Association of urinary heavy metals with chronic pain depression co-morbidity: based on NHANES

Introduction Accumulating evidence indicates that environmental exposure to toxic metals poses significant risks to human health, yet limited evidence exists regarding the neuropsychiatric effects of mixed metal exposure, particularly in the context of pain-depression co-morbidity (PDC). Methods To address this gap, we analyzed data from the National Health and Nutrition Examination Survey (NHANES) to evaluate individual and synergistic associations between 12 urinary metals and PDC risk using multi-variable logistic regression, restricted cubic spline (RCS) analysis, and Bayesian kernel machine regression (BKMR). Results This cross-sectional study of 1,202 participants identified a PDC prevalence of 12.4% ( n = 149). Fully adjusted logistic regression identified four metals with significant positive associations with PDC: cadmium (Cd) (odds ratio [OR] = 1.293, 95% confidence interval [CI]: 1.116–1.500, p = 0.001), cobalt (Co) (OR = 1.300, 95% CI: 1.089–1.548, p = 0.003), thallium (Tl) (OR = 1.243, 95% CI: 1.042–1.478, p = 0.015), and tungsten (Tu) (OR = 1.158, 95% CI: 1.017–1.317, p = 0.026). Linear regression confirmed these associations, with uranium (Ur) showing an additional significant link ( β = 0.039, p = 0.033). RCS analysis revealed a nonlinear relationship for Tu ( p = 0.036). BKMR modeling demonstrated a positive overall effect of mixed metal exposure, with Tu (posterior inclusion probability [PIP] = 0.91), Tl (PIP = 0.88), Cd (PIP = 0.85), and Co (PIP = 0.82) as the predominant contributors. In single-metal exposure profiles, PDC scores increased dose-dependently with rising concentrations of Tu, Tl, and Cd when co-exposures were fixed at their 25th, 50th, and 75th percentiles. These findings identify urinary Tu, Tl, Cd, and Co as critical biomarkers for PDC risk, revealing their non-monotonic and dose-responsive neurotoxic effects. The BKMR-derived synergy among metal mixtures underscores the necessity of evaluating environmental exposures holistically rather than in isolation. Discussion These results advance our understanding of metal-induced neuropsychiatric pathophysiology and support the integration of metal exposure screening into clinical assessments of affective-somatic disorders.