Document NEBeMZyD2VXajg23L9Npv7oOV

.. r DATE OF REQUEST: 4/3/87 NOT NEEDED AFTER: INTERLIBRARY LOAN SCHOOL OF VETERINARY MEDICINE LIBRARY LOUISIANA STATE UNIVERSITY BATON ROUGE, LOUISIANA 70803-8414 -rTTk i /I/O *i/3 / ^^Mail request Fax request DATE SENT DATE DUE / V * # H th ! f taivatAa iiO. ZZss FOR USE OF: Lelia Hopewell STATUS: DEPT: PERIODICAL TITLE, VOL. AND DATE OR (BOOK AUTHOR) ANNALS OF THE NEW YORK ACADEMY OF SCIENCE. Vol. 271, 1976. PERIODICAL ARTICLE AUTHOR. TITLE, PAGES OR (BOOK TITLE, EDITION, PLACE, YEAR') Maltoni, C. : Occupational carcinogenesis. Predictive value of carcinogenesis bioassays. Pg. 431-43. ( ) IK USE VERIFIED: IM Vol. i8( 1977, pg. 3248. ( ) NOT OWNED ( ) OTHER LENDING: LIBRARY LU-M DATE RECEIVED DATE RETURNED ? Request complies with ____108(g)(2) Guidelines (CCG) yj other provision of copyright law (CCL) AUTHORIZED BY: T,,,ty ..niarltwhAar Rwlrd TITLE -ILL. FROM LU-0 04/01/SG 09:17 430 Annals New York Academy of Sciences GGC 002094 able to the economic consequences of control. He and his institutions are pi necessity, therefore, in a position of forced objectivity. Thus his is a critical voice to be heeded. The participation of organized labor is not automatic. A positive effort mint be made, an effort I call "positive public advocacy." This is an essential govern ment responsibility, involving the public in decision-making processes such u the assessment of environmental risk. The passage of the Occupational Safety and Health Act of 1970 has resulted in a steady progression of "discovery" in the world press: the carcinogen-of-lhemonth, old horrors revisited (lead and mercury poisoning), and millions of workers and their families at risk from asbestos exposure. Response is slow in a democracy. New forms of collectivism, such as the trade association, appear without inherent mechanism or control. Unrestrained collectivism--which must be controlled before movement can take place--h characterized essentially by the lowest common denominator. These denomina tors in a collectivist structure have incredible leverage. They can become, as the years of secret studies by trade associations of vinyl chloride demonstrated, it almost insurmountable obstacle at the heart of inquiry: the transmission d information and its examination. The consequence is that the prevailing ideology of the world of Percival Pott who discovered occupational cancer 200 years ago, the ideology of Bentham persists. But its influence is waning, partly because the worker is an increasing!* effective agent of change. He will not tolerate hundreds of thousands of cast* of occupational cancer. Increasingly he is becoming intellectually and eco nomically able to act. Thus, it is not necessary, even in a world the majority ol whose societies are either fascist or communist expressions of the collectivist state, to believe that we must make by adaptation or selection collective decisions in the determination of socially acceptable risk. References t. Schweitzer, A. 1957. The Philosophy of Civilization. (Translated by C. T. Campion.) Macmillan. New York, N.Y. 2. Haver, F. A. 1944. The Road to Serfdom. University of Chicago Press. Chicago. III. 3. de Tocqltf.ville, A. 1945. Democracy in America. (Translated by Reeve! Bowen.) Knopf. New York, N.Y. 4. Friedman, M. 1970. The social responsibility of business is to increase id profits. New York Times Magazine. September 13: 32. 5. Bentham, J. 1939. In The English Philosophers from Bacon to Mill. E. A. Bint. E. s 802. Random House. New York, N.Y.; Bentham, J. 1918. Felicific calcuhn Polit. Sci. Quart. 33, June, 6. Kapp, K. W. 1971. The Social Costs of Private Enterprise, t xxiv. Schoclm New York, N.Y. 7. Brodeur, P. 1974. Expendable Americans. Viking. New York, N.Y. 8. Galen. 