Pharmacokinetics of vinylidene chloride in the rat.
The metabolism of inhaled vinylidene chloride in rats represents a balance of biotransformation pathways leading to the formation of a reactive alkylating species which is normally detoxified by conjugation with glutathione. Detoxification of the reactive intermediate formed from inhaled VDC is dependent upon the availability of hepatic glutathione (GSH); as VDC exposure concentrations are increased, the fraction of the dose detoxified by conjugation with GSH decreases markedly, commensurate with depletion of hepatic GSH. This reactive intermediate in the absence of GSH alkylates hepatic macromolecules and causes cell death. Similarly, hepatic GSH plays a vital role in the detoxification of the reactive metabolite formed from inhaled vinyl chloride (VC). However, the dose--response relationships for the utilization of GSH and the accumulation of alkylating metabolites following inhalation exposure to either VDC or VC point to distinct differences which may explain the differing biological activities of the two materials. Finally, preliminary pharmacokinetic data for inhaled VDC in mice indicate an enhanced susceptibility to VDC by virtue of an increased ability for production of alkylating VDC metabolites over that observed in the rat. The importance of these findings in light of recent evidence for a carcinogenic effect of VDC in mice is discussed.
D000818:Animals; D001711:Biotransformation; D004000:Dichloroethylenes / Q000378:metabolism* / Q000633:toxicity; D004781:Environmental Exposure; D005978:Glutathione / Q000502:physiology; D006843:Hydrocarbons, Chlorinated / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D009374:Neoplasms, Experimental / Q000139:chemically induced; D051381:Rats; D014752:Vinyl Chloride / Q000378:metabolism
D004000:Dichloroethylenes; D006843:Hydrocarbons, Chlorinated; D005978:Glutathione; D014752:Vinyl Chloride