The Potential Carcinogenicity of Long-Term Polymetallic Exposure on the Development of Primary Liver Cancer: Nested Case-Control Evidence from the Jinchang Cohort Study

With the rapid development of global metal exposure, while there is evidence indicating the toxicity of individual metals, the combined impact of mixed exposure of multiple metals on primary liver cancer (PLC) risks remains inadequately characterized. Therefore, we conducted this nested case-control study within the Jinchang cohort, including 129 incidents of PLC cases after 10 years of follow-up and 387 healthy controls matched by propensity score matching methods. Our findings showed that long-term exposure of chromium (Cr, Q2: OR = 10.63, 95% CI: 4.21-26.81; Q3: OR = 5.42, 95% CI: 2.14-13.70), zinc (Zn, Q2: OR = 2.37, 95% CI: 1.10-5.11; Q3: OR = 2.79, 95% CI: 1.32-5.88; Q4: OR = 2.83, 95% CI: 1.33-5.98), iron (Fe, Q4: OR = 0.26, 95% CI: 0.12-0.60), and aluminum (Al, Q4: OR = 0.26, 95% CI: 0.11-0.64) was identified as key contributing factors of the incidents of PLC. Serum Cr exhibited a nonlinear relationship with PLC risk (ρ_overall < 0.001, ρ_nonlinear < 0.001), whereas Zn demonstrated a near-linear positive trend (ρ_overall = 0.023, ρ_nonlinear = 0.395). In contrast, Fe, lithium (Li), and Al showed inverse associations with PLC incidence. Sensitivity analyses further confirmed these relationships. Additionally, significant interactions were observed among serum Cr, Zn, Fe, and Al in modulating PLC risk (ρ_interaction < 0.05). These results highlighted the complex dose-dependent effects and interactions of multimetal exposures in the PLC pathogenesis and underscored the need for further mechanistic investigations.