• Clarification of which human enzymatic isoforms are the most important in disposing of trichloroethylene and its metabolites.

  • Better characterization of the impact of physiologic conditions and disease states on trichloroethylene toxicity.

  • Evaluation of intersubject variation in pharmacodynamics across life stages and in various subpopulations is needed before pharmacodynamic factors can be quantitated in risk assessment. Before such pharmacodynamic data can be generated, the critical targets and modes of action must be clarified from animal or in vitro studies.

Mixtures:

  • Toxicokinetic and toxicodynamic studies with mixtures to evaluate the effect of coexposures to other chemicals on toxic outcomes of trichloroethylene and its metabolites. Studies designed to evaluate modes of action in the presence of most commonly occurring toxicants are likely to yield more meaningful results than testing various combinations of compounds and doses.

  • Testing the impact of lifestyle factors (e.g., alcohol consumption, chronic drug intake, caloric restriction), disease (e.g., diabetes), and special physiologic states (e.g., pregnancy, aging) on the toxicity of trichloroethylene.

PBPK Modeling:

  • Future PBPK models for trichloroethylene risk assessment should include a description of dermal absorption.

  • Studies to evaluate how well alternative dose metrics predict toxic response. PBPK models should be used to investigate alternative study designs.

  • PBPK models should be developed for other toxicity end points, such as neurotoxicity and developmental outcomes. There may be little or no data available to confirm model predictions for certain tissue concentrations (e.g., brain) of trichloroethylene and metabolites in humans. However, inclusion of all relevant uncertainties can be formalized under Bayesian inference and implemented with Markov chain Monte Carlo approaches. Description of uncertainties in prior simulation might indicate that the approach is not practical without collecting additional data.

  • Development of a combined PBPK model for trichloroethylene and ethanol.



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