Metabolism of trichloroethylene

A major focus in the study of metabolism and disposition of trichloroethyle ne (TCE) is to identify metabolites that can be used reliably to assess flu x through the various pathways of TCE metabolism and to identify those meta bolites that are causally associated with toxic responses. Another importan t issue involves delineation of sex- and species-dependent differences in b iotransformation pathways. Defining these differences can play an important role in the utility of laboratory animal data for understanding the pharma cokinetics and pharmacodynamics of TCE in humans. Sex-, species-, and strai n-dependent differences in absorption and distribution of TCE may play some role in explaining differences in metabolism and Susceptibility to toxicit y from TCE exposure. The majority of differences in susceptibility, however ,. are likely due to sex-, species-, and strain-dependent differences in ac tivities of the various enzymes that can metabolize TCE and its subsequent metabolites. An additional factor that plays a role in human health risk as sessment for TCE is the high degree of variability in the activity of certa in enzymes. TCE undergoes metabolism by two major pathways, cytochrome P450 (P450)-dependent oxidation and conjugation with glutathione (GSH). Key P45 0-derived metabolites of TCE that have been associated with specific target organs, such as the liver and lungs, include chloral hydrate, trichloroace tate, and dichloroacetate. Metabolites derived from the GSH conjugate of TC E, in contrast, have been associated with the kidney as a target organ. Spe cifically, metabolism of the cysteine conjugate of TCE by the cysteine conj ugate P-lyase generates a reactive metabolite that is nephrotoxic and may b e nephrocarcinogenic. Although the P450 pathway is a higher activity and hi gher affinity pathway than the GSH conjugation pathway, one should not auto matically conclude that the latter pathway is only important at very high d oses. A synthesis of this information is then presented to assess how exper imental data, from either animals or from in vitro studies, can be extrapol ated to humans for risk assessment.