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POSSIBLE LONG-TERM HEALTH EFFECTS OF
SHORT-TERM EXPOSURE TO CHEMICAL AGENTS
Volume 2
Cho1inesterase Reactivators, Psychochemicals,
and Irritants and Vesicants
Prepared by the
Panel on Cholinesterase Reactivator Chemicals
Panel on Paychochemicale
Pane' on Irritants and Vesicants
Committee on Toxicology
Board on Toxicology and Environmental Health Hazards
Commission on Life Sciences
National Research Council
National Academy Press
Washington, D. C. 1984
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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 draw 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 appro-
priate balance.
This report has been reviewed by a group other than the authors
according to procedures approved by a Report Review Committee con-
sisting of members of the National Academy of Sciences, the National
Academy of Engineerlng, 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 lB63,
which establishes the Academy as a private, nonprofit, se~f-
goveraing membership corporation. The Counci1 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 supported by funds provided by the Department of the
Army through contract DAMDi7-83-C-3045 between the U.S. Army
Research and Development Command and the National Academy of
Sciences.
Copies available from:
National Academy Press
2101 Constitution Avenue, N.W.
Washington, D.C. 20418
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PANEL ON CHOLLNESTERASE REACTIVATOR CHEMICALS
Donald Ecobichon, McGill University, Quebec, Cantata, Chairman
Mohamed Abou-Donia, Duke University Medical School, Durham,
North Carolina
Won Of D. Det~cbarn, Vanderbilt University School of Medicine,
Nashville, Tennessee
Walderico M. Generoso, Oak Ridge National Laboratory, Oak
Ridge, Tennessee
Wayland Hayes, Vanderbilt University School of Medicine,
Nashville, Tennessee
Richard Johns, Johns Hopkins University School of Medicine,
Baltimore, Maryland
Lewis H. Kuller, UP versity of Pittsburgh, Pittsburgh,
Pennsylvania
Frank S. Standaert, Georgetown University Medical School,
Washington, D. C.
Irwin Wilson, University of Colorado, Boulder, Colorado
Technical Consultants
Ronald J. Kassel, U. S. Army Chemical Systems Laboratory,
Aberdeen Proving Ground, Maryland
Joseph S . Wiles, Baltimore, Maryland
J. Henry Wills, Uniformed Service s University of the Health
Sciences, Bethesda, Maryland
PANEL ON PSYCHOCHEMICALS
Robert Snyder, Rutgers University, New Brunswick, New Jersey,
Chairman
Monique C. Braude, National Institute on Drug Abuse,
Rockville, Maryland
Sidney Cohen, Uni~reraity of California, Los Angeles,
California
Walter J. Decker, U=1 versity of Texas Medical Branch,
Galveston, Texas
Reese T. ~Jones, University of California, San Francisco,
California
Marvin S. Legator, University of Texas Medical Branch,
Galore ston, Texas
William R. Martin, University of Kentucky, Lexington, Kentucky
A. Thomas McLellan, Veterans Administration Medical Center,
Philadelphia, PennsylYa=1 a
Charles P. O'Brien, University of PenneyI,rar~ia, Philadelphia,
Penn Sylvania
Wolfgang H. Vogel, Thomas Jefferson University, Philadelphia,
Pennsylvania
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Technical Consultants
Ronald J. Kassel, U. S . Army Chemical Systems Laboratory,
Aberdeen Proving Ground, Maryland
James S . Ketchum, University of Cal if ornia at Los Angeles,
School of Medicine, Los Angeles, California
S .N. Pradhan, Howard Urn versity, Washington, D. C.
