Environmental and occupational exposures to chlorinated and brominated hydrocarbons pose significant threats to human health. Damage to human pulmonary tissues may occur through a variety of different routes and mechanisms. An increasing number of xenobiotics have been shown to be selectively pneumotoxic to animals after systemic circulation of the compounds, but the causative mechanisms for species, organ, and cellular-selective toxicities of these chemicals is largely unknown. The susceptibility of man to most of these pneumotoxins is also unknown. This research will address the basic biochemical, chemical, and molecular biological mechanisms for the pneumotoxicity of three halogenated hydrocarbons: trichloroethylene (TRI); 2-(4-chlorophenyl)-2- (4-chlorophenyl)-1,1-dichloroethane (DDD); and 1,2-dibromoethane (DBE), in animals. These results will be extrapolated to human exposures to these pneumotoxins and to the general mechanisms of human pneumotoxicities that are caused by systemically circulated toxins. TRI, DDD, and DBE are selectively toxic to Clara and type II pneumocytes in animals. Lung injury is probably mediated by cytochrome P-450-dependent oxidative bioactivation of the compounds to produce electrophilic intermediates which are responsible for selective damage to the lungs. The major goal of this research is to determine the precise mechanisms of TRI, DDD, and DBE bioactivation and toxicities in pulmonary cells and cellular fractions, and to relate these mechanisms to lung injury in humans. This goal will be realized through the following methods: 1) separation of Clara, type II, and macrophage lung cells from rabbits and evaluations of cytotoxicities of the pneumotoxins, including the effects of several enzyme inhibitors on the cytotoxicities to determine the mechanisms of bioactivation; 2) utilization of stable isotopes and metabolic profiles from isolated cells and cellular fractions (microsomes, cytosol, and S-9) to determine the chemical mechanisms of bioactivation and detoxication; 3) expression of individual human cytochrome P-450 isozymes in human pulmonary cells using human P-450 cDNA probes in a vaccinia viral expression system, to predict the susceptibility of human pulmonary cells to the halogenated hydrocarbons and to ascertain whether genetic susceptibilities to the toxic effects of these chemicals might exist. The long-term objectives of this research are to determine the mechanisms of pneumotoxicity of the halogenated pneumotoxicants to animals and man, and to provide important information about the basic biochemical mechanisms that control human susceptibilities to circulating pneumotoxins.
