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Development of PBPK Models for Gasoline in Adult and Pregnant Rats and their Fetuses
Citation:
Martin, S., W. Oshiro, P. Evansky, J. Ford, L. Degn, H. El-Masri, W. Lefew, E. Mclanahan, D. MacMillan, W. Boyes, AND P. Bushnell. Development of PBPK Models for Gasoline in Adult and Pregnant Rats and their Fetuses. Presented at Society of Toxicology, March 10 - 14, 2013.
Impact/Purpose:
This is an abstract for a poster presentation that will be given at the Society of Toxicology Annual Meeting March 10-14, 2013. The deadline for submission is October 3, 2012.
Description:
Concern for potential developmental effects of exposure to gasoline-ethanol blends has grown along with their increased use in the US fuel supply. Physiologically-based pharmacokinetic (PBPK) models for these complex mixtures were developed to address dosimetric issues related to selection of exposure concentrations for in vivo toxicity studies. Sub-models for individual hydrocarbon (HC) constituents were first developed and calibrated with published literature or QSAR-derived data where available. Successfully calibrated sub-models for individual HCs were combined, assuming competitive metabolic inhibition in the liver, and a priori simulations of mixture interactions were performed. Blood HC concentration data were collected from exposed adult non-pregnant (NP) rats (9K ppm total HC vapor, 6h/day) to evaluate performance of the NP mixture model. This model was then converted to a pregnant (PG) rat mixture model using gestational growth equations that enabled a priori estimation of life-stage specific kinetic differences. To address the impact of changing relevant physiological parameters from NP to PG, the PG mixture model was first calibrated against the NP data. The PG mixture model was then evaluated against data from PG rats that were subsequently exposed (9K ppm/6.33h gestation days (GD) 9-20). Overall, the mixture models adequately simulated concentrations of HCs in blood from single (NP) or repeated (PG) exposures (within ~2-3 fold of measured values of most HCs), indicating that the data from PG rats were not highly sensitive to PG-specific physiological parameters. This PG model will be used to estimate internal HC concentrations in the total fetus during in utero exposure to HC vapors. This is an abstract of a proposed presentation and does not necessarily reflect EPA policy.