Phthalate exposure and male reproductive outcomes: A systematic review of the human epidemiological evidence

Abstract

Objective: We performed a systematic review of the epidemiology literature to identify the male reproductive 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 male reproductive effects in humans, and outcomes were selected for full systematic review based on data availability.

Study evaluation and synthesis methods: For each outcome, studies were evaluated using criteria defined a priori for risk of bias and sensitivity by two reviewers using a domain-based approach. Evidence was synthesized by outcome and phthalate and strength of evidence was summarized using a structured framework.

Results: The primary outcomes reviewed here are (number of included/excluded studies in parentheses): anogenital distance (6/1), semen parameters (15/9), time to pregnancy (3/5), testosterone (13/8), timing of pubertal development (5/15), and hypospadias/cryptorchidism (4/10). Looking at the overall hazard, there was robust evidence of an association between DEHP and DBP exposure and male reproductive outcomes; this was based primarily on studies of anogenital distance, semen parameters, and testosterone for DEHP and semen parameters and time to pregnancy for DBP. There was moderate evidence of an association between DINP and BBP exposure and male reproductive outcomes based on testosterone and semen parameters for DINP and semen parameters and time to pregnancy for BBP. DIBP and DEP were considered to have slight evidence of an association. For DIBP, the less conclusive evidence was attributed to a more limited literature base (i.e., fewer studies) and lower exposure levels in the population, decreasing the ability to observe an effect. For DEP, the findings were consistent with experimental animal data that suggest DEP does not haves as strong an anti-androgenic effect as other phthalates.

Conclusions and implications of key findings: Overall, despite some inconsistencies across phthalates in the specific outcomes associated with exposure, these results support that phthalate exposure at levels seen in human populations may have male reproductive effects, particularly DEHP and DBP. The relative strength of the evidence reflects differing levels of toxicity as well as differences in the range of exposures studied and the number of available studies. The views expressed are those of the authors and do not necessarily represent the views or policies of the U.S. EPA.

Fig. 1.

Literature flow diagram for male reproductive effects of phthalates. *Did not include studies on male reproductive effects.

Fig. 2.

A–F. Association between phthalate metabolite levels measured in maternal urine samples during pregnancy and AGD in boys. *p < 0.05, results that support an association are shaded. Dark gray represents one or more of the following: p < 0.05, large effect size (e.g., OR ≥ 1.5, β ≥ − 0.5), or exposure-response trend across categories of exposure. Light gray represents other supportive results. ^β recalculated to reflect ln transformation of metabolite (from log10). ^‡Exposure levels from (Swan et al., 2015). Exposure level on x-axis is population median for each study, and the axes are scaled the same for all phthalates to facilitate comparison of exposure levels, with the exception of DEHP and DINP, which were reported in nmol/L instead of ng/mL. Each panel depicts results for a metabolite(s) from a different parent phthalate. Studies within each phthalate are sorted by exposure levels. Effect estimates are change in anogenital distance in mm per ln-unit of exposure.

Fig. 2.

A–F. Association between phthalate metabolite levels measured in maternal urine samples during pregnancy and AGD in boys. *p < 0.05, results that support an association are shaded. Dark gray represents one or more of the following: p < 0.05, large effect size (e.g., OR ≥ 1.5, β ≥ − 0.5), or exposure-response trend across categories of exposure. Light gray represents other supportive results. ^β recalculated to reflect ln transformation of metabolite (from log10). ^‡Exposure levels from (Swan et al., 2015). Exposure level on x-axis is population median for each study, and the axes are scaled the same for all phthalates to facilitate comparison of exposure levels, with the exception of DEHP and DINP, which were reported in nmol/L instead of ng/mL. Each panel depicts results for a metabolite(s) from a different parent phthalate. Studies within each phthalate are sorted by exposure levels. Effect estimates are change in anogenital distance in mm per ln-unit of exposure.

Fig. 3.

Summary of epidemiologic evidence of male reproductive effects associated with phthalates.