Exposure to per- and polyfluoroalkyl substance (PFAS) mixtures increases papillary thyroid cancer risk and clinicopathological aggressiveness: Findings from a case-control study and risk assessment

Per- and polyfluoroalkyl substances (PFAS) have been reported to possess endocrine-disrupting and tumor-promoting activity. However, the association between PFAS exposure and papillary thyroid carcinoma (PTC) remains poorly understood. This case-control study investigated whether PFAS exposure is associated with PTC risk, and if so, whether this association is mediated through thyroid hormone disruption and linked to specific clinicopathological and genetic features of the tumor. We recruited 60 PTC patients and 60 healthy controls from Shanghai, China. Serum levels of PFAS and thyroid hormones were measured. Multiple linear regression, weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) were used to analyze associations between PFAS mixtures and individual congeners with PTC risk and thyroid function. A chronic reference dose (CRfD) for PFOS was derived from animal studies using benchmark dose modeling. PTC patients had significantly elevated serum levels of several PFAS, including perfluorooctane sulfonate (PFOS), perfluorodecanoic acid (PFDA), and 8:2 chlorinated perfluoroalkyl ether sulfonic acid (8:2Cl-PFESA), compared to controls. WQS regression indicated a significant positive association between PFAS mixture exposure and PTC risk (OR = 2.01, p = 0.023), with 8:2CI-PFESA, PFDoDA, PFBS, and PFOS identified as the primary contributors. Furthermore, specific PFAS congeners were associated with more aggressive tumor features, including advanced TNM stage and with high-risk genetic alterations such as TERT mutation, and RAS&TERT promoter co-mutations. In terms of hormonal effects, Furthermore, perfluorobutanesulfonic acid (PFBS) and 8:2Cl-PFESA showed significant negative dose-response relationships with FT3 levels in patients, suggesting a potential link between PFAS-induced thyroid disruption and carcinogenesis. The derived oral CRfD for PFOS, based on triiodothyronine reduction, was 40 ng/kg·bw/day. Our findings indicate that PFAS exposure is associated with an increased risk of PTC, potentially through mechanisms involving thyroid hormone disruption and the promotion of more aggressive tumor characteristics. These results underscore the need for stricter regulation of industrial PFAS emissions and enhanced thyroid function monitoring in high-risk populations. • PFASs mixture exposure was positively associated with PTC risk. • High level of PFAS (PFOS, PFHxS, etc.) in PTC correlated with tumor aggressiveness. • PFBS and 8:2Cl-PFESA showed negative dose-response associations with FT3 in PTC. • Derived human oral CRfD for PFOS based on T3 reduction was 40 ng/kg·bw/day.