The use of halogenated hydrocarbons is widespread and chronic exposure of many individuals is common. Toxicity is associated with the formation of highly reactive intermediates implicated to be involved in the necrosis which occurs in the tissue producing the reactive metabolites. We have shown that CCl4, halothane and trichloroethylene are metabolized to free radical products, both in vivo and in vitro, which can be trapped and studied using electron spin resonance techniques. The clinically used chemical metyrapone inhibits the formation of these free radicals in vivo, and studies will be done to determine if metyrapone can prevent liver injury observed histopathologically. Studies now in progress will be extended to determine if free radical formation observed during the metabolism of commercially used halogenated hydrocarbons in the liver is correlated with the extent of liver injury as assessed by histopathology and serum sorbitol dehydrogenase determinations. The compounds to be studied include 1,1,1-trichloroethane, 1,1,2-trichloroethane, vinylidene chloride (1,1-dichloroethylene) and trichlorofluoromethane (Freon 11). Using a new spin-trapping agent, 2,4,6-trimethoxyphenyl-t-butylnitrone and 13CCl4, lipid radicals (L) have been trapped in vivo and lipid and lipid oxy (LO) radicals have been trapped in vitro. This new free radical trapping agent shows promise for studying the metabolism of halocarbons to free radical products and radical intermediates in tissue injury. The advantage of using 13CCl4 to identify these lipid radicals derived from tissue, and the CCl3 radical has been shown. Studies will similarly be done using 13C-trichloroethylene to determine whether the radicals which are formed are oxygen- or carbon-centered. It is important to determine the extent to which various types of halogenated hydrocarbons form free radicals when metabolized by the mixed function oxidase system, and if any of the biological effects of exposure to these compounds can be related to free radical events occurring in vivo, their relation to liver damage and if the free radical formation and liver injury can be prevented.

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National Institute of Environmental Health Sciences (NIEHS)
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Toxicology Study Section (TOX)
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Oklahoma Medical Research Foundation
Oklahoma City
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