A Systems Approach to Nanotoxicology
Contact: Dr. Brian Thrall
Pacific Northwest National Laboratory's systems
approach integrates responses of multiple
levels of biological processes, and enables
an understanding of the effects of
nanomaterials on cell and organism
function. Through integration of the
Exposure Sciences and Systems Toxicology,
our goal is to provide the
science and tools necessary to
enable personalized risk analysis
and guide nanotechnology development
for the future.
Nanotoxicology is a multidisciplinary challenge that draws on the broad expertise in the Systems Toxicology group. The PNNL systems approach integrates responses of multiple levels of biological processes and enables an understanding of the effects of nanomaterials on cell and organism function. Through integration of the Exposure Sciences and Systems Toxicology, our goal is to provide the science and tools necessary to enable personalized risk analysis and guide nanotechnology development for the future.
Biocompatible design of nanomaterials requires unprecedented levels of collaboration between scientists of multiple disciplines, which, as a National Laboratory, PNNL provides. Traditional fields associated with safety assessment—toxicology, pathology, biology, pharmacokinetics and biochemistry—must work closely with material science, modeling, and others to ensure nanomaterial toxicity and biocompatibility studies produce conclusive, interpretable data for risk assessment.
Coordinated, Integrative, and Systems-Level Approach and Capabilities
PNNL has one of the nation's most experienced, multidisciplinary nanotoxicology teams, which is playing a leading role in the nation's effort to understand the fundamental rules underlying biocompatibility of emerging nanomaterials. The combination of talented staff and a comprehensive, state-of-the-art suite of instrumentation is changing nanotoxicology research from a phenomological approach to a quantitative strategy grounded in cell dosimetry and realistic dose-response extrapolations. Our capabilities include:
- Design, synthesis, and characterization of custom nanomaterials
- Novel measurement and computational tools for cellular and systemic dosimetry
- Elucidating mode-of-action from integrated 'omics: proteomics integrated with transcriptomics, biological pathway analysis, and computational statistics to identify biosignatures and discover biomarkers
- Advanced cellular and animal imaging to understand nanomaterial disposition
- Realistic simulation of respiratory tract function across species (the "Virtual Lung")
- Inhalation toxicology and pulmonary pathology
- Atmospheric chemistry and physics.
Foundations for Nanomaterials Expertise
The Environmental Molecular Sciences Laboratory (EMSL), a world-class Department of Energy scientific user facility at PNNL, provides a broad range of capabilities for molecular studies including those associated with synthesis, characterization, theory and modeling, analysis, and testing of dynamic system properties relevant to a wide range of engineered and naturally occurring nanomaterials.
Cutting-edge Molecular and Cellular Nanotoxicology
PNNL's molecular and cellular toxicologists work with a broad array of materials including metals, metal oxides, fullerenes, silicates, and carbon nanotubes. Working closely with material scientists, we use high-throughput methods to assess the potency of nanomaterials as modulators of innate immunity, oxidative stress, and other important endpoints of toxicity. For example, multiplexed assays for inflammatory cytokines are used to assess multiple markers of inflammation.
We apply global genomics, proteomics, and metabolomic profiling when broader measures of response are necessary to define a toxicity profile or mode of action. Many of these assays are performed in parallel with real-time visualization of nanoparticle deposition, cellular uptake, and trafficking. This broad set of capabilities is particularly important when testing multiple surface chemistry modifications for biocompatibility.
Leading Dose Extrapolation for Hazard and Risk Assessment
Researchers at PNNL are leading the development of experimental and computational tools for predicting cellular dose of particles and nanomaterials in rodents and humans that include:
- The "Virtual Respiratory Tract": An anatomically correct 3D computational model of rodent and human respiratory tracts to predict nanomaterials dose to specific lung regions and extrapolate from delivered doses in animals to humans
- TA computational model of cell culture system "particokinetics" and dosimetry which provides experimentally verified estimates of cell dose needed for comparison of biological potencies of nanomaterials and extrapolation between in vitro and in vivo results.
These tools and our associated expertise in particle dosimetry offer unequalled capability to extrapolate the results of nanoparticle toxicity studies across dose, study type, species and sensitive populations.
Zhang H et al. 2011."Quantitative Proteomic Analysis of Adsorbed Plasma Proteins Classifies Nanoparticles with Different Surface Properties and Size." Proteomics 11(23):4569-4577. DOI: 10.1002/pmic.201100037.
Orr GA et al. 2011. "Cellular Recognition and Trafficking of Amorphous Silica Nanoparticles by Macrophage Scavenger Receptor A." Nanotoxicology. 5(3):296-311. DOI: 10.3109/17435390.2010.513836.
Hinderliter PM et al. 2010. "ISSD: A Computational Model of Nano and Micro Particle Sedimentation, Diffusion and Target Cell Dosimetry for In vitro Toxicity Studies." Particle and Fibre Toxicology 7:36. DOI: 10.1186/1743-8977-7-36.
Waters KM et al. 2009. "Macrophage Responses to Silica Nanoparticles Are Highly Conserved Across Particle Sizes." Toxicological Sciences 107(2):553-569. DOI: 10.1093/toxsci/kfn250.