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DEVELOPMENT OF A PHYSIOLOGICALLY BASED PHARMOKINETICS (PBPK) MODEL TO COMPARE DIFFERENCES IN DISPOSITION OF TRICHLOROETHYLENE (TCE) IN ADULT VERSUS ELDERLY RATS
Citation:
Evans, M V., R. TORNERO-VELEZ, M J. DeVito, M S. Okino, A M. Geller, J N. Blancato, AND L S. Birnbaum. DEVELOPMENT OF A PHYSIOLOGICALLY BASED PHARMOKINETICS (PBPK) MODEL TO COMPARE DIFFERENCES IN DISPOSITION OF TRICHLOROETHYLENE (TCE) IN ADULT VERSUS ELDERLY RATS. Presented at Society of Toxicology Annual Meeting, New Orleans, LA, March 06 - 10, 2005.
Description:
Due to the increasing number of elderly in the American Population, the question as to whether the aged have different susceptibility to environmental contaminants needs to be addressed. Physiologically based pharmacokinetic (PBPK) models are used to extrapolate between rodents (toxicological database) and humans. We used an established PBPK model for TCE. PBPK comparisons were made in two different F344 rat age groups: 6 months and 2 years old. A single inhalation exposure of 100 ppm for 1 hour was used as the basis for the comparison. The compartments evaluated were: brain, lung, adipose, kidney, liver, rapidly perfused and slowly perfused tissues. Both organ flow and organ size changes were examined. The metabolic scheme involved P450 oxidation of the parent TCE to both trichloroethanol (TCOH) and trichloroacetic acid (TCA). TCOH was further metabolized to TCA, and glucurodinated trichloroethanol(TCOG) for excretion by the kidneys. Acute neurotoxicity is related to the parent chemical concentration present in the brain, while chronic nephrotoxicity is related to TCOG in the kidneys. Simulation results show no differences in the concentration of TCE present in the brain for the two ages studied. There were obvious differences between ages in the time course of TCOG excretion, both at the early part of the time course and for the steady state component. In comparison to the young, the amount of TCOG excreted by the kidney in elderly rats was decreased by 12% , 24 hours after exposure. After repeating a second 1 hour exposure, the differences between the adult and elderly simulations were more obvious. In summary, the PBPK modeling results suggest that metabolite amount excreted may be different in the elderly, and that PBPK modeling should play a role in predicting potential experiments needed to confirm these predictions. (This abstract does not reflect EPA policy).