Evaluating noncancer effects of trichloroethylene: dosimetry, mode of action, and risk assessment.

Abstract

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.

Probabilistic methods for addressing uncertainty and variability in biological models: application to a toxicokinetic model

“…This highly fat-soluble compound is rapidly absorbed into the bloodstream, and has been shown to accumulate in the adipose (fat) tissue of humans and animals [1,2]. Known and suspected toxic effects of TCE and its metabolites in laboratory animals and/or humans include acute effects such as dizziness, drowsiness, headaches and fatigue, as well as chronic effects such as developmental defects and lung, kidney and liver tumors [3][4][5][6][7][8][9][10].…”

“…Transport of TCE between the capillary region and the other two adipose subcompartments (interstitial and adipocyte) is modeled in the PDE (10). The variables C B (t), C I (t) and C A (t) denote concentrations of TCE in the capillary, interstitial and adipocyte regions respectively, while C a (t) and C v (t) represent the systemic arterial and venous blood concentrations of TCE.…”

Human variability and susceptibility to trichloroethylene.

“…An association, but no direct cause-and-effect relationship, was found between elevated levels of chlorinated hydrocarbons, including TCE, and chromium in drinking water and congenital heart disease in children whose parents were exposed to this contaminated drinking water (16,17); follow-up studies in rats showed that TCE was a cardiac teratogen, but not a general teratogen during fetal organ development (18). An association between TCE exposure and cardiac anomalies and eye malformations has been found (18)(19)(20). Other studies, however, found no adverse reproductive effects in humans exposed to TCE in drinking water (12,21).…”

“…Long-term exposure to TCE can result in hepatotoxicity, nephrotoxicity, and neurotoxicity, as reviewed by Bull (22), Lash (23), and Barton (20), respectively. Several studies in humans have investigated the relationship between TCE exposure and cancer.…”

Dose-response analyses of the carcinogenic effects of trichloroethylene in experimental animals.

“…* The understanding of the mechanisms of carcinogenic action of TCE has improved. * The U.S. EPA has issued proposed revisions to its preferred methodology for conducting carcinogen risk assessment (10), which include procedures somewhat different than those used in previous agency analyses of TCE. Many of these developments are discussed more thoroughly in the accompanying stateof-the-science articles (6,9,(16)(17)(18)(19)(20) Together they raise a number of possibilities for new, more rigorous, and more biologically insightful analyses of whether and how much TCE may increase cancer risks in humans exposed to environmental concentrations.…”