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Chemical Fate, Biopersistance, and Toxicology of Inhaled Carbonaceous Nanoscale MaterialsEPA Grant Number: R832527
Title: Chemical Fate, Biopersistance, and Toxicology of Inhaled Carbonaceous Nanoscale Materials
Investigators: McDonald, Jacob D. , Dix, Kelly J. , Gigliotti, Andrew , Seagrave, Jean Clare , VanderWal, Randall L.
Current Investigators: McDonald, Jacob D. , Gigliotti, Andrew , Seagrave, Jean Clare , VanderWal, Randall L.
Institution: Lovelace Respiratory Research Institute , NASA-Glenn
EPA Project Officer: Karn, Barbara
Project Period: December 1, 2005 through November 30, 2008
Project Amount: $350,000
RFA: Exploratory Research: Nanotechnology Research Grants Investigating Environmental and Human Health Effects of Manufactured Nanomaterials: A Joint Research Solicitation - EPA, NSF, NIOSH (2005) RFA Text | Recipients Lists
Research Category: Health , Safer Chemicals , Health Effects , Nanotechnology
Observations of significant respiratory toxicity of carbon nanotubes compared to historical positive controls administered by instillation into rodent lungs has raised many questions regarding the biocompatibility of these materials that have significant potential in nanotechnology. There is an immediate need to confirm and extend those observations using methods that better mimic actual exposure conditions that have been measured or predicted for occupational or environmental exposures. This proposed research will directly compare the biological disposition, persistence, and toxicity of two commercial nanoscale carbonaceous nanomaterials of potential wide utilization to a control material of known toxicity. Concentration matched (by mass) inhalation exposures of carbon nanotubes and fullerenes will be compared to inhaled crystalline silica. To compare with previous studies, inhalation results will be compared directly to instilled materials suspended in aqueous media.
The proposed studies will test several hypotheses: 1) The toxicity of inhaled carbon nanotubes and fullerenes, due to their relative non-reactive surface chemistry, is low relative to crystalline silica when administered by inhalation; 2) The preferential carbon nanotube toxicity observed (in prior studies) by instillation is an artifact of dose and dose administration technique; 3) fullerenes and carbon nanotubes are not completely eliminated from the nasal or lung regions after 17 weeks.
Hypotheses 1 and 2: C57bl/6N mice will be exposed for 30 consecutive days (6 hr/day) to fullerene or carbon nanotube inhalation atmospheres suited to match plausible human exposure scenarios for particle size and concentrations. Lung lavage white blood cell count/differentials, cytokines, protein and histopathology will be determined after 30 days or after a 17 week hold. In parallel, matched cumulative doses will be administered as a single bolus by tracheal instillation and animals will be sacrificed 30 days or 30 days plus 17 weeks later for the same analysis as inhalation. In both cases, crystalline silica will be used as a positive control. The time points proposed are based on pilot data from our laboratory showing the formation of significant silica induced granulomas at 17 weeks. The characterization of disposition will be conducted at the same timepoints mentioned above. Fullerenes will be measured in tissues by a validated LC/MS/MS assay that has been developed in our laboratory. Carbon nanotubes in tissues will be determined by a method we are currently developing that involves thermal analysis after tissue digestion.
We expect to improve the current understanding of the toxicity associated with inhalation of carbon nanomaterials compared with instillation of the same material. This will allow better understanding both of those materials and the utility of instillation for evaluating hazards of these types of materials. We expect improved biocompatibility when administered by inhalation (but not instillation). We will show, for the first time, the disposition and persistance of inhaled carbonaceous nanomaterials.