Assessing the human health risks of per- and polyfluoroalkyl substances: A need for greater focus on their interactions as mixtures.

Humans are exposed to complex mixtures of per- and polyfluoroalkyl substances (PFAS). However, human health risk assessment of PFAS currently relies on animal toxicity data derived from individual substance exposure, which may not adequately predict the risk from combined exposure due to possible interactions that can influence the overall risk. Long-chain perfluoroalkyl acids (PFAAs), particularly perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are recognised as global emerging contaminants of concern due to their ubiquitous distribution in all environmental media, wildlife, and humans, persistency, bioaccumulative-, toxic-, and human health-risk potentials. This article reviews the current understanding of the human health risks associated with PFAS exposure focusing on more recent toxicological and epidemiological studies from 2010 to 2020. The existing information on PFAA mixtures was also reviewed in an attempt to highlight the need for greater focus on their potential interactions as mixtures within the class of these chemicals. A growing number of toxicological studies have indicated several adverse health outcomes of PFAA exposure, including developmental and reproductive toxicity, neurotoxicity, hepatotoxicity, genotoxicity, immunotoxicity, thyroid disruption, and carcinogenicity. Epidemiological findings further support some of these adverse human health outcomes. However, the mechanisms underlying these adverse effects are not well defined. A few in vitro studies focusing on PFAA mixtures revealed that these compounds may act additively or interact synergistically/antagonistically depending on the species, dose level, dose ratio, and mixture components. Hence, the combined effects or potential interactions of PFAS mixtures should be considered and integrated into toxicity assessment to obtain a realistic and more refined human health risk assessment.