Tissue dosimetry, metabolism and excretion of pentavalent and trivalent dimethylated arsenic in mice after oral administration.
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 in mice after acute oral administration. Adult female mice were administered [(14)C]-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 were administered unlabeled DMA(V) (0.6 or 60 mg As/kg) or dimethylarsinous acid (DMA(III)) (0.6 mg As/kg) and sacrificed at 2 or 24 h. Tissues (2 h) and urine (24 h) were collected and analyzed for arsenicals. Absorption, distribution and excretion of [(14)C]-DMA(V) were 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 at 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), trimethylarsine 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 its 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.
US Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC 27711, USA. hughes.michaelf@epa.gov
Michael F
MF
Hughes
Vicenta
V
Devesa
Blakely M
BM
Adair
Sean D
SD
Conklin
John T
JT
Creed
Miroslav
M
Styblo
Elaina M
EM
Kenyon
David J
DJ
Thomas
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001152:Arsenicals / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008745:Methylation; D051379:Mice; D013054:Spectrophotometry, Atomic
D001152:Arsenicals