TERA, Cincinnati, Ohio 45223, USA.
Emulate Inc., Boston, Massachusetts 02210, USA.
Toxicol Sci. 2022 Feb 28;186(1):12-17. doi: 10.1093/toxsci/kfab134.
New approach methodologies (NAMs), including in vitro toxicology methods such as human cells from simple cell cultures to 3D and organ-on-a-chip models of human lung, intestine, liver, and other organs, are challenging the traditional "norm" of current regulatory risk assessments. Uncertainty Factors continue to be used by regulatory agencies to account for perceived deficits in toxicology data. With the expanded use of human cell NAMs, the question "Are uncertainty factors needed when human cells are used?" becomes a key topic in the development of 21st-century regulatory risk assessment. M.D., PhD, the coauthor of an article detailing uncertainty factors within the U.S. EPA, and L.E., PhD., Executive Vice President, Science, Emulate, who is involved in developing organ-on-a-chip models, debated the topic. One important outcome of the debate was that in the case of in vitro human cells on a chip, the interspecies (animal to human) uncertainty factor of 10 could be eliminated. However, in the case of the intraspecies (average human to sensitive human), the uncertainty factor of 10, additional toxicokinetic and/or toxicodynamic data or related information will be needed to reduce much less eliminate this factor. In the case of other currently used uncertainty factors, such as lowest observable adverse effect level to no-observed adverse effect level extrapolation, missing important toxicity studies, and acute/subchronic to chronic exposure extrapolation, additional data might be needed even when using in vitro human cells. Collaboration between traditional risk assessors with decades of experience with in vivo data and risk assessors working with modern technologies like organ chips is needed to find a way forward.
新方法学（NAMs），包括体外毒理学方法，例如从简单的细胞培养到人类肺、肠、肝和其他器官的 3D 和类器官模型中的人类细胞，正在挑战当前监管风险评估的传统“规范”。监管机构继续使用不确定因素来解释毒理学数据中被认为存在的缺陷。随着人类细胞 NAMs 的广泛应用，“当使用人类细胞时是否需要不确定因素？”这个问题成为 21 世纪监管风险评估发展的关键议题。本文的合著者 M.D.，PhD，详细阐述了美国环保署内的不确定因素，以及参与开发类器官模型的 Emulate 公司的执行副总裁 L.E.，PhD.，就该主题进行了辩论。辩论的一个重要结果是，在芯片上的体外人类细胞的情况下，可以消除种间（动物到人类）不确定因素 10。然而，在种内（普通人类到敏感人类）的情况下，需要 10 的不确定因素，以及额外的毒代动力学和/或毒效动力学数据或相关信息，以减少而不是消除这个因素。在其他目前使用的不确定因素的情况下，例如从最低可见不良反应水平到无可见不良反应水平外推、缺失重要毒性研究以及从急性/亚慢性到慢性暴露外推，即使使用体外人类细胞，也可能需要额外的数据。需要具有数十年体内数据风险评估经验的传统风险评估人员与使用器官芯片等现代技术的风险评估人员之间进行合作，以找到前进的道路。
