NORA Manufacturing Sector Strategic Goals
927Z1LW - Systematic Microvascular Dysfunction Effects of Ultra Fine vs. Fine ParticlesStart Date: 10/1/2005
End Date: 9/30/2010
Principal Investigator (PI)Name: Vincent Castranova
Funded By: NIOSH
Primary Goal Addressed9.0
Secondary Goal Addressed
Attributed to Manufacturing
Nanotechnology is one of the fastest growing emerging technologies in the US and across the world. The NIOSH Nanotechnology Research Center identified elucidation of cardiovascular effects of airborne nanoparticles as a critical issue. This study will help to define the possible adverse health and environmental impact of exposure to nanomaterials and determine if pulmonary exposure to nanoparticles causes cardiovascular dysfunction. The project supports the manufacturing sector, specifically nanotechnology by addressing respiratory disease and cardiovascular issues. Data will be disseminated by presentation at scientific meetings, publications in journals, summaries in the NIOSH e-News and Nanotech Web page, and meetings with partners to support risk assessment and development of prevention.
Available evidence indicates that engineered nanoparticles, or ultrafine particles (<100nm in diameter), exhibit a higher deposition fraction in all regions of the respiratory tract compared to fine particles (0.1-2.5µm in diameter) (Kreyling et. al., 2002; Daigle et. al., 2003). Once deposited in the airways, ultrafine titanium dioxide migrated more rapidly to the interstitium and then to the lymph nodes than fine titanium dioxide (Oberdorster et. al., 1994). Pulmonary inflammation in response to ultrafine titanium dioxide far exceeds that observed with exposure to an equivalent mass of fine titanium dioxide by intratracheal instillation (Oberdorster 2001) or by inhalation (Oberdorster et. al., 1994). In addition, pulmonary inhalation of ultrafine titanium dioxide adversely affects the ability of the lung to clear particles to an extent not predicted from exposure to an equivalent mass of fine titanium dioxide (Oberdorster et. al., 1997).
Epidemiologic evidence has linked inhalation of particulate matter (PM) to increased incidence of cardiovascular morbidity and morality (Goldberg et. al., 2000; Goldberg et. al., 2001, Samet et. al., 2000). Although the epidemiologic evidence is convincing, the biologic mechanisms by which PM evokes systemic effects remain unclear, although cytokines generated from exposed lung cells, movement of soluble metals to systemic sites, and translocation of PM to systemic sites have to be proposed. Evidence suggests that inhaled ultrafine particles may enter the blood and deposit in systemic tissues to a greater extent than fine particles (Oberdorster et. al., 2002). Therefore, cardiovascular effects of exposure to nanoparticles is a concern. Pulmonary exposure to fine titanium dioxide or fine residual oil fly ash has been shown to significantly inhibit endothelium-dependent dilation of systemic microvessels (Nurkiewicz et. al., 2001). The current proposal will evaluate the effect of pulmonary exposure to particles on the function of the systemic microvasculature and evaluate the role of oxidant stress at the systemic arteriole endothelium in this response. This project will compare the potency of ultrafine vs. fine titanium dioxide to determine if nanoparticles are of particular concern. The central hypothesis of this project is that acute exposure to ultrafine particles causes a greater systemic microvascular dysfunction than fine particles of the same composition, and that this dysfunction is mediated by inflammation at the systemic microvasculature. To test this hypothesis, rats will be exposed by inhalation to equivalent mass concentrations of fine (1µm) and ultrafine (21nm) titanium dioxide (TiO2). Endothelial dependent dilation of arterioles in the spinotrapezius muscle will be monitored by intravital microscopy while pulmonary response will be evaluated by monitoring bronchoalveolar lavage markers of inflammation and damage or by histology of lung tissue.
This project has four aims: 1) Determine the dose dependence and temporal relationship between ultrafine and fine TiO2 and systemic microvascular dysfunction. 2) Identify the microvascular regulatory mechanisms affected by pulmonary exposure to PM. 3) Determine the role of systemic leukocytes in this PM effect. 4) Determine the role of reactive oxygen species (ROS) in this PM effect.
This project responds to a critical gap identified by the NIOSH Nanotechnology Research Center (NTRC) to determine if pulmonary exposure to nanoparticles causes cardiovascular dysfunction. This supplemental project will integrate with the original Nanotechnology Research Program and work through the NTRC to respond to questions concerning the potential health effects of exposure to nanoparticles and the need for implementation of good handling practices, controls, and personal protective equipment.
