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.