EVALUATING HUMAN VARIABILITY IN CHEMICAL RISK ASSESSMENT - HAZARD IDENTIFICATION AND DOSE-RESPONSE ASSESSMENT FOR NONCANCER ORAL TOXICITY OF TRICHLOROETHYLENE

Human variability can be addressed during each stage in the risk asses sment of chemicals causing noncancer toxicities, Noncancer toxicities arising from oral exposure to trichloroethylene (TCE) are used in this paper as a case study for exploring strategies for identifying and in corporating information about human variability in the chemical specif ic hazard identification and dose-response assessment steps. Toxicity testing in laboratory rodents is the most commonly used method for haz ard identification. By using animal models for sensitive populations, such as developing fetuses, testing can identify some potentially sens itive populations, A large variety of reproductive and developmental s tudies with TCE were reviewed. The results were mostly negative and th e limited positive findings generally occurred at doses similar to tho se causing liver and kidney toxicity. Physiologically based pharmacoki netic modeling using Monte Carlo simulation is one method for evaluati ng human variability in the dose-response assessment, Three strategies for obtaining data describing this variability for TCE are discussed: (1) using in vivo human pharmacokinetic data for TCE and its metaboli tes, (2) studying metabolism in vitro, and (3) identifying the respons ible enzymes and their variability. A review of important steps in the metabolic pathways for TCE describes known metabolic variabilities in cluding genetic polymorphisms, enzyme induction, and disease states. A significant problem for incorporating data on pharmacokinetic variabi lity is a lack of information on how it relates to alterations in toxi city. Response modeling is still largely limited to empirical methods due to the lack of knowledge about toxicodynamic processes. Empirical methods, such as reduction of the No-Observed-Adverse-Effect-Level or a Benchmark Dose by uncertainty factors, incorporate human variability only qualitatively by use of an uncertainty factor. As improved data and methods for biologically based dose-response assessment become ava ilable, use of quantitative information about variability will increas e in the risk assessment of chemicals.