1947. On the Natural Faculties (Translated by Brock.) : 27. Harvard University Press. Cambridge, Mass. PREDICTIVE VALUE OF CARCINOGENESIS BIOASSAYS Cesare Maltoni Institute oj Oncology and Tumour Cei^TERtAL MAY BE PROTECTED Bologna, Italygy COPYRIGHT LAW It has been estimated that from 80 to 90% of human tumors are caused by factors present in the occupational and general environment. Therefore, cancer must be largely considered an ecotogic disease. On the other hand, the number and quantity of oncogenic agents in the occupational and general environment have progressively increased in the last few decades, due mainly to the following factors: the concentration of onco genic agents already present in the Earth's surface, surfacing of oncogenic agents from beneath the Earth's surface, and production of new potentially oncogenic compounds by chemical and petrochemical industries. The major problem is now represented by the multitude of products of synthetic chemical industries, especially the petrochemical industry, that are unknown to animal and human protoplasm and of whose effects we are there fore fully ignorant. Factories represent the observatory: there, the compounds are planned, produced, and released into the general environment as consumer goods and pollution; there, the most exposed population works. In this situation, one should be therefore aware that tools are needed for assessing the risk of agents concentrated, or brought, or introduced de novo into the occupational and general human environment. This need is strengthened by the following basic facts: The potentially oncogenic agents in the human environment are progres sively increasing. Different oncogenic agents may have additive effects. Changes produced by oncogenic agents are largely irreversible. Oncogenic agents may exert their effects on different organs and tissues and widely affect the target organs. A large part of the natural history of tumors occurs without any clinically, and sometimes otherwise, detectable pathologic changes. Cancer is not a reversible disease. The potential oncogenic risk for man by occupational and environmental agents has so far been identified when the incidence of a particular type of lumor in an exposed population has been especially high or on (he basis of retrospective epidemiologic studies. The gravity of the present situation, however, no longer permits the old policy of "let's wait and see." In other words, we must now predict oncogenic risks to avoid human exposure to such agents. It is a fact that the three most important cases of environmental and occupational tumors, discovered after 1970. were indirectly or directly predicted experimentally. The first case was the adolescent clear-cell vaginal adenocarcinoma found in girls bom from mothers treated during pregnancy with synthetic nonsteroid 431 Anna!* New York Academy ef Sciences estrogen therapy. It should he noted that, in 1938. Lacassagne 1 had alreadi reported that mammary carcinomas arose in male mice treated with stilbestrol. several years later, it was shown, by several scientists, that the same hormone was producing a variety of tumors in hormone-dependent and -independent tissues among different experimental animal species.2 The second case was pulmonary carcinoma among workers exposed to his(chloromethyl)cther. This new type of occupational tumor was discovered by experimental evidence: Van Duuren ef at.3 and Laskin ef at.4 showed, re spectively, that, when injected subcutaneously into rats or applied to the skin of mice, Ihc compound was producing subcutaneous fibrosarcomas and skin carcinomas, and that, when inhaled by rats, it induced squamous cell carcinomas