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Biologic Markers In Pulmonary Toxicology Subcommittee on Pulmonary Toxicology Committee on Biologic Markers Board on Environmental Studies and Tox~colog;y Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS Washington,D.C. 1989

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NATIONAL ACADEMY PRESS 2101 Constitution Avenue, NVV Washington, DC 20418 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 report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of 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 of scientific and technical matters. Dr. Frank Press 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. Robert M. White 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. Samuel O. Thier 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. Frank Press and Dr. Robert M. White are chairman and vice chairman, respectively, of the National Research Council. The project was supported by the Environmental Protection Agency, the National Institute of Environmental Health Sciences; and the Comprehensive Environmental Response, Compensation, and Liability Act Trust Fund through cooperative agreement with the Agency for Toxic Substances and Disease Registry, U.S. Public Health Seance, Department of Health and Human Sen~ces. Library of Congress Cataloging-in-Publication Data National Research Council (U.S.). Subcommittee on Pulmonary Toxicology. Biologic markers in pulmonary toxicology. Includes bibliographical references. 1. Pulmonary toxicology. 2. Biochemical markem Diagnostic use. I. Title. {DNLM: 1. Air Pollutants- tOXiCiq. 2. Biological Markers. 3. Respiratory Syste~drug effects. 4. Respiratory System pathology. 5. Respiratory Syste~physiopathology. WA 754 N295b] RG732.N38 1989 616 ''0071 89-37280 ISBN 0-309-039924 ISBN 0-309-03990-8 (pbk.) Copyright 1989 by the National Academy of Sciences No part of this book may be reproduced by any mechanical, photographic, or electronic process, or in the form of a phonographic recording, nor may it be stored in a retrieval system, transmitted, or other copied for public or private use, without written permission from the publisher, except for the purposes of official use by the U.S. government. Printed in the United States of America

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Subcommittee on Pulmonary Toxicology Rogene F. Henderson, Chairman, Lovelace Biomedical and Environmental Research Institute, Albuquerque, New Mexico Marie Amoruso, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey Arnold R. Brody, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina Edward D. Crandall, Cornell Medical College, New York, New York James D. Crapo, Duke University Medical Center, Durham, North Carolina Ronald P. Daniele, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Carl Franzblau, Boston University School of Medicine, Boston, Massachusetts Allen G. Harmsen, Trudeau Institute, Saranac Lake, New York Gary W. Hunninghake, University of Iowa Hospitals and Clinics, Iowa City, Iowa Philip J. Landrigan, Mt. Sinai Medical Center, New York, New York Joe L. Mauderly, Lovelace Biomedical and Environmental Research Institute, Albuquerque, New Mexico Robert Roth, Michigan State University, East Lansing, Michigan Richard Schlesinger, New York University Medical Center, Tuxedo, New York Frank Speizer, Harvard University, Boston Massachusetts Mark J. Utell, University of Rochester School of Medicine, Rochester, New York Ad risers Robert Baughman, University of Cincinnati, Cincinnati, Ohio Hillel Koren, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina Nicholas A. Matwlyoff, University of New Mexico Medical School, Albuquerque, New Mexico Daniel P. Schuster,Washington University School of Medicine, St. Louis, Missouri Mark R. Schuyler, Veterans Administration Medical Center, Albuquerque, New Mexico Staff, National Research Council Richard D. Thomas, Project Director Norman Grossblatt, Editor Beulah S. Bresler, Administrative Secretary - .

