Systematic reviews and meta-analyses of human and animal evidence of prenatal diethylhexyl phthalate exposure and changes in male anogenital distance

ABSTRACT

Male reproductive alterations found in animals and humans following in utero phthalate exposure include decreased anogenital distance (AGD) and other reproductive-tract malformations. The aim of this investigation was to conduct systematic reviews of human and animal evidence of the effect of in utero exposure to diethylhexyl phthalate (DEHP) on anogenital distance (AGD) in males. PubMed, Embase, and Toxline were searched for relevant human and experimental animal studies on August 15, 2016. Search results were screened for relevance, and studies that met the inclusion criteria were evaluated for quality and data extracted for analysis. Confidence in the human and animal bodies of evidence was assessed and hazard conclusions reached by integrating evidence streams. The search yielded 6 relevant human studies and 19 animal studies. Meta-analysis of 5 human observational prospective cohort studies showed that increased maternal urinary concentrations of DEHP metabolites were associated with decreased AGD in boys (−4.07 [CI, −6.49 to −1.66] % decrease per log₁₀ rise in DEHP metabolites). Meta-analysis and meta-regression of the 19 experimental animal studies found reduced AGD with DEHP treatment, with a dose-response gradient, and with heterogeneity explained by species and strain. There is a moderate level of evidence from human investigations and a high level of data from animal studies that in utero exposure to DEHP decreases AGD. Based upon the available human and animal evidence, and consideration of mechanistic data, DEHP is presumed to be a reproductive hazard to humans on the basis of effects on AGD.

KEYWORDS:

• Reproductive toxicity
• phthalate
• anogenital distance
• epidemiology

Acknowledgments

Funding was provided by a contract to the National Academies of Sciences, Engineering, and Medicine from the US Environmental Protection Agency. The authors thank Robyn Blain and Pamela Hartman at ICF International for their assistance with data extraction and Jaime Blanck at the William H. Welch Medical Library at Johns Hopkins University for her assistance with planning and performing the literature searches to support the systematic reviews. Selected tables, figures, and selected text from a 2017 report of the National Academies of Sciences, Engineering, and Medicine, Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals are reprinted with permission from the National Academies Press, Washington, DC.

Competing financial interest declaration

The authors declare they have no actual or potential competing financial interests.

Disclosure statement

No potential conflict of interest was reported by the authors.

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