of the lung. The third example is the history of vinyl chloride canceroeenicily.5-10 In 1971, following our early observations on the increased incidence of atypical cells in the sputa of workers exposed to vinyl chloride and the results of Viola ef of.,*'-12 which showed that rats that experimentally inhaled 30,000 ppm of this monomer developed Zymbat gland carcinomas, we undertook a large program of experiments to study the effects of vinyl chloride, administered at different doses and by different routes, on animals of different species, strains, sexes, and ages. In August 1972, we realized that this compound was producing angio sarcomas of the liver and of other sites and nephroblastomas other than Zymbal gland carcinomas. These results were communicated by us, among others, to the factories that supported our studies, and to the Manufacturing Chemists Association, to enable them to adopt adequate preventive measures and to promote these epidemiologic investigations, which in December 1973 first identified an occupational tumor, a liver angiosarcoma in a worker of a United States.factory (B. F. Goodrich in Louisville, Kentucky) that was producing vinyl chloride-polyvinyl chloride (VC-PVC). No histologic difference could be found among the angiosarcomas in animal) and in man exposed to vinyl chloride. Updated results of some experiments on VC carcinogenicity are shown in Table t-9. The onset of several hepatomas among animals experimentally treated with VC (Table tO) is particularly relevant, in tight of recent observations by Selikoff12 and Popper" of a few cases of these tumors among workers of VC-PVC industries. All types of tumors in man that have so far been found to be correlated in some way to VC exposure are included among those already observed in animals (Table 11). Experiments arc now underway in our laboratories on the effects on tats of inhalational exposure to 23, 10, 3, and 1 ppm of VC and of oral administra tion of 1, 0.3, and 0.03 mg/kg of body weight of the monomer, with the same schedule of experiments BTI and BTt 1, respectively. From the results presented on VC carcinogenicity in laboratory animals, it appears that experimental bioassays may predict carcinogenicity, give indica tions of target organs, give information on the risk level based on the doseresponse relationship, and may be able to assess the risk in function of the route of exposure. , At present, much emphasis is focused on VC carcinogenicity. We hope that I VC, 0,000 II VC, 0,000 III VC, 6000 IV VC, 2300 V VC, 500 VI VC, 250 V II VC, 50 VIII No eatme Tot Maltoni: Predictive Value ot bioassays 433 s a0** o Oz< o to o tfl o' o c* S o' Rx --w Q* 8.S8 *s H u- < a* $ g - 5 Ul UJ -- j n a. < O5s HQ g<"< Cvn IQ >s CQ U> _ PC Pfi DO O 0* UJ HCD az < HCQ V> Z ul 3? ft Ul UXJ a m.m TS a A rt w Du C1* = 1111111 = 10 64 4 1 l1 2 11 1 1 3 2 26 3B J e A rt 2 wi a H 5 rt g m Z jo - r- m V! | | | |W rt A -- -- -- M HI j | | 00 Su' sg Ifi X 2 o s I'il * $ VJ u 13 12 11 31 31 43 11 1 i 5.2 c < JS 1 92 o 6 7#-> a h* M 6ot> o A O '5c c Ul u> <J 8 -- m -- |-- 47 6 13 4 [3 59 3 JL I." a 0- E z- "3 "2-a a E2s a b =rous Ajr--, i t- jMsi efr I| I| I|2^ (9 Q dO s-- 2 S> s Hx B G.'