ExxonMobil Biomedical Sciences, Inc., Annandale, VA, USA.
Shell International, Shell Health, Houston, TX, USA.
Crit Rev Toxicol. 2022 May;52(5):345-357. doi: 10.1080/10408444.2022.2082269. Epub 2022 Jul 21.
The National Research Council's vision of using adverse outcome pathways (AOPs) as a framework to assist with toxicity assessment for regulatory requirements of chemical assessment has continued to gain traction since its release in 2007. The need to expand the AOP knowledge base has gained urgency, with the U.S. Environmental Protection Agency's directive to eliminate reliance on animal toxicity testing by 2035. To meet these needs, our goal was to elucidate the AOP for male-rat-specific kidney cancer. Male-rat-specific kidney tumors occur through the ability of structurally diverse substances to induce α2u-globulin nephropathy (α2u-N), a well-studied mode of action (MoA) not relevant in humans that results in kidney tumor formation in male rats. An accepted AOP may help facilitate the differentiation from other kidney tumors MoAs. Following identification and review of relevant and literature, both the MIE and subsequent KEs were identified. Based on the weight of evidence from the various resources, the confidence in this AOP is high. Uses of this AOP include hazard identification, development of assays to determine if the MoA is through α2u-N and not relevant to humans resulting in decreased use of animals, and regulatory applications.
自 2007 年发布以来，美国国家研究委员会（NRC）一直致力于将不良结局途径（AOP）作为一种框架，协助进行毒性评估，以满足化学评估的监管要求。由于美国环保署（EPA）的指令要求到 2035 年消除对动物毒性测试的依赖，因此扩展 AOP 知识库的需求变得更加紧迫。为了满足这些需求，我们的目标是阐明雄性大鼠特异性肾肿瘤的 AOP。雄性大鼠特异性肾肿瘤是通过结构多样的物质诱导α2u-球蛋白肾病（α2u-N）的能力发生的，α2u-N 是一种经过充分研究的作用模式（MoA），与人类无关，导致雄性大鼠肾脏肿瘤的形成。一个被接受的 AOP 可能有助于促进与其他肾脏肿瘤 MoA 的区分。在确定和审查了相关文献之后，确定了中间事件（MIE）和随后的关键事件（KE）。基于来自各种资源的证据权重，该 AOP 的置信度很高。该 AOP 的用途包括危害识别、开发用于确定 MoA 是否通过α2u-N 以及与人类无关的测定，从而减少对动物的使用，以及用于监管应用。
