Trichloroethylene risk assessment: Relevance of interindividual differences

Interindividual variability in the disposition and effects of xenobiotics i n humans and related inter-species differences should play a major role in human risk assessment. In particular for low-dose exposures to potentially carcinogenic compounds, novel tools and concepts are necessary to assess ri sks of chemical exposure, preferably based on susceptibility of sensitive i ndividuals rather than on 'average populations'. For trichloroethylene (TRI ), significant controversy surrounds assessment of the carcinogenic potenti al associated with human exposure. Ample evidence exists that bioactivation of TRI via glutathione (GSH) S-transferase (GST)-mediated pathways, includ ing the formation of chemically reactive S-containing intermediates by P-ly ase in the kidney, is relevant for the mutagenic and carcinogenic potential of TRI. Using a novel, descriptive 'bottom-up' PBPK modeling approach, the relative and overall contribution of critical metabolic pathways can be pr edicted and compared between humans and laboratory animals. From these stud ies it is evident that humans: (a) show a minimal potency for GSH-conjugati on of low-doses of TRI, (b) are in principle subject to large interindividu al variations in this and in Cyt P450-dependent pathways of metabolism, and (c) show a much lower capacity for GSH conjugation of TRI than the rat. Ta king these findings into consideration as well as the fact that kidney toxi city and kidney carcinogenicity of TRI are dose dependent and typically a f eature of high and continuous exposure to TRI, it is unlikely that the neph rocarcinogenic potential of TRI observed in rat is a relevant human health hazard at currently reasonably foreseeable low levels of occupational and e nvironmental exposure to TRI.