ExxonMobil Biomedical Sciences, Inc., US Highway 22 East, Annandale, NJ, 08801 USA.
Shell International B.V., The Netherlands.
Toxicol Lett. 2020 Nov 1;334:78-86. doi: 10.1016/j.toxlet.2020.09.005. Epub 2020 Sep 14.
Understanding the Mode of Action (MOA) for a chemical can help guide decisions in development of Occupational Exposure Limits (OELs). Where sufficient information exists, it can provide the OEL developer the basis for selecting either a health-based or risk-based approach. To support the development of an OEL for benzene, scientific information relevant to MOA assessment for risk-based and health-based OEL approaches was reviewed. Direct-acting mutagenicity was considered as a basis for a risk-based OEL, versus MOAs consistent with a health-based approach: indirect mutagenicity via topoisomerase II inhibition, indirect mutagenicity via reactive oxygen species generation, or an immune-based bone marrow dysfunction. Based on the evidence against direct DNA reactivity, threshold expectations for remaining MOAs, and evidence for dose rate affecting acute myeloid leukemia and myelodysplastic syndrome risk, the weight of evidence favors a health-based OEL approach. In the case of benzene, development of an OEL based on observations of earlier key events (i.e., hematologic changes and genetic toxicity) is anticipated to provide protection from later adverse outcomes such as leukemia.
了解化学物质的作用模式 (MOA) 有助于指导职业接触限值 (OEL) 的制定决策。在有足够信息的情况下，它可以为 OEL 开发人员提供选择基于健康还是基于风险的方法的依据。为了支持苯的 OEL 制定，审查了与基于风险和基于健康的 OEL 方法的 MOA 评估相关的科学信息。直接致突变性被认为是基于风险的 OEL 的基础，而与基于健康的方法一致的 MOA 为：拓扑异构酶 II 抑制的间接致突变性、通过活性氧生成的间接致突变性或基于免疫的骨髓功能障碍。基于对直接 DNA 反应性的证据、对剩余 MOA 的阈值预期以及对剂量率影响急性髓性白血病和骨髓增生异常综合征风险的证据，证据权重支持基于健康的 OEL 方法。就苯而言，预计基于早期关键事件（即血液学变化和遗传毒性）的观察结果制定 OEL 将提供对白血病等后期不良后果的保护。
