Health Effects of Beryllium Exposure

A Literature Review

Committee on Beryllium Alloy Exposures

Committee on Toxicology

Board on Environmental Studies and Toxicology

Division on Earth and Life Studies

NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, D.C.
www.nap.edu



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Health Effects of Beryllium Exposure: A Literature Review Health Effects of Beryllium Exposure A Literature Review Committee on Beryllium Alloy Exposures Committee on Toxicology Board on Environmental Studies and Toxicology Division on Earth and Life Studies NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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Health Effects of Beryllium Exposure: A Literature Review THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This project was supported by Contract W81K04-06-D-0023 between the National Academy of Sciences and the U.S. Department of Defense. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number 13: 978-0-309-11167-6 International Standard Book Number 10: 0-309-11167-6 Additional copies of this report are available from The National Academies Press 500 Fifth Street, NW Box 285 Washington, DC 20055 800-624-6242 202-334-3313 (in the Washington metropolitan area) http://www.nap.edu Copyright 2007 by the National Academy of Sciences. All rights reserved. Printed in the United States of America.

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Health Effects of Beryllium Exposure: A Literature Review THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and Medicine The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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Health Effects of Beryllium Exposure: A Literature Review COMMITTEE ON BERYLLIUM ALLOY EXPOSURES Members CHARLES H. HOBBS (Chair), Lovelace Respiratory Research Institute, Albuquerque, NM PATRICK N. BREYSSE, Johns Hopkins University School of Public Health, Baltimore, MD SCOTT BURCHIEL, University of New Mexico, Albuquerque LUNG CHI CHEN, New York University School of Medicine, Tuxedo, NY DAVID DIAZ-SANCHEZ, University of California, Los Angeles DAVID G. HOEL, Medical University of South Carolina, Charleston LOREN D. KOLLER, Loren Koller & Associates, Corvallis, OR DAVID KRIEBEL, University of Massachusetts, Lowell MICHAEL J. MCCABE, JR., University of Rochester School of Medicine, Rochester, NY CARRIE A. REDLICH, Yale University School of Medicine, New Haven, CT ROSALIND A. SCHOOF, Integral Consulting, Mercer Island, WA NANCY L. SPRINCE, University of Iowa, Iowa City SUSAN M. TARLO, University of Toronto, Ontario, Canada LAURA S. WELCH, Center to Protect Workers’ Rights, Silver Spring, MD Staff SUSAN N. J. MARTEL, Project Director NORMAN GROSSBLAT, Senior Editor MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center TAMARA DAWSON, Senior Program Assistant Sponsor U.S. DEPARTMENT OF DEFENSE

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Health Effects of Beryllium Exposure: A Literature Review COMMITTEE ON TOXICOLOGY Members WILLIAM E. HALPERIN (Chair), UMDNJ–New Jersey Medical School, Newark LAWRENCE S. BETTS, Eastern Virginia Medical School, Norfolk EDWARD C. BISHOP, HDR Engineering, Inc., Omaha, NE JAMES V. BRUCKNER, University of Georgia, Athens GARY P. CARLSON, Purdue University, West Lafayette, IN MARION F. EHRICH, Virginia Polytechnic Institute and State University, Blacksburg SIDNEY GREEN, Howard University, Washington, DC MERYL H. KAROL, University of Pittsburgh, Pittsburgh, PA JAMES N. MCDOUGAL, Wright State University School of Medicine, Dayton, OH ROGER G. MCINTOSH, Science Applications International Corporation, Abingdon, MD GERALD N. WOGAN, Massachusetts Institute of Technology, Cambridge Staff SUSAN N. J. MARTEL, Senior Program Officer for Toxicology EILEEN N. ABT, Senior Program Officer for Risk Analysis KULBIR S. BAKSHI, Senior Program Officer ELLEN K. MANTUS, Senior Program Officer JENNIFER SAUNDERS, Associate Program Officer AIDA NEEL, Program Associate MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center TAMARA DAWSON, Senior Program Assistant RADIAH A. ROSE, Senior Editorial Assistant

