The importance of developing a predictive nano-toxicology framework, based on the association of ENM properties to ENM toxicity profiles. A comprehensive discussion about the importance of developing a predictive toxicology paradigm to assess ENM safety has been included in Section B of the Overall Research Plan. In this proposal we implement the foundation for a quantitative predictive toxicology paradigm for ENM in the lung. Our approach builds on rapid throughput screening data in cells to establish a relationship between ENM properties and cellular or bio-molecular injury pathways. The in vitro structure-activity relationships are then used by our in silico methods to perform hazard ranking and make predictions about in vivo toxicological outcomes in the rodent lung. The ENM libraries provided by the Scientific Core have been s.elected to highlight key physicochemical properties that are relevant to a number of cellular injury mechanisms that we propose may lead to pulmonary toxicity and can therefore be used for making predictions, potentially leading to cellular and molecular injury mechanisms of toxicity in the lung. The in vitro studies that will be conducted in Project #1 will concentrate on cellular oxidant injury, cytotoxicity, infiammation, signaling pathway activation and membrane lysis, which hypothetically is linked to ENM properties such as composition, size, size distribution, state of dispersal, charge, shape, surface reactivity, dissolution, shedding of metal ions and ability to induce abiotic and biotic oxygen radical production. These properties will be reflected in the different material compositions as well as the variation of specific properties that will be investigated in terms of toxicological injury, cellular uptake and subcellular processing. More specifically, we will utilize low solubility metal and metal oxides libraries to compare the ENM properties that define putative low (Ti02, CeOg, AI2O3, Au) and high reactive (Co, Ag, Cu) metal and metal oxide nanoparticles, with particular emphasis on explaining the response generation in terms of surface area, surface reactivity, ROS generation and shedding of metal ions. The contribution of surface area and surface reactivity will then be further explored by using combinatorial variations of size and shape changes as well as varying the material phase. A second group of library materials will be used to explore the role of different silica phases as well as the surface reactivity of nano-quartz particles that will be synthesized to display different silanol chemistries on the surface. These materials will be used to dissect the well known propensity of crystalline silica to induce severe pulmonary inflammation and fibrosis. We will also use metal-releasing silica nanoparticles and mesoporous silica particles coated with a cationic polymer to dissect the role of metals released intracellulariy and cationic charge as hazardous material properties. Finally, we will utilize nano-ZnO as well as iron-doped ZnO to dissect the cellular and pulmonary toxicity of a highly dissolvable ENM that in incidental exposures to welders can induce metal fume fever. A comprehensive discussion of the scientific hypothesis guiding the consideration of these ENM libraries appear in the Overall Research Plan, as well as in the Project #1 proposals. Specific information about the ENM composition and their characterization appear in the Scientific Core.
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