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NIOSH Program Portfolio

 

Manufacturing

NORA Manufacturing Sector Strategic Goals

927ZBEG - Potential Effects of Silicon-Based Nanowires on Lung Toxicity

Start Date: 10/1/2007
End Date: 9/30/2010

Principal Investigator (PI)
Name: Stephen Leonard
Phone: 304-285-5831
E-mail: sel5@cdc.gov
Organization: NIOSH
Sub-Unit: HELD
Funded By: NIOSH

Primary Goal Addressed
9.0

Secondary Goal Addressed
5.0


Attributed to Manufacturing
100%

Project Description

Short Summary

As the field of nanotechnology continues to expand, new forms of nanomaterials, such as silicon-based nanowires, are being generated and introduced into the workplace. Toxic effects of pulmonary exposure to dust generated during the manufacturing and processing of silicon-based nanowires has not been investigated. The study will investigate pulmonary toxicity associated with silicon nanowires. Cellular and cell-free systems will be used to determine the potential for nanowire samples to produce toxins. An animal model will be employed to define the potential of the nanowires to induce lung injury, inflammation, oxidative stress, and disease in vivo. Information collected from the proposed study may be used by IBM (note MOU) in development of material safety data sheets and exposure limits, and for risk assessment to establish safe workplace practices and reduce respiratory disease in the Manufacturing Sector, specifically nanotechnology.



Description

The potential toxicity of silicon-based nanowires in the lung has not been investigated. Nanowires are anisotropic in nature with large length to diameter ratios and are currently being manufactured for use as bio-sensors, gas sensors, and field electric transistors. In an effort to be pro-active in protecting workers and product manufacturers from potential health hazards, a research representative from International Business Machines (IBM) has contacted NIOSH directly to identify potential pulmonary responses to nanowire-exposure that can occur during manufacturing, material handling, and manufacturing of end-use products. The objective of the study is to characterize the ability of silicon-based nanowires with specific lengths and diameters to induce pulmonary toxicity which may lead to increased incidence of disease. Because of the size, shape, and chemical reactivity of the nanowires, we hypothesize that pulmonary exposure to silicon-based nanowires will lead to free-radical production in lung cells, induce pulmonary injury and inflammation, increase collagen deposition in the lung, and alter lung defense mechanisms. Samples of silicon-based nanowires of specific lengths and diameters will be provided by the stakeholder. Electron spin resonance will be used to measure Fenton-like reactions with the nanowires and their ability to produce hydroxyl radicals. Electron spin resonance will also be used to measure production of reactive oxygen species in primary macrophages after exposure to nanowires. Inhibitors and chelators will be used to define the reactive oxygen species involved and generation mechanism. Primary macrophages will also be used to monitor nanowire-induced changes in oxygen consumption, hydrogen peroxide production and nitric oxide production. These investigations should define which, if any, reactive oxygen species are involved in toxicity and the mechanism of activation. To investigate lung toxicity in vivo, the potential for nanowire-induced effects on acute lung injury, inflammation, oxidant production, and alteration in immune responses will be examined. In addition, pulmonary deposition, clearance, and fibrogenic potential of silicon-based nanowires will be monitored over time. To determine the acute toxicity of the nanowires, separate groups of Sprague-Dawley rats will be intratracheally-instilled with the different nanowire samples in a dose-dependent manner. 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. In addition, histological evaluation, confocal microscopy, and electron microscopy will be performed on lung tissue at multiple time points post-exposure to monitor nanowire deposition and clearance, and morphological indicators of lung disease. The in vitro and in vivo studies will be conducted concurrently over a 3-year period. The findings from the study will be directly disseminated to the stakeholder to allow them to translate the information into safe workplace practices to protect workers involved in manufacturing and material processing from respiratory exposure to the nanomaterial. In addition, the findings of this study will address the gaps in knowledge identified in the strategic plan for NIOSH nanotechnology research by characterizing the properties of the nanomaterial that are associated with biological effects. The information will aid in evaluation of risk assessment and provide information for development of exposure limits and material safety data sheets. The information will allow federal health and regulatory agencies (Environmental Protection Agency, Occupational Safety and Health Agency, National Institute for Occupational Safety and Health) set and enforce exposure limits, and establish safe workplace practices in an effort to reduce occupational risk factors.



