Moving From External Exposure Concentration to Internal Dose: Duration Extrapolation Based on Physiologically Based Pharmacokinetic Derived Estimates of Internal Dose

The potential human health risk(s) from chemical exposure must frequently be assessed under conditions for which adequate human or animal data are not available. The default method for exposure-duration adjustment, based on Haber's rule, C (external exposure concentration) or C ⁿ (the ten Berge modification) × t (exposure duration) = K (a constant toxic effect), has been criticized for prediction errors. A promising alternative approach to duration adjustment is based on equivalence of internal dose, that is, target-tissue dose levels, across different exposure durations. A proposed methodology for dose-duration adjustments for acute exposure guideline levels (AEGLs) based on physiologically based pharmacokinetic (PBPK) estimates of dose is illustrated with trichloroethylene (TCE). Steps in this methodology include: (1) selection and evaluation, or development and evaluation, of an appropriate PBPK model; (2) determination of an appropriate measure of internal dose; (3) estimation with the PBPK model of the tissue dose (the target tissue dose) resulting from the external exposure conditions (concentration, duration) of the critical effect; (4) estimation of the external exposure concentrations required to achieve tissue doses equivalent to the target tissue dose at exposure durations of interest; and (5) evaluation of sources of variability and uncertainty. For TCE, this PBPK modeling approach has allowed determination of dose metrics predictive of the acute neurotoxic effects of TCE and dose-duration adjustments based on estimates of internal dose.

Acknowledgments

The authors gratefully acknowledge the contributions of Dr. Paul Janssen and Chris Eklund to the concept and execution of the use of PBPK models in duration adjustment for AEGL values. The authors thank Tony McDonald for excellent technical support and Drs. L. S. Birnbaum, G. Foureman, and E. Kenyon for thoughtful manuscript review.

The research described in this article has been reviewed by the National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency or the Acute Exposure Guideline Levels Advisory Committee, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.