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POSSI BLE LONG-TERkl HEALTH EFFECTS OF
SHORT-TERM EXPOSURE TO CHEMICAL AGENTS
Vo fume 3
Final Report: Current Health Status of Test Sub jects
Committee on Toxicology
Board on Toxicology and Environmental Health Hazards
Commission on Life Sciences
National Researc h Council
National Academy Press
Washington, D.C. 1985
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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 Research Council was established 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 of advising the federal government. The Council
operates in accordance with general policies determined by the
Academy under the authority of its congressional charter of 1863,
which establishes the Academy as a private, nonprofit, self-governing
membership corporation. The Council has become the principal
operating agency of both the National Academy of Sciences and the
National Academy of Engineering in the conduct of their services to
the government, the public, and the scientific and engineering
communities. It is administered jointly by both Academies and the
Institute of Medicine. The National Academy of Engineering and the
Institute of Medicine were established in 1964 and 1970, respectively,
under the charter of the National Academy of Sciences.
This study was prepared under Contracts DAMD-17-83-C-3185 and
DAMD-17-83-C-3045 between the National Academy of Sciences and the
Department of the Army.
Limited number of copies available from:
Committee on Toxicology
Board on Toxicology and
Environmental Health Hazards
National Research Council
2101 Constitution Avenue, N.W.
Washington, D.C. 20418
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COORDINATING SUBCOMMITTEE
Possible Long-Term Health Effects of Short-Term
Exposure to Chemical Agents
Howard Malbach, University of California School of Medicine, San
Francisco, California, Chairman
William Blot, National Institutes of Health, Bethesda, Maryland
Donald Ecobichon, McGill University, Montreal, Quebec, Canada
Barbara Hulka, University of North Carolina, Chapel Hill,
North Carolina
Lewis Kuller, University of Pittsburgh, Pittsburgh, Pennsylvania
George Mandel, George Washington University, Washington, D.C.
A. Thomas McLellan, University of Pennsylvania, Veterans
Administration Medical Center, Philadelphia, Pennsylvania
Robert Snyder, Rutgers University, New Brunswick, New Jersey
Peter S. Spencer, Albert Einstein College of Medicine, Bronx,
New York
COMMITTEE ON TOXICOLOGY
Roger O. McClellan, Lovelace Inhalation Toxicology Research Institute,
Albuquerque, New Mexico, Chairman
Carol Angle, University of Nebraska Medical Center, Omaha, Nebraska
Rose Dagirmanjian, University of Louisville, Louisville, Kentucky
David W. Gaylor, National Center for Toxicological Research,
Jefferson, Arkansas
Richard Griesemer, Oak Ridge National Laboratory, Oak Ridge, Tennessee
William Halperin, National Institute for Occupational Safety and Health,
Cincinnati, Ohio
Clark W. Heath, Jr., Emory University School of Medicine, Atlanta, Georgia
Rogene F. Henderson, Lovelace Environmental and Biomedical Research
Institute, Albuquerque, New Mexico
Meryl Karol, Graduate School of Public Health, Pittsburgh, Pennsylvania
Kathleen Taylor, General Motors Research Laboratory, Warren, Michigan
Thomas R. Tephly, The University of Iowa, Iowa City, Iowa
National Research Council Staff
Devra Lee Davis, Executive Director, BOTEHH
Francis N. Marzulli, Project Director
Kulbir S. Bakshi, Staff Officer
Seymour Jablon, Medical Follow-Up Agency
Robert J. Keehn, Medical Follow-Up Agency
Norman Grosstlatt, Editor
Edna W. Paulson, Chemical Information Specialist
Marvin Schneiderman, Consultant, Biostatistician
Diane Wagener, Consultant, Epidemiological Geneticist
Beulah S. Bresler, Administrative Secretary
Jean E. Dent, Senior Secretary
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BOARD ON TOXICOLOGY AND ENVIRONMENTAL HEALTH HAZARDS
Gerald N. Wogan, Massachusetts Institute of Technology, Cambridge,
Massachusetts, Chairman
Donald Hornig, Harvard University, Boston, Massachusetts,
Co-Vice-Chairman
Philip Landrigan, Mt. Sinai Medical Center, New York, New York,
Co-Vice-Chairman
John Doull, University of Kansas Medical Center, Kansas City, Kansas
Herman N. Eisen, Massachusetts Institute of Technology, Cambridge,
Massachusetts -
Emmanuel Farber, University of Toronto, Toronto, Ontario, Canada
David G. Hoel, National Institute of Environmental Health Sciences,
Research Triangle Park, North Carolina
Richard Merrill, University of Virginia Law School, Charlottesville,
Virginia
Emil Pfitzer, Hoffmann-La Roche Tnc., Nutley, New Jersey
Joseph V. Rodricks, Environ Corporation, Washington, D.C.
