Document mBXKb2Qrd9QKDyyY92Mv3VB7b

R&S 108969 /' BIO-MEDICAL research document description form 63 68 69______________ 76 Duplicate in all cards:--> year as-1961- y 0 U u 2* 9 y File number [Right justify [Numeric only] 77______ 78 -Jse- Sub-Index Code Author(s), as Last Name FS (No Punctuation) and coden for journal as JAMA preceeded by one blank space 1 20 21 _______ 40 41____________________________ 60 61 62 11 12 13 Title of Report; end with space-hyphen-hyphen-space. Follow with Index Terms, separated from each other with comma-space. Avoid other punctuation; do not abbreviate. .... ol oZ 21 22 23 24 Source (Journal, Vol., Number, Pages, Date ) 12 Li / ^ - .? 7 /' ??<) ^-- - 61 62 31 32 Brief Summary 12 10 SUMMARY: 61 62 61 62 63 64 The Value of Predictive Experiments Environmental Carcinogeneses 00020, An Example: Vinyl Chloride BY CESARE MALTONI 33 (/) o 00 CO o The vinyl chloride story demonstrates the need for experimental carcinogenicity testing of chemical compounds before they are released into the occupational and general environment. It is increasingly demonstrated and accepted that the high and rising incidence of tumors, especially in particular sites (lung, urinary tract, hemopoietic tissues), is due to the extensive and growing diffusion of oncogenic agents in the environment. Furthermore it is assumed that 80 to 90 percent of tumors depend on causes which are, or may be identified as being, part of the human environment. Recognition of such causes and protection from their effects could significantly reduce tumor morbidity and mortality. This increasing diffusion of environmental oncogenic agents is a phenomenon particularly correlated to the growth of industrialization, and especially to those industries producing and manufacturing new synthetic compounds. In modern times, from 100 000 to 200 000 new chemical compounds are produced annually, and we know very little about their effects on man. There is a strict correlation between occupational and general environmental carcinogeneses. Potential carcinogenic agents spread in fact throughout the general environment from the factories where they are produced, thus rapidly creating an ecological problem. Hence, results of studies in the field of occupational oncogenesis, directed towards identifying on cogenic industrial agents and assessing protective measures for workers, can be extrapolated easily to general environmental oncogenesis. Environmental and occupational carcinogeneses arc, there fore, socially important. As regards occupational carcinoge nesis, it is one of the most interesting, tragic and difficult fields in oncology: it is interesting from a scientific standpoint because it represents, dramatically, an experiment on human beings which has taught us much about the natural history of tumors; tragic because work, which is, per se, a natural necessity of life, should not cause cancer, and difficult because the care of workers' health often conflicts with the producti\e goals of industry and with major economic and political in terests. NEED FOR PREDICTIVE CARCINOGENICITY BIOASSAYS Most of the oncogenic occupational and environmental agents have been identified when the incidence of a particular type of tumor in an exposed population has been outstanding, or on the basis of retrospective epidemiological studies. Progress in these areas of oncology should facilitate system atic experimental carcinogenicity testing of agents which are. or will be, released in the general and occupational environ ment, These testing should be carried out before the exposure of humans to potentially oncogenic agents takes place (since the specific effects on tissues produced by carcinogens arc irreversible) and before economical, political and social in terests are well established (as then they can not easily be changed). Carcinogenicity experimental bioassays are surprisingly few as compared with the need. This is due to several factors scepticism concerning the validity of testing, the vast amount  ioassays in Occupational and --.