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Development of in vitro vs. in vivo models to evaluate fibrogenic and carcinogenic potential of carbon nanotubes.

Wang-L; Mishra-A; Stueckle-T; Derk-R; Rojanasakul-Y; Castranova-V
NORA Symposium 2011: Achieving Impact Through Research and Partnerships, July 12-13, 2011, Cincinnati, Ohio. Cincinnati, OH: National Institute for Occupational Safety and Health, 2011 Jul; :63
Carbon Nanotubes (CNT) possess unique physicochemical properties which exhibit different biological effects compared to micro-sized particles. The nano-scale size and dispersion status of the CNT play critical roles in their unique bioeffects. Among the adverse effects reported, CNT have been shown to induce rapid interstitial lung fibrosis and persist in the lung. This raises a human risk concern and brings up a challenge, since information and specific methods are lacking which would allow one to predict the biological activity of these new nanomaterials. To address this issue, our objective is to determine "Nanoparticle properties and mechanisms causing lung fibrosis" which is a funded NORA project (2008-2012). Published or ongoing research results provide novel findings of unique bio-effects of CNTs and specific nano-research methods which are summarized below: 1) Survanta, a natural lung surfactant, effectively disperses single-walled CNT (SWCNT) or multi-walled CNT (MWCNT) agglomerates into small structures, which are similar in size to aerosolized SWCNT structures. Plus, at the concentration of Survanta used for the dispersion, it showed no toxic effects and did not mask surface activity of particles; 2) dispersed SWCNT or MWCNT exhibited an acute biphasic effect on cells inducing proliferation at low doses and causing toxicity at high doses, while their non-dispersed forms had no significant effects; 3) dispersed SWCNT or MWCNT upregulated collagen expression from cultured lung fibroblasts and lung tissue in a mouse model, whereas their non-dispersed forms showed a significant lesser effect; 4) well known fibrogenic mediators, such as Transforming Growth Factor beta (TGF-beta1) or Matrix Metallopeptidase (MMP9), were induced by SWCNT or MWCNT in vitro, which is consistent with in vivo observation from our and other published reports. These mediators, therefore, could serve as bio-markers to evaluate early events of nanotoxicity; 5) low dose, long term exposure of lung epithelial cells to dispersed SWCNT or MWCNT caused cell transformation towards a tumorigenic phenotype. The above data from both cell culture and animal models support our proposed hypothesis that physicochemical properties of CNT are key factors in determining their bioactivities, which leads to a novel mechanism of unique nanoparticle-induced lung fibrosis. Present developed in vitro models using human lung cells provides a great advantage to study mechanistic detail of nano-toxicity and may represent a potential simple, rapid, less costly, high throughput screening tool to predict the fibrogenic or carcinogenic potential of nanomaterials. This information will be useful for researchers, industry, and governmental regulatory agencies to conduct risk assessment and develop prevention strategies.
Biohazards; Biological-effects; Biological-systems; Biomarkers; Exposure-assessment; Fibrogenicity; Laboratory-animals; Laboratory-techniques; Laboratory-testing; Lung-fibrosis; Measurement-equipment; Microbiology; Nanotechnology; Particulates; Pulmonary-disorders; Pulmonary-system-disorders; Quantitative-analysis; Respiratory-hypersensitivity; Respiratory-infections; Respiratory-irritants; Risk-analysis
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NORA Symposium 2011: Achieving Impact Through Research and Partnerships, July 12-13, 2011, Cincinnati, Ohio