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.

中文翻译：

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邻苯二甲酸盐暴露与男性生殖结果：人类流行病学证据的系统回顾

 客观的

我们对流行病学文献进行了系统回顾，以确定与邻苯二甲酸盐暴露相关的男性生殖影响。

数据来源和研究资格标准

审查中包括六种邻苯二甲酸酯：邻苯二甲酸二(2-乙基己基)酯(DEHP)、邻苯二甲酸二异壬酯(DINP)、邻苯二甲酸二丁酯(DBP)、邻苯二甲酸二异丁酯(DIBP)、邻苯二甲酸丁基苄酯(BBP)和邻苯二甲酸二乙酯(DEP) 。最初的文献检索（PubMed、Web of Science 和 Toxline）包括所有有关人类男性生殖影响的研究，并根据数据可用性选择结果进行全面系统评价。

研究评估和综合方法

对于每项结果，两名评审员使用基于领域的方法，使用先验定义的偏倚风险和敏感性标准对研究进行评估。根据结果​​和邻苯二甲酸盐合成证据，并使用结构化框架总结证据强度。

 结果

这里审查的主要结局是（括号中纳入/排除的研究数量）：肛门生殖器距离（6/1）、精液参数（15/9）、怀孕时间（3/5）、睾酮（13/8）、时间青春期发育 (5/15) 和尿道下裂/隐睾 (4/10)。从总体危害来看，有强有力的证据表明 DEHP 和 DBP 暴露与男性生殖结果之间存在关联；这主要基于对肛门生殖器距离、精液参数和睾酮（DEHP）以及精液参数和妊娠时间（DBP）的研究。根据 DINP 的睾酮和精液参数以及 BBP 的精液参数和怀孕时间，有中等程度的证据表明 DINP 和 BBP 暴露与男性生殖结局之间存在关联。 DIBP 和 DEP 被认为有轻微的关联证据。对于 DIBP，结论性证据较少是由于文献基础更有限（即研究较少）和人群暴露水平较低，从而降低了观察效果的能力。对于 DEP，研究结果与实验动物数据一致，表明 DEP 没有其他邻苯二甲酸盐那么强的抗雄激素作用。

主要发现的结论和意义

总体而言，尽管邻苯二甲酸盐在与暴露相关的具体结果方面存在一些不一致，但这些结果支持人类中所见水平的邻苯二甲酸盐暴露可能会对男性生殖产生影响，特别是 DEHP 和 DBP。证据的相对强度反映了不同的毒性水平以及研究的暴露范围和可用研究数量的差异。

所表达的观点仅代表作者的观点，并不一定代表美国环保署的观点或政策。