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Health Effects of Beryllium Exposure: A Literature Review BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY1 Members JONATHAN M. SAMET (Chair), Johns Hopkins University, Baltimore, MD RAMÓN ALVAREZ, Environmental Defense, Austin, TX JOHN M. BALBUS, Environmental Defense, Washington, DC DALLAS BURTRAW, Resources for the Future, Washington, DC JAMES S. BUS, Dow Chemical Company, Midland, MI RUTH DEFRIES, University of Maryland, College Park COSTEL D. DENSON, University of Delaware, Newark E. DONALD ELLIOTT, Willkie Farr & Gallagher LLP, Washington, DC MARY R. ENGLISH, University of Tennessee, Knoxville J. PAUL GILMAN, Oak Ridge Center for Advanced Studies, Oak Ridge, TN SHERRI W. GOODMAN, Center for Naval Analyses, Alexandria, VA JUDITH A. GRAHAM, American Chemistry Council, Arlington, VA WILLIAM P. HORN, Birch, Horton, Bittner and Cherot, Washington, DC WILLIAM M. LEWIS, JR., University of Colorado, Boulder JUDITH L. MEYER, University of Georgia, Athens DENNIS D. MURPHY, University of Nevada, Reno PATRICK Y. O’BRIEN, ChevronTexaco Energy Technology Company, Richmond, CA DOROTHY E. PATTON (retired), Chicago, IL DANNY D. REIBLE, University of Texas, Austin JOSEPH V. RODRICKS, ENVIRON International Corporation, Arlington, VA ARMISTEAD G. RUSSELL, Georgia Institute of Technology, Atlanta ROBERT F. SAWYER, University of California, Berkeley KIMBERLY M. THOMPSON, Massachusetts Institute of Technology, Cambridge MONICA G. TURNER, University of Wisconsin, Madison MARK J. UTELL, University of Rochester Medical Center, Rochester, NY CHRIS G. WHIPPLE, ENVIRON International Corporation, Emeryville, CA LAUREN ZEISE, California Environmental Protection Agency, Oakland Senior Staff JAMES J. REISA, Director DAVID J. POLICANSKY, Scholar RAYMOND A. WASSEL, Senior Program Officer for Environmental Sciences and Engineering EILEEN N. ABT, Senior Program Officer for Risk Analysis SUSAN N.J. MARTEL, Senior Program Officer for Toxicology KULBIR BAKSHI, Senior Program Officer KARL E. GUSTAVSON, Senior Program Officer ELLEN K. MANTUS, Senior Program Officer STEVEN K. GIBB, Program Officer for Strategic Communications RUTH E. CROSSGROVE, Senior Editor 1 This study was planned, overseen, and supported by the Board on Environmental Studies and Toxicology.

