BACKGROUND:
Phthalate (PAE) exposure has been linked to increased mortality. However, the relationship between the patterns of PAE exposure and all-cause mortality, as well as the underlying mediation mechanisms, remains unclear.

METHODS:
Analyses were conducted on 10,939 participants in the National Health and Nutrition Examination Survey (NHANES) 2003-2014. Latent class analysis was performed to identify PAE exposure patterns. Survey-weighted Cox proportional hazards models were developed to examine associations of PAE patterns with all-cause mortality. Causal mediation analysis, incorporating a four-way decomposition framework, was applied to assess the mediating roles of chronic diseases as well as oxidative stress and inflammation.

RESULTS:
Four mutually exclusive exposure patterns were identified: Low PAEs (n=6,144), Moderate Low PAEs (n=2,068), Moderate High PAEs (n=1,612), and High PAEs (n=1,115). Over a median follow-up of 10·83 years, 1,445 deaths occurred. Compared with the Low PAEs, population in the Moderate Low and High PAEs groups exhibited significantly increased mortality, with hazard ratios (HRs) of 1·21 (95% CI:1·03, 1·42) and 1·27 (95% CI:1·06, 1·53), respectively. Associations were more pronounced among heavy smokers (HR up to 1·61, P for interaction <0·05). Chronic diseases (e.g., CVD) and biomarkers of oxidative stress and inflammation (UA, GGT, NLR, MLR, NMLR, SIRI, SII) mediated 2·34-28·17% of the elevated mortality risk, with diabetes, GGT, NLR, MLR, NMLR, SIRI exhibiting interactions, simultaneously.

CONCLUSIONS:
Exposure to elevated levels of PAE was related to a higher risk of all-cause mortality, partly through cardiometabolic, oxidative, and inflammatory pathways. These findings highlight potential intervention targets and support integrating plasticizer regulation with chronic disease prevention to reduce phthalate-attributable mortality.