-- . R&S 108971 of agents to be tested, complications in performing elaborate tests, lack of experimental units and conflict of responsibilities. Let us briefly and critically review these points: Scepticism. Too frequently in the past, environmental and occupational agents have been tested improperly so that the results could not be extrapolated to man. Consequently, experi mental testing has often been considered obsolete for predict ing carcinogenic risks. In our opinion, one should not be scep tical of the validity of carcinogenicity bioassays, but rather critically evaluate the methods of testing. Vast amount of agents. Since this is a reality, one must estab lish priorities for the products which are, or will be, most widely diffused. Complications in performing elaborate testings. The more experimental tests on animals reproduce the conditions of human exposure, the more relevant they are to man. Agents to be examined should follow a pattern of tests which progress in degree of preciseness and scrutiny, so as to filter out and expose the more dangerous compounds. Lack of experimental units and conflict of responsibilities. The number oF oncological units throughout the world performing carcinogenicity bioassays is indeed low (if one does not include those centers or agencies whose activity is devoted mainly to promoting public relations in this field) and are not sufficiently coordinated. Moreover it is often difficult to assess (because of the large number and lack of correlation between govern mental and intergovernmental agencies) who is responsible for promoting such studies, verifying the results and undertaking proper protective measures. A permanent intergovernmental commission, together with representatives from interested par ties, should: 1) plan the programs and priorities, 2) promote at an international level an adequate and integrative network of experimental units, and 3) critically evaluate the results anil decide on proper preventive programs. In sharp contrast to the insufficient attention given experi mental carcinogenicity bioassays for predicting potential risks, there arc numerous projects which study the carcinogenic effect on experimental animals and the metabolic patterns of agents which are already known to be carcinogenic for man. These studies, of course, may be of some interest for basic oncology, but they have little bearing on the prevention of occupational and environmental tumors. Furthermore, medical controls have been given great em phasis. In our opinion, the value of medical examinations is mainly to determine the risk; that is, they may provide epi demiological data. In fact, as collective information and our own experience have shown, the carcinogens exert their effects on a broad range of organs in exposed humans and affect widely the target organs, and the tumors which arise arc potentially multicentric. Consequently very little can be done after the tumors have arisen. The major value of experimental testing in the prevention of occupational and environmental oncogeneses is demonstrated clearly by the story of vinyl chloride carcinogenicity. VINYL CHLORIDE CARCINOGENESIS