Associations between volatile organic compound mixtures and allostatic load: Evidence from the Green Heart Louisville...

Allostatic load (AL) represents the cumulative physiological burden from activation of adaptive response systems. High AL, resulting from multisystemic dysregulation after chronic activation of response systems, is associated with chronic disease risk. Volatile organic compound (VOC) exposure may contribute to this dysregulation, but the impact on AL is unclear. In this study, we evaluated the association between urinary VOC metabolites and AL in 959 adult participants of the Green Heart Louisville Project across four visits (2018 or 2019, 2021, 2022, 2023). We quantified AL using a Mahalanobis Distance-based index (AL-MD) derived from 15 biomarkers spanning cardiovascular, metabolic, immunoinflammatory, and neuroendocrine systems. In spot urine samples, we assessed seven metabolites of six parent VOCs (acrolein (3HPMA), 1,3-butadiene (34HBMA), N,N-dimethylformamide (MCaMA), ethylbenzene/styrene (PGA; MADA), and xylene (2MHA; 3MHA+4MHA)). Quantile-based g-computation was used to estimate the mixture effects on AL adjusting for covariates. A one quartile increase in this VOC metabolite mixture was associated with a 0.10 [0.02, 0.19] standard deviation higher AL-MD score. Effects were more pronounced in middle-aged (40-64 y/o; 0.15 [0.03, 0.26]) and older adults (65+ y/o; 0.14 [-0.06, 0.35]) compared with young adults (25-39 y/o; <0.01 [-0.13, 0.13]). This association was also stronger in males (0.15 [0.01, 0.29]) than females (0.07 [-0.04, 0.18]). Metabolites of acrolein, ethylbenzene/styrene, and xylene were consistent key drivers of physiological dysregulation. These findings suggest that VOC exposure could be a contributor to multisystemic dysregulation, as reflected by higher AL, providing a framework to detect environmental exposure-related subclinical effects linked to higher cardiovascular disease risk.