Perfluorooctanoic acid: Relationship between repeated inhalation exposures and plasma PFOA concentration in the rat

A large database exists describing the pharmacokinetic behavior of perfluorooctanoic acid (PFOA) following oral exposure. The objective of this study was to examine the concentration- and time-dependence of the pharmacokinetics of inhaled PFOA in rat plasma to determine equivalent inhalation and oral (from literature values) exposure levels. The study was comprised of two separate experiments: a single 6-h inhalation exposure and repeated inhalation exposures for 3 weeks (6 h per day, 5 days per week). In both experiments, male and female rats were exposed nose-only to aerosol atmospheres of either 0, 1, 10, or 25 mg/m3 PFOA. In the single exposure experiment, blood was drawn via the tail vein pre-exposure, four times concurrent to exposure, and six times post-exposure up to 24 h. In the repeated exposure experiment, blood was collected immediately before and after exposure 3 days per week. Plasma PFOA concentrations were quantitated by liquid chromatography–mass spectrometry (LC–MS). Following the single exposures, plasma PFOA concentrations were directly proportional to airborne concentrations in both male and female rats. Elimination of PFOA from the plasma was sex-dependent, with female rats eliminating PFOA much more rapidly than male rats. Following repeated PFOA exposure, there was little daily PFOA carryover observed in plasma samples from female rats, while males demonstrated an accumulative pattern over the 3-week period. Peak post-exposure PFOA plasma concentrations in female rats averaged 1, 2, and 4 μg/mL when exposed to 1, 10, and 25 mg/m3 PFOA, respectively, and returned to baseline levels by the time of the next pre-exposure sample collection. Male rats reached steady state plasma concentrations of 8, 21, and 36 μg/mL (ppm) after 3 weeks of exposure to 1, 10, and 25 mg/m3 PFOA, respectively. These results demonstrate that the pharmacokinetic properties of inhaled PFOA in male and female rats are similar to those observed in male and female rats following oral dosing with PFOA. It is thus possible to use this internal dose metric (plasma PFOA) for route-to-route dose extrapolation, with inhalation exposures of 1, 10, and 25 mg/m3 PFOA corresponding to oral doses of approximately 0.3, 1.0, and 2.0 mg/kg in rats.