Vinyl Chloride (VC) has been produced in many countries for more than 30 years. It is the constituent of polyvinyl chloride (PVC) which today is the plastic industrial material most often used and diffused throughout the world. Moreover, it is used as a copolymer in Saran and other plastics, as a chemical inter mediate, as a solvent, and as a propellant. In the past, for only a short period, it was also used as an anaesthetic. VC at present is produced at a rate of almost 12 million tons per year. The following population groups may be exposed to VC: 1) workers engaged in the production of PVC and VC. and in the use of VC for other industrial purposes; 2) workers manu facturing PVC; 3) residents in areas neighboring factories pro ducing PVC and VC; and to a much lesser extent 4) people consuming 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 plastic made by VC. Valuable bioassays on the long term efFects of VC were not available until 1970. This situation reflects the scarce con sideration which has been given until now to experimental bioassays in predicting the oncogenic effects of environmental and occupational agents on man. At the end of 1970 we planned a project of correlated in vestigations to clarify the type and degree of carcinogenic risk from VC. 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, inges tion, peritoneal anil subcutaneous injection), at different con centrations (by inhalation: 30 000, 10 000, 6000, 2500, 500, 250, 200, 150, 100, 50, 25. 10. 5, 1 ppm), for varying periods of time (by inhalation: from 52 weeks to i week), by continuous or intermittent treatment, on animals of different species (rats, mice, hamsters), strains (Sprague-Dawley and Wistar rats), sex and age (adults, newborn, embryos). The planning of the program and the preparation of suitable experimental conditions, particularly the building of an appa ratus for inhalatory exposure, took until May 1971. In July 1971 we started experimenting. The exposure by inhalation was generally performed 4 hours daily, five days per week. The chambers of exposure, basically built of stainless steel and glass, have been designed to deliver concentrations of gaseous agents varying from 30 000 ppm to 1 ppm of VC, The. VC concentration in the chambers is controlled by gas chrom- t.^v/VvTv-' ^ - (-;''%? ^ *a . -4; 0 , ^....VV "V^V V *- -"A ,^ ^ ,~'V : * ' -o'. ` * *%..<"&..'.'* V \ -..~VU^JV* .-">''*- *-*. . y. . * %%'*y . : * -; ?* * \ ~* *1% V* <*A V* V V *Vj *t>`" -? *?} ,(% . * ^ f * * , ***, *> '-^4'- 5,-^.ft * *K * 'V .**, ~y'?r'?.i { >* t . lh ^ >* *' `v. * *, *p - *. -5?^< *'J ' feS-t.'s**' * : v-* '- -. ** 'Vvi V- '.= ^ / a *,. .-.' "' ,* . _ - ,,* "?*- ,, ' ei- . > *-> - -- "" , --S , t, . ^ ," ^ - v5;/V' V '* *v : . ; -- i*.>'--;'****..*W*/-' * *!*' f *t, , rU`^^ \; #.*.` 1 **' " -4* r ' .,,V .. *. -y-r- *. ':-#* v , ^ -u .t ** - C7 * ey * _ -'-:' -- ^ . ,. * ,"> v * ft 'k ^-v * j! w Figure 1. Liver angiosarcoma In a rat treated with VC. H.-E. X 125. atocraphy and now wc simultaneously may treat 2500 rodents. Fifteen experiments (BT1 --15) were started. Some of them were programmed at the beginning, and others were started after results were obtained from the initial experiments. All the animals arc kept tinder observation until spontaneous death. The animals arc controlled weekly and weighed every two weeks during the treatment period and monthly after treatment is completed. All detectable gross pathological changes arc recorded during the control. The animals when moribund are isolated in order to avoid cannibalism. A complete autopsy is made on each animal. Histological examinations are performed on Zymbal glands, intcrscapular 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 path ological lesions. The current results up to September 10 of several experi ments (BT I, 3. 