Biologic Markers in Immunotoxicology

Subcommittee on Immunotoxicology

Committee on Biologic Markers

Board on Environmental Studies and Toxicology

Commission on Life Sciences

National Research Council

NATIONAL ACADEMY PRESS
Washington, D.C.
1992



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Biologic Markers in Immunotoxicology Biologic Markers in Immunotoxicology Subcommittee on Immunotoxicology Committee on Biologic Markers Board on Environmental Studies and Toxicology Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS Washington, D.C. 1992

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Biologic Markers in Immunotoxicology NATIONAL ACADEMY PRESS  2101 Constitution Ave., N.W. Washington, D.C. 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 competencies 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 on 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 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. Kenneth Shine 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 Service, Department of Health and Human Services. Library of Congress Catalog Card Number 91-67588 International Standard Book Number 0-309-04389-1 Additional copies of this report are available from the National Academy Press, 2101 Constitution Avenue, N.W., Washington, D.C. 20418 S538 Printed in the United States of America First Printing, February 1992 Second Printing, June 1992 Third Printing, July 1992 Fourth Printing, October 1992 Fifth Printing, January 1996

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Biologic Markers in Immunotoxicology Subcommittee on Immunotoxicology DAVID W. TALMAGE, Chairman, University of Colorado Health Sciences Center, Denver DAVID E. BICE, Lovelace Inhalation Toxicology Research Institute, Albuquerque JOHN CHARLES BLOOM, Lilly Research Laboratories, Greenfield, IN LOREN D. KOLLER, College of Veterinary Medicine, Oregon State University, Corvallis MICHAEL E. LAMM, Institute of Pathology Case Western Reserve University, Cleveland MICHAEL I. LUSTER, National Institute of Environmental Health Sciences, Research Triangle Park WILLIAM J. MEGGS, East Carolina School of Medicine, Greenville, NC ALBERT E. MUNSON, Medical College of Virginia, Richmond KATHLEEN E. RODGERS, Livingston Laboratories, Los Angeles NOEL R. ROSE, Johns Hopkins University, Baltimore PAUL A. SCHULTE, National Institute for Occupational Safety and Health, Cincinnati CURTIS C. TRAVIS, Office of Risk Analysis, Oak Ridge National Laboratory, Oak Ridge ERNEST S. TUCKER, California Pacific Medical Center, San Francisco ROBERT F. VOGT, JR., Centers for Disease Control, Atlanta THOMAS A. WALDMANN, National Cancer Institute, Bethesda, MD Technical Adviser GARY R. BURLESON, U.S. Environmental Protection Agency, Research Triangle Park Staff RICHARD D. THOMAS, Program Director ROBERT P. BELILES, Program Officer MARVIN A. SCHNEIDERMAN, Senior Staff Scientist KATE KELLY, Editor RUTH E. CROSSGROVE, Information Specialist DANIELLE CORRIVEAU, Project Assistant (until 1/91) JOYCE WALZ, Project Assistant Sponsors National Institute of Allergy and Infectious Disease National Institute of Environmental Health Sciences U.S. Environmental Protection Agency U.S. Public Health Service, Agency for Toxic Substances and Disease Registry

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Biologic Markers in Immunotoxicology Committee on Biologic Markers BERNARD GOLDSTEIN, Chairman, UMDNJ-Robert Wood Johnson Medical School, Piscataway JAMES GIBSON, Dow-Elanco, Indianapolis ROGENE F. HENDERSON, Lovelace Biomedical and Environmental Research Institute, Albuquerque JOHN E. HOBBIE, Marine Biological Laboratory, Woods Hole, MA PHILIP J. LANDRIGAN, Mount Sinai Medical Center, New York DONALD R. MATTISON, University of Arkansas for Medical Sciences and National Center for Toxicological Research, Little Rock FREDERICA PERERA, Columbia University, New York EMIL A. PFITZER, Hoffmann-La Roche, Inc., Nutley, NJ ELLEN K. SILBERGELD, Environmental Defense Fund, Washington, DC Staff RICHARD D. THOMAS, Program Director

