The association between environmental toxin exposure and frailty: A full exposure group approach using NHANES 2013–2016

Evidence indicates that exposure to environmental chemicals may be related to frailty; however, most existing research has focused on single-exposure scenarios. This study aims to systematically evaluate the relationships between multiple environmental toxin exposures and frailty using a comprehensive exposure group approach and to investigate potential mechanisms mediated by systemic inflammation. Data from 2354 participants in the 2013-2016 National Health and Nutrition Examination Survey (NHANES) were analyzed. Environmental toxins were categorized into 10 groups, encompassing 61 substances. Frailty was assessed using a 36-item Frailty Index (FI). We applied an exposure‑wide association study (ExWAS; to screen for individual toxin-frailty associations) and deletion/substitution/addition (DSA; to identify key exposures in multi‑exposure contexts) models, and used Bayesian kernel machine regression (BKMR; to evaluate joint relationships and potential interactions among selected exposures). The role of systemic inflammation was evaluated through mediation analysis. Of the 2354 adults analyzed, 657 (27.9 %) were classified as frailty. ExWAS and DSA models identified total nicotine equivalent-2, tungsten, cobalt, tin, and N-acetyl-S-(2-carboxyethyl)-L-cysteine as significant exposures associated with frailty. BKMR analysis revealed a positive correlation between key exposures and frailty. Mediation analysis indicated that systemic inflammation mediated 2.5-14.6 % of these associations. To our knowledge, this is the first comprehensive study to report associations between three categories of five environmental toxins and frailty in U.S. adults, with inflammation potentially serving as a partial mediator. These findings are critical for identifying hazardous environmental chemicals and developing targeted strategies to promote healthy aging.