RESEARCH REPORT Particle Characteristics Responsible for Effects on Human Lung Epithelial Cells

CoverSpreadWeb.qxd 11/24/2002 6:42 PM Page 1 REPORT 110 RESEARCH REPORT Particle Characteristics Responsible for Effects on Human Lung Epithelial Cells Epithelial Lung for Effects on Human Characteristics Responsible Particle HEAL TH HEAL TH Particle Characteristics EFFE CTS EFFE CTS INSTITUTE INSTITUTE Responsible for Effects on Charlestown Navy Yard Human Lung Epithelial Cells Number 110 120 Second Avenue December 2002 Ann E Aust, James C Ball, Autumn A Hu, JoAnn S Lighty, Boston MA 02129-4533 USA Kevin R Smith, Ann M Straccia, John M Veranth, +1-617-886-9330 and Willie C Young www.healtheffects.org RESEARCH REPORT Number 110 November 2002 Includes a Commentary by the Institute’s Health Review Committee November 2002 November back cover of book 8.5” Front cover of book 8.5 “ Spine .25” Spine CoverSpreadWeb.qxd 11/24/2002 6:42 PM Page 2 Spine .2 Spine BOARD OF DIRECTORS Richard F Celeste Chair Purnell W Choppin President, Colorado College President Emeritus, Howard Hughes Medical Institute Donald Kennedy Vice Chair Alice Huang The Health Effects Institute, established Editor-in-Chief, Science; President (Emeritus) and Bing Professor of Senior Councilor for External Relations, California Institute HEALTH Biological Sciences, Stanford University of Technology EFFECTS in 1980, is an independent and unbiased Richard B Stewart INSTITUTE source of information on the health Archibald Cox Chair Emeritus University Professor, New York University School of Law, and Director, Carl M Loeb University Professor (Emeritus), Harvard Law School New York University Center on Environmental and Land Use Law effects of motor vehicle emissions. HEI Robert M White studies all major pollutants, including President (Emeritus), National Academy of Engineering, and Senior Fellow, University Corporation for Atmospheric Research regulated pollutants (such as carbon monoxide, ozone, nitrogen dioxide, and HEALTH RESEARCH COMMITTEE particulate matter) and unregulated Mark J Utell Chair Stephen I Rennard Professor of Medicine and Environmental Medicine, University Larson Professor, Department of Internal Medicine, University of pollutants (such as diesel engine exhaust, of Rochester Nebraska Medical Center methanol, and aldehydes). To date, HEI Melvyn C Branch Howard Rockette Professor and Associate Dean, College of Engineering and Applied Professor and Chair, Department of Biostatistics, Graduate School of has supported more than 200 projects at Science, University of Colorado Public Health, University of Pittsburgh institutions in North America and Europe Kenneth L Demerjian Jonathan M Samet Professor and Director, Atmospheric Sciences Research Center, Professor and Chairman, Department of Epidemiology, Bloomberg and has published over 130 research University at Albany, State University of New York School of Public Health, Johns Hopkins University reports. Peter B Farmer Frank E Speizer Professor and Section Head, Medical Research Council Toxicology Unit, Edward H Kass Professor of Medicine, Channing Laboratory, Harvard Typically, HEI receives half its funds University of Leicester Medical School and Department of Medicine, Brigham and Women’s from the US Environmental Protection Helmut Greim Hospital Agency and half from 28 manufacturers Professor, Institute of Toxicology and Environmental Hygiene, Technical Clarice R Weinberg University of Munich Chief, Biostatistics Branch, Environmental Diseases and Medicine and marketers of motor vehicles and Rogene Henderson Program, National Institute of Environmental Health Sciences engines in the United States. Senior Scientist and Deputy Director, National Environmental Respiratory Center, Lovelace Respiratory Research Institute Occasionally, funds from other public and private organizations either support HEALTH REVIEW COMMITTEE Daniel C Tosteson Chair Thomas A Louis special projects or provide resources for Professor of Cell Biology, Dean Emeritus, Harvard Medical School Professor, Department of Biostatistics, Bloomberg School of Public a portion of an HEI study. Regardless of Ross Anderson Health, Johns Hopkins University funding sources, HEI exercises complete Professor and Head, Department of Public Health Sciences, Edo D Pellizzari St George’s Hospital Medical School, London University Vice President for Analytical and Chemical Sciences, Research autonomy in setting its research John C Bailar III Triangle Institute priorities and in reaching its Professor Emeritus, The University of Chicago Nancy Reid John R Hoidal Professor and Chair, Department of Statistics, University of Toronto conclusions. An independent Board of Professor of Medicine and Chief of Pulmonary/Critical Medicine, William N Rom Directors governs HEI. The Institute’s University of Utah Professor of Medicine