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NIOSH Safety and Health Topic:Nanotechnology |
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Strategic Plan for NIOSH Nanotechnology Research: Filling the Knowledge Gaps
Appendix B. NIOSH Position Statement on Nanotechnology - Advancing Research on Occupational Health Implications and ApplicationsNIOSH is the federal agency that conducts research and makes recommendations for preventing work-related injuries, illnesses, and deaths. NIOSH is part of CDC in the U.S. Department of Health and Human Services. As a member of the Nanotechnology Science, Engineering, and Technology Subcommittee (NSET) of the National Science and Technology Council Committee on Technology, NIOSH works closely with other federal agencies and private sector organizations to plan, conduct, and facilitate research that will support the responsible development and use of nanotechnology. With the Food and Drug Administration, NIOSH co-chairs the NSET interagency working group on Nanotechnology, Environmental and Health Implications (NEHI). At the nanoscale level, materials exhibit unique properties that affect their physical, chemical, and biological behavior. Those properties raise questions as to potential health effects that might result from occupational exposures during the manufacture and use of nanomaterials. To answer those questions, scientists need to fill significant gaps in current knowledge. For example, do engineered nanomaterials pose unique work-related health risks? In what ways might employees be exposed to nanomaterials in manufacture and use? In what ways might nanomaterials enter the body during those exposures? Once in the body, where would the nanomaterials travel, and how would they interact physiologically and chemically with the body? Can those interactions cause acute or chronic adverse effects? What are appropriate methods for measuring and controlling exposures to nanometer-diameter particles and nanomaterials in the workplace? NIOSH is working strategically to fill those gaps and others through an active intramural and extramural research program. NIOSH multidisciplinary research builds on the Institute’s experience in defining the characteristics and properties of ultrafine particles such as welding fume and diesel particulate, which have some features in common with engineered nanomaterials. NIOSH is capable of conducting advanced health effects laboratory studies and has demonstrated historic leadership in industrial hygiene policies and practices. The NIOSH program also builds on the Institute’s close partnerships with diverse stakeholders in industry, labor, the government, and academia. NIOSH is committed to conducting and supporting studies that will improve scientists’ ability to identify potential occupational health effects of nanomaterials. NIOSH will facilitate the translation of those findings into effective workplace practices. Those goals are critical for helping the United States remain strong and competitive in the dynamic nanotechnology market. In addition, NIOSH is evaluating the unique benefits that nanotechnology may bring to improving sensors and control devices in occupational safety and health. As specific actions in support of occupational health research and nanotechnology, NIOSH has accomplished the following:
For more information on the nanotechnology program, visit the NIOSH Web site: http://www.cdc.gov/niosh/topics/nanotech/ Appendix C. Intramural Nanotechnology Research ProjectsThe following projects pertaining to ultrafine or nanoparticles have been funded as NIOSH intramural research projects and demonstrate the breadth of research activities ongoing at NIOSH since 2005. Results obtained from projects listed in this appendix will be used to further NIOSH’s understanding of the behavior of engineered nanoparticles. Generation and Characterization of Occupationally Relevant Airborne Nanoparticles Mounting evidence shows that the toxicity of some aerosols may be closely associated with the number or surface area of inhaled particles. Low-solubility ultrafine (typically smaller than 100 nm) and high-specific, surface-area particles are of particular concern. This project is part of a wider research program aimed at studying the toxicity of workplace-related aerosols in this category, including those associated with nanotechnology. Methods are being developed to generate and deliver well characterized particles to exposure systems, enabling particle characteristics responsible for specific toxic responses to be investigated in a systematic manner. The research includes the development of off-line and on-line aerosol and particle characterization techniques, including methods to measure aerosol surface area, and methods to characterize the composition and structure of nanometer-diameter particles. Pulmonary Toxicity of Carbon Nanotube Particles This project will evaluate mechanisms of pulmonary toxicity in response to in vitro or in vivo exposure to carbon nanotubes. Aims are to (1) study mechanisms of cytotoxicity of carbon nanotubes in culture systems of bronchial epithelial cells, macrophages and alveolar type II cells; (2) determine the effect of pharyngeal aspiration of carbon nanotubes in a mouse model—determine dose-response and time course; (3) develop a generation system for carbon nanotube aerosols; and (4) conduct inhalation exposure to aerosolized carbon nanotube particles and monitor the pulmonary response in a mouse model. Role