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194 Annals New York Academy of Sciences Popper about the reversibility of the phenomenon, particularly if caught early. If workers arc exposed to moderate to low levels for relatively short periods of time, has there been any evidence that there is any irreversible change, or docs the progression that you were documenting take time? Dr. Poiter: The only real experience we had was a case which Dr. Berk presented. In this ease, after discontinuation of the exposure, fibrosis persisted, hut other features were absent. The characteristic disturbing activation of the hepatoeytes was no longer seen. 1 am not surprised. From experience with hepatic fibrosis in circumstances other than vinyl chloride, it is known that fibrous tissue may not disappear once present. I suspect, but do not know, that the person may be left with innocent scars in the liver which possibly may not interfere with his life expectancy. One patient, however, is really no proof. Part II. Carc:ino<;i;nesis Associated with Vinyl Chloride A. Kiprritucntill Studio* CARCINOGENICITY DIOASSAYS OF VINYL CHLORIDE: CURRENT RESULTS Cesars Maltoni and Giuseppe Lefcminc Utituto di Oncologia and Centro Tuition Bologna, Italy Introduction Vinyl chloride (VC) has been produced in many countries for more than 30 years. It is the constituent of polyvinyl chloride (PVC), which nowadays is the plastic industrial material most used and diffused in the world. Moreover, it is used as a copolymer in Saran and other plastics, as a chemical intermediate, as a solvent, and as a propellant; in the past, for a short period, it was also used as an anesthetic. VC is at present produced at a rale of near 12 million tons per year. The following population groups may be exposed to VC; (I) workers engaged in the production of PVC and of VC and in the use of VC for other industrial purposes; (2) workers manufacturing PVC; (3) residents in areas neighboring on factories producing PVC and VC; and to a much lesser extent (4) people using products containing VC, as some propellent sprays; (5) people having contact with resins made with VC and with materials containing these resins; and (6) populations consuming food contained in plastics made with VC. Uioassays on the long term effects of VC were not available until 1970. This situation reflects the limited consideration which has been, up to the present, given to experimental bioassays in predicting the oncogenic effects on man of environmental and occupational agents. In part this is due to industrial and economical interests, in part to deficiencies in technical-scientific facilities, to the dilettantism of many experimental workers, and to the inadequacy of n any experiments performed in the past. What is now happening with vinyl chloride and the story of vinyl chloride carcinogenicity should bring about greater consideration of experimental bioas says and finally induce a new turn in the field of occupational and environmental carcinogenesis. In other words, experimental prediction on the pathogenetic potential of occupational and environmental agents before they arc produced and released on a large scale into the human environment should preclude the need for later epidemiological evidence. History In 1970 Professor Viola presented, at the X International Cancer Congress (Houston), the results of a pilot experiment, which then were extensively pub lished in 1971.' Professor Viola reported to have observed in 26 rats exposed by inhalatory route to 50,000 ppm of VC 4 h daily, 5 days weekly, lor 10-- 12 months, surviving 10 months or more, 17 skin tumors, 7 pulmonary tumors, mainly carcinomas, and 5 osteochondromas. 