa9daapnlssemlolt3bebhaasueeulrs)stlylleiiaaa.heeaeertoolttydmWatieai3igffr2sonostb)are)hfcthw.ndne.stooenoeiassosamicltnntfetlce2aha1eeutoaduxn4rd8nmrtlforeped-edirfamlranocmeseealratcrasdemaostengretasptntaedt/da,sthatmhisatlhrhetettetseeraohh3esisextibn,eee1lonpi6woeganrn1rtosnett6eodye-ihtst,d-rdvraroe,owiefeutmd1t1toiuf1aahr8s8sfntla1stlte-uhiwoit-c,tmglcin,ehautoen6aiag1geanronliln8ecifn/glanfwmildyodencoimocfnewtand3aefi2cis1ngmltpgthi4eyi8aet/g1ahimlm-nexl-cy8nscmtcmtphseesi3ir,tfeootmagoywouirsinstncrnentdifguweetuaostciyh/rrhamnnpdnremee.teteyr-eafiiIae3rcs,ennrln(resietmNnttewdgieleetbvaodondharThrrotetusaiiliaieefPemletmilctniydhdnesss, BRONCHOALVBEIOOLCAHREMLIASVTRAYGE AND LUNG tcsBrfbsttiffeetaoeeaeoylyrsermmnrtsuFnosststel5tsionaamdnh(n)illlcfian.leeezlnpeohbtuIsssyndrwotn),ioitmohs.ditahtitcavehlnWheewoadvwisgsedtfedee2lihareaavorit4ebsigvethnelli-iiearaeoneodwmaoogrvnscdsufacepoliha,soaspgotrneleolvsfosmhuustmalexahtutasna-eigpeiitlcrgrniicdeealdeenineadrdctlwgttgaylao(ie(atnTe)toa(TlrhraelTrdsniawdaandemabpgnibdelonblieeluulrenagfeelnrenmcevcfvt6geo4lnmahrabu)l7e)rgoellenhm,eauuaetargtoespnmlanaeeadfmotudbtddlsarioufloioolmponcixieppnlgndenrisiaaboseocl;atwlrtrmnonithhaataectataayemhmenhiotarssneodywnnereemaeredtttsoasvfpTemeeauesuupanarrlapnaeslgsrrmtbausoieachcnl(attartmteaThthiientdainoneaiaveaae8sndngdtt., cewotetsglimapwttoaccGiowtpptTtimlfifmrNTilorISi1ucoinihhnsecnheheeenealoxbpobalhbfrf9oocaaeaioaosic3nxaoommcTcrqreetooapmTpTTlrtints9etsinllncv)tsavisirtuecyolltgduuihyeuectpoerhreosP3oedtuiu,chacaarhho.eeelo,dnbeissveeikprrltnewds)idcllold"dndeeRrenRtayovfovmssf.ttixeeWclurtrBrasshoeMlceon.imgeuNeenaehtoiarassa-btuiHefrtecdsertNrsyddmassaoepstmOwapiandiseetdthupoopfatauweeklnxveitcTinssilolalse(rtufauoeuoicTaroevmaomstofcxiattcsohdToeee,iftwrirlaacnsrnnPCcnrhalthdtnca.eonneerhhrtdsrditusPnset,eapeni1ooegttsdtbesiyrretmsyipssfsun.aoTochgbeoaoe9losdoocsob.rttvlaoi.imwtpaenaaomumfenTaahonenllttt9siahhrynafetfnewrrcceleeusmhrsii.gdnlamditslehIer4e,lesegatiarniscarStadcnisresitdmnouoeseaoccse,ei)eenaeenthmltp.ammoiotnmlcvm.ewsensnicutdhamrlnds,rtmputWpdr3timiliocmgcaiael,eh.oam,ahgnsIonaaehe.nooari-elttiarbirdrtsaiRtiptesitrcatoeachorsronops8tteoTstaignrtcrnneasch.sioskiseeis(ttthalts.idtatra;oena.oeenotwhduhvThseteebuseitr.tbweaaItpnliupear,hnufthInnseddTdeuedirnetmNnn(avteaaushiTtlxitiscgdohtielatGaohcrsialemhsbitstahpjsoianretewepeyawTshterwhao.usqeisnulactdahdalilrolexspomtdCtooalsirctuesinSoereuseudiiPxinyeoeeaoalaesasctorrpestsfensbeelnaorauad.sstnartdrehetovl,sn2oteykrdtnesraysrdaaiipdstmhowutmicotimioai)sdpnceeosnmispdptotftdktsde1is,opthtanmiowtifiabiitesrucnxoiichen,eiaowueipet9emropbttsuatascnialnturyrloauebgbhidiuhieoefeq9assschhenuereetrlancaqenrllivntprisareissdeoae3teul.trecaect,stiodoh,letoeuitceststoiithpdaasssltss)nhinl-asilehesahfledepaeyhrIma.pntospireiie1flierboittnwfretnahnsaerdenstewioalmor(seenevn9neloylopgeiIbietooolNllgeuttdaNfsrtno9ccwntsiaeootufiiidrfhrhtrboevnttfantrhemoichutca0tiotaneoanTeanfttnchbeiheTneihaetftaaingoaypn,ldchpegpdmrtvssttiechgemovselgcPtetdntaltetnsvepPiraeuehtstyle1hstshreaaNesrattiee,txaehod,idscelhetaioalNicho9te"iedumrelteossnomnipadefarabonohtetwiiuTn9h1xtadmrslteicpionhsnTiffuu(oochti,ufnipaeaeiNl49aioeiepotefnloaPtoNegltuniihecsssscesssaanei9P)ltdtoanrpnminrmwtraeesunnhiiiT.aihrutamnnd3geTesexmsctoi,lwectrhas;odvtpagrdennuaTleuiy)aaBhhdcoPnhia(smrnerPitfoacanmt.rr.iicsiden1aclnltietsayaoataeothneintlo,tReursshi,rithit8T(paonbvgyTiiiilscrucaxogaooieiodsiiasilNsnnlvaofsetoesiy1Nncteohsthdelmnisfhqnrqetutramtetiitdrpc9iionatonddhcaTieitooodnethsutnnptuntnTttabaria9coiotnlhhoenhshhgxtasbtnibexcePaotlaaoauaoctil2eooaonPnyirediedeocledotnee/eeees.srl;tttltf,f ANALYSIS--NTP TECHNICAL REPORT 421 TABLE 4 Bronchoalveolar Lavage Fluid Enzymes of Rats at the 24-Month Interim Evaluation" 0 mg/m3 6 mg/m3 18 mg/m3 FMeT/T/AGaLAGLm33looaaell--llakkuuGGccttlaaaatttetllaaaalllluuiittttppnncchheeuurreeiiddoooorrppooeettnneehhnnhheeiiooiiyynnddrrssdd''aaeepprrssddoohheeuuggaa66ccetteaattnnaassaasseesseeee 1301631164...3070.47839 00511..4464457.0043 41123016.70.352..35680 00321..06.297.6279 591339781..2.9138.32568 06381.06.9626..48079* 481315439.3.5003..56602 40472..439234..9674******* 11861895002..4.2679.42799 03011.8.445503.552***4*** 215519444.E1.763 21127E1.32**1***** 41620.9.06 04.42.88*** *'6**/UTUS>ainngb;iinttl0ssei.f0ppiFc1rr4aee.,nssNeetlnnyattteedidodifnfaaaesslrmemTnogltUx/(giP/cgcoolcono0gtnr.y0otr5lPo)lrluoflnrguogrnm.agm.th, e19c9o3n.trol gToup by Dunn's and Shirley's test. 247 cwcgebaotmoiin11sniooxn%ue9rciciageTnpm8scstafclihnai3uceolenhi(gopt,;lmnrssPtceseunnorme,hcirrHeadisgudeiPe<fdoliadetnnaiaedhtvlce"sidisso=i0etafaennegg.ehr.irnnt0ccm0uneiIatahiste1hand.nialtt0ead)nleahnor2ttncaecthoet1hfl4ia1l,eegc8nestiet)er8vonhhoeaccstmerM(eemamreiihloNdnd"ascugogmflTeeoe5ootT.ui/,nh/d%gmtrnmDtomlhPucoedd1anpe3ea,mnr3iwn9(lsbscd'itPee1c8scouaeaoxx9io6aosvtrmns<9)pi)Pnisefifc.ne3eoont.owrxtrg0w)psA<foehro.c.eahta,n0telteHdhsh0essrh5cteeeaho.5oha)arda0(race3wtriame1tielgcht%nedda.ecsiiharvsrnnvrTocaleiweeiieeoensmonsthlnsioerre;gtmg,ait,armorpesohdenltriPcplnhoteeoaiamishyofsnelssii=eteftu(egemcocueHrssnfdnamwom0mppoadunia.nwrrof0inaalstooisssln0lsedscaaearhdeit6tmsas,taoua2tt;tnr(hhttucetn7adbatfihhe%naalnleetesedyeessttt, btyctssrirffirnrhnhnioaeaaipoeeentcatpattrTotaoneteesswtrnnohrnutud,heisrareetnsonaeoi1ta1naen(sfsarl0otnt%Rsndeeaht%pcsefeali.eeatchtohcni1louasmTnyue(9uaddenlbRe,or8hscsiaiperitct0caaeeloebhohesaaphnorsnaephaeelteihrs.cFieecmnlooo,fnesNaetn3ooducma1oagsa4nrhlTy9omclaledo41d.sr9fhtP,,oc9.