Syngenta Crop Protection, LLC, P.O. Box 18300, Greensboro, NC, 27419-8300, United States.
The Dow Chemical Company, Toxicology & Environmental Research & Consulting, Midland, MI, 48674, United States.
Regul Toxicol Pharmacol. 2018 Jul;96:106-120. doi: 10.1016/j.yrtph.2018.04.001. Epub 2018 Apr 16.
Methods for investigating the Mode of Action (MoA) for rodent liver tumors via constitutive androstane receptor (CAR) activation are outlined here, based on current scientific knowledge about CAR and feedback from regulatory agencies globally. The key events (i.e., CAR activation, altered gene expression, cell proliferation, altered foci and increased adenomas/carcinomas) can be demonstrated by measuring a combination of key events and associative events that are markers for the key events. For crop protection products, a primary dataset typically should include a short-term study in the species/strain that showed the tumor response at dose levels that bracket the tumorigenic and non-tumorigenic dose levels. The dataset may vary depending on the species and the test compound. As examples, Case Studies with nitrapyrin (in mice) and metofluthrin (in rats) are described. Based on qualitative differences between the species, the key events leading to tumors in mice or rats by this MoA are not operative in humans. In the future, newer approaches such as a CAR biomarker signature approach and/or in vitro CAR3 reporter assays for mouse, rat and human CAR may eventually be used to demonstrate a CAR MoA is operative, without the need for extensive additional studies in laboratory animals.
本文概述了通过激活组成型雄烷受体（CAR）来研究啮齿动物肝脏肿瘤作用机制（MoA）的方法，这些方法基于目前关于 CAR 的科学知识和全球监管机构的反馈。关键事件（即 CAR 激活、基因表达改变、细胞增殖、焦点改变和腺瘤/癌增加）可以通过测量关键事件和关联事件的组合来证明，这些事件是关键事件的标志物。对于作物保护产品，通常应在显示出在肿瘤发生和非肿瘤发生剂量水平之间的剂量水平下产生肿瘤反应的物种/品系中进行短期研究，以作为主要数据集。数据集可能因物种和测试化合物而异。例如，用硝呋吡咯（在小鼠中）和炔丙菊酯（在大鼠中）进行的案例研究进行了描述。基于物种之间的定性差异，导致这种作用机制在小鼠或大鼠中产生肿瘤的关键事件在人类中不起作用。将来，可能会使用新的方法，例如 CAR 生物标志物特征方法和/或用于小鼠、大鼠和人 CAR 的体外 CAR3 报告基因测定，以证明 CAR MoA 是有效的，而无需在实验动物中进行广泛的额外研究。
