Cardiovascular

Phthalate and Terephthalate Mixtures, Cardiometabolic Risk Factors, and the Role of Oxidative Stress: Evidence from NHANES 2015-2018.

TL;DR

Exposure to a mixture of phthalate/terephthalate metabolites was associated with disrupted glucose and lipid metabolism markers in a cross-sectional study of U.S. adults, with oxidative stress potentially playing a limited mediating role.

Key Findings

A one-decile increase in phthalate/terephthalate mixtures dominated by mono(2-ethyl-5-hydroxyhexyl) terephthalate was associated with higher fasting glucose.

  • Estimate: 1.95 (95% CI: 0.75, 3.14) for fasting glucose
  • The mixture was also associated with higher fasting insulin (9.10%; 95% CI: 6.32%, 11.95%)
  • HOMA-IR was higher by 9.86% (95% CI: 6.86%, 12.94%)
  • HbA1c was higher by 0.05 (95% CI: 0.03, 0.07)
  • Analysis was conducted using multivariable weighted quantile sum (WQS) regression on 2,336 U.S. adults from NHANES 2015-2018

Phthalate/terephthalate mixtures were associated with lower HDL-C, LDL-C, and total cholesterol.

  • HDL-C was lower by -0.93 (95% CI: -1.26, -0.60)
  • LDL-C was lower by -2.28 (95% CI: -3.54, -1.02)
  • Total cholesterol was lower by -1.89 (95% CI: -2.86, -0.93)
  • These associations were identified using WQS regression in the same sample of 2,336 U.S. adults

Phthalate/terephthalate mixtures were associated with higher fasting triglycerides.

  • Fasting triglycerides were higher by 2.98% (95% CI: 0.77%, 5.23%)
  • This finding was observed alongside the lower HDL-C, suggesting a mixed lipid profile disruption
  • Analysis used multivariable WQS regression on NHANES 2015-2018 data

Gamma-glutamyltransferase (GGT) as a marker of oxidative stress mediated only a limited number of the associations between phthalate/terephthalate mixtures and cardiometabolic outcomes.

  • GGT was used as a proxy biomarker for oxidative stress in mediation analyses
  • Mediation by GGT was described as limited across glycemic and lipid outcomes
  • Results suggest oxidative stress may play a role in some but not all associations between phthalate/terephthalate exposure and cardiometabolic risk factors

A higher oxidative balance score (OBS) attenuated adverse associations between phthalate/terephthalate mixtures and select lipid outcomes among females.

  • OBS is a composite score reflecting dietary and lifestyle anti- and pro-oxidants
  • Effect modification was assessed by including product terms (WQS index*OBS) in linear regressions
  • Attenuation was observed specifically for HDL-C and TC/HDL-C ratio outcomes
  • This modifying effect was found among females but the abstract does not report the same pattern for males

The study analyzed fifteen phthalate and terephthalate metabolites in relation to nine cardiometabolic outcomes in a nationally representative U.S. adult sample.

  • Sample size was 2,336 U.S. adults from NHANES 2015-2018
  • Glycemic outcomes included fasting glucose, fasting insulin, HOMA-IR, and HbA1c (four outcomes)
  • Lipid outcomes included HDL-C, LDL-C, total cholesterol, fasting triglycerides, and TC/HDL-C ratio (five outcomes)
  • Study design was cross-sectional, limiting causal inference

What This Means

This research suggests that exposure to a group of common plasticizer chemicals — phthalates and terephthalates found in food packaging, personal care products, and other consumer goods — is linked to multiple markers of poor metabolic health in American adults. Using nationally representative data from over 2,300 U.S. adults collected between 2015 and 2018, researchers found that higher combined exposure to these chemicals was associated with elevated blood sugar levels, insulin resistance, higher triglycerides, and lower HDL ('good') cholesterol, while also being linked to lower LDL and total cholesterol. The chemical driving many of these associations was mono(2-ethyl-5-hydroxyhexyl) terephthalate, a metabolite of a terephthalate plasticizer increasingly used as a replacement for traditional phthalates. The study also explored whether oxidative stress — a type of cellular damage caused by an imbalance between harmful free radicals and the body's defenses — might help explain these chemical-health links. A liver enzyme called GGT, used as a marker of oxidative stress, mediated only some of the associations, suggesting oxidative stress is part of but not the complete explanation. Notably, among women, having a healthier diet and lifestyle (reflected in a higher 'oxidative balance score') appeared to reduce some of the harmful associations between these chemicals and cholesterol levels, hinting that healthy behaviors might offer some protection. This research matters because phthalates and terephthalates are ubiquitous in modern environments, and metabolic conditions like diabetes and cardiovascular disease are leading causes of death worldwide. However, because this was a cross-sectional study — meaning it captured a single snapshot in time — it cannot prove that these chemicals directly cause metabolic harm. The authors note that longitudinal studies and randomized trials are needed to confirm these findings and to determine whether reducing exposure or improving diet and lifestyle can meaningfully lower health risks associated with these chemicals.

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Citation

Webb M, Sathyanarayana S, Day D, Trabulsi J, Park J, Melough M. (2026). Phthalate and Terephthalate Mixtures, Cardiometabolic Risk Factors, and the Role of Oxidative Stress: Evidence from NHANES 2015-2018.. Cardiovascular toxicology. https://doi.org/10.1007/s12012-026-10188-7