Modeling Single and Repeated Dose Pharmacokinetics of PFOA in Mice

Abstract

Perfluorooctanoic acid (PFOA) displays complicated pharmacokinetics in that serum concentrations indicate long half-lives despite which steady state appears to be achieved rapidly. In this study, serum and tissue concentration time-courses were obtained for male and female CD1 mice after single, oral doses of 1 and 10 mg/kg of PFOA. When using one- and two-compartment models, the pharmacokinetics for these two dosages are not consistent with serum time-course data from female CD1 mice administered 60 mg/kg, or with serum concentrations following repeated daily doses of 20 mg/kg PFOA. Some consistency between dose regimens could be achieved using the saturable resorption model of Andersen et al. In this model PFOA is cleared from the serum into a filtrate compartment from which it is either excreted or resorbed into the serum by a process presumed transporter mediated with a Michaelis-Menten form. Maximum likelihood estimation found a transport maximum of T(m) = 860.9 (1298.3) mg/l/h and half-maximum concentration of K(T) = 0.0015 (0.0022) mg/l where the estimated standard errors (in parentheses) indicated large uncertainty. The estimated rate of flow into and out of the filtrate compartment, 0.6830 (1.0131) l/h was too large to be consistent with a biological interpretation. For these model parameters a single dose greater than 40 mg/kg, or a daily dose in excess of 5 mg/kg were necessary to observe nonlinear pharmacokinetics for PFOA in female CD1 mice. These data and modeling analyses more fully characterize PFOA in mice for purposes of estimating internal exposure for use in risk assessment.

Prenatal Exposure to PFOS or PFOA Alters Motor Function in Mice in a Sex-Related Manner

“…Despite the variation in serum levels, brain and liver concentrations of PFOS seem to be more similar in rats and mice of different sexes Liu et al 2009a). Sex-related differences in the renal clearance of PFOA become apparent during the onset of sexual maturation in rats (Hinderliter et al 2006) but not in mice (Kudo and Kawashima 2003;Lou et al 2009). Therefore, we think it is unlikely that sex-related behavioral differences observed in the present study may be due to toxicokinetic differences between males and females.…”

Immunotoxic and hepatotoxic effects of perfluoro-n-decanoic acid (PFDA) on female Harlan Sprague–Dawley rats and B6C3F1/N mice when administered by oral gavage for 28 days

“…Preliminary toxicokinetic (TK) studies estimated that the half-life of PFDA in female HSD rats was 32 d, following a single gavage administration of 2 mg PFDA/kg, with no signs of acute toxicity (unpublished data). Published TK evaluations of PFOA and perfluoronanoic acid (PFNA) indicate longer half-lives in mice compared to rats (Rodriguez et al 2009;Tatum-Gibbs et al 2011), and modeling of PFOA in mice suggests non-linear kinetics at daily doses of 5 mg PFOA/kg or higher compared with lower doses (Lou et al 2009). Serum/plasma concentration of PFDA has been measured by the Centers for Disease Control to assess human exposure to PFASs (CDC 2014), with broad variation among the specific compounds.…”

“…PFNA, a 9-carbon PFAS, induced splenic atrophy and altered immune cell populations in C57BL/6 mice at 0.1 mmol PFNA/kg, but with a 31-38% decrease in body weight for both male and female mice, relative to control (Rockwell et al 2013(Rockwell et al , 2017. Published reports demonstrated the pharmacokinetics of PFOA and PFOS were dependent on the magnitude and frequency of dosing (Lou et al 2009) and on the species (Rodriguez et al 2009;Chang et al 2016). The serum/plasma half-life was shortest in rats (2-4 h in female rats for PFOA and 1-2 month in rats for PFOS), and longest in humans (3-5 yr for PFOA and PFOS).…”

Toxicokinetics of perfluoroalkyl carboxylic acids with different carbon chain lengths in mice and humans

“…This model described the time courses of serum concentrations containing single 3.13 µ mol (1.3 mg for PFOA)/kg doses via gavage administration. To evaluate this model, we applied it to the toxicokinetics of serum concentrations with repeated gavage doses of 20 mg/kg 24) . The dose model, shown in Figure S2, using a gavage dose of 20 mg/kg was selected because single gavage doses of 40 mg/kg or more were necessary to observe any nonlinear pharmacokinetics for PFOA in mice 24) .…”

“…To evaluate this model, we applied it to the toxicokinetics of serum concentrations with repeated gavage doses of 20 mg/kg 24) . The dose model, shown in Figure S2, using a gavage dose of 20 mg/kg was selected because single gavage doses of 40 mg/kg or more were necessary to observe any nonlinear pharmacokinetics for PFOA in mice 24) . PFOA serum concentrations reached a steady state by about 8 days after the first dose, and the minimum and maximum serum levels were approximately 260 and 185 µ g/ml, respectively, for males and 300 and 400 µ g/ml, respectively, for females.…”