Phthalate exposure and metabolic effects: a systematic review of the human epidemiological evidence.

objectiveWe performed a systematic review of the epidemiology literature to identify the metabolic effects associated with phthalate exposure. DATA SOURCES AND STUDY ELIGIBILITY CRITERIA: Six phthalates were included in the review: di(2‑ethylhexyl) phthalate (DEHP), diisononyl phthalate (DINP), dibutyl phthalate (DBP), diisobutyl phthalate (DIBP), butyl benzyl phthalate (BBP), and diethyl phthalate (DEP). The initial literature search (of PubMed, Web of Science, and Toxline) included all studies of metabolic effects in humans, and outcomes were selected for full systematic review based on data availability. STUDY EVALUATION AND SYNTHESIS

methodsStudies of diabetes and insulin resistance were evaluated using criteria defined a priori for risk of bias and sensitivity by two reviewers using a domain-based approach; studies identified with a pre-defined critical deficiency were excluded. Evidence was synthesized by outcome and phthalate and strength of evidence was summarized using a structured framework. Studies of obesity and renal effects received "screening level" reviews to determine whether full systematic review was warranted.

resultsThe primary outcomes reviewed here are (number of included/excluded studies in parentheses): type 2 diabetes (1/3), insulin resistance (13/3), and impaired glucose tolerance and blood glucose in pregnancy (4/2). For DEHP exposure, there was consistency among studies of insulin resistance and coherence with the single included study of diabetes, as well as an observed exposure-response gradient observed in a study of insulin resistance. This evidence is considered moderate. Similarly, for DBP and DIBP exposure, the evidence is considered moderate due to strong positive associations in the diabetes study and coherent results for insulin resistance. For DINP, BBP, and DEP, the evidence is considered slight. No association was reported in the single study of diabetes with BBP and DEP exposure (DINP was not investigated). The available evidence does indicate an association between exposure to these phthalates and insulin resistance, but the small number of studies and the lack of coherence with diabetes decreases confidence. The screening level reviews for obesity and renal effects determined that the currently available evidence is inadequate to assess the associations between these outcomes and phthalate exposure. CONCLUSIONS AND IMPLICATIONS OF KEY

findingsOverall, these results support that phthalate exposure at levels seen in human populations may have metabolic effects. Given the mechanistic support, the large effect sizes for incident diabetes in the single available study, and the coherence with insulin resistance, the association between phthalate exposure and diabetes risk should be considered when assessing the risks and costs of exposure to specific phthalates in humans. The views expressed are those of the authors and do not necessarily represent the views or policies of the U.S. EPA.