Trichloroethylene risk assessment: Relevance of inter-individual differences

Interindividual variability in the disposition and effects of xenobiotics in 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 risks of chemical exposure, preferably based on susceptibility of sensitive individuals rather than on 'average populations'. For trichloroethylene (TRI), significant controversy surrounds assessment of the carcinogenic potential associated with human exposure. Ample evidence exists that bioactivation of TRI via glutathione (GSH) S-transferase (GST)-mediated pathways, including the formation of chemically reactive S-containing intermediates by β-lyase 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 predicted and compared between humans and laboratory animals. From these studies it is evident that humans: (a) show a minimal potency for GSH-conjugation of low-doses of TRI, (b) are in principle subject to large interindividual 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. Taking these findings into consideration as well as the fact that kidney toxicity and kidney carcinogenicity of TRI are dose dependent and typically a feature of high and continuous exposure to TRI, it is unlikely that the nephrocarcinogenic potential of TRI observed in rat is a relevant human health hazard at currently reasonably foreseeable low levels of occupational and environmental exposure to TRI