Metabolism and disposition of arsenic species from controlled dosing with dimethylarsinic acid (DMA) in adult female CD-1 mice. V. Toxicokinetic studies following oral and intravenous administration.

Arsenic species contaminate food and water, with typical dietary intake below 1 μg/kg bw/d. Exposure to arsenic in heavily contaminated drinking water is associated with human diseases, including cardiovascular and respiratory disorders, diabetes, and cancer. Dietary intake assessments show that rice and seafood are the primary contributors to intake of both inorganic arsenic and dimethylarsinic acid (DMA) and at similar magnitudes. DMA plays a central role in the toxicology of arsenic because enzymatic methylation of arsenite produces DMA as the predominant metabolite, which may promote urinary clearance but also generates reactive intermediates, predominantly DMA, that bind extensively to cellular thiols. Both inorganic arsenic and DMA are carcinogenic in chronically exposed rodents. This study measured pentavalent and trivalent arsenic species in blood and tissues after oral and intravenous administration of DMA (50 μg As/kg bw). DMA underwent extensive first-pass metabolism in the intestine and liver, exclusively by reduction to DMA, which bound extensively to blood and tissues. The results confirm a role for methylation-independent reductive metabolism in producing fluxes of DMA that presumably underlie arsenic toxicity and indicate the need to include all dietary intake of inorganic arsenic and DMA in risk assessments.