Metabolism and disposition of arsenic species from controlled oral dosing with sodium arsenite in adult female CD-1 mice. I. Pilot study to determine dosing, analytical measurements, and sampling strategies

Arsenic (As) is ubiquitous in the earth's crust, with typical dietary intake in developed countries <1 μg/kg bw/d, and atypical groundwater exposures in developing countries approaching 50 μg/kg bw/d. Arsenic exposures are linked with human diseases and doses of toxicological concern are similar to typical dietary intake estimates. The methylation of arsenite by arsenite-3-methyltransferase (As3MT) promotes the clearance of arsenic as pentavalent species, but also generates reactive trivalent intermediates. This study measured inorganic arsenic and its metabolites in pentavalent and trivalent states in blood, tissues, and excreta after oral administration of arsenite (50-200 μg/kg bw). While liver was a major site for clearance of arsenite and formation of methylated species, it also had extensive binding of trivalent intermediates; however, thiol exchange and oxidation reactions of trivalent arsenic were facile since dimethylarsinic acid (DMAV) was the predominant species in blood and urine. Consistent evidence was observed for a non-linear relationship between doses above 50 μg/kg bw and levels of bound trivalent As metabolites. The abundance of protein-bound trivalent arsenic within target tissues should correlate with disruption of critical cellular processes, which rely on defined interactions of thiol functional groups, and could provide dose-response relationships from animal models for human risk assessment.