195 2207300X % 1% Annals New York Academy of Sciences In 1967 our Institute started a large investigation, among workers of several Italian industrial plants, to determine the cllccts of the exposure to different chemicals on respiratory cpithclia. The pathological changes were studied bv sputum cytology. In 1970 this research was extended also to workers in VC-PVC industries. A significant increase of cellular changes in bronchial epithelium such as marked squamous metaplasia and squamous dysplasia, were found among the workers more heavily exposed to VC. 6 Immediately after the Houston Congress, we contacted Professor Viola who kindly put some slides of his experimental tumors at our disposal. According to our interpretation, the malignant tumors observed by Professor Viola in the skin were carcinomas arising from the Zymbal gland (a sebaceous gland of the ex terior acoustic duct), which is responsive to a large number of carcinogens. The malignancies of the lung, in our opinion, were mctastascs from Zymbal gland tumors. At that time (end of 1970) we planned a project of correlated investigations to further clarify the type and degree of the carcinogenic risk from VC. The project was encouraged and supported by Montedison (Italy), which later was joined by other major European companies, that is, ICI (U.K.), Solvay (Belgium), and Rhonc-I'rogil (France). I lie lle.ul of the Health Services of Montedison supplied us with all the technical data dealing with occupational exposure; this made possible the repro duction in our experiments of the most important parameters of occupational conditions. Pl.ANNINfi, MATERIALS, AND METHODS This project included a series of experiments, which were started in sequence. They were designed to study the effects of VC, administered through different routes (inhalation, ingestion, and peritoneal and subcutaneous injection), at differ-' cut concentrations, for varying periods of time, by continuous or intermittent treatment, on animals of different species (rats, mice, hamsters), strains (Spraguc- Duwlcy and Wistar rats), sex and age (adults, newborns, embryos). The planning of the program and the preparation of suitable experimental conditions, particularly the building of an apparatus for inhalatory exposure, took us until May 1971. In July 1971 we started experimenting. The chambers of exposure arc built basically of stainless steel and glass. They have been designed to deliver concentrations varying from 30,000 to 1 ppm of VC, and to treat simultaneously nearly 1,500 rodents. The VC concentration in the chambers is controlled by gas chromatography. The VC is supplied by Montedison. Each stock is analyzed in the Montedison Research Unit." impurities and their maximal levels in the VC employed have been as follows: HjO Acetic aldehyde IDO ppm 5 ppm Acetylene 2 ppm Allcne 5 ppm Butane 1,3-I3utadicnc 8 ppin 10 ppm Clilofoplicnc 10 ppm Diacetylene Vinyl acetylene I'ropine Methyl Chloride 4 ppm 10 ppm 3 ppm 100 ppm Maltoni & Lefemine: Carcinogenicity Bioassays '97 The experiments utilized mainly Spraguc-Dawlcy rats; Wistar rats, Swiss mice, and hamsters have also been used. All the animals, except the hamsters, arc bred in our Institute for years and, whatever their use, arc all examined at death by com