(p0uhrnrp1o8y1tm;rocaafhoh33o9ctaNtmttooet/eec9sni4(mrlcdou,T0oboteHe8yh)creciudPab,,rnthaeyinsioey,dst2srntoc.Nmoeo71eggistneen9m%hmm.pmTaod,m9weos)aoaitPa3isnhneinscNkn)iittdte.snsyahtecaoaThtIttrcinucaibonnteenaPsaaedosmdactra,rloesinifscocaedcharruRoetimn-sevrdasnavst,aoqgeilirroepnolitueldhepnygiria,neaoaotfertcnthics1senmihnfneosicim9e,ieb5gddoayn9ctte.neaslnh2p2theefnplairoe)-eaeefonac.to7fiFmsfshec.ntUrtlt3lt1tihaeaaeathg4%1nnstisaliltoh4neecs0ssst TABLE 5 Bronchoalveolar Lavage Fluid Cell Populations of Rats at the 24-Month Interim Evaluation" 0 mg/m3 6 mg/m3 18 mg/m3 FMeaMPLEPLMEmlooyyeppaaallmmiilccyyttehhrrmmppooeehhppllooooiihhrraaccppaallyyghhgcctteeooeeeesssnnslllluuss cc llee aa rr cells6 cells 0.333 + 0.167 9036.0..060700 + 303...06310.702 0.625 0.315 09.10.0308 01..07050 8.00 2.01 207440..54..82013507 + 0221....52543155*78* 2057..1277..27222828 +0202....91565870*83***** 63022.45...72505500 0311....05770550*00* 3751.74.03..03330333 + 0421....6665672078***** 06*TUSPaingibintl0sei.f0piFc1r5ae.,nsNetlnyattediodifnfaaeslrpeTneortxc(iePcnotalaog0ge.y0o5Pf)rtoforgtoarmalmcteh,lle1s9.c9o3n.trol group by Dunn's and Shirley's test. 248' JAY I. GOODMAN TABLE 6 Lung Collagen Metabolism and Protein Synthesis in Rats at the 24-Month Interim Evaluation" 0 mg/m3 6 mg/m3 18 mg/m3 MFeaTLCCTNLCCNmlaaoeoooooooavvlltlltnnlllllaaaaeaaaaccllggggggooeleleeeelluullnnnnffannallggugguppddeeiirreeccddononggooododccrrllaooauuulluaaddlsslccggllatataappeeiittggoonrrinioeooeonn"nnnttn"'eeoo'iiuunnssssppyyeennpptttthhiieeddsseeiissss4' 331191341...2.7685.97718 + 05011....40617.77052 07111.84479...32843.71229 00321..4.1164..8564654 421167591...9.9796.94880 +06021...2.1354.71912** 1321112195.85...9503.54986 +08491...0.1695.419894*** 73199181..2..2168.13288 ++++03211...03332..58627***3* 1325796.542...47463.17438 + 03111..03.3367.4953*7*6***** *"4*1'd**UUUTUUSPaninnnngbiiiii0nttttltsssses.i0faaaaaiF1cirrrr7eeeaee.,npppppNtrrrrlreyeeeaesssstsdeieeeeoninnnnfnttttfteaeeeeedlddddreTaaaaanossssstxdpmnp(iPpecgegmorr/c/gclgoeeXc0gnnco.ytot01anan05gPtg3tr)eerr/ooogflnnrgloecelrlumwowuannmngcpttgh.ro,r.ooel1llta9celg9ouie3nnnn..gt.r.ol group by Dunn's and Shirley's test. " btpBpleni1ianmihh9ecocoTo9ueetkpaah2ouolhrlsa)eosccodes.rhhyaf'ltsimyrryeranooedrcaammae)wsirpttvdkooeaaipieteetdcncrhnidwoyydscatptttieonoihtnrochmimiecafmiaernlaatetlhaesshtyalrimesss(ieisnaetannoi(sNlgwdirrentanifTshhcettiteseoafPmhii.nlwncaeaTTadutsalhsnehpitracphdetiolascoorniataannrewtpntRatcisaponnrtenieurhednpcoaeloaiocodspocutrurerauehtspi,ttsaaaoehlsvietJfdieneinduentcdchnPgdibuiwdiedaesrvseeeitipnt2aantnnhulco3gcupmep-neett2arthhooo4earieesrff, ssieonntetdhaint