Noncancer Effects of Trichioroethylene: Pharmacokinetics and Risk Assessment.
Abstract
This report provides an evaluation of the noncancer effects of trichloroethylene (TCE) exposure and presents alternatives for the development of reference doses (RfDs) and reference concentrations (RfCs). These alternatives are organized within a framework for dose-response assessment - exposure: dosimetry (pharmacokinetics): mode of action (pharmacodynamics): response. This framework provides a consistent organization within which to make scientific judgments about available information, its interpretation and use. These judgments occur in the selection of potential critical studies, choices of intern dose metrics based upon mode of action, selection of pharmacokinetic models, interspecies extrapolation pharmacodynamics, and of pharmacodynamics and selection of other uncertainty factors. Potentially limiting endpoints identified included developmental eye malformation, liver effects, immunotoxicity, and kidney toxicity form oral exposure and neurological, liver, and kidney effects by inhalation. Default analyses used the traditional no-observed-adverse-effect-level (NOAEL) divided by uncertainty factor (UF) approach, as well as the benchmark dose (BMD)/UF method. Following the default analyses, mode of action and quantitative pharmacokinetic information were incorporated. A physiologically-based pharmacokinetic (PBPK) model for TCE and it's major metabolites was used to estimate internal dose metrics for the exposure scenarios used in each experimental study. The utility of this approach was demonstrated for neurological and kidney toxicities among others. For neurological effects, use of peak trichloroethanol concentration linearized the response data, supporting its role as the active agent. The BMDs for kidney toxicity, following oral and inhalation (truncated)
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 1998
- Accession Number
- ADA358389
Entities
People
- Harvey J. Clewell Iii
- Hugh A. Barton