Subchronic toxicity study of sodium arsenite in methyl-deficient male C57BL/6 mice

Arsenic is an established human carcinogen. The mechanistic pathway by which arsenic causes cancer is not understood. In preparation for a 24-month chronic study assessing cancer in methyl-deficient male C57BL/6 mice, a 130-day subchronic study of sodium arsenite was undertaken to establish baseline toxicity data. Mice were administered arsenic via drinking water: 0, 2.6, 4.3, 9.5 or 14.6 mg sodium arsenite/kg/day. Dosing continued 7 days a week for the length of the study. Deaths of 3 of the control animals (methyl-sufficient/no arsenic) at Day 111 of the study did not appear to be compound-related. The death of a single animal in the high-dose group did appear to be treatment-dependent A dose-related reduction was observed for liver weight. Mild to severe fatty infiltration was observed in the livers of methyl-deficient/arsenic treated animals. Severe liver damage was noted in 2 animals from the 2.6 and 4.3 mg/kg/d groups. In addition, hypertrophy/ hyperplasia of the bladder was found in 43/60 mice treated with sodium arsenite. No histopathological changes were evident in any other tissue examined. The no observed effect level (NOEL) and no observed adverse effect level (NOAEL) of this study could not be determined as the lowest dose administered produced detrimental effects. The maximum tolerated dose (MTD) for animals maintained on methyl-deficient diets was 2.6 mg/kg/d.