Document MJ66QGMeobOYrkwEmQVodejZx

Ales/. L/iwn i >li vinilc Il'VM) a risrhio sia -Jii.l.lro clinii'O ck1!vu-W.-no. Vi-nyono (47si m-1 momlo .vocsi in if.icstu!. : soiii-mru !nolire I yj.j relrospclllvj piu che surficicnti ie.noU'niche ncccs- i ,i .i-ro. 7 iI'Dship between >i olher conditions llusiraieii in order study on workers tress the need for . I.M.. Fievez C, !... lllMNSO.N M.N. *>il Assoc. )., 16. m WM. (1969): C.imssHim; K.S. ..roM)!. Moscj -- mpal -- I.A.R.C tnicrnazionale per i S.. Veltman G. odvt ipslufcn. Atti i Ini Arch. Ar i-rric Chcm. Ind "4 at: Rend. Sci., oiM G. (197-lb): ::tut Sup. Sanita, -iilla Tossiciti del tutu H.I.. LeeER.. Petens M.J, Smirnova (1961): M'flIE* C.. Suctu t tick VC'. (1969)196)1: Med. Inlovaltla. Praj-ii. -- 'hinpton. D.C. __ -- V till. A P.L. mi a P.L. (1974): -miir. Puhl. 411 ic personale. -- - W11 son R.H.. 201, 377-581. v,j. .,. ii i:. i'i~J Isiitiito ift Oncolopi i c t Lin-I- I'mii-in llnliiyna Dircimiv: I'n-f. (. M.ih.--.: I 'I VINYL CHL0R1DL CAR(!IN(KENESIS: CURRENT RESULTS AND PERSPECTIVES C. MALTON1. CE l.CrilMIM., IV Ulll.t.n ami IX)\AIA C.AICkl.lll I) Intkoih'ctiun Vinyl chloride (VC!) has been produced industrially lor more than V> \vai . in many countries, such as the U.S.A . Japan. Western ant! I.astern laito|s-. -Russia, Canada, South Africa, Australia, the I'hilipim-s ativ! Hia/il V(! is tin. constituent of polyvinyl chloride (PVC), which today is the plastic iistlit-trr.tl material most often uscvl and dilfu>c>l throuylioiu tl.- world It is used as j copolymer in Saran and other plastics, as a chemical imcrmc-hatc. as a soUciu. anil as a propellant; in the past, for only a slxui |x-riial. it a as also iis,.| ,i. an anaesthetic. Some sectors of industry ami modern life*, heavily ilc|x-udcni on Vt ami PVC! prixlncts, include huililiny and cimstim lion. the auloimiltilv imlu.-liv electrical wires amI cables, industrial ami linuseliold eijiiipiiuni, |cx kayni;' prixlncts. IkuiscIioIiI (urnishinys and medical pnxliicis. < )dx r |iuI)iiict-> ion (aininy vinyl'chloride ate useil in Ithtes and siulace co.iiiiiys. V(! iiiihxhik i is the sinyle most iin|xtriani market lot the chloride caustic industry. The nihlx-i. paper ami plass industries also ilc|x-ml heavily on the pnxlmtion of Vt!. VC! is presently produced at a wuild-widc rate ol appidsttnaicly 12 million tons per year, mcaniny the entire VC-l'Vl! industry has a Mib-iamial im|uu on the world's economy. For instance, in just the U.S., which prixluced mote titan ' > of tlx- world s VC!, approximately 14,000 workers are employed in nearly 50 monomer and resin plants, and an estimated 50,000 workers are employed in plants pnxvssiny PVC! into numerous prixlncts, which in turn are used by an estimated 800.000 to 900,000 more workers in prixluce industrial poods anil individual consuim i prixlncts. The economic value in the U.S. of o|vrations ile|x*ndent upon V(!I'V( prixluction is measured in many billions of dollars. The UVihingf>: I'm/ reported on lune 26. 1974 the lollowiny: "Ihc American plastiis indu-ii\ warned yesterday that proposed yovemment rules to slash \tnyl ililood.in factories to eliminate the ilanycr of cancer mold cost the nation u|< t> .' million jobs ami as much as 90 billions U.S. doll.us in animal piodmn-n n v ; 53 \M 1 & A :c2i i ttE ruxrrarsE racr M. Ij` l' i* i!i- |it.11>i- .a V( i> evaluated at approximately 72u.nm> in!)' ; u I !m' pi-slu nu\ i iiia*" ol \'( PW ,itv Mmitedist n. S!vj\. I innuii.i. AN!* ..ml I iij'iivliinm. I lu followin': (**>pol.i ti**m nwy Iv excised It' VC: I) worker?* in the jMixiiufMn n| PVC and VC, and dre ttse ol VC Jor odwr Mi.lnstMiil |hii|m%vs; 2\ wotlteis manufaciuiiui* PVC; H residents in ureas ii- i'.'lil * it i u^* factories podium*: PVO ami VC; mnl lo a much leaser extern; h j'topic i#vin* products toinaiiuu*; VC, Midi as some pm)vllcttt *pia\%; m people having tontnci uiih tesiio nude with VC and with materials con i. mmii*;! ilu.se ii-siis. and ri }mpu].ttioHs const miintu h*d contained in pljsiicx ii. ul* fiv VC l^Mss.iys on <In* Ion.*: nun elicits of VC vceie not available until l'>7tV Iliis Min.iiinn icfkvts dw l.u k ol consideration given tmiif now lo cx|vrnm*ni,i! in pu'ifii ti*i;t tin* inn*enu clkvt on uun of cm imuincui.r! am! - agents We U heve ifi.it the events related lo \tml diforiJe cauim* mm iir nInniM indm r rn iri titieiesi in cvjvrimcutal bioassa\s. Ill Hisrnn\ fn W7it Ihnfessot VmiA presented l Viol 1^70) at rite X International .mm Congress (H-mi-uimii iIk* results of a |>iloi experiment, which were later ) iMolu il m detail (Vim a et al . |*)7lL Professor Viola reunified to have "i>'/rvnl iu 26 rats excised hy tlie inhalatnry route to 3<UMl ppm of V(. I 11*H11s daily; *> <lay% weekh. lor 10-12 months, surviving 10 months or more. I * skin turnouts. 7 pulmonary tumours, tnainle carcinomas, ami ^ iMeivhon< !x mi.is In 1067 our institute initiated a large investigation among workers ot r.i raf Italian industrial plain-* to determine the effects of the e\|?osurc to `lilfmiit iliemicals on respiratory cpithclut. The padudogwal changes were liulietl hv sputum eviolo;*v. In 1070 this research was extended fo workers hi VC PVC imlustrie*'. A significant increase ol cellular changes in hrtMwlit.il I'lfU limu. sii !i as marked stjuanuMis utetaplasia atul svjuamous dysplasia. was florid among die uorkris more heavik c.xpnscd in VC. Iimnediaielv aftet the I louston <'ont*rcs>. we contaetevl Prols`<sor \ no.A I. * I mdlv put some slides of hi> experimental tumours at tuir <lis|vsal t-ioidtue t* our iim*ipjei.nitn. the malignant tumours I'hserved hy l>iotesM*r t`H \ in the skin were eaieiiumias arising: fronj tin* /.ymha! yl.md <a sv'hieo'ns .kind o} ihe exterior acotistit duett, which is rcsfmnMve ti a larpe intmlvr oJ ."'in''pus 'Ike malirinatuies ol the luny. in our opinion, were metuMjse-* 0 in /.wiikal pland tumours. YJ to. *i II!' Al dial i holopna w die tyfM.* and . The prolater was ioir. (UcicHim' an ! 'The He, technical dai. >f die most 11 Our pu-* I'erirnemal re* l \ \\XVl KIVU Oi \ n k i A! PAn;//.*: I K;t prm.* U' suuh tin- .** tunea! anf *.-h hy eomintKHO . .strain* (Spraet Propram C'nstnvtt<>n r were startcJ > The ehj* Kvtl de*:ne.l to simuharH*' amtrvilied h* VC! o * Rc*.*areh Ca; i as ftllt'M'i' H.O Avftu Avitvl AlVo. Bnta: * I.5 l*v iTilo?. I \y^: Vin\! Prop i Meih* SpM>U` hamsters ar M period K < nutopsy. In SPt-03205 k____ .tfij l.uiitrn 'iciv 720.000 ions onteslison. Sstlvav 11 workers *'l H' for otlwr t'i.ients in ureas .ivh lesser extent vupcllcni s|'IUVs tth materials coa Mines/ in p/asties lulile until 1070. e to experimental tv ironmental ami i eliloriilc card no a\ s. : .\ International Itieh were later i|v'tieil ti> have ''it ppm of VtI ttionihs or tmvre, isi ' ostcoehon- < me workers of live exposure to ehaiijjes were i let I to workers es in hronchial il'splasiu. was `rolessor Viol a i* our slis|Hisal. .si In Prolessor is? *.( seh.tseous trite utimlvr ol . ere meljst.ises u :: I'i'j vis. i i tt.i nsna i si*. ,\t that time len.l tl )')7lliai tin- Instuitts -( ttmolimv an.I Im..... ( i.t. i .I Isoloeoa we plaimeil a proj.vt ol eoriela:e>l mvesiijiaiious r. luitln-i * I*. the tvpe an.l slejtree ol the r.itsiiiapnn is|. lem live ptojeet was emouiayeil ami ip|-;:. ! |v. Mot . .!i-- I l.ilv I.us i v ,i ioim\l hy oilier nuioi l.i.to|v.m ..imp s. tlus : l< I y., i In-leuim t attsl Ivltoits* Pioait lli.tmet Ills I le.ul ol the llealtlt Senisi-s ol M.'-u .: r. - ;|ii|; ,! . tsslmis.il sl.ua slealitV): with oeettpaiumal s\|-'-ns t! is s-ual .*.! il i i. i -1 .. ol tin to*ist nnjss.riotti parameters "I oempatiott tl . I::: : : i t*slie, (W present knovt JeJ^te on (he .anwoivin 'f ol \i t- l*a-t.l n|- u , ivrimcnt.il results ami elinieal eptsleittiolii.eii.il il.ia III) li.Nfl HI Ml M VI I )\ I.V II li.XI'l KIMI NTS l-l HI (IKMI It A I Till Ixsilll II Ol < >M 11| < .V ANI. Tl ` t. it V l il Nil K IN IklllX.N.V. It AI V A I Pl.lKIlbl'i. IlltlU'IUlis itUil t'/C/bnJf. Out pn'HYl iiK'liulo 4 ol r\|rnnirni\ Upm m IIk\ wn- *1 to >huiv |)k rlUvo* ol VC ;*imiuiMrlril iltllriru: umiIon i mli.il.itimi. inp.rxii.iii (OlH'.li .Hill Mllvilt ill tllllr.rtll xlMHYHU-tti'M).. In: V.lli:ii*; I*- II* ill' . *1 lilt' in or imrrminrni trr.ilmrni. on ainiiuU ol tlnlruut sfviJi' 11*:<*. iniir Ittm .. I *ir.tiiu \ Npi.tjmr Dan-Icy int Wisiai i.iio. s\ .m*! ap. i.klnli' n. ! * * I'loiit.im pl.mnmn aiul piI'p.it.do; .! miii.iM. . |* timn.i t! . **.!;t m> |tn. ionMt;ui:on ol .in inliataiory i*\|hwm. .ipp.u.ttnv i.*! n- mi:' \.r. 1^.1 J.\p m wt,, xi.HUvl in hilv I lull vinn- yr.ii Mir tii.milvo ol r\f>o"*wv .nr Ivn*.iII\ !****lt Invu .IrMiOUil to ticlivcr lomvniraiioio v.irxmi hom .`.I rl.t ' Ilf1 ppm I ppm t| V* .I to >iiu:i!uituou>i\ i rc.it nr.iily i*IiIn I In* iTMiiiitlU.I K r:,ix rltiom.iu'jiiaphv V( ;n s-.pp)ir! In MonirJ.son .mil i.uli lu'VJn l: l'u;i I Ik1 impnniH' .tn.l llu i. iii.i\mhmhi I- im. rinr.it''*-* n 11 > iImi.iI iuUmiI ! n lit *j . m Mi-in .mp!