Recent advances in arsenic carcinogenesis: Modes of action, animal model systems, and methylated arsenic metabolites

Recent advances in our knowledge of arsenic carcinogenesis include the deve lopment of rat or mouse models for all human organs in which inorganic arse nic is known to cause cancer-skin, lung, urinary bladder, liver, and kidney . Tumors can be produced from either promotion of carcinogenesis protocols (mouse skin and lungs, rat bladder, kidney, liver, and thyroid) or from com plete carcinogenesis protocols (rat bladder and mouse lung). Experiments wi th p53(+/-) and K6/ODC transgenic mice administered dimethylarsinic acid or arsenite have shown some degree of carcinogenic, cocarcinogenic, or promot ional activity in skin or bladder. At present, with the possible exception of skin, the arsenic carcinogenesis models in wild-type animals are more hi ghly developed than in transgenic mice. Recent advances in arsenic metaboli sm have suggested that methylation of inorganic arsenic may be a toxificati on, rather than a detoxification, pathway and that trivalent methylated ars enic metabolites, particularly monomethylarsonous acid and dimethylarsinous acid, have a great deal of biological activity. Accumulating evidence indi cates that these trivalent, methylated, and relatively less ionizable arsen ic metabolites may be unusually capable of interacting with cellular target s such as proteins and even DNA. In risk assessment of environmental arseni c, it is important to know and to utilize both the mode of carcinogenic act ion and the shape of the dose-response curve at low environmental arsenic c oncentrations. Although much progress has been recently made in the area of arsenic's possible mode(s) of carcinogenic action, a scientific concensus has not yet been reached. In this review, nine different possible modes of action of arsenic carcinogenesis are presented and discussed-induced chromo somal abnormalities, oxidative stress, altered DNA repair, altered DNA meth ylation patterns, altered growth factors, enhanced cell proliferation, prom otion/progression, gene amplification, and suppression of p53.