Association Between Per‐ and Polyfluoroalkyl Substances ( <scp>PFAS</scp> ) Exposure and <scp>LDL</scp> Cholesterol in US Adults: Evidence From <scp>NHANES</scp>

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants increasingly implicated in cardiometabolic risk. This study evaluates the association between serum PFAS exposure and lipid dysregulation, focusing on low-density lipoprotein cholesterol (LDL-C), a key cardiovascular risk factor. We analyzed 998 adults from the 2017 to 2020 National Health and Nutrition Examination Survey (NHANES), representing a weighted sample of 240 million US adults. Serum concentrations of nine PFAS compounds including perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluoroundecanoic acid (PFUnDA), and perfluorohexane sulfonic acid (PFHxS) were measured. Double/debiased machine learning (DML) estimated the association between PFAS exposure and LDL-C and triglyceride levels, adjusting for demographics, clinical, and behavioral covariates. The median total PFAS concentration was 9.23 ng/mL (interquartile range: 9.67 ng/mL). The weighted mean LDL-C and triglyceride levels were 112.5 mg/dL (95% CI: 112.5-112.5) and 115.6 mg/dL (95% CI: 115.6-115.6), respectively. Total PFAS exposure was significantly associated with higher LDL-C (β = 0.30; 95% CI: 0.05-0.54; p = 0.016). Perfluoroundecanoic acid (PFUnDA), linear PFOS, and methyl-perfluorooctane sulfonic acid (Sm-PFOS) were also significantly associated with elevated LDL-C (β = 12.1, 0.44, 2.83; all p < 0.05). PFHxS was inversely associated with triglycerides (β = -2.26; p = 0.031). In this representative sample of US adults, PFAS exposure is independently associated with lipid dysregulation, particularly elevated LDL-C. However, results should be interpreted with caution given the cross-sectional design, modest effect sizes, and potential residual confounding from unmeasured environmental or dietary factors.