Structural drivers of per- and polyfluoroalkyl substances environmental fate, bioaccumulation kinetics, and sub-cellular toxicity: A systematic review of legacy and emerging alternatives

Abstract

Per - and polyfluoroalkyl substances (PFAS) pose a critical global challenge due to extreme persistence and multi-media migration. Following PRISMA 2020 guidelines, this systematic review synthesized data from 22 core studies to evaluate environmental fate, bioaccumulation, and sub-cellular toxicity using an adapted Joanna Briggs Institute appraisal. The findings revealed a structural division: hydrophobic long-chain compounds (PFOS, PFOA, PFNA) and chlorinated substitutes (8:2 Cl-PFESA) sequestered in solid repositories, exhibiting sediment-water partition coefficients ( log K d ) from 1.64 to 4.14 with a direct linear increase ( R 2 = 0.99 ) per carbon atom. Soluble short-chain variants (PFBA, PFBS) and ether substitutes (GenX) tracked with stormwater and translocated into edible foliage. In aquatic webs, linear PFOS showed extreme biomagnification in apex predators (Trophic Magnification Factors 3.7–9.3), accelerated by slow in-situ transformation of sediment SAmPAP precursor reservoirs. Epidemiological tracking indicated traditional water-based one-compartment toxicokinetic models systematically under-predicted real-world serum burdens (up to 116.2 μ g / L for PFOA) in high-exposure cohorts by omitting multi-media pathways like topsoil dust and local produce ingestion. At the sub-cellular scale, in silico docking verified that short-chain alternatives like PFBS possessed high competitive binding affinities for fish estrogen receptors, triggering multi-generational reproductive failure, altered endocrine signaling, and disrupted adipocyte lipogenesis. While shortening fluorocarbon chains minimizes human serum accumulation, it heightens environmental mobility and introduces sub-cellular metabolic risks. Future research must resolve baseline data deficits across the Global South and adopt multi-media toxicokinetic frameworks to establish internationally standardized reference doses.