of Carbon Nanotubes in Cardiopulmonary Inflammation and COPD-Related Diseases This project will evaluate mechanisms involved in the cardiopulmonary responses to exposure to carbon nanotubes using molecular biology procedures and transgenic animal models. Specific aims are to (1) monitor changes in gene expression of lung tissue associated with intratracheal exposure to carbon nanotubes; (2) determine the role of TNF-alpha in these responses using TNF-alpha receptor knockout mice; (3) evaluate the role of carbon nanotubes in the induction of emphysema using a emphysema susceptible mouse (TSK+); and (4) characterize the cardiovascular reactions to pulmonary exposure to carbon nanotubes, using a mouse model (apo E-/-) susceptible to atherosclerosis. Particle Surface Area as a Dose Metric This project will determine whether the high inflammatory reaction of the lung to ultrafine particles compared with an equal mass of fine particles of similar composition is due to a unique toxic property of ultrafine particles or could be explained by their high surface area, i.e., is particle surface area a more appropriate metric for exposure dose than particle mass? Specific aims are to (1) expose alveolar type II epithelial cells, bronchial epithelial cells, and alveolar macrophages to ultrafine and fine crystalline silica, titanium dioxide, or carbon black and determine toxicity on a particle surface area/cell surface area basis; (2) determine whether titanium dioxide and carbon black exhibit similar in vitro toxicity on a particle surface area basis while silica exhibits greater toxicity; (3) determine the pulmonary response to inhalation of ultrafine vs. fine titanium dioxide on an equivalent deposited particle surface area/pulmonary epithelial cell surface area basis; and (4) provide in vitro and in vivo data to EID for modeling. Ultrafine Aerosols from Diesel-Powered Equipment This project will identify and evaluate the nanometer and ultrafine aerosols emitted by diesel-powered equipment and formulate control technologies to reduce the exposure of workers to these particles, thereby reducing the associated occupational health risks. The physical and chemical properties of the nanometer and ultrafine diesel aerosols will be characterized through a series of engine/dynamometer tests both at the NIOSH Lake Lynn Laboratory experimental mine and at participating active metal and coal mines. The knowledge obtained from this study will strengthen our understanding of the health implications related to exposure to diesel particulate matter and aid in assessing the potential of various control technologies for reducing this exposure. Nanotechnology Safety and Health Research Coordination The goals of this project are to (1) increase collaboration among project investigators, (2) track progress of program projects, and (3) disseminate results and accomplishments. Thus far, this project has held an annual retreat of program scientists and other update sessions. This project has submitted an annual report for publication in the NIOSH eNews, provided information for articles in the lay press, and developed partnerships with the University of Rochester, the University of Pittsburgh, the University of Minnesota, the National Toxicology Program, NASA, Oak Ridge Labs, and FDA. NIOSH cosponsored symposia on nanotechnology health issues in Minneapolis, MN, (October 3–6, 2005) and Research Triangle Park, NC, (October 26–28, 2005). Nanoparticles: Dosimetry and Risk Assessment This project will develop quantitative methods to describe exposure, dose, and response relationships for inhaled particles of varying size and composition including evaluation of dose metric (e.g., particle mass or surface area). Biomathematical and statistical models will be developed to estimate internal dose and disease risk in workers exposed to nanoparticles and to support the development of occupational safety and health recommendations and guidance. As part of this project, research contracts have been awarded to the Hamner Institutes for Health Sciences and the Institute of Occupational Medicine. Nanoparticles in the Workplace The objective of this project is to provide NIOSH and the occupational safety and health community with a better understanding of the nature and extent of current and emerging occupational exposures to nanoparticles and to foster development of a comprehensive and scientifically sound occupational health protection strategy for emerging nanotechnologies. This project was initially funded to identify areas of research for NIOSH and will be replaced by a portfolio of projects. Web-Based Nano-Information Library Implementation The primary objective of this project is to implement and maintain the Web-based programming for the NIOSH Nanoparticle Information Library (NIL) that is being developed to support the Nanoparticles in the Workplace project. This work will provide NIOSH and the occupational safety and health community with access to knowledge as to the variety and extent of nanomaterials being produced worldwide, along with information concerning their physical and chemical properties, processes of origin, and possible health effects. Filter Efficiency of Typical Respirator Filters for Nanoscale Particles Manufactured nanoparticles may exist as separate particles of only a few nanometers. Respirator theory predicts that as particle size decreases from 300 nm, diffusion becomes increasingly effective in capturing the particles on the filter filters. However, a