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Biologic Markers in Immunotoxicology Board on Environmental Studies and Toxicology PAUL G. RISSER (Chairman), University of New Mexico, Albuquerque GILBERT S. OMENN (Immediate Past Chairman), University of Washington, Seattle FREDERICK R. ANDERSON, Washington School of Law, American University JOHN C. BAILAR, III, McGill University School of Medicine, Montreal LAWRENCE W. BARNTHOUSE, Oak Ridge National Laboratory, Oak Ridge GARRY D. BREWER, Yale University, New Haven EDWIN H. CLARK, Department of Natural Resources & Environmental Control, State of Delaware, Dover YORAM COHEN, University of California, Los Angeles JOHN L. EMMERSON, Lilly Research Laboratories, Greenfield, Indiana ROBERT L. HARNESS, Monsanto Agricultural Company, St. Louis ALFRED G. KNUDSON, Fox Chase Cancer Center, Philadelphia GENE E. LIKENS, The New York Botanical Garden, Millbrook PAUL J. LIOY, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey JANE LUBCHENCO, Oregon State University, Corvallis DONALD MATTISON, University of Pittsburgh, Pittsburgh GORDON ORIANS, University of Washington, Seattle NATHANIEL REED, Hobe Sound, Florida MARGARET M. SEMINARIO, AFL/CIO, Washington, DC I. GLENN SIPES, University of Arizona, Tucson WALTER J. WEBER, JR., University of Michigan, Ann Arbor Staff JAMES J. REISA, Director DAVID J. POLICANSKY, Associate Director and Program Director for Applied Ecology and Natural Resources RICHARD D. THOMAS, Associate Director and Program Director for Human Toxicology and Risk Assessment LEE R. PAULSON, Program Director for Information Systems and Statistics RAYMOND A. WASSEL, Program Director for Environmental Sciences and Engineering

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Biologic Markers in Immunotoxicology Commission on Life Sciences BRUCE M. ALBERTS (Chairman), University of California, San Francisco BRUCE N. AMES, University of California, Berkeley J. MICHAEL BISHOP, Hooper Research Foundation, University of California Medical Center, San Francisco MICHAEL T. CLEGG, University of California, Riverside GLENN A. CROSBY, Washington State University, Pullman LEROY E. HOOD, California Institute of Technology, Pasadena DONALD F. HORNIG, Harvard School of Public Health, Boston MARIAN E. KOSHLAND, University of California, Berkeley RICHARD E. LENSKI, University of California, Irvine STEVEN P. PAKES, Southwestern Medical School, University of Texas, Dallas EMIL A. PFITZER, Hoffman-LaRoche, Inc., Nutley, New Jersey THOMAS D. POLLARD, Johns Hopkins Medical School, Baltimore JOSEPH E. RALL, National Institutes of Health, Bethesda, Maryland RICHARD D. REMINGTON, University of Iowa, Iowa City PAUL G. RISSER, University of New Mexico, Albuquerque HAROLD M. SCHMECK, JR., Armonk, New York RICHARD B. SETLOW, Brookhaven National Laboratory, Upton, New York CARLA J. SHATZ, Stanford University School of Medicine, Stanford TORSTEN N. WIESEL, Rockefeller University, New York, NY JOHN E. BURRIS, Executive Director

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Biologic Markers in Immunotoxicology Preface The American people have become increasingly aware of the potential for exposure to toxic material in our environment and of a need for accurate, objective information on the health effects of pollutants. In keeping with that need, the Agency for Toxic Substances and Disease Registry of the U.S. Public Health Service, the Office of Health Research of the U.S. Environmental Protection Agency, the National Institute of Environmental Health Sciences, and the National Institute of Allergy and Infectious Disease requested 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" has been used by the National Research Council's Committee on Biologic Markers to refer 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 to consider the areas of environmental research in which the use of biologic markers offered the greatest potential for major contributions. Four biologic systems were chosen: the reproductive system, the respiratory system, the immune system, and the urinary system. A companion report, Environmental Neurotoxicology, emphasizes biologic markers for the nervous system. This report is the product of the Subcommittee on Immunotoxicology, which included clinicians, epidemiologists, toxicologists, pathologists, and biochemists. Our intent was to consider various kinds of basic research that might reveal markers of environmental exposure and disease, even if the original goal of the research had nothing to do with such markers. Eventually, the subcommittee decided to place major emphasis on biologic markers of three types: markers originating from the immune system, markers related to immunosuppressive toxicants of exposure, and markers of effects of environmental pollutants. Markers of susceptibility to environmental materials also were considered important and were included especially if they were of a genetic nature and could serve to identify individuals who are susceptible to autoimmune diseases. The subcommittee decided to organize this report according to types of action on the

