Systems and Cellular Medicine, University of Dundee, Dundee, DD1 9SY, UK.
F1000Res. 2023 Aug 10;11:1164. doi: 10.12688/f1000research.123077.1. eCollection 2022.
Chemical risk assessment ensures protection from the toxic effects of drugs and manmade chemicals. To comply with regulatory guidance, studies in complex organisms are required, as well as mechanistic studies to establish the relevance of any toxicities observed to man. Although toxicity models are improving, studies remain central to this process. Such studies are invariably time-consuming and often involve large numbers of animals. New regulatory frameworks recommend the implementation of "smart" approaches to toxicity testing that can effectively assess safety for humans and comply with societal expectations for reduction in animal use. A major obstacle in reducing the animals required is the time-consuming and complexity of the pathological endpoints used as markers of toxicity. Such endpoints are prone to inter-animal variability, subjectivity and require harmonisation between testing sites. As a consequence, large numbers of animals per experimental group are required. To address this issue, we propose the implementation of sophisticated stress response reporter mice that we have developed. These reporter models provide early biomarkers of toxic potential in a highly reproducible manner at single-cell resolution, which can also be measured non-invasively and have been extensively validated in academic research as early biomarkers of stress responses for a wide range of chemicals at human-relevant exposures. In this report, we describe a new and previously generated models in our lab, provide the methodology required for their use and discuss how they have been used to inform on toxic risk (likelihood of chemical causing an adverse health effect). We propose our approach is more informative (refinement) and reduces the animal use (reduction) compared to traditional toxicity testing. These models could be incorporated into tiered toxicity testing and used in combination with assays to generate quantitative adverse outcome pathways and inform on toxic potential.
化学风险评估可确保药物和人为化学物质的毒性作用得到保护。为了符合监管指导，需要在复杂生物体中进行研究，并进行机制研究，以确定观察到的任何毒性与人类的相关性。尽管毒性模型在不断改进，但研究仍然是这一过程的核心。此类研究通常既耗时又费力，而且往往涉及大量动物。新的监管框架建议实施“智能”毒性测试方法，这些方法可以有效地评估对人类的安全性，并符合社会减少动物使用的期望。减少所需动物数量的主要障碍是用作毒性标志物的病理终点的耗时和复杂性。这些终点容易受到个体间变异性、主观性的影响，并且需要在测试地点之间进行协调。因此，每个实验组都需要大量的动物。为了解决这个问题，我们提出实施我们开发的复杂应激反应报告小鼠。这些报告模型以高度可重复的方式以单细胞分辨率提供毒性潜力的早期生物标志物，这些生物标志物也可以进行非侵入性测量，并已在学术研究中广泛验证为广泛化学物质在人类相关暴露下的应激反应的早期生物标志物。在本报告中，我们描述了我们实验室中以前生成的新型模型，提供了使用它们所需的方法，并讨论了如何将它们用于告知毒性风险（化学物质引起不良健康影响的可能性）。我们提出，与传统毒性测试相比，我们的方法更具信息性（细化），并减少了动物的使用（减少）。这些模型可以纳入分层毒性测试，并与测定结合使用，以生成定量不良结局途径并告知毒性潜力。
