RELATIVE GENOTOXIC POTENCY OF ARSENIC AND ITS METHYLATED METABOLITES

Arsenic is one of the few identified human carcinogens that has yet to be shown to cause cancer in rodents when the standard bioassay protoc ols are used. The reasons for this apparent interspecies difference ar e unclear but may be related to differences between humans and rodents in their detoxification capabilities. Detoxification of arsenic may o ccur through a methylation pathway. If, in fact, methylation does deto xify arsenic, one would predict that the methylated arsenicals might b e less genotoxic than the inorganic arsenicals. To evaluate the hypoth esis that the inorganic arsenicals are more mutagenic than the organic arsenicals, we tested sodium arsenite, sodium arsenate, monomethylars onic acid (MMA) and dimethylarsinic acid (DMA) for their relative muta genic and clastogenic potentials. We used the L5178Y/TK+/- mouse lymph oma assay which allows the detection of chemicals inducing a broad spe ctrum of different types of genetic damage. Sodium arsenite and sodium arsenate were active at concentrations of 1-2 mu g/ml and 10-14 mu g/ ml, respectively. MMA was active between 2500-5000 mu g/ml; while DMA required almost 10 000 mu g/ml to induce a genotoxic response. The org anic arsenicals are thus much less potent as mutagenic agents than the inorganic arsenicals. All four of these arsenicals appear to act by m echanisms that cause chromosomal mutations.