Per- and Polyfluoroalkyl Substance Toxicity and Human Health Review: Current State of Knowledge and Strategies for Informing Future Research

Abstract

Reports of environmental and human health impacts of per- and polyfluoroalkyl substances (PFAS) have greatly increased in the peer-reviewed literature. The goals of the present review are to assess the state of the science regarding toxicological effects of PFAS and to develop strategies for advancing knowledge on the health effects of this large family of chemicals. Currently, much of the toxicity data available for PFAS are for a handful of chemicals, primarily legacy PFAS such as perfluorooctanoic acid and perfluorooctane sulfonate. Epidemiological studies have revealed associations between exposure to specific PFAS and a variety of health effects, including altered immune and thyroid function, liver disease, lipid and insulin dysregulation, kidney disease, adverse reproductive and developmental outcomes, and cancer. Concordance with experimental animal data exists for many of these effects. However, information on modes of action and adverse outcome pathways must be expanded, and profound differences in PFAS toxicokinetic properties must be considered in understanding differences in responses between the sexes and among species and life stages. With many health effects noted for a relatively few example compounds and hundreds of other PFAS in commerce lacking toxicity data, more contemporary and high-throughput approaches such as read-across, molecular dynamics, and protein modeling are proposed to accelerate the development of toxicity information on emerging and legacy PFAS, individually and as mixtures. In addition, an appropriate degree of precaution, given what is already known from the PFAS examples noted, may be needed to protect human health. Environ Toxicol Chem 2021;40:606-630. © 2020 SETAC.

Keywords: Contaminants of emerging concern; Per- and polyfluoroalkyl substances; Perfluorooctane sulfonate; Perfluorooctanoic acid; Persistent compounds.

FIGURE 1:

Effects of per- and polyfluoroalkyl substances on human health. Used with permission from European Environment Agency (2019). Original sources for this figure: National Toxicology Program (2016), C8 Science Panel (2012), IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (2017), Barry et al. (2013), Fenton et al. (2009), and White et al. (2011b).

FIGURE 2:

Example of proteins that are known to influence per- and polyfluoroalkyl substance toxicokinetics through binding (which affects tissue distribution and accumulation) and facilitation of membrane transport (which affects clearance and reabsorption). Illustrated for kidney and blood. L-FABP = liver fatty acid binding protein; Oat1 = organic anion transporting 1; Oatp1a1 = organic anion transporting polypeptide 1a1; Ost = organic solute transporter.

FIGURE 3:

Simulations based on Cheng and Ng (2017), perfluorooctanoic acid (PFOA) toxicokinetic model for Sprague-Dawley rats. (A) Effect of dose on initial half-life. (B) Effect of higher and lower levels of serum albumin, which binds to PFOA, on serum clearance dynamics. (C) Effect of extent of reabsorption in kidney on serum half-life, based on organic anion transporting polypeptide 1a1 activity. (D) Effect of dose on elimination kinetics when half-life is longer because of higher albumin binding. Oat1 = organic anion transporting 1; Oat3 = organic anion transporting 3; Ost = organic solute transporter.