Fred Sidell, Biomedical Laboratories, Aberdeen Proving Ground,
Maryland
Jo seph S . Wi ~ es, Ba ~ t imore, Maryland
PANEL ON IRRITANTS AND V-ESICANTS
Howard I. Maibach, University of California, San Francisco,
California, Chairman
William J. Blot, National Institutes of Health, Bethesda,
Maryland
George Hoffmann, Holy Cross College, Worcester, Massachusetts
Frederick Oehme, Ransas State University,
Manhattan, Kansas
Charles J. Stahl, E. Tennessee State University, Johnson City,
Tennessee
Marshall Steinberg, Hazleton Laboratories America, Vienna,
Virginia
Kim Thorbu`", University of California at Los Angeles,
California
John H. Weiaburger, American Health Foundation, Valhalla, New
York
William Willoughby, Johns Hopkins University Medical School,
Bait imore, Maryland
John Zapp, Kennett Square, Pennsylvania
Technical Consultants
. .
Charles Hassett, Towson, Maryland
Ronald J. Kassel, U.S. Army Chemical Systems Laboratory,
Aberdeen Proving Groaned, Mary and
National Research Council Staff
Francis N. Marsulli, Project Officer, Panel on
Cholinesterase Reactivator Chemicals,
Panel on Paychochemicale, and Panel on
Irritants and Vesicants
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Devra Lee Davis, Executive Director, Board on Toxicology and
Environmental Health Hazards ( BOTEHH)
Seymour Jablon, Director, Medical Follo~up Agency
Robert J. Keehn, Statistician, Medical Follow-up Agency
Edna Paulson, Manger, Toxicology Information Center (BOTEHH)
Virginia Mite, Reference Verifier, Toxicology Information
Cent er ~ BOTEHH)
Jean E. Dent, Secretary, Panel on Cholinesterase Reacti~rator
Chemica1 s, Panel on Paychochemicals, and Pane1 on
Irritants and Vesicants
Norman Grosablatt, Editor
COMMITTEE ON TOXICOLOGY
Roger O. McClellan, Lovelace Inhalation Toxicology Research
Institute, Albuquerque, New Mexico, Chairman
Richard R. Bates, Health Effects Institute, Cambridge,
Massachusetts
Donald Ecobichon, McGill University, Montreal, Quebec, Canada
David W. Gaylor, National Center for Toxicological Research,
Jef ferson, Arkansas
Richard Griesemer, Oak Ridge Nationa1 Laboratory, Oak Ridge,
Tennessee
William Halperin, National Instiute for Occupational Safety and
Health, Cincinnat i, Ohio
Clark W. Heath, Jr., Emory University School of Medicine,
Atlanta, Georgia
Howard I. Maibach, University of California School of
Medicine, San Francisco, California
Robert E. Menzer, University of Maryland, College Park,
Maryland
Robert Snyder, Rutgers University School of Pharmacy, New
Brunswick, New Jersey
Ronald Spanggord, SRI International, MeDlo Park, Cal if ornia
Peter S . Spencer, Albert Einstein College of
Medicine, Bronx, New York
Lloyd B. Tepper, Air Products and Chemica1 s, Inc., Allentown,
Penn syl~rallia
Clarence J. Terhaar, Eastman Kodak Company, Rochester, New York
National Research Council Staff
.
Francis N. Marzul li, Pro ject Of ficer
lbir S. Bakshi, Staff Officer
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BOARD ON TOXICOLOGY AND ENVIRONMENTAL HEALTH HAZARDS
Gerald N. Wogan, Massachusetts Institute of
Technology, Cambridge, Maseachusetts, Chainean
Donald Hornig, Harvard University, Boston, Massachusetts,
Co-Vice-Chairman
Philip Landrigan, National Institute for Occupational Safety
and Health, Cincinnati, Ohio, Co-Vice-Chairman
Edward Bresnick, University of Nebraska Medical Center, Omaha,
Nebraska
Herman N. Elsen, Massachusets Institute of Technology,
Cambridge, Massachuset to
Ronald Estabrook, University of Texas Medical School
(Southwestern), Dallas, Texas
Emma Duel Farber,
University of Toronto, Toronto,
Canada
David G. Hoel, National Institute of Environmental Health
Sciences, Research Triangle Park, North Carolina
Michael Lieberman, Washington Uni~reraity School
of Medicine, St . Louis, Missouri
Abraham M. Lilienfeld, Johns Hopkins Uni~reraity, Baltimore,
Maryland
Richard Merrill, University of Virginia, Charlottesville,
Virginia
Vaun A. Newill, Exxon Corporation, New York, New York
John Peters, University of Southern Californ' a, School of
Medicine, Los Angeles, California
Joseph V. Rod~ricks, Environ Corporation, Washington, D.C.