This project responds to a critical gap identified by the NIOSH Nanotechnology Research Center to determine if pulmonary exposure to nanoparticles causes cardiovascular dysfunction. The central hypothesis of this project is that acute exposure to ultrafine particles causes a greater systemic microvascular dysfunction than fine particles of the same composition, and that this dysfunction is mediated by inflammation at the systemic microvasculature. To test this hypothesis, rats will be exposed by inhalation to equivalent mass concentrations of fine (1µm) and ultrafine (21nm) titanium dioxide (TiO2). Endothelial dependent dilation or arterioles in the spinotrapezius muscle will be monitored by intravital microscopy. The project has four aims: 1) Determine the dose dependence and temporal relationship between ultrafine and fine TiO2 and systemic microvascular dysfunction. 2) Identify the microvascular regulatory mechanisms affected by pulmonary exposure to PM. 3) Determine the role of systemic leukocytes in the PM effect. 4) Determine the role of reactive oxygen species (ROS) in this PM effect.
Outputs of this project will be presentations and publications of the result in scientific conferences and journals. Outcomes will impact of results on the state of science in the field, impact on the direction of scientific research by other institutions, impact on recommendations by NIOSH on "Good Handling Practice for Nanomaterials", and impact on development of prevention strategies and risk assessment efforts by NIOSH, OSHA, EPA, and DOD.
Achievement of project goals will be determined by: 1) completion of project milestones, 2) number of presentations and publications, 3) the number of times these outputs are cited by the scientific community and/or mentioned in the lay press, 4) the influence on NIOSH publications such as "Frequently Asked Questions" and "Good Workplace Practices" documents, and 5) the usefulness in development of prevention strategies and risk assessment efforts by NIOSH, OSHA, EPA, and DOD.
Nanotechnology is one of the fastest growing emerging technologies in the US and across the world. Defined as the manipulation of matter at near-atomic scales to produce new materials, structures and devices with unique properties, nanotechnology has potential applications for integrated sensors, semiconductors, medical imaging, drug delivery systems, structural materials, sunscreens, cosmetics, and coatings (Roco, 2004). By 2015, the global market for nanotechnology-related products is predicted to reach $15 trillion employing 1 million workers in the US.
Engineered nanostructed materials are formed from nanoparticles, having a diameter of <100nm. Due to their small size, nanoparticles exhibit unique physical/chemical properties not associated with similar materials of the micrometer scale. Evidence exists that low solubility ultrafine particles (<100nm in diameter) exhibit greater pulmonary inflammation than an equivalent mass of fine particles of the same composition. It has been proposed that this elevated toxicity is related to the high surface area of nanometer-sized particles. Nanometer-diameter particles are also capable of penetrating the interstitium after lung deposition, and there is some evidence for translocation to systemic sites. Inhalation of ambient particulate matter is associated with an increase in cardiovascular mortality and morbidity. Proposed mechanisms for adverse cardiovascular responses to particles deposited in the lung include: 1) production of inflammatory mediators by lung cells and effects at systemic sites, 2) transmission of soluble metals from particles deposited in the lungs to systemic sites, and 3) translocation of pulmonary particles directly to systematic sites. Since nano-sized particles are more inflammatory, have a greater surface area for dissolution of metals, and have a greater ability to translocate from the lung than fine particles, the cardiovascular effects of inhalation of nanoparticles is a concern noted by the NIOSH Nanotechnology Research Center in their list of Critical Issues. For these reasons, the potential toxicity of newly developed nanomaterials cannot be predicted from the toxicity of the component bulk materials alone. Indeed, the Royal Society and the Royal Academy of Engineering has noted the need for research to define the possible adverse health and environment impact of exposure to nanomaterials in a recent review in 2004. This project will address these issues by exposing rats to ultrafine vs. fine particles of the same composition and monitor the dose-response and the time course of responses in the lung are systemic micro vessels. Results will support risk assessment and development of recommendation for prevention.
Research results will address the following goals: 1) Goal 9 of the Manufacturing Sector (100%): "Enhance the state of knowledge related to emerging risks to occupational safety and health in manufacturing." 2) Goal 5 of the Respiratory Disease Cross-Sector (50%): "Prevent respiratory and other diseases potentially resulting from occupational exposure to nanomaterials;" Intermediate Goal 1 (09PPRDRIG5.1) Determine respiratory toxicities of nanoparticles/nanomaterials." Activity/Output Goal (09PPRDRAOG5.1.1) "Perform basic in vitro and in vivo toxicology studies". 3) Cardiovascular Diseases Cross-Sector (50%) Strategic Goal 3 (09PPCRCSG3): Reduce the incidence and mortality of workrelated cardiovascular disease; Intermediate Goal 3.1 (09PPCRCIG3.1): Conduct research to better define the contribution of workplace exposures and workplace factors (e.g., levels of activity or inactivity) to the overall incidence of and mortality from cardiovascular disease (CVD); Activity/Output Goal 3.1.2. (09PPCRCAOG3.1.2); Assess the association of workplace factors and exposures, using biomonitoring, toxicological, or other methods, with sub-clinical/clinical CVD in workers or laboratory animals. 4) Nanotechnology Goal 1 (100%): "Determine if nanoparticles and nanomaterials pose risks for work-related injuries and illness." Intermediate Goal 2 (09PPNANIG2.1) "Key factors and mechanisms".
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