Human exposure and toxicity of per- and polyfluoroalkyl substances: Narrative review and perspectives

In this paper, the status of per- and polyfluoroalkyl substances (PFAS) is narratively reviewed from the perspective of toxicity mechanisms, biodistribution, species differences, human exposure sources, human biomonitoring, and epidemiology. Although toxicological investigations have been conducted, interspecies differences in toxicological mechanisms and toxicokinetics are not fully understood. For example, peroxisome proliferator-activated receptors (PPARα) are a target receptor of PFAS. Although there are distinct differences in response between rodents and humans, human PPARα can be activated at a high dose and PPARα-independent effects are also observed. In addition, epidemiological studies provide mechanistic evidence in carcinogenesis (epigenetics and immunomodulation). In humans, the biological half-lives of several PFAS over years are longer than in other species because of low renal clearance. Genetic differences in transporter proteins (e.g. OAT) may explain the long half-lives in humans. We present data from Japan for human exposure and biomonitoring. Exposure to PFAS is still caused via contaminated drinking water and consumption of contaminated foods around military bases (Okinawa, western Tokyo, etc.) and fluorochemical plants (Osaka, etc) due to past PFAS uses. Even without specific contamination, seafood consumption is a common route of exposure in Japan and East Asian countries, resulting in elevated baseline in blood PFAS levels. For sustainable economic progress, it is necessary to properly prevent or manage the negative effects of various chemicals while making good use of their positive characteristics. Consequently, it is necessary to understand their mechanisms of toxicity, elucidate the kinetics in the human body, and consider combined exposure effects. A normative approach and establishment of a management system are required for PFAS in the future.