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Committee on Biologic Markers Bernard Goldstein, Chairman, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey James Gibson, Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina Rogene F. Henderson, Lovelace Biomedical and Environmental Research Institute, Albuquerque, New Mexico John E. Hobble, Marine Biological Laboratory, Woods Hole, Massachusetts Philip J. Landrigan, Mount Sinai Medical Center, New York, New York Donald R. Mattison, University of Arkansas for Medical Sciences and National Center for Toxicological Research, Little Rock, Arkansas Frederica Perera, Columbia University, New York, New York Emil A. Pfitzer, Hoffmann-La Roche, Inc., Nutley, New Jersey Ellen K. Silbergeld, Environmental Defense Fund, Washington, D.C. Project Staff Senior Staff: Devra Lee Davis Alvin G. Lazen Lee R. Paulson Andrew M. Pope Richard D.Thomas Diane K. Wagener Research Staff: Robin Bowers Victor Miller Linda Miller Poore Anne M. Sprague Leslye B. Wakefield Bernidean Williams 1V Editors: Norman Grossblatt Lee R. Paulson Support Staff: Beulah S. Bresler Mireille Mesias Erin Schneider Susan Tawfik Julie Walker

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Board on Environmental Studies and Toxicology Gilbert S. Omenn, Chairman, University of Washington, Seattle, Washington Frederick R. Anderson, Washington School of Law, American University, Washington, D.C. John Bailar, McGill University School of Medicine, Montreal, Quebec David Bates, University of British Columbia Health Science Center Hospital, Vancouver, British Columbia Joanna Burger, Nelson Laboratory, Rutgers University, Piscataway, New Jersey Richard A. Conway, Union Carbide Corporation, South Charleston, West Virginia William E. Cooper, Michigan State University, East Lansing, Michigan Sheldon K. Friedlander, University of California, Los Angeles, California Bernard Goldstein, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey Donald Mattison, University of Arkansas for Medical Sciences and National Center for Toxicological Research, Little Rock, Arkansas Duncan T. Patted, Arizona State University, Tempe, Arizona Emil Pfitzer, Hoffmann-La Roche, Inc., Nutley, New Jersey William H. Rodgers, University of Washington, Seattle, Washington F. Sherwood Rowland, University of California, Irvine, California Liane B. Russell, Oak Ridge National Laboratory Milton Russell, Oak Ridge National Laboratory Ellen K. Silbergeld, Environmental Defense Fund, Washington, D.C. I. Glenn Sipes, University of Arizona, Tucson, Arizona Staff Devra L. Davis, Director James J. Reisa, Associate Director Karen L. Hulebak, Exposure Assessment and Risk Reduction Program Director David J. Policansky, Natural Resources and Applied Ecology Program Director Richard D. Thomas, Human Toxicology and Risk Assessment Program Director Lee R. Paulson, Manager, Toxicology Information Center v

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Commission on Life Sciences Bruce M. Alberts, Chairman, University of California, San Francisco, California Perry L. Adkisson, Texas A&M University, College Station, Texas Francisco J. Ayala, University of California, Irvine, California J. Michael Bishop, University of California Medical Center, San Francisco, California Freeman J. Dyson, Institute for Advanced Study, Princeton, New Jersey Nina V. Fedoroff, Carnegie Institution of Washington, Baltimore, Maryland Ralph W.F. Hardy, Boyce Thompson Institute for Plant Research (Cornell), Ithaca, New York Richard J. Havel, University of California School of Medicine, San Francisco, California Leroy E. Hood, California Institute of Technology, Pasadena, California Donald F. Hornig, Harvard School of Public Health, Boston, Massachusetts Ernest G. Jaworski, Monsanto Company, St. Louis, Missouri Simon A. Levin, Cornell University, Ithaca, New York Harold A. Mooney, Stanford University, Stanford, California Steven P. Pakes, University of Texas, Dallas, Texas Joseph E. Rall, National Institutes of Health, Bethesda, Maryland Richard D. Remington, University of Iowa, Ames, Iowa Paul G. Risser, University of New Mexico, Albuquerque, New Mexico Richard B. Setlow, Brookhaven National Laboratory, Upton, New York Torsten N. Wiesel, Rockefeller University, New York, New York John E. Burris, Executive Director V1

