Movia Dania, Bruni-Favier Solene, Prina-Mello Adriele
Laboratory for Biological Characterisation of Advanced Materials (LBCAM), Department of Clinical Medicine, Trinity Translational Medicine Institute, Trinity College, The University of Dublin, Dublin, Ireland.
AMBER Centre, CRANN Institute, Trinity College, The University of Dublin, Dublin, Ireland.
Front Bioeng Biotechnol. 2020 Jun 3;8:549. doi: 10.3389/fbioe.2020.00549. eCollection 2020.
When assessing the risk and hazard of a non-pharmaceutical compound, the first step is determining acute toxicity, including toxicity following inhalation. Inhalation is a major exposure route for humans, and the respiratory epithelium is the first tissue that inhaled substances directly interact with. Acute inhalation toxicity testing for regulatory purposes is currently performed only in rats and/or mice according to OECD TG403, TG436, and TG433 test guidelines. Such tests are biased by the differences in the respiratory tract architecture and function across species, making it difficult to draw conclusions on the potential hazard of inhaled compounds in humans. Research efforts have been therefore focused on developing alternative, human-relevant models, with emphasis on the creation of advanced models. To date, there is no model that has been accepted by regulatory agencies as a stand-alone replacement for inhalation toxicity testing in animals. Here, we provide a brief introduction to current OECD test guidelines for acute inhalation toxicity, the interspecies differences affecting the predictive value of such tests, and the current regulatory efforts to advance alternative approaches to animal-based inhalation toxicity studies. We then list the steps that should allow overcoming the current challenges in validating alternatives for the successful replacement of animal-based inhalation toxicity studies. These steps are inclusive and descriptive, and should be detailed when adopting in house-produced 3D cell models for inhalation tests. Hence, we provide a checklist of key parameters that should be reported in any future scientific publications for reproducibility and transparency.
在评估非药物化合物的风险和危害时，第一步是确定急性毒性，包括吸入后的毒性。吸入是人类主要的接触途径，呼吸道上皮是吸入物质直接相互作用的首个组织。目前，出于监管目的的急性吸入毒性测试仅根据经合组织TG403、TG436和TG433测试指南在大鼠和/或小鼠中进行。此类测试因物种间呼吸道结构和功能的差异而存在偏差，因此难以就吸入化合物对人类的潜在危害得出结论。因此，研究工作一直集中在开发与人类相关的替代模型，重点是创建先进的模型。迄今为止，尚无一种模型被监管机构接受作为动物吸入毒性测试的独立替代方法。在此，我们简要介绍经合组织目前的急性吸入毒性测试指南、影响此类测试预测价值的种间差异，以及当前推进基于动物的吸入毒性研究替代方法的监管努力。然后，我们列出了为成功替代基于动物的吸入毒性研究而验证替代方法时应克服当前挑战的步骤。这些步骤具有包容性和描述性，在采用自制的3D细胞模型进行吸入测试时应详细说明。因此，我们提供了一份关键参数清单，任何未来的科学出版物都应报告这些参数，以确保可重复性和透明度。
