Document 3Qgqz6zBqNqYL79jO87056Bd3

R&s 135334 HOSPITALS OF BOLOGNA Regional Hospital Institution k tin '(/ C--O THE ONCOGENIC EFFECTS OF VINYL CHLORIDE ADMINISTERED BY ORAL ROUTE IN THE RAT Cesare Maltoni, Adriano Ciliberti, Luciano Gianni, Pasquale Chieco Extract Iron the journal "C-li Ospedali della Vita" Volume 2, Number 6, July-Becember 1975 R&S 135335 IN THE FIELD OF RESEARCH December 1975 The Oncogenic Effects of Vinyl Chloride Administered by Oral Route in the Rat. Cesare Maltoni, Adriano Ciliberti, Luciano Gianni and Fasquale Chieco (Institute of Oncology and Tumor Center, Bologna) SECOND PRELIMINARY NOTE As has already been reported, a vast program of experimental re search was initiated at our institution to define the oncogenic activity of vinyl chloride (VC) administered by.different routes (inhalation, oral, subcutaneous, intraperitoneal) at different doses, to animals of Various species (rats, mice, hamsters) and different strains. From these experiments it has become apparent that vinyl chloride, when administered by inhalation, provokes various types of tumors in different animal species: in the rat, carcinomas of the Zymbal glands, nephroblastomas, angiosarcomas and angiomas of the liver and of other anatomical regions, cutaneous carcinomas, hepa tomas, neuroblastomas, mammary carcinomas and probably carcinomas of the salivary glands; in the mouse, pulmonary adenomas (frequently in the stage of malignant transformation), mammary carcinomas (often with acantotic components), angiosarcomas and angiomas of the liver and of other anatomical regions, cutaneous epithelial tumors; in the hamster, angiosarcomas and angiomas of the liver, R&S 135336 trichoepitheliomas and cutaneous basalomas, melanomas, papillomas and acanthomas of the fore-stomach, hepatomas and probably lymphomas (Maltoni, 1975; Maltoni and Lefemine, 1974 a, b: Maltoni and coll., 1974: Maltoni and Lefemine, 1975)* Recently we have observed a significant incidence of papillomas and acanthomas of the fore stomach in rats treated with vinyl chloride by inhalation at the rate of 50,000 ppm (unpublished data). It' was following the first announcement of our results that the clinical observations got underway and the epidemiological in vestigations that have led to the finding of occupational angio sarcomas in working populations exposed to the monomer and, in the same populations, a higher incidence of encephalic neoplasia, pulmonary carcinoma, lymphoma and leukemia. On February 22, 1-975, we made known the very first results of our experiment BT 11 on the oncogenic activity of vinyl chloride ad ministered by oral route: 50 weeks- after the beginning of the ex periment, an angiosarcoma of the thymus and a hepatic angio sarcoma were observed respectively in the two groups of rats treated with the highest doses---that is, 50 mg/kg of body weight and 16.65 mg/kg of body weight -- 4 to 5 times a week for 50 weeks (Maltoni and coll.,`1975) Since polyvinyl chloride and other plastics in which vinyl chloride is a constituent are used as containers for liquid and solid food materials, and since traces of the monomer may migrate from the plastic to drinks and foods, the possible carcinogenic effect of vinyl chloi-ide by oral route takes on obvious importance for public health. Since the studies on the oncogenic activity of vinyl chloride by oral route were first undertaken in our Institute and the only results on the subject are the very preliminary ones communicated by us this past February, vie receive requests for information periodically from investigators' who are responsible for the health of various countries, institutions and entities and who want to be brought up to date on the development of this experiment of ours. In consideration of this, with this second preliminary note we are making public the results after 85 v/eeks of experimenta- tion. In experiment 3T "11; on which we are-..