Effects of SKF 525A, Phenobarbital, and 3-Methylcholanthrene on Ethylene Dichloride Toxicity Following Inhalation Exposure

Abstract

The effect of cytochrome P-450-dependent metabolism on ethylene dichloride (EDC) toxicity was investigated in mice. Prior to exposure to EDC, groups of male CD-1 mice were pretreated with phenobarbital or 3-methylcholanthrene to induce metabolism. Other mice were administered SKF 525A before EDC exposure to inhibit cytochrome P-450 metabolism. Following the different pretreatments, mice were exposed to EDC at selected concentrations (1000 ppm, 1250 ppm, or 1500 ppm). Exposure to EDC, without pretreatment, produced a dose-dependent increase in mortality at 24 and 48 hours postexposure. This response was enhanced at all concentrations of EDC by phenobarbital pretreatment and attenuated by the administration of SKF 525A. Pretreatment with 3-methylcholanthrene prior to EDC exposure at 1000 ppm also produced an increase in mortality as compared to EDC exposure without pretreatment. Exposure to EDC was associated with an increased kidney weight:body weight ratio. SKF 525A pretreatment prevented the increase in the kidney weight:body weight ratio at an EDC exposure concentration of 1000 ppm. Pathological changes produced in the kidneys of mice exposed to EDC were decreased by SKF 525A pretreatment. These results support the hypothesis that a product of the cytochrome P-450-dependent metabolism of EDC is involved in the toxicity produced following acute inhalation exposure to this chemical.