plete autopsy, giving us extensive information concerning their current pathology. The animals have been weaned and classified by sex when 4-5 weeks old, at which time they have been numbered by car punch and divided into groups by litter distribution. From weaning, the animals have been fed, ad libitum, an adequate commercial diet. During the period of treatment, the animals are housed 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 makrolon cages, with tops made of stainless steel wire. A shallow layer of white wood shavings serves as bedding. The animals are kept in a temperature-controlled laboratory at 19-20'C. Fifteen experiments have been started in sequence. Some of them were pro grammed at the beginning; for some others the need appeared on the basis of the first experimental results. The plan of the experiments and the up-to-date situa tion is shown in Ta/ile 1. Experiment I studies the effect of the atmospheric exposure to 10,000, 6,000, 2,500, 500, 250, 50 ppm of VC, 4 h daily, 5 days weekly, for 12 months. Two groups of animals were added as control; one untreated, as for all the following experiments, and one treated with vinyl acetate (VA) at 2.500 ppm, under the same conditions. This dose of VA appeared to be the maximum possible dose for a chronic exposure. Experiment 2 was performed to investigate in a larger number of animals the effect of doses between 250 to 50, that is 200, 150 and 100. under the same con ditions as in Experiment I. It was started after it was clear that a dose of 250 ppm was still showing oncogenic effects. Experiment 3 was planned to study the effects of a shorter period of exposure, keeping all the other conditions of Experiment I. Experiment 4 studies the effects of the same type of exposure as in Experi ment I in another species (mice). 1 he treatment lasted 7 months in consideration of the higher mortality and the shorter life span of the mice of our line as com pared with rats. Experiment 5 was undertaken as a pilot investigation on the possible effects of the atmospheric exposure, during pregnancy, on offspring. Experiment 6 was planned to reproduce the same conditions as in Professor Viola's experiments. Experiment 7 was planned to study the effects of the same type of exposure as in Experiment I in another strain of rats (Wistar). Experiment 8 studies the effects of the same exposure as in Experiment 1, in a third species (hamsters) for the same period as in Experiment 4. Experiment 9 was planned, before tumors were observed at 50 ppm in experi ment BTI, to assess further whether inhalation of VC has any effect at a dose level of 50 ppm. Experiment 10 studies whether a high, but limited and/or intermittent at mospheric exposure has any effect. Experiment 11 was performed to evaluate the effects of VC by ingestion. Experiment 12 studies the third general route of exposure. Experiment 13 was started to assess whether VC acts on tissues directly or through metabolites. Experiment 14 has been included to study the responsiveness of newborns. >. A o Co-0 >o> w C3: c to on 2* H to 3 to H CO 3 HCO tHs CO N oe FF **- i>. CnJ g fir 2. g g IT g c gST KT gccr. 8 r* k 2i ^w Co n . `I o IK2" o S5 a*"*.. *<8*aJ4I I Do3? * s". ay< ? Ui la p TJ O TJ ?3 oS tS O o 8 2. o"3 f B -| cI 1* If . =**T ^w 3"- I" 7|=1J| e& 3 ." * S h* -I' ga a<r Sm S3 ' a N"<J *O=<- aW VI*Ci* ^gJJ-; cr R- x w"!icBr-&u. sHs4 ptr c^kr p* au ^** _ TVJ) ,_ CO/1 in a! DS Ss ;s ?? 