Although epidemiologic evidence shows an association between inorganic
arsenic in
drinking water and increased risk of skin, lung, and
bladder cancers, no animal model for
arsenic carcinogenesis has been successful. This lack has hindered mechanistic studies of
arsenic carcinogenesis. Previously, we and others found that low concentrations (< or =5 microm) of
arsenite (the likely environmental
carcinogen), which are not mutagenic, can enhance the mutagenicity of other agents, including ultraviolet radiation (UVR) and
alkylating agents. This enhancing effect appears to result from inhibition of DNA repair by
arsenite, but not via inhibition of
DNA repair enzymes. Rather, low concentrations of
arsenite disrupt p53 function and upregulate
cyclin D1. Failure to find an animal model for
arsenic carcinogenesis might be because
arsenite is not a
carcinogen per se but acts as an enhancing agent (cocarcinogen) with a genotoxic partner. We tested this hypothesis with solar UVR in hairless but immunocompetent Skh1 mice. Mice were given 10 mg/L
sodium arsenite in
drinking water (or not) and irradiated with 1.7 KJ/m(2) solar UVR 3 times weekly. As expected, no
tumors appeared in any organs in control mice or in mice given
arsenite alone. After 26 weeks irradiated mice given
arsenite had a 2.4-fold increase in skin
tumor yield compared with mice given UVR alone. The
tumors were mostly
squamous cell carcinomas, and those occurring in mice given UVR plus
arsenite were much larger and more invasive. These results are consistent with the hypothesis that
arsenic acts as a cocarcinogen with a second (genotoxic) agent by inhibiting DNA repair and/or enhancing positive growth signaling.
Skin cancers in populations
drinking water containing
arsenic may be caused by the enhancement by
arsenic compounds of
carcinogenesis induced by UVR (or other environmental agents). It is possible that lung and
bladder cancers associated with
arsenic in
drinking water may also require a carcinogenic partner.