*\.l !. ,l> hlloux. 11.0 \. rl*. AiJrln.l \rri\I. nr MU-rn Mill.m.' 1.1 rmi.nlirtn- 1 liloiopirnr I ):.KVi\irnr Viu\ 1 \rrl> Irnr I'litpiu. \inii ci.ua 11 JO ppm ^ ppm : ppm > ppm S ppm l< ppm 10 pptii l ppm 10 ppm l ppm 11Hi ppm Npuij-.ur M.m U i.d' an h 'll r\p. mil t. .1 Ml.ii. .i!m. iim1 ilir .iipiimU .1*. I i * * ' .1 p II.si l vr.il' .mil. tiY-ISillrw. . 11: | ..'>* ..> .! I ' I- JMi'iN -I . ! ! * it .1 l!P'\ lilt's ^i>i'h i|>. llii'il lAlil-.' \- i y M / 1 1 'S 'N i'i ii.i t MM .Wit/ VtJ aJ. I M2. /'**- I' Ill wi.mul .llal i.i-,:lird l-\ v\lkH 4 ' kivkx old. n wllivh time I Ivy >* h* .m t.it I. n,| dpid.l intu t<*n** l )ifi.*r u*iv ! i imm.i!\ jj. kd. ;n| .m .idsju.iii' tnmK*fiul diet. During treatment. they ........ * **|H* 'M m.iuiKss xin*l win* iu^-s will? a solid button of the same vf[ | |HTiiitriit.il I'r.nnnni lu, ended ilu* .miuul, aic ki-pi in groups of 5 in * .n?: - wit! i*pk tn.j.K if si.tijik vN xtevl win*. A uhallou layer f white wood * ``s dm (. Uddi!i;. Ilu* aimn.il. .mkepi in a iem|vr:Mure conmvlled Ldxwjinn I *1 :* * p ;nieui> {111 I Hi wen* m.iiioI S*miv i*l diem were programmed it flw it.;* "Iiil, ;liris Iv^.in .ilicr icxuhs were obi.tiiK-d from tlk* initial experiment*. The 1 : l p!-m .iihl Hirreni siiuaiiMu nnul Sepiemlvr 10, 197*1 are shown in table I. The animals are peri*), and monrhlv .if are recorded durinp cor. TK' animals, when mo A complete autop tn\ Z>Tnbal planils. inr. fcplevn, tumijch. dillert feet and any other o:y All animals exp*^ innknirv are* examine,! examinations are made i ' ** 1 -1 ***!h , .Ik elfivl mI lb* aimfspherie explore to lOjlHhl, 2.VW. 50U. ',n ppM *l V(.. *1 hour* ilaiK. 5 days weekly, for 12 month*. Two otlvr primps i ,i.'iii.)|s tie added as loniml, one untreated. as for all subsequent expermwntx. I in ued wiili vinvl avelate < V AI ai 2.^*1 ppm. administered under ihe same VfJ hi* VA ikrs.i^N- app.Ht*! to Iv tlv maximmu amount lor chronic ' | *ie ; it--. 2 in.estimates in a large* unuilvt ol animals the effect of dt*scs between 2*I to *M d.u i* 2<*}. HO ami I mi, undei tle same conditions of oxfvrimont I. This was N-' ! let it va* tlear dial .'ni ppm was Mill causing mci*goniv effect*. RI Results. The ctirrcm i< 2. 3. 7. 5. 4. SI, iti not yet available. Different type* Zvntbal glam! 1 J *1 iiiln*s die elfivis o| a slmiici c\|*>Mirc period nmlcr the same condition* a I [ innrip I. ` faxpiently reprixltii glanJ. but often th i //. * / vithlies die elhris ot die same ivpc and degree of expmure as in e\|vriment I in .I'l itlni sjkmVs. lltai is mie Ireaintcni lasictl 7 immdis K*canc nl dv hipher m< : *' t \ rate and shorter life spin ot ur nme a* comparxxl with rats. / ;-n 1 i.h timleriaken a* a piloi imestipalion to study cIk* psrssihle elfects of aimtss p|: i:. . vpiMtte during preptiaiuv on otf^prinp. 1 / ;/. ' lepimtiuvs the Mime eunduiom of Professor Viola's experiments. nmrphoiis patterns, same tumour. Met; Nepbroblaston reminds us of an e and brain. Hyperj*' kidney of treated < / / : / -indies die elfivts ol die same exposure as in experiment I in another strain nl i.rv dial is W'istar. Angiosarcoma' more than one site I V simlies ihe effects of the same exposure as in experiment 1 in a third species. d. ; luitis|, rs. lot die Mime rkrttnl a* in exivrimeni 4. Hepatic and extrak morphologically sii ! ; * '> was planneil. before tumours were observed at ppm in experiment Bll. metastasize and. a: !> I th t assess whether inha!ati*m ol V<! has any clfwi at a dose lcs*e! ol 50 ppm. l most frequent site / pi sjudi'-s whether a hiph, but limited aiul/or imermittent atmospheric e\p*sure iMs I if, ,, I II evaluates lIk* elhvis ol V(! by inpestion. 1 ' i ' M idies di third penet.d it*me t*f e\|^sure. f I .i's-ss > klk tln r Vl a. is n iissues dirivtly nr throuph nwtalxiiiies /1 I I- !n:i itklndetl to sj.jdv die res|knsiveness of newborns. 1 N ias Maned as soon as we loimd I liver anpiosjrcnma, I cxtralwp-uic anpit * < .ei.l I ii: pluobt.tsiotiM. in ihov animals of the first experiment. e\|xsi\! to 5|l . i \ { I u I sear, ami sur\i\iuu I '5 u'txks Irom ihe lx*pinninp H the treatment. Blood vessels . vritb cellular atypi tissues in treated angiomas. Thercfot be considered svste , in the liver and or; From the hi* genesis of maligna hyperplasia, angi<>i and angiomas, ane Fibro-angiobla i in the spleen of tf i spl-03207 "1 M.J I .tmrn .* uhich jinx* they ih.ii *'n. I'rom uea on** treatment. they :s*n-*n of the Mine f pTHips of 5 jn *c: il while wiuxl 'nrroJled JjhoruMry u:\imnvJ .it the .* rvoriuuui' The *h*-*:i in table I. *. 2MKI 500. I" other groups :v|uent experiments, ml it ruler the same amount for chronic s.* between 250 to Mtc:i: I. This was odciis ) < vimo conditions ' in cxivriniem . >v ol the higher t r.p.s I efhvts ol atmos sieno ! m mother strain n .i third >|xviev. exjviiment HTl. ; Vi o| 50 ppm s'iicrii exposure v:jh.htes. i-.iricpattc jnpio i to 50 '* t!v treatment i \ i.' ./ ///.'./ 1 ' vivo * >ii Mf ii*t i \r* i*. . i'i' The .iimn.il> .; i.MluoJIed mw } I1. ami uctrh..! t-o v-t I.- ;{ l: . p.ti.sl. and montlm aUc; uv.e.im. . Hupl.-nd : ;..uhk p.tih-T , hd i ate recorded dnisnc *onir..| All ,,ic ki*p: :>d. : .it: >n :! - t .! I Ilk- .Hiun.Cv l.ben in.*!!*.! .Ill ,*-,.i:.il. m .-I . i : i ! i! . \ oMi[*'Ui .|.Uoj*>\ ; 'Midi i j. .....i! :. o:i Amba! id.mdv nn. j m ap :!.i; i.u >!. . .piecn. st n.i h. dill.-.in .rii. ! :k. ;; ; ti.-j and .n\ .:!vr m .-tl p<:;- _t. il |. i! .`.1 "1 ; 0 : ! . ii > . \li .nni.iS ' *1..- -.a. . t.iMio.M' .m .\.nnin-d t.uh"'o,.'.. .i:' .i ' me in... ' es.untiut:oMs .ire m.idv on hum * . : * t .. : .u : i :i~( .. 4I . ;,i` .1. . d, II) Rt'it<//v The eitrivm results itnnl hepteuilvr I * * ! sever;il e\|XTiinett' till I 1 2, 5, 7. 5, 4. Ml, .ire shown in t;illc> 2-1* I **t tie latter e.\|x*ftment\. iIm.i .n \M vet available. DilFcrent t\jv> ol immnu> m.iv lx* pioMiu in the saute .iiiiumK /vnilul ^l.iiul e.ituiKHii.o tin 1 .itnt m.r. he InLtur.il I lt>ioh*ou.il| th. (rci]ucntlv repuxlvwe. to a cenain esiem. liu 'intitule ol ihi nntin.il /. ittl.il I'laiul, hut often they pn*seni ^%|u.iimihi'. pl.nnliii.n. solnl, aitapl.isiiv .ml j..d morphou> patterns. Several ol these ililleu nt pi. lines may U* ol^etvnl in tin same tumour. Metasta'es id the'e tuiuoiu' aie MumiiiiK' lomal in ih Inur Wphrohlastom.ts (in r.ii'i .iu often htf itit.il Iheii |.i>i|..;'h.iI pi. inf remituls tis oi an emhrvoiul kidnev IIkv tmt.i'i.ia/e to the Inn. 'plan. I.u.: aiul hrain. Ilyjvrplasia ol nephtohl.istonia like ti"He i> olteii <>letvid to tl. kiilue\ ol ireatei) rats, with or without nephi..N.i'toin.i, Aneio'.uvoma' an.l .iij;i.*iM.i- 1 m tat-. nn*e. haui'iei'l mar Is- I** 11*.I . mote than one site in the same .nuuul In ih liui iIk-v are oh.-n p.ih<< t,m. 1 lep.il k.ltul i-\U.ilk-p.U u .inpio'.iuom.i'.ne hm.ii .| less tlilleu uit.ti'l II. 11 morphok^ii.illy similar in ran. nine an.l h.m.r.t' Aneio'.inmii.o ml mct.iM.iM/e aiul. as tar as liver anyio'.moin.i u.- iMmemeil. tIn Inn;- 1 tl. most lrei|tient site ol lii'iani nrei.M.isc' lilmnl vessels eetasias. eiulotheli.il h\js pS m a"oii.iul i n**t .!' md with 1vll11l.it atvpias. are oltcn ol'viveil in il*. hvet aiul in othei ore-m an.l tivsnes in tti.neJ auim.ih. with or veitltoru ks.tl 01 distant .ni^io'.noH-/.1. >>> anuioin.i' rhereh>re. the elleet il Vf * on hi *.! vo"i l' an.l ei.Juiheh t Im.mI.I lx* viMisi^lere.l systematic AnMUhl.i'in piolileiaiii* i angioma-, ami a`i^i..ai.an 1 in the. liver aiul other sites mav 01 tnav not U- .O'.stated v.nh liho-pl.i i- l:rom the hi'tolocival lseivaii*ii'. 11k {n.-iui- ol 1ik.iI (hint's ;.t ih. uenesis ol malignant v.iscul.n minouis .tpjx.n t* lx- as lnllv. s- 1 n.l- ah* |..*l lnjxTpla>ia. angiomas, aivpi.i' ol eiuloihcha! .11 iu hvpeipl.i't: * * I. |!<t. and angioma'. anj:u'auonu' lihro anuitihlasiie prolihratiou uin}eie>au:;: tthi.-.i' i' lieipiet; I ! . in the spleen ol the tteateil rat' ami min i ,1 * fi -< $ 4* -7* *< .^s -v -T 'N MfJ. Ljt'uro M /.V ; // t:. V>74 vixvi t nioRini '< iv.j \ si's I*/ ss S g8 SL&Ji SSCLlO* *9,.2u 2* ,c2-*" to O LO 3 <2o/).0*" ,e2.* lOS i/2c>.--* 2eo.O*" * >< ~ _r x uI:!l ^iatv^>?**n^ ; >- a* a ^ ti( 'O'n i! 2^ uO^ * 5- ^ r-i ^ j tn ^ b- 3 == i i 2 *0 ** x jJ-S>* ^i8-9# *,,3 5--=> ;I*n>--- TH. =* iSS 13 if Is Jn r 3 v*. *o ;--*T?f*, a*w0 / 2 ' ']E l" S8 r0to*-3* 'O C VlS J.C 95 E' 2 k? 8 w rs *? ic.t^ - .1 M. >. 1 s^ ^i5 *5 - 1U Jji~islvE> 5 " o c 5 8 oo.5U VoU 3 E529 1 a. *2 !Hm 8 33 ; _P *V 2 so* t ( -' V Iaj \U; ii !a! ih-. ! m \w ' s?. *'% Or* r- cn: . '`\ i Vis' : :M j > ;*/ [ .