7, 5, 4, 8) are shown in Tables 1--6. Among 60 Spraguc-Dawley rats exposed by inhalation to 30 000 ppm of VC for 52 weeks (BT6) in the same way as the animals of experiment BT1, within 61 weeks from the beginning of the experiment, Zymbal gland carcinomas have been found in 30 animals and liver angiosarcomas in 13 animals. For the latte experiments, data arc not yet available. Different types r tumors may be present in the same animal. Zymbal gland carcinomas (in rats) may be bilateral. Histole gically they frequently reproduce, to a certain extent, th, structure of the normal Zymbal gland, but often they prcxcr. squamous, glandular, solid, anaplastic and polymorphous pat terns. Nephroblastomas (in rats) are often bilateral. Their histolo gical picture reminds us of an embryonal kidney. Hspcrplast. of ncphroblastcma-like tissue is often observed in the kidnes c treated rats, with or without nephroblastoma. Angiosarcomas and angiomas (in rats, mice, hamsters) mr. be found at more than one site in the same animal. In the li\c they are often polyccntric. Hepatic (Figure 1) and extrahepat; angiosarcomas are more or less differentiated. Blood vessel ectasias, endothelial hyperplasia, associated c not associated with cellular atypias, are often observed in tf liver and in other organs and tissues in treated animals, withr without local or distant angiosarcomas or angiomas. Therefor, the effect of VC on blood vessels and endothelia should b considered systematic. Animals with lumor* Treatment () VC 13000 ppm VC 6020 ppm VC 2503 ppm VC 500 ppm VC 250 Ppm VC 50 ppm No treatment Total Animals Zymbal gland (Sprague-Dawley carcinomas (c) rats) Nephroblastomas (e) Angiosarcomas Sub cutane Sktn Liver (0 Other sites ous angio* mas carci nomas Hepa tomas Brain neuro blasto mas Other type and/or site (g) Tolal (h) Cor Average rected Total number No. /. latency (<i) time No. V. Cd> (H) (weeks) Average latency time (weeks) No. V* (d) Average latency time No. (weeks) No. No. No. No. No. gNo, 69 SI 16 26 50 53 59 9 15 64 3 (i) 4 72 60 7 12 62 47 65 13 22 70 3 (1) 3 74 59 23 33 6 10 74 13 22 78 3 (k) 3 67 59 A 79 47 S3 7 12 91 2 (U 1 67 59 ---- -- 6 10 80 47 79 2 fm) -- 61 59 -- -- 12 135 1 2 135 1 (n) 1 63 53 ---- -- ---- -- ---- -- -- 577 464 29 -- -- 25 -- -- 47 -- -- 14 12 31 11 12 13 * 1-- ---- 11 7 7 7 (O) 3 8 (P) 5 > (Q) -- 4 (r) -- 3 (3) -- 9 (t) -- '0 (u) 15 45 3^V 31 32 22 16 10 6 155 (a) The animals were treated by inhalation for 4 hours daily, 5 days weekly, for 52 weeks. (b) Animals alive after 25 weeks, when the first tumor (a Zymbal gland carcinoma) was observed. The percentages are referred to the corrected number, (c) Metastases to lung. (d) Percentage of corrected number. (e) Metastases to liver, lung, spleen and brain. (f) Metastases to lung. (g) Several cases of breast fibroadenomas, adrenal and pituitary tumors {generally adenomas) have not been considered, since their distribution in the different groups does not vary, (h) Several animals with 2 or more tumors. (i) 1 angiosarcoma of the lips: 1 angiosarcoma of the nose; 1 intra-abdo- mmai angiosarcoma (next to liver). (j) 1 angiosarcoma in subcutaneous fibrosing angioma; 1 ossifying parauri- cular angiosarcoma; 1 intra-abdominal angiosarcoma (next to liver). (k) 2 mtra-abdominal angiosarcomas (1 next to spleen and 1 next to ovary); t ossifying angiosarcoma of the neck. (l) 