Evaluating health impacts of exposure to PFAS mixtures: a systematic review of epidemiological studies using mixture methods

Per- and polyfluoroalkyl substances (PFAS) continue to be an emerging chemical class of concern due to their long half-lives in nature and in the human body. There have been many epidemiology studies published in the scientific literature on PFAS and various health effects. Until recently, these studies have focused on assessing exposure to individual PFAS rather than exposure to mixtures of PFAS. Over the past two decades, mixture methods-statistical methods for investigating the association of mixtures-have been developed, making it possible to more accurately assess the risk of adverse health effects associated with exposure to PFAS. To help provide a resource for the overall evaluation of potential health effects of PFAS mixtures, we applied a consistent set of examination methods and criteria for all epidemiology studies that examined the potential relationship between exposure to PFAS mixtures and various types of health outcomes. We identified 233 cohort studies, 39 case-control studies, and 89 cross-sectional studies that evaluated general background-level exposures, exposure from contaminated sites, and occupational exposure to PFAS mixtures and health outcomes including metabolic, cardiovascular, and immune system effects, fetal development, pregnancy outcomes, reproductive effects, liver function, and respiratory effects. We extracted study characteristics and results in a systematic manner and performed a formal study quality evaluation and classified studies into tiers based on their methodological strengths and weaknesses. We found 42 prospective cohort studies, five nested case-control studies, and one traditional case-control study that qualified for inclusion in the highest tier of quality (Tier I). Overall, the weight of evidence from this systematic review indicates that the available epidemiology studies currently support an association between exposure to PFAS mixtures and adiposity, increased total cholesterol, and hypertension, while the evidence for all other health outcomes is suggestive or limited.