Arsenic in
drinking water, a mixture of
arsenite and
arsenate, is associated with increased skin and other
cancers in Asia and Latin America, but not the United States.
Arsenite alone in
drinking water does not cause
skin cancers in experimental animals; therefore, it is not a complete
carcinogen in skin. We recently showed that low concentrations of
arsenite enhanced the tumorigenicity of solar UV irradiation in hairless mice, suggesting
arsenic cocarcinogenesis with sunlight in
skin cancer and perhaps with different carcinogenic partners for lung and
bladder tumors. Cocarcinogenic mechanisms could include blocking DNA repair, stimulating angiogenesis, altering DNA methylation patterns, dysregulating cell cycle control, induction of
aneuploidy and blocking apoptosis.
Arsenicals are documented
clastogens but not strong
mutagens, with weak mutagenic activity reported at highly toxic concentrations of inorganic
arsenic. Previously, we showed that
arsenite, but not
monomethylarsonous acid (
MMA[III]), induced delayed mutagenesis in HOS cells. Here, we report new data on the mutagenicity of the trivalent methylated
arsenic metabolites
MMA(III) and
dimethylarsinous acid [DMA(III)] at the gpt locus in Chinese hamster G12 cells. Both methylated
arsenicals seemed mutagenic with apparent sublinear dose responses. However, significant mutagenesis occurred only at highly toxic concentrations of
MMA(III). Most mutants induced by
MMA(III) and DMA(III) exhibited transgene deletions. Some non-deletion mutants exhibited altered DNA methylation. A critical discussion of cell survival leads us to conclude that clastogenesis occurs primarily at highly cytotoxic
arsenic concentrations, casting further doubt as to whether a genotoxic mode of action (MOA) for
arsenicals is supportable.