Phthalates and attributable mortality: A population-based longitudinal cohort study and cost analysis

Context: Accelerating evidence of endocrine-related morbidity has raised alarm about the ubiquitous use of phthalates in the human environment, but studies have not directly evaluated mortality in relation to these exposures. Objectives: To evaluate associations of phthalate exposure with mortality, and quantify attributable mortality and lost economic productivity in 2013–4 among 55–64 year olds. Design: This nationally representative cohort study included 5303 adults aged 20 years or older who participated in the US National Health and Nutrition Examination Survey 2001–2010 and provided urine samples for phthalate metabolite measurements. Participants were linked to mortality data from survey date through December 31, 2015. Data analyses were conducted in July 2020. Main Outcome Measures: Mortality from all causes, cardiovascular disease, and cancer. Results: Multivariable models identified increased mortality in relation to high-molecular weight (HMW) phthalate metabolites, especially those of di-2-ethylhexylphthalate (DEHP). Hazard ratios (HR) for continuous HMW and DEHP metabolites were 1.14 (95% CI 1.06–1.23) and 1.10 (95% CI 1.03–1.19), respectively, with consistently higher mortality in the third tertile (1.48, 95% CI 1.19–1.86; and 1.42, 95% CI 1.13–1.78). Cardiovascular mortality was significantly increased in relation to a prominent DEHP metabolite, mono-(2-ethyl-5-oxohexyl)phthalate. Extrapolating to the population of 55–64 year old Americans, we identified 90,761–107,283 attributable deaths and $39.9–47.1 billion in lost economic productivity. Conclusions: In a nationally representative sample, phthalate exposures were associated with all-cause and cardiovascular mortality, with societal costs approximating $39 billion/year or more. While further studies are needed to corroborate observations and identify mechanisms, regulatory action is urgently needed.