Consideration of pathways for immunotoxicity of per- and polyfluoroalkyl substances (PFAS)

Abstract

Background: Per- and polyfluoroalkyl substances (PFAS) are of public health concern, because of their ubiquitous and extremely persistent occurrence, and depending on their structure, their bio-accumulative, mobile and toxic properties. Human health effects associated with exposure to PFAS include adverse effects on the immune system. In 2020, EFSA (the European Food Safety Authority) defined adverse effects on the immune system as the most critical effect for human health risk assessment, based on reduced antibody responses to childhood vaccines and similar effects observed in experimental animal studies. Likewise, the U.S. EPA (Environmental Protection Agency) considers PFAS-induced immunotoxicity, especially in children, as the critical effect for risk assessment. However, the mechanisms by which antibody concentrations are impacted are not completely understood. Furthermore, other targets of the immune system functions have been reported in the literature.

Objective: The aim of this review is to explore PFAS-associated immune-related effects. This includes, relevant mechanisms that may underlie the observed effects on the immune system, immunosuppression as well as immunoenhancement, such as i) modulation of cell signalling and nuclear receptors, such as NF-κB and PPARs; ii) alteration of calcium signalling and homoeostasis in immune cells; iii) modulation of immune cell populations; iv) oxidative stress and v) impact on fatty acid metabolism & secondary effects on the immune system.

Methods: A literature research was conducted using three databases (Web of Science, PubMed, and Scopus), which were searched in July 2021 for relevant studies published in the time frame from 2018 to 2021. In total, 487 publications were identified as potentially eligible and following expert-based judgement, articles relevant for mechanisms of PFAS induced immunotoxicity are discussed.

Conclusions: Taken together, we show that there is substantial evidence from both in vitro and in vivo experimental as well as epidemiological studies, supporting that various PFAS, not only PFOA and PFOS, affect multiple aspects of the immune system. Timing of exposure is critical, because the developing immune system is especially vulnerable to toxic insults, resulting in a higher risk of particularly adverse immune effects but also other organs later in life.

Keywords: HBM4EU; Immune function; Immunotoxicity; Molecular mechanisms; Per- and polyfluoroalkyl substances; Vaccination response.

Fig. 1

Illustration of the literature research. Figure Legend: For details on the search terms, please see Table 1 in Appendix

Fig. 2

Mechanistic considerations of modulation of (developmental) immune functions by PFAS. Figure Legend: Relevant mechanisms that may underlie the observed effects on the (developmental) immune system are: i) modulation of cell signalling and nuclear receptors, such as NF-κB, PPARs and others; downstream signalling might vary due to receptor crosstalk; ii) alteration of calcium signalling and calcium homoeostasis in immune cells (having an impact on oxidative stress, inflammasome activation, nuclear receptors such as NF-κB, cytokine levels and degranulation of mast cells); iii) modulation of key cell populations necessary for an antibody response; iv) modulation of NK cells; v) modulation of mast cells and IgE influencing hypersensitivity; vi) oxidative stress and vii) impact on fatty acid metabolism and secondary effects on the immune system. Green arrows indicate induction, red arrows inhibition, grey arrows modulation in either direction and dashed lines potential modulation (with a higher degree of uncertainty)