recent study suggests that as particles reach sizes of a few nanometers, capture efficiency begins to decline. To increase knowledge and understanding of these smaller particles, NIOSH funded a study in 2005 at the University of Minnesota’s Center for Filtration Research. The purpose of the study was to measure the penetration of nanoparticles between 3nm and 20nm in size through various filter media, including glass fiber, electret, and nanofiber. The respirator filter media tested in this study effectively collected nanoparticles down to 3nm in size. There was no evidence that particles in this size range pass through filter media at a higher rate than the larger particles. NIOSH is planning studies to validate these findings using NIOSH-approved respirators, and to evaluate the likelihood of worker exposure to nanoparticles when the respirator does not fit the person correctly. These findings will also allow NIOSH to make recommendations regarding the effectiveness of respirator filter media for engineered nanoparticles on the basis of experimental data. Respiratory Effects of Particulate Exposures in Wildland Firefighters This project will determine the age-adjusted prevalence of airways obstruction in Federal wildland firefighters and examine predictors of decreased lung function in these workers at baseline and of short-term changes in lung function (pre-post fire), adjusting for competing and confounding factors. Predictors of airways inflammation and FEV1 and FVC as well as the relationship between these two measures will be examined. In addition, the size distribution of the smoke aerosol (<100 nm – 10 um) will be determined to ascertain the free radical concentration in the products of combustion. Emerging Issues for Occupational Respiratory Disease This project is addressing emerging issues for respiratory disease, including agents involving very fine, ultrafine, or nanomaterials such as cobalt and tungsten carbide in the hard metal industry, vapors and particles of concentrated flavorings, and fungal fragments for indoor air quality. Direct Reading Instrument Metrology Accurate measurement of indoor and industrial contaminants generated by current technology and emerging nanotechnology is an important component of occupational and environmental hygiene practice. Direct reading instruments are frequently used to determine the effectiveness of engineering controls and the quality of indoor air. The study assesses the effects of temperature, humidity, and concentration on commercially available direct-reading instruments. Other concerns are the uncertainties associated with standard factory calibrations. The results of this study are revealing limitations and opportunities for improvements in current instrumentation and will be valuable in choosing appropriate direct-reading instruments for use in field evaluation of industrial and other ventilation systems. NIOSH Current Intelligence Bulletin: Evaluation of Health Hazard and Recommendations on Occupational Exposure to Titanium Dioxide A Current Intelligence Bulletin (CIB) was developed to provide an updated review of the scientific literature pertaining to adverse health effects in workers exposed to titanium dioxide, including epidemiology studies and experimental studies in animals. A quantitative risk assessment was performed using both lung cancer and noncancer (pulmonary inflammation) data in rats inhaling either fine or ultrafine titanium dioxide. The rat-based estimates of internal particle surface area dose in the lungs (at specified risk levels) were extrapolated to humans using lung dosimetry models, and the rat-based excess risk estimates for lung cancer were compared with the confidence intervals on risk from the epidemiological studies. Recommended exposure limits were derived based on particle surface area differences at given mass concentrations of fine or ultrafine titanium dioxide, as well as associated differences in toxicity. The current cancer classification for titanium dioxide was evaluated, and updated recommendations were provided. The CIB has undergone external peer review in 2006 and is currently being revised to address peer review comments. NIOSH Current Intelligence Bulletin (CIB): Risk of Parkinsonism in Welders A Current Intelligence Bulletin (CIB) was drafted in 2006 to provide a critical scientific review of the potential risk to welders for developing neurobehavioral effects. Welding fumes are nano-structured aerosols that can deposit in the respiratory tract and systemically transfer to other organ sites. Neurobehavioral effects, including a type of parkinsonism, has been observed in welders and is thought to be associated with environmental factors including exposure to manganese found in the fume at certain welding processes. The CIB also considers whether other toxicants present in welding fumes may contribute to the reported signs and symptoms of neurotoxicity. A draft for internal review has been developed by a cross-Institute team; external peer review of the document is expected in 2008. Neurotoxicity After Pulmonary Exposure to Welding Fumes Containing Manganese Millions of workers worldwide are exposed to welding aerosols daily. It has been suggested that welders are at an increased risk for the development of neurodegenerative diseases due to the presence of manganese in welding fumes. Epidemiology studies regarding the neurological health of welders are inconclusive. An experimental model is needed that will