NORA Manufacturing Sector Strategic Goals
927ZJJQa - Bioassay Screen of Lung Toxicity of Silver Nanoparticles (NTRC)Start Date: 10/1/2009
End Date: 9/30/2012
Principal Investigator (PI)Name: Jenny Roberts
Funded By: NIOSH
Primary Goal Addressed9.0
Secondary Goal Addressed
Attributed to Manufacturing
Despite the rapid growth in engineering of silver nanoparticles, there is relatively little information available regarding health risks associated with respiratory exposure to nano-sized silver particles in the workplace, or in animal models assessing particle toxicity. The purpose of the proposed research is to examine the potential of silver nanoparticles to induce toxic effects in the lungs using an established animal bioassay screen that investigates dose-dependent lung toxicity, interstitial lung disease, and alterations in pulmonary immune responses. The information obtained from this study addresses the goals of the nanotechnology research center, as well as the manufacturing sector and the respiratory disease cross-sector, in relationship to the identification of the emerging risks of work-related disease that may be associated with respiratory exposure to nano-sized silver particles.
The long-term objective of the proposed research is to examine the potential of silver nanoparticles to induce toxic effects in the lungs. In order to address the mission of the National Institute for Occupational Safety and Health, which is to prevent work-related illness and reduce risk factors in the workplace, an established animal bioassay will be used to screen the potential of silver nano-compounds of varying sizes and doses to induce lung injury, to alter lung immune function, and to induce respiratory disease. The information gained from these studies will address knowledge gaps related to the potential risk of silver nanoparticles to induce respiratory illness in the workplace by assessing toxicity in relationship to dose, and potential mechanisms of toxicity. The specific aims of the study which will be conducted over a 3 year period are: (1) characterize lung injury, inflammation, and oxidative stress associated with acute or repeated pulmonary exposure to various doses of silver nanoparticles, (2) to determine biodistribution and pulmonary clearance of silver nanoparticles after exposure, and to assess any morphological changes in the lung indicative of disease that may occur due to persistence of particles over time, and (3) to characterize alterations in lung immune function after pulmonary exposure to silver nanoparticles using animal models of infectious disease and allergy.
Prior to in vivo toxicity studies, the physical properties of the silver nanoparticle samples will be characterized to evaluate size distribution, surface area, surface reactivity, and degree of agglomeration in saline containing a dispersion solution. To investigate lung toxicity in vivo, Sprague-Dawley rats will be intratracheally-instilled with a dispersed silver nanoparticle sample in a dose-dependent manner. Separate studies examining the effects of a single acute dose versus low concentration repeated doses will be conducted. Pulmonary responses will be examined at a various time points ranging from 1 day to 3 months post-exposure. Bronchoalveolar lavage will be performed and the lavaged cells and fluid will be retained for analysis of indicators and mechanisms of lung injury, inflammation, and oxidative stress. Lung tissue will also be preserved for histopathological analysis to evaluate lung injury and morphological indicators of lung disease. Confocal microscopy and electron microscopy will be performed on lung tissue in conjunction with histological analysis at multiple time points post-exposure to monitor silver nanoparticle deposition and clearance from the lung. In addition, elemental analysis of silver content will be measured in lung, lung-associated lymph nodes, blood, brain, heart, spleen, kidneys, liver, and thymus to further characterize pulmonary clearance and systemic translocation of the silver nanoparticles. To address effects on pulmonary immune function, a bacterial infectivity model will be used to assess susceptibility to infection after silver nanoparticle exposure. In this model, rats will be intratracheally-inoculated with bacteria after pulmonary exposure to the silver nanoparticles. Pulmonary bacterial clearance, alterations in lung phagocyte activity, and lymphocyte function will be assessed at multiple time points up to 1 week post-infection. In addition to assessing susceptibility to infection as an indicator of alteration in lung immune function, an animal model of pulmonary allergic disease will also be employed to determine the potential of nano-sized silver to induce airway hyperreactivity, and to act as an adjuvant or a sensitizer. In this model, rats will be exposed to silver nanoparticles prior to or post-sensitization with an allergen (ovalbumin). Airway reactivity, pulmonary lymphocyte responses, and systemic and local allergen specific lymphocyte responses will be measured.