> *- < 1/3 gO* Q _e 3. e "i u rt ^ os r* ~ n ne&a bn^^ r" n w w,e v> E EE ESE E B,o,a5,g.a,g,,, o, o. o. S o. o- ik e ^-- _ fl 26 S3 Most o f these tumors occurred in the sebaceous glands. ctro-. Q & O o oCO 1 434 Annals New York Academy of Scicrtccs Table 2 Experiment BT2: Exposure nv Inhalation to VC in Am at 200, 150, and 100 ppm eor 4 -Hr Daily, 5 Days per Week for 52 Weeks. Results After 89 Weeks Groups and Treatment I VC, 200 ppm II VC, 150 ppm m VC, 100 ppm IV No treatment Total An imals (Sprague-Dawley rats) 9 and d Total Survivors 120 41 120 45 120 49 185 76 545 211 No. of Animals with Tumors Zymbal Gland mas Nephro blastomas Angiosarcomas Liver Sites 2 71 ____ 4 3 I i 8 1 ___ i -- --1 2 14 11 3 this emphasis will not mask the more general problems and the multitude of needs of occupational cancerogencsis. In our Institute, other compounds have been or are being tested. Experi mental bioassays have been performed on chromium compounds and other inorganic pigments by subcutaneous injection of rats {Table 12). These results point out the potential risk of some of the most widespread inorganic pigments. Experiments have also been performed to assess the oncogenic potential of asbestos on peritoneal mesotheiium, by injecting crocidolite into the abdominal cavity (Table 13). Our data are consistent with the well-known epidemiologic results that point out the high risk among asbestos workers of developing peritoneal mesotheliomas. Carcinogenicity bioassays on several other compounds produced and dis tributed on a large scale are now underway; the compounds being tested include monomers used in plastic industries, such as styrene, acrylonitrile, and vinylidene chloride; polymers; estrogens and progestins; and petroleum proteins. Let us hope that experimental bioassays will no longer be procrastinated due to skepticism of their validity, based on past results; fatalistic resignation, because of the huge number of newly produced compounds; and complications of elaborate testing procedures. In regard to skepticism, I think that we should now critically review the methods and results of past experiments, which may now appear to have been poorly conducted. With regard to the large number of compounds, it is true that there are already millions of newly produced chemicals; however, those that urgently need to be tested, mainly because of their widespread use, actually number only in the hundreds. Concerning complications in performing elaborate testing procedures, it is true that the more experimental tests on animals reproduce the conditions of human exposure, the more relevant they are to man; it should be pointed out, Maltoni: Ercmctivc vatuc ui uiua.ssays UJ SCU a. o oz li xUl ,, *3 b Tw-* f*"k tft a? 3 2 t M M | | s 6# ww M -* | r* <n P ^ 'W' W -- I I sO O' o 04 O o o o o I2o. 1 at * : "* *ui [Si v>t < ft D mi rt 3 s t ^ " Si oo.S W4 - N 2 II 3> tCS GO B Sc u * NO aDcOftl flu UX3 I 3 e S < Ef HCO 1o/1. Jv5 >* 63 N S-2 o S S oo v> H Z ill S suQ*l UXJ i an Q. Q V 3 g s o2 c<4 rt oB H a. Ok Q. o. o 88 hOh oO >> Or O. a. a D. Q. w CuQ.fR s 8 oo vy v-y C Vj an N M *3 M> > > > | u uyu o > > > >2 Jfj rGaUt -cnus uO.JS B'Z .* c 436 Annals New York Academy of Sciences es| ro 3 2 2 ** -- i II I 2 cCi X 0* ae vi M 8: gK g* X-- U. j H X UJ ut >< tt) U) < oo BJ X op SAU,i tf u VI ^ VT *2^ g|fr3*Id<s<2i X- ix >- ^ o UeX4. t-* H 2 X ui WeX, Is o IN ~ (N "fr fn W N M N ^ Wm W rWJ --W< "*"1111 at E 4B5 M9.S5 N art O ^ fl v* h<i-sSjl IIII I M S*o <1 + '* O 00 -- (SO C3OuL TCr5t Xfurit as H | Ebb Gbb 8 o G Sb' >n Gbb 8 sn bB 8 (S bG o? Su G 2c"SN> > > 2 _ u 2 S! z0 [o2 I * ss Maltoni: Predictive Value ol Wioassays 4J / Table 5 Experiment BT5: Exposure of Breeders by Inhalation to VC in Air at 10,000 and 6000 ppm 4 Hr Daily for 1 Week (from 12th to 18th Days of PREGNANCY). RESULTS AFTER 115 WEEKS Groups and Treatment 1 VC, 10,000 ppm, breeders If VC, 6000 ppm, breeders m VC, 10,000 ppm, offspring JV VC, 6000 ppm, offspring Total Animals (Sprague-Da wley rats) Total Survivors 30 30 54 12 32 8 146 20 No. of Animals with Tumors Zymbal Gland Cardnomas Nephroblastomas Angiosarcomas Other Liver Sites I ----I 3 l --2 1 -- --2 5 1--5 r-~ oO'. oo oo o however, that tests of agents should follow a pattern that progresses in