examine the potential neurotoxic effects after inhalation to welding fumes. A completely automated, computer-controlled welding fume generation and inhalation exposure system for laboratory animals has been developed. This project will assess the pulmonary and neurotoxic effects of animals exposed by inhalation to welding fumes that are composed of varying concentrations of manganese. Results will provide mechanistic information concerning welding fume exposure and be useful for risk assessment and the development of prevention strategies to protect exposed workers. Pulmonary Toxicity of Metal Oxide Nanospheres and Nanowires The objective of this project is to study the pulmonary effects of occupationally relevant engineered metal oxide nanospheres and nanowires. The project objectives will be accomplished as a result of both in vitro and in vivo studies. We expect that engineered nanomaterials of the same chemical composition, but different shapes, i.e., nanospheres versus nanowires, will exhibit different toxicities. The toxicological data obtained will dramatically increase our understanding of the potential exposure hazard passed by TiO2 and SnO2 nanospheres and nanowires. This knowledge will provide some of the initial, critical data needed for hazard identification and would also aid in the design of future experiments. Such data would contribute to risk assessment studies which may ultimately establish exposure standards and recommended handling practices to avert significant human health risks in the futures. Pulmonary Toxicity of Diesel Exhaust Particles The objective of this project is to characterize the role of generation of reactive oxygen species in pulmonary toxicity resulting from exposure to diesel exhaust particles. Specifically, the role of reactive oxygen species will be evaluated in the induction or degradation of pulmonary P450 enzymes and the resulting effects on xenobiotic metabolism and metabolic-dependent mutagenicity. Sources of reactive oxidant production will be characterized in response to diesel exhaust particle exposure, such as reactive-oxygen species production from P450 enzymes or nitric oxide production from nitric oxide synthase. Respirator Testing and Certification This project addresses the implementation of NIOSH’s mandated respirator certification responsibilities through the testing, approval, and audit of respirators and manufacturing site quality systems in accordance with federal standards. The project develops the processes needed to provide certification of respirator protection in a manner to address contemporary hazards and new technologies. Although this project does not currently focus on nanoparticles or nano-enabled respirators, depending on the results of future research, special respirator testing protocols may be implemented in this project. As new nano-enabled technologies for respiratory protection become commercially available, new test methods, policies, and performance standards may also be required if NIOSH certification is needed. End of Service Life (ESLI) Technologies This project is examining sensor technologies that can be incorporated into respirator canisters to indicate when their useful life will expire. Prototype chemiresistor-based ESLI devices have been developed using monolayer-protected nanoclusters to detect trace levels of organic vapors inside a carbon bed to simulate a respirator cartridge. Collaborations with respirator manufacturers have been initiated to integrated prototype devices into actual respirator cartridges. Respiratory Protection Against Nanoparticles Recent advances in nanotechnology have increased the amount of airborne engineered nanoparticles in industrial workplaces. NIOSH approved respirators are used for protection against particulates in workplaces. Previous studies show that NIOSH-approved particulate respirators efficiently capture particles down to the size of 20 nm diameter, while the penetration of particles smaller than 20 nm size is not as well understood. This project will investigate the penetration of particles ranging from 4 to 400 nm through NIOSH approved particulate respirators. Smaller size nanoparticles have high mobility. Little data on face/mask interface leakage for smaller size nanoparticles is available. This issue will be addressed by investigating the effect of face/mask interface leakage of various size particles. The research data from this project will enhance our understanding of the performance of respiratory protection devices against a wide range of nanoparticles to ensure worker safety and health. The research findings of this project will be incorporated into NIOSH nanotechnology guidance documents and international standards including ASTM and ISO. Development of Protocols for Particulate Penetration Measurements of Protective Clothing and Ensembles Protective clothing and ensembles are critically important items for workers when exposed to hazardous conditions. In order to determine how well ensembles protect wearers, it is necessary to test the entire suit system while it is worn to measure potential leakage through seams, closures, areas of transition to other protective equipment, and any leakage due to movement and activities. The objective of this project is to develop innovative methodology for measurement of aerosol particle penetration through protective clothing and ensembles. A test method for aerosol particles including nanoparticles that does not depend on filtration will be developed. A