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Biologic Markers in Immunotoxicology immune system (hypersensitivity or suppression), rather than according to specific pollutants, on the grounds that it is 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, several additional scientists were called on to provide information. The subcommittee especially wishes to recognize the contributions of Gary Burleson of the U.S. Environmental Protection Agency. This report could not have been produced without the untiring efforts of the National Research Council staff, especially Robert P. Beliles, the program officer; Joyce Walz, the project assistant; Danielle Corriveau, the administrative secretary; Tania Williams, who prepared the camera copy; Kate Kelly and Norman Grossblatt, the editors of the report; Devra Davis, resident scholar; and Richard D. Thomas, associate director, and James J. Reisa, director of the Board on Environmental Studies and Toxicology. David Talmage, Chairman Subcommittee on Immunotoxicology

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Biologic Markers in Immunotoxicology Contents     LIST OF TABLES AND FIGURES   xiii     LIST OF ABBREVIATIONS   xv     SUMMARY   1     Hypersensitivity   2     Autoimmunity   2     Immune Suppression   3     Clinical Application of Existing Immunotoxicologic Biomarkers   4     Role of Biologic Markers of Immunotoxicity in Epidemiology   4     Indoor Air Pollution and Multiple Chemical Sensitivity   5 1   INTRODUCTION   9     Biologic Markers   11     Validity of Biologic Markers   19     Uncertainty and Risk   21     Ethical and Practical Issues   21     Structure of the Report   22 2   THE STRUCTURE AND FUNCTION OF THE IMMUNE SYSTEM AND MECHANISMS OF IMMUNOTOXICITY   23     Development and Function of the Immune System   24     Mechanisms of Chemically Induced Immune Disease   26     Effects of Xenobiotics on the Immune System   30 3   BIOLOGIC MARKERS FOR IMMUNE-MEDIATED DISEASE   33     Definition of the Problem   33     Exposure Through Inhalation (Pulmonary Hypersensitivity)   34     Exposure Through Ingestion   37     Dermal Exposure   38     Nonspecific Immune Enhancement   40     Biologic Markers of Hypersensitivity   41     Animal Models for Detecting Chemically Mediated Hypersensitivity   43     Summary   49

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Biologic Markers in Immunotoxicology     Recommendations for Future Research   50     IgE and Cellular Immunity   51 4   AUTOIMMUNE DISEASES   53     Definition of the Problem   53     Incidence of Autoimmune Diseases   53     Susceptibility Versus Exposure   55     Xenobiotic-Induced Autoimmunity   56     Mechanisms   57     Animal Models   58     Biologic Markers   59     Major Histocompatibility Complex   59     Immunoglobulin Allotypes   59     Other Genetic Markers   59     Rate of Acetylation   60     Summary and Conclusions   61 5   THE CAPACITY OF TOXIC AGENTS TO COMPROMISE THE IMMUNE SYSTEM (BIOLOGIC MARKERS OF IMMUNOSUPPRESSION)   63     Consequences of Immunosuppression   64     Environmental Contaminants   68     Inhalation and Immunosuppression   74     Skin and Immunosuppression   77     Myelotoxicity and Immunosuppression   77     Difficulties in Establishing Human Risk   78     Factors That Affect Susceptibility   78     Importance of Mechanistic Studies   80     Summary   80     Recommendations   81 6   ANIMAL MODELS FOR USE IN DETECTING IMMUNOTOXIC POTENTIAL AND DETERMINING MECHANISMS OF ACTION   83     Animal Immunotoxicity Bioassays   83     Assays of Pulmonary Immunocompetence   90     Assays Requiring Additional Development   91     Use of Immunotoxicity Bioassays   92     Summary   97     Recommendations   97 7   HUMAN IMMUNE-SYSTEM BIOLOGIC MARKERS OF IMMUNOTOXICITY   99     Tests for Assessing Immunity   99     Tests of the Humoral Immune System   100     Cellular Immune System   102     Other Tests   104     Opportunities for Development of Biologic Markers That Assess the Effect of Immunotoxicants   105     Proposed Testing Regimen   108

