Internal Relative Potency Factors Based on Immunotoxicity for the Risk Assessment of Mixtures of Per- and Polyfluoroalkyl Substances (PFAS) in Human Biomonitoring

Abstract

Background: Relative potency factors (RPFs) for per- and polyfluoroalkyl substances (PFAS) have previously been derived based on liver effects in rodents for the purpose of performing mixture risk assessment with primary input from biomonitoring studies. However, in 2020 the European Food Safety Authority (EFSA) established a tolerable weekly intake (TWI) for four PFAS assuming equal toxic potency for immune suppressive effects in humans.

Objectives: The aim of this study was to explore the possibility of deriving RPFs for immune suppressive effects using available data in rodents and humans.

Methods: Lymphoid organ weights, differential blood cell counts, and clinical chemistry from 28-day studies in male rats from the National Toxicology Program (NTP) were combined with modeled serum PFAS concentrations to derive internal RPFs by applying dose-response modelling. Furthermore, a novel approach was used to estimate internal RPFs based on epidemiological data by dose-response curve fitting optimization, looking at serum antibody concentrations and key cell populations from the National Health and Nutrition Examination Survey (NHANES).

Results: Internal RPFs were successfully derived for eight PFAS based on rat thymus weight, spleen weight, and globulin concentration. The available dose-response information for blood cell counts did not show a significant trend. Immunotoxic potency in serum was determined in the order PFDA > PFNA > PFHxA > PFOS > PFBS > PFOA > PFHxS. The epidemiological data showed inverse associations for the sum of PFOA, PFNA, PFHxS, and PFOS with serum antibody concentrations to mumps and rubella, but the data did not allow for deduction of reliable internal RPF estimates.

Discussion: The internal RPFs for PFAS based on decreased rat lymphoid organ weights are similar to those previously established for increased rat liver weight, strengthening the confidence in the overall applicability of these RPFs.

Note:

Funding Information: This work received funding from European Union’s Horizon 2020 research and innovation program under Grant agreement No 733032 HBM4EU (www.HBM4EU.eu), and received co-funding from the authors’ organizations.

Declaration of Interests: The authors have no conflict of interest to declare.

Keywords: human biomonitoring, PFAS, chemical mixtures, immunotoxicity, risk assessment, HBM4EU, RPF