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Sponsors National Heart, Lung, and Blood Institute National Institute of Environmental Health Sciences U.S. Environmental Protection Agency U.S. Public Health Service, Agency for Toxic Substances and Disease Registry Government Liaison Group John R. Fowle III, Chairman, U.S. Environmental Protection Agency, Washington, D.C. Henry Falk, Centers for Disease Control, Atlanta, Georgia W. Harry Hannon, Centers for Disease Control, Atlanta, Georgia Suzanne Hurd, National Heart, Lung and Blood Institute, Bethesda, Maryland Dennis Jones, Agency for Toxic Substances and Disease Registry, Atlanta, Georgia James Lamb, U.S. Environmental Protection Agency, Washington, D.C. George Lucier, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina Carol Mapes, Food and Drug Administration, Washington, D.C. Michael D. Waters, U.S. Environmental Protection Agency, Washington, D.C. - V11

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Preface The American people have become increasingly aware of the potential for exposure to toxic material in the air we breathe and have developed a need for accurate, objective information on the health effects of inhaled pollutants. In keeping with that need, the National Heart, Lung, and Blood Institute, the National Institute of Environmental Health Sciences, the Office of Health Research of the U.S. Environmental Protection Agency, and the Agency for Toxic Substances and Disease Registry of the U.S. Public Health Service asked the Board on Environmental Studies and Toxicology in the National Research Council's Commission on Life Sciences to examine the potential for use of biologic markers in environmental health research. The term "biologic markers" refers to indicators of events in biologic systems or samples. It is useful to classify biologic markers into three types-markers of exposure, of effect, and of susceptibility-and to describe the events peculiar to each type. The Committee on Biologic Markers was organized and considered the subj ects of environmen- tal research in which the use of biologic markers had the greatest potential for major contributions. Three biologic systems were chosen: the reproductive system, the respiratory system, and the immunologic system. This report is the product of the Subcommittee on Pulmonary Toxicology. The subcommittee comprised a wide variety of persons working in the field of respiratory health effects, including clinicians, epidemiologists, toxicologists, physiologists, pathologists, aerosol scientists, and biochemists. The intent was to consider various kinds of basic research wherein phenomena under study might have the potential for use as markers of environmental exposures and disease, even if the original goal of the research had nothing to do with such markers. The major topics of discussion at the first meeting of the subcommittee were the meaning of the term "biologic marker" in the respiratory system and how these markers could be used in environmental health research. Eventually, the subcommittee decided to place major emphasis on biologic markers of two types: markers of exposure and markers of effects of environmental pollutants. Markers of susceptibility to environmental materials were also considered important, but, because of limitations of resources, were included only if they could also serve as markers of exposure or effects. Finding biologic markers that can be used to measure the extent of exposure to and effects of environmental pollutants is not easy. In exposed persons, a marker must be able to detect an extremely small increase in a disease due to environmental exposures against a large background of the same or similar diseases from other causes. Inevitably, 1X

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x AL4RKERS IN PULMONARY TOXICOLOGY then, the subcommittee expanded its consideration of markers to examples of exposures in industrial situations. That was considered to be valid because of the potential use of such markers or their modifications in occupational applications. The subcommittee decided to organize its report according to types of biologic markers (markers of exposure and of effects), rather than according to specific pollutants, on the grounds that it was more important to discuss general approaches than to attempt to compile a list of pollutant-specific markers. In the course of the subcommittee's deliberations, many additional scientists were called on to provide information. The subcommittee especially recognizes the contributions of John Catrava, Medical College of Georgia, Augusta, Georgia; Delores Graham, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina; Anton Jetten, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina; Barbara Meyrick, Vanderbilt University, Nashville, Tennessee; and Barry Peterson, University of Texas, Tyler, Texas. This report could not have been produced without the untiring efforts of the National Research Council staff. Beulah Bresler was the administrative secretary and Linda Poore was the bibliographer. Devra Davis, Alvin Lazen, and James Reisa provided encouragement and helpful insight. Norman Grossblatt edited the report. Finally, the subcommittee gratefully acknowledges the persistence, patience, and expertise of Richard Thomas, the project director, in bringing this report to its final form. ROGENE F. HENDERSON, Chairman Subcommittee on Pulmonary Toxicology