In order to address the long range goal of Nanotechnology Research Center, to address knowledge gaps in the field of nanotechnology related to establishing risk of work-related injuries or illness after exposure to nanomaterials through scientific research, the proposed study will utilize a bioassay screen to address the potential pulmonary toxicity associated with silver nanoparticles. The proposed study will address the gaps in knowledge identified by the NTRC, specifically, (1) pulmonary toxicity of nano-sized silver related to dose, (2) biodistribution in the lung and through the body after pulmonary exposure, and the relationship of distribution and clearance to lung disease, and (3) the potential for the nano-sized silver particles to alter pulmonary immune function. Physical properties of elemental silver and silver oxide nanoparticles, size surface area, and reactivity will be characterized before use in the bioassay screen for toxicity. To investigate dose-dependent lung toxicity in vivo, acute lung injury, inflammation, and oxidant production over time will be evaluated in rats after an acute single dose or a repeated low dose intratracheal-instillation of silver nanoparticles. Bronchoalveolar lavage will be performed at a variety of time points post-exposure and the lavage cells and fluid will be retained for morphological and biochemical analysis, and lung tissue will be preserved for histopathological analysis of disease. In addition, histological evaluation, confocal and electron microscopy, and morphometrical analysis will be performed on lung tissue at multiple time points post-exposure to monitor nanoparticle deposition in and clearance from the lung, and to characterize morphological indicators of lung disease in relation to particle distribution. Systemic particle biodistribution and translocation from the lung will also be evaluated using metal analysis of peripheral organ systems. Finally, the effects of silver nanoparticles on pulmonary immune function after intratracheal-instillation will be evaluated in rat models of lung infection and pulmonary allergy. Bronchoalveolar lavage will be used to assess biochemical indicators of lung immune function, lung cells and associated lymph node cells will be characterized to evaluate alterations in innate and adaptive immune responses, and lung function will be monitored to assess airway reactivity. Success of the project will be determined by (1) the number of resulting publications, (2) the number of presentations of the data at national and international scientific conferences, (3) the number of seminars at workshops conveying the findings of the studies, (4) the usefulness of the data to NIOSH / NTRC in fulfilling the goals related to conducting risk assessment, making exposure limit recommendations, and using the information for risk management purposes to reduce workplace exposure and increase workplace safety, and (5) usefulness of results to OSHA, EPA, and CPSC in developing standards.
The National Science Foundation has estimated that 2 million workers will be needed to support nanotechnology industries worldwide within 15 years. Market research reports indicate that silver nanoparticles are emerging as one of the fastest growing categories of manufactured materials in the nanotechnology industry, and they are currently the most common component listed in nanotechnology-based products, such as non-odor clothing, bandages, and anti-microbial product. Despite the rapid growth in engineering of silver nanoparticles, there is relatively little information available regarding health risks associated with respiratory exposure to nano-sized silver particles which may occur in workers during manufacturing or by consumers during end -use of the products containing the particles. The long-term objective of the proposed research is to examine the potential of silver nanoparticles to induce toxic effects in the lungs.
The study was designed to address the goals of the of the nanotechnology research sector, as well as the manufacturing sector and the respiratory disease cross-sector, in relationship to the identification of the emerging risks of work-related disease that may be associated with respiratory exposure to nanoparticles. Because of the prevalence of nano-sized silver in commercial products, and the rapid growth in industry involved in engineered silver nanoparticles, the need for toxicity data on silver nanoparticles in particular has been identified by a number of regulatory agencies, both nationally and internationally. The Consumer Product Safety Commission (CPSC) has raised concerns over the potential toxicity of silver nanoparticles, and the EPA has recently held a FIFRA scientific advisory panel on hazards and exposures to nanosilver pesticide products which established that there are significant gaps in knowledge and lack of data concerning toxicity of nanosilver. In addition, the Organization of Economic Co-operation and Development (OECD), has designated silver nanoparticles as one of the priority nanomaterials in need of being tested for associated health hazards and environmental safety.
To address the lack of information related to the potential toxicity associated with silver nanoparticle exposure, an established animal bioassay will be used to screen the potential of silver nano-compounds of varying size and dose to induce lung injury, to alter lung immune function, and to induce respiratory disease. The information gained from these studies will address knowledge gaps related to the potential risk of silver nanoparticles to induce respiratory illness in the workplace by assessing toxicity in relationship to dose, and potential mechanisms of toxicity and disease. The information obtained from this study will also address the goals of the nanotechnology research sector, as well as the manufacturing sector and the respiratory disease cross-sector, in relationship to the identification of the emerging risks of work-related disease that may be associated with respiratory exposure to nano-sized silver particles. Specifically, utilizing this bioassay screen that employs an animal model to assess toxicity of silver nanoparticles addresses critical research areas designated by the following intermediate goals of the nanotechnology research center: (1) to investigate physical and chemical properties of engineered nanoparticles related to their potential toxicity; (2) to address knowledge gaps concerning mechanisms of pulmonary toxicity after respiratory exposure to an engineered nanomaterial; (3) to determine distribution and clearance of silver nanoparticles from the lungs, as well as pulmonary translocation to other systems, and to identify mechanisms of actions for these responses; and (4) to utilize animal models of acute pulmonary toxicity and alterations in lung immune responses to characterize silver nanoparticle toxicology in the lung. The data obtained from the proposed study will be useful to agencies involved in risk assessment of nanomaterials, will aid in the establishment of safe workplace practices to reduce occupational risk factors and prevent lung disease in workers, and will allow regulatory agencies to better develop exposure level limits and safe handling practices for this form of material, and other materials with similar characteristics.
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