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TISSUE DISTRIBUTION OF INORGANIC ARSENIC (AS) AND ITS METHYLATED METABOLITES IN MICE FOLLOWING ORAL ADMINISTRATION OF ARSENATE (ASV)
Kenyon, E M., L. M. Del Razo, AND M F. Hughes. TISSUE DISTRIBUTION OF INORGANIC ARSENIC (AS) AND ITS METHYLATED METABOLITES IN MICE FOLLOWING ORAL ADMINISTRATION OF ARSENATE (ASV). Presented at SOT, San Francisco, CA, March 25 - 29, 2001.
TISSUE DISTRIBUTION OF INORGANIC ARSENIC (iAs) AND ITS METHYLATED METABOLITES IN MICE FOLLOWING ORAL ADMINISTRATION OF ARSENATE (AsV). E M Kenyon1, L M Del Razo2, and M F Hughes1. 1NHEERL, ORD, US EPA, RTP, NC, USA; 2CINVESTAV-IPN, Mexico City, Mexico.
The relationship of exposure dose and tissue concentration of parent chemical and metabolites is a critical issue in cases where toxicity may be mediated by a metabolite or parent chemical and metabolite acting together. This has emerged as an issue for arsenic (As) because its principle methylated metabolite, dimethylarsinic acid (DMA), induces lung-specific DNA damage in multiple species, is a multiorgan tumor promotor in rats and mice, and a complete bladder carcinogen in rats. In this study, the time-course tissue distribution of iAs and its methylated metabolites was determined in blood, liver, lung and kidney of female B6C3F1 mice given a single oral dose of 0, 10, or 100 mol/kg sodium AsV. Blood concentrations of iAs, MMA and DMA were uniformly lower across both dose levels and time points compared to other organs. Liver and kidney concentrations of iAs were very similar for both dose levels and peaked at one hour post dosing. Inorganic As was the predominant form of As in both liver and kidney up to one and two hours post dosing with 10 and 100 mol/kg, respectively. After those times, DMA was the predominant metabolite in liver and kidney. Three to 4-fold higher concentrations of MMA were achieved in kidney compared to other tissues by one hour post dosing. Peak concentrations of DMA in kidney were achieved at two hours post dosing for both dose levels. Notably, DMA was the predominant metabolite in lung at all time points following dosing with 10 mol/kg. DMA concentration in lung equaled or exceeded that of other tissues from 4 hours post dosing onward for both dose levels. These data demonstrate distinct organ-specific differences in the distribution and methylation of IAs and its metabolites that will be important to consider when investigating mechanisms of arsenic-induced toxicity. (This abstract does not necessarily reflect EPA policy.)