passive aerosol sampler (PAS) using magnetic force will be developed and iron (II, III) oxide particles will be used to generate challenge aerosols. An aerosol chamber will be fabricated for evaluating the particulate penetration for particle sizes between 60 and 500 nm; a wind tunnel will be used for larger particles up to 10 μm. Iron oxide collected on the PAS will be quantified using a colorimetrical method or transmission electron microscopy. Performance of the PAS will be evaluated under various test conditions, including particle size, particle concentration, wind speed, exposure duration, relative humidity, and sampler orientation. A deposition velocity model will be developed to calculate sampling rates of the PAS. Penetration of nanoparticles through fabrics and protective clothing swatches will be measured with other reference samplers to compare the performance of the PAS. The research findings will be used for revised and new ASTM and NFPA standards. Evaluating Real Time Monitors for Diesel Particulate in Mines This project aims at evaluating real time monitors for measuring diesel particulate matter in mines. Much of the work has been done with a focus on providing a method for estimating tailpipe emissions during maintenance. Part of this work focuses on the characterization of nanoparticles that increase in certain situations, including the application of new clean-burning diesel engines. Research plans also include evaluating nanoparticle emissions from a variety of internal combustion engines and designing a portable sampler for collecting nanoparticle samples in the field. Characterization and Communication of Chemical Hazards This project has three distinct goals: (1) to characterize workers’ exposures to various chemical hazards; (2) to develop new analytical methods; and (3) to communicate the health effects associated with exposure to chemicals to workers. Much of the work is tailored to requests for technical assistance from industrial (mining) stakeholders. For this reason the work has naturally evolved to focus on exposures to such hazards as refinery fumes, welding fumes, blasting fumes, and metal bearing aerosols. In some cases, the aerosols are nanoscale particles and this project often deals with determining the origin and fate of metal-bearing nanoparticles. NIOSH has identified critical research needs for workers exposed to ultrafine and fine TiO2 , including the measurement and characterization of workplace airborne exposures to TiO2 in manufacturing and end-user facilities and evaluation of the exposure response relationship between TiO2 and human health effects. The goal of this study is to measure and characterize workplace exposure to fine and ultrafine TiO2 in both manufacturing and end-user facilities. The specific objectives are threefold: 1) characterize airborne TiO2 exposure metrics by job or process, 2) obtain quantitative estimates of exposure in workers to fine and ultrafine TiO2 particle sizes by relating the measured exposure metrics to worker exposure, and 3) evaluate a strategy for measuring workplace exposure to fine and ultrafine TiO2. A full shift combined with a task based sampling scheme consisting of various real-time and mass based area and personal aerosol sampling will be employed. In addition, information will be collected on the use of personal protective equipment (PPE) and the types of controls and work practices used to minimize worker exposures to TiO2. Monitoring Methods for Nanoaerosols This project is an umbrella project in the DART aerosol group that supports multiple, nano-related pilot research projects. Current focus areas include: development/evaluation of off-line and on-line (real-time) nanoaerosol characterization methods for use in toxicology studies and for workplace monitoring. A fast, real-time instrument for measurement of nanoparticle size distributions are under development. In addition, nanoaerosol generation methods, nanoparticle transport, and novel approaches for surface area measurement are being investigated. This project also supports detailed field screening surveys of workplaces that use nanomaterials. Previous field studies have employed a suite of real-time instruments for characterization of nanomaterial releases, and collection of air and surface samples for laboratory analyses. Dustiness of Nanomaterials This project is aimed at investigating the relative dustiness of nanomaterial powders. Dustiness is a relative measure of the propensity of a bulk powder to aerosolize through handling. It is an important property of powders if dust inhalation is of concern. This project will aid nanomaterial manufacturers, by targeting their exposure control efforts most effectively. Systemic Microvascular Dysfunction: Effects of Ultrafine versus Fine Particles Evaluation of the Pulmonary Deposition and Translocation of Nanomaterials Dermal Effects of Nanoparticles Nanoparticles are new materials of emerging technological importance in different industries. Because dermal exposure is likely in a number of occupational settings, it is very important to assess whether nanoparticles could cause adverse effects to skin. The hypothesis is that nanoparticles are toxic to the skin and the toxicity is dependent on their penetration to skin, induction of oxidative stress, and content of transition metals. Because inflammation provides a redox environment in which transition metals can fully realize their pro-oxidant potential, a combination of inflammatory response with metal oxide particles, or iron-containing SWCNT will synergistically enhance damage to cells and tissue. Results obtained from these studies provide critical knowledge about mechanisms of dermal toxicity of nanoscale materials and will be used by regulatory agencies (OSHA and EPA) and industry to address strategies for assurance of healthful work practices and safe environments. Measurement of Nanoscale Carbonaceous Materials This project has two specific aims: 1) Apply multiple methods to characterize carbon nanofiber/nanotube materials in bulk, surface, and air samples. Metrics include: particulate carbon; metals; adsorbed organic fraction; particle size, shape, and elemental composition. 