Chloroform is used as an industrial solvent and as an intermediate in the manufacture of polymer materials. At present, the main use of chloroform is in the production of R-22 refrigerant commonly used in the air conditioning industry. Reports from several laboratories indicate that acute nephrotoxicity of chloroform is species, strain, and sex dependent (Eschenbrenner and Miller 1945; Hill, etc., 1975; Larson, etc. 1993199 4; Bohr et al. 1984; Smith et al. 1983198 4; Torkelson et al. 1976), and male mice are more susceptible to infection than rats, rabbits, or dogs, whereas female mice are resistant. Tubule swelling, necrosis, and casting, mainly confined to proximal tubules, are the major histopathological changes in the kidneys of experimental animals exposed to chloroform. Chloroform induced nephrotoxicity is also associated with elevated blood urea nitrogen concentrations, proteinuria and glycosuria. The in vitro absorption of organic anions and cations by renal cortical sections is also inhibited by in vivo chloroform treatment (Kluwe and Hook 1978). Although human exposure to chloroform has been associated with oliguria, proteinuria, increased blood urea nitrogen, and tubular necrosis, the threshold dose for acute chloroform nephrotoxicity in humans is not known. Localization of human renal injury to proximal tubules suggests a common mechanism of chloroform nephrotoxicity in most mammalian species.
The oxidative and reducing pathways of chloroform metabolism have been described, although in vivo data are limited. Carbon dioxide is the main metabolite of chloroform produced by metabolic oxidative pathways in the body. The oxidation pathway also produces active metabolites, including phosgene (Pohl and Krishna 1978; Pohl et al. 1977), which was determined in vitro by phenobarbital induction (Testai and Vittozzi 1986; Tomasi et al. 1985; Wolf et al. 1977), while the reduction pathway generates dichloromethyl carbene radicals (measured in vitro and in vivo, with and without phenobarbital induction). Both oxidative and reductive metabolism proceed through a cytochrome P450 (CYP) -dependent enzymatic activation step. The balance between oxidative and reductive pathways depends on species, tissue, dose, and oxygen tension (Ammann et al. 1998; Testay and Vitozzi 1986). In intact mammals, oxidative tension may prevent any significant metabolism through the reductive pathway (Mansuy et al. 1977; Pohl, etc. 1977). Phosgene is produced by chloroform oxidation, dechlorination to trichloroethanol, and spontaneous dehydrogenation of trichloroethanol. One molecule of hydrochloric acid is generated by dechlorination of trichloromethane ethanol, and another two molecules of hydrochloric acid are generated by hydrolysis of phosgene, so three molecules of hydrochloric acid are generated during the conversion of chloroform to carbon dioxide (Pohl et al. 1980).