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Health Effects of Beryllium Exposure: A Literature Review OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Models in Environmental Regulatory Decision Making (2007) Toxicity Testing in the Twenty-first Century: A Vision and a Strategy (2007) Sediment Dredging at Superfund Megasites: Assessing the Effectiveness (2007) Environmental Impacts of Wind-Energy Projects (2007) Scientific Review of the Proposed Risk Assessment Bulletin from the Office of Management and Budget (2007) Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues (2006) New Source Review for Stationary Sources of Air Pollution (2006) Human Biomonitoring for Environmental Chemicals (2006) Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment (2006) Fluoride in Drinking Water: A Scientific Review of EPA’s Standards (2006) State and Federal Standards for Mobile-Source Emissions (2006) Superfund and Mining Megasites—Lessons from the Coeur d’Alene River Basin (2005) Health Implications of Perchlorate Ingestion (2005) Air Quality Management in the United States (2004) Endangered and Threatened Species of the Platte River (2004) Atlantic Salmon in Maine (2004) Endangered and Threatened Fishes in the Klamath River Basin (2004) Cumulative Environmental Effects of Alaska North Slope Oil and Gas Development (2003) Estimating the Public Health Benefits of Proposed Air Pollution Regulations (2002) Biosolids Applied to Land: Advancing Standards and Practices (2002) The Airliner Cabin Environment and Health of Passengers and Crew (2002) Arsenic in Drinking Water: 2001 Update (2001) Evaluating Vehicle Emissions Inspection and Maintenance Programs (2001) Compensating for Wetland Losses Under the Clean Water Act (2001) A Risk-Management Strategy for PCB-Contaminated Sediments (2001) Acute Exposure Guideline Levels for Selected Airborne Chemicals (five volumes, 2000-2007) Toxicological Effects of Methylmercury (2000) Strengthening Science at the U.S. Environmental Protection Agency (2000) Scientific Frontiers in Developmental Toxicology and Risk Assessment (2000) Ecological Indicators for the Nation (2000) Waste Incineration and Public Health (2000) Hormonally Active Agents in the Environment (1999) Research Priorities for Airborne Particulate Matter (four volumes, 1998-2004) The National Research Council’s Committee on Toxicology: The First 50 Years (1997) Carcinogens and Anticarcinogens in the Human Diet (1996) Upstream: Salmon and Society in the Pacific Northwest (1996) Science and the Endangered Species Act (1995) Wetlands: Characteristics and Boundaries (1995) Biologic Markers (five volumes, 1989-1995) Review of EPA's Environmental Monitoring and Assessment Program (three volumes, 1994-1995) Science and Judgment in Risk Assessment (1994) Pesticides in the Diets of Infants and Children (1993) Dolphins and the Tuna Industry (1992) Science and the National Parks (1992) Human Exposure Assessment for Airborne Pollutants (1991) Rethinking the Ozone Problem in Urban and Regional Air Pollution (1991) Decline of the Sea Turtles (1990) Copies of these reports may be ordered from the National Academies Press (800) 624-6242 or (202) 334-3313 www.nap.edu

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Health Effects of Beryllium Exposure: A Literature Review OTHER REPORTS OF THE COMMITTEE ON TOXICOLOGY Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants, Volume 1 (2007) Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents (2005) Review of the Army's Technical Guides on Assessing and Managing Chemical Hazards to Deployed Personnel (2004) Spacecraft Water Exposure Guidelines for Selected Contaminants, Volume 1 (2004), Volume 2 (2007) Toxicologic Assessment of Jet-Propulsion Fuel 8 (2003) Review of Submarine Escape Action Levels for Selected Chemicals (2002) Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals (2001) Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity (2001) Acute Exposure Guideline Levels for Selected Airborne Contaminants, Volume 1 (2000), Volume 2 (2002), Volume 3 (2003), Volume 4 (2004), Volume 5 (2007) Review of the US Navy’s Human Health Risk Assessment of the Naval Air Facility at Atsugi, Japan (2000) Methods for Developing Spacecraft Water Exposure Guidelines (2000) Review of the U.S. Navy Environmental Health Center’s Health-Hazard Assessment Process (2000) Review of the U.S. Navy’s Exposure Standard for Manufactured Vitreous Fibers (2000) Re-Evaluation of Drinking-Water Guidelines for Diisopropyl Methylphosphonate (2000) Submarine Exposure Guidance Levels for Selected Hydrofluorocarbons: HFC-236fa, HFC-23, and HFC-404a (2000) Review of the U.S. Army’s Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents (1999) Toxicity of Military Smokes and Obscurants, Volume 1(1997), Volume 2 (1999), Volume 3 (1999) Assessment of Exposure-Response Functions for Rocket-Emission Toxicants (1998) Toxicity of Alternatives to Chlorofluorocarbons: HFC-134a and HCFC-123 (1996) Permissible Exposure Levels for Selected Military Fuel Vapors (1996) Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 1 (1994), Volume 2 (1996), Volume 3 (1996), Volume 4 (2000)

