Subchronic Dispositional and Toxicological Effects of Arsenate Administered in Drinking Water to Mice

Abstract

Exposure to the drinking water contaminant arsenate is a daily occurrence and there are concerns that this exposure may lead to cancer. Although the acute dispositional effects of arsenate have been studied in detail, there is minimal information on the disposition and toxicological effects of it after continuous exposure. The objective of this study was to examine in mice the effect of a 4-wk treatment with arsenate administered in drinking water. Female B6C3F1 mice (3/cage) were housed in metabolism cages and given water and food ad libitum. Two groups (A, B) of mice were treated (4 cages/treatment/group) with distilled water (control, C) or water containing 0.025 mg/L (L) or 2.5 mg/L (H) arsenate. Group A was sacrificed on d 28 and plasma and urine samples were taken for determination of clinical chemistry parameters. Liver and kidney tissue samples were taken for histopathological analysis. The reduced nonprotein sulfhydryl (NPSH) content in several tissues was determined. Group B was gavaged with [⁷³As]arsenate on d 28 and continued the arsenate drinking water exposure for 48 h. Excreta and tissues were collected and analyzed for⁷³ As. Urine was further analyzed for arsenate and its metabolites. There were no effects on the mean daily amount of water and food consumed, whereas the mean daily urine volume excreted was significantly elevated by 10% in the H-treated animals compared to C and L. A dose-related hepatic vacuolar degeneration in the liver was observed, but no histological changes were evident in the kidney. Only clinical chemistry parameters in plasma were altered by the arsenate treatment. Glucose was significantly lower at the H dose compared to C and L, triglycerides were significantly greater in C than L and H, and creatinine was significantly greater in H than C. Hepatic NPSH content in the H animals was significantly lower than C and L animals, whereas no effects in lung and kidney were detected. The weights of liver, lung, and kidney, as well as their tissue/body weight ratios, were significantly decreased in the H animals. ⁷³As was primarily eliminated in urine, and its elimination was not affected by dose. No effects on the 48-h As cumulative excretion (urine + fecal) were detected. The ⁷³As distribution was low in amount and widely dispersed throughout the animal (<3% of the ⁷³As dose). The kidney had the highest As concentration of the tissues (0.01% As dose/g tissue). Dimethylarsinic acid was the major metabolite detected in urine, with lower amounts of arsenate, arsenite, and monomethylarsonate. There were no differences between the treatment groups in the amount of urinary metabolites after a single dose of [⁷³As]arsenate. Several toxicological effects were observed in animals administered arsenate in drinking water, but no changes in the disposition of this arsenical were detected at the doses used in this study.