PFASs: What can we learn from the European Human Biomonitoring Initiative HBM4EU.

Per- and polyfluoroalkyl substances (PFASs) were one of the priority substance groups selected which have been investigated under the ambitious European Joint programme HBM4EU (2017-2022). In order to answer policy relevant questions concerning exposure and health effects of PFASs in Europe several activities were developed under HBM4EU namely i) synthesis of HBM data generated in Europe prior to HBM4EU by developing new platforms, ii) development of a Quality Assurance/Quality Control Program covering 12 biomarkers of PFASs, iii) aligned and harmonized human biomonitoring studies of PFASs. In addition, some cohort studies (on mother-child exposure, occupational exposure to hexavalent chromium) were initiated, and literature researches on risk assessment of mixtures of PFAS, health effects and effect biomarkers were performed. The HBM4EU Aligned Studies have generated internal exposure reference levels for 12 PFASs in 1957 European teenagers aged 12-18 years. The results showed that serum levels of 14.3% of the teenagers exceeded 6.9 µg/L PFASs, which corresponds to the EFSA guideline value for a tolerable weekly intake (TWI) of 4.4 ng/kg for some of the investigated PFASs (PFOA, PFOS, PFNA and PFHxS). In Northern and Western Europe, 24% of teenagers exceeded this level. The most relevant sources of exposure identified were drinking water and some foods (fish, eggs, offal and locally produced foods). HBM4EU occupational studies also revealed very high levels of PFASs exposure in workers (P95: 192 µg/L in chrome plating facilities), highlighting the importance of monitoring PFASs exposure in specific workplaces. In addition, environmental contaminated hotspots causing high exposure to the population were identified. In conclusion, the frequent and high PFASs exposure evidenced by HBM4EU strongly suggests the need to take all possible measures to prevent further contamination of the European population, in addition to adopting remediation measures in hotspot areas, to protect human health and the environment. HBM4EU findings also support the restriction of the whole group of PFASs. Further, research and definition for additional toxicological dose-effect relationship values for more PFASs compounds is needed.

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

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.