Nanotechnology

Carbon Black Nanoparticle Instillation Induces Sustained Inflammation and Genotoxicity in Mouse Lung and Liver

Nanomaterials (NMs) are increasingly being used in the marketplace in a wide range of products and substances that Health Canada is responsible for regulating.  While there are a great many new applications and benefits, there is inadequate information on risks associated with NMs at this time.  Nanoparticles (NPs) are extremely small (1-100 nanometers in at least one dimension) particles that when inhaled, either in ambient air or occupational settings, may penetrate deep into the lungs and move into the blood and peripheral organs.  To better understand the potential health risks in the workplace and from environmental exposures, Health Canada undertook a study to determine what NP exposure levels cause toxicity, the precise mechanisms of toxicity, and the duration of toxicity in the lung and other affected tissues.  In this study, signs of damaged DNA and inflammation were measured in mice that were exposed to the model NP, carbon black.  It was found that damage to DNA occurred in both the lungs and liver of the mice.  The damage to DNA persisted long after exposure and was found to correlate strongly with inflammation, suggesting inflammation likely played an important role in the DNA damage.  This is important because damage to DNA can lead to cancer.  These results will help Health Canada determine what health effects may occur in humans from exposure to NMs and aid in setting exposure limits. This study was done in collaboration with the Danish National Research Centre for the Working Environment and the University of Copenhagen and was published in Particle and Fibre Toxicology (2012 Feb 2), 9(1):5-18.

Pulmonary Response to Surface-Coated Nanotitanium Dioxide Particles Includes Induction of Acute Phase Response Genes, Inflammatory Cascades, and Changes in Micrornas: A Toxicogenomic Study

Nanomaterials (NMs) are very small in size (1 to 100 nanometers in at least one dimension) and are increasingly being used in products that Health Canada is responsible for regulating.  Due to their small size, many NMs exhibit different properties compared to the larger-scale materials with the same chemical composition.  Nano-sized titanium dioxide is widely used in a variety of consumer products, and this work was undertaken to help Health Canada and its international partners develop a greater understanding of the biological impacts of this material.  Using genomics approaches, which investigate the responses of all the genes within an organism to a stressor, this study aimed to understand the potential toxicity and to identify the underlying molecular mechanisms of toxicity of surface modified nano-sized titanium dioxide in a mouse model.  The results suggested that inhalation of a dose level of surface-modified nano-sized titanium dioxide, which is comparable to what people could be exposed to occupationally, elicits lung inflammation in mice.  The use of genomics approaches further revealed specific biological mechanisms of the inflammation process that were activated.  The study provided greater understanding of the detailed mechanisms behind lung responses to the inhalation of nano-sized particles. Such studies will be useful in identifying some biological markers of exposure or effects of exposure to NMs that could be used as early identifiers or predictors of potential adverse outcomes in humans.  This study, a  collaboration with the Danish National Research Centre for the Working Environment, was published in Environmental and Molecular Mutagenesis (2011 Jul), 52(6):425-439.

Poly(Ethylene Imine) Nanocarriers do not Induce Mutations nor Oxidative DNA Damage In Vitro in Mutamouse Fe1 Cells

Poly(ethylene imine) or PEI has been widely used as a polymer to carry genetic material (i.e., DNA) due to its ability to form stable nanoscale (i.e., 1 to 100 nanometers in at least one dimension) complexes.  This ability has stimulated research on the use of PEI polymers to carry genetic material into diseased tissue (e.g., cancerous tumours) for treatment purposes.  These polymers are desirable because they provide an alternative to using virus particles; however, there is concern regarding their ability to generate reactive oxygen species (ROS) that can induce undesirable genetic damage.  Several other nanoscale materials, including carbon black, zinc oxide (ZnO), and titanium dioxide (TiO₂), have been highlighted for their ability to induce toxic effects via the generation of ROS and inflammation.  Health Canada conducted this study to increase the understanding of the effects of nanoparticles and to better characterize the genetic toxicity of a material with potential therapeutic use.  A mouse cell culture model was employed to assess the ability of several PEI-based polymers to induce genetic damage and mutations.  In addition, oxidative damage was assessed in exposed cells.  The results showed that none of the PEI-based polymers investigated could induce toxic effects, oxidative DNA damage or genetic mutations.  In contrast, the reference compound, benzo[a]pyrene induced significant levels of DNA damage and genetic mutations.  The absence of genotoxic activity for the PEI polymers examined suggests that they may be applicable in a clinical setting, information which may be useful for product assessment purposes.  This study was a collaboration with the German Research Center for Environmental Health and Philipps-Universität Marburg and was published in Molecular Pharmaceutics (2011 Jun 6), 8(3):976-981.

Mutation Spectrum in Fe1-Muta™ Mouse Lung Epithelial Cells Exposed to Nanoparticulate Carbon Black

Carbon black is a major industrial nanoscale (1 to 100 nanometers in one dimension) chemical produced by incomplete combustion of petroleum products.  It is used in inks, paints, rubber, and plastics, with global production exceeding 10 million tonnes in 2005.  Since carbon black has established human health effects, it is widely used as a model in research investigations to increase the understanding of the potential health effects caused by nanoparticles (NPs).  In an earlier study, it was shown that exposure of cultured mouse cells to NPs of carbon black from a standard known as Printex 90 induced DNA damage and genetic mutations.  The present study was conducted by Health Canada to provide more detailed information on the types and locations (spectrum) of the genetic mutations in order to determine how carbon black causes mutations.  Cells exposed to the NPs of carbon black showed a substantially different spectrum of mutations in comparison to the unexposed control cells.  Analysis of the results showed a highly significant difference between the exposed cells and the control cells with respect to the location of the DNA mutation, as well as the type of mutations.  Overall, the results obtained provide support for the contention that the effect of carbon black exposure on the genetic material of these cultured cells is caused by the generation of highly reactive oxygen molecules.  This reactive oxygen damages the DNA and elicits permanent changes in genetic coding (i.e., mutations).  Developing an understanding of how NPs of carbon black cause mutations will provide insight into the nature and extent of potential human health risks attributable to nanomaterials, which will be useful in risk assessment.  This study was conducted in collaboration with the Danish National Research Centre for the Working Environment and the University of Copenhagen and was published in Environmental and Molecular Mutagenesis (2011 May), 52(4):331-337.