Methylated arsenicals: the implications of metabolism and carcinogenicity studies

Monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) are active ingredients in pesticidal products used mainly for weed control. MMAV and DMAV are also metabolites of inorganic arsenic, formed intracellularly, primarily in liver cells in a metabolic process of re-peated reductions and oxidative methylations. Inorganic arsenic is a known human carcinogen, inducing tumors of the skin, urinary bladder, and lung. However, a good animal model has not yet been found. Although the metabolic process of inorganic arsenic appears to enhance the excretion of arsenic from the body, it also involves formation of methylated compounds of trivalent arsenic as intermediates. Trivalent arsenicals (whether inorganic or organic) are highly reactive compounds that can cause cytotoxicity and indirect genotoxicity in vitro. DMAV was found to be a bladder carcinogen only in rats and only when administered in the diet or drinking water at high doses. It was negative in a two-year bioassay in mice. MMAV was nega-tive in 2-year bioassays in rats and mice. The mode of action for DMAV-induced bladder cancer in rats appears to not involve DNA reactivity, but rather involves cytotoxicity with consequent regenerative proliferation, ultimately leading to the formation of carcinoma. This critical review responds to the question of whether DMAV-induced bladder cancer in rats can be extrapolate