Oral toxicity of 1,1-Dichloroethylene in the rat: Effects of sex, age, and fasting

摘要

Mortality curves for groups of fasted male rats treated with single, oral doses of 1,1-dichloroethylene (1,1-DCE, vinylidene chloride) were not monotonically increasing sigmoids, but were complex with maxima or extended plateaus in the region of dose between 100 and 700 mg of 1,1-DCE/kg. The exact shape was a function of the size (age) of the rat used. When groups of rats of various sizes were dosed with 50 mg/kg, mortality and hepatotoxicity were greatest for those groups whose average weight was between 100 and 150 g. Smaller and larger male rats were less susceptible to 1,1-DCE intoxication. The toxicity of 1,1-DCE was less severe in female rats and there was no significant effect of rat size on 1,1-DCE toxicity in females. In rats of both sexes the dose dependence of the hepatotoxic response was complex, possessing a threshold level, a region of precipitous increase, and a plateau, where larger doses were ineffective in increasing hepatotoxicity. The threshold in male rats of 100–150 g occurred near 50 mg/kg, and for females it was closer to 100 mg/kg. Considered in their entirety these data suggest that 1,1-DCE is metabolized to a toxic intermediate via some saturable pathway. Based on the effects of pretreatment with microsomal enzyme inhibitors and activators on 1,1-DCE toxicity in rats of various sizes, it appears that there are at least two microsomal reactions involved in 1,1-DCE metabolism.