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X ST B T able 1 Pl a n of the E xperiments up to M ay 5, 1974 weekly, weekly, 80 70 44 240 480 4b La LA O ao LoA s o00 LA SO *. 1o o oLrf Os. 00 14 o. ooc 320 1 160 4k M O * o S w sXcSSUOUl /()!3|Uo8oUpJC3 lOUjlUDJD'J 7p 1U01|C(^ N> . 8I 0 v< *1 "'ll na ns , I M K) Q\ DO MO 8& 88 l s ?? aw g.'* "O^"VtS-r..vMWSBV7io lilf SDDUOjDS jo XiuopcDV ^1J0A M0N s|i:imv 8C 200 inis New York Academy of Sciences Maiiom 6c Leiemme: t-aremogemeuy umassivys 'u i Average latency lime | 1 155 V 3 (2 wu 0a x--Ho0.t*: 9 2 S 3 <1-3 i w OjD erooroNmfcSn \iSoov^> *t"-* 0*0 "" rt C Tf ffnc O*.n 0 rrrt r- m *r\ *0 VC va r-4 ui CmQ4 n--' " HUJ *MyO a t1o2 usr* 0ai 3 a A * ^ t/9> Cde CS* 38 VM A ** M O" E &* 2 s g -x Ma9o 1>* 3 <-2~~ t? 6 X J E ai X d X *- -- <N r*i m --^ - T m m - c^> m m cfs r*s --< (N f'Ot Or- 00 0--0 1O^.' mo ~Pli2r''N Ovn n *-( vO>i'vOo'rt>rioOo'pn ooh>OrsOM 'O't'O'f'O- rr > vnO a JoB h xo> deo d Xi E>% N jajo^i H p N &ft JS * Stj <r toa Ur <* ~ 6? d X 0 fS Ov vnO^iNnh vo <n Tf NO) S?.o ogV'. 0vt''0-**C0`00!O0i'O0<\0Oi0O0 ^"T 3 H0 'OO\0vc(rN~-r->v0'0'0v000 <rr^o- 6E6 3 PoD..oOa. Q0,.q0,.EftaC11Ca1--: H TJ ^ovo>r8^." 9 a oI ''l.u-uVa-u>z <^>>^>^ 2 m3s2:>>>> .*c MUv -- -- -- 0-a- .~<d>*s*u-coyoi2*~_witwi.tii_2u,min_***2_u^m^i"/i>i d^ou5d5S<2i..rS*3"2C*SP*MiwrSS/cti ou c 0 fc- P " w a r. fo ws>-se S E8MSc|tiJ?i gg^eag-Sg?* S S c ra "= C.E a 5,-2 ?ie-e "< "ssrsf -6CE 2 E--c1_E ^gl95-Eb-2Hrt -P>?'1 .'j>NTM.c5n>'SaEc.EsNm,c5 ^w 1: uco^aoP^coJXEMcWecvcui!'' 0^u.hOOOOOOh I f>. o .? r*? Q fas'* \JL /Wmu5 Alev* i uin zsluuhhj lji Experiment (5 js started ns soon as we found 1 liver angiosarcoma, l xtrnhcpntic angiosarcoma, and 1 nephroblastoma in 3 animals of the first cxicrimcnt, exposed to 50 ppm of VC for 1 year, and surviving 135 weeks from he beginning of the treatment. The animals are controlled weekly and weighed every 2 weeks during the criod of treatment and monthly after the treatment is over. All the delectable ross pathological changes are recorded during the control. All the animals are ept under observation until spontaneous death. The animals, when moribund, re isolated, in order to avoid cannibalism. A complete autopsy is made on each animal. Histological examinations are erformed on Zymbal glands, intcrscapular brown fat, salivary glands, tongue, ings, liver, kidneys, spleen, stomach, different segments of the intestine, bladder! rain, bones of the legs and feet, and any other organ with pathological lesions. All the animals exposed to the highest doses (30,000 and 10,000 ppm), with r without tumors, arc examined radiologically, during treatment and/or at cath; moreover, radiological examinations are made on all animals bearing imors, although exposed to the lower doses. Results The current results of several experiments arc shown in the Tahles 2-9. omc others arc still not available. Tumors of different types may be present in the same animals. Zymbal gland carcinomas may be bilateral. Histologically they may reproucc, to some extent, the structure of the normal Zymbal gland (Figure 1), but (ten they present squamous, glandular, solid, anaplastic, and polymorphous atlcrns. Several of these different pictures may be observed in the same tumor, lctastascs of these tumors arc sometimes found in the lung (Figure 2), Nephroblastomas arc often bilateral. Their histological picture reminds us of, n embryonal kidney (Figure 3). They metastasize to the liver, spleen, lung, and rain. Hyperplasia of nephroblastoma-like tissue is often observed in the kidney f treated rats, with or without nephroblastoma. Angiosarcomas and angiomas may be found at more than one site in the amc animal. In liver they arc often polyccntric. Hepatic and cxtrahcpatic angio-' arcomas arc more or less differentiated (Figures 4-9). They are morphologically Table 3 Experiment RT6: Results After 41 Weeks Animals (SpragueDawley Rats) Animals with Tumors Groups anti Treatment : VC, 30,000 ppm Total Corrected no.