-c ;'N M "U : '. A tuMin SPI-03210 V-` SPl-03213 TABLE 5 EXPERIMENT BTJ: RESULTS AFTER 86 MEEKS <i> i'nu-v s*nnisnmj uh w \i Mil, < .III IIMIIU M' III.lit,! I IK ,111.1 muv appear |rei|Ucmh In arise trout -l.i m| Iii, !i ili, v m.e u piinliu'c in some I'Meni inorplHioy;ic,d I' II .11 II I Kill s ; 11, |<.n*iiii.is lin mis i me iimi.iIIv well iliirercnii.mil. Meiasiascs have liccii i 'll, ' tvi .1 ill till- lull;;. Ili.iiu iieiiriiM'.isioiii.is mi i.us) are very similar lo the human medulloIil.i-iion.is Sinn- iliev mav Ik- i|iiile small mill iliorelore imt easily- ileiivlcd iii.ii in i ii|ni .illv, we me lime in.il.liij; serial hviinns ol llie brains ol the lre.mil i'i i" obtain mule pivtise inluriii.ilit>ii on ihcir real incidence. i I I.iiuy adeiiiim.is I in min ) ate usually inuliiceiiiric: their miiiiiIkt is higher in iiniii.ils lle.iiriI with heavier doses Mam ul these liiinuuis ap|>c.ir m iinJcryu iai!\ i>i.iho11.,,11 |r.nisfifimaiiiin i Mammary taiciiiumas im mite and raist are usually well differentiated ul, iiuian iiiumas with imu nin> |*11mis hi |Hilviin)r|<lioiis arrangement. Mammary i.ii.iimmas uf mice, may Ik- solitary or tmilii|>le. and their must distinctive 1 lime is the liti|uciicy with which they present areas of squamous metaplasia. Vyei.d ul die iiiiiuhiis produced In VC' are i|iiite rare or exceptional. I i ii I inw ledge lixet ,m;;insuenmas. nephroblastomas and neuroblastomas I, i-e ii, y ei Iki-ii deseiilnd as s|Hinimieoiisly mnirrin" in rats. I.ieer and extra- I p un anj;ios.u11iiii.is hay. Iki-ii iiiduivd only in a lew instances in e\|vrinternal u .1' in. rais, hamsiers an,I mice (lor relcrenees see M.wio.vi aiul 1.1 11 o i I`t74l. As lar as yee It now this k the lirsi lime in which nephroblastomas ! ui.l ui-m.ihlasiumas have In-en experimentally reprtnlueed. I In Kill experiment which deal' wiilt (lie elleel of VC administered by *i,!' -nun (sioniaeli iiiIk-i n pmgtessing yeell. showing a gins! survival rate ot i1,, animals I lahle 101. 4tul If o| It \ ' Mll'l ()> 4 , II. ................ e Ilf. \i t it it...t 1 1 *BI t to rxn Kiwi si boi kim i is *ni k moves AnitiuK (SptlfUv l*4k) 1 taisl ------ -- ---- 1 TuUl Swtnnft tKtiitnmf. No Ncptm^ hUtl.vnax No Animal* lti iwihwit AnfNMarwma* Lnct Otlirr mw Nit No. CAIwr vpr t*l * Mils' No Toul No AO M 80 80 ?: sn ?? 3211 29*1 - Cl Gii.v/riu I I Lite animals s|kvas prelimina 2) The VC'hen givet nepliroM.isi, > carcinomas. I in mice, him mary e.ireino other siies i early cvidcu. stomach pap obscrvn! in 51 tn 50 ppm. -I I Fro relationship concerned, it ami from T' 51 A i c.x|x>scd for ,hat the nei concerned. 61 Thi i.c. Sprague the strain ! 7) Ti ". gland carcit 7 days, apt 8) Tl.-- a neyv orier exposed to ' 9) No should be p Compound y allow a cor D) Impleir Our vl sponsoring Beforeinducing in SPI-03219 \!`J l^Jf'trn to arise Irom morphological je> hu\ c Ixxn . nun medulloe.isily detected of ilw treated cr is higher in ..ir to undergo dillerenti.tted cm. Mammary ist distinctive ms metaplasia. >r exceptional, neuroblastomas ver and extra-n experimental . i.\i and Ltt-t- - rphroblastonvas .'ministered by irvival rate of 1 Othct l>pf ! K Ult 1" j ii litUl Si 1 i l 1 1 i iv ..V ii i: VIM f > III IIMIH i ly. I -I sr- (.. ) ( m/chn/ril/i. 1 ) Ibnler our c\|x:nmeiHj! cun.liiinns. Vt r>iod<Kcd ioi'i..iir- n. ih. i!.i . animals s|vcicx studied rat-, mice ami h.iuistiis d.ii.i dio.ilil 'till l>. - >ri.ol. . .I a* I'lvIiir.inai'V in haaisici s I. 2 I I Ik- r.mac ol induced inmouis vane- e-.n isiich. lo.i.i -j-d> j. . , WIkiI iriv11 In inli.il.ilion Vt pinduii' in inv /.iinb.i! idm.l . ii.n - ... neplnnbl.isiom.is. anyio-.iuoni.o ami .mpoiu.i- the livrt ami utli- i Ii . iaiciiiom.lv lic|ulomav brain neuroblastomas .m.l i*--il.l * ini.t *. v in it . -i. ill lime, lime adenoma- I lrci|itcnll\ midi leuii.: m dicuaiil II.in -! m.i:. -n i ii.am man carcinomas ol a |vuili.ir t .|<c. annim.ii. nin.i- an.I .m^ioma.. ol tin- In i i,..! oilici Mies an.l skin cpiilicli.il liimoinv in li.uii-n is. liver aiieinsaKiMiM. an I a carli evidence seems to 'iijtjjC'l. skin liiiii.vpiilii lininns. lyntpluiuin- ami . stomach papillomas and acanthomas. Iiteident.illi. liver an^iosaroitnas ban )...: observed in all llnee animal species. 'I In lire HI'I and HI'-I cx|K`riincni'. \'t -Imvvs a cancem^enic ell-. i >| it- ppm. -4 1 I rom HI'I experiment (die onlv on. n.inpleii.i: a d. sc n |.. : relationship i- clearly sImivvii. as lar as anni..u.oin.i. and iiepliioM.i-toin.i , , concerncil, in llic loner dose ranees: Irom Sno ppm to 10 ppm l>n auci.-san-.uii aiul Irom ^mi ppm io 50 ppm Ini' ncphrohi.isi.i:i.is 5 I A comparison ol the results available ai t!v prescni iiinn.-.ni n. i.e cx|viscd for 12 months atkl 4 months tUTl ami HT5 e.x|Kriimuts) .hat tile neoplastic re*|mse, as lar as audios ii,.ua.is and ncphinlil.ision,, ( . concerned. is .ilfectcd In the len^ih ol exposiiic to V<! (i I Tlte comparison of tire results obtained in lats o! two dith-ten! -n .m i.e. Sprague D.tvvlei l III I l and W'istar tlii,'- pic-cnlli sivu.s n. i i|,,i the strain laetor consider.ilili allccls 11 Is ucnpli-iu ies|sm . 7 1 live onset ol two snlvtuaneons .mni.-.lunina- and ..I . .. .' i..i .! eland c.ncinoiita in the ollsprin;: ol I'lceilci- i |isi-i| sm: po "ii.n- I : 7 ilais. ap|v.trs to indicate a iraii'pl.iccni.il . lie. i ol \'t K) The observation ol a lew discs .4 . il-iun. .111^10-.in m:, >. s....... ,i a new orientation in the pathogenetic inteipii i.ition ol a. rostd'l-. si ju I . C\|Klscd to W. \*> I No tumours have Ivcn obscivcd in I II- i \|<oscl to V\ II.me i should Iv pointed out lli.it. nil. Id out c\|k I mi. m.il . on. Ill ion .. . .|. ..i. - i-. ii: coin|KMind caiiscil tile death ol utosi i>| ihi- .mini.it- viiilun a |K-ii.si iIi.it di-l u-.i l allow a coircd carciiioitcniciiv test. 1)1 I .1/ J.il.i Our data have I veil |vi imlii all- n.insuuii.d the I 111 - ] 11. n.: spoiisoiinc the project and ate .nail.iblc n dl uu. u-sic.l paiti. - lieloic the cud ol ll)/2. a s|i..ii mu. ill. 1 ii vi.is know-. u vt . induiiny in i.iis not ouli /vinbal eland nui....:i- but ab . ii.pl'io!*1. ..... .. u-! \ I ! cs I 1 r~f -.-s `f-'sj -3- I `' \1 '. I OlS| I I <*l I \t . l ii .pin -'.pipMin i :iipii- pimiIes piv p;i\pip (pi dip- M.ionl.uitiiiin: < Ips'inist. A '.pihi.pii.pii (.\U A I ik pin I's II11-. iiilppp in.iiiippi pinmou.l piiiilp.il inpp''ii:viti..ip. ppIhiIi iii IKmiiiIipi l".V |..i pin- liisi limp.'. iilemilip.il lupi .1 ii^.irp..>iii.i in j -piiil.pi cl ,i IkS l.iiicpp ill I. (IpuhIiipIi in I iPiiisville, kv'iiliukv i I'Tp v.ii u-'titt; V*. 1 . .is .in iH i ii|i.ii ii iii.il i tiiii ipir (fin ii|> ic pl.iip tx-siilis li;i\i* Ikvii publishes! i Mai ih\i.. 197V Mm tom mill III i mini. 1974. ;i. |i. in |np'ss), iinil reported in 1^7-1 in. tuo hearings help I hv ('i iiip.iiiiiiipil S.ileu .iiis) Health Ailmiiiisir.iltun lOSHAl c! the I'.S Department of I .alvir. ami in many svm|xi.si.i. conferences anil iiipviiipes iire.iiii/eil i >v I lie American Cancer Sneietv. Italian Department of l.alsir. Ii.ilian Su|crii'i lipsliliiip- uf I fp'.ilili, Nevp %*ppp'ls Aciiplemy nl Science, k.I.C. Inteiii.iiippn.pl Accnev l"i Ih-scanli mi (mini (IA Is < i. I'N'I.Sl.ll. li.ili.m Inviinite .'I Svi.i! Medicine .iiiil IIpiIpp^ii.i liisiiinie nl ( >jic. * ill . li.ili.m I cplermii'n t <1 (tip* I'niniispil ('hcniic.il Winkers lIHI.Cl, liileiii.ilinii.il I'cdi'ralion ol Chemical .iii.I (.icncr.il Workers' I 'nilms (ICC) mill Mciliplu-iii. .'I I V PI HI Ml \ I s p| II . n:\ll |: |l\ nllll KP A l I'n,j Ym!,i /*i-f1 Ai 11 ic iinviin^ nl .i Wnikine Croup on VI! Iield he the lntern.iiion.il Apiinv Inr Kese.iuli on ( mipei (lAKCl in l.ymi on lime 24 .M ll,74. Plot. \ nil v levp-alepl ili.u in liMiilc^ip.illp reviewing liis nuieri.il ol past c\|vriiucnis. In al.ip tleiivieil in nils iicilnl with \'l., an^ios.ireoni.is ol die liur. lo.-nilier ppiiIi ppiliei inaliypii.mt'ip-s ol ilip- skin, limp ami intestine. Mi>rcovcr lie eimi iniiiiipaieil in luce iiiilupppl skin ipantliomas .mil lun^ .iplems.iieiin'in.is in r.il'l'ils in.uni with V(. In iuli.il.il |. .1 lot 4 liours ilails. ^ pl.os vpvvklv, Ip'r a |vrii\l ol .11 Ii .isi | i in.mills III ln,ln\/ii,il lilt I II W / .-'! /,. ' /: v/*. roe./t/.i llipsp- e\|vriinenis weie si.nti.l in Sp-piemlvr. 197V In M.iv. 1974 m i W .iikinp liiimp mi iIn- I iisipiiv ol VC I'VC Iielpl Isy llic New A ork Aeaileiive I V i-'ines, preliminaiv lesiilis icvc.ilpd (li.it also in that laU'raiory lieer atijiios.inniii.is. mul inmimi.iip .noI pulmonary turnouts were observesl in tuiee exposed In VC he i111i.il.uinn I V I I I'llM Mllll lli.il M 0.\ l \ I I IP I K VM.IIIS.PKI CM \ Since the first pIimuppip nl an occiipuiion.il liver angiosarcoma c.inseil hv i s|Hisine li> vine I eltloiiile. 'll pases ppf liver anniosarvi'nias lip ppiir knowledge have |peen oh'i'rveil ainony: wp'ikp is ol VC-I'VC inilustries in the U.S anpl several lmni|peiin vonnirics fl.ihle III Most of these timiPHirs arose Ivlore 1971 (die -4 c< -1 - c SPI-03221 1 Mi-J. Ijt'oriit taring Chemists .il investigations igios.trcuma in it joky) producing W73. M ALTON! lit two hearings !Ai of the U.S. vtings organized Italian Superior rational Agency Social Medicine ons of Chemical aitcral Workers' * International 2* 1974, Prof, isl experiments, liver, together i over he com* . .tna> in rabbits lor a iktukI of [ ) May. 1974 at ' ork Academy ry liver angio* t mice ex]xiseJ nta causeil In tr knowledge V and several re 1971 (the -v: i '* : * ; i /f mm him ro i M-J. Ljrnr* ` 11 4 *,s' d.itcs hum Infill. Inti in absence of experimental data. thc\ ii.! link'd iii ilie iKiiip.inon.il e\|Kisurc. and as a mailer of fact, flvev often i i...i |n.i(.ily diagnosed. Tin- majority of case* did n<u occurr until 15 or :i'' ' " .ilia 11 it- (irM cxjioMiie in vinyl ehloritle. This latcncv perioj is ."i;lr i-i ilim observed in oilier iKuipaiional tumours. 'I ^ 11 III K MAI ICNAN'Clr.S. Aii iwcess mortality for earners of lIk respiratory tract, blood forming n ia > .uni brain lias been observed among U.S. workers of VC polvmcrization l.uilnit' < I K. VC'auini.k. Stateiueni Iwlore iIk Sulx'ommiiiee on the Environin. in nl ilie IJ.S. Senate Comincree Committee. August 21, 19741 (See table 121. I In- results of Dr. Wagoner's study are consistent with the mortalite 'tiiil- undertaken at Mt. Sinai School of Medicine by Dr. I. Selikoit. | 1- (*.*>. HI 1f - is '* 1 if | at x <*t <+\ t ' t\9 ` *n J S'imaU i '*i <t. uni mrmtk t<nnm AM>'*sattonArt mvmva**h*rtwfi < aims among hiktiiihnonis OF plllt'JlM hl M IMIIUATHIN ftMUITin P.4S-* tnt M.t AU nwti ixF tst Uf IMS <*Ai ' *) * 12 II '.7T sit ~rr-- IS 2 >1 2 1 Mil ti m SI " 7<iT $ u* *12) IW I.IJ* mmi ItWfWrt mmd tMItt W* tit IMS Tx> Utt TxJ-- OH 22 0 1 so Is 'jft------- Til 20 " T in ` i 0* | .] h ~ 4 III < 2 *i t T------- - IT- ! 4 ~J5 i 00 10 ID Ml 114 HI n? 2 A* in is! 14] * *4 10 m OtS 2 JJ________ ) 1 f) lit tilt' I N Sf i - * a* | A"! VVlien controls were made on employees of VC-PVC Italian factories i I'*/n and IV71) by sputum cytologic examinations, we noticed a high incidence ol i bailees in the respiratory epithelium. Such changes consist of squamous metaplasia and typical adenomatous proliferation of varying degrees (Cvtoli'g'c.i! ilasses II anti II +1, anti more or less pronounced squamous dysplasia and anpiial .iileiionutous proliferation (Classes 11 ++ and III) (tables 13-151. Tlmi are now to our knowledge various epidemiological investigations kmc. on.I.ui.ikon in many parts of the world, such as the U.S., U.K.. Italy, I i..n< t . (i in.mv. etc. V> Mr.AM.iRt. oi Prevention. Mu milv real effective preventive measure in occupational and environmental i an inoitrnrsvs is to avoid exposure to potential carcinogenic agents. That is the prim,in ptvvvntion. \w /.. n it n. v>:4 EARLY RESULTS OF : OF VC-PVC MONTE' CAR1T IVAlfAt" riRA-noK ao of s PACTOUU IK TIKSI U|M tl np*w>* tlfWl *lit' N. I- J 0-10 IMS S IS $ RESULTS OF ST WORKERS O' SP1-03223 Mi'J iMirtrn imemal data, they of fact, they often <curr until 15 or latency period is ;ct. blood forming ' C polymerization e on the Environ' "!) i See table 121, 'ith the mortality Sr:ut;orK. tfvtinoru* iikmi ilF*^ i 1 is 1 > 4k MS ImM t 4f Ml t 1----- i1.4) }i 'V.*4"" 1----- Italian factories si a high incidence t'ist of squamous t(! decrees <Cv|o- ^uamous dysplasia lit (tables 13-15). . ical investigations U.S.. U.K.. Italy, and environmental' Cents, That is the W r-v 11 12. lIMi ir*'ini,l i ui r . i - : sf. (ahh ts ARt V RK5ULTS OF SPUTUM t YlOl.OOK \l t \ WIINATIONS AMONt# WOKM kS OK V( rvt MON M LMSON I U tOKHS IN 11 KM \M> KRINOIM 01 M YHIV/ti| Oj'W' 1 SJ'S'S N-m t 1 II 11 ami it * i in Tot at 7 s 12 3 25 ~f~ 4 iu -- tK ti RplM <ll *'*"*'* 1) HP II 15 f**n i Mil 1 MAIl AtlltS Of im |S IIMM f Ilf V* U>M sttmn AMI AfMlAtua K<Kt tf ftAttW.N AND Of MjTAMiHS ASIA A*#V. Ol'tVIl Ol VTFVI VUNffMSJiN I At IOMOSI.N mtsi 4M*INU* tl A) % Mil f I \MI lOlS All A IAIN 1 11 Si.ltl (* ( V*m t I )(skl <4i>P \ ttuMria** `T~ { IA> |-e* | { A4.--a.... { ft itfctal' -* Is t1 T Vf-* . Af* h A MA 4 I J *5 ` : *rt 11.. .' ii 1* I l > .1 l P 2u l TAB*! 15 RESULTS OF SFUTUM ANO UK1NF O UH tXUL'Al TiXAVINaMONS AWi/NU WORKERS OF VOPVC ANK' FACTORY IN KAVF.NNA (MAIN MtV7Jl. Cktsws 1 Xf'OWit VkOlkc) . Sputum I'mif i 14 II II > II III (n.tud<uv'itt material Total 30 27 Hi 12 2 7 63 224 33 2lt M 4 1 *4 224 A . 1 hi i,i-i ol Vt . .1 urn!.I I.!, M.\i -i.imlanl lui' not vet Ivin e-tabii-!ieil. I I m i in il.i IS, l >sl I \ i i.i- .! iiili.1 in iviliin allnwal'le VC air level- it' I ili.m I (>(>((> llu- mu ilhl n.mi ili-uvl.il'li- level - tint tup llv S bnur v -i! in;: i|.i\. wiilt it ^ ppm t iliii:; lm .1 iiin\iiiiiiiii IS minnle- daily. Ilii- || 1 I mu Inllnlffri tlx' nli-et \ ,ll || 'll ill.II IIh` l`V|tti-ule I" SO (>f<M) tl \`t I ill air i.i -nil tan-influiiiiiin- i iii, lii.liii;-. am-.in-arioma-i in nil- ami mice. llu- MAI! -ijihI.iviI level. iln MAC lime period. the l>|V> <! mmiiinrint:. in,f On HUM "I <>l j lit' on -niii <i iiih .ii,- nujiii iiipit- ol tli-cu-simi uniat iitiiimj: ini- n -lol I'.irlie-. i f tminii-. in ln-iiii - .uni pntermiielils. Mi-ilii nl tniKiiil- ii iji ,i I iii i fit lit l ft- In (act, t'lianfe- prodmed he M * mi iii < .in iiiiiHfim .(.! in. iii ii n-vvi-ililf. esix-rimenial an-1 eptileiniolopical i.Ii ii. i- imlit mi ll ill.II V< in.I* nnslme luiiiiiin- ,u ilillerem sites: ixcupatiimal inn,,,hi- ,i- j- mu in i|n I ,.. nl ihi upat imi.it .in'.'.iiis.iinnn.i lire u-uallv I in.tin, i mi it , mill (null'. ,i. n n.inl- in litvr ;u >" ii *-.n 11 utia. we li.it e Oeillu-r ilinn.il mu l.ilmulm- m. ili,-! .Iv ii-iin;; ii- preenr-nrs, .i|'.in Iri'in lapa- \ n * -1 n ami I iffi l>in| i-t I VI i I iii I i --ii\ \'nt. /. >. II. II Carciiinpcfu This is tine tn vast amount nt testiops. laek if \X'e behest representatife- priorities: 2' pr netwnrk ol e\|prt'i-er prevent; VC farcin-tlirtinp oneopei : VC lias causes5 epidcminlopical anpiosarcom.i-. i nNtnttiM- Ii i- uu le.i-ittfilt ill ini.ii'iuii il .nnl .ii'iepietl tli.it llie bij:li and ri-inn t in i.liim nl iiimniir-. e-|'ni.illi m p.iniitil.ii site- tlunp. urinary tr.M. liemo- I">i, in li.-ne-l. i- tine In llu esten-ive .mil frint iny Jilfusinn nl millIi:fi)K hi in- in llu ixvupali-Hial and pent ml eut iionmein. Itirtliermore it i- Klsitally i niiii >1 ili.il SO tn OO' i. nl iiimnni- ate related in c.m-es tvliieli are. nr may he liltinilieil a- Ix-iiif. j-.ni nl iln liinn.m eiivirniiment. Rccopnilion nf these i.iii-i- ainl 1'iniininn limn ilun elltM- cnulil sipnilicanlly retliitv uimnnr mi ii I <ii litt anil iiinrialiie. l lu- imieasinp tlilln-inii nl ent imiiiiieiltal oncopenic apetifs i- a |i|>em'mfiinii , ji.iiitiul.nl! iurn laitxl In llie pt.nuli n| iiulii-tliali/alinn. ailtl es|xviall\ in llin-f imln-i i in- pimlminp ami iitaiinl.u mi inp new synthetic fnini'ninitl-. In nixlfrii i|.ie. finm 100,000 in 200,ooo new ilieinit.il it'ni|xHnuls are produced annually, nl tee I in \f vert little alsmt tlteii ellit I im man. I Mi i-l nl ilie onn ift'liii ntenp.ilinn.il anil envilnntnenlal apen I- lute Iven il *niilii J -t lien llie ii it it It i it - "I a p.itiitiil.n tt|v n| itnnnur in an expo-ed |,|"-l.ni.in lia- Isvn niti-iaii.il i;' anil'ni nil tin- ha-i- nl rolln-ivstiff epidemi <1.........1 |inlie\. i I'l-v-ii-- in tltc-e ana- il . .e. -I. iff -Imulil l.it'iluale -t-(fitufie c\|vriineiilal m in.,pmin itt te-liiif e! a;-ent* "huh aie. nr w ill he, relea-evl in the tvi'tip.i la,nil am! ;i in lal emiinimieiit lie -e le-lin-; -linnlil lx- earrietl nnl hefi'lt- lit-' > |'i'-nii n| linman- n> |ioienii.illt i-iimpt-uiv apt-ills lake- plate i-inec the I - * llu t llu i mi ii--in-- pimlnml I- laieim'pt'ii- aie irrefer-il'le) ami Ix-lnrc \ i -- immit al |mitth al aiul -txial inn tests aie ttell e-l ihli-ltfil l-inee tlx-n (lift { an mn easily l\- cli.mpt'dl I t UtMriH ! ' ' I- I'lirtlierinei a basis for as-vs It is our lio example to nry ct-mpounds .ttttl but whose etfee! 1 ! VC c-arcinoj. A) A comp will be H) We are liculare ellects t ami rre \ % SPf-03225 Ljturo *n CMabli>hcd. <' air-levels to e the 8 hour is 4l.i11v. i his "I V(! in ;tir >1 Hike. 'I miMiimrhij:, l.xliy antimn pro. I new I bv piilcmioliyical . ikYtiputionnl - arc usually have neither in I Mill lapa- uh anil rising > tract, hetno- ol oncogenic it is basically h are. nr may rtinii ol these ciluvc tiiiiintir i I'hctii'incniin \ I.till to |!h'nC is In tnoilcm 1 iieil annually. tits have Ivcn in an c\|<nscil .jvetive epiilc- a e\|vriment.il in the ivctipa<'iit Ivlnre the a.e i since the anil Ivlnre nee then thev V. mil IHIMKM'I * llill'ilMsh CiarciiHiftcnicity experimental hinass.ivs ate -snrp:isiii);|v lav Kl-nv the ms .I Ihi' is line to several factors: past scepticism comet miii: the vah.liu ol icxtiii;;. \ asi .iiitutiiii ol audits (t1 Iv lesie.l i 'll i] '1 ii .i; t I'sl I! to S . I.It k ol l - s |K1'I I It'll 1.11 mills nil!I li*iMt itllI:.iI lu pci fm imnu ,-| its ii .ti ll >(HI||S|! ,l!'| It . \\ t- hi In u that a |vt tiianeni inti i U"\ el mm : I lll'IlMIIStll ill !..;( |I I III, i t*pi i stin.i! n cs (tom mii'ii'sifil p.niir-. sh. ml,i piioiui.s, _'i pi.imotc at an init'i n it i. 