ttahlec NcaTuPseTs aplhceRocehproormt doocyntootmwaasrirnanrattas.conclu CONCLUSIONS peNficexeimTTpctytoPahe.sledeCuTrlaraeetalpoacttpsrhRreaecoevxtappiupfrdoasoieaeirsnltteectidolesucttonroohefgnastcchutaltelutruthcsmhiieinniogooMnmhrgsTeadtonrDokuiscenbewddeaaaeccsntdrhidervraxcoitwtcaonyelnnicecoddfiiflesturtidoanonmlgniocnsttwottehhxaxoeesf TABLE 7 Proteinase A ctivity in LavaagtethFelu2i4d-ManodnLthunIngtHeroimmoEgvenalauteatSiounp"ernatant Fluid of Male Rats 0 mg/m3 6 mg/m3 18 mg/m3 Lavage fluid HoAANmcceCCCCPMioiuddMaaaagtatrptttpechhhhaNrrnreeeeloooapppppttetpeeessssrlhiiaiiiionnsnnnnastuaagteDBBaDsspeisneeeeearlsncaeaastttahasneept scfliounlildGagnase 000...919942474 +000...1434127594 00018..2.0724...512399355920 +000000......490612114961988 01..589696 00..117540 1.267 0.094 02111.3.4.7449...841503214786 000000......23963040027724**7** 421...348082770 000...123416785*** 422.4154...5101703340..05000011..050..355""6706*7****** **4"**TnUSPain=gbi0ntl1se.i;0faniF1cro8ae.,nspNttarlyeatistsdieotinifncftaeecldraeTlancostuxml(iaPctgoe=/ldSho.0gr/.y0m5Pg)rofcrgoornmatmroth,l 1lu9n9g3.. e control group by D un n's and Shirley's test. ANALYSIS--NTP TECHNICAL REPORT 421 TABLE 8 Proteinase A ctivity in Lavagaet Fthlue i2d4a-MndoLnuthngInHteormimogEevnaaltueaStiuopne"rnatant Fluid of Female Rats 0 mg/m3 6 mg/m3 .18 mg/m3 HLaoAANvmacceCCCCPMgiiouddMeagaaatartpptttefchhhhaNnlrrruleeeeoooaipppppttetdpeeesssslrhiiaiioiinnsnnnnastuaagetaBDBDsspienseeeeearlsncaeaasttthaasenept scfilonulildGagenase 0.110..165125 000...102216*5 00011...340607...584900459485 000000......196500458883277 132.3..411650 000...2239232** 524026..9.2300...544496163708 000011....421..601167078815********** 46.20..004153 000...715377*8*** 1133220808...203...629113135237 021111......468651219092***486******** **6*TUPS=aingSbintl0sei.f0aiFc1r8ea.,npNtrlyeastdieoinfntfaeeldreTanostxm(iPcgo/lho0gr/.y0m5Pg)rofcrgoornmatmroth,le1lu9cn9og3n..trol group by Dunn's and Shirley's test. 249 dccdtdpcleeadvvthgpvdspaasasmth1uiahuetxeosnrrreooaeoeiee9rieroulgn3egerieeetsaenllTpnln9rsdsuacntiioidoshnghldsceei2ecocsrdmb-nehyarcpype.,otktoe;lor(.setmodonmteiirutnMifsaaenTolnctTfsmuenoartduGteuodahtctdpluauugeathmlseheylbnicefsithyaloldlecstmncidetoesfeCgteievte,mototooiesoauitsetihyddxenoigeornvrnihdttrbpnsdtheanaraauentnogtrnaycmseandeeridreihltcsrfmdoslamdlncgakcttloreeanditueereadheatomedhpoemfrotteidnhaondneiedtoeMsslnd.twontreidtolnetrxdec,aihrvssa,TelvttpeeNlwditwanthoTc,raeosieweervpt1a1oehdradsiohtcaileDTioxdtlec9bh9vicaeiycseerrnerutnruhounlt9h8aieeoPinoaevrrvotrmidtaeualln4totae9nhsinlneieadopo(uswtesmt)bfT)tceeldKsnefpitwil.esr.foofrcehhenltclv"dnoaeoreidaaaeuoocApremxresAoaitldtdaoleldnlonqocnfhkcifpesaamsutdnttao,nterciugmngusteomintnylebucestRhmenbaiitbectmshadgebvnoaotoonotsaiereeoeehuehsamta,roaiancdnocndrtithpmltallielNttclyhghnhoesraroyeintpieteo1atvisfitrhmnutpfxoesotMTlodrw9,lhrterirrwaimeiprrtothtdemeee8cdccemeahaPisentaimrTxslelhdlor7aihi.gtletvaeooareattkcaathspiu)lsDefanayiFatcaancsp.l.ctdeaaoeelhrd.elsmiatrhpdugalohr,usecddsoxhoiiads.HissprTisegnrntn.litnaatbesegttrbe.antuodrhrhcdohhhoteetntsnhroiTta.hgfMmeechiaweeeeosssitoonptdmpemhraorsesdrstraiouftddepetiovoTmoeremeuohsotaaafvtgoriiftmesdlnebstssDhdeaoi"luaoteewhhedcrae,orseatuetnrietrrttnaiyneepe(sgani,hshtieoaomaotrisrNot6rsioosrehonsa,cifoitsfetodhnsittpsahhttTmitlenrithlustapaidnttdrheofotraoihgvih.hbPkoatpnttoengoelcewwiwsioohaeieeecassrtrs,/ REFERENCES Goqicouodil.rme3am,ne1,n-J7t..fIo.r(i1n9c9o0r)p. oTrhateiocnarocfinboiogleongibcaiolaisnsfaoyrminatpioenrs.pIenctViviter:oATorex G oc5tNhoo1Tedl-o5mPug9sya.BenPo,oraJfo.rbdgIi.rooa(lf1moS9g9ci(c4iNea)nl.TtAiiPnf)ifrc,oa trCfimiononaautlanilosraeenppl:opoArrrsont. aoRacfnehgtahultyoel.srAiTissodkoxvifaicstsoohslre.eysPNsRhmaaetevrimonientawarcelobqTly.uoi1trxhe9ies, Hacsineomgaenn,iJc.itKy .st(u1d98ie3s).. FAurnedeaxmam. Ainpaptli.onTooxficfoall.se3-,p3o3si4t-iv3e39r.ates for car Haaosnfeidmmuaaanll ,ccaoJr.nctKirno.o,lgWgernoiniucbpitusysthso,tueJds.iteiSms..,aFatenudnfdaOalsm'eD.poAonspnipteillv.l,eTMorxa.itceWosl..in7(1,l9a5b876o3)r-.a5tU8o4rsy.e Haccshoeanmntrgaoenls,F,Ji.asnKcdh.,eairnn3td4e4rR-l(aaFob3,oG4r4.a/NtNo.r)y(1ra9vt9sa2.r)iTa. obExiflificetoyclt.soPnoafttchuoomrl.no2or0ilo,,ct5icm2u-re6r-0ern.eclaeteidn Komvciriebonant,.: RHH.eoJaw.lt(sh1h9Po8eu7rl)sd.pIteshcsetu. eM7s6Ti,nD1b6bio9ec-1she7el4me.citceadl afoprpclihcraotinoincsbtiooarsisskayass?seEsns MAcCmo.nCnoellll., TEo.xi(c1o9l8. 98),. 1T1h1e5-m11a2x0im. um tolerated dose: The debate. J. Nas5to7iro,y3n1are7lv2Ti1eow-x3i1cbo7yl3oth0ge.y NPrToPgrBamoar(dNoTfPS)c(ie1n9t9i2fi)c. FCionuanl sreelpoorsr.t Fofedth. eReagdivsti. N aomBtni6aoCntnh3aSeFle1trTovxomicixcieicocsel,o.olNgoNygaTtyaiPonPndTraoclRgaIrrn4acs2mint1io.tu(gUNtee.nTSseP.os)iDfsH(es1pet9uaa9drl3ttihme)..seNonftTtoPaflctHeicenhaFnlti3hc4aa4ln/Nrde pHaonurdt RaEttohrue,onslG.tdi1.ss,8Nin,S6.,.F1-3HL74.a04s(./e1Nm99ar0an)t,.sJGd.uroKriwn.,gthGa, rnubmeoldebyveeiwnn,-eyiSge.ha,tr,Cpsreaurwirovfdiov.radTl,,oxDaicn.odlDogt.,u.maPnoadr Soc(nNitnaIogHg,e)J.n.DMbHi.o,EaPWsasagPye,uibNni.. sPNm.o,a.all7n6dr-o8Sd0ae1fn,iotWst.tia,NsUhai.tni(og1nt9oa7nl6,)ID.nGCstu.itiduetelisneosf fHorecalatrh