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Application of physiologically based pharmacokinetic (PBPK) model of trichloroethylene in rats for estimation of internal dose
Citation:
EKLUND, C. R., M. V. EVANS, AND J. E. SIMMONS. Application of physiologically based pharmacokinetic (PBPK) model of trichloroethylene in rats for estimation of internal dose. Presented at Society of Toxicology 49th Annual meeting, Salt Lake City, UT, March 07 - 11, 2010.
Impact/Purpose:
ScientificNHSRC demonstration project
Description:
Potential human health risk from chemical exposure must often be assessed for conditions for which suitable human or animal data are not available, requiring extrapolation across duration and concentration. The default method for exposure-duration adjustment is based on Haber's rule which states that a constant toxic effect (K) is a function ofexposure concentration (C or Cn) and exposure duration (t), K = C (or C'' )xt.. This approach has been criticized for poor predictability, with errors increasing as the extrapolation interval increases. The purpose ofthe present work is estimation ofthe internal doses that result from various exposure concentrations and duration using a PBPK model developed in our laboratory for trichloroethylene (TCE) (Simmons et a1., 2005). The model compartments are liver, brain, fat, richly-perfused and slowly-perfused tissues. TCE is a volatile organic compound and a common environmental pollutant ofair, water and food. Mortality data from experimental animals are used in setting acute exposure guideline level-3 (AEGL-3) values as these represent air concentrations above which exposure could result in life-threatening adverse health effects or death (NRC, 2001). We compared results from simulations oftwo inhalation exposure scenarios reported to cause 50% mortality (LCso) in rats, 26,000 ppm for one hour and 12,000 ppm for four hours. These resulted in simulated arterial blood concentrations at the end ofthe exposure period of 888 and 733 mg/L, respectively. While there was a 4-fold difference in the exposure duration and a 2.17 fold difference (percent difference, 74%) in the external exposure concentration, there was only a 1.2fold difference (percent difference, 19%) in the estimated arterial blood concentrations. These results highlighttheutility ofPBPKmodeling for estimation ofinternaldosewhenconsidering the health implications ofexposures ofvarying duration and concentration and for extrapolation from one concentration-duration to another. (This abstract may not reflect EPA policy.)