-reporting again here, the VC was administered to Sprague-Dawley rats 15 v/eeks old, dis solved in olive oil, by means of a gastric tube, 4---5 times a v/eek for 52 v/eeks, I The experiment involved four groups of 80 animals each, treated with an equal volume of oil solution of vinyl chloride at vari ous concentrations (20/1000, 6/60/1000, and 1;32/1000 respective- 'f * * ly) so as to treat with 50 mg, 16.65 mg and 3*53 mg/kg of the animal^ body weight, and with olive oil alone. R&S 135337 To adjust the quantity of-vinyl chloride to the weight increase of -the animals, the volume of solution administered was in creased, varying from 0.42-rc to 1.12 cc.. R&S 135338 The plan of the experiments and the 85-week results are shown in Table 1; Prom the results given there it can be seen that vinyl chloride administered by oral route at 50 mg and at 16.65 mg/kg of body weight is carcinogenic and provokes a large part of the tumors observed in the same species and strain when the monomer is administered by inhalation, although they are predominantly hepatic angiosarcomas. None of these tumors have been observed to date in the animals treated with vinyl chloride at doses of 3*33mg/kg of body weight nor in the controls treated with olive oil alone. Since the doses used by us are very high in comparison with those that night migrate into foodstuffs from containers made of plastic materials based on vinyl chloride, we have undertaken another ex periment, BT 27, since first finding tumors in experiment BT 11, in order to test the monomer at lower doses. r experiments is reproduced in Table 2. The plan of these Table I Experiment BT 11: Treatment: administration by oral route (gastric catheter) of vinyl chloride in olive oil at doses of 50*00, 16.65, 3*33 mg/kg of body weight once a day for four to five days a week for 52 weeks. Results after 85 weeks. Groups and treatments Animals (Sprague- Dawley rats) Totals Survived Carcinomas of glands of Zymba'l N. Animals with tumors Nephro blas tomas Angios arcoma3 Liver Other Loca tions Other types and/or loca tions (b) N. N. 14. N. Total N. I VC 50.00rag/kg 80 II VC 16;65mg/kg 80 III VC 5* 33mg/kg 80 IV Olive 'oil (control) 80 Total 320 23 32 39 35 129 1 -- -- 1 --- -- 1 -- ------ 1 8 1 (a) i 3 (c) 5 ----- ---- -- - - ----- -- 13 1 ----3 11 (d) 7 -- ... , 18. a) 1 angiosarcoma of the thymus. b) Various cases of mammary, fibroadenoma and tumors (generally adenomas) of the adrenals and of the hypophysis were not taken into consideration because their distribution in the different groups did not vary. c) 1 mammary carcinoma; 2 papillomas of the pre-stomach. d) 1 animal with 2 tumors. R&S 735339 Table 2 R&S 135340 Experiment BT 27: Treatment: administration by oral route (gastric catheter) of vinyl chloride in olive oil at doses of 1, 0,5 and. 0,05 mg/lcg of body weight once a day for four to five days a week for 104 weeks. Results after 22 weeks. Groups and treatments Animals Animals with tumors (Sprague Carcinomas Nephro- Angiosarcomas Dawley of glands blas- Biver Other rats) of Zyrnbal . tomas Loca- Totals Survived , - tions .N. .N. T. T. Other types and/or loca tions N. Total N. I VC 1 mg/kg 158 II VC 0.5 mg/kg 159 III VC 0.05 mg/kg 165 IV Olive oil (control) 159 Total 659 147 145 147 148 585 -- -- _ --- -- -- ...... --- .__ ___ ----- - ----- r -- --... -- ...... . .- - -. . _ . . ._. ... ____ R&S 135341 Bibliography MALTON! C,: Oecuput tonal careinogenes Ii. II International Symposium. on Cancer Detection and Prevention. Bologna. 1975, in Advances in Tumour Prevention. Detection and Characterization. Excerpts Medico, vol. 2, a Cancer detection and prevention 19-25. 1974. MALTONJ C.. CfLIBERT! A.. `ClANVS L. e CHSECO ?.: Insorgenza di angioscrcomi in ratti, in seguito a somm.ir.istrazione per via orclc di cloruro di vinile. Cli Ospedali della Vita*. 11/1. 65-65. 1975: MALTONl C. e LEFEMINE G.i. Carcinogenicity bio-assays of vinyl chloride. 1. Research plan and early results. Environmental Res., 7: 5S7-405, 1974 a. MALTONi C. e LEFEMINE G.: Lc potenzialita dci saggi speruncalcli mils pred-zionc dci rischi oncogen: ambientali. Uit esempio: il cloruro di vinile. Accademir. Noziouute dei Li>:cei, Rendiconti delta Clusse di Science Fisiclte. Matetnatiche e Natural 1. Vol. LVl. Serie VIU. Ease. 5. marzo 1974 b. MALTONI C. e LEFEMINE C.: Carcinogenicity bio-assays of vinyl chloride: current results. Annals of the New York Academy of Sciences, 246, 195-218. 1975. MALTONt C..' LEFEMINE G.. C.HIECO P. e CARRETTl D.: La canccrogenesi ambientalc e professioncle: mtove prospettive alia luce della canccrogenesi da cloruro di vinile. Cli Ospedali della Vita . 1/5-6. 4-66, 197-t. VIOLA P. L.: '' CuncerOgenic effect of vinyl chloride. X International Cancer Congress. Houston. Abstr. Vol. 29. 1970. viola p. l.. Btcorrt ,1. e CA PC TO A.r . Oncogenic response of rut skin, lungs and bones to vinyl chloride. Cancer Res., 5J: 516-519, 1971.