Pharmacokinetic modeling of perfluorooctanoic acid during gestation and lactation in the mouse

Perfluorooctanoic acid (PFOA) is a processing aid for the polymerization of commercially valuable fluoropolymers. Its widespread environmental distribution, presence in human blood, 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 serum/plasma half-lives across species. Estimated half-lives for humans, monkeys, mice, and female rats are 3-5 years, 20-30 days, 12-20 days, and 2-4h, respectively. Developmental toxicity is one of the most sensitive adverse effects associated with PFOA exposure in rodents, but its interpretation for risk assessment is currently hampered by the lack of understanding of the inter-species pharmacokinetics of PFOA. 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 a lactating dam to a growing pup litter compartment. Postnatal serum levels of PFOA for 129S1/SvImJ mice at doses of 1mg/kg or less were reasonably simulated while prenatal and postnatal measurements for CD-1 mice at doses of 1mg/kg or greater were simulated via the addition of a biologically based saturable renal resorption description. Our results suggest that at low doses a linear model may suffice for describing the pharmacokinetics of PFOA while a more complex model may be needed at higher doses. Although mice may appear more sensitive based on administered dose of PFOA, the internal dose metrics estimated in this analysis indicate that they may be equal or less sensitive than rats.