PBTK Model of Methylmercury Toxicity in the Fetal Rat. T. A. Lewandowski, S. M. Bartell, C. H. Pierce, R. A. Ponce, and E. M. Faustman, Department of Environmental Health, University of Washington, Seattle, WA
We have developed a model of the disposition (pharmacokinetics) and cellular action (pharmacodynamics) of methylmercury (MeHg), a developmental neurotoxicant. This model can be used to estimate health outcomes for various levels of exposure. A linked toxicokinetic-toxicodynamic model for MeHg exposure and neurodevelopmental toxicity has been developed for the rat. The toxicokinetic model incorporates changes in organ size and blood flow associated with gestation. The toxicodynamic model estimates changes in the population of fetal midbrain neural cells by using MeHg-dependent rates of cellular death, proliferation and differentiation observed in vitro. The toxicokinetic model demonstrates an adequate fit to toxicokinetic data reported in the scientific literature. For example, 3 days after a dose of 1 mg/kg (given on day 16 of gestation), the model predicts fetal brain and fetal blood levels within 10% of the values observed by Wannag (1976). The toxicodynamic model predicts 20% and 65% decreases in the number of committed neural cells (on gestational day 15, relative to untreated baseline) at fetal brain concentrations of 10 and 50 mmol/kg. We are currently determining rates for model variables in vivo using osmotic pumps and BrdU-Hoechst flow cytometry. This model may be extended to address other species (e.g., humans) and other developmental toxicants acting by similar mechanisms (i.e., cell cycle disruption).
Sponsored by the following grants: USDOE 95EW55084, USEPA R825358 and CRH25173 and NIEHS T32ESO-7032.
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