1 pulmonary angiosarcoma; 1 angiosarcoma of the uterus. (m) 1 intra-abdominal angiosarcoma (next to spleen}; 1 Intrathoracic ossify ing angiosarcoma. (n) t intra-abdominal diffused angiosarcoma. (o) 2 Zymbal gland adenomas: 3 mammary carcinomas; 1 neurilemmoma; 1 ovarian cystoadenocarcmoma, (p) 4 Zymbal gland adenomas; 1 salivary gland adenocarcinoma; 2 hepatic and 1 peritoneal angiomas. (q) 1 Zymbal gland adenoma; 1 mammary carcinoma; 2 ependymomas. (r) 1 mammary carcinoma; 2 lymphomas; 1 pulmonary fibrosarcoma. (s) 1 Zymbal gland adenoma; 1 mammary carcinoma; 1 lymphoma. (t) 3 Zymbal gland adenomas; 2 mammary carcinomas; 1 subcutaneous angiopercdoma; 3 uterine adenocarcinomas (1 with sarcomatous compo nent), (u) 1 Invasive acanthoma of Zymbal gland; 1 subcutaneous fibrosarcoma; 2 peritoneal hbroangiomas. 2 uterine adenocarcinomas (1 with sarcomatous component); 1 uterine leiomyosarcoma; 1 ovarian fibrosarcoma; 1 pul monary rhabdomyosarcoma; 1 lymphoma. Table 2. Experiment BT3: Results after 88 weeks Treatment (a) Number of animats (Sprague-Dawley rats) _Tot.a!. Syourrsvl- Zymbal gland carcinomas Nephrobla stomas VC 10000 pprn VC 6000 ppm VC 2500 ppm VC 500 ppm VC 250 ppm VC 50 ppm No treatment Total 60 60 60 60 f-0 CO 190 550 9 5 (16) - ( 5) 16 4 ( 7) - ( <) 33 1 ( 2) 2 ( 4) 37 - ( 3) - ( 2) 15 18 -- 1 ( *) -- 128 -- -- 256 11 (27) ___ (a) The animals were treated by inhalation 4 hours daily, 5 hours weekly, for 17 weeks. (b) Between brackets are recorded the tumors found in experiment BT1 after 96 weeks. (c) Several cases of breast fibroadenomas, adrenal and pituitary tumors (generally adenomas) have not been considered, since their distribution in the different groups does not vary. (d) Several animals with 2 or more tumors, (e) 1 subcutaneous angiosarcoma. Number of animals with tumors (b) Angiosarcomas Liver . Other sites Brain neuro blastomas Other type and/or site (c) Total (d) - ( 9) - (ID - ( 9) - { 3) - ( 2) -- -- - (31) 1 (e) ( 3) - ( 3) - ( 3) - ( 2) - (1) 1 (0 -- 2 (12) 6 ( 7) 2 ( 3) 2 ( 2) -- -- -- -- 10 (12) 3 (g) (is) 7 (h) ( 9) - ( 7) 2 (') ( 7) 2 (1) ( 5) - ( 3) 3 (k) ( 3) 17 (49) 15 ( 4Q) 10 ( 27) 5 ( 23) 2 ( 13) 3 ( 9) 1 ( 3) 2 ( 2) 38 (117) 1 orbital angiosarcoma 1 parauncular fibrosarcoma; 1 nasal papilloma; 1 renal adenoma. 1 Zymbal gland fibroangioma; 2 skin carcinomas; 1 subcutaneous an gioma; 1 mammary carcinoma; 1 forestomach papilloma; 1 cranial osteoma. 2 lymphomas. 1 Zymbal gland adenoma; 1 retrobulbar fibroma. 1 Zymbal gland adenoma; 2 lymphomas. R&S 108973 able 3. Experiment BT7: Results after 61 week3 Treatment (a) VC 10000 ppm VC 6030 ppm VC 2503 ppm VC $00 ppm VC 250 ppm VC 50 ppm No treatment Tolal Number of animals (Wlstar rats) Tolal 30 30 30 90 30 30 40 220 Survi vors a 13 s 16 16 22 34 117 Zymbal gland carcinomas - ( 7) - ( 1) - ( 1) - ( 1) _ _ - (10) Nephrobla stomas 1 (3) - (1) - (1) __ _ 1 (5) Number of animats with tumors (b) Angiosarcomas Liver Other sites lulu neuro blastomas 2 (3) - (2) - (1) _1 __ 3 (6) - (i) -<n - (2) ___ - (<) 1 (2) - (1) _ __ 1 (3) (a) The ammais were treated by inhalation for 4 hours daily, 5 days weekly, tor 52 weeks. (b) Between brackets are recorded the tumors found In male Sprague* Dawley rats of the experiment BT1, after 71 weeks. (c) 2 Zymbal gland adenomas. (d) 1 angioma of the caecum. Other type and/or site 2 W (7) - (D - (D 1 (d) _ 3 (9) Total 5 (18) - ( 6) - 5> 1 ( 1) 1 _ 7 (30) AMBIO, 1975 21 I - " ^ p* =............ ICJUIIJ UmCI ' Treatment (a) VC 10000 ppm VC 6000 ppm VC 10000 ppm VC 6000 ppm Total Breeders Breeders Offspring Offspring Number of animats (Sprague-Oawfey rats) Zymbal gland Nephro Total Survivors carcinomas blastomas 30 8 -- -- 30 2 -- -- 54 31 1-- 32 15 -- -- 146 56 1 -- Number of animals with tumors Angiosarcomas Liver Other sites ---- ---- -- i (b) -- 1 (c) --2 Other type and/or site -- -- -- -- (a) The breeders were treated by inhalation lor 4 hours daily, from the 12th (b) Subcutaneous angiosarcoma on a 24-weeks-old male, to the 18th day of pregnancy. (c) Subcutaneous angiosarcoma on a 22-weeks-old female. Total -- -- 2 t 3 | Table 5. Experiment BT4: Results after 61 weeks Animals (Swiss mice) Animals with tumors I Treatment (a) Total Corrected number (b) Survivors Pulmonary tumors (c) Mammary carcinomas (d) Liver Vascular tumors of Epithelial angio sarcomas other type and/or site tumors of the skin Other type Total and/or site (e) i Average Average d d d No. d9 9 d9 9 d9 9 */. latency time No, /. (weeks) latency time (weeks) No, ' ^ -No. No. No. No. _vc ioooo ppm 30 30 60 22 28 50 -- 35 70 36 13 47 31 8 9 (f) 3 CO 2 (0) 35 VC 6000 ppm 30 30 60 26 28 54 -- -- -- 38 70 33 8 28 33 5 9 (g) 6 (m) 4 (a) 33 VC 2500 ppm 30 30 60 23 30 63 -- -- -- 30 57 43 9 30 35 11 12 (h) 3 (n) 3 fr) 31 VC 500 ppm 30 30 60 29 29 58 -- 2 2 38 66 41 7 24 37 11 16 (1) 1 (0) 1 (S) 42 VC 250 ppm 30 30 60 29 29 58 3 1 4 31 53 42 11 32 39 11 U (l) -- 3 (t) 33 VC 50 ppm 30 30 60 27 30 57 1 9 10 1 2 56 10 33 37 1 11 (k) -- 1 (u) IS No treatment 80 70 150 74 67 1*11 24 31 53 4 3 53 ---- -- ---- -- 1 (V) 5 Total 260 250 510 230 241 471 28 46 74 177 -- -- 58 -- -- 47 71 13 14 207 (a) The animals were treated by inhalation for 4 hours daily, 5 days weekly, for 30 weeks. (b) Animals alive after 16 weeks, when the first tumorfa mammary carcinoma) was observed. The percentages are referred to the corrected number. (c) Adenomas, some of which undergoing malignant transformation. (d) In females. (e) Several cases with 2 or more tumors. (f) 4 liver fibroangiomas; 3 subcutaneous angiomas, 1 heart fibroangioma; 1 ossifying mterscapular angioma. (g) 4 liver angiomas; 2 liver fibroangiomas; 1 subcutaneous angiosarcoma; 1 renal fibroangioma, 1 thymic angioma. (h) 3 liver angiomas; 3 subcutaneous angiosarcomas; 1 subcutaneous an gioma; 2 intra-abdommal angiosarcomas; 2 renal angiosarcomas; 1 pul monary angioma. (i) 1 liver angioma, 3 liver fibroangiomas; 2 subcutaneous angiosarcomas; 1 subcutaneous angioma; 1 subcutaneous fibroangioma; 1 intra-abdo minal fibroangioma; 3 intra-abdominal angiosarcomas; 1 angioma of the caecum; 1 renal angiosarcoma; 1 pulmonary fibroangioma; 1 testicular fibroangioma. ()) 5 liver angiomas; 5 liver fibroangiomas: 2 intra-abdominal angiosar comas, 1 pulmonary angioma; 1 scrotal angioma. (k) 2 liver angiomas; 2 liver fibroangiomas, 1 subcutaneous angiosarcoma, 2 subcutaneous angiomas; 1 subcutaneous fibroangioma; 1 intra-abdo minal angioma: 1 intrathoracic fibroangioma, 1 angioma of the interscapular fat pad (l) 2 squamous carcinomas; 1 invasive acanthoma. (m) 5 squamous carcinomas; 1 acanthoma. (n) 1 squamous carcinoma; 2 acanthomas. (o) 1 acanthoma, (p) 1 Zymbal gland adenoma; 1 forestomach papilloma (q) 1 lymphoma; 1 subcutaneous leiomyosarcoma, 1 forestomach papilloma, 1 Harderian gland adenoma. (r) ` 1 forestomach papilloma; 1 parotid gland mixed tumor. (s) 1 Zymbal gland adenoma. (t) 1 Zymbal gland adenoma; 1 lymphoma: 1 Leydig cell tumor. (u) 1 parotid gland adenomcarcmoma. (v) 1 lymphoma. Table 6. Experiment BTB; Results after 48 weeks Treatment (a) VC 10000 ppm VC 6000 ppm VC 2500 ppm VC 500 ppm VC 250 ppm VC 50 ppm No treatment Total Number of animals (Golden bannsters) Total Survivors 35 9 32 8 33 11 33 