* (> Sur vivors Zymbal gtaad Angio carcinomas sarcomas No. % Nephro Average latency blasto mas time Liver Otlwr sites Other type and/or site (M Total 60 60 48 12 20 35 12 * Animals alive after 24 weeks, when the first tumor (a Zymbal gland carcinoma) vas observed. The percentages are referred to the corrected number. Mnltoni & Letemme: Carcinogenicity uiuassays z"' Taiu.f. 4 Experiment liT2: Ruxulis After 41 Weeks Groups and Treatment Animats (Spraguriiawley Rats) Total Survivors Animals with Tumors Zymbal gland carci nomas iVbelm'apashst.roo-* saAr.cnogmioa-s Other type and/or site 1: VC, 200 ppm It: VC, 150 ppm 111: VC, 100 ppm IV: No treatment Total 120 115 120 109 120 112 185 171 545 507 it * One subcutaneous fibroangioma. similar in rats, mice, and hamsters. Angiosarcomas frequently metastasize; as far as .the liver angiosarcomas are concerned, the lung is the most frequent site of distant mctastascs. Blood vessels ectasias, endothelial hyperplasia, associated or not associated with cellular atypia, arc often observed in the liver and in other organs and tissues in treated animals, with or without local or distant angiosarcomas or angiomas. Therefore, the effect of VC on blood vessels and endolhelia should be considered systematic. Angioblastic proliferation, angiomas, and angiosarcomas in the liver and in other sites may or may not be associated with fibroplasia. From the histological observations, the sequence of local changes in the genesis of malignant vascular tumors appears to be as follows: endothelial hyperplasia, angiomas, atypias of endothelial cells in hyperplasia (dysplasia) and angiomas, angiosarcomas. Fibroangioblastic proliferation undergoing fibrosis is frequently observed in the spleen of the treated rats and mice. Skin carcinomas in treated rats appear frequently to arise from sebaceous glands, of which they may reproduce in some extent the morphological charac ters (Figure 10). The hepatomas observed in treated rats arc usually well differentiated. Mctastascs have been observed in the lung. Brain neuroblastomas are very similar to the human medulloblastomas (Fig ure 11). Since they may be quite small and therefore not easily macroscopically detectable, we arc now making serial sections of lh,c brains of the treated rats, to obtain more precise information on their real incidence. The lung adenomas in treated mice arc usually multicentric; their number is higher in animals treated with heavier doses. Many of these tumors appear to undergo early malignant transformation. Mammary carcinomas may be solitary or multiple. They arc usually well differentiated adenocarcinomas, with monomorphous or polymorphous arrange ment. The most distinct feature of these tumors is the frequency with which they present areas of squamous metaplasia (Figure 12). Up to the present no acroostcolytic lesion has been observed on our treated animals. Several of the tumors produced by VC arc quite rare or exceptional. To our knowledge liver angiosarcomas, nephroblastomas, and neuroblastomas have oi-'W f Vf /-;< L h x IN /KaUUll) ui OCtCllLCS fSnfONr* 4- + 40* I" II O rO II no \ *n -- r* a $ w ^ H <9 t2\i. cvwi 2,rs rf 5E "G .M2 CC G* III <c 9 Ia H o irtns. c2 w r* TQ3J 3 3 fie" wt 'jv*i ^* * *n i n8 wOE3 u.