Accumulation and metabolism of arsenic in mice after repeated oral administration of arsenate Michael F. Hughes, a, * Elaina M. Kenyon, a Brenda C. Edwards, a Carol T. Mitchell, a Luz Maria Del Razo, b and David J. Thomas a a U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Experimental Toxicology Division, Research Triangle Park, NC 27711, USA b Toxicology Section, CINVESTAV-IPN, AP-14-740, Mexico D.F. 07000 Received 22 April 2003; accepted 14 May 2003 Abstract Exposure to the human carcinogen inorganic arsenic (iAs) occurs daily. However, the disposition of arsenic after repeated exposure is not well known. This study examined the disposition of arsenic after repeated po administration of arsenate. Whole-body radioassay of adult female B6C3F1 mice was used to estimate the terminal elimination half-life of arsenic after a single po dose of [ 73 As]arsenate (0.5 mg As/kg). From these data, it was estimated that steady-state levels of whole-body arsenic could be attained after nine repeated daily doses of [ 73 As]arsenate (0.5 mg As/kg). The mice were whole-body radioassayed immediately before and after the repeated dosing. Excreta were collected daily and analyzed for arsenic-derived radioactivity and arsenicals. Whole-body radioactivity was determined 24 h after the last repeated dose, and five mice were then euthanized and tissues analyzed for radioactivity. The remaining mice were whole-body radioassayed for 8 more days, and then their tissues were analyzed for radioactivity. Other mice were administered either a single or nine repeated po doses of non-radioactive arsenate (0.5 mg As/kg). Twenty-four hours after the last dose, the mice were euthanized, and tissues were analyzed for arsenic by atomic absorption spectrometry (AAS). Whole-body radioactivity was rapidly eliminated from mice after repeated [ 73 As]arsenate exposure, primarily by urinary excretion in the form of dimethylarsinic acid (DMA(V)). Accumulation of radioactivity was highest in bladder, kidney, and skin. Loss of radioactivity was most rapid in the lung and slowest in the skin. There was an organ-specific distribution of arsenic as determined by AAS. Monomethylarsonic acid was detected in all tissues except the bladder. Bladder and lung had the highest percentage of DMA(V) after a single exposure to arsenate, and it increased with repeated exposure. In kidney, iAs was predominant. There was a higher percentage of DMA(V) in the liver than the other arsenicals after a single exposure to arsenate. The percentage of hepatic DMA(V) 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. © 2003 Elsevier Inc. All rights reserved. Keywords: Arsenic; Arsenate; Disposition; Repeated exposure; Metabolism; Accumulation Introduction Humans are chronically exposed to arsenic, which is present in food, water, soil, and air. Chronic exposure to inorganic arsenic (iAs) that occurs as a natural contaminant in drinking water is associated with the development of skin cancer in populations worldwide (Tseng et al., 1968; Ce- brian et al., 1983). Increased incidences of internal cancers (liver, lung, kidney, and urinary bladder) have also been associated with chronic exposure to iAs in drinking water (Chiou et al., 1995; Hopenhayn-Rich et al., 1996; Smith et al., 1992). The relationship between chronic iAs exposure and the development of specific target organ toxicity is not completely understood. A better understanding of the dis- position of arsenic at target organs with an emphasis on identification of arsenic species present at critical sites will * Corresponding author. U.S. EPA/NHEERL, MD B143-05, Research Triangle Park, NC 27711. Fax: +1-919-541-4284. E-mail address: hughes.michaelf@epa.gov (M.F. Hughes). R Available online at www.sciencedirect.com Toxicology and Applied Pharmacology 191 (2003) 202–210 www.elsevier.com/locate/taap 0041-008X/03/$ – see front matter © 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0041-008X(03)00249-7