Hartung Thomas
Center for Alternatives to Animal Testing (CAAT), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
University of Konstanz, Konstanz, Germany.
Appl In Vitro Toxicol. 2018 Dec 1;4(4):305-316. doi: 10.1089/aivt.2016.0026. Epub 2018 Dec 8.
Quantitative to extrapolation (QIVIVE) is broadly considered a prerequisite bridge from 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 . 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 complexity: The 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.
定量外推法（QIVIVE）被广泛认为是从研究结果到剂量范式的必要桥梁。细胞系统的质量和相关性是QIVIVE的首要前提。信息丰富的机制性终点（生物标志物）可改善外推，但复杂的终点并不能使糟糕的细胞模型变好。接下来需要的是逆向毒代动力学（TK），它可估算达到活性组织浓度所需的剂量。约翰霍普金斯大学动物实验替代中心（CAAT）制定了无动物全身毒性测试路线图，其中阐述了不同全身毒性背景下TK的需求和机遇。该报告在2012年于布鲁塞尔和2013年于华盛顿举行的两次利益相关者论坛上进行了讨论；关键建议在此总结。与普遍看法及“万物皆有毒”的帕拉塞尔苏斯范式相反，大多数工业化学品并无毒性。因此，增强替代方法用于危害识别的阴性结果的可信度，可避免QIVIVE的需求。在此，综合测试策略中的方法组合最具前景。另外两种截然不同的方法旨在克服建模复杂性问题：一种方法旨在通过微生理系统重现生物体的大部分复杂性，即通过微流控技术组合的器官等效物。与此同时，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）倡导的不良结局途径或人类毒理组计划中的毒性途径）进行高通量筛选、生物表型分析，并最终通过与计算机建模整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此类方法外推至人类风险评估的前提条件。
