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THE EFFECT OF UNCERTAINTY FACTOR PLACEMENT IN A PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK) MODEL OF TRICHLOROETHYLENE (TCE) FOR ACUTE EXPOSURE GUIDELINE LEVELS (AEGL).
Citation:
EKLUND, C. R., W. K. BOYES, J. E. SIMMONS, AND M. V. EVANS. THE EFFECT OF UNCERTAINTY FACTOR PLACEMENT IN A PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK) MODEL OF TRICHLOROETHYLENE (TCE) FOR ACUTE EXPOSURE GUIDELINE LEVELS (AEGL). . Presented at 45th Annual Society of Toxicology Meeting 2006, San Diego, CA, March 05 - 09, 2006.
Description:
PBPK models may be used in risk assessment to reduce uncertainties associated with dosimetry; however, other considerations may still lead to incorporation of uncertainty factors (UF). We investigated the consequences of incorporating UFs at three different steps in the modeling sequence including: to the air concentration that served as the point of departure, to the internal dose metric, or to the final air concentrations. We illustrated this by using a PBPK model to extrapolate across exposure durations while evaluating risk of acute exposures to TCE. AEGL values were developed for 10 min, 30 min, 1 hr, 4 hr, and 8 hr exposure durations, and were designated for three levels of increasing severity (AEGL-1 to AEGL-3). Adverse outcomes appropriate for AEGL-1, 2, or 3 were selected from the literature, and then a PBPK model was used to predict the arterial blood concentrations (Ca) associated with those outcomes. The model was then used in a boot-strap approach to estimate the atmospheric concentration sufficient to produce the same Ca level for each exposure duration. A UF of 3 was used to examine the effect of its placement on the final AEGL value. The results showed that relative to applying the UF to the final air concentrations, the results of the other approaches differed by less than 20%, 20% and 2% for AEGL1, 2, and 3, respectively. Therefore, changing the placement of the UF had only a modest impact on the final AEGL air concentrations for this example. This would argue for placement of the UF outside the PBPK model for greater transparency of the risk assessment process (This abstract does not reflect EPA policy.)