Environmental exposure to metals is widespread, yet evidence on the association between blood metal mixtures and hyperuricemia remains limited. We examined the associations of five blood metals, individually and as a mixture, with hyperuricemia in U.S. adults and explored whether the systemic immune-inflammation index mediated these associations. We conducted a cross-sectional analysis of 13,285 adults aged 20 years or older from the National Health and Nutrition Examination Survey 2011–2018. Blood lead, cadmium, mercury, manganese, and selenium were evaluated using survey-weighted logistic regression, weighted quantile sum regression, and Bayesian kernel machine regression. Hyperuricemia was defined as serum urate concentrations of at least 7.0 mg/dL in men and at least 6.0 mg/dL in women. In fully adjusted models, higher blood lead and selenium concentrations were associated with greater odds of hyperuricemia. The weighted quantile sum index showed a positive association with hyperuricemia, with lead and selenium contributing the largest weights. Bayesian kernel machine regression further suggested an adverse overall mixture effect at higher exposure levels and identified mercury and lead as relatively influential mixture components. Mediation analysis showed little evidence that the systemic immune-inflammation index meaningfully mediated the association between the metal mixture and hyperuricemia. In this nationally representative study, blood metal mixtures were positively associated with hyperuricemia, with lead showing the most consistent signal across analytic approaches. Prospective studies are needed to clarify temporality and underlying biological mechanisms.

We analyzed NHANES 2011–2018 data among adults aged ≥20 years (analytic sample N = 13,285). Blood lead (Pb), cadmium (Cd), mercury (Hg), manganese (Mn), and selenium (Se) were imputed below the limit of detection as LOD/√2, ln-transformed, and (when required) z-score standardized. HUA was defined as serum urate ≥7.0 mg/dL (men) or ≥6.0 mg/dL (women). Primary inference used the NHANES complex design (SDMVSTRA/SDMVPSU) and 8-year metal subsample weights (WT_8YR_METAL). Associations were estimated using survey-weighted logistic regression (ORs). Mixture effects were assessed using WQS (q=4, rh=10, validation=0.6, b=500, positive constraint) and BKMR (random subsample N=3000, binomial, varsel=TRUE). Causal mediation analysis (CMA) evaluated SII mediation on the risk difference (RD) scale.

In fully adjusted single-metal models, higher Pb (OR 1.34, 95% CI 1.20–1.50) and Se (OR 1.99, 95% CI 1.14–3.47) were associated with higher odds of HUA. WQS indicated a positive mixture association (OR 1.32, 95% CI 1.20–1.46), with the largest weights for Pb and Se. BKMR suggested an increasing overall joint effect at higher exposure quantiles and higher variable importance for Hg (PIP 0.742) and Pb (PIP 0.529). CMA showed little/no evidence of mediation via SII (primary ACME RD ≈ 0), while the total effect was driven by the direct effect (TE RD ≈ 0.028).

In a nationally representative U.S. adult sample, blood metal mixture exposure was associated with higher odds of hyperuricemia, with Pb consistently implicated across methods. SII did not meaningfully mediate the mixture–HUA association. Prospective studies are warranted to confirm temporality and elucidate alternative mechanisms.