Alternatives for developing chronic exposure limits for noncancer effects of trichloroethylene (TCE) were evaluated. These alternatives were organized within a framework for dose-response assessment-exposure:dosimetry (pharmacokinetics):mode of action (pharmacodynamics):response. This framework provides a consistent structure within which to make scientific judgments about available information, its interpretation, and use. These judgments occur in the selection of critical studies, internal dose metrics, pharmacokinetic models, approaches for interspecies extrapolation of pharmacodynamics, and uncertainty factors. Potentially limiting end points included developmental eye malformations, liver effects, immunotoxicity, and kidney toxicity from oral exposure and neurological, liver, and kidney effects by inhalation. Each end point was evaluated quantitatively using several methods. Default analyses used the traditional no-observed adverse effect level divided by uncertainty factors and the benchmark dose divided by uncertainty factors methods. Subsequently, mode-of-action and pharmacokinetic information were incorporated. Internal dose metrics were estimated using a physiologically based pharmacokinetic (PBPK) model for TCE and its major metabolites. This approach was notably useful with neurological and kidney toxicities. The human PBPK model provided estimates of human exposure doses for the internal dose metrics. Pharmacodynamic data or default assumptions were used for interspecies extrapolation. For liver and neurological effects, humans appear no more sensitive than rodents when internal dose metrics were considered. Therefore, the interspecies uncertainty factor was reduced, illustrating that uncertainty factors are a semiquantitative approach fitting into the organizational framework. Incorporation of pharmacokinetics and pharmacodynamics can result in values that differ significantly from those obtained with the default methods. Key words: benchmark dose, chloral, developmental toxicity, dose-response assessment, kidney toxicity, liver toxicity, neurotoxicity, PBPK modeling, A consistent framework has been evolving for analyzing dose-response information that reflects relevant biological processes (6,7). Depending on the availability of information, different methods can be used within the overall exposure-dosimetry modeof-action response framework (Figure 1). All dose-response assessment methods begin with the identification of a toxic effect and then estimate acceptable exposure levels protective of human health (7-10). The default approach, in the absence of information, identifies a no-observed adverse effect level (NOAEL) or lowest-observed effect level (LOAEL) and then makes assumptions about mode of action and dosimetry embodied in standard uncertainty factors and adjustments to continuous or daily exposure (11)(12)(13)(14). An This article is part of the monograph on Trichloroethylene Toxicity.