~oc---Su* o o JC SS^SSSS gE* s ex a S n c c u ftftats S3 So Q,o><a u->JU>U>,^ur>^u z ,, -S3^>>> o H *TTOuVbfkOkVl33..j.s--^IScg&k--ubz-.Sowooo v1) iw8: J*3o*O>* 5gl S2 oro 1| sjs crI| stx. *gc-5 g~C o C v G OOoO Maltoni & Lclcniinc: Carcinogenicity uioassays "O Taiile 6 Experiment BT7: Results After 41 Weeks Animals (U'ist.ir Rats) Animals with Tumors* Groups and Treatment Total Survi vors Zymbal gland carci nomas Angiosarcomas Nephro blasto mas Liver Other sites Other type and/or site Total I: VC, 10,000 ppm II: VC, 6,000 ppm III. VC, 2,500 ppm IV: VC, 500 ppm V. VC, 250 ppm VI: VC, 50 ppm VII: No treatment .70 27 - (i) 30 26 30 23 - (i) 30 27 - (i) 30 26 30 28 40 38 Total 220 195 - (3) - (t) - (i) it - (2) - (1) -- (1) - (1) 1 - (i) i (i) 1 (5) * In parentheses arc recorded the tumors found in male Sprague-Dawlcy rats of experiment UT1, after 41 weeks. 1 One angioma of the cecum. Taiile 7 Experiment BT5: Results After 75 Weeks Groups and Treatment Animals (Spraguc-lJawley Hats) Total Surv|. vors Animals with Tumors *,aft? roblas* no"ma*s tom.s Angiosarcomas Iliviveer f(Ithee#r Other atnydp/eor Total site 1: VC, 10,000 ppm (breeders) II: VC, 6,000 ppm (breeders) Ml: VC, 10,000 ppm (ofisprings) IV: VC, 6,000 ppm (offsprings) Total 30 21 30 24 54 48 32 30 146 123 t* 1 it 1 22 Subcutaneous angiosarcoma on a 24-wcck-old male, t Subcutaneous angiosarcoma on a 22-wcck-old female. never been described as spontaneously occurring in rats. Liver and extrnhepatic angiosarcomas have been induced only in a few instances in experimental rodents (rats, hamsters, and mice) (for references see Maltoni and Lcfeminc'). As far as we know (his is the first time that nephroblastomas and neuroblastomas have been experimentally reproduced. I Conclusions 1. Under our experimental conditions, VC produced tumors in the three animal species studied: rats, mice, and hamsters (as far as the last species is con cerned, the data should still be considered as preliminary). `L vO s*. ^ o Cv U)Z '061 X `giyH 'lCJ u! buioui3Jc:> puq8 |cqui.<z psiciiuwsjjjp 1PM S s' WO O* 3n O3O3O3O0O3O3O3O3W? * C>2-a>r 3 a<n * =r c O-'O n t S^SncoeUc3a^2HT'y^i3U-gC0lUrTf.%3UgrC>rnT,,c 3 3 I v< 32 cr g 3rt *3 O oo ;I 3P n ?nSS*-s* O?cS-5^-ocwooncoowtE_i 6* rO In: Ow o;| .5 = 5 rw> o5o ow A 1 1c "37-w3230n nr. 03 n 3 o v> 5O 303 3 f, o * 3v o 2; i5 o 3 c3" -3 o u 3WW 3_ 0) o a "f U3 3 t> a* *> = ~t 33 3O cr 3 nu ou o %3 If33 S' O I 3 3u cj * P 4A O-- <<< ~ _ *3 H zO n- .| 4 3 ^O -9 n3^ 0= n S88 gn-o -33 ' 33 ss s 000 o c '<588 8 8 8 37 o vO -- -- -fp A nim il* M tir A nim ats w ith Tum ors dnoJ8 stm ut psAJDsqo sbm S3SB)SB)3iu XjBuouqnd qjiM BUJ03JBS0I3UB J3aij j `uoiiBSiiqnd joj p'stiiui -qns sbm uodoj siqi jo ijBjp |BU9 oqj qsiqM uo (t^i6I Joqwaidss) amp aqi iv t SJouini j qj| |buiiub auQ . fr l c z Zil 89Z 11 I 1 i- lI l 1 l1 6t> 01 CZ cc 81 zc CZ cc 61 cc IZ zc 61 it CVUJO u|W CtUiO qduiX*] StUIOI *poimptJ!) IVUIOD/Vf -0|tlu* J^AI'l "MS tJOAlAing l'lX moum qj s|*uiiuy (fiJ9|1UJt|| u^ppo) k|ui;uy |B)L IU31U1B3J) ON :IIA uidd o? `DA ;IA uidd OSZ 'DA - A uidd 00S 'DA :AI uidd 005'Z `DA :III mdd 000'9 DA :H uidd QOO'Ol DA :l )u9ui)taJX p" 4 3* 14 O -- |4 W s t kllliutj 1 1C II 4v/*rw t W.IUUII y UI Ocii;iict5 IVlttllOMI IX LAiClIliiiC. ^uiVIU^ctlictt; iitUUJJi JO \jy A-VJ* r\ ^ 2. The range of