Human Exposure Pathways to Per- and Polyfluoroalkyl Substances (PFASs)—A Comprehensive Review of Sources, Physicochemical Properties, and Human Health Risk Assessment

Per- and polyfluoroalkyl substances (PFASs) present a critical challenge to global public health and environmental integrity due to the exceptional stability of the carbon–fluorine (C–F) bond. This review synthesizes current knowledge on PFAS physicochemical properties, exposure pathways, and toxicological outcomes, while evaluating global regulatory efficacy. A central problem addressed in this review is the widening discrepancy between rigid, yet deeply fragmented, international regulatory frameworks and the increasingly complex, non-linear epidemiological data regarding PFAS health risks. While historical paradigms focused heavily on direct carcinogenicity, recent high-resolution data reveal significant heterogeneity and methodological inconsistencies in cancer links. Instead, robust evidence points to severe systemic toxicities—including hepatotoxicity, immunotoxicity, and maternal–fetal disruptions—frequently driven by mixture co-exposures and sex-specific metabolic dimorphisms. Furthermore, the industrial transition to short-chain substitutes has inadvertently compounded the crisis due to their high environmental mobility and resistance to conventional water treatment. By critically evaluating these toxicological and regulatory contradictions, this review demonstrates that current substance-by-substance legislative models fail to mitigate real-world pollution trends. Ultimately, we emphasize the urgent need to transition to holistic mixture modeling, implement unified class-based global regulations, and accelerate advanced destructive remediation technologies to mineralize the resilient C–F bond.