Cardiovascular risks of plastic-associated chemicals: Integrating mixture modeling and SHAP-explained machine learning to unravel linear and non-linear associations.

INTRODUCTION: Plastic-associated chemicals (PACs) are widely detected environmental contaminants, yet their cardiovascular relevance in the context of concurrent exposure remains unclear. We evaluated individual and mixture-level associations of urinary PAC biomarkers with cardiovascular disease (CVD) status among U.S. adults. METHODS: We analyzed 3,831 adults from the National Health and Nutrition Examination Survey (NHANES) 2005-2016. CVD was defined using questionnaire-reported physician diagnoses of congestive heart failure, coronary heart disease, angina pectoris, myocardial infarction, or stroke. Eleven urinary PAC biomarkers were assessed using adjusted single-pollutant models, restricted cubic splines, Weighted Quantile Sum (WQS) regression, Bayesian Kernel Machine Regression (BKMR), linear discriminant analysis (LDA) with SHAP attribution, and lipid mediation analyses. RESULTS: Most PACs showed limited linear associations with CVD after multivariable adjustment, whereas spline analyses suggested non-linear patterns for selected biomarkers. WQS regression indicated a positive mixture association in the primary split (OR = 1.647, 95% CI: 1.235-2.196), with larger weights for ΣDEHP, MiBP, BPA, MCPP, and MBzP. BKMR highlighted triclosan (PIP = 0.6976) and BPA (PIP = 0.4440) as the leading mixture signals. LDA showed good discrimination in the validation set (AUC = 0.813, 95% CI: 0.780-0.847), and SHAP identified age, hypertension, BMI, and selected PACs as prominent contributors to model output. In lipid mediation analyses, the estimated HDL-C-related mediation proportions were 20.8% for BPA, 39.6% for ΣDEHP, and 14.1% for PrP, while the triglyceride-related mediation proportion was 9.7% for the PrP-CVD association. CONCLUSION: Urinary PAC biomarkers and mixture metrics were associated with CVD status among U.S. adults. Prospective studies with repeated exposure assessment and validated cardiovascular outcomes are needed.