Accumulation and metabolism of arsenic in mice after repeated oral administration of arsenate.
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.
D000284:Administration, Oral; D000818:Animals; D001149:Arsenates / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D001151:Arsenic / Q000493:pharmacokinetics*; D001152:Arsenicals / Q000032:analysis / Q000378:metabolism; D002101:Cacodylic Acid / Q000032:analysis / Q000378:metabolism; D003433:Crosses, Genetic; D005243:Feces / Q000737:chemistry; D005260:Female; D051379:Mice; D011868:Radioisotopes; D014018:Tissue Distribution; D014915:Whole-Body Counting
D001149:Arsenates; D001152:Arsenicals; D011868:Radioisotopes; C052920:trimethylarsine oxide; D002101:Cacodylic Acid; C020300:monomethylarsonic acid; D001151:Arsenic; C025657:arsenic acid