Perspectives on In Vitro to In Vivo Extrapolations.
Perspectives on In Vitro to In Vivo Extrapolations.
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DOI：
10.1089/aivt.2016.0026
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发表时间：
2018-12-01
影响因子：
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通讯作者：
Hartung, Thomas
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文献类型：
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作者：
Hartung, Thomas
体外到体内定量外推（QIVIVE）被广泛认为是从体外研究结果到剂量模式的必要桥梁。细胞系统的质量和相关性是QIVIVE的首要前提条件。信息丰富且具有机制性的终点（生物标志物）可改进外推，但一个复杂的终点并不能使一个糟糕的细胞模型变好。接下来需要的是逆向毒代动力学（TK），它可估算达到体外有活性的组织浓度所需的剂量。约翰霍普金斯动物实验替代方法中心（CAAT）制定了无动物全身毒性测试的路线图，其中在不同全身毒性的背景下详细阐述了毒代动力学的需求和机遇。该报告在2012年布鲁塞尔和2013年华盛顿的两次利益相关者论坛上进行了讨论；本文总结了关键建议。与普遍观点以及帕拉塞尔苏斯的“万物皆有毒”范式相反，大多数工业化学品没有表现出毒性。因此，增强替代危害识别方法阴性结果的可信度可避免QIVIVE的需求。在这里，综合测试策略中多种方法的结合尤其具有前景。另外两种截然不同的方法旨在克服体内复杂性建模的问题：芯片上的人体运动旨在通过微生理系统（即通过微流体连接的器官等效物）重现生物体大部分的复杂性。同时，21世纪毒性测试（Tox - 21c）运动旨在采用机制性方法（如经济合作与发展组织（OECD）所倡导的不良结局途径或人类毒组学项目中的毒性途径）进行高通量筛选、生物表型分析，并最终通过与计算机建模相结合实现系统毒理学方法。这些21世纪的方法也需要21世纪的验证，例如通过循证毒理学。最终，QIVIVE是将Tox - 21c等方法外推到人类风险评估的必要条件。
Quantitative in vitro to in vivo extrapolation (QIVIVE) is broadly considered a prerequisite bridge from in vitro findings to a dose paradigm. Quality and relevance of cell systems are the first prerequisite for QIVIVE. Information-rich and mechanistic endpoints (biomarkers) improve extrapolations, but a sophisticated endpoint does not make a bad cell model a good one. The next need is reverse toxicokinetics (TK), which estimates the dose necessary to reach a tissue concentration that is active in vitro. The Johns Hopkins Center for Alternatives to Animal Testing (CAAT) has created a roadmap for animal-free systemic toxicity testing, in which the needs and opportunities for TK are elaborated, in the context of different systemic toxicities. The report was discussed at two stakeholder forums in Brussels in 2012 and in Washington in 2013; the key recommendations are summarized herein. Contrary to common belief and the Paracelsus paradigm of everything is toxic, the majority of industrial chemicals do not exhibit toxicity. Strengthening the credibility of negative results of alternative approaches for hazard identification, therefore, avoids the need for QIVIVE. Here, especially the combination of methods in integrated testing strategies is most promising. Two further but very different approaches aim to overcome the problem of modeling in vivo complexity: The human-on-a-chip movement aims to reproduce large parts of living organism's complexity via microphysiological systems, that is, organ equivalents combined by microfluidics. At the same time, the Toxicity Testing in the 21st Century (Tox-21c) movement aims for mechanistic approaches (adverse outcome pathways as promoted by Organisation for Economic Co-operation and Development (OECD) or pathways of toxicity in the Human Toxome Project) for high-throughput screening, biological phenotyping, and ultimately a systems toxicology approach through integration with computer modeling. These 21st century approaches also require 21st century validation, for example, by evidence-based toxicology. Ultimately, QIVIVE is a prerequisite for extrapolating Tox-21c such approaches to human risk assessment.