Mapping the Human Toxome by Systems Toxicology

描述(由申请人提供)：毒性测试通常涉及研究高剂量毒物对动物的不利健康后果，然后根据较低剂量的预期人类反应进行外推。该系统依赖于已有40多年历史的拼凑而成的动物试验，这些试验费用昂贵(每年花费超过30亿美元)、耗时、吞吐量低，而且往往提供的结果对人类健康影响的预测价值有限。目前的毒性测试方法(对工业化学品、杀虫剂和药物基本上相同)的低吞吐量导致积压了8万多种人类可能接触的化学品，其潜在毒性在很大程度上仍不清楚。2007年，美国国家研究委员会(NRC)发布了一份名为《21世纪的毒性测试：愿景与战略》的报告，该报告制定了一项长期的战略计划，以改变毒性测试。该计划的主要组成部分包括使用预测性、高通量、基于细胞的分析(来自人类)，以评估关键毒性途径的扰动，并针对这些途径进行有针对性的测试。这种方法将极大地提高我们使用合理的、基于风险的方法来确定化学优先级的方法来测试巨大的化合物“仓库”的能力，并提供比目前的方法更能预测人体毒性的测试结果。虽然已经确定了一些毒性途径，但大多数只有部分人知道，而且没有共同的注释。绘制这些途径(即人类毒素组)的全貌将是一项大规模的努力，可能会在人类基因组计划的范围内进行。在这个项目中，我们建议全面绘制内分泌干扰的路径图，这是绘制人类毒素组图的第一步。我们将利用我们对基因、蛋白质和小分子如何相互作用形成维持细胞功能的分子途径的快速发展的科学理解，应用正交的“组学”方法(转录组学、代谢组学)来绘制和注释一组定义的内分泌干扰物的毒性途径。在确定毒性途径后，我们将举办一系列利益攸关方研讨会，以制定一个以共识为导向的途径注释、验证、共享和风险评估程序，并开发一个关于毒性途径的公共数据库，提供一个公共的、社区可访问的框架，使毒物学社区能够使用综合测试策略全面和合作地绘制人类毒素组图。最后，我们将验证已确定的毒性途径，将概念扩展到其他毒物、细胞系统和内分泌干扰物危害，以及其他组学平台和剂量反应建模。

DESCRIPTION (provided by applicant): Toxicity testing typically involves studying adverse health outcomes in animals subjected to high doses of toxicants with subsequent extrapolation to expected human responses at lower doses. The system relies on the use of a 40+year-old patchwork of animal tests that are expensive (costing more than $3B per year), time-consuming, low-throughput and often provide results of limited predictive value for human health effects. The low-throughput of current toxicity testing approaches (which are largely the same for industrial chemicals, pesticides and drugs) has led to a backlog of more than 80,000 chemicals to which humans are potentially exposed whose potential toxicity remains largely unknown. In 2007, the National Research Council (NRC) released the report "Toxicity Testing in the 21st Century: A Vision and a Strategy", that charted a long-range strategic plan for transforming toxicity testing. The major components of the plan include the use of predictive, high-throughput cell-based assays (of human origin) to evaluate perturbations in key toxicity pathways, and to conduct targeted testing against those pathways. This approach will greatly accelerate our ability to test the vast "storehouses" of chemical compounds using a rational, risk-based approach to chemical prioritization, and provide test results that are far more predictive of human toxicity than current methods. Although a number of toxicity pathways have already been identified, most are only partially known and no common annotation exists. Mapping the entirety of these pathways (i.e. the Human Toxome) will be a large-scale effort, perhaps on the order of the Human Genome Project. In this project, we propose to comprehensively map pathways of endocrine disruption, representing a first step towards mapping the human toxome. We will leverage our rapidly evolving scientific understanding of how genes, proteins, and small molecules interact to form molecular pathways that maintain cell function, applying orthogonal "omics" approaches (transcriptomics, metabolomics) to map and annotate toxicity pathways for a defined set of endocrine disruptors. Following the identification of toxicity pathways, we will conduct a series of stakeholder workshops to enable development of a consensus-driven process for pathway annotation, validation, sharing and risk assessment, and develop a public database on toxicity pathways, providing a common, community-accessible framework that will enable the toxicology community at large to comprehensively and cooperatively map the human toxome using integrated testing strategies. Finally we will validate the identified pathways of toxicity extend the concepts to additional toxicants, cell systems and endocrine disruptor hazards as well as to additional omics platforms and to dose response modeling.