Liane B. Russell, Oak Ridge National Laboratory, Oak Ridge, Tennessee
Ellen Silbergeld, Environmental Defense Fund, Washington, D.C.
Peter S. Spencer, Albert Einstein College of Medicine, Bronx, New York
National Research Council Staff
Devra Lee Davis, Executive Director
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PREFACE
In the spring of 1980, the Department of the Army asked the
Committee on Toxicology of the National Research Council's Board on
Toxicology and Environmental Health Hazards to study the possible
chronic or delayed adverse health effects incurred by servicemen who
had been exposed experimentally to various chemicals at the U.S. Army
Laboratories, Aberdeen Proving Ground, Edgewood, Maryland, during
1955-1975. The Edgewood tests were conducted to learn how potential
chemical warfare agents might affect humans over a short period and
how such affected humans might respond to therapy for the effects of
such agents. The Army believed that relevant information could not be
obtained from animal experimentation alone and that it was necessary
to confirm animal findings by using human volunteers.
Some 6,720 soldiers took part in this program. To understand the
extent to which they might have experienced unanticipated long-term or
delayed adverse effects, an extensive search for reports, records, and
other data was undertaken. The search and the study and evaluation of
all available information on the five major categories of chemicals
involved (anticholinesterases, anticholinergics, cholinesterase
Deactivators, psychochemicals, and irritants and vesicants) were
accomplished by panels of experts under the direction of the Committee
on Toxicology.
The present report was prepared by a coordinating committee made
up of the chairmen of the five panels involved in earlier reports,
epidemiologists who had served on those panels, and one newly
appointed person. It is based largely on the work of Robert Keehn of
the National Research Council's Medical Follow-up Agency, which had
primary responsibility for conducting a questionnaire survey of test
subjects to evaluate aspects of their current health, family status,
and lifestyle.
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ACKNOWLEDGMENTS
The following person
provided technical assistance:
Virginia Dunkel, Food and Drug Administration, Washington, D.C.
Ronald J. Kassel, U.S. Army Chemical Systems Laboratory,
Aberdeen Proving Ground, Maryland
Mary S. Lyon, Harwell Dicot, England
Benjamin J. Tepping, Statistical Consultant, Silver Spring,
Maryland
Henry Wills, Uniformed Services University of the Health Sciences,
Bethesda, Maryland
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EXECUTIVE SUMMARY
At the request of the Department of the Army, the Committee on
Toxicology in the Board on Toxicology and Environmental Health Hazards
of the National Research Council's Commission on Life Sciences under-
took a study to investigate possible delayed and long-term effects of
experimental chemicals administered to soldiers at the U.S. Army
Laboratories, Edgewood, Maryland. A total of 6,720 soldiers volun-
teered, of whom 4,826 were exposed to some experimental chemicals.
The Edgewood tests, conducted over a 20-year period ending in 1975,
were intended to investigate the immediate and short-term human-
performance effects of short-term exposure to various chemicals with
warfare potential and the subjects' responses to therapy for such
effects.
Five panels of about 10 scientists each, with appropriate
expertise, reviewed the available information on the test chemicals,
which were divided into five categories according to pharmacologic
class. Available information included reports of acute effects by
physician observers and published reports in the scientific literature.
Volume 1 of this series was concerned with the possible long-term
effects of 15 anticholinesterase and 24 anticholinergic chemicals and
was issued in 1982. Volume 2 was concerned with four cholinesterase
Deactivators, 12 psychochemicals, mustard gas, and a variety of
irritant substances; it was issued in 1984. This report is Volume 3
of the series.
