Systemic Inflammation Mediates the Association Between Blood Trihalomethane Concentrations and Cardiovascular Disease in U.S. Individuals Over 45: Insights from NHANES 2005-2012.

Trihalomethanes (THMs), the major byproducts of water chlorination which are associated with various adverse health outcomes. However, the relationship of THMs with cardiovascular disease (CVD) in aging populations remains underexplored. We analyzed data from 5,400 participants in the National Health and Nutrition Examination Survey (NHANES) 2005-2012. Associations between blood THM concentrations and CVD were evaluated using weighted multivariable logistic regression. Weighted quantile sum (WQS) regression was applied to identify the most relevant THM components. We also performed mediation analysis to evaluate the role of inflammatory markers, including neutrophil-to-lymphocyte ratio (NLR), white blood cell count (WBC), and systemic inflammation response index (SIRI). Network toxicology analysis was used to explore the biological pathways linking THM exposure, CVD, and aging. Elevated blood concentrations of THMs, particularly chloroform (TCM) and total THMs (TTHMs), were significantly associated with increased odds of CVD. Stratified analyses revealed stronger associations among older adults, males, individuals with higher BMI, and those with hypertension. WQS regression identified TCM as the predominant contributor to the THM-CVD association, accounting for 58.0% of the mixture's effect. Mediation analysis showed that NLR partially mediated the association between TTHMs and CVD, explaining 7.12% of the total effect. Network toxicology analysis highlighted inflammation-related pathways, including the IL-17 signaling pathway, as key mechanisms linking THM exposure, CVD, and aging. Our study revealed elevated blood TCM and TTHM concentrations are associated with increased prevalence of CVD among U.S. adults aged 45 years and older. Network toxicology and mediation analysis suggest that systemic inflammation may play a mediating role in this relationship.