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Marked Synergism of Dimethylnitrosamine Carcinogenesis in Rats Exposed to Cadmium¹

Department of Pathology, Boston University School of Medicine Boston, Massachusetts 02118

The combined carcinogenic effect of cadmium and dimethylnitrosamine (DMN) was examined in male Wistar rats, to test whether the previously observed synergism in mutagenicity between cadmium and 2 N-nitroso compounds would be paralleled by a synergism in carcinogenicity. In experiment 1, 50 five-month old rats received 18 mg DMN/kg i.p. followed by cadmium i.m. in two injections totaling either 1.5 or 3.0 mg Cd²⁺/kg. In experiment 2, 30 weanling rats received five i.m. doses totaling 6 mg Cd²⁺/kg followed by 18 mg DMN/kg. After 52 weeks, the incidence of renal tubular neoplasms was significantly increased above additivity in both experiments (P = 0.0005 to 0.017). Experiment 1 also showed a synergistic increase in the incidence of neoplastic (P = 0.024) and preneoplastic (P < 0.01) microscopic liver lesions, of tumors of organs other than liver and kidney (P < 0.01), of malignant versus benign tumors (P = 0.038), and of multiple versus single tumors (P = 0.0019). In experiment 2, the incidence of DMN-induced hepatocellular adenomas was significantly lower than additivity, suggesting an antagonistic, protective effect of cadmium pretreatment. The overall incidence of tumors of any type was 17.5 versus 67.7% in control (one agent or none) versus test animals. Malignant tumors included carcinomas, sarcomas, and lymphomas, involving nine different sites. Cadmium appears to enhance the initiation of carcinogenesis induced by DMN. Both cadmium and nitrosamines are known environmental contaminants present in air, food, water supplies, and tobacco smoke.

¹ Supported in part by American Cancer Society Institutional Grant IN97 to Boston University and by USPHS Grant CA 27324 awarded (to R. M.) by the National Cancer Institute.

² To whom requests for reprints should be addressed.

Received 4/10/87. Revised 7/ 9/87. Revised 9/18/87. Accepted 9/23/87.