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Contents EXECUTIVE SUMMARY Concepts and Definitions,2 Extrapolation from Animals to Humans, 3 Markers of Exposure,4 Markers of Physiologic Effects in Intact Organisms,5 Markers of Altered Structure or Function,5 Markers of Inflammatory and Immune Response,6 Markers of Cellular and Biochemical Response,7 Recommendations,7 1 INTRODUCTION Types of Biologic Markers, 12 Validation of Biologic Markers, 13 Use of Biologic Markers in the Respiratory Tract, 14 Structure of the Report, 15 2 MARKERS OF EXPOSURE Deposition of Inhaled Material in the Respiratory Tract, 18 Clearance of Inhaled Material from the Respiratory Tract,23 Monitoring for Inhaled Material,26 Mathematical Modeling of Exposure,38 Clinical Techniques for Gathering Data,39 Summary,42 3 MARKERS OF PHYSIOLOGIC EFFECTS IN INTACT ORGANISMS Respiratory Function,44 Airway Hyperreactivity,57 Clearance of Particles from the Respiratory Tract,6 1 Injury to Air-Blood Barrier,66 Summary,80 X1 1 11 17 43

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~ X11 4 MARKERS OF ALTERED STRUCTURE OR FUNCTION Whole Lung,83 Airways,83 Parenchyma,85 Pulmonary Vasculature,86 MARKERS OF INFLAMMATORY AND IMMUNE RESPONSE Inflammatory Response to Inhaled Toxins,9 1 Inflammatory Response to Microbial Infections,92 Immune Response,93 6 MARKERS OF CELLULAR AND BIOCHEMICAL RESPONSE Sources of Respiratory Tract Markers, 105 Potential Markers in Respiratory Tract Fluids, 1 13 Molecular Markers, 127 7 CONCLUSIONS AND RECOMMENDATIONS Dosimetry, 1 33 Physiologic Measurements, 134 Structure and Function, 135 Cellular and Biochemical Response, 135 REFERENCES BIOGRAPHIES INDEX AL4RKERS OF PULMONARY TOXICOLOGY 83 91 105 133 137 167 171

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Tables and Figures TABLES 1-1 2-1 2-2 2-3 2-4 Example of a Matrix for Determining the Validity of a Biologic Marker Relative Strength of Various Magnetic Fields Sensitivities of Various Magnetic Detectors Thoracic Dust Burdens in Humans as Determined by MPG Biologic Questionnaire Data That Can be Used to Predict Chronic Respiratory Disease in Adults 3-1 Assays of Respiratory Function 3-2 Methods for Detecting Excess Extravascular Lung Water Accumulation 3-3 Summary of Characteristics of Physiologic Assays 5-1 Immunologic Mechanisms of Tissue Injury 6-l Results of Survey on BAL Technique in 62 Centers in 19 Countries 6-2 Techniques for Detecting Markers of Inflammatory and Immune Response 6-3 Biologic Markers of Inflammatory and Immune Response in Humans FIGURES 2- l Particle deposition efficiency in human respiratory tract 2-2 Particle deposition efficiency in human upper respiratory tract 2-3 Particle deposition efficiency in human tracheobronchial tree 2-4 Particle deposition efficiency in human alveolated airways 3-1 Decline of FEND at normal rate and at accelerated rate 3-2 Clearance pathways for markers in the airspaces 3-3 10 cm H2O PEEP increases DTPA clearance rate 3-4 Albumin clearance discriminates between lung injury and lung inflation 3-5 Compartment analysis of DTPA clearance 5- l Cellular interactions involved in generation of immune response ~ x~ 14 29 30 31 40 45 73 79 99 106 114 115 20 20 21 22 46 70 71 72 72 94

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