Dibutyl phthalate (DBP) and di(2-ethylhexyl) phthalate (DEHP), two common types of phthalates, are known to cause reproductive and developmental toxicity in animals and humans. The reference doses (RfD) of DBP and DEHP should be determined by sensitive endpoints. We here aimed to identify sensitive endpoints for DBP- and DEHP-induced such toxicity using published literatures. By examining the impacts of maternal exposure to DBP or DEHP on anogenital distance (AGD) and semen quality of offspring, we discovered that DBP or DEHP caused AGD decline in boys but increase in girls with DBP being more potent and the first 14weeks of pregnancy being more susceptible, suggesting a chemical- and time-dependent phenomenon. We also identified AGD shortening and total sperm count reduction as two sensitive endpoints for DBP- or DEHP-induced reproductive and developmental toxicity, respectively. Based upon these two endpoints and the employment of the Bayesian benchmark dose approach with an uncertainty factor of 3,000, we estimated the RfD values of DBP and DEHP were 15 μg/kg/day and 36 μg/kg/day, respectively. Thus, we uncover previously unrecognized phenomena of DBP- or DEHP-induced reproductive and developmental toxicity and establish new and comparable or more conservative RfDs for the risk assessment of phthalates exposure in humans.

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确定评估邻苯二甲酸盐引起的生殖和发育毒性的敏感终点：文献挖掘研究

邻苯二甲酸二丁酯 (DBP) 和邻苯二甲酸二(2-乙基己基)酯 (DEHP) 是两种常见的邻苯二甲酸酯，已知会对动物和人类造成生殖和发育毒性。 DBP 和 DEHP 的参考剂量 (RfD) 应根据敏感终点确定。我们的目的是利用已发表的文献来确定 DBP 和 DEHP 引起的此类毒性的敏感终点。通过检查母亲接触 DBP 或 DEHP 对后代肛门生殖器距离 (AGD) 和精液质量的影响，我们发现 DBP 或 DEHP 导致男孩 AGD 下降，但导致女孩 AGD 增加，其中 DBP 更有效，并且怀孕前 14 周更容易受到影响，表明存在化学和时间依赖性现象。我们还确定 AGD 缩短和精子总数减少分别是 DBP 或 DEHP 诱导的生殖和发育毒性的两个敏感终点。基于这两个终点以及采用不确定性因子为 3,000 的贝叶斯基准剂量方法，我们估计 DBP 和 DEHP 的 RfD 值分别为 15 μg/kg/天和 36 μg/kg/天。因此，我们发现了以前未被认识的 DBP 或 DEHP 引起的生殖和发育毒性现象，并建立了新的、可比较的或更保守的 RfD，用于评估人类邻苯二甲酸盐暴露的风险。