PNNL

Abstract

Background: In July 2017, the National Academies released a report applying systematic review (SR) methods in the evaluation of low dose endocrine effects including an assessment of male reproductive toxicity following in utero phthalate exposure. Objective: We evaluated human and animal evidence of the effect of in utero exposure to diethylhexyl phthalate (DEHP) on anogenital distance (AGD) in males. Methods: PubMed, Embase, and Toxline were searched for observational studies in humans and experimental studies in non-human mammals on August 15 2016. Two trained staff independently screened search results, assessed risk of bias for individual studies, and extracted data sequentially. Confidence in the human and animal bodies of evidence was assessed and hazard conclusions reached by integrating evidence streams. Results: The search yielded 24 relevant studies. Meta-analysis of five human observational prospective cohort studies showed consistent evidence that increased maternal urinary concentrations of DEHP metabolites were associated with decreased AGD in male offspring (-4.07 [CI, -6.49 to -1.66] percent decrease per log10 increase in DEHP metabolites). Meta-analysis and meta-regression of 19 experimental animal studies similarly found consistent evidence of decreased AGD with DEHP treatment, with a dose-response gradient, with heterogeneity explained by species and strain. Conclusions: There is a moderate level of evidence from human studies and a high level of evidence from animal studies that in utero exposure to DEHP decreases AGD. Based on the available human and animal evidence, and consideration of mechanistic data, DEHP is presumed to be a reproductive hazard to humans.