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Biologic Markers in Immunotoxicology     Summary   110     Recommendations   111 8   APPLICATION OF BIOLOGIC MARKERS OF IMMUNOTOXICITY IN EPIDEMIOLOGY   113     Epidemiology   113     Contribution of Biologic Markers to Epidemiology   114     Variability in Reference Populations   115     Sensitivity, Specificity, and Predictive Value   115     Authentication of the Event Status   117     Study Design   119     Reference Populations   120     Case Studies   121     Recommendations   125 9   USE OF BIOLOGIC MARKERS IN CONTROVERSIAL AREAS OF ENVIRONMENTAL HEALTH   127     Evidence of Exposure to Organic Chemicals   128     Health Effects of Indoor Air Contaminants   128     Case Definitions of Multiple Chemical Sensitivity Syndrome   132     Immune-System Dysfunction in MCS Patients   134     Biologic Markers of Sensitivity to Chemicals   136     Antibodies to Formaldehyde-Human Serum Albumin Adducts   137     Conclusions   137     Recommendations   138 10   SUMMARY AND RECOMMENDATIONS   141     Chemical-Induced Immunosuppression in Humans   143     Role of Environmental Chemical Exposure in Hypersensitivity and Autoimmune Diseases   145     Animal and In Vitro Models   145     Markers of Skin and Mucosal Responses   147     Education and Training   147     Environmental Exposures and Sensitivity Syndromes   148     REFERENCES   149     GLOSSARY   183     BIOGRAPHIES   193     INDEX   199     ADDENDUM: MULTIPLE CHEMICAL SENSITIVITY SEPARATE VOLUME

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Biologic Markers in Immunotoxicology Tables and Figures TABLES 1-1   Health Effects Associated with Immune Dysfunction,   14 1-2   Factors Influencing the Immune System and Associated Markers,   17 2-1   Immunologic Reactions,   28 3-1   Methods of Detecting Chemicals That Produce Contact Hypersensitivity,   45 4-1   Xenobiotics Incriminated in Human Autoimmunity,   54 4-2   Autoimmune Diseases Related to Specific Xenobiotic Exposure,   55 5-1   Consequences of Immunosuppression,   65 5-2   Species Comparison of Immune Responses Suppressed by Cyclosporin A,   67 5-3   Classes and Examples of Chemicals Causing Immunological Changes,   70 5-4   EPA Survey Concentrations of Groundwater Contaminants and Composition of a Complex Chemical Mixture Representing a Contaminated Groundwater Sample,   75 6-1   Approaches to Animal Immunotoxicity Testing,   85 6-2   Validated Rodent Immunoassays,   86 7-1   Tier 1 (All Persons Exposed to Immunotoxicants),   108 7-2   Tier 2 (All Persons with Abnormal Tier 1 Results and a Fraction of the Total Exposed Population to be Determined by Statistician),   109 7-3   Tier 3 (To be Considered for Those with Abnormalities in Tier 2 Tests or for a Random Fraction of the Entire Population in Tier 2),   110 8-1   Three examples of the Relationship between Exposed Subjects and the Presence (+) or Absence (-) of Markers Illustrating the Interaction of Prevalence, Sensitivity, Specificity, and Predictive Value,   116 8-2   Interrelationship Among Prevalence, Sensitivity, and Specificity,   118 9-1   Randolph's Characterization of MCS,   129 9-2   Agents Reported to Cause Symptoms in Chemically Sensitive Individuals,   133 9-3   Cullen's MCS Case Definition,   134

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Biologic Markers in Immunotoxicology FIGURES 1-1   Simplified Flow Chart of Classes of Biologic Markers,   12 2-1   Cellular Interactions Involved in the Generation of an Immune Response,   25 2-2   Model of the Competent Immune System, Depicting Normal Interrelation of the Major Components,   26 2-3   Model of the Competent Immune System, Depicting Sites of Potential Effects on the Major Components by Toxins     3-1   Sensitization and Elicitation,   47 3-2   Selected Methods Over Time for Detecting Chemicals That Produce Contact,   48

