Potential of in vivo stress reporter models to reduce animal use and provide mechanistic insights in toxicity studies.
Potential of in vivo stress reporter models to reduce animal use and provide mechanistic insights in toxicity studies.
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DOI：
10.12688/f1000research.123077.1
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发表时间：
2022
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化学品风险评估确保免受药物和人造化学品的毒性影响。为了符合监管指南，需要在复杂生物体中进行研究，以及进行机制研究，以确定观察到的任何毒性对人体的相关性。尽管体外毒性模型正在改进，但体内研究仍然是这一过程的核心。这些研究总是很耗时，而且往往涉及大量的动物。新的监管框架建议实施“智能”体内毒性测试方法，可以有效评估对人类的安全性，并符合减少动物使用的社会期望。减少所需动物的一个主要障碍是用作毒性标志物的病理学终点的耗时和复杂性。这些终点容易出现动物间变异性、主观性，需要在试验中心之间进行协调。因此，每个实验组需要大量的动物。为了解决这个问题，我们提出了复杂的压力反应报告小鼠，我们已经开发的实施。这些报告模型以高度可重复的方式在单细胞分辨率下提供毒性潜力的早期生物标志物，其也可以非侵入性地测量，并且已经在学术研究中被广泛验证为人类相关暴露的各种化学品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新的和以前生成的模型，提供了使用它们所需的方法，并讨论了它们如何用于告知有毒风险（化学品造成不良健康影响的可能性）。我们提出，与传统毒性试验相比，我们的体内方法信息量更大（细化），并减少了动物使用（减少）。这些模型可以被纳入分层毒性测试，并与体外试验结合使用，以产生定量的不良后果途径，并提供潜在的毒性信息。
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 in vitro toxicity models are improving, in vivo 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” in vivo 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 in vivo 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 in vitro assays to generate quantitative adverse outcome pathways and inform on toxic potential.