Early in this study, the Committee decided that the information on
the test materials would be incomplete if the long-term morbidity and
mortality among the test subjects were not investigated. It was
recognized that the Edgewood tests were intended for short-term and
not long-term study and were therefore deficient in adequate long-term
controls. The Committee, recognizing these limitations, nevertheless
believed that the study might detect major effects if they were
present and that the limitations of the study could be appropriately
described so its conclusions would not be overinterpreted. Mortality
was reported in Volume 1 and is updated in this volume. Morbidity was
analyzed through use of a questionnaire that was sent to all living
test subjects whose current addresses could be located and through
study of Army and Veterans' Administration (VA) hospital admissions of
the participants after testing.
This volume was prepared cooperatively by the Medical Follow-up
Agency of the Commission on Life Sciences and a coordinating committee
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composed of prior panel chairmen, three epidemiologists who had served
on the panels, and one newly selected epidemiologist. The charges to
the reporting group were as follows:
· To prepare a final report for the series Possible Long-Term
Health Effects of Short-Term Exposure to Chemical Agents on the basis
of results of a questionnaire regarding current health status of test
subjects.
· To evaluate the implications of findings from the questionnaire
for any of the conclusions reported in Volumes 1 and 2.
Edgewood test subjects who were alive and could be located
received a mailed questionnaire intended to assess their current
health status; 82% of those who received the questionnaire responded
to it.
The long-term health effects of most interest included the
possibility of excess cancer risk and adverse mental, necrologic,
hepatic, and reproductive effects that might have resulted from
experimental exposure to chemicals at Edgewood.
Subjects tested with anticholinesterase chemicals, anticholinergic
chemicals, cholinesterase reactivators, or psychochemicals did not
differ significantly from control subjects or from those tested with
other classes of drugs in their replies to questions about their
current health status. Almost 90% of all these respondents reported
no health problems related to the exposures under scrutiny, and 79%
reported good to excellent health. (Subjects tested with LSD were not
within the purview of the Committee's investigation, because they had
been evaluated and reported on earlier by the U.S. Army, whose
evaluation was based on physical examinations. Analysis of responses
to the Committee's questionnaire did indicate, however, that there was
an increased use of LSD after the Edgewood tests, but there was no
evidence of adverse health effects among these subjects.)
The subjects tested with irritants and vesicants, including those
who developed skin burns from mustard gas, reported no increased
prevalence of significant skin cancer or other adverse health
effects.
The test subjects' current use of tobacco and alcohol and their
histories of use of recreational drugs were not unusual.
When the observed fertility of men exposed to anticholinergic
chemicals was compared with age-adjusted expected values, based on the
experience of the men who were tested with other chemicals, there
appeared to be a decrease in fertility. However, the men who were
exposed to anticholinergics were, by and large, tested during the
second half of the 20-year testing period. Because of the national
trend toward delayed and smaller families, these analyses were further
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adjusted for the date of testing. When adjustment for age of volunteer
when last tested was performed, there was no difference between the
observed fertility pattern of the men exposed to anticholinergic
chemicals and that expected on the basis of men who were exposed to
other chemicals.
A review of records of admissions to Army hospitals in calendar
years 1958-1983 and admissions to VA hospitals in calendar years
1963-1981 produced some interesting findings with regard to Edgewood
test subjects: a barely statistically significant ~ ~ ~ ~
to VA hospitals for malignant neoplasms among men exposed to
anticholinesterases and statistically significant
admissions to VA hospitals and Army hospitals for nervous system and
sense organ disorders among men exposed to LSD.
increase in admissions
increases in
However, the numbers of
_
these admissions were small, no dose relationships were noted, and, in
the case of anticholinesterase exposures, no clustering of specific
chemicals in relation to tumor sites was noted.
The experimental methods and the available comparison groups were
such that only large effects were likely to be uncovered. The large
standard errors, the initial differences between the exposed and
nonexposed groups, the possibility that more than one exposure might
have led to the same adverse effect, and the self-reporting nature of
the questionnaire study all would tend to obscure small differences.
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CONTENTS
Introduction
The Medical Follow-up Study
Analytic Problems
Methods of Study
Results
Discussion
Conclusions
Tables
References
1
3
7
/
12
25
31
33
63
Appendix A. Executive Summaries of Volumes 1 and 2 67
Appendix B. Updated Mortality Study (Summary) 75
Appendix C. Interpretability of the Follow-up Questionnaire Data 83
Appendix D.
Appendix E.
Cohort Adjustment of Fertility for Anticholinergic
Group Using No-Chemical-Test Group for Comparison
The Questionnaire and Related Material (Exhibits A, B.
C, D, and E)
87
89
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