Phthalate exposure and all-cause and cause-specific mortality in overweight and obese adults: a national cohort study

Importance: Phthalate exposure has been found to be associated with an increased risk of obesity. It remains unknown whether exposure to phthalates further impact the health of individuals who are already obese. Objective: To examine the risk of mortality associated with phthalate exposure among individuals with overweight and obesity. Design: A nationally representative sample of adults aged 40 years or older who participated in the US National Health and Nutrition Examination Survey 2001–2010 and provided urine samples for phthalate metabolite measurements. These participants were linked to mortality data from the survey date through December 31, 2019. Exposures: Phthalate metabolites in urine samples were measured by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. Main Outcome Measures: Mortality from all causes, cardiovascular disease (CVD), and cancer. Results: This cohort study included 3,845 adults aged 40 years or older (mean age 56.5 [0.3] years). During 46,261 person-years of follow-up (median 12 years; maximum 19 years), 990 deaths occurred, of which 304 were from CVD and 246 were from cancer. Elevated concentrations of high-molecular-weight (HMW) urinary phthalate metabolites and di-2-ethylhexylphthalate (DEHP) were associated with a 46% and 36% increased risk of all-cause mortality, respectively. Regarding low-molecular-weight (LMW) phthalates, higher exposure was specifically linked to a 43% excess risk of CVD mortality. Bayesian kernel machine regression (BKMR) analyses indicated a 7.3% increase in all-cause mortality associated with phthalate co-exposure (75th vs. 50th percentile). Conclusions and Relevance: In this nationally representative study, phthalate co-exposure was significantly positively associated with all-cause and CVD mortality among individuals with overweight and obesity. Higher levels of HMW and DEHP exposure were linked to increased all-cause mortality, while high LMW exposure was associated with elevated CVD mortality. Further studies are necessary to confirm these findings and investigate the underlying mechanisms.