Borgert Christopher J
Applied Pharmacology and Toxicology Inc, Gainesville FL, 32605 and University of Florida College of Veterinary Medicine, Dept. Physiological Sciences, Gainesville FL, 32610.
EXCLI J. 2025 Mar 27;24:479-507. doi: 10.17179/excli2024-7822. eCollection 2025.
Ethylbenzene (EB) was placed on List 2 for Tier 1 endocrine screening in the U.S. EPA's two-tiered Endocrine Disruptor Screening Program (EDSP) and was scheduled for evaluation under TSCA. Results of toxicology studies on EB were used to evaluate estrogen, androgen, thyroid, and steroidogenic (EATS) endpoints by a Weight of Evidence (WoE) methodology, as required by U.S. EPA and OECD guidelines for evaluating a chemical's endocrine disruptive potential. The WoE method involved problem formulation, systematic literature search and selection, data quality evaluation, relevance weighting of endpoint data, and application of specific interpretive criteria. Data on EB were sufficient to assess its effects on endpoints that would be expected to respond to chemicals that operate via EATS modes of action (MoAs) in various screening assays (Tier 1) and toxicity tests (Tier 2) that evaluate reproduction, development, and sub-chronic and chronic toxicity. In those studies, EB produced a pattern of responses inconsistent with the responses that would be expected for hormones and chemicals known to operate via EATS MoAs. Endocrine-sensitive endpoints that respond to EB administration generally do so only at dose levels above its kinetic maximum dose, indicating a lack of relevance to potential effects at lower dose levels in either the test species or humans. This comprehensive WoE evaluation demonstrates that EB lacks the potential to exhibit endocrine disruptive properties and cannot be deemed an endocrine disruptor or potential endocrine disruptor. Because this WoE evaluation was based largely on Tier 2-level studies of the type considered by the U.S. EPA and OECD to be more definitive than results of Tier 1 EDSP screening results, no additional useful information would be obtained by subjecting EB to further endocrine screening. As such, further endocrine screening of EB would be unjustified from animal welfare perspectives. This analysis supports a regulatory decision to halt further testing of EB for endocrine disruption unless unique and compelling data to the contrary arise. See also the graphical abstract(Fig. 1).
乙苯（EB）被列入美国环境保护局（EPA）两级内分泌干扰物筛选计划（EDSP）的一级内分泌筛选清单2，并计划根据《有毒物质控制法》（TSCA）进行评估。按照美国EPA和经济合作与发展组织（OECD）评估化学品内分泌干扰潜力的指南要求，采用证据权重（WoE）方法，利用乙苯的毒理学研究结果来评估雌激素、雄激素、甲状腺和类固醇生成（EATS）终点。WoE方法包括问题形成、系统的文献检索与筛选、数据质量评估、终点数据的相关性加权以及特定解释标准的应用。关于乙苯的数据足以评估其对各种筛选试验（一级）和毒性测试（二级）中通过EATS作用模式（MoA）起作用的化学品预期会产生反应的终点的影响，这些试验和测试用于评估生殖、发育以及亚慢性和慢性毒性。在这些研究中, 乙苯产生的反应模式与已知通过EATS MoA起作用的激素和化学品预期的反应不一致。对乙苯给药有反应的内分泌敏感终点通常仅在高于其动力学最大剂量的剂量水平下才会出现反应，这表明在受试物种或人类中，较低剂量水平下的潜在影响缺乏相关性。这种全面的WoE评估表明，乙苯没有表现出内分泌干扰特性的潜力，不能被视为内分泌干扰物或潜在内分泌干扰物。由于这种WoE评估主要基于美国EPA和OECD认为比一级EDSP筛选结果更具确定性的数据类型的二级研究，因此对乙苯进行进一步的内分泌筛选不会获得更多有用信息。因此, 从动物福利的角度来看，对乙苯进行进一步的内分泌筛选是不合理的。这一分析支持一项监管决定，即除非出现相反的独特且有说服力的数据，否则停止对乙苯进行进一步的内分泌干扰测试。另见图1（图形摘要）
