Toxicity testing in the 21st century: a vision and a strategy.
Toxicity testing in the 21st century: a vision and a strategy.
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DOI：
10.1080/10937404.2010.483176
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发表时间：
2010-02
期刊：
影响因子：
--
通讯作者：
Zeise L
中科院分区：
文献类型：
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作者：
Krewski D;Acosta D Jr;Andersen M;Anderson H;Bailar JC 3rd;Boekelheide K;Brent R;Charnley G;Cheung VG;Green S Jr;Kelsey KT;Kerkvliet NI;Li AA;McCray L;Meyer O;Patterson RD;Pennie W;Scala RA;Solomon GM;Stephens M;Yager J;Zeise L
随着2007年美国国家科学院发布的具有里程碑意义的报告《21世纪的毒性测试：愿景和战略》，毒性测试的方式发生了重大变化。它设想通过从目前昂贵且冗长的体内试验（具有定性终点）过渡到使用机器人高通量筛选（具有机械定量参数）对人类细胞或细胞系进行体外毒性途径测定，从而提高毒性试验的效率并减少动物使用。对接触人群的风险评估将侧重于避免这些毒性途径的重大扰动。将采用计算系统生物学模型来确定通路功能扰动的剂量-反应模型。将体外结果外推至体内人血液和组织浓度将基于给定暴露条件的药代动力学模型。与传统的毒理学测试策略相比，这种做法将增强测试结果的人类相关性，并将涵盖几种测试剂。由于实现这一愿景所需的所有工具目前都已具备或处于高级开发阶段，实现这一范式转变的关键先决条件是科学界致力于变革，而对这一愿景进行广泛讨论可有助于实现这一转变，并获得必要的资源，以提高目前的知识，途径扰动和途径分析在人类和实施计算系统生物模型这些战略的实施将导致一个新的毒性测试范式牢固地基于人类生物学。
With the release of the landmark report Toxicity Testing in the 21st Century: A Vision and a Strategy, the U.S. National Academy of Sciences, in 2007, precipitated a major change in the way toxicity testing is conducted. It envisions increased efficiency in toxicity testing and decreased animal usage by transitioning from current expensive and lengthy in vivo testing with qualitative endpoints to in vitro toxicity pathway assays on human cells or cell lines using robotic high-throughput screening with mechanistic quantitative parameters. Risk assessment in the exposed human population would focus on avoiding significant perturbations in these toxicity pathways. Computational systems biology models would be implemented to determine the dose-response models of perturbations of pathway function. Extrapolation of in vitro results to in vivo human blood and tissue concentrations would be based on pharmacokinetic models for the given exposure condition. This practice would enhance human relevance of test results, and would cover several test agents, compared to traditional toxicological testing strategies. As all the tools that are necessary to implement the vision are currently available or in an advanced stage of development, the key prerequisites to achieving this paradigm shift are a commitment to change in the scientific community, which could be facilitated by a broad discussion of the vision, and obtaining necessary resources to enhance current knowledge of pathway perturbations and pathway assays in humans and to implement computational systems biology models. Implementation of these strategies would result in a new toxicity testing paradigm firmly based on human biology.