degree of precision and scrutiny so as to eventually filter out and expose the most dangerous compounds. Finally, I should mention that we must place emphasis on both scrutiny of compounds already produced and in widespread use and on compounds yet to be produced, before economic, social, and political interests become so en trenched that solution of these problems will be difficult indeed. Table 6 Experiment BTI4: Exposure of Newborn Rats by Inhalation to VC in Air at 10,000 and 6000 ppm 4 Hr Daily, 5 Days Weekly, for 5 Weeks (FROM I DAY TO 5 WEEKS OF ACE) Results After 48 Weeks Groups and Treatment 1 VC, 10,000 ppm II VC, 6000 ppm Total Animals (Spraguc-Dawley rats) and cf SurviTotal vors No. of Animals with Tumors Zymbaf Ci land Angiosarcomas Card- Nephrobla- Other nomas stomas Liver Sites Hepatomas 46 42 1-- 1 43 41 -- -- l -- 2 89 83 -- -- 2 -- 3 i 438 Annals New Y o rk Academ y o l Sciences | Table 7 Experiment BT4- Exposure by Inhalation to VC in Air at 10,000, 6000, 2500, 500, 250 and 50 ppm for 4 hr Daily, 5 Days Weekly, for 30 Weeks. Results After 81 Weeks (end of the experiment) Groups Treatment i VC, 10,000 ppm II VC, 6000 ppm III VC, 2500 ppm IV VC 500 ppm V VC, 250 ppm VI VC, 50 ppm VII No treatment Total Animals (Swiss mice) 9 and <S Total Survivors 60 -- 60 -- 60 -- 60 -- 60 -- 60 -- 150 -- 510 -- No. of Animals with Tumors Liver Pulmonary Mammary AngiosarTumors Carcinomas * comas Vascular Tumors of Other Types and/or Sites Epithelial Tumors of the Skin T Pregastric Papillomas 35 '3 8 9 3 1 38 8 J 9 6 1 30 9 11 12 3 1 38 7 11 18 1 -- 33 11 11 22 2-- 2 12 1 13 -- -- 8 -- - 1 184 60 47 84 15 3 * Most included squamous metaplasia. + Some occurred in sebaceous glands. Experiment BT8: Table 8 Exposure by Inhalation to VC in Air at 10,000, 6000, 4 hr Daily, 5 Days Weekly, for 30 Weeks. 2500, 500, 250 and 50 ppm Results After 76 Weeks No. of Animals with Tumors Groups and Treatment I VC, 10.000 ppm Animals (Golden hamsters) Liver Tumors Angiosar A . . * Total Survivors comas mas Hepa tomas Skin Trichoepi theliomas and Melano Basaliomas mas 35 1 -- -- -- 6 1 11 VC, 6000 ppm III VC, 2500 ppm IV VC, 500 ppm 32 3 33 4 33 4 --2 1 --3 1 Z---- 22 1-- 3-- V VC, 250 ppm VI VC, 50 ppm VII No treatment Total 32 4 33 5 70 14 268 35 ------ ------ 252 3 6 2 23 * Average latency times were 48 weeks in treated animals and 92 weeks in controls. 1 a Pregas- tric Papillo mas and Lympho- Acantho mas * mas 4 24 18 14 1-- 12 2-- 8 22 QGC 002095 Others 2 (1 subcutaneous angioma) (1 adenocarci noma of gall bladder) (1 subcutaneous angioma) (1 bronchial carcinoma) 4 M ultum : I'rcdieiivc Value ol bioassays 43V 440 Annals New York Academy of Sciences Table 9 Experiment BTtl: Exposure by Ingestion (stomach tube) to VC in Olive Oil at 50.00, 16.65, and 3.33 mg/kg Body Weight, Once Daily, 4-5 Days Weekly, for 52 Weeks. Results After 55 Week. Groups and Treatment I VC, 50.00 mg/kg II VC, 16.65 mg/kg HI VC, 3.33 mg/kg IV Control: olive oil Total Animals (Sprague-Dawley rats) Total Survivors No. of Animals with Tumors Zymbal Gland Card- Nephrobla- nomas stomas Angiosarcomas Other Liver Sites SO 57 SO 66 SO 62 SO 6S 320 253 ;j 11 1-- 21 Table 10 Hepatomas Observed So Far on Rats and Hamsters Exposed by Inhalationt to VC in Air, 4 hr Daily, 5 Days 'Weekly Animals Species, Strain, Age Sprague-Dawley rats 13 weeks old Sprague-Dawley rats, 1 day old Wistar rats, 11 weeks old Golden hamsters 11 weeks old Total No. 60 69 72 74 67 46 43 30 32 33 Treatment 30,000 ppm, 52 weeks 10,000 ppm, 52 weeks 6000 ppm, 52 weeks 2500 ppm, 52 weeks 500 ppm, 52 weeks 10,000 ppm, 5 weeks 6000 ppm, 5 weeks 6000 ppm, 52 weeks 6000 ppm, 30 weeks 2500 ppm, 30 weeks No. of Hepatomas 1 1 I 2 3 1 2 1 1 1 14 Mammary Carci nomas 03Q , Maltoni: Predictive Value of Bioassays z 5 az< PzUao) OS j i UJ Sj SuAXst*lt zo oz ~ X-<51 mUJi > on Ha D U2XJ U > H0 s 5 S o rwi JX H* UJ Uet O* oe S } b .iyc x2 Sterss ncj cre Sb o. a, ^ +++ <5 & + ++ X ++ , aw to.ia..B So EW E +++ ^ E (2 o 3 fl S p 3 g o 3 o 5 G + + JfSuSog oE s OM B O.H + sr X) jj* 3 ihl|l +++ C u ew J < Is la-ai s eeSS'e AS y"N, ++ g * Bo J ++w +w gc 3 b , s M h |EoI C8 < *4 + 4- +++ + 441 J4: Anna!