Estimation of species- and sex-specific PFAS pharmacokinetics in mice, rats, and non-human primates using a Bayesian hierarchical methodology

The carbon chain length, degree of fluorination, and functional group of per- and polyfluoroalkyl substances (PFAS) influences the bioaccumulation and half-lives of these substances in humans and laboratory animals. Pharmacokinetic (PK) studies using laboratory animals characterize the absorption, distribution, metabolism, and excretion (ADME) of a PFAS and can provide the underlying data for inter-species extrapolation to inform human pharmacokinetics. However, variations in ADME arise due to differences in protein binding and renal and hepatobiliary clearance mechanisms. In particular, sex- and species-specific differences in active transporter abundance and PFAS binding affinity challenge body weight-based extrapolation assumptions from animal models to human PK parameters. Because these protein-dependent changes in ADME do not always scale with species body weight, classic allometric scaling assumptions can fail to account for species-specific transporter-mediated clearance. In addition, study-dependent differences in pharmacokinetic modeling approaches and parameterization techniques can result in large differences among the PK parameters reported in the literature. To better quantify PFAS pharmacokinetics and characterize the underlying uncertainty, we implemented a Bayesian inference hierarchical model to estimate PFAS PK parameters for multiple species (mice, rats, and non-human primates) using numerous single-dose animal studies. Through an alternative parameterization of the one- and two-compartment models, this method improved parameter identifiability and allowed for the use of prior information on PFAS absorption rate, clearance, and volume of distribution. Using reported time-course concentration data, we estimated sex-specific clearance, volume of distribution, and half-life across mice, rats, and non-human primates using a consistent modeling methodology for eight PFAS: PFHxA, PFHxS, PFNA, PFDA, PFBS, PFBA, PFOA, and PFOS. The resulting comparison to available human data demonstrated that standard volume of distribution body-mass scaling (BW¹) for PFAS generally agrees with reported human values while standard assumptions for allometric scaling of clearance (BW^3/4) are not appropriate for most of the PFAS investigated in this study. In addition, we demonstrated that there may be considerable differences in clearance for PFAS in some species when comparing across different sexes and routes of exposure.