TRICHLOROETHYLENE CANCER RISK - SIMPLIFIED CALCULATION OF PBPK-BASED MCLS FOR CYTOTOXIC END-POINTS

Cancer risk assessments for trichloroethylene (TCE) based on linear ex trapolation from bioassay results are questionable in light of new dat a on TCE's likely mechanism of action involving induced cytotoxicity, for which a threshold-type dose-response model may be more appropriate . Previous studies have shown that if a genotoxic mechanism for TCE is assumed, algebraic methods can considerably simplify the use of physi ologically based pharmacokinetic (PBPK) models to estimate virtually s afe environmental concentrations for humans based on rodent cancer-bio assay data. We show here how such methods can be extended to the case in which TCE is assumed to induce cancer via cytotoxicity, to estimate environmentally safe concentrations based on rodent toxicity data. Th ese methods can be substituted for the numerical methods typically use d to calculate PBPK-effective doses when these are defined as peak con centrations. me selected liver and kidney as plausible target tissues, based on an analysis of rodent TCE-bioassay data and on a review of r elated data bearing on mechanism. Tumor patterns in rodent bioassays a re shown to be consistent with our estimates of PBPK-based, effective cytotoxic doses to mice and rats used in these studies. When used with a margin of exposure of 1000, our method yielded maximum concentratio n levels for TCE of 16 ppb (87 mu g/m(3)) for TCE in air respired 24 h r/ day, 700 ppb (3.8 mg/m(3)) for TCE in air respired for relatively b rief daily periods (e.g., 0.5 hr while showering/bathing), and 210 mu g/liter for TCE in drinking water assuming a daily 2-liter ingestion. Cytotoxic effective doses were also estimated for occupational respira tory exposures. These estimates indicate that the current OSHA permiss ible exposure limit for TCE would produce metabolite concentrations th at exceed an acute no observed adverse effect level for hepatotoxicity in mice. On this basis, the OSHA TCE limit is not expected to be prot ective. (C) 1997 Academic Press.