Dose-dependent disposition of sodium arsenate in mice following acute oral exposure.

The effect of dose on arsenate disposition was studied in adult female B6C3F1 mice, dosed po with 0.5 to 5000 micrograms/kg [73As]-arsenate in water. Urine was collected at 1, 2, 4, 8, 12, 24, and 48 hr and feces at 24 and 48 hr postexposure. The mice were euthanized at 48 hr and tissues were removed. Recovery of arsenate-derived radioactivity ranged from 83 to 89%; 66-79% of the dose was excreted in urine, 10-18% in feces, and < 1% remained in the tissues. Although dose had no effect on the 48-hr excretion of radioactivity, the level of radioactivity in several tissues increased significantly with dose. The urine was analyzed for arsenic metabolites by using ion chromatography to analyze for arsenate, methylarsonic acid (MMA), and dimethylarsinic acid (DMA); ion-pairing high-performance liquid chromatography was used for arsenite analysis. Arsenate elimination ranged from 3 to 15%. DMA was the predominant metabolite excreted (51-64% of dose), but no effect of dose on its elimination was detected. As the dose of arsenate increased, the amount of MMA excreted (0.1-1.0% of dose) significantly increased. At 5000 micrograms/kg arsenate, a significant increase in arsenite excretion was observed. At doses of arsenate < or = 500 micrograms/kg, peak elimination of DMA occurred within 4 hr postexposure. At the 5000 micrograms/kg dose, DMA peak elimination shifted to 8 hr and a lower amount was excreted. In addition, at the 5000 micrograms/kg dose, there was an increase of arsenate and arsenite in the 1- and 2-hr urines. These results suggest that an acute dose of arsenate can affect the metabolism of arsenicals. High doses lead to the accumulation of intermediates that are more reactive than DMA, and this response may lead to increased toxicity.