* New York Acadcmv of Sciences f E-" --5i UXJ tj vi r* Z 0 1 s D O zu SQ oX D V) bou Uz1 uo sa Si 6 C m Ogg uE pc III!b o 8B 2.3 S 5 2 |S O ) |oIO8JJ2Dl !OBO j.Osgo 2* 2*2S52"" 51 i5l G 'S u rt GG *- rt aa a II2o 3s E sa V) G u sO 6 oa flj P oE Js 8 Eegg E g B 8 6 g OS jjo 0.0 0X3 0.0 2 2 2:f S'* *- Crt .Cu 3G Gu 3G Xu rGt &2P a ' > m P It < nJ II kz 5 UJ ^ 5O E <5 ui O tt) -{5 8S P CO 2 ?o .b 2 O 03 Zui S s UJ At X (U -- oSjio oiSE 7 C? 3 ^ L- 2- | p at Iq o. C/J II ''t 't II I I I II R e e 2 O E 5i E2 28 J3 uz N* 73 j<y4 *2 u -- 6 Tr3t *o 3? rt *2 L* X oa o pG E 3 II E 2 -e 12 S .c 2u UU " <4 >. i3sS i >s,2 ' G sP O gS O 2 U ^ * W^ ^ O c o bU pg e k Uf l X Maltoni: Predictive Value of Bioassays 443 Experiment BOS: Table 13 Treatment by One Endoperitoneal Injection of 25 mg of Crocidolite in 1 cc of Saline Groups and Treatment I. Crocidolite II, Saline (control) Animals rats) (Sprague-Daw ley Sex No. 9 50 50 9 45 J 15 Cor rected No.* 49 48 45 15 Animals with Peritoneal Mesotheliomas Average Latency Time No. % (weeks) Animals with Metastases 34 69.3 31 64.5 ---- -- 73 65 -- 13 38.2 13 41.9 --- --- * Animals alive when the first peritoneal tumor arose. References 1. Lacassagne, A. 1938. Apparition d'adlnocarcinomes mammaires chez des souris males t rallies par une substance oestrogine synthitique. C. R. Soc. Biol. 129:641. 2. Lacassagne, A. 1950, Les Cancers Produit par des Substances Chimiques Endogines. Herman. Paris, France. 3. Van Duuren, B. L,, A. Sivak, B. M. Goldschmidt, C. Katz 4 S. Melchionne. 1969. Carcinogenicity of hato-elhers. J. Nat. Cancer Inst. 43: 481-486. 4. Laskin, S., M. Kuschner, R. T. Drew, V. P. Cafpiello 4 N. Nelson. 1971. Tumors of the respiratory tract induced by inhalation of bis(chloromethyl) ether. Arch. Environ. Health 23: 135-136. 5. MALTOM, C. (Ed.) 1974. Occupational carcinogenesis. In Advances in Tu mour Prevention, Detection and Characterization. Vol. II: 19-26. Excerpta Medica. Amsterdam, The Netherlands. 6. Maltoni, C. 4 G. Lefemine. 1974a. Carcinogenicity bio-assays of vinyl chlo ride. I. Research plan and early results. Environ. Res. 7: 387-405. 7. Maltoni, C. Sc G. Lefemine. 1974b. Le potenzialitJ dei saggi sperimenlali nella predizione dei rischi oncogen: ambientali. Un esempio: it cloruro di vinile. Accademia Nazionale dei Lined, Rendiconti della Classe di Scienze Fisiche, Matematiche e Naturali, Vol. LVI, Ser. VIII, Fasc. 3. 8. Maltoni, C. & G. Lefemine. 1975. Carcinogenicity bio-assays of vinyl chlo ride: current results. Ann. N. V. Acad. Sci. 246: 195-218. 9. Maltoni, C., G. Lefemine, P. Chieco 4 D. Carretti. 1974. La cancerogenesi ambientale e professionale: nuove prospettive alia luce della cancerogenesi da cloruro di vinile. Gli Osped. Vita 1: 5-6,4-66. 10. Maltoni, C., A. Ciliberti, L. Gianni 4 P. Chieco. 1975. Insorgenza di angiosarcomi in ratli, in seguito a somministrazione per via orale di cloruro di vinile. Gli Osped. Vita 2(1): 65-66. 11. Viola, P. L. 1970. Cancerogenic effect of vinyl chloride. In Xth International Cancer Congress, Houston, Vol. 29. 12. Viola, P. L., A. Bioom 4 A. Caputo. 1971. Oncogenic response of rat skin, lungs and bones to vinyl chloride. Cancer Res. 31: 516-519. 13. Seukoff, I. J. 1975. Personal communication. 14. Popper, H. 1975. Personal communication. oo ?oi o o Cl a -err