<p>Quartiles of Plasma metal.</p>

Environmental metals are established thyroid carcinogens, yet how their co-exposure collectively reshapes carcinogenic mechanisms remains elusive. This study used ICP-MS to quantify plasma concentrations of 18 metals in 368 thyroid cancer patients and matched controls, with free thyroxine (FT4) levels abstracted from medical records. Subsequently, we applied integrative statistical modeling comprising WQS regression, BKMR modeling, interaction analysis, and causal mediation analysis to elucidate exposure-response relationships and mediating pathways. Cases exhibited elevated plasma levels of Cr, Co, Mn, Ni, Cu, As, Cd, and Sn. WQS regression prioritized Sn, Cd, Ni, and As as risk-contributing metals demonstrating positive weight values, while Sb, Pb, and Zn showed inverse associations. BKMR modeling visualized exposure-response relationships, indicating elevated thyroid cancer risks at higher quantiles of co-exposure. A critical synergistic interaction was identified between the Cd-Sn pair. Causal mediation analysis confirmed FT4 mediates 46–69.3% of thyroid cancer risk for Sn, Cd, Ni, and As. Collectively, these findings highlight the need to incorporate metal mixture surveillance and FT4-based endocrine pathway screening into precision prevention frameworks.