Project 3: Mathematical Risk Modeling

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，方法是实施、调整和扩展现有的最先进的多尺度建模系统，用于剂量-效应序列（图P3.1）， 总风险研究（MENTOR 1）和剂量反应信息和分析系统（DORIAN 2）的建模环境，在下文中被识别为MENTOR/DORIAN-ENM。这个综合框架的两个具体实现将集中在项目1和2中确定的纳米颗粒的选定“家族”，即： 碳纳米管（CNT）和银纳米颗粒（nAg）。在此框架内，我们将评估主要物理、化学和生物因素以及与环境纳米材料生命周期中以下每个阶段相关的不确定性：（1）来源（生产和/或环境释放/处置），（2）环境转归和迁移，（3）在特定微环境中的累积（包括职业接触）以及各种环境介质和生物群中的接触，（4）来自制造、消费者使用和 环境累积（5）靶器官剂量和生物利用度，（6）毒理动力学过程，以及（7）相关病理生理学终点。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， 还包括科学文献中现有或即将出现的所有相关信息：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证明的方法，翻译的知识在体外和体内的影响ENM到一个全面的风险分析和评估框架。拟议的努力将开始作为一项为期两年的发展活动，然后预计在第三至第五个 多年的努力，将继续作为整个RESAC联盟的合作努力，将项目1和2的结果以及一般文献整合到RENM-KB和MENTOR/DORIAN-ENM中， 应用于CNT和nAg曝光。MENTOR/DORIAN-ENM方法被设想为“假设生成器”，其将允许关于作为生物学基础的机制的各种假设的制定和初步检验。 和毒性动力学（选定的）ENM，从而提供了一种方法，以优化收集额外的数据和设计新的和创新的体外和体内实验研究，为更广泛的ENM在未来。

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.