13 32 6 33 11 70 35 268 95 Liver angio sarcomas -- -- -- 1 -- -- -- 1 Skin trichoepi theliomas (b) 3 2 3 2 13 Number of animals with tumors Melanomas Lymphomas Forestomach papillomas and acantho mas ----_ 3 ---- 4 --1 ---- -- ---- -- 24 8 (a) The animals were treated by Inhalation for 4 hours daily, 5 days weekly, for 30 weeks. (b) Several cases with acanthosis and some undergoing malignant trans formation. (c) Several animals with 2 or more tumors. (d) 1 hepatocarcmoma. (e) 1 subcutaneous angioma. Other type and/or site ___ i (d) -- i (e) -- -- -- 2 Total (c) 3 5 4 4 7 5 2 25 R&S 108974 Table 7. Tumors presently correlated to VC exposure (by Inhalation) on experimental rodents and man. Species Rat Mouse Hamster Man Angio sarcomas of liver 4- + 4- + Tumors of brain < -i Tumors of lung + (+i Lymphomas and leukemias + (+i Angiosarcomas and angiomas of other sites TUMORS Nephro blastomas + !+ Sebaceous carcinomas 4-1- Squamous tumors of epidermis 4. -h Mammary carcinomas 4- Hepq. tomas 4- Forestomach papillomas and acanthomas h a wom vr>r 4 mo t ii w i a L.t' li, tlnu aU5^-J4tvt...4J lit 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 an- ~ giomas, angiosarcomas. Fibro-angioblastic proliferation undergoing fibrosis is fre quently 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 to some extent the morphological characteristics. Hepatomas observed in treated rats are usually well dif ferentiated. Metastases have been observed in the lung. Brain neuroblastomas (in rats) are very similar to the human medulloblastomas. Lung adenomas (in mice) are usually multicentric: their number is higher in animals treated with heavier doses. Many of these tumors appear to undergo early malignant transforma tion. Mammary carcinomas (in mice) may be solitary or multiple. They are usually well differentiated adenocarcinomas, with monomorphous or polymorphous arrangement. The most dis tinct feature of these tumors is the frequency with which they present areas of squamous metaplasia. Sescral of the tumors produced by VC are quite rare or exceptional. To our knowledge liver angiosarcomas, nephro blastomas and neuroblastomas have never been described as spontaneously occurring in rats. Liver and extrahepatic angio sarcomas have been induced only in a few instances in experi mental rodents (rats, hamsters and mice) [for references see Maltoni and Lefemine (1)]. As far as we know, this is the first time in which nephroblastomas and neuroblastomas have been experimentally reproduced. tions wmt-n in uecemoer 1*0. tor me tirst time, luennneu a liver angiosarcoma--in a worker of a US factoiy producing VC-PVC--as occupational. Since then epidemiological investi gations have led to the discovery of nearly 30 liver angiosar comas (Figure 2) among workers of VC-PVC industries in the USA and several European countries. Most of these tumors arose before 1973 (the first known case dates from 1961), but in absence of experimental data, they were not linked to the occupational exposure, and as a matter of fact, they were ofte not properly diagnosed. VC has caused in one or more of the three animal species used in our experiments, all types of tumors, which at present, on the basis of available epidemiological evidence, are cor related to occupational exposure, ie liver angiosarcomas, brain and lung tumors, lymphomas and leukemias (Table 7). CONCLUSIONS It is our hope that the story of VC carcinogenicity may serve as a convincing example to urgently promote experimental bioassays for all new industrial compounds, and for those compounds which are already produced and widespread, but whose effect we still ignore. References and Notes: 1. C Maliom, G Lefemine, Environmental Research. 