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ACCUMULATION AND METABOLISM OF ARSENIC IN MICE AFTER REPEATED ADMINISTRATION OF ARSENATE
Hughes, M F., E M. Kenyon, B C. Edwards, C T. Mitchell, D J. Thomas, AND L. M. Del Razo. ACCUMULATION AND METABOLISM OF ARSENIC IN MICE AFTER REPEATED ADMINISTRATION OF ARSENATE. TOXICOLOGY AND APPLIED PHARMACOLOGY. Academic Press, New York, NY, 191:202-210, (2003).
Accumulation and metabolism of arsenic in mice after repeated oral administration of arsenate, Hughes, M. F., Kenyon, E. M., Edwards, B. C., Mitchell, C. T., Del Razo, L. M., and Thomas,
The human carcinogen inorganic arsenic (iAs) is a pervasive environmental contaminant and exposure to it occurs daily. There is, however, minimal information on the disposition of arsenic after continuous exposure to it. The objective of this study was to examine the disposition and metabolism of arsenic after repeated po administration of arsenate. Adult female B6C3F1 mice were administered a single oral dose of [73As]-arsenate (0.5 mg As/kg). The mice were monitored by whole-body radioassay to determine when steady-state levels of whole-body arsenic could be attained. This was determined to be after nine daily doses. Mice were then administered nine daily po doses of [73As]-arsenate (0.5 mg As/kg). Whole body [73As] was determined immediately before and after each administered dose. Excreta were collected daily and analyzed for [73As] and arsenicals. Twenty-four h after the last repeated dose, whole-body [73As] levels were determined. Five mice were then euthanized and tissues were analyzed for [73As]. Whole-body [73As] levels were determined in the remaining mice for eight additional days. These mice were then euthanized and tissue [73As] levels were determined. Another group of mice was administered either a single or nine repeated po daily doses of non-radioactive arsenate (0.5 mg As/kg). Twenty-four h after the last dose, the animals were euthanized, and tissues were removed and analyzed for total and speciated arsenic by hydride generation atomic absorption spectrometry (HGAAS). Whole-body [73As] was rapidly cleared from the mice after a single or repeated dose of [73As]-arsenate. Urinary excretion was the predominant means of arsenic elimination. The repeated exposure to [73As]-arsenate did not affect [73As] elimination. The rank order of urinary metabolites in terms of mass was dimethylarsinic acid >> arsenate>arsenite > monomethylarsonic acid. The highest accumulation of arsenic occurred in bladder, kidney, and skin after nine repeated doses of [73As]-arsenate. The rate of clearance of arsenic following repeated exposure of [73As]-arsenate was different among the major organs examined. The clearance of arsenic was most rapid in the lung and slowest in the skin. There was an organ-specific distribution of arsenic as determined by HGAAS. Monomethylarsonic acid was detected in all tissues except the bladder. The lung and bladder lung had the highest percentage of dimethylarsinic acid compared to the other organs after a single exposure to arsenate, and the percentage increased with repeated exposure. In kidney, iAs was predominant. The liver had a higher percentage of dimethylarsinic acid than the other arsenicals after a single exposure to arsenate. The percentage of dimethylarsinic acid in the liver decreased and that of iAs increased with repeated exposure. A trimethylated metabolite was also detected in the liver. Tissue accumulation of arsenic after repeated po exposure to arsenate in the mouse corresponds to the known human target organs for iAs-induced carcinogenicity.