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MODES OF ACTION FOR THE CARCINOGENICITY AND TOXICITY OF ARSENIC - MOVING TOWARDS A MORE QUANTITATIVE RISK ASSESSMENT
Citation:
KITCHIN, K. T. AND K. WALLACE. MODES OF ACTION FOR THE CARCINOGENICITY AND TOXICITY OF ARSENIC - MOVING TOWARDS A MORE QUANTITATIVE RISK ASSESSMENT. Presented at International Congress of Toxicology, Montrreal, QC, CANADA, July 15 - 19, 2007.
Description:
Arsenic exposures can lead to human tumors in skin, lung, urinary bladder, kidney and liver. Three likely initial stages of arsenical¬macromolecular interaction are (1) binding of trivalent arsenicals to sulfhydryl groups of peptides and proteins, (2) arsenical-induced generation of free radicals and (3) altered DNA methylation status. At present, oxidative stress, chromosomal abnormalities, enhanced cell proliferation-dependent pathways (from both stimulation and necrosis) and DNA methylation changes are the modes of action (MOA) with the most positive evidence. Additional possible carcinogenic MOA for arsenic are altered DNA repair, promotion/progression, gene amplification and suppression of p53. Recent binding studies have shown arsenite binds to the zinc finger region of the human estrogen receptor. Arsenite forms complexes with peptides (either inter- or intra- molecularly) in a mono-, bi-, or tri¬dentate fashion. The half lives of these arsenite-peptide complexes are less than 1 second, 1 minute and 2 hours, respectively). Oxidative stress studies of 11 arsenicals with pBR322 DNA have shown that the most active genotoxic forms of arsenic were trimethylarsine, dimethylarsine, dimethylarsinous acid and monomethylarsonous acid. Drinking water exposures to arsenite, monomethylarsonous acid and dimethylarsinic acid induced skin papillomas in K6/ODC transgenic mouse skin. More data establishing the causal carcinogenic species of arsenic and more agreement on the MOA of arsenic will reduce the uncertainty of future quantitative risk assessments of arsenic.