'rial lei cl .i.let|i .iu' .in.! irii- n [*'.ll ill. |.|.i-.-i i:n .11-- ' t ucImoiI. ol espci imcntal mills, aiul ii iiitualh c'.ili.ilc the Hsuh .mil pitipet pisicnliic nieasiiit s \t carcinogenesis has slmuu the lalne ol c-avtimcni.i! Ino.issais m | o ilicttn.!'. oikiyaenic risks. In one or moic ol llv limt aititiu! s|x\ics ve test .I. \( has i.iiisitl until now all tv|vs ol ninioui' iihitli. hast,I on mail.ill, cpitleniioItt.L'ical ilaia. ate Ivins' cornlaleil to oiinpatioual exposure, i.e 11 , aiiuio'.iicom.is. ht.iin un.l Imi" Imnouis. ami limpliom.o ami leukemias liable I >> mu it TIMt Wl I'OSOHI 1 tltWUI Aim Mile IVIMV 111 nllAI SltuSi IIS | Ml MSI SI II Mil SIS tM tlt.S I Imonii | Imnnn i Nl-n ' hap t >.f+.MWs | SijAMo ml * Ht il|IM|t ol nttirf Mlt x i fVii n- IvMtwi s ' WtiMmi J tt 7 fcr-* j Tt.tM*s | Ikpa 'max r *r*- Msl J ii--r., : !! i , !i . i 1t. j1 ; 4t - ............... - I1 J 111111111111011'. e\|vi imenlal hio.tss.ns on V< . n. mot'euiuis ha\e pio'ul'tl a basis lor assessinj; new MAl! sinmlaitls It is our ho|v (hat the story ol Vt iait iiiovi nit il, max serve a. a convim in - t'oiiipoinitls anil Ini thosi' com|'otiiitls u hiili a'e alo a-l piotl-uv.l aiul witlespo a*l hut wht'sv ellivl' \ie still tenure. V11 1 Oi l; O.xi.nt.M. IVo-a '' t' I I Vt carcinoyeniciti hmassays: At A couiplele >l.nistii.il analisis ol ai.nl ihk not will Iv piihlisheil shot 11'.. Ill W'e arc awaiting the coinplelion o! c |stn Iti'iil.ui lll lo ami It'I'IV wliiili mu s.ipp! ellecls ol he.ivv esposure loi short aiul u t> nniiieiii ami prolonged exposure Ix'low an |.pm I I MM I M.J L,n <1 Studies arc now pun;: mi u> impure knowledge ol ilic morphologic ami itictiilxtlic prec urs<n> <4 iimmurs j>r<hluictl hv V(.. with particular refe rence in liver imuiiiviiiiiiiimn in ililferenl s|tevics. - I VC'c have Marled nose es|vi imein.\ lor cancertiocnicily I'io.i'tiiys ol otlxT inmminers heavily produced ly plastic industries. SUMMARY Available experimental ami epnl.minloyiial tlai.i on careinttyetivsis he VC arc reviewed. Mu- cviK-rimenial hntasstiyx mii (lie iirxoyinic potentialities W Vi.. pcrtttnncd at the linliiyiia Institute iif (fmuluyt aiul Timimir (c-iiler, arc tlcscrilxxl in dciail. Il.isi-il mi ilwsc |vriimiii.. wlit-n yiill! In- inlialaiiiMi. Vi. prixltices: in rats. Xymh.il yl.iml laicintiinas, neplirultlasitiiii.it. aiiyiosari-niuas ami juyinin.it of tin- liver aixl other siteI.in tarcinoin.is, liepaioitias. Iiram iieiirnhlasitHixis, anti |xissihly mammary careiixinijs; in miic. Inn): ihlemnius I lrvt|iienily iiiuliryniny tnali|!iian! transformation t, nummary vareinomas ol a |xrnliar tyjx-. anyinsareniuat ami iinyiiII1L1:, oi llie liter anti ol tiht-r siu^. ami skin pitln-lial liiiiiniirs: in liamsiers. list r .myinsiirenui.it ami. as early evitlenee stx-ms in surest, tl in irii fiix-piilieliniuas. lyiiiplmin.it. ami liiirMnni.KIi p.ipillotnas anti aeantlxxiusHii. t-ai Iv ri-snlis ol die |lnl";:ii.i t*V|K-riim*n|s pnam'ieil t"lini-:il anti i-pidianiotoyieAt n* isltyallnns tvliitli letl In 1 In- ilwoiere ol ixvitpalinilul liver anyins.lHniil.ls Jimmy wntkrts ..I VI.I'VI! imlntiriev l ilt- siory of VC. i'.ntin* yiium- snyyetit die mvtl ol experimental e.i-t iisyenitl;t l.:o.1 .if. Ini all iml'isirial u sii| t" 111.1. Ix-lore (Ih-v are pri t Ii nisi ami widespread III ASM l\TO M'i In'l Ii., I.ill.mini ti.. I lium I'.. Cmuotii IlnxAlt -- Cjrtnu^-'u-*! Ilirli rt\ull,ltl ./I tl'.tll i- pi.it/.r/,*.-lv Jt N'lin Mali p.ittiili ill rassi-|-.n.i i il.ni s|x-riiiK-nlali txl vpiilemioloyit 1 "ilia eareinnyem-st .1- < \' I s.iyyi s)HTiiiieniali siiflr pnieii.'iatita "iHOyiiH' clt-l 1A. nixie:!i presto I I'MI'.IIM il: tin. nlocia e (ienirti Tinnori tli ll-loyna. sono staii rilerili in tk-llaylio. Sulla hast- tli i|nesli rs|x-riimnti. il (IV. tpi.imlo somministrato per inala/innc. pnxltiee: 11 1 rani, tareiiioini tlelle ylitamli'lt1 tli `/.vnitxil, nelroltlasiiimi, anyittsareonii txl anytomi tie! I y im t tli altri tlistrelli anatoiniei. eaieinoini tlella title, epatomi. netiptMasutini cneelaltei. e prifl-.ititfiiK-ntc careinomi maiiiniari. mi topi. aJt-nnmi del polnxme (in nH'lii easi in tratlMrma/ioin- nuliyna), carcinonii mamtnari tli tipn pariicnlarc. anyixMareomi c anyiomi del ft-yain e di allri distrelti anaiMiniei. e lumori cpileiiali tlella one; nci criceii. jnyioxjrenm: M-.-l (ey-ain e, come daii preliminari semhrano imlicarc. iricocpiidiotni cutanci. linfutni. c p.ipil''tiui t* acamomi del presimmitn I primi risuliad iliyli cs|x-riiiienii di lloloyna hanno promottso It* indayini clintchy ed 1 piili-iiiiolnyicht- che hanno p-'rl.il" alia sco|K-rta di anyiosarcomi cpaiiei professional! trJ Ittoiai'iri tli indtisirie di (.V IM.V l a Sinri.i delta cameniyem-ti 1I.1 (!V sia atl imlitare la nccrssiia di sayyi sperimcntali >1. . anii-rnyenieiia per luni 1 tom|xsii imlosiriali. prima elx- c-ssi siami prixloiii e tliiTiiti 1 l.uy.i stala. mi ikuncks Miiimni I '.. (19741. (henpaiinn.il can moyenesis. Il Iniernational Syin|xtsium on (ianeer 11* i.-> lion ami Prevention. lioloyna 197 V In Advances in Tumour Preeontinn. IX-ieeiion and * harai leri/aiion, Kxeerpta Metfua. col. . (antvi deteetinn and prevetnion. 19-iP. -- Mai.tosi 1 . I.IIIMIM (i. 11974 at: r.neironmenial Res.. 7. 1K7-4HY -- Mai toni (... LriKMlNt. G. 11974 hi: Rend. St`i l:is. M;ii. N.11. Aiv.ul. I.intvi. V*. Serie R. ntarro. -- Mmioni C.. I.iiimini (I: (iarvinoyenieiiy hio.ats.iys ol vinvl thloride: curreni iysiili. Annals of the *Siti- Ynik Aeatlcme of Seieiues tin pressl. -- Yioia P.I.. II97UI; (ianeeroyenic etleci* of . inel t ldnride X liucritaiitaul I .nil rr I miyress. 1 lixislill. Altslr, col. 29. *-- \ hlLA P.L.. Itnairn A.. OiH'ru A (|97||. (amei Res.. If. 516^19. V'ctf. n. 11 11. RESOCON. Ritcahe :: neyli animali c primi c.isi di Liloriu. Quesio rdustrie di CV . indagini epidv fosse dato ini/: Maltoni e Li II 19.12 Kentucky, U nale. L'autops Questo Cii professionals II caso I periodo preccc^ con I'esposizii Da allor. stria di CV-l*1 trati negli U..' in Norvegia i ' (!), per un tt slovacchia) n Si tratca sole (20 su 24 dei 1973 (il prim Riferiar. CV. Si tratt.i SPI-03227 U\ (1972*. 'xfiao - Iowa .State ; 'putic Mirrn- U s? Virginia. '1'i^ornnv i>y Idrm on 5<* Toxic. l.(ifr>[oslcront-* Jortion in (he ENVIIIOSMEVTAL RESEARCH 7, 387-405 (1974) Carcinogenicity Bioassays of Vinyl Chloride I. Research Plan and Early Results1 CkSARIC MaLTOM AM) Giusetpe Lefeminf. httinta th Ottcofocfo "F, AiUlariC and Centro Turned, Sofopin, Italy Received March IJ, J97J T)k*sc mvcsHuatinn* ;>rr concerned with determinin'; the oncogenic potentialities of vjnvl chluritlr (VC) in experimental animal*. The eTect f this compound is being Studied in relation to various experimental factors, such as route of administration, dose level, length uf treatment, species, strain, and aee of live: animals. Preliminary results are presented. When gi\m by inhalation, VC induces in rats, ZymK'il gland eareiiKHimx. nephroblastomas, and angiosarcomas of the liver and of other anatomical sites; and in mice, pulmonary aden'xnas, mammary carcinomas and liver angiosarcoma*. A direct relationship has been found IxUurcn doe and length of treatment and neoplastic response. Vinyl chloride (VC)(CH: = CIICI) is a chemical compound of increasing industrial importance. It is used in the production of polyvinyl chloride resin, as h copolymer in Saran and other plastics, as a chemical intermediate, as a solvent, and as a propellent; in the past, for a short period, it was also used as anaesthetic. It is at present produced at a rate of near 12 million tons per year. The following population groups may he exposed to VC: (1) workers en gaged in the production of polyvinyl chloride ; PVC) and of VC, and in the use of VC for other industrial purposes; (2) workers manufacturing PVC; (3) residents about factories producing PVC and VC; and (4) to a much lesser extent, people undergoing contact with resins made with VC, with materials containing these resins or consumer products containing VC, as some propellant sprays. The present research includes a series of correlated and integrated experiments dealing with carcinogenicity hioassays of this monomer. This research followed the preliminary results of the pioneering work of P. L. Viola, presented at the X International Cancer Congress (Houston, 3970) and published in 1971 (Viola ' cl al., 1971). Viola's results indicated that exposure to 30,000 ppm of VC, 4 hours a day, 5 times a week for 10 months, produced tumours in rats, and that these occurred in skin, lungs and bones. Immediately after the report in Houston, we communicated with Professor Viola, who kindly put at our disposal the manuscript of his extensive report, then in press, and several slides of the tumours. On the basis of his results and material, we reached the following conclusions. ' This project has ix-'-ii supported In the European (Inoperative Cruup (ECO.) which includes Montedison (Italy), 101 (V. K.), Snhav (Beteium). niinnc-Pmijil (France). 