7, 387 (1974). R&S 108975 SUMMARY OF FINDINGS In conclusion we found that: 1. Under our experimental conditions, VC produced tumors in the three animals species studied: rats, mice and hamsters. 2. The range of induced tumors varies to some extent from species to species. When given by inhalation VC produced: in rats, Zymbal gland carcinomas, nephroblastomas, angiosar comas and angiomas of the liver and other sites, skin carcino mas, hepatomas and brain neuroblastomas: in mice, lung adenomas, mammary carcinomas of a peculiar type, angio sarcomas and angiomas of the liver and other sites, skin epi thelial tumors: in hamsters, liver angiosarcomas and, as early evidence seems to suggest, skin trichoepitheliomas, lymphomas and forestomach papillomas and acanthomas. Incidentally, liver angiosarcomas have been observed in all three animal species. 3. In the BT1 and BT4 experiments, VC shows a cancerogenic effect at 50 ppm. 4. From the BT1 experiment (the only one completed) a dose-response relationship clearly emerges, as far as angiosar comas and nephroblastomas are concerned, in the lower dose ranges: ie from 500 ppm to 50 ppm for angiosarcomas, and from 250 ppm to 50 ppm for nephroblastomas. 5. A comparison of the results available at the present moment in rats exposed for 52 weeks and 17 weeks (BT1 and RT3 experiments) shows that the neoplastic response, par ticularly as far as angiosarcomas and nephroblastomas arc concerned, is affected by the length of exposure to VC. 0. The comparison of the results obtained in rats of two different strains, ie Sprague-Dawlcy (BT1) and Wistar (BT7), at the present moment, seems to suggest that the strain factor considerably affects the neoplastic response, 7. Die onset of two subcutaneous angiosarcomas and of one Zymbal gland carcinoma in the offspring of breeders exposed during pregnancy for 7 days, appears to indicate a transpla cental ctfeet of VC. Our data have been periodically transmitted to the European companies which have supported our research, and are avail able to all interested parties. Before the end of 1972, a short time after it was known that VC was inducing in rats not only Zymbal gland tumors, but also nephroblastomas and liver angiosarcomas, these results were also made known to the US Manufacturing Chemists Associa tion (MCA), This information promoted the clinical observa Professor Doctor Cesare Maltonl, MD. Professor of Genera! Pathology and of Experimental Oncology, has been Director of the Bologna Center for Prevention and Detection of Tumors and Onconologicat Research since the Center's foundation. He has been Director of Istitulo dl Oncologia in Bologna since 1954. Ho is present President of the Malian Society for Prevention and Diagnosis of Tumors. Vice-President of the Italian Society for Therapy of Tumors, and member of the Executive Board of the International Study Group for Cancer Prevention and Detection (De P Ca), and is past-president of the European Coordinating Committee on Human Tumors Investigation (1971--1973). Among his many professional activities, he is Editor of a new series entitled Advances in Tumor Prevention, Detection and Charac terization published by Excerpta Medica, and is co-editor of Acta Oncologica (Malian journal of oncology). The results of his re search and scientific activities have been reported in 132 publica tions. His address: Istifuto dl Oncologia "Felice Addarii", Ospedalt di Bologna, Ente Ospedaliero Reglonale. Viaie Ereolanl 4/2, 401 38 Bologna, Maly.