Llane B. Russell, Oak Ridge National Laboratory, Oak Ridge,
Tennessee
Ellen Silbergeld, Environmental Defense Fund, Washington, D.C.
National Research Council Staff
Devra Lee Davis, Executive Director
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ACKNOWT EDGlIENTS
The following persons provided technical assis~cance:
Gary Keilson, University of Virginia Medical School, Charlottesville,
Virginia
Lester Miller, U. S . Army Chemical Systems Laboratory, Aberdeen Proving
Ground, Maryland
Gordon Newell, EPRI, Palo Alto, California
James Norman, Medical Fol~ow-up Agency, National Research Council
Robert Tardiff, Environ Corporation, Washington, D.C.
James Vick, Food and Drug Administration, Washington, D.C.
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PREFACE
The Department of the Army asked the Committee on Toxicology, in
the Board on Toxicology and Environmental Health Hazards of the
Commission on Life Sciences, National Research Council (NRC) to
conduct a study of the possible chronic adverse health effects on
servicemen of experimental exposure to various chemicals at the U.S.
Army Laboratories (formerly the Army Chemical Center), Edgewood,
Md. The Edgewood tests were conducted over a 20-yr period ending in
1975, to learn how five major classes of chemicals tested for
various military applications may affect humans. Some 6,720
soldiers took part in the programs, and 254 chemicals were
administered by various routes.
In 1982, the Committee reported (Volume I) on possible long-term
effects of two pharmacologic classes of chemicals
(anticho~inesterases and anticholinergica) tested at Edgewood. This
volume reports on long-term effects of three additional classes of
chemicals tested at Edgewood:
~ It_ _ _ ~ ~ ~ ~ ~ ~ . _
cholinesterase reactivators,
psycnocnem~ca~s, ana ~rrz~ants and vesicants. Studies of these
substances, including LSD (discussed in a separately prepared
report), constituted the main thrust of the Edgewood experiments.
After completion of Volume I, three new panels were established
to identify and assess evidence on the possible long-term health
effects or delayed sequelae of the three chemical classes tested.
This wan done over a period of a year, during which each pane' met
three times. Pertinent material was examined to evaluate the
possibility that experimental exposure of soldiers may have resulted
in untoward health effects. The three panels were separately
concerned with four cholinesterase Deactivator chemicals (oximes);
two types of paychochemd cals (phencyclidine and dimethylhepty~pyran
and congenera), administered in pure form, as opposed to street
drugs; and mustard gas and severe' lacrimatory and respiratory
irritants (such as ON, CS, CR, and CA).
The charges to each panel were as follows:
~ To determine whether there was sufficient evidence to assess
the likelihood that the test chemicals had had long-term health
effects or delayed sequelae.
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· To determine, on the basis of this evidence, whether
the chemicals, as administered, are likely to have produced
such adverse effects in the test subjects.
As part of aches undertaking, the MRC staff conducted
interviews with administrators, irlves~cigators, nurses, and
technicians and reviewed documents to identify practices and
procedures followed in testing chemicals at Edgewood. The
interviews included persons who had a wide spectrum of
viewpoints, but who were essentially in agreement regarding
the conduct of h'' - n testing. Committees were formed at
Edgewood to retried classif fed chemicals and develop reports
for deciaselfication and use by NRC panels. Extensive
extracts were prepared of precli~cal animal and human
protocols and of technical reports at Edgewood libraries and
other facilities. A repository was established at Edgewood
(August 1980) for storing selected reports and needed
information obtained from other sources. Research and
experimental case files on volunteers were extracted and
summarized. Digests of the literature were prepared.
