Carcinogenicity of dimethylarsinic acid (DMA^V)

Dimethylarsinic acid (DMA^V) administered at high doses in the diet or drinking water produces bladder tumors in rats, with females being more susceptible than males. In contrast, tumors are not produced when even higher doses are administered to mice, and in short-term studies (10 weeks) there are no toxic or preneoplastic changes in the urinary tract of hamsters. Cytotoxicity of the urothelium is induced within 6 h of administration, with consequent regenerative hyperplasia beginning after 3 days of administration. The toxicity and regeneration follows a dose response similar to the carcinogenic effects seen in a 2-year bioassay, and the hyperplasia is reversible after 10 weeks of administration. The two major urinary products of rats treated with DMA^V are DMA^V itself and trimethylarsine oxide (TMAO). However, micromolar concentrations of dimethylarsinous acid (DMA^III) are also produced. DMA^III is a highly cytotoxic organic trivalent metabolite of DMA^V and other arsenicals, and is a possible proximate form of DMAV that produces the cytotoxicity of the urothelium. In vitro studies show comparable cytotoxicity of rat and human urothelial cell lines at micromolar concentrations for the trivalent arsenicals, but require millimolar concentrations of organic pentavalent arsenicals, such as DMA^V and TMAO. Extrapolation of these findings in rodents to human risk must be made cautiously, because the doses used in these studies are several orders of magnitude greater than potential human exposures, and the metabolism of DMA^V appears to differ significantly among species, especially in the rat.