induced luniors varies (o some extent from species to species. When given by inhalation VC produced: in rats, Zymbal gland carcinomas, neph roblastomas, angiosarcomas, and angiomas of the liver and other sites, skin car cinomas, hepatomas, and brain neuroblastomas; in mice, lung adenomas (fre quently undergoing malignant transformation), mammary carcinomas, of a peculiar type, angiosarcomas and angiomas of the liver and of other sites, skin epithelial tuniois; in hamsters, liver angiosarcomas and, as early evidence seems to suggest, skin trichoepitheliomas and lymphomas. Incidentally, liver angio sarcomas have been observed in all three animal species. 3. In the BTt and BT4 experiments, VC shows a carcinogenic effect at 50 ppm. 4. From the BT1 experiment (the only one completed) a dose-response rcla- tionship clearly emerges, as far as angiosarcomas and nephroblastomas are con cerned, in the lower dose ranges: from 500 to 50 ppm for angiosarcomas and from 250 to 50 ppm for nephroblastomas. 5. A comparison of the results available at the present moment in rats ex posed for 12 and 4 months (DTI and BT3 experiments) shows that the neoplastic response, as far as angiosarcomas and nephroblastomas arc concerned, is affected by the length of exposure to VC. 6. The comparison of the results obtained in rats of two different strains, i.e., Spraguc-Dawley (BTI) and Wislar (BT7), at the present moment, seems to sug gest that the strain factor considerably affects the neoplastic response. 7. The onset of two subcutaneous angiosarcomas in the offspring of breeders exposed during pregnancy for 7 days appears to indicate a transplacental effect of VC. r, o "v* o o 'O W co 0 CJ 1" O 'c DAd'DA Sujanpojd Xjoioej V STl c J J3MJ0" B "I `ascosip pruojjKdna -30 UK SI! `BUJOOJKSOjSlIB J3AI| B JO Xj3A03Sip ISJtJ Oqi Ol pD| 61 J3qiU333(] Uj qaiqM `suojiESjisOAUj |caj3o|OjiU3pjda pun suojiKAJOsqo juDjiijp poioiuojd uojiEiu -jojuj s;qx ( v s n) VDIV 3*JI l ua\ou>j 3puiu osp: 3J3a\ sqnsoJ osaqi `suuioajcs -oi3ue J3ai| pun scuioisi:|qojqd3U osp; mq 'sjoiuiq puc|3 |i;quiXz Xjuo jou sjcj u; Supnpin sem Oa iuqi ua\ou^j sum )j jdjjk DUJji poqs i: `U6I J pu3 34l 3J]38 sD||JBd p3iSDJDju| ||c oi 3|qc|jUAU Dju put: qaJBosoj jno po|joddns 3Acq qajqM S3iuudui03 ucadoJna aqi oi paiijuisuEJi X||B3jpojJDd uoaq DAcq Bjsp jno >jSBl ipiDlJJip Jno JO 3JBMB 3JB ]CjJ3)BUI |U]U3UIUadx3 JO 9ujU33J3S |K3i8o|oqicd u; po3u3uo osoqi icqi 3Jns uiu j `a\ou oi dn sapqs 000*001 unqi 3Joui uooq 3ABq 3Joqi aoujjj sisonbaj aqrpuu siuoad oqj jo ajnssaid aqi `aidoi oqi jo `061 x `3VH "JUJ u! bujosjbsoiSub J3Aiq -j Hunoij ;>.i f* Ui T jVy? *'*** a 33UB|Joditi| oq> jo asnBDsq Xjessooou opciu uooq si:q sjjnsDi oi3|diuoaui puc Xjci -UUJ|3Jd 3l|) JO 3SB3|3J oqx '3|3|dUK>0UI 3JOU1 U3A0 U33q DAi:q S|Jod3J SIlOIASjd uo -C3J J3||B| aqi joj SJOiuiq poiaoppun `sinujiu `pupm a\du ovopsjp Xkiu 'suoipo |BDi3o|ois|q H-'ijos JsqiJnj jo *Xi;a\ jspun mou si qojqA\ `uojiuuiiuuxo luaidoosojom dmbui3)sXs puu punojojd sjoiu b osnEoaq 3iD|diuo3iij :s33bis p;ii;tii oqi pi oiu'o pun 'sssjSojd Uj )|i)S 3jb smomusdxa oqi jo isoiu odujs Xjuujuiipjd :o|3|diuo3L pus XJBUjujj|3jd qioq pojopisuoo sq p|noqs )jodoj siq) uj poiuosojd sqnsoj sqj 'DA t l)3so -\3 SJ35(JOA\ UI SISX|031SOOJDB JO UOj|B|3JdjO|U! DlpusSoqiwd oqi Uj 1101 JCJUOlJ M3U B SISDS3uS SI!IU03JUSO(3uB 3ujXjjSS0 JO S3SCD M3J B JO UOjlKAJOSqO oqj, '8 061 X '3H IBJ Uj BlUO3JBS0j8uu J3AJT > 3UHOIJ c "MMUMnn "V> IMOJIOUI SODUDDq |0 Xlltopcov 3JOA, MOM SIBIIIIV OI o o O b ?