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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,
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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
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
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
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
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
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
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
Tables and Figures
TABLES
1-1 |
Health Effects Associated with Immune Dysfunction, |
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1-2 |
Factors Influencing the Immune System and Associated Markers, |
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2-1 |
Immunologic Reactions, |
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3-1 |
Methods of Detecting Chemicals That Produce Contact Hypersensitivity, |
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4-1 |
Xenobiotics Incriminated in Human Autoimmunity, |
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4-2 |
Autoimmune Diseases Related to Specific Xenobiotic Exposure, |
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5-1 |
Consequences of Immunosuppression, |
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5-2 |
Species Comparison of Immune Responses Suppressed by Cyclosporin A, |
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5-3 |
Classes and Examples of Chemicals Causing Immunological Changes, |
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5-4 |
EPA Survey Concentrations of Groundwater Contaminants and Composition of a Complex Chemical Mixture Representing a Contaminated Groundwater Sample, |
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6-1 |
Approaches to Animal Immunotoxicity Testing, |
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6-2 |
Validated Rodent Immunoassays, |
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7-1 |
Tier 1 (All Persons Exposed to Immunotoxicants), |
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7-2 |
Tier 2 (All Persons with Abnormal Tier 1 Results and a Fraction of the Total Exposed Population to be Determined by Statistician), |
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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), |
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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, |
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8-2 |
Interrelationship Among Prevalence, Sensitivity, and Specificity, |
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9-1 |
Randolph's Characterization of MCS, |
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9-2 |
Agents Reported to Cause Symptoms in Chemically Sensitive Individuals, |
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9-3 |
Cullen's MCS Case Definition, |
FIGURES
1-1 |
Simplified Flow Chart of Classes of Biologic Markers, |
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2-1 |
Cellular Interactions Involved in the Generation of an Immune Response, |
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2-2 |
Model of the Competent Immune System, Depicting Normal Interrelation of the Major Components, |
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2-3 |
Model of the Competent Immune System, Depicting Sites of Potential Effects on the Major Components by Toxins |
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3-1 |
Sensitization and Elicitation, |
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3-2 |
Selected Methods Over Time for Detecting Chemicals That Produce Contact, |
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
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
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