Project 3: Mathematical Risk Modeling

项目3：数学风险建模

• 批准号: 8068439
• 负责人: PANOS GEORGOPOULOS
• 金额: $ 20.93万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-28 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8068439
• 关键词: Accounting; Aerosols; Affect; Area; Arts; Biological; Biological Availability; Biological Factors; Biological Models; Biota; Carbon Nanotubes; Charge; Chemicals; Collection; Computer Simulation; Data; Development; Dose; Drug Formulations; Engineering; Environment; Equation; Equilibrium; Exposure to; Family; Future; In Vitro; Investigation; Knowledge; Life Cycle Stages; Liquid substance; Literature; Mentors; Methods; Modeling; Occupational; Online Systems; Organ; Organism; Population Dynamics; Process; Property; Research; Research Design; Risk; Risk Assessment; Shapes; Silver; Source; Staging; Surface; System; Systems Analysis; Testing; Tissues; Toxicogenomics; Toxicokinetics; Translating; Uncertainty; base; design; exposed human population; hydrophilicity; in vivo; information system analysis; innovation; knowledge base; lipophilicity; molecular scale; multi-scale modeling; nanomaterials; nanoparticle; novel; particle; physical property; programs; prototype; research study; response

The overall objective of Project 3 is to define, demonstrate, and test a prototype generalized risk analysis framework for engineered nanomaterials (ENMs) by implemenfing, adapfing, and expanding available state-of-the-art multiscale modeling systems for the exposure-to-dose-to-effect sequence (Figure P3.1), the Modeling ENvironment for TOtal Risk studies (MENTOR 1) and the DOse Response Informafion and ANalysis system (DORIAN 2), to be identified in the following as MENTOR/DORIAN-ENM. Two specific implementations of this integrative framework will focus on the selected "families" of nanoparticles identified in Projects 1 and 2, i.e. carbon nanotubes (CNT) and silver nanoparticles (nAg). Within this framework, we will evaluate major physical, chemical and biological factors and uncertainties associated with each of the following stages in the ENMs' life cycle: (1) sources (manufacturing and/or environmental release/disposal of ENMs), (2) environmental fate and transport, (3) accumulation in specific microenvironments (including occupafional) and in various environmental media and biota, (4) human exposure (including occupafional) from manufacturing, consumer usage, and environmental accumulation (5) dose at target organs and bioavailability, (6) toxicodynamic processes, and (7) relevant pathophysiological endpoints. In order to ulfimately produce a meaningful and generalizable risk assessment framework, we will utilize not only the data and parameters to be obtained through projects 1 and 2, but also all relevant information that is available or will appear in the scientific literature: a pilot "Knowledge Base" to support Risk studies for Engineered NanoMaterials (RENM-KB). So, the proposed research will develop and demonstrate approaches that translate the knowledge ofthe in vitro and In vivo effects of ENM into a comprehensive risk analysis and assessment framework. The proposed effort will begin as a two-year developmental activity and then it is expected that during the third through fifth years of the effort, will continue as a collaborative effort across the RESAC consortium, integrating results from Projects 1 and 2, as well as from the general literature, into RENM-KB and into MENTOR/DORIAN-ENM for applications to CNT and nAg exposures. The MENTOR/DORIAN-ENM approach is envisioned as a "hypothesis generator" that will allow formulation and preliminary tesfing of various hypotheses regarding the mechanisms underiying the biokinetics and toxicodynamics of (the selected) ENM, thus providing a way to optimize the collection of additional data and the design of new and innovative in vitro and in vivo experimental studies for a wider range of ENMs in the future.

项目3的总体目标是定义、演示和测试工程纳米材料(ENM)的原型通用风险分析框架，方法是实现、适应和扩展用于暴露于剂量-效应序列的最先进的多尺度建模系统(图P3.1)。 总风险研究的建模环境(MENTOR 1)和剂量反应信息和分析系统(DORIAN 2)，下文将确定为MENTOR/DORIAN-ENM。这一综合框架的两个具体实施将侧重于项目1和2中确定的选定的纳米颗粒“家族”，即 碳纳米管(CNT)和银纳米颗粒(NAG)。在这个框架内，我们将评估与环境污染物生命周期中每个阶段相关的主要物理、化学和生物因素和不确定性：(1)环境污染物的来源(制造和/或环境释放/处置)，(2)环境命运和运输，(3)在特定微环境(包括占有性)和各种环境介质和生物群中的积累，(4)来自制造、消费和使用的人类暴露(包括占有性)，以及 环境累积(5)目标器官的剂量和生物利用度，(6)毒理动力学过程，(7)相关的病理生理终点。为了最终产生一个有意义和可推广的风险评估框架，我们不仅将利用通过项目1和2获得的数据和参数， 而且还包括现有或将出现在科学文献中的所有相关信息：支持工程纳米材料风险研究的试点“知识库”(RENM-KB)。 因此，拟议的研究将开发和演示将ENM的体外和体内效应的知识转化为全面的风险分析和评估框架的方法。拟议的努力将作为一项为期两年的发展活动开始，然后预计在第三至第五年期间 多年的努力将继续作为整个RESAC财团的合作努力，将项目1和2以及一般文献的结果整合到RENM-KB和Mentor/Dorian-ENM中 应用于CNT和NAG暴露。Mentor/Dorian-ENM的方法被设想为一个“假设生成器”，它将允许关于生物动力学基础机制的各种假设的公式化和初步测试 和(选定的)ENM的毒理动力学，从而提供了一种方法，以优化额外的数据收集和设计新的和创新的体外和体内实验研究，在未来更广泛的ENM。