and Environmental Medicine and Chief of Pulmonary and Critical Care Medicine, New York University Health Research and Health Review Thomas W Kensler Professor, Division of Toxicological Sciences, Department of Medical Center Committees serve complementary Environmental Sciences, Johns Hopkins University Sverre Vedal Brian Leaderer Professor, University of Colorado School of Medicine; Senior Faculty, scientific purposes and draw National Jewish Medical and Research Center Professor, Department of Epidemiology and Public Health, Yale distinguished scientists as members. University School of Medicine The results of HEI-funded studies are OFFICERS & STAFF made available as Research Reports, Daniel S Greenbaum President Debra A Kaden Senior Scientist which contain both the Investigators’ Robert M O’Keefe Vice President Geoffrey H Sunshine Senior Scientist Jane Warren Director of Science Annemoon MM van Erp Staff Scientist Report and the Review Committee’s Sally Edwards Director of Publications Terésa Fasulo Senior Administrative Assistant evaluation of the work’s scientific quality Jacqueline C Rutledge Director of Finance and Administration Gail A Hamblett Office and Contracts Manager and regulatory relevance. Richard M Cooper Corporate Secretary L Virgi Hepner Senior Science Editor Cristina I Cann Staff Scientist Jenny Lamont Science Copy Editor Aaron J Cohen Principal Scientist Francine Marmenout Senior Executive Assistant Maria G Costantini Principal Scientist Teresina McGuire Accounting Assistant Spine .25” Spine Aust.book Page 1 Saturday, November 30, 2002 1:37 PM STATEMENT Synopsis of Research Report 110 Effects of Metals Bound to Particulate Matter on Human Lung Epithelial Cells INTRODUCTION was produced in the laboratory and separated into four size fractions. (They also performed experiments Inhaled particulate matter has been associated with using particles from gasoline and diesel exhaust, nat- both acute and chronic health effects. Concerns about ural soils, and ambient Utah air.) This multifaceted these effects derive primarily from epidemiologic study focused mainly on the ability of iron (the major studies that associate short-term increases in particle transition metal in coal fly ash) to produce reactive concentration with increases in daily morbidity and oxygen species and inflammatory mediators in cul- mortality from respiratory and cardiovascular dis- tured lung epithelial cells. eases. Over the past decade much research has been directed toward identifying plausible mechanisms linking particulate matter and pathophysiologic RESULTS AND INTERPRETATION effects. Although progress has been made, many crit- This study was performed by experienced investiga- ical aspects are not understood. Thus, studies of the tors with demonstrated excellence in the area of metal- properties of particles that might induce pathologic catalyzed oxidative stress and particle-associated effects are critical to establishing the mechanisms of injury. The study was of high scientific quality, was particulate matter toxicity and to producing informa- well conceived and executed, and adds substantially to tion necessary to target regulation of the sources that our knowledge of the biologic properties of particles. generate the most toxic particles. Aust and colleagues found that more iron was Studies using laboratory animals have implicated released from the smaller particles than from larger metals associated with particulate matter in adverse ones. They confirmed that soluble extracts of coal fly health effects. Coal-fired power plants produce partic- ash generated reactive oxygen species in vitro and ulate residues called fly ash. Coal contains metals that that transition metals were likely responsible. Fur- vaporize during combustion and then condense on ther, the smallest particles, which were rich in iron, the surface of the ash. Inhaled coal fly ash could be a were the most active. The investigators then exam- health hazard because metals solubilized from fly ash ined the effects of coal fly ash on human lung epithe- within lung cells may cause toxic reactions. lial cells in culture. First, they demonstrated that coal fly ash particles entered the cells and stimulated syn- thesis of the protein ferritin. Ferritin binds iron and is APPROACH produced in response to increasing iron levels; thus, Dr Ann Aust and colleagues at Utah State Univer- its presence indicates that iron was released intracel- sity, the University of Utah, the University of Cali- lularly and that iron was available to provoke an fornia, Davis, and Ford Motor Company hypothesized inflammatory response by forming reactive oxygen that transition metals (metals that can participate in species. The investigators obtained indirect evidence possibly toxic oxidative reactions)

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