Dose-dependent effects on the disposition of monomethylarsonic acid and dimethylarsinic acid in the mouse after intravenous administration.
The organic arsenicals monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) are the primary metabolites of inorganic arsenic, a known human carcinogen. The objective of this study was to examine if dose would affect the excretion and terminal tissue disposition of MMA and DMA in the mouse. 14C-MMA (4.84 and 484 mumol/kg) and -DMA (8.04 and 804 mumol/kg) were administered to female mice via the tail vein. The mice were placed in metabolism cages for collection of urine (1, 2, 4, 8, 12, and 24 h) and feces (24 h). The animals were then sacrificed at 24 h and tissues were removed and analyzed for radioactivity. The urine was also analyzed for parent compound and metabolites. Urinary excretion of MMA- and DMA-derived radioactivity predominated over fecal excretion. Dose did not affect the overall urinary excretion of both compounds. However, fecal excretion was significantly lower in the low-dose MMA-treated animals as opposed to in the high-dose group, whereas in the high-dose DMA-treated group excretion was lower than in the low-dose DMA group. The retention of radioactivity was low (< 2% of dose) and the distribution pattern similar for both compounds, with carcass > liver > kidney > lung. The concentration of radioactivity (% dose/g tissue) was greater in kidney than in liver, lung, and blood for both compounds. The distribution and concentration of MMA-derived radioactivity was significantly greater in the liver and lung of the high-dose group. The MMA-treated animals excreted predominantly MMA in urine and lower amounts of DMA (< 10% of the dose). The percentage excreted as DMA was significantly higher in the low-dose MMA group. In the urine of DMA-treated animals, an unstable metabolite and the parent compound were detected. Overall, it appears the dose of organic arsenical administered has a minimal effect on its excretion and terminal tissue disposition in the mouse. The rapid elimination and low retention of MMA and DMA explain in part their low acute toxicity.
Hughes
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MF
National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. hughes.michaelf@epamail.epa.gov
Kenyon
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EM
D000818:Animals; D001152:Arsenicals / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002101:Cacodylic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D002852:Chromatography, Ion Exchange; D004305:Dose-Response Relationship, Drug; D005260:Female; D006540:Herbicides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D051379:Mice; D014018:Tissue Distribution
D001152:Arsenicals; D002250:Carbon Radioisotopes; D006540:Herbicides; D002101:Cacodylic Acid; C020300:monomethylarsonic acid