This report presents the conclusions of the three panels
based on available toxicologic and epidemiologic data,
including specific information on the frequency, routes, and
amounts of the substances administered and the known immediate
and long-term effects of the substances under the prevailing
experimental conditions.
A third report is intended to provide a final evaluation
of the chemicals tested. Volume 3 will report on ache current
health status of the soldier participants on the basis of a
recent questionnaire and interpret its impact on the
conclusions reported in Volumes ~ and 2. The followup
questionnaire to volunteer subjects may add descriptive data,
but, because of the km] ted sample size, it is unlikely to
protrude evidence of a cause-and~ef feet relation between
exposure to these chemicals and development of delayed disease.
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EXECUTIVE SUMMARY
In 1980, the Board on Toxicology and Environmental Health
Hazards of the National Research Council's Commission on Life
Sciences began a program to evaluate the long-term health
effects of chemical agents administered to military volunteers
at the Army Chemical Center, Edgewood, Md., during the 1950s,
1960s, and 1970~. This work was conducted at the request of
the Department of the Army. The tests were conducted to find
out how various potential chemical warfare agents affect human
performance. It was felt that animal tests were inadequate
for this type of evaluation and that only humans could provide
d ef ini t ive inf orma t ion .
The first report (Volume l) reviewed data on 15
anticholinesterase and 24 antichollnergic agents, to which
almost half of some 6, 700 sub jects were exposed at Edgewood.
The current report, prepared by three panels of the
Board's Committee on Toxicology, evaluates possible delayed
health ef fee to of three additional classes of compounds that
were tested on most of the remaining volunteer subjects:
cholinesterase reacti~rators, paychochemicals, and irritants
and vesicants (blistering chemicals). The cholinesterase
reactivators, of which there are four, are used as antidotes
for antlchotinesterase poisoning. The paychochemlcals income
phencyclidine, an anesthetic with substantial disorienting
ef fects that is also available (with impurities) as the street
drug PCP, and 10 related dibenz opyrans that are central
nervous system depressants capable of producing orthostatic
hypotension. The irritants include the well-known lacrimatory
chemical ON, the riot-control agent CS, and other ocular and
re spiratory irritants . Mustard gas was the vesicant whose
ef fects were studied.
The Committee established three panels to identify and
assess evidence on the possible long-term health effects or
delayed sequelae of the chemicals tested. As in the work that
led to Volume I, the chairman of each panel was selected from
the Committee on Toxicology.
The specific charges to each panel were as follows:
· To determine whether there was sufficient evidence to
assess the likelihood that the test chemicals had had
long-term health effects or delayed sequelae.
· To determine on the basis of this evidence whether the
chemicals, as administered, are likely to have produced such
adverse ef fects in the test subjects.
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The conclusions in this volume are based on available
epidemiologic, toxicologic, and mortality data that were
reported in Volme l. They also rely on a review of
teat-subJect exposure data obtained from Edgewood, an of
which were available to pane] membere. Long-term clinical
fo~owup was not conducted. The subjects tested were
healthier than the control subjects with whom they were
compared, an both groups were healthier than the general
population, reflecting the better health status of those in
mid ~ tary service. The analyses presented here necesearily
reflect the limitations of the available data. These
conclusions might change in the light of information gained
through a study of morbidity, which will be based on a
questionnaire arid an analysis of admissions to Army and
Veterans' Administration hospitals (to be reported in Volume
3~.
CHOLINESTERAS E REACTIVATORS
On the basis of an examination of toxicologic literature,
case reports from Edgewood volunteers, and a retried of
mortality data conducted by the National Research Council
Medical Follow~up Agency, the Committee fond no evidence of
chronic disease in anir~=ts or humus associated with single or
repeated doses of the cho t ~ nesterase reacti~ratore ~ oximes) .
The lack of followup data on volunteers pretreats certainty in
predicting occurence or absence of delayed effects. The
compounds are eliminated very rapidly from the body, but they
produce a variety of acute effects that are short-lived an
reversible, such as gastrointestinal distress after oral
administra~cion, pain at an injection site, dizziness,
headache, and ocular dlacomfort. The Committee found no
conclusive studies of carcinogeniclty, mutagenicity,
teratogen~city, or reproductive anomalies associated with the
four oxides and therefore did not reach a conclusion in this
regard.
