Temporal and Geographic Variability of Urinary Phthalates Metabolite Levels in Humans: A Systematic Review and Meta-Analysis of International Biomonitoring Data

Phthalates are endocrine-disrupting chemicals (EDCs) that alter hormone functions throughout the lifespan. Growing awareness of the adverse health effects of phthalate exposure has led to regulating certain phthalates in the United States, Canada, and Europe. However, international comparisons of urinary phthalate metabolite concentrations as biomarkers of exposure are sparse, and few studies have controlled for cohort-specific variables like pregnancy. We aimed to examine trends in urinary phthalate monoester metabolite concentrations in non-occupationally exposed populations globally, excluding locations where representative data are already available at the country level. We systematically reviewed studies published between 2000 and 2023 that reported urinary phthalate monoester concentrations. We examined changes in metabolite concentrations across time, controlling for region, age, and pregnancy status, using mixed-effects meta-regression models with and without a quadratic term for time. We identified heterogeneity using Cochrans Q-statistic and I2 index, adjusting for it with the trim-and-fill method. The final analytic sample consisted of 216 studies. Significant differences in phthalate metabolite concentrations were observed across regions, age groups, and between pregnant and non-pregnant cohorts. Our meta-regression identified a significant non-linear trend with time for Mono-n-butyl phthalate and Mono-isononyl phthalate concentration internationally and in Eastern and Pacific Asia (EPA). We also observed significant non-linear associations between time and Mono(2-ethyl-5-hydroxyhexyl) phthalate, Mono(2-carboxymethylhexyl) phthalate, and Mono(3-carboxypropyl) phthalate concentration internationally and/or in EPA, along with Mono(2-ethylhexyl) phthalate, Mono-carboxy-isononyl phthalate, and Mono-ethyl phthalate. Additionally, Mono-ethyl phthalate concentration showed a significant negative linear association with time in Latin America and Africa. Heterogeneity was high, indicating potential bias in our results. Our findings indicate the need for increased awareness of phthalate exposure. Further analysis of the attributable disease burden and cost at regional and international levels, especially in low- and middle-income countries, is essential to understanding these and other EDCs impact on population health and the economy. HighlightsO_LISome phthalate levels significantly differed by region, age, and pregnancy status. C_LIO_LIMany phthalates had non-linear associations internationally from 2000 to 2023. C_LIO_LIMnBP and MiNP levels increased, driven by Eastern and Pacific Asia results. C_LIO_LIMost phthalate metabolites levels declined overall and region-specific over time. C_LIO_LIThere was insufficient data on phthalate metabolite levels for many regions. C_LI