Studies on the acute toxicity of ethylene dichloride following inhalant exposure (metabolism, p-450, glutathione)
Description
Ethylene dichloride (EDC) is a chemical of substantial economic importance and environmental concern. It has produced injury in both man and animal following its acute administration. Mutagenic and carcinogenic potentials have also been demonstrated for EDC in experimental investigations. In the present studies, the toxicity produced by EDC was evaluated in mice following exposure by inhalation. Animals were subjected to vapors of EDC for four hour periods in a specially designed exposure system. There was a dose-dependent increase in mortality following exposure to EDC over a range of concentrations of 200 - 2000 ppm. The mortality at post-exposure periods of 24 and 48 hours was enhanced by pretreatment with phenobarbital (PB) or 3-methylcholanthrene (3-MC). Meanwhile, SKF-525A offered protection from the lethal effects of EDC. The administration of diethylmaleate (DEM) produced a potentiation of the fatal response at concentrations of EDC of 500 and 1000 ppm. Conversely, when N-acetylcysteine (NAC) was given to mice prior to exposure to EDC, there were fewer deaths in comparison to untreated animals Pathological changes were evident in hepatic and renal samples of exposed animals and the nephrotoxic effect of EDC was more pronounced than was the hepatic response. Pretreatment with SKF-525A reduced the amount of renal tubular damage caused by EDC at concentrations of 1000, 1250, and 1500 ppm. Likewise, administration of NAC prevented the increase in organ weight (as a percentage of body weight) of livers and kidneys of mice exposed to EDC. There was a significant interaction between EDC and acetaminophen in respect to the depletion of hepatic GSH and the production of hepatotoxicity. The combination treatment produced a greater effect as compared to the administration of either agent by itself. This finding may be of relevance to individuals working in an occupational setting, where the potential exists for exposure to both chemical agents. At a non-lethal inhalant concentration of 250 ppm, there was no evidence of renal or hepatic damage in the exposed mice. Pretreatment with agents associated with enhanced toxicity at higher concentrations of EDC, PB and DEM, did not alter the response to EDC. These investigations suggest a role for a cytochrome P-450-generated metabolite of EDC in the toxicity produced by this chlorinated hydrocarbon. The involvement of glutathione (GSH) in the detoxification of EDC is also suggested by these findings