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Biologic Markers in Immunotoxicology List of Abbreviations ADCC Antibody-dependent cell-mediated cytotoxicity ACGIH American Conference of Governmental Industrial Hygienists ACTH Adrenal cortical trophic hormone AIDS Acquired immune deficiency syndrome ATSDR Agency for Toxic Substances and Disease Registry BALF Bronchoalveolar lavage fluid B-cell system Humoral immune system B16F10 Mouse tumor cell model (melanoma) C1-C9 Complement system components cAMP Cyclic adenosine monophosphate CD Cluster of differentiation, e.g. CD3 CD3 T-cell surface marker associated with the T-cell receptor for antigen CD4 T-cell surface marker identifying the helper (or inducer) subset of T cells CD8 T-cell surface marker identifying the suppressor (or cytotoxic) subset of T cells CD4:CD8 Helper/suppressor cell (ratio) CD19 B-cell surface marker CD20 B-cell surface marker CD22 B-cell marker present on the membrane of mature B cells and in the cytoplasm of immature B cells CD25 T-cell surface marker identifying marker for IL-2 receptor CFU Colony-forming unit CFU-B Colony-forming unit, basophils CFU-G Colony-forming unit, granulocytes CFU-GM Colony-forming unit, granulocytes and macrophages CH50 Hemolytic complement CMI Cell-mediated immunity C1q Subunit of first component of complement Con A Concanavalin A CsA Cyclosporin A

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Biologic Markers in Immunotoxicology CSF Colony-stimulating factor CTL Cytotoxic T lymphocyte DT Diphtheria-tetanus (vaccine) DPT Diphtheria-pertussis-tetanus (vaccine) DTH Delayed-type hypersensitivity EAE Experimental allergic encephalomyelitis EBV Epstein-Barr virus EI Environmental illness ELISA Enzyme-linked immunosorbent assay Fc Fragment cystalline- The fragment of an antibody that is responsible for binding to antibody receptors on cells and the C1q component of complement FEV-1 Forced expiratory volume in one second Gm Gammaglobulin GM-CSF Granulocyte-macrophage colony-stimulating factor Gmfb Gammaglobulin allotype GVH Graft versus host HAH Halogenated aromatic hydrocarbon HIV Human immunodeficiency virus HLA Human leukocyte antigen HLA-B27 HLA associated with ankylosing spondylitis HLA-Rw4 HLA associated with Pemphigus vulgaris HSA Human serum albumin IFN Interferon Ia Murine class II major histocompatibility complex antigen Ig Immunoglobulin class; A, D, E, G, M IL-1 -IL-8 Interleukin, one through eight IU International unit K562 Sensitive cell target for NK cell assay (leukemic cell line) kg Kilogram KLH Keyhole limpet hemocyanin LAK Lymphokine-activated killer (cells) LALN Lung-associated lymph nodes LPS Lipopolysaccharide, a B-cell-specific mitogen MCMV Murine cytomegalovirus MCS Multiple chemical sensitivity MDI Methylene diphenyl diisocyanate mg Milligram MHC Major histocompatibility complex MLC Mixed-lymphocyte culture MLR Mixed-leukocyte response mm3 Cubic millimeter NK Natural killer cell PAF Platelet activating factor PAH Polycylic aromatic hydrocarbon PBB Polybrominated biphenyl PCB Polychlorinated biphenyl PFC Plaque-forming cell

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Biologic Markers in Immunotoxicology PHA Phytohemagglutinin, T-cell mitogen PHSC Pluripotent hematopoietic stem cell PPD Purified protein derivative ppm Parts per million PRP Polyribose phosphate PWM Pokeweed mitogen, a T-and B-cell mitogen PYB6 Mouse tumor cell model (fibrosarcoma) RBC Red blood cells SAC Staphylococcus aureus Cowen strain activator SBS Sick building syndrome SCID Severe combined immunodeficiency SLE Systemic lupus erythematosus SRBC Sheep red blood cell T-cell system Cellular immune system TEAM Total Exposure Assessment Methodology study Thy-1 T-cell marker related to thymic maturation VOC Volatile organic compound YAC-1 Mouse tumor cell model (lymphoma) used to test NK activity

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