2) Generate filter samples of carbonaceous aerosols with known organic and elemental carbon (OC-EC) content. Evaluate suitability of filter sets for quality assurance measurements on nanoscale carbonaceous aerosols. Nanoaerosol Surface Area Measurement Methods The overall objective of this project is development and evaluation of methods to measure the surface area of airborne nanomaterials with different physicochemical properties over a wide size range of interest. One objective of this project is to investigate the differences between instrument responses to spherical and nonspherical particles, as well as between sub-100nm and super-100 nm particles. This work may permit extension of the existing theory of diffusion charging and of the instrument to surface area measurements on non-spherical particles. Overall, the complete characterization of surface area instruments and methods, and their application to determining the toxicity of nanomaterials, will provide a basis for understanding whether surface area is a more appropriate measure than mass for evaluating toxicity. Nanoscale Reference Materials for Respiratory Disease Prevention The purpose of this project is to provide a scientific basis for development of methods to ensure accurate measurement of engineered nanomaterials (EN) size and surface area in industrial hygiene samples. It is hypothesized that nanoscale colloidal gold nanospheres can be used as reference materials for nanoparticle size and surface area. This project aims are to develop nanoscale reference materials for use in quantifying EN particle size and particle surface area. In this project, various sizes of electro statically stabilized gold nanospheres will be will be generated and particle size characterized using multiple complimentary analytical techniques (microscopy, x-ray diffraction, liquid suspension counter, etc.). Knowing particle size, it will be possible to characterize particle porosity then particle surface area using complimentary techniques (gas adsorption, microscopy, etc.). It is anticipated that results from these studies will contribute towards qualifying these gold nanospheres as Respirable Masses (RMs) Ultrafine TiO2 Surface and Mass Concentration Analysis The purpose of this project is to test the hypothesis that ultrafine titanium dioxide (μTiO2) surface area can be measured with specificity on heterogeneous particle-laden filter samples using surfactant isotherms and/or fluorescence labeling. This project aims are to: develop a model for quantifying bulk ultrafine TiO2 powder specific surface area using lung surfactant and/or fluorescent labeling; extend the model to evaluate surface area of aerosolized TiO2 particles collected on filter media in a laboratory chamber; and test the proposed model in a ultrafine TiO2 primary production workplace. Exposure Assessment in Tungsten Refining and Manufacturing The proposed 3-year research project will determine if airborne tungsten oxide (WOX) fiber concentrations and physicochemical properties vary with production and manufacturing processes in the tungsten industry, and other down-stream industries that consume and incorporate tungsten in their products. The study design is an observational IH exposure assessment of approximately four similarly exposed groups, consisting of 20 workers. The research will identify groups at elevated risk of exposure, document exposure patterns among occupational cohorts, and characterize airborne particle morphology in domestic tungsten production and use among six facilities. Investigations of Multi-Walled Carbon Nanotube Toxicity Carbon nanotubes are in commercial use, and thus the possibility that persons will be exposed to carbon nanotubes is a reasonable expectation via occupational settings or from attrition of materials that contain carbon nanotubes. Thus, we are investigating multi-walled carbon nanotube-induced toxicity in both the lung and brain. Mice will be exposed to multi-walled carbon nanotubes (0, 10, 20, 40 and 80 μg/mouse) by pharyngeal aspiration. At 1, 7, 28 and 56 days post-exposure, multi-walled carbon nanotube-induced toxicity will be evaluated in the lung and brain. Translocation of multi-walled carbon nanotubes from the lung and deposition in other major organs will also be determined. The results of this study will be used in hazard and risk analyses, and will contribute to the development of occupational health and safety recommendations. Potential Aneuploidy Following Exposure to Carbon Nanotubes The data from the in vivo and in vitro studies indicate that SWCNT are capable of inducing progenitor cell proliferation, DNA damage, increased inflammation and oxidant stress as well as multinucleate cells and dysplasia in the mouse lung. In vivo exposure to SWCNT and MWCNT