Cumulative PFAS exposure: a scientific basis for redefining public health policy

Abstract Problem Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals known for their persistence, bioaccumulation, and toxicity. NHANES biomonitoring data (2017-2018) demonstrate widespread PFAS detection in human blood. Although EFSA established a tolerable weekly intake (TWI) for four PFAS compounds in 2020, current regulatory frameworks primarily assess individual substances, overlooking cumulative risks from real-world mixture exposures. Addressing cumulative exposure is critical to ensuring effective public health protection. Description of the problem This review critically assessed existing cumulative risk models, including dose addition, Relative Potency Factor (RPF), and Toxic Equivalency (TEF) approaches, evaluating their applicability to human biomonitoring datasets. Emphasis was placed on integrating mixture toxicity principles and predicting health risks at environmentally relevant exposure levels. The main questions addressed were: (1) To what extent do PFAS mixtures exceed current health-based guidance values? (2) How well do existing regulatory frameworks account for cumulative risks? Results Mixture risk assessment revealed that cumulative PFAS exposure exceeded health-based guidance values in up to 24% of European adolescents, with Hazard Index values reaching 5.8. PFOS and PFOA were predominant contributors. Elevated immunotoxic risks were detected even among individuals with exposure levels previously considered safe, highlighting a mismatch between regulatory thresholds and real-world health risks. Lessons The findings underscore the urgent need to integrate cumulative exposure science into regulatory frameworks. To better protect vulnerable populations, mixture-based risk assessment approaches must be adopted. The lessons learned are applicable across diverse national settings facing widespread PFAS contamination, and they call for harmonized, precautionary public health actions. Key messages • Cumulative PFAS exposure poses health risks even below current regulatory thresholds. • Policy frameworks must urgently adopt cumulative risk assessment approaches.