Urinary organophosphate flame retardants and risk of sarcopenia and sarcopenic obesity among middle-aged and older adults: a systematic investigation integrating epidemiological and adverse outcome pathway analyses

Sarcopenia affects 10–20% of older adults worldwide, with prevalence rising sharply after middle age. However, the health impact and the underlying mechanisms of organophosphate flame retardants (OPFRs) on sarcopenia in this population remain unclear. Our study aimed to explore the associations of metabolites of OPFR (m-OPFR) with sarcopenia and sarcopenic obesity in U.S. adult populations, and to decipher potential biological mechanisms through the integration of epidemiological and toxicogenomic approaches. Data from U.S. adults in NHANES 2011–2018 were analyzed. Five urinary OPFR metabolites with sufficient detection frequencies were included. Survey-weighted logistic regression and restricted cubic spline models assessed individual and exposure–response relationships. Mixture effects were evaluated using Bayesian kernel machine regression, quantile g-computation, and weighted quantile sum regression. Mediation analysis and adverse outcome pathway (AOP) network integration were conducted to explore potential mechanisms. Urinary dibutyl phosphate (DBuP) was positively associated with both sarcopenia and sarcopenic obesity. BCIPP and BDCIPP showed weaker but consistent associations. Mixture analyses consistently indicated a positive relationship between combined OPFR exposure and both outcomes, with DBuP as the primary contributor. Associations were stronger among older adults. Serum albumin partially mediated the DBuP–sarcopenia relationship. AOP network analysis suggested the involvement of IL6, TNF, TP53, and NFE2L2 in inflammation- and oxidative stress-related pathways that may underlie the observed associations. DBuP was consistently associated with both sarcopenia and sarcopenic obesity in middle-aged and older adults. Integrated mixture–mediation–AOP analyses suggest that inflammatory and oxidative stress pathways may underlie these associations.