PSYCHOCH~ICALS
The Committee found the evidence on the long-tenm health
ef facts of the tested psychochemicale to be sparse. The
target organs that may be involved in prolonged or delayed
effects of phencyclidine are the brain and cardiovascular
system. Target mental or cardiovascular effects did not take
place within a week of espo sure to the drug. No case reports
have identified long-.cerm effects or mental or cardiovascular
effects soon after first exposure.
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The margin of safety of a tested chemical is sometimes
estimated by considering the ratio of the lethal dose to the
pharmacologically effective 608e ~ the 608e at which some
detectable biologic ef feet occurs) ~ On the basis of animal
data on the psychochemlcals tested, the margin of safety for
short-term effects is large for acute intravenous,
inttagastric, intraperitoneal, and subcutaneous administration
and somewhat amass er for inhalation of the aerosolized form.
On the basis of the scientific literature alone, it is not
possible to predict whether any long-term effects would be
asoclated with the small exposures used. However, evaluation
of thi ~ toxicity literature and the Edgewood studies led this
Committee to conclude that, at the doses and frequencies of
phencycl1dine used at Edgewood in a small number of test
subjects, it is unlikely that detectable long-term or delayed
effects have occurred or win occur.
Acute administration of the dibenzopyrans
(dimethy~hepty~pyran and congellera) produced various degrees
of physical incapacitation in Edgewood subjects, mainly
because of moderate to marked and prolonged or~chostatic
hypotension. The duration and intensity of effects varied
among most doses and subjects. Despite the variations, there
is a large pharmacologic margin of safety in the use of these
compounds in animals. The dibenzopyrans produced more potent
long-lasting orthostatic hypotension and weaker (but otherwise
similar) paychologic effects thand-9-tetrahydrocann~blool
during the Edgewood experiments. There is no laformation on
chromic effects of dibenzopyrane.
IRRITANTS AND VESICANTS
The Committee analyzed published studies describing the in
viva and in vitro properties of the agents used and reviewed
short-term data collected by the U.S. Army on volunteers. The
ability to provide defluitlve answers to the questions raised
by the charge to the Committee was limited by the absence of
long-term for owup studies of the so1diere and by the
sparsenese of chronic effects studies of these compounds in
animate or in h''mAns after industrial exposure.
In general, the Committee found insufficient evidence to
evaluate these chemicals, except mustard gas. Mustard gas is
an experimental mutagen and human carcinogen at high doses.
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Data on the irritan~cs are insufficient to evaluate their
mutage~clty, carcinogenlcity, or other long-term ef feces.
Tests of all theses chemicals involved few exposures and low
doses.
MUSTARD GAS ~ H)
Mustard gas is highly reactive and has vesicant and
systemic toxic effects. It is an alkylating agent that is
mutagenic ire various laboratory test systems, including
mammalian germ cells, but data are inadequate to predict the
extent of its genetic risk in humans. Mustard gas is also
carcinogenic in experimental animals and humans. Other
possible long-term ef fects of mustard gas are related to its
|~4t toxicity; specifically, it can cause blindness,
po ssible skin tumors from some cases of permanent scarring of
the skin, and chronic bronchitis . Reported ~ nstaneee of
long-term injury, such as carcinogenesis in workers tn a
Japanese mustard production plant, were associated with
exposure at high, long-term dosages. Information is
insufficient to project risks associated with smaller
exposures to mustard gas; however, serious long-term adverse
effects in the small number of soldiers who received one or a
few low~dose exposures at Edgewood seem unit ikely (except for
possible skin tumors and some cases of permanent scarring) .
