Document qdD04v81rdGvQvZegnenNb7Dn

Rev -~'T Likjuy NOTICE This material is protected by the U. S. Code 17 copyright law. - Suitable Models for Long-Term Bioassays of Therapeutic and Toxic Effects of Antiblastic Drugs: Brain Tumours of Neuronal Cells and Primitive Bipotential Precursors Produced in Sprague-Dawley Rats by Vinyl Chloride C;I CoTTl) L. (vALUI.MIGLi) A.^AXDRIOlAtHd C.iOIaltoni) At present, very little is known about the chemotherapy of brain tumours of neuronal cells and of their primitive bipotential precursors, i. e., of medulloepitheliomas, medulloblastomas and neuroblastomas. A suitable experimental model, providing an animal equivalent to the human situation, would be a useful tool to improve our knowledge in this field. It has been shown in our Institute that exposure by inhalation to vin3'l chloride, at doses varying from 2,500 to 10,000 ppm, can induce tumours of neuronal cells and of their precursors in Sprague-Dawley and Wistar rats (Maltoni and Lefejiine. 1975: Maltoni, 1977; Maltoni et al, 1980). In this report we describe experimental means of inducing a high incidence of these tumours over a relatively short period, and therefore of making available a sufficient number of these tumours for testing antiblastic drugs. Sprague-Dawley rats were exposed by inhalation to 2,500 ppm of the monomer from the 12th day of embryonal development to one year of age: Breeders were exposed 4 hours daily, from the 1 .`ith day of pregnancy to delivery; offspring were exposed 4 hours daily, 5 days weekly, for 5 weeks, and then 7 hours daily, 5 days weekly, for 50 weeks. The incidence and the latency of the tumours obtained are shown in Table 1. Micros copically, the tumours displayed different potentialities, which varied from tumour to tumour and in different areas of the same tumour, and which represent the equi- Table 1. Incidence of brain tumours of neuronal cells and primitive bipotential precursors in SpragueDawley rats exposed from 12-day embryonal life for 57 weeks to vinyl chloride in air at 2,500 ppm, 4 -- 7 hours daily. 5 days weekly Animals used Sex m F M and F Mo. at start 03 G5 128 Corrected no." 57 57 114 Animals with brain tumours No. o/ A) 27 47.4 28 49.1 55 48.2 Average latency (weeks)'7 45.5 48.4 47.0 " Animals alive at 35 weeks, when the first tumour was observed b with respect to the corrected number c From start of treatment 376 R&S 005847 Fig. 1. Medulloepithelioma in Spraguc-Dawley rat, following exposure to vinyl ehloride by in halation. H.-E. X 80. Fig. 2. A detail of Figure 1. X 130. Fig. 3 Fig. 3. A detail of Figures 1 and 2. X 200. Fig. 4. A detail of Figure 1. X 200. Fig. u. Medulloepithelioina in Sprague-Dawley rat, following exposure to vinyl ehloride by inha lation. H.-E. X 200. Fig. G. Medulloblastoma in Sprague-Dawley rat, following exposure to vinyl chloride by inhala tion. H.-E. X 200. r Fig. 7 ' t.*' Fig. 8 Fig. 7. Medulloblastoma in Sprague-Dawlev rat, following exposure to vinyl chloride by inhala tion. H.-E. x 200. Fig. 8. Medulloblastoma in Sprague-Dawlev rat, following exposure to vinyl chloride by inhala tion. H.-E. X 320. valent of the human medulloepithelioma, medulloblastoma and neuroblastoma. Typical pictures are shown in Figures 1--8. It is of particular interest for the testing of drugs that these tumours manifest themselves with characteristic symptoms several days before the death of the animal. The major symptoms are a reduction in muscle tone, hypomotility, ruffling of hair, re duction in food intake, loss of body weight and exophthalmia. References 1. Maltoni, C. (1977): Vinyl chloride carcinogenicity: an experimental model for carcinogenesis studies. In: Hiatt, H. H., Watson, I. D. & Wilson, J. C., eds.. Origins of Human Cancer, Cold Spring Harbor, NY, Cold Spring Harbor Laboratory, pp, 119 -- 140 2. Maltoni) C. and Lefemine, G. (1975): Carcinogenicity bioassays of vinyl chloride: current results. In: Selikoff, I. J. & Hammond, E. C., eds.. Toxicity of Vinyl Chloride - Polyvinyl Chloride, New York, New York Academy of Sciences, pp. 195 -- 218 3. Maltoni, C., Lefemine, G., Ciliberti, A., Com, G. and Carketti, D. (19S0): Vinyl chloride carcinogenesis bioassays (BT project) as an experimental model for risk identification and assessment in environmental and occupational carcinogenesis. In: Epidemiologie animate et epidemiologic humaine: Ie Cas du Chlorurc de Vinyle monomcre, Paris, Publications Essentielles, pp 15 -- 112 378