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Pharmacokinetic Modeling Of Perfluorooctanoic Acid During Gestation And Lactation In Mice
Citation:
RODRIGUEZ, C. E., R. W. SETZER, AND H. A. BARTON. Pharmacokinetic Modeling Of Perfluorooctanoic Acid During Gestation And Lactation In Mice. Presented at Society of Toxicology Annual Meeting, Baltimore, MD, March 15 - 19, 2009.
Impact/Purpose:
The model incorporated changes in body weight, placental blood flow, milk yield, and PFOA-specific pharmacokinetic information. Postnatal serum levels of PFOA for 129 S1/SvlJ mice at doses of 1 mg/kg or less were reasonably simulated while prenatal and postnatal measurements for CD-1 mice at doses of 1 mg/kg or greater were simulated via addition of a biologically-based renal resorption description. Our results suggest that a linear model may suffice for describing the pharmacokinetics of PFOA at low doses while a more complex model may be needed to describe non-linear behavior at higher doses. Based on internal dose estimates, the mouse achieves much higher levels as compared to rats which may help explain the observed differences in developmental toxicity in these two species.
Description:
Perfluorooctanoic acid (PFOA) is used industrially as a processing aid in the polymerization of commercially valuable fluoropolymers. Its widespread environmental distribution, presence in human serum, and adverse effects in animal toxicity studies have triggered attention to its potential adverse effects to humans. PFOA is not metabolized and exhibits dramatically different plasma half-lives across species. Estimated plasma half-lives for humans, monkeys, mice, and female rats are 3-5 years, 20-30 days, 12-20 days, and 2-4 hours, respectively. Developmental toxicity is one of the most sensitive adverse effects associated with PFOA exposure in rodents. In mice, developmental delays and reduced postnatal growth and survival occurred at much lower administered doses as compared to rats. Risk assessment of PFOA is currently hampered by the lack of understanding of its cross-species pharmacokinetics in animal toxicity studies. To address this uncertainty, a biologically-supported dynamic model was developed whereby a two-compartment system linked via placental blood flow described gestation and milk production linked the lactating dam to a growing pup litter compartment.