Inorganic arsenic (arsenate and arsenite) is a known human carcinogen, inducing tumors of the skin, urinary bladder, and lung. Understanding the mechanism of inorganic arsenic carcinogenesis has been hampered by a lack of animal models. To define the urothelial effects of inorganic arsenic, we administered arsenate and arsenite in the diet or drinking water to rats and mice in several short-term experiments (2-10 weeks). Treatment with arsenate or arsenite in the drinking water or diet induced cytotoxicity and necrosis of the urothelial superficial layer and hyperplasia in rats and mice. Arsenate-induced changes occurred later in mice compared with arsenite-induced changes, but not in the rat. Hyperplasia in rats was evident by light microscopy at an earlier time point (2 weeks) than previously observed after treatment with dimethylarsinic acid (DMA(V)). The bromodeoxyuridine labeling index was increased in treated rats. We were unable to determine the bromodeoxyuridine labeling index in mice. The effects of inorganic arsenicals on the bladder were greater when administered in the drinking water than in the diet in rats and mice, but so was the overall toxicity to the animal. The female rat appeared more sensitive to the effects of inorganic arsenic than the male rat, but effects were similar in female and male mice. The mode of action of inorganic arsenic in rats and mice appears to involve urothelial cytotoxicity, increased cell proliferation and ultimately tumors. Cytotoxicity is likely due to the generation of reactive trivalent arsenicals excreted in the urine.