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Health Effects of Beryllium Exposure: A Literature Review Preface Beryllium is a light-weight metal that is used for its exceptional strength and high heat-absorbing capability. Beryllium and its alloys can be found in many important technologies of the defense and aeronautics industries, including electro-optical targeting and infrared countermeasure devices, missile systems, radar systems, nuclear devices, satellite systems, rocket propellants, and navigational systems. Pulmonary disease associated with exposure to beryllium has been recognized and studied since the early 1940s, and an occupational guideline for limiting exposure to beryllium has been in place since 1949. Over the last few decades, much has been learned about chronic beryllium disease and factors that contribute to its occurrence in exposed people. In addition, beryllium has been classified as a likely human carcinogen by several agencies (e.g., the International Agency for Research on Cancer, the National Toxicology Program, and the U.S. Environmental Protection Agency). Those developments have led to debates about the adequacy of the long-standing occupational exposure limit for protecting worker health. To help determine the steps necessary to protect its workforce from the effects of beryllium used in military aerospace applications, the U.S. Air Force asked the Committee on Toxicology of the National Research Council to conduct an independent review of the scientific literature on beryllium and to estimate chronic inhalation exposure levels that are unlikely to produce adverse health effects in military personnel and civilian contractors. In response to the agency’s request, the National Research Council convened the Committee on Beryllium Alloy Exposures, which prepared this report. The members of the committee were selected for their expertise in pulmonary and occupational medicine, epidemiology, industrial hygiene, inhalation toxicology, immunotoxicology, pathology, biostatistics, and risk assessment (see Appendix for biographic information on the members). The committee was asked to produce two reports. The first is to provide a review of the scientific literature on beryllium, and the second will expand more critically on that review in considering the maximum chronic inhalation exposure levels that are unlikely to produce adverse health effects, estimating carcinogenic risks, and developing guidance on testing methods for surveillance and monitoring of worker populations. In this, its first report, the committee identifies the scientific literature that will help to form the basis of its recommendations in the second report. The review focuses on the most important health risks: beryllium sensitization, chronic beryllium disease, and cancer. To help the committee in its review, two data-gathering meetings were held in early 2007. The committee is grateful to the people who gave presentations on their research in and experience with beryllium exposure and disease. They include John Balmes, of the University of California, San Francisco; David DeCamp, of the Air Force Institute of Operational Health; Terry Gordon, of the New York University School of Medicine; Kathleen Kreiss, of the National Institute for Occupational Safety and Health; David Louis, of the Air Force Materiel Command; Lisa Maier, of the National Jewish Medical and Research Center; Aleksandr Stefaniak, of the National Institute for Occupational Safety and Health; and Paul Wambach, of the U.S. Department of Energy. This report has been reviewed in draft form by persons chosen for their diverse perspectives and technical expertise in accordance with procedures approved by the National Research Council’s Report

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Health Effects of Beryllium Exposure: A Literature Review Review Committee. The purpose of the independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards of objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We thank the following for their review of this report: Scott Bartell, University of California at Irvine; David Deubner, Brush Wellman, Inc.; Meryl Karol, University of Pittsburgh; Kathleen Kreiss, National Institute for Occupational Safety and Health; Joseph Landolph, Jr., University of Southern California; and Lisa Maier, National Jewish Medical and Research Center. Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by Frank Speizer, Harvard Medical School. Appointed by the National Research Council, he was responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the author committee and the institution. The committee is grateful for the assistance of National Research Council staff in preparing the report. It particularly wishes to acknowledge the support of Project Director Susan Martel, who coordinated the project and contributed to the committee’s report. Other staff members who contributed to this effort are James Reisa, director of the Board on Environmental Studies and Toxicology; Tamara Dawson, senior program assistant; Norman Grossblat, senior editor; and Mirsada Karalic-Loncarevic, manager of the Technical Information Center. Finally, I thank all the members of the committee for their efforts throughout the development of this report. Charles H. Hobbs, DVM Chair, Committee on Beryllium Alloy Exposures

