Novel Per- and Polyfluoroalkyl Substances (PFAS) Associated with Thyroid Cancer

Abstract Globally, the incidence of thyroid cancer has increased over recent decades. This increase cannot be fully explained by improved detection and diagnostic imaging, suggesting potential environmental contributors. While per- and polyfluoroalkyl substances (PFAS) have been implicated in thyroid dysfunction and cancer, prior research has focused on a limited subset of targeted PFAS, despite nearly 10,000 catalogued PFAS to date. Therefore, we used an untargeted workflow to identify suspected fluorinated substances (FS), including PFAS, and investigate their association with thyroid cancer. Archived plasma from thyroid cancer patients (n = 88) and matched controls (n = 88) in a diverse population were obtained from BioMe, a medical record-linked biobank at the Icahn School of Medicine at Mount Sinai. Plasma liquid chromatography–high-resolution mass spectrometry analysis identified suspected FS features with FluoroMatch software. Hierarchical clustering and logistic regression were used for dimension reduction and FS feature selection, respectively. Mixture analysis was then used to evaluate FS-thyroid cancer relationships. A total of 2566 suspected FS and eight legacy PFAS clustered into three chemically distinct groups. Cluster 1, which contained structurally heterogeneous FS features with weak or null associations with thyroid cancer, was excluded from downstream modeling. Cluster 2 contained six validated legacy PFAS, including perfluorooctanesulfonic acid (PFOS). A mixture comprised of PFOS and other novel PFAS from Cluster 2 that were strongly correlated with PFOS was significantly associated with thyroid cancer in the total population (OR = 1.60, 95% CI: 1.08–2.37). Cluster 3, consisting of a mixture of non-PFAS FS and probable PFAS unique from those in Cluster 2, was also positively associated with thyroid cancer (OR = 1.67, 95% CI: 1.05–2.65). This study contributes novel evidence linking both legacy and previously uncharacterized PFAS to thyroid cancer and highlights the need for expanded surveillance to understand coexposure patterns and toxicity of uncharacterized FS.