Mapping the Human Toxome by Systems Toxicology

描述（由申请人提供）：毒性试验通常包括研究受高剂量毒物影响的动物的不良健康结果，随后推断低剂量下预期的人体反应。该系统依赖于使用40多年前的拼凑动物试验，这些试验昂贵（每年花费超过30亿美元），耗时，低通量，并且通常提供的对人类健康影响的预测价值有限。目前毒性测试方法的低通量（工业化学品、农药和药物的毒性测试方法基本相同）导致人类可能接触到的8万多种化学物质积压，这些化学物质的潜在毒性在很大程度上仍然未知。2007年，美国国家研究委员会（NRC）发布了《21世纪的毒性检测：远景与战略》报告，描绘了毒性检测转型的长期战略计划。该计划的主要组成部分包括使用预测性的、高通量的基于细胞的测定（人类来源）来评估关键毒性途径中的扰动，并针对这些途径进行靶向测试。这种方法将极大地加快我们使用合理的、基于风险的方法对化学物质进行优先排序的能力，并提供比现有方法更能预测人类毒性的测试结果。虽然已经确定了许多毒性途径，但大多数毒性途径只是部分已知，并且没有共同的注释。绘制这些路径的完整图谱（即人类弓形虫组）将是一项大规模的工作，可能与人类基因组计划（Human Genome Project）相当。在这个项目中，我们建议全面绘制内分泌干扰的途径，这是绘制人类毒素组的第一步。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“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。在确定毒性途径之后，我们将开展一系列利益相关方研讨会，以开发共识驱动的途径注释、验证、共享和风险评估过程，并开发一个毒性途径的公共数据库，提供一个共同的、社区可访问的框架，使毒理学界能够利用综合测试策略全面合作地绘制人类毒素组。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额外的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.