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Health Effects of Beryllium Exposure: A Literature Review Contents     SUMMARY   1 1   INTRODUCTION   5      Historical Review of Occupational Exposure Limits,   5      Other Exposure Guidelines,   7      Committee’s Task,   8      Committee’s Approach,   8      Organization of the Report,   9 2   EXPOSURE ASSESSMENT   10      Sources and Uses,   10      Toxicokinetics,   13      Review of Exposure Data,   14      Review of Air Sampling and Analytical Methods,   26      Exposure Metrics,   26      Summary,   31 3   SENSITIZATION AND CHRONIC BERYLLIUM DISEASE   32      Epidemiology and Clinical Disease,   32      Pathogenesis and Mechanisms of Action,   47      Genetic Susceptibility,   51      Animal Models of Pulmonary Immunotoxicity,   56      Summary,   59 4   GENOTOXICITY AND CARCINOGENICITY   60      Genotoxicity,   60      Carcinogenicity,   63      Summary,   69 5   ASSESSMENT OF OTHER HEALTH END POINTS   70      Reproductive and Developmental Effects,   71      Other Effects,   72      Summary,   72     REFERENCES   73     APPENDIX   86

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Health Effects of Beryllium Exposure: A Literature Review BOX S-1   Statement of Task for the Committee on Beryllium Alloy Exposures,   2 FIGURE 3-1   Immune Response to Beryllium,   48 TABLES 1-1   Selected Exposure Guidelines and Actions Taken on Beryllium,   6 2-1   Anthropogenic and Natural Emissions of Beryllium and Beryllium Compounds to the Atmosphere,   11 2-2   Releases of Beryllium Metal to the Environment for Facilities that Produce, Process, or Use Beryllium,   12 2-3   Releases of Beryllium Compounds to the Environment from Facilities that Produce, Process, or Use Them,   13 2-4   Industries that Use Beryllium,   14 2-5   Summary of Beryllium Airborne Exposure Studies,   16 2-6   Summary of Beryllium Skin and Surface Exposure Studies,   25 2-7   Summary of Beryllium Biomonitoring Exposure Studies,   25 2-8   Physical and Chemical Properties of Beryllium and Beryllium Compounds,   27 2-9   Comparison of Beryllium Concentrations and Particle Size Obtained with Different Operators in a Precision Machining Plant,   29 3-1   Summary of Recent Epidemiologic Studies of Chronic Beryllium Disease,   34 3-2   Summary of Association Studies on HLA-DPB1 Glu69 and TNF-α as Susceptibility Factors in Chronic Beryllium Disease and Beryllium Sensitization,   53 4-1   Genotoxicity Studies of Beryllium Compounds,   61 4-2   Inhalation Carcinogenicity Studies of Beryllium,   66

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Health Effects of Beryllium Exposure: A Literature Review Abbreviations ACGIH American Conference of Governmental Industrial Hygienists AEC Atomic Energy Commission ATSDR Agency for Toxic Substances and Disease Registry BAL bronchoalveolar lavage BeLPT beryllium lymphocyte proliferation test BeS beryllium sensitization CBD chronic beryllium disease CI confidence interval COT Committee on Toxicology DLCO carbon monoxide diffusing capacity DLCO/VA carbon monoxide diffusing capacity per liter of alveolar volume DOE U.S. Department of Energy EPA U.S. Environmental Protection Agency HLA human leukocyte antigen HRCT high resolution computed tomography IARC International Agency for Research on Cancer LANL Los Alamos National Laboratory LOAEL lowest-observed-adverse-effect level MHC major histocompatability complex MIF migration inhibitory factor MMAD mass median aerodynamic diameter MOUDI micro-orifice uniform deposition impactor NIOSH National Institutes of Occupational Safety and Health NRC National Research Council NTP National Toxicology Program OEL occupational exposure limit OR odds ratio OSHA Occupational Safety and Health Administration PPE personal protective equipment PPV positive predictive value RfD reference dose SMR standardized mortality ratio SSA specific surface area SUF serum ultrafiltrate TGF transforming growth factor TLV Threshold Limit Value TRI Toxic Release Inventory TWA time-weighted average VD/VT ratio of dead space to tidal volume

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