Differential Associations of Internal and Residential Lead Exposure Pathways with Body Mass Index: A Mixture Analysis of Biomarkers and Household Dust

Background: Human lead exposure is a multi-pathway phenomenon that integrates internal biological burden with persistent residential environmental reservoirs. Although individual lead metrics have been linked to cardiometabolic dysfunction, current research often fails to capture the ‘exposome’ reality of joint, nonlinear, and interaction-dependent effects on metabolic outcomes like BMI. Objectives: To evaluate associations between biological (blood and urinary) and residential dust (window and floor) lead measures and BMI, and to characterize nonlinear and interaction-dependent mixture effects using Bayesian Kernel Machine Regression (BKMR). Methods: We analyzed data from NHANES 2001–2002, a nationally representative survey of the U.S. noninstitutionalized civilian population. Window and floor dust lead (µg/ft2) were obtained from the NHANES household dust component, and blood lead (µg/dL) and urinary lead (µg/L) were measured using standardized NHANES laboratory protocols. BMI was calculated from measured height and weight. Missing data were addressed using multivariate imputation by chained equations. Descriptive statistics and multivariable linear regression were used to estimate adjusted associations between individual lead metrics and BMI, controlling for age, gender, income, race/ethnicity, and education. BKMR was then applied to evaluate joint mixture effects, estimate univariate and bivariate exposure–response functions, and quantify relative exposure importance using posterior inclusion probabilities (PIPs). Results: In covariate-adjusted linear regression, blood lead (β = −0.485; 95% CI: −0.566, −0.405; p < 0.001) and window dust lead (β = −0.00047; 95% CI: −0.00067, −0.00026; p < 0.001) were inversely associated with BMI, whereas floor dust lead was positively associated (β = 0.258; 95% CI: 0.209, 0.306; p < 0.001). Urinary lead was inversely but not significantly associated with BMI (β = −0.111; 95% CI: −0.235, 0.013; p = 0.079). In BKMR, blood lead was the dominant contributor, with a posterior inclusion probability (PIP; proportion of iterations in which an exposure is selected) of 1.00. Window dust lead showed modest inclusion (PIP = 0.26), whereas urinary and floor dust lead were not selected (PIP = 0.00). Exposure–response functions indicated modest nonlinearity for blood lead and greater divergence for the blood lead–window dust lead pairing at higher exposure levels. The overall mixture effect declined across increasing joint exposure quantiles, crossing the null near the median and becoming increasingly negative at higher mixture levels. Conclusions: In our study, lead metrics showed heterogeneous associations with BMI, and BKMR indicated that internal lead burden (blood lead) primarily drove mixture-related BMI patterns, with evidence that window dust lead may modify mixture effects at higher co-exposure levels. These findings support evaluating multiple lead exposure pathways jointly and using flexible mixture models to capture nonlinear and interaction-dependent relationships with BMI.