Enhancement of 1,1-Dichloroethylene Toxicity by Pretreatment of Fasted Male Rats with 2,3-Epoxypropan-1-01

Abstract

The efficacy of pretreatment with various low molecular weight epoxides in increasing the toxicity of orally administered 1,1-dichloroethylene (1,1-DCE) has been determined in fasted male rats. Rats were dosed ip with either 2,3-epoxypropan-1-01 (EP), 1,1,1-trichloropropane-2,3-oxide (TCPO), styrene oxide (SO), cyclohexene oxide (CHO), butadiene monoxide (BMO) or the sulfhydryl reagent, diethylmaleate (DEM) 1 hr before intubation with 1,1-DCE. Increases in plasma aspartate transaminase (AsT) 24 hr after 1,1-DCE intubation were used as a measure of toxicity. In rats pretreated with 278 mg of EP/kg the acute LD50 of 1,1-DCE was reduced by a factor of 5 (to less than 40 mg/kg) and doses of 1,1-DCE as low as 12.5 mg/kg increased AsT levels. While 25 mg of 1,1-DCE/kg did not increase plasma AsT activities in naive rats, this dose did increase AsT levels in rats pretreated with 30 mg of EP/kg. The severity of 1,1-DCE toxicity in EP pretreated rats was greater in large, mature rats than in small, immature rats. On a molar basis the abilities of these various epoxides and DEM to exacerbate 1,1-DCE toxicity were related as follows: EP>SO>TCPO>CHO>DEM>BMO. These epoxides appeared to increase the toxicity of 1,1-DCE by interfering with the metabolism of a toxic product of the microsomal oxidation of 1,1-DCE.