Association between mixed per- and polyfluoroalkyl substance exposure and thyroid hormone levels in the general population of Shandong, China.

Per- and polyfluoroalkyl substances (PFAS) are recognized endocrine disruptors; however, evidence on PFAS mixture effects, exposure thresholds, and mechanisms of thyroid disruption in Chinese populations remains limited. In this cross-sectional study, 22 serum PFAS congeners were quantified by ultra-high-performance liquid chromatography-tandem mass spectrometry in 165 adults in Shandong, China. Multivariable linear regression and Bayesian kernel machine regression assessed individual and mixture associations with free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH). Benchmark dose (BMD) modeling, network toxicology, and molecular docking were conducted to identify exposure thresholds and potential mechanisms. Eleven PFAS congeners were positively associated with FT3, whereas HFPO-DA showed an inverse association. Five congeners were positively associated with FT4, while PFPeS was inversely associated with TSH. PFAS mixtures showed positive exposure-response relationships with FT3 and FT4 and a negative relationship with TSH. PFOS was an important contributor to FT3 mixture effects (PIP = 0.543). The PFOS BMDL10 was 5.37 ng/mL and exceeded by 73.3% of participants. Network toxicology and molecular docking suggested that PFOS may be associated with thyroid hormone alterations through PI3K-Akt and MAPK signaling pathways. These findings provide population-specific evidence for PFAS mixture-induced thyroid disruption and PFOS risk assessment.