A Systematic Literature Review of Toxicological Studies on Per- and Polyfluoroalkyl Substances (PFAS)

Per- and Polyfluoroalkyl substances (PFAS) encompass a diverse group of industrial chemicals comprising thousands of compounds resistant to both environmental degradation and metabolic breakdown, due to the strong carbon-fluorine (C-F) bonds dominating their structures and are thus collectively referred to as “forever chemicals”. PFAS products originating from fluorotelomer precursors have fully substituted methyl or methylene groups, chain lengths ranging from 4 to 14 carbon atoms and a carboxylic or sulfonic acid group. These chemical features have been associated with bioaccumulation and bioconcentration. Within this group, perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) have been extensively studied showing they are globally detected in humans, biota and the environment. They are recognized as persistent organic pollutants (POPs) and are regulated under international agreements such as the Stockholm Convention and, within the European Union, under the POPs Regulation (EU 2019/1021) due to their documented long-term toxicity, persistence, bioaccumulation, and links to adverse effects on human health and the environment. To compile the latest PFAS toxicity data, we conducted a systematic review spanning from January 2019 to December 2023, following the PRISMA guidelines, encompassing epidemiological studies in humans and toxicological studies in experimental animals, in vitro assays on human cells, and studies combining experimental and in silico approaches. We assessed the available toxicological data and performed an in-depth analysis of studies focusing on potential human health effects, with the aim of leveraging the findings within a cheminformatics framework. Our investigation identified a total of 360 suitable studies. Human exposure studies identified immunotoxic effects as being among the most prevalent endpoints in PFAS toxicity. According to our findings, hepatotoxicity linked to peroxisome proliferator-activated receptor alpha (PPARα) activation, neurotoxicity, developmental and endocrine effects, and associations with various types of cancer were found amongst the negative health outcomes associated with PFAS exposure. The findings highlight the need for further research to prevent regrettable substitutions and to enable implementation of PFAS-free technologies.