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Cancer Induction by an Organic Arsenic Compound, Dimethylarsinic Acid (Cacodylic Acid), in F344/DuCrj Rats after Pretreatment with Five Carcinogens¹

First Department of Pathology [S. Y., Ts. M., Ta. M., M-A. S., S. F.], Second Department of Biochemistry [I. M-Y., S. O.], and Department of Preventive Medicine and Environmental Health [Y. K., G. E.], Osaka City University Medical School, 1-4-54 Asahi-machi, Abeno-ku, Osaka 545, and Osaka City Institute of Public Health and Environmental Sciences, Osaka 543 [K. K.], Japan

Arsenic (As) is environmentally ubiquitous and an epidemiologically significant chemical related to certain human cancers. Dimethylarsinic acid (cacodylic acid; DMA) is one of the major methylated metabolites of ingested arsenicals in most mammals. To evaluate the effects of DMA on chemical carcinogenesis, we conducted a multiorgan bioassay in rats given various doses of DMA. One-hundred twenty-four male F344/DuCrj rats were divided randomly into 7 groups (20 rats each for groups 1–5; 12 rats each for groups 6 and 7). To initiate multiple organs and tissues, animals in groups 1–5 were treated sequentially with diethylnitrosamine (100 mg/kg body weight, i.p., single dose at the commencement) and N-methyl-N-nitrosourea (20 mg/kg body weight, i.p., 4 times, on days 5, 8, 11, and 14). Thereafter, rats received 1,2-dimethylhydrazine (40 mg/kg body weight, s.c., 4 times, on days 18, 22, 26, and 30). During the same period, the animals were sequentially administered N-butyl-N-(4-hydroxybutyl)nitrosamine (0.05% in the drinking water, during weeks 1 and 2) and N-bis(2-hydroxypropyl)nitrosamine (0.1% in the drinking water, during weeks 3 and 4; DMBDD treatment). After a 2-week interval, groups 2–5 were given 50, 100, 200, or 400 ppm DMA, respectively, in the drinking water. Groups 6 and 7, which were not given DMBDD treatment, received 100 and 400 ppm DMA during weeks 6–30. All rats were killed at the end of week 30. In the initiated groups (groups 1–5), DMA significantly enhanced the tumor induction in the urinary bladder, kidney, liver, and thyroid gland, with respective incidences in group 5 (400 ppm DMA) being 80, 65, 65, and 45%. Induction of preneoplastic lesions (glutathione S-transferase placental form-positive foci in the liver and atypical tubules in the kidney) was also significantly increased in DMA-treated groups. Ornithine decarboxylase activity in the kidneys of rats treated with 100 ppm DMA was significantly increased compared with control values (P < 0.001). In conclusion, DMA is acting as a promoter of urinary bladder, kidney, liver, and thyroid gland carcinogenesis in rats, and we speculate that this may be related to cancer induction by As in humans.

¹ This work was supported by a Grant-in-Aid for Cancer Research from the Ministry of Education, Science and Culture of Japan.

² To whom requests for reprints should be addressed.

³ Present address: Department of Food and Nutrition, Faculty of Human Life Science, Osaka City University, Osaka 558, Japan.

Received 10/ 6/94. Accepted 1/18/95.

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