Association of mixed metal exposure with kidney injury and benchmark dose estimation in Chinese adults aged 40 years and older.

Mixed exposure to metal elements is associated with an increased risk of kidney injury, but the underlying mechanism remains rather complex, making risk assessment difficult. We selected 842 adults aged between 40 and 75 from Sichuan Province, and concentrations of eight metals (Mg, Ca, Fe, Zn, As, Cd, Cu, Pb) were measured in blood and urine. Weighted quantile sum (WQS) regression, Bayesian kernel machine regression (BKMR), and explainable machine learning (ML) approaches were integrated to systematically evaluate the associations between metal mixtures and kidney injury. The mediating effect model and benchmark dose (BMD)/benchmark dose lower bound (BMDL) analysis were then used to estimate the risk thresholds for individual and combined exposure of key metals. The results showed that blood metal mixtures were significantly and positively associated with kidney injury risk, driven primarily by Cd and Pb. BKMR analysis revealed that there was a synergistic relationship between Cd-Pb and Cd-Fe, while there was an antagonistic relationship between Ca-Cd. Explainable ML revealed that Zn has an antagonistic effect on Cd/Pb, while Ca/Zn has a certain protective effect. Mediation analysis revealed that mALB and β2-MG were potential mediating factors in the association between cadmium/lead exposure and chronic kidney disease. β2-MG exhibited a more stable indirect effect. The BMD results showed that among the total population, the BMDL05 value of urinary lead was the lowest (0.44 μg/g Cr). These results provide a quantitative basis for the risk prevention and health standard setting of mixed metal exposure in the middle-aged and elderly population.