U.S. Environmental Protection Agency, National Center for Environmental Assessment, United States.
Brown University, School of Public Health, United States.
Environ Int. 2018 Dec;121(Pt 1):764-793. doi: 10.1016/j.envint.2018.07.029. Epub 2018 Oct 16.
We performed a systematic review of the epidemiology literature to identify the male reproductive effects associated with phthalate exposure.
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.
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.
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.
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.
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酯暴露相关的男性生殖效应。
本综述纳入了 6 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）、邻苯二甲酸丁基苄基酯（BBP）和邻苯二甲酸二乙酯（DEP）。最初的文献检索（PubMed、Web of Science 和 Toxline）包括了所有关于人类男性生殖效应的研究，根据数据可用性，选择了对所有研究进行全面系统综述。
对于每个结局，两位评审员使用基于领域的方法，根据事先定义的偏倚风险和敏感性标准对研究进行评估。根据结局和邻苯二甲酸酯对证据进行综合，并使用结构化框架总结证据强度。
本综述中主要回顾的结局是（包括/排除的研究数量）：生殖器-肛门距离（6/1）、精液参数（15/9）、妊娠时间（3/5）、睾酮（13/8）、青春期发育时间（5/15）和尿道下裂/隐睾（4/10）。总体来看，有强有力的证据表明 DEHP 和 DBP 暴露与男性生殖结局有关；这主要基于 DEHP 的生殖器-肛门距离、精液参数和睾酮以及 DBP 的精液参数和妊娠时间的研究。基于 DINP 的睾酮和精液参数以及 BBP 的精液参数和妊娠时间的研究，有中等强度的证据表明 DINP 和 BBP 暴露与男性生殖结局有关。DIBP 和 DEP 被认为有轻度关联。对于 DIBP，证据不太确凿归因于文献基础更有限（即研究较少）以及人群中暴露水平较低，这降低了观察到影响的能力。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酯那样强烈的抗雄激素作用。
总体而言，尽管不同邻苯二甲酸酯在与暴露相关的具体结局方面存在一些不一致，但这些结果支持人群中所见的邻苯二甲酸酯暴露可能对男性生殖有影响，尤其是 DEHP 和 DBP。证据的相对强度反映了不同的毒性水平以及研究中暴露范围和可用研究数量的差异。所表达的观点是作者的观点，不一定代表美国环保署的观点或政策。