> BUlODJCSOlgUB J3AI1 JO MSBJSCpUl *JBUOlU|nl 9 JUn;MJ unonni ,Q soninnc in Jnnniwv 'mi mom cimm' 717 ^4 H<v*4 o C` j b fy >. "061 X `3TH 'ssnoui UJ buio3Jbsoi3ub *3upi}{ <; avnoij * '061 X `aVH 'IBJ u! Buioupjos `paivpuajsjjip ||sm `snoaacqw U|ns '01 3noij / i. sXcSSUOtfl XjniUOSoiipjBf) tDUUUOJDT T$ IIIoq[GJAJ MMm-tr' Trv fimnnM/ vin l 017 218 Annals New York Academy of Sciences Figure 12. Mammary adenocarcinoma with squamous metaplasia in mouse. II&E, x 190. May I recommend again that the VC carcinogenesis may serve as a convinc ing example for urgently promoting experimental bioassays for all new industrial compounds and for those compounds that arc already widespread but whose effect we still ignore, to avoid occupational cancers. Our Institute is now undertaking projects of carcinogenicity bioassays of other monomers employed in the plastic industry. References ' 1. Vital x, P. [.., A. Rigotti & A. Caputo. 1971. Oncogenic response of rat skin, lungs and bones to vinyl chloride. Cancer Res. 31: 516-519. 2. Mai.toni, C. A Ci. Lit fmine. 1974. Carcinogenicity to bionssnys of vinyl chloride. I. Research plan and early results. Environ. Res. 7; 387-405. INTERIM RESULTS OF EXPOSURE OF RATS, HAMSTERS, AND MICE TO VINYL CHLORIDE M. L. Keplinger, J. \V. Goode, D. E. Gordon, and J. C. Calandra Industrial Bio-Test Laboratories, Inc. Northbrook, Illinois 60062 The following data arc partial results of a study in progress at the Industrial Bio-Test Laboratories, Inc. The studies arc being coordinated for sponsoring companies by the Manufacturing Chemists Association. The data arc very in complete but because of their significance were first presented to EPA, NIOSH, and OSIIA on April 15, 1974. In this study which was designed to complement Maltoni's studies, 100 rats, hamsters, and mice of both sexes (600 total per exposure group) arc being ex posed to either 0, 2500, 200, or 50 ppm of vinyl chloride vapor 7 h/day 5 days/ week. Mice will be exposed for 9 months and kept lor an additional 9 months. Rats and hamsters will be exposed for 12 months and kept for an additional 12 months. The rats arc COBS Charles River, mice arc CDI Swiss Charles River, and the hamsters arc Golden Syrian front the same source. Food is removed during ex posure. water is present and no bedding is used at any time. Morihund and dead animals (when possible) receive gross autopsies and arc photographed. The major organs of all animals arc fixed for histological exami nation. Only the tissues from a few animals have bcc.n examined so far. Table 1 shows the results to date (about 8 months exposure). Note that no direct numeri cal comparisons can be made with the control groups as they have not been se lected in the same way. Only mice with tumors have been examined in the ex- Table 1 Interim Summary of Tumors in Mice Exposed to Vinyl Chloride for 8 Months* Exposure Group No. ol Mortalities with Neoplasms ToUl Milt Female Type ami Location of Tumor Alvcologrnic Angio adenomas, sarcoma, lung liver Adeno- Metastasis squamous of carcinoma, mammary mammary tumor gland to lung Control f 0 (7) (2) 50 ppm J 41 3 200 ppm J 15 3 12 2500 ppmt 30 6 24 0 000 2 222 12 11 3 1 28 28 6 1 * I'rcliminary 'findings front MCA Administered Study at Industrial Bio-Test Laboratory, April, 1974. t Seven male and 2 female control mice have been examined histologically. None had tumors in spleen, liver, kidneys, heart or lung. I Only mice with grossly visible tumors have been examined histologically. 219