Mapping the Human Toxome by Systems Toxicology

描述（由申请方提供）：毒性试验通常涉及研究动物在高剂量毒物下的不良健康结果，随后外推至较低剂量下的预期人体反应。该系统依赖于使用40多年的动物试验拼凑而成，这些动物试验昂贵（每年花费超过30亿美元），耗时，低通量，并且通常提供对人类健康影响的预测价值有限的结果。目前毒性测试方法的低通量（对于工业化学品、农药和药物基本相同）导致积压了80 000多种人类可能接触的化学品，其潜在毒性在很大程度上仍然未知。2007年，美国国家研究理事会（NRC）发布了题为《21世纪的毒性测试：愿景与战略》的报告，为改变毒性测试制定了长期战略计划。该计划的主要组成部分包括使用预测性、高通量的基于细胞的测定（人源性）来评价关键毒性途径的扰动，并针对这些途径进行有针对性的检测。这种方法将大大加快我们使用合理的、基于风险的化学优先级排序方法来测试化合物的巨大“仓库”的能力，并提供比现有方法更能预测人类毒性的测试结果。虽然已经确定了一些毒性途径，但大多数只是部分已知，没有共同的注释。绘制这些通路的整体（即人类毒素组）将是一项大规模的工作，可能与人类基因组计划相当。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，我们将举办一系列利益相关者研讨会，以便为途径注释、验证、共享和风险评估开发一个共识驱动的过程，并开发一个关于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，使毒理学界能够使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，并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响应模型。

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.