Citation:

Simmons, J E., M V. Evans, AND W K. Boyes. MOVING FROM EXTERNAL EXPOSURE CONCENTRATION TO INTERNAL DOSE: DURATION EXTRAPOLATION BASED ON PHYSIOLOGICALLY-BASED PHARMACOKINETIC-MODEL DERIVED ESTIMATES OF INTERNAL DOSE. Presented at DOD Risk Assessment Conference, Dayton, OH, April 26-30, 2004.

Description:

The potential human health risk(s) from exposure to chemicals under conditions for which adequate human or animal data are not available must frequently be assessed. Exposure scenario is particularly important for the acute neurotoxic effects of volatile organic compounds (VOCs). Trichloroethylene (TCE) and other VOCs are included among the 33 pollutants identified as priority pollutants in the Integrated Urban Air Toxics Strategy of the U.S. EPA. Concentration-duration functions can be fit to experimental data to predict the concentrations of a compound that would be toxic at specific exposure durations. When the experimental data are inadequate to develop an empirical concentration-duration function, the default method for exposure-duration adjustment assumes a linear relationship between exposure concentration and duration, based on Haber's Rule, C (concentration) x t (exposure duration) = K (a constant toxic effect). An alternative approach, proposed here, is to calculate duration adjustments based on achieving equal target tissue dose levels at different exposure durations. We evaluated the linear form of Haber's Rule in comparison with dose-based duration adjustments for the acute neurotoxic effect(s) of TCE on the rat visual system as measured by alterations in visual evoked potentials (VEPs). The male Long-Evans rat was used, as it is well suited for investigation of toxicant-mediated disturbances of the visual system. A physiologically-based pharmacokinetic (PBPK) model for inhaled TCE with an explicit brain compartment was developed with specificity for the Long-Evans rat. This model was used to explore the relationship between various measures of internal dose (blood/brain area under the concentration curve (AUC), blood/brain tissue concentration at the time of neurological assessment). Haber's Rule did not hold for the effect of TCE on VEPs. PBPK modeling results demonstrated that the AUC, the dose metric typically associated with the chronic effects of VOCs, did not predict the acute neurotoxicity of TCE. In contrast to Haber's Rule and the AUC, which were not predictive, the concentration of TCE in either the blood or brain at the time of toxicity assessment (momentary chemical concentration) was predictive of the effect of TCE on VEPs. A PBPK modeling approach to duration adjustments for Acute Exposure Guideline Levels (AEGLs), based on internal dose, is illustrated. In conclusion, PBPK modeling, moving from external exposure concentration to internal dose, has allowed us to determine dose metrics predictive of the acute neurotoxic effects of TCE. (This abstract may not reflect EPA policy.)

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