Oral toxicity of 1,1-dichloroethylene in the rat: effects of sex, age, and fasting.
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.
D000284:Administration, Oral; D000367:Age Factors; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D004000:Dichloroethylenes / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005215:Fasting; D005260:Female; D006843:Hydrocarbons, Chlorinated / Q000633:toxicity*; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D007770:L-Lactate Dehydrogenase / Q000097:blood; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects; D008297:Male; D051381:Rats; D012737:Sex Factors
D004000:Dichloroethylenes; D006843:Hydrocarbons, Chlorinated; D007064:L-Iditol 2-Dehydrogenase; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase