Associations of Organophosphate Pesticide Metabolite Mixtures with Epigenetic Age Acceleration

Organophosphate (OP) pesticide exposure occurs as complex mixtures, yet joint associations with DNA methylation-derived aging measures remain poorly characterized. We examined six urinary dialkylphosphate (DAP) metabolites in relation to epigenetic age acceleration (EAA) among 427 adults aged ≥50 years in the 1999–2002 National Health and Nutrition Examination Survey. EAA was derived from the Horvath, Hannum, PhenoAge, GrimAge, and GrimAge2 clocks. Metabolites were measured in a single spot urine specimen, so exposure reflects recent rather than cumulative exposure. Survey-weighted multivariable linear regression estimated conventional associations, and unweighted Bayesian kernel machine regression (BKMR) characterized potentially nonlinear mixture associations. No DAP–clock association reached nominal significance or survived Benjamini–Hochberg false-discovery-rate correction across 30 tests. BKMR suggested heterogeneous, clock-dependent patterns: posterior mean mixture–response estimates increased at higher quantiles for Horvath, Hannum, and PhenoAge but not for GrimAge or GrimAge2. DEDTP had the highest posterior inclusion probability in each primary model, though magnitudes were modest for the GrimAge clocks. No association survived FDR correction after leukocyte-composition adjustment. Posterior support for pairwise interactions was weak, and credible intervals were wide. Given the cross-sectional design and discordant directions across clocks, these exploratory findings do not establish that DAP exposure accelerates biological aging and warrant longitudinal confirmation.