3.S7 Copyright (f) 1971 by Aeademie Press, Jnc. All rights nf reproduction in any fnrui reversal. SPI-03228 iv V O v cv?- vv i ' C 4w V - V. r ;:;v :v&. vV: ;b - tr 4 f t! ~'>,,v f V?# : -** f: V w 358 MALTON1 AND LEFEM1XE (1) Under Professor \'iola's experimental conditions, VC definitely showed a carcinogenic eifcct on rats; (2 ) 30,000 ppm of VC was an extremely high level of exposure; (3) The tumours described as cutaneous arose from Zymbal glands, which in rats are responsive to a large spectrum of carcinogens: e.g., 2-acetvlainino-fluorene (Wilson el al., 1941), benzidine (Spitz ct a\., 1950), 3,2-dimethyl-4-amtnobiphcnyl (Walpole ct al., 1952), 4-aininostiIbcncs (Haddow et al., 194S), 9,ld-dirnethyl-l,2-benzanthracene (Geyer cl al., 1953), 3-niethoxy-4-aminoazobenzcne (Miller and Miller, 1961), urethan (Tannenbaum cl al., 1962), and others. (4) The pulmonary tumours were most likely metastases from Zymbal gland carcinomas. These lesions were in fact morphologically similar to the Zymbal gland carcinomas, and all were observed in animals bearing Zymbal gland tumours. It appeared useful to further investigate the nature and extent of the carcino genic effect of VC, with particular emphasis on experimental factors related tu exposure, such as route, concentration, duration, continuity or intermittence, etc., which could give more direct information concerning the risk of occupational -and environmental exposure, and other factors related to tile animals studied, such as species, strain, sex, and age. For these reasons, we were contacted by Professor Bartalini, Director of the Health Services of Montedison who offered die support of his Company for an experimental study of the biological effect of VC. Montedison was soon joined by 1CI, Solvay and Rhone-Progil. MATERIALS AND METHODS The construction of an apparatus for programmed and controlled exposure took several months. The chambers were designed to deliver concentrations varying from 30,000 ppm to 50 ppm and to simultaneously treat nearly 1200 experimental rodents. Basically, it is built of stainless steel and glass. The contru! of VC concentrations is by gas chromatography. VC has been supplied by Montedison. Each hatch has been analyzed in tinchemical research laboratory of Montedison before use to assess its degree nf purity (99.99X). The experiments largely utilized Sprague-Dawley rats. Wistar rats, Swiss mice, and hamsters have also been used. All the animals, except the hamsters, have been bred in our Institute for years and, whatever their use, are all examined at death by complete autopsy, giving us extensive information con cerning their current pathology. Tile animals have been sseaned and classified lv sex when 4-5 weeks old. at which time they have been numbered by ear punch, and divided into groups by litter distribution. From weaning, flit- animals base been fed, ad libitum, an adequate commercial diet. During the period of treatment, the animals are boused in groups of 10 in stainless steel wire cages with a solid bottom of the same metal. After the period of experimental treatment, the animals are kept in groups of 5 in niakrolon cages, with tops made of stainless steel wire. A I shallow kept in j 1 Fourte at the oi results. 1 Experimt Experi 10,000, & for 12 li as with a at 2.50-j ma.ximt. Expcrimr Experi i the eflee' the same still slum Expcrimci This wu constant t Experimc: Expei ii in auotliei higher mu Expcrimi". This wu atinosphei. Expcrimcn Experim Expcrimcn This exp as in Expt Experimen Experim- species, i.e Experiment This was effect at a '* c a-, t-uV::.j.y,- '\ r <:c l>- -ry-c' ` SPI-03229 ,,4. *- \\ **;S. showed . which -acctyl- 19.5!')), tilbrncs r cl (il.. 1961). '/ymbal .similar animal'' carcinn -latod to ice, etc., .palional studied, ictcd by i offered id effect I'Nji.-surc mirations irly 1200 ic coni ml ri in the legree of us. Swiss hamsters. . are all ion enn- eeks old. ,in groups iiitnm. an imals are run of the . arc kept 1 wire. A VINYL ClILOniDE CAKCIN'OCENESI.S 3S9 shallow layer of white wood shavings served as bedding. The animals were kept in a temperature controlled lalmrntnry at 19-20C. Fourteen experiments have been started in sequence. Some were programmed at the onset. The need for others appeared on the basis of initial experimental results. The plan of the experiments is shown in Table 1. Experiment 1 Experiment 1 was to investigate the effect of the atmospheric exposure to 10,000, 6000, 2500, 500, 250, and 50 ppm of VC, 4 hours daily, 5 days weekly, for 12 months. Two groups of animals were added as controls; one untreated, as with all the following experiments, and one treated with vinyl acetate (VA) at 2500 ppin, under the same conditions. This dose of VA appeared to be the maximum possible dose for a chronic exposure. Experiment 2 Experiment 2 was performed to obtain data in a larger number of animals on the effect of doses between 250 and 50 ppm, i.c., 200, 150, and 100 ppm, under the same conditions as in Expt 1. It was begun after it liecame clear that 250 ppm still showed oncogenic effects. Experiment 3 This was planned to study the effects of a shorter period of exposure, keeping constant the other conditions of Expt 1. F.xpcrimenl 4 Experiment 4 studies the effect of the same type of exposure as in Expt 1, in another species, i.c., mice. The treatment lasted 7 months in view of the higher mortality, and the shorter life span of the mice of our line. Experiment .5 This was undertaken as a pilot investigation on the possible effects of the atmospheric exposure during pregnancy, on offspring. Experiment Ci Experiment 6 reproduced the conditions of Viola's experiments. Experiment 7 This experiment was designed to study the effects of the same type of exposure as in Expt 1 in another strain of rats, i.e., Wistar. Experiment S Experiment 8 studies the effects of the same exposure as in Expt 1 in a third species, i.e., hamsters, for the same period as in Expt 4. Experiment 9 This was planned to further .assess whether or not inhalation of VC has anv effect at a dose level of 50 ppm in experimental animals. * L -- SPI-03230 ", 'jV$ v:?f; i&n? v:i ,r ^ "f1' % Mi F:1 i.: : ... *>.' -/ :;3s! UM ' -' ' /-/, '. * V. fM . -: v- V.;; V *. : r 390 MALTO.VI AND LEFLMiVE tiill 43 ss .2 1 s s I5 3 3S SI = S 8 I *' = * ?: ?, g !? s p. g1 !Wi wt it, ` Si | I 35 11 3 ,,g s! gf >. . 5. i;l i --1*. r--e ">. I! I ?IJi|Ji!pII I I1 I ill im ir i JIL Ssl* fill = ' --S Iji3 iii ! r- x. = | 3 m; ii MpP ii i iii i=i ii , ' I . -j?r7P5*5fiSpgBS 5* $!&53 . r */? ' *r-. ,i>r- .*; SPl-03231 ' - ~ 392 M ALTON! AND LEFITMINE Experiment 10 Experiment 10 studies the effect of a high, but sliort and/intermittent atmo spheric exposure. Experiment 11 This was performed to evaluate possible effects of VC by ingestion. Doses have been chosen on the basis of early data on the release of VC from food containers made of PVC, and following suggestions of EEC. Experiment 12 This experiment studies a third general route of exposure ' namely the peritoneal cavity. Experiment 13 Experiment 13 was started to assess whether the VC acts on tissues directly or through metabolites. Experiment 14 This experiment lias been included to study the responsiveness of newborn animals. The animals are examined weekly, and weighed every 2 weeks during the period of treatment, and monthly after the treatment is completed. All de tectable gross pathological changes are recorded during examination. Atl ani mals are kept under observation until spontaneous death. Moribund animals arc isolated, in order to avoid cannibalism. A complete autopsy is made of every animal. Histological specimens include Zymbal glands, interscapular brown fat, salivary glands, tongue, lungs, liver, kidneys, spleen, stomach, different segments of the intestine, bladder, brain, bones of the legs and feet, and any other organ with pathological lesions. The tissues are fixed in alcohol, processed, sectioned, and routinely stained by hema toxylin and eosin and with Van Ciesons method; in selected cases, other stain ing techniques have also been used. All animals exposed to the highest doses (30,000 and 10,000 ppm) with or without tumours, are examined radiologically, during treatment and/or at death. Moreover, radiological examinations are made of all animals bearing tumours, even if exposed to the lower doses. RESULTS Preliminary results and other current data of Expts BT1, BT3, and BT4 are given in Tables 2-4. Special aspects of Expt JVT5 and 11T6 arc discussed in the text. Insofar as the other experiments are concerned, results are awaited. In Table 2 are listed the observations on the oncogenic effect of graded concen trations of VC within a range of 50-10,000 ppm. It is evident that the overall occurrence of tumours decreases with decreasing concentrations from 391 tumour <; roiifrv at i reuUncn i VA i'.oo i>i II VC UJ.IHJO in VC 6000 i.