Some of those exposed at Edgewood suffered skin injuries that
took several weeks to resolve. However, in view of the small
number of persons tested (about 150 healthy men) and the very
low dosages involved, it is unlikely that a statistically
signif icant increase in the flak of cancer or other chronic
disease can be detected in those exposed to mustard gas at
Edgewood. Then exposed, the Edgewood subjects were wearing
gas masks and impregnated clothing--an ensemble being tested
for efficacy against toxic contamination.
o-CHLOROBENZY[IDENE MALONONITRILE ~ CS ~
-
Results of experimental studies in microorganisms and
short-~cerm elopements in laboratory animals suggest that
long-c erm medical abnormalities in soldiers exposed deco CS are
unlikely. Acute tissue changes produced in animals and humans
seem reversible and not likely to become chronic in the
absence of recurrent exposures. Follownp information on the
long-term state of health of exposed soldiers is not
available, but no reports indicate that Edgewood subjects have
experienced any long-term sequelae.
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CHLOROACETOPHENONE ( CN)
ON, a moderately toxic irritant, has immediate effects on
the eyes, skin, and respiratory tract. CN is a strong
skin-sensitizing agent, but is rarely lethal. The Committee
found no e~rldence of lasting ocular or respiratory effects in
99 volun~ceers exposed esperlmentally at Edgewood between 1958
and 1972 when subjects were evaluated 2 wk after cutaneous
administration or inhalation of aerosol. Allergic contact
dermatitis or hypersensitivity in these volunteers on
re-exposure to CN in possible. There has been no systematic
study of the possible mutagenic and s~eoplasm-promotir~g effects
of CN with current scientific methods.
DIBENZlb, f] [1,4]0XAZEPINE (CR)
CR, a mild lacrimatory irritant, manifests less acute
toxicity than CN and CS. At low doses, it causes transient
effects. There are a few studlee on long-term health effects,
including potential mutagenicity and teratogenicity. The
available data are insufficient to predict long-term health
effects. The small number of exposures and the Small number
of subjects exposed to CR at low doses at Edgewood make the
occurrence of demonstrable ef fects in these sub jects unlikely.
CHLOROPICRIN ( PS )
PS is acutely toxic and has a variety of sensory effects
in animals. It has not been evaluated thoroughly for
mutagenicity or carcinogen city. Like those exposed to
mustard gas, the subjects exposed to PS were wearing gas
masks, and small numbers of soldiers were exposed to small
doses. PS is unlikely to have produced detectable long-term
hew th effect'' in volunteers exposed at Edgewood.
BROMBENZYL CYANIDE (CA), DIPHENYI~IINOCHLORARSINE (DM), and
1-METHOXY-1 3 5-CYCLOHEPTATRIENE (CHT)
. ,
CA, DM, and CHT are unlikely to have produced measurable
long-term hew th effects in volunteers exposed at Edgewood.
But there are no specific toxicologic data on the mutagenicity
and carcinogenicity of these compounds. CH1 is less toxic
than CN or DM when administered acutely.
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NONANOYL MORPHOLIDE
The Committee does not expect long-ter~ health effects in
volunteers tested with nonanoyl morpholide at the dosages used
at Edgewood. As with CA, DM, and CHT, specific toxicologic
data regarding its potential in this regard are not available.
123 IRRITANT CHEMICALS
.
A total of 123 irritant chemicals were tested on only two
subjects each. There are no data on their mutagenicity,
carcinoger~icity, or other long-term health effects. However,
because the exposures were Small, detectable adverse effects
seem unlikely.
OVERVIEW
.
The Army~s studies on hen subjects were designed
ent ire ly to evaluat e short-term physiologic and pharmacologic
effects. A review of all available data reveals that these
data are inadequate to provide defluiti~re answers regarding
the likelihood that the test chemicals produced or did not
produce long-term health effects or delayed sequelae.
Information on long-term health effects of the teat chemicals
on aMmals or humans is lacklug, as is followup information on
the current health statue of the subjects. It therefore
cannot be determined whether some subjects may have sustained
long-ter~ or delayed effects. Analysis of a questionnaire and
of admissions to Army and Veterans' Administration hospitals
(Volume 3) may provide further information on the current
health status of these subjects.
