Systems Toxicology of Nanomaterials
National and Scientific Challenges
The last few years have seen a dramatic increase in research at the nanometer scale. New opportunities have become evident through this research; the nation is watching nanomaterials effectively revolutionize energy production, manufacturing, electronics, communication and pharmaceuticals. It is projected by 2014, that 10 million jobs will produce $2.6 trillion in manufactured nano-enabled goods annually (Lux Research). However, with a growing public concern about the safety of nanomaterials, and an increasing number of Intent to Manufacture Notices for nanomaterials and the products containing nanomaterials, regulatory agencies must address, methods for rapidly determining nanotoxicity. These concerns include our lack of understanding of the health effects of engineered nanoparticles and the need to characterize associated exposure, fate and transport, dose-response relationships, and control mechanisms. National challenges exist around leading global applications in nanomaterials science, while at the same time ensuring appropriate protective measures for human and ecosystem health.
PNNL's Integrative Approach
PNNL is developing an integrated capability, including tools and scientific expertise, to predict toxicity of nanomaterials with the intent of guiding development, commercialization, and regulation of safe nanomaterials. Research will focus on biosignature identification based upon characterization of the properties of nanomaterials, novel imaging approaches to describe the molecular and cellular fate of nanomaterials, and systems toxicology-based integrative approaches to identify molecular mechanisms of toxicity. This integrated approach will facilitate understanding the properties of nanomaterials that lead to toxicity and advance the field of biomarker discovery for environmental respiratory tract diseases associated with exposure to nanomaterials. The outcome will enable clients to use new nanomaterials safely and help meet needs in energy, security, and the environment. More broadly, the outcome will be protection of American workers, consumers, and the environment, and secure our nation's position of economic competitiveness in the global marketplace.
All projects will use the same model systems that include both the nanomaterials and the biological system. Nanomaterials selected include crystalline silica, titanium oxide, single-wall carbon nanotubes, multi-wall carbon nanotubes, and polystyrene beads. Criteria for selection and investigation include size distribution, modifiable surfaces, commercial use, biological activity and human toxicity. Murine cell lines, the commonly used RAW 264.7 macrophage cell line along with Type II pulmonary epithelial cell lines, were selected as biological systems. The C57/BL6 mouse strain will be used for inhalation exposure studies.
The work flow of the projects starts with design, synthesis, and characterization of the nanoparticles used for both the imaging and biological response projects. Imaging studies are carried out to elucidate cellular fate and processing of nanomaterials. These results are then used in conjunction with computational and experimental dosimetry to determine actual exposure of cells during in vitro and in vivo studies on biological response. Molecular and pathway analysis tools are used to understand cellular or tissue processes. Subsequently, predictive computational tools will be used to relate nanomaterial characteristics to biological response.
Specific capabilities are being developed as part of the following projects:
- Biosignature Integration for Inference of Biomarkers from Complex Systems
- Discovery of a Biomarker Signature in Response to Nanoparticle Exposure
- Modeling Nanoparticle-Cell Interactions
- Model Nanoparticles for Discovery and Validation of PM Biomarkers
- Nanomaterial Exposure and Respiratory Effects Biosignature Discovery
- Nanoscale Insight into the Living Cell Membrane Responses to Ultrafine PM- Implications to Toxicity Screening Methods
- Non-invasive Real-time in situ Spectroscopic Monitoring of Macrophage-Particulate Matter Interactions
- Proteomic Methods and QSAR Models to Predict Nanoparticle Surface Chemistry Interactions
- Secretome Analysis of Environmental Particulate Matter Induced Biomarkers
- Signatures of Oxidative Stress Associated with Inhaled Particulate Matter
Focus Area Point of Contact: Joel Pounds