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Responses of Lung Cells to Metals in Manufactured Nanoparticles

John M. Veranth, Christopher A. Reilly, and Garold S. Yost
University of Utah, Salt Lake City, UT

This project is based on the hypothesis that transition metals in particles induce pro-inflammatory signaling and cell damage through the production of reactive oxygen species. Established cell culture models and toxicology assays are being applied to the analysis of manufactured nanomaterials. Based on the literature and our own data, we expect that the small physical size and high surface area of nanoparticles (d < 30 nm) will increase cellular uptake and increase induction of pro-inflammatory signaling compared to larger particles with the same elemental composition. In vitro studies with human and rat lung cells are being used to evaluate the effects of manufactured nanoparticles. The emphasis is on lower-cost nanomaterials that are sold in powder or liquid suspension form because these materials are expected to be produced and ultimately released in the largest amount.

We are currently in the first phase of the study, using low-cost assays to screen a wide range of samples with sufficient replicates for statistical power. This phase (Figure 1) emphasizes measurement of cytotoxicity, induction of the proinflammatory cytokine IL-6, and dissolution rate in simulated lung fluid. Materials selected in the screening phase will be used for more detailed, mechanistic studies. The second phase will test selected materials for particle uptake by the cells, for the induction of additional cytokines, and for the effect of antioxidants. Phase two physical characterization will include electron microscopy, BET surface area, zeta potential, and trace element analysis. In the third phase, the most inflammatory and most benign nanomaterials will be used in hypothesis-based toxicology experiments to evaluate plausible mechanisms by which the particles induce specific responses in cells. Cell culture toxicology studies with BEAS-2B cells, an immortalized human lung epithelial cell line, are emphasized and are consistent with the goal of refining, reducing, and replacing animal use. To establish the relevance of cell culture data to whole animals and to human health, experiments using normal macrophages and normal epithelial cells that are freshly harvested from rats will be conducted to test the ability of the cell culture assays to predict the induction of inflammation by specific nanomaterials.

Figure 1. Using in vitro Cell Culture To Measure Cytotoxicity of and IL-6 Induction by a Range of Nano- and Micro-Sized Particles

The vendors' nominal size of selected powders sold as nanomaterials has been verified (Figure 2). Some supermicron size particles appear to have internal porosity. The tentative result of the in vitro assays used in the screening phase is that the nano-size particles of metal oxides are not highly potent compared to micron-sized particles of the same compound or compared to positive controls that are representative of environmental PM. This may be good news for those concerned about the potential health effects from nanoparticles in consumer products, but much more work is needed to confirm these results before publication.

This is the first year of a three-year study. Verification of the relatively low potency of nano-sized particles will be added to the cell culture and physical characterization studies already planned.

Figure 2. BET Surface Area for Nominal Micron and Nano Particles. Bars are marked with the elemental symbol of the metal, but particles were in the oxide form.

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