Objectives

In order to address the long range goal of the respiratory disease cross-sector program to prevent respiratory disease and reduce risk factors in the workplace, the proposed study will investigate pulmonary toxicity associated with exposure to silicon nanowires in vitro and in vivo. The following long-term goals for the proposed study are: (1) measure and define the potential for nanowires to generate reactive oxygen species (ROS) in a non-cellular and cellular system, (2) characterize lung injury, inflammation, immunotoxicity, and fibrogenicity associated with nanowire exposure in vivo, (3) and to characterize the fate of nanowires in the lung (deposition, translocation, and clearance). Samples of gold-tipped silicon-based nanowires of specific lengths and diameters will be provided by IBM. Electron spin resonance (ESR) will be used to measure possible Fenton-like reactions with silicon-based nanowires and their ability to produce hydroxyl radicals. ESR will also be utilized with primary macrophages after exposure to nanowires for ROS production. Various inhibitors and chelators will be used to define the ROS involved and generation mechanism. Primary macrophages will be used to monitor nanowire-induced changes in oxygen consumption, H2O2 production and nitric oxide production. These investigations should help define which, if any, ROS are involved in toxicity and the mechanism of activation. To investigate lung toxicity in vivo, the potential for nanowire-induced effects on acute lung injury, inflammation, oxidant production, fibrotic responses and alteration in immune defense mechanisms will be examined. In addition, translocation and clearance of silicon-based nanowires after deposition in the lung will be monitored over time. To determine the acute toxicity of the nanowires, separate groups of Sprague-Dawley rats will be intratracheally-instilled with nanowires of different lengths and diameters in a dose-dependent manner. 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. In addition, histological evaluation, confocal microscopy, and electron microscopy will be performed on lung tissue at multiple time points post-exposure to monitor nanowire translocation and clearance from the lung, and to characterize morphological indicators of lung disease. Success of the project will be determined by (1) the number of publications and presentations which result, (2) the usefulness of the results in allowing IBM to make informal decisions concerning control measures and handling practices, and in development of material safety data sheets and (3) the usefulness of the data to NIOSH / NTRC in conducting risk assessment and making recommendations.



Mission Relevance

As the field of nanotechnology continues to expand, new forms of nanomaterials, such as silicon-based nanowires, are being generated and introduced into the workplace. It is estimated that within the next 10 years, over 2 million workers will be employed in the field of nanotechnology, and workers involved in manufacturing and processing are exposed to dusts that are generated during these processes. There is currently no information on the toxicity of silicon nanowires in the lung. In an effort to be proactive in protecting workers from respiratory exposure to silicon nanowires, International Business Machines (IBM) has requested that NIOSH conduct studies aimed at addressing pulmonary responses to the nanowires. To address the long range goal of the Respiratory Disease Cross-Sector program, the overall objective of the proposed study is to characterize pulmonary toxicity associated with exposure to silicon nanowires with different aspect ratios in order to develop safe workplace practices, prevent respiratory disease, and reduce risk factors in the work place. The long-term goals of the proposed study are: 1) to measure and define the potential for nanowires to generate reactive oxygen species in a non-cellular and cellular system; 2) to characterize lung injury, inflammation, immunotoxicity, and fibrotic responses associated with nanowire exposure in vivo; 3) and to characterize deposition, translocation, and clearance of nanowires of varying lengths and diameters in the lungs. Information from this study will be directly disseminated to the stakeholder to allow them to translate the information into safe workplace practices to protect workers from respiratory exposure to the nanomaterial. The data generated from this study will be invaluable to a number of federal health and regulatory agencies involved in risk assessment, to product manufactures in the development and implementation of exposure limits and material safety data sheets, and to professional trade unions involved in education and protection of exposed workers.





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 Diseases Cross-Sector (100%): "Prevent respiratory and other diseases potentially resulting from occupational exposures to nanomaterials."; Intermediate Goal 5.1 (09PPRDIG5.1) "Determine the potential respiratory toxicities of nanomaterials"; Activity/Output Goal 5.1.1 (09PPRDRAOG5.1.1) "Perform basic in vitro and in vivo toxicology studies". 3) Nanotechnology (100%): Goal 1 of the nanotechnology cross-sector (100%): "Understand and prevent work-related injuries and illnesses possibly caused by nanoparticles/nanomaterials." Intermediate Goal 2 (09PPNANIG2) "Toxicity and internal dose".



Page last updated: June 3, 2011
Page last reviewed: May 23, 2011
Content Source: National Institute for Occupational Safety and Health (NIOSH) Office of the Director

 

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