| IV VC ivm i ) v VC .r00 opt VI VC 2/>0 pp vn VC 50 pp-i VIII No tmtlSlK Total - Mcl*sl * Mi-last r Meia-o 4 Anci"- * Tuo Muroima of r One |r. * One n `Two 7. mlcnorsrci ' Seimo< Zvmt. i ` Mi..; . ' One " Tolu! iticidenc ppm, re: J limited t | controls i hhtstuui; J ' tttith/urs. j tin tliv* c / of twpos | (Titbit* : i mm: ? j?-.*-j*-- ` SPI-03233 ;t anno- 41. D"S(\S rorn uiely the i rectiy or newborn iiins flic All deanimals . include U*. liver, r. brain, uns. The iv bemaivr stninwitli nr at death, rumours. BT4 are at as the ; owncon i' overall tumour VINYL CIlLORtOF. CARCINOGENESIS 393 TABU': _> Km'Kiiiuknt ISTJ: Hksci.ts irrwi lai \V; kk* (irtiufis it<| lientinoul Amm:N (Sprague Dawlcv r:t i *} SnrviToil voin AniniMil* villi tumours Zymbal giaiuis rarrii>mas4 No. NeplirobU'- Ionia.** No. AtCMs.*rinmas Other iype l.iver < Nhw site* N... No. ?iic tal No. No . I VA 2"b0 ppm ii VC III.IKXI ppm Ml VC Of 100 ppm IV VC 2.500 ppm V VC 'iiH) ppm VI VO -."() ppm VII VC .*0 ppm VIII No liealment 00 (ip 72 74 (17 (17 w 6S -- -- -- 1 1 in .1 j a a6 .. 11 i4 0 9 3:t i or 0 2 2' _ 5` 27 1* 21 1<' 21 1* lfi 2' 11 _ Tut nl 077 0 23 20 35 s 10 06 * Metnstusev !< lung. * Meluxtaxcs to liver and/or tr> lung rutd spleen. ' .Mclnsln.es to lung. 4 Angiosarcoma in mibrulniimitR filmising angioma. ' Two intrn-alxlominnl angiosarcomas (1 contiguous lo spleen aw! I to ovary); I ossifying angio sarcoma of neck. f One pulmonary angiosarcoma; 1 angiosarcoma of atoms. One intra-abdominal angiosarcoma (near lo spleen); 1 in trathoracic ossifying angiosarcoma. * Two Zymhal gland adenomas; 1 neurilemmoma of the car; 1 mammary carcinonui; 1 rystondcnnearcinnma of ovary. * Seliaceons gland earr.inonm of skin. ` Xvmbal gland adenoma. * .Minimal deviation hepatoma. 'One Zymhal gland adenoma; I salivary gland rcurinonia. * Total No. of tumours. incidence at 10,000 ppm. 295 at 6000 and 2500 ppm to 24" and 165 at 500 and 250 ppm, respectively. Fifty (50) pptn did not cause tumour development in the limited number of animals so exposed, and no neoplasms were found in untreated controls and in rats exposed to VA 2500 ppm. Zymbal gland carcinomas, nephro blastomas and angiosarcomas of the liver and other sites were the prevailing tumours. The development of the latter 2 neoplasms was not always dependent oil the concentration of the toxic agent, but to a higher degree on the duration of exposure. If exposure time was reduced from 52 weeks (Table 2) to 17 weeks (Table 3) the number of tumours after 60 weeks is markedly smaller: their per- SPI-03234 T (imupA atul treatment AiiittiaN (Sprayin' I)avvU\\ rat>) Zyinli.il Blamh Survi- rarrinumu* Total vuns No. AuimaU wiilt tuoi<.m> Ntphrobla-Oo- in:t? No. Aiti'io-.himmx* Ollier lv|K- nmt *>r l.ivtrr Otliersitcs >iu* Total No. No. No. No* I VC t(l,(KI0 ppm 11 VC 0001< ppm 111 VC 2.100 ppm li ve 500 ppm V VC 250 ppm VI VC 50 ppm VII No treatment 60 00 60 00 (ill IPO Total WO :* 4S 54 50 44 511 is;; 471 :i (Mi 1 cu -- 12; -- (1- -- ... 4 (17 i - t|i -- fit -0) -- -- -- -- -Gi) -(I) --/.i) -- M] - til - - til - -- Hi -- -- -- -- *7) -- -- "(1) -- (4i 3(17) -- HM - (i) - (5) - a) -- Cl! -- -tlj ---- ---- - (} Tumour* fining in experiment JJTf after 60 week* are re*oitli'd in pareioliiitis. * Touil No. of imiiuiir.<. centage is 5'V at VC 10,000 ppm and 1.7? at 6000 ppm; at this time no tumours were found after administration of the lower concentrations. It is also worthy of note that all malignancies in this series were Zymbal gland carcinomas. After 35 weeks of exposure to 30,000 ppm (Expt BTC) 2 Zymbal gland carcinomas have been observed among 60 rats (5S survivors). In Expt BT5, two groups of 30 mature breeder rats were exposed to VC 10,000 ppm and 6000 ppm fur 7 days during pregnancy. No tumours were observed after 69 weeks among the 2S survivors of each group. Angiosarcomas of the subcutaneous tissue in curred in their offspring; one tumour in one of the 54 rats of the 10,000 ppm group at the age of 24 weeks; tire other tumor in one of the 36 animals of the 6000 ppm group was found at 22 weeks of age. Fifty and 30 rats, respectively, of the litters are still alive and under observation. Table 4 indicates that mice respond to VC inhalation of 10,000-50 ppm in a similar manner as rats. While 50 ppm is again ineffective alter 35 weeks, 302, 152, and $.4`.' neoplasms were found after 10,000-6000, 2500-500, ami 250 ppm, respectively. It is perhaps not surprising that in mice, pulmonary and mammary tumors were more frequent than other localizations, but the presence of angiosarcomas of the liver also occurred in this genus. At present, 5 distinct types of tumours induced by VC have been observed, i.c., angiosarcomas, particularly of the liver (in rats and mice uephioblaxtoneo (in rats), Zymbal g'and carcinomas (in rats) and pulmonary adenomas, some of (inmjts jttfl I \'C Id,(MW# II Y(` Cm HI ppm m VC 2-\no ppm IV VC* 500 p{<f:l V VC- ppm VI VC iUi ppm 5 VII Sit I M\'t I ll!4'I Total * In fninitlfs. * One mj* r Oil* >km .mj * Tola! NV i which under Macroscop in Figs. 1-2.3 The frequt i are somethin i can show d r (Fig. 2) apr I present \ari< (Fig. 4*), s. metustases c; blastemas (I but can also the liver in i growth and metast.ises | hlasloma oci appear gene * Figures m: SPI-03235 59? !w` T..-.: No.* :t i l 7 > 1 (S', -- ,o) -CA) ) -- 4 i.vl) amours . . worthy ...w Alter icinomas unnips ppm for .. among ,j|r OC" i .Ki ppm is of tin* _ actively. mi in a ' weeks. VKh ami .u.oiuny : tilt tin* itMTWll. i.Momns Millie of VINVl. C1II.OHII)': CAnClNOC.NKSIS 3U-: TU'.I.K 4 I isi'iailMI AT ItTI: III -ILTS UTt.i; \Vki.k> (nni|r* :tti:I tmitinrus Ant!''-il- .. (Swis* mi v I _ _. Trr;*io.l Survivt ip* 'IV T.u lal ' v'7 1 :tl Animal- *vi;li "ininnr. ------------------------------------ l'lliftlo- M:iM- Liver I I'.hrr u.iiy m.irv t\*|>c In- i*nrn- *:- and or niem^ h ina>* nm:L< MIC Tct.,1 Ne. N<i. Nn. No. Nn.4 i VC m.iHKi ppm :id ;io 01 0. Is ji u 4 __ :i* IM II VC Omni ppm :i.i :;o (VI 11 IS j*i l-J :i 1 2' IS Hi \`C --'WK1 |)Jffu IV :n .Tl on II 22 :;:i i j - -- f> VC Ann ppm :<*i :t) on Li 2> :ts - -- 2 --9 \' VC -J.VI ppm : :ui CM in 41 4 i -' -- 5 VI VC An ppm :tn :tn GO i:t ji :i7 - -- -- ---- VII No lrt*:iimiMil Ml 7(1 ICO i;i n 122 - - ---- Tel M ja'i JAO SIM IT 1ST :<JI 4J in 5 CO In 4 Our skin Mpinmorollnlar enrvin. m*: I skin invivovr ucimthnnm; 1 *mI>rui;tneon hem/weinmn; r Ono <kin M|ii:tmnrrliubr rArriimma; 1 thymic fymplHMitrt'.im:). No. of tmnoiM. which undergo malignant transformation and inannnary carcinomas (in mice). Macroscopic and microscopic illustrations of the tumours induced are shown in Figs 1-25. The frequent Zymhal gland carcinomas can reach considerable size (Fig. 1*).' arc sometimes bilohated and show a tendency to hemorrhages. Their structure can show different patterns. The arrangement of the norma! Zymbal gland (Fig. 2) appears often in a disorganized form in the tumours. The carcinomas present various different histological patterns, e.g., glandular (Fig. 3), solid (Fig. 4*), squamous, anaplastic, and polymorphous. The frequent pulmonary metast.iscs carry the characteristics of the primary lesion, (Fig. 5). The nephro blastomas (Figs. (5-fi) lead to numerous inctastascs in the liver (Figs. 9*. 10*) lint can also involve spleen and kings. The frequently found angiosarcomas of the liver in rats (Figs. 11*. 12*, 13*. and 14) are characterized by the vascular growth and hemorrhagic appearance which is also present in pulmonary inctastascs (Fig. 15*). Occasionally, both angiosaicmaa of the liver and nephro blastoma occurred in the same animal (Fg 10*). Ang osarcom.is of other sites appear generally as more or less hrmnrrhag'c ma scs developing in the al>- 1 I'igmps marked l>y ustcriskN { * ) appear on the mini plalrv Mhti-:1 fpP l'Sm. PR'S fePI ITS ;v>s,'.:.'. P-PP i':'--' - Ffef' e-,-- ..