resulted in anaphase bridges and multinucleate cells indicating the possibility of spindle aberrations. Preliminary in vitro data demonstrated the induction of DNA damage in established A549 lung cancer cells, however, the response in normal mouse and human respiratory epithelial cells has not been determined. We therefore will analyze the spindle apparatus and chromosome number in normal mouse and human respiratory epithelial cells after exposure to equal weight doses of MWCNT and SWCNT. Specific Biomarkers for Unusual Toxicity of Nanomaterials Nanomaterials are potentially toxic to humans. Unfortunately, critical understanding of the adverse health effects has not been achieved. A key factor to this limited success is the lack of appropriate in vitro tests which are predictive of in vivo response to nanomaterials. Recent studies have shown that single-walled carbon nanotubes can induce lung fibrosis in animal models. The proposed studies will investigate the potential fibrogenicity of diverse nanomaterials using newly developed in vitro models. It is expected that the results of these studies will provide key information on risk assessment and development of preventive and intervention strategies for nanomaterial-induced lung fibrosis. The proposal addresses NIOSH Nanotechnology research Center goal to evaluate toxicity of nanoparticles and conduct studies supportive of risk assessment of carbon nanotubes. Determination of Diameter Distribution for Carbon Nanotubes by Raman Spectroscopy The goal of this proposal is to develop a method to determine the diameter distribution and the dispersion of carbon nanotubes (CNT) in various forms: powder, air samples, suspended in aqueous solution, and mixture of CNT and surfactant. Based on these measurements, we will quantify the amount of CNT in a sample. This study seeks to provide a methodology to qualitatively and quantitatively determine a biologically-relevant metric of exposure associated with CNT material. We will address this issue by using Raman spectroscopy combined with photoluminescence (PL). Lung Effects of Resistance Spot Welding Using Adhesives Aerosols formed during resistance spot welding may cause respiratory irritation in exposed workers. Information about the composition of substances generated during resistance spot welding is lacking. A robotic welding arm in the NIOSH lab will be configured and programmed to perform resistance spot welding to expose laboratory animals using process parameters common in the automotive industry. By using an animal model to mimic workplace exposures, the goal is to determine which component of the aerosols generated during resistant spot welding may be potentially toxic to exposed workers. Occupational Exposures and Potential Neurological Risks Occupational exposure to aerosolized nanoparticles, ultrafine and fine particles or chemical agents can result in translocation of these materials to the brain and elicit transient, irreversible, or progressive damage to the nervous system. Currently there is little information on the adverse neurotoxicological effects of industrial materials, especially nanomaterials and new chemical agents. To predict and reduce the risk of occupational illnesses, it is important to establish their neurotoxicity. This project will evaluate neurological effects of industrial materials, particularly nanomaterials and new chemical agents. A 3-tiered approach to evaluate neurotoxicity will be implemented. Results from this study will be used to develop hazard and risk assessment paradigms emphasizing mechanisms of causation and significantly contribute to occupational safety standards. Cell-based Assessment for Iron Nanoparticles Induced Health Effects This project is to develop an in vitro screening model for assessing the potential vascular toxicity of nanoparticles and to provide a basis for recommendations and guidance on the safe handling of nanoparticles. Specifically the project will identify the molecular mechanisms by which iron nanoparticle induces production of reactive oxygen species (ROS) in endothelial cells and study the regulatory roles of ROS in iron nanoparticle induced endothelial cell barrier damage, which can lead to cardiovascular dysfunction. The research strategies applied within this project may provide a rapid inexpensive in vitro alternative to the use of animal models to study the cardiovascular health risks of occupational exposure to various nanoparticles. Mutagenicity Assessment of Carbonaceous Nanomaterials Exposure to ultrafine particles has been linked to respiratory diseases, cardiovascular diseases and lung cancer. Lung cancer is currently the leading cause of cancer mortality in the United States. A preliminary study revealed potential mutagenicity of SWCNT and some hyperplasia in the lung of tumor-resistant mice exposed to SWCNT. Therefore, a more complete study is required to determine the mutagenic/carcinogenic potential of carbonaceous nanomaterial in the lung. Elucidation of mechanisms involved in lung cancer development may lead to the strategies for early detection in susceptible workers. Data obtained from these studies will be used for hazards identification, risk assessment, and management of carbonaceous engineered nanomaterial with respect to occupational exposures and will be used by regulatory agencies and industry to address strategies for assurance of healthy work practices and safe environments.
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Appendix B