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Tissue, Dosimetry, Metabolism and Excretion of Pentavalent and Trivalent Dimethylated Arsenic in Mice after Oral Administration
HUGHES, M. F., D. Vicenta, B. ADAIR, S. CONKLIN, J. T. CREED, S. Rybb, E. M. KENYON, AND D. J. THOMAS. Tissue, Dosimetry, Metabolism and Excretion of Pentavalent and Trivalent Dimethylated Arsenic in Mice after Oral Administration. TOXICOLOGY AND APPLIED PHARMACOLOGY. Academic Press Incorporated, Orlando, FL, 227(1):26-35, (2008).
Dimethylarsinic acid (DMA(V)) is a rat bladder carcinogen and the major urinary metabolite of administered inorganic arsenic in most mammals. This study examined the disposition of pentavalent and trivalent dimethylated arsenic inmice after acute oral administration. Adult female mice were administered -DMA(V)(0.6 or 60 mg As/kg) and sacrificed serially over 24 h. Tissues and excreta were collected for analysis of radioactivity. Other mice wer administered unlabeled DMA(V)(0.6 or 60mg As/kg) or dimethylarsinous acid (DMA(III))(0.6 mg As/kg) and sacrified at 2 or 24 h. Tissues (2-h) and urine (24-h) were collected and analyzed for arsenicals. Absorption, distribution and excretion of [14C]-DMA(V) was rapid, as radioactivity was detected in tissues and urine at 0.25 h. For low dose DMA(V) mice, there was a greater fractional absorption of DMA(V) and significantly greater tissue concentrations of radioactivity at several time points. Radioactivity distributed greatest to the liver (1-2% of dose) and declined to less than 0.05% in all tissues examined after 24 h. Urinary excretion of radioactivity was significantly greater in the 0.6 mg As/kg DMA(V) group. Conversely, fecal excretion of radioactivity was significantly greater in the high dose group. Urinary metabolites of DMA(V) included DMA(III), mtrimethylarsine oxide (TMAO), dimethylthioarsinic acid and trimethylarsine sulfide. Urinary metabolites of DMA(III) included TMAO, dimethylthioarsinic acid and trimethylarsine sulfide. DMA(V) was also excreted by DMA(III)-treated mice, showing it sensitivity to oxidation. TMAO was detected in tissues of the high dose DMA(V) group. The low acute toxicity of DMA(V) in the mouse appears to be due in part to its minimal retention and rapid elimination.
Purpose: Knowledge of the metabolic fate of arsenic derived from orally administered DMA(V) will facilitate evaluation of the role of DMA(V) and its metabolites in arsenic-induced toxicity. Objective: The objective of the present study was to examine the dosage dependency on the tissue dosimetry, metabolism and excretion of arsenicals following the oral administrtion of DMA(V) or DMA(III) in the mouse.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL EXPOSURE RESEARCH LAB
MICROBIOLOGICAL AND CHEMICAL EXPOSURE ASSESSMENT DIVISION
CHEMICAL EXPOSURE RESEARCH BRANCH