-C- t;r' i'V.T' - .c,:: . f'r (S- -P -;r . ' C :; fP t mri t.: * -'T v-'v'sv-^ *Z a :v r-f?. E' : SPI-03236  -? v 396 MALTON! AN't) LLKEMINK dominal cavity (Fig. 17), in the subcutaneous tissue (Fig. 22) in the uterus (Fig. IS), or in the lung (Fig. 19). The ossifying angiosarcoma (Figs- 20, 21) and the salivary gland carcinoma (Figs. 23 and 24) occurred rarely (see Tabic 2, group VI). Figure 25 shows a liver angiosarcoma of a mouse. CONCLUSIONS AND DISCUSSION From the results presented in the tables, from the pathological and histological observations, the following early conclusions may be drawn. (1) VC is oncogenic under our experimental conditions. It induces, in rats, carcinomas of the Zymbal glands, nephroblastomas and angiosarcomas in liver and other sites; in mice, liver angiosarcomas, pulmonary adenomas and mammary carcinomas. (2) A direct relationship exists between the dose and length of treatment, and the neoplastic response. (3) Zymbal gland carcinomas and nephroblastomas may be bilateral. (4) Liver angiosarcomas arc often multiccntric. (5) Blood vessel ectasias and endothelial hyperplasia, associated or not with cellular atypia, are often observed in liver and in other organs and tissues in treated animals, with or without .angiosarcomas. There fore, the effect of VC on blood vessels and endothelia should be con sidered systemic. (6) The onset of 2 ossifying angiosarcomas suggests a new orientation in the pathogenetic interpretation of acroosteolysis in workers exposed to VC. (7) To the present no -acroosteolytie lesions have been observed in our ex posed animals'. (8) No tumours have been observed in rats exposed to VA (2500 ppm). Zymbal gland carcinomas, nephroblastomas and liver angiosarcomas have never been observed to occur spontaneously in our breed of Sprague-Dawley rats. Although Zymbal glands, in rats, are responsive to a large number of carcino gens, only 3 spontaneously occurring cases of Zymbal gland carcinomas have been recorded in this species (Taimenbaum et ul., 1962). To our knowledge, no spontaneous nephroblastomas and liver angiosarcomas of rats have been reported Ik: 1. Hat with Zymbal gland carcinoma. Fic. 4. Zymbal gland carcinoma, solid pattern; in rat. W-K X 15S. Fig. 9. Hat with nephroblastoma; metastases in liver. Fic. 10. Liver metastasis from nephroblastoma; in rat. H-E X 15S. Fic. !1. Hat with liver angiosarcoma. Fie. 12. . Rut with liver angiosarcoma with lung metastasis. Fic. 13. Liver an; lusurcoma; churactcrLtie p.iUcru; in rat. M-E-X I5S. Fig. 15. Pulmonary metastasis of liver angiosarcoma; in rat. H-E X 15S. Fig. 10. Liver angiosarcoma + nephroblastoma in rat. K:u. 20. Lateiwervieal ossifying angiosarcoma; in rat. II--K x 158. Fic. 21. Pulini.'tury metastasis of ossifying angiosarcoma; in rat. Il-F. X 40. Fm. 22.' Hat with sulieutaneous angiosarcoma. ( & 7 a' r SPI-03237 3 VV -V 1 '.i\`LV:-sh YTtJr^mi i1^ ^ "** *" ^ !'! uterus 20*. 21*) T.i'uie 2, uilogical in rats. arcomas iimonary vatment. .{5: ' >`'-1 jT-TflT---" . ` X.' . I T;V iv*<.VT ?'a; i i>r not nrgans . There in' con- .liion in ;vised to i orir ex- ;; ppm). :.;S have -i).uvlcy a rci noMs have liar, no vported B- ' vffTrt-*'-! r-'-^i^tltvilTf-"IiVii-n-ni*'-- - IlftTtfc&fc** ,,f-y ; '4 t t- .1^.' :- ; r ` 11 12 t , SPI-03238 fV-.r I-*.-. ff-.V' t. ir'. ^ .;-v It p s* t I ft'-- . - V (V K: tv-? ` 'y: * ' / *, K*. - 7 SPI-03239 VINYL CHLORIDE CAIICIN'OC.ZStS\S 39 .'.'ALTOV, .AVI; I.KJfv.jv, Fic 5 Z.'-mha? gland carcinoma; pulmonary metastasis: in rat. H-E X 46. i Jr m. * '' 6- -\tp!ir(ifn;tN[unu j(J TA( SPI-03241 Zfr20-ldS snjruautoi3 c Olfr * 3"H _. , fu***f&'............- X 3~H `sitsippwwp !jw jo cutc;SE;qoJi(do\' pij ----------- i m: ,WMaOStDHV3 .4CII-.I0 1I1) 100 .ALTON) AVD LITEM INK pdife'. 3 r?^Sr. - =;;<; -v z:M* angiosarcoma; characteristic pattern in a rat. H-E x 185. SPI-03243 VINYL CIXLOnjDK CARCIN'OCCNESIS 401 Fic. 18. Uterus angiosarcoma; io rat. H-E X 470. :I ,'!i: i >i Fic 19. Angiosarcoma of lung, in rat. H-E x 185. S PI-03244 4 402 MAI.TOM AM) UIFKMIN'K 4 ? : * &r^&&gpgi-: s ;.;/' : '' '!' ' A ;''' . I ! 7? .v-v- h *: A- 1i V7 2 ? y:yy.s '.:?>:*> ^ r /,'.* v.*V*\ : rr.~ Tv. T? . *>.r > " 'V:'* \ .. y * .v> , rVv* . , or>' ; iXC4! ; . > , - w-.i, ' 1 ,,' * r '- --. ..y.. %-'*. ' > ! : .. - i\.'.i > v'i.nij adcnofiuciiionia; in r.il. ] I-K X 1S-3. in literature reported as 1 Hepatic ai and Lee, 196 1973) and in been induceand by p-d'.i In the rah';: and Speiser. In man, . 1 cases were <; liver. Induction 1 a liver anjin Cases of in: thorotrast (.'.. Ilorta et o' Tiie rcsi:!.-: members of i a half ajto, it nephroblastoi. to major Arne t SPI-03245 VI.VYL CUl.OlllnK CAHCINOCKNCSIS 403 in literature and as far as we know, kidney nephroblastomas have never been reported as being experimentally induced. Hepatic angiosarcomas have been experimentally induced in rats (Rcuber and Lee, 1963; Iladjiolov. 1972), in mice (Roe and Salnman, 1954; Cardesa el at, 1973) and in hamsters (Toth, 1972). In mice, extrahepatic angiosarcomas have been induced by o-aminonzotoluene (Andervont ct a!., 1942; Andervont, 1950) and by p-dimcthylaminobenzenc-l-azo-2-nnphthaiene (Mulay and Saxen, 1953). In the rabbit, angiosarcomas have been produced by thorotrast (Zeitlhofer and Speiser, 1954). In man, angiosarcomas are quite rare. One hundred-seventeen documented cases were collected to 195S (Landclls, 195S), of which only 21 arose in the liver. Induction of liver angiosarcomas have been reported in humans. In one case, a liver angiosarcoma followed the insertion of a radium needle (Ross, 1932). Cases of liver angiosarcomas have been reported following administration of thorotrast (Mac.Mahon ct'nL, 1947; Liidin, 1953; llaserga el cl., I960; Da Silva Ilorta ct al., 1965) and exposure to arsenic (Roth, 1957). The results of our investigations have been periodically transmitted to the members of the European Cooperative Croup. When, approximately a year and a half ago, it became definitely clear that VC was able to induce angiosarcomas, nephroblastomas and other malignancies, our results were also communicated to major American manufacturers of VC and PVC. to orient clinical observations s y 4; % / ** 404 malto.m a.vo lei-emin;: and epidemiological investigatious, and to guide industrial hxgiene measures needed for prevention of diseases which might be associated v\.`th VC exposure. Sl'MMAKY This project of investigations is concerned with determining the oncogenic potentialities of vinyl chloride (VC). The effect of this compound is studied in relation to various experimental factors, such as route of administration, dose level, length of treatment, and species, strain and age of the animals. The preliminary results are presented. When given by inhalation VC induces, in rats, Zymbal gland carcinomas, nephroblastomas atid angiosarcomas of the liver and of other anatomical sites, and in mice, pulmonary adenomas, mammary carcinomas, and liver angiosarcomas. A direct relationship between dose and length of treatment, and neoplastic response has been found. 4 i ) REFERENCES ANuknvovr, H. IV, Cnauv, It. G., asm Euwaiid, J. K. 11942). Induction of hepatic lesions, hepatomas, ptdmonary tumors, and heniaiigio-endothclioiuus in mice with o-uniinnu/m toluene. J. Xatt. Cancer hut. 3, 131 --1 S3. Aviiehxovt, H. B. (1950). Induction of htfman^imendothelioiiia.v und sarcoma* in mice with o-aniino*7.oto!t>enc. J. Sat!. Cancer hut. 10, 927-941. Basehca. R., Yokoo, H., and Hemecar, C. C. (I960). Thorutrastdnduced cancer hi man. Cancer 13, 1021-1031. Caiuikxa, A., Poem, Althokf, J., am* L\ (1073). Vascular tnmors in fcntalc Svvivs mice after intrnperitonea! injection of dimethxlnitrnvjunnc. J. Sat!. Cancer ht$t. 51, 201-20S. Da Silva IIohta, Y., Auuat, J. D., Caxuixa Da Mori a, L., and Rohiz, M. L. (1965). Malignancies ond other Utc effects following udnmnVa atimi of thorutrost Lancet 2, 201- 205. Ceykr, R. P., Bmvant, J. E., Bixisrti, V. R., Puhce, E. M., and Stahl, F. J. (1953). Ef fect of dose and hormones on tumor piodnction in ruts eiwn emulsified 9.10-iliinclli>|.|,2- benzanthraceme intravenously. Canter Res. `13, 503-506. ITaduOw, A., Hahhis, R. J. C., h`o\, G. A. R., ano Roe, E. M. F. (1945). The ynmdi- inhihitory and carcinogenic properties of 4-auiino>til!KMU* and deri\a'i\ev Phil. Tram. Hoy. Hoc, London, Scr. A. 241, 147-195. HaUJJOLOv, D. (1972). Hcinunpocmlothehn! sarcomas of the liver in ruU induced I\ dicthyliutrosamim*. Kcofthutna 19, 111-114. Lan'uells, J. W. (195S). Malignant tumours of the heart and Mood vrwlv hi (It. \\\ ltnvcn, Ed.), "Cancer/* Vol. 2, pp. 512-524, BuUcrxvorth, London. Luniv, M.t Jn. (1953). Hue*m4tijio-K)>dothelummttKe von Let*T mt! \!dy hei Thunitiust- speichenmg. Schue:z. Z. Pathol. 16, 9S7-994, MacMauOX, H. E., Mvrphy, A. S., ANO RaTKj, M. i. (l94?i. Knd.vheli.d-cell varumu rf fixer following thnroU.rst injections. .\ncr. J. Pathol. 23. 5X5-3ho. MtHJlt, J. A., AM) Mlti.K>' K. C. .'Uhl). The carunoacnu t> id .him lliu\\.4umuH> we end Us \'*mcti.>l devisutixo lor rxtmlu p.Uic ttson-v of the Convrr Rcj. 21. 106S-1U72. Met ay, A. S. ami Saxkv, K. A. (|U5.'j. Ia'sIohv induced in miw !y painting vifli j* ,.'uH,th)*l.innnoiiao!)en/eiit>lu/.i)*2-uuph'!t.druc. J. Seti Cutucr, Inst. 13, 125*4-127.1. Rnuum, M. U. axu La::, C. \V. (1966*. Effect of ane and sex on hep.itlr lesions in Rullido x*ruin rats iiiKestiuj: ihcthyluiU').s.uninc. J. Sutl. Cumvr ht\t. 41, 1133*1110. Rov. R ! .mi S.xi..x\i a, !f. II. (1951). A (pi.-.nftt.iUxr stmlv .! ihv power i,,( i i\ I X3i i i 't i I J persistence c Cancer S, 6f Ross. J. M. ( Badvriol. 31 Roth, F. (1 465-503. Srin, S., Mac dine. Cance. Ta N` N K V HA CM, Multipoint). Torn. B. (1 hydru/iuc di Viola, P. L. Congrtri*. JJ" Viola, P. L,, and l>on<*-. *. Walpole, A. action of 4 255-263. Wilson, R. H activity of 2 ZglTUtOt'CR, J. expcrintcnte: -T* SPI-03247