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1
INTROD UCT ION
H ISTORY OF THE EDGEWOOD TESTING PROGRAM
Human experimentation appears to have been an integral part of
the history of the U.S. Amy chemical warfare (COO) research efforts
until its suspension in 1975. On June 2B, 1918, the President
directed the establishment of the Chemical Warfare Service . (BUS) .
Four years later, in October 1922, the CWS created a Medical Research
Di~rislon to conduct research directed at pro~riding a defense against
chemical agents. No matter how exhaustively an agent was tested in
animals, it was felt that its efficacy in humans also had to be
s tudied .
In early 1941, the threat of war increased the urgency of the
development of protection against CW agents and, consequently,
engendered a need for a larger source of volunteers. Formal authority
to recruit ant use volunteer subjects in CW experiments was initiated
in 1942. The Secre tary of War was asked to rule on the permissibility
of using enlisted men for testing agents of the mustard-gas type. In
July 1943, the CONS was assigned responsibility for all medical
research relates to CW. This extension of the CWS mission included
toxicologic research and the study of hazard s to the health of
personne 1 in the CWS .
The i ssue of the use of human volunteers was considered by the
Armed Forces Medical Policy Council during the early 1950' s. The
Council concluded that essential data could not be obtained unless
human volunteers were used, and the use of humans in medical research
was author) zed . By 1954, the Chemical Corps ~ formerly CUS ) had
established a framework within which to conduct human experimentation,
but i t lacked an adequate pool of volunteers. In 19 55, i ~ was decided
that the most practical source of volunteers would be enlisted men
stationed at Army installations in the vicinity of Edgewood Arsenal.
It was emphasized Chat voluntary consent of each human subject was
absolutely essential. It was also stated that, in all experiments
involving volunteer subjects, the subjects would be thoroughly
inf orbed of all procedures and of what might be expected as a result
of each tent. Furthermore, each volunteer would be free to determine
whether he desired to participate in a given experiment. In October
1959, approval wee granted for the conduct of research on voluneeera
to investigate defense against incapacitating CH agents.
The search for incapacitating agents intensified when the Kennedy
administration took office. The involvement with incapacitating
agents represented a departure from an earlier period, begun in 1946,
when inters st in highly toxic (acute) anticholinesterase chemicals
resulted from their development in Germany during World War Il. The
basic purpose of a military incapacitating agent is to produce
temporary ineffectiveness without permanent injury or death.
Incapacitating agents (anticholinergic chemicals) and highly toxic
(acute) anticholinesterase chemicals produce functional and structural
effects on the nervous system which cause rapid or delayed effects on
an individual's performance and behavior.
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PROCEDURES USED AT THE EDGEWOOD CHEMICAL TESTING PROGARM
A fairly extensive diacussion of the procedures used is provided
in the Inspector General's report, Use of Yolunteera in chemical Agent
Research, prepared by Colenel James R. Taylor and MaJor William H.
Johnson ant dated March 1976 (listed in Appendixes C,D).
RECRUITMENT OF VOLUNTEERS
Recruiting teams (initially a/ministrative officers, but later
often including military physicians from the Edgewood laboratory)
visited Army installations where a briefing, usually with a film and
handouts, was presented to a large number of enlisted men. Generally
10 to 20 percent of the audience expressed interest and these men were
asked to complete a personal history. which included medical and
psychologic items and the Minnesota Mule~phasic Personality Inventory
(MMPI). It was not unusual for 400-600 men to request aasignment in
the course of a tour of Seven to ten inatallations. Of these' no more
than 100 were selected and eventually assigned for a 1- to 2- month
period of temporary duty at Edgewoot Arsenal.
The incentivea for volunteering consisted of a small monetary
allowance (approximately gI.SO a-day for temporary duty), the
assignment of only light duties while at Etgewood, ant almost every
weekend free. Some volunteers were genuinely interested in the
scientific and experimental aspects; however, if curiosity or the
desire to "test one ~ s self " seemed too Stool, the applicant was
usually not accepted.
As a group, the volunteers were above average in physical and
mental quallflcations, with a mean IQ near 110, good behavior records,
and "normal" Maps with profiles generally within two standard
deviations of the population mean on all scales.
GUIDELINES FOLLOWED IN THE PROTECTION OF SUBJECTS
. . .
The Nuremberg and Helsinki guidelines were regarded by the
investigators ant their supervisors as appropriate constraints in
studies performed on volunteere, although this was not clearly
articulated in official memoranda until the seit-1960s. The provision
of accurate, luformatlve explanations of what was planned ant what
might be expecter was regarded as essential to the continuance of the
program. Written consents, witnessed by medical staff members, were
required from the outset ant became more elaborate with time. However,
minutes of hearings conducted by the U.S. Senate Subcommittee on Health
ant Subcommittee on Administrative Practice ant Procedure, September
10-12, 1975, atatet that the consent information wee inadequate by
current standards.
INVESTIGATORS
. ,
When BZ studies were begun in 1960, the need for a psychiatrist
with biologic training and interest was recognized, ant one was
assigned tO the program in January 1961. Physicians trained in
internal medicine, anesthesiology, cardiology, surgery, dermatology,
ophthalmology, neurology, and other specialties were assigned as the
program proceeded. Many were research-orientet and have since gained
excellent reputations in academic medicine at leading universities.
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SELECT ION OF 00 SES FOR HU.~*AN TESTS
. .
Subchreshold doses based on estimates from animal potency studies
were used in the first few subjects. For example, the earliest
exposures to BE, one of the antichollnergic test compounds, were at
doses between 0.1 and 0.5 ~g/kg, which was less than one-tenth the
incapacitating dose (ID) ultimately established at approximately 5.5.
g/kg. The intravenous route was preferred initially, but other routes
of administration were also used. Inhalation studies were sometimes
undertaken after a compound had been thoroughly studied by one of these
parenteral routes. Oral ant percutaneous studies were performed when
effectiveness via these routes was of interest.
As the program developed, it became customary to test agents at
dose Increments of 40 percent, once the approximate effects of the
lower doses were known. Placebos were used in some studies, but the
cost with respect to subject confinement time, staff workload, and
delay in achieving estimates of potency made this impractical except in
special cases (e.g., evaluation of antagonists). Instead, low and high
doses were assigned in a randomized manner by someone not involved in
an experiment. Placebo responses were minimal. Signs of drug effects
at all but the lowest doses were significant and made the value of
placebo or no treatment inconsequential.
RANGE 0E DOSES
_ ,.
Rarely did the intramuscular or intravenous doses exceed 1.5 times
the incapacitating dose. Inhalation doses were higher, but potencies
were lower by this route (usually about 60 percent of that by the
intravenous or intramuscular route). Compared with doses described in
the scientific literature on atropine coma therapy (18-23) or
scopolamine therapy (19), the BZ doses to which volunteers were exposed
appear modest. As much as 20 times the IDso of atropine and 30-40
times the IDso of scopolamine have been administered in the past by
clinicians--often to older and less robust patients. Many patients
received multiple exposures of this magnitude over a period of days or
weeks. these therapeutic procedures, reported several decades ago in
refereed journals, actually stressed and advocated the benefits of such
treatment, despite occasional deaths (most of which appear to have been
caused by hyperthermia).
SAFETY MARGIN
The safety margin of a drug is defined as the ratio of the lethal
dose (LD) to the effective dose (ED). Sometimes, ratio of the LDso
to ED,o is used, although a more conservative approach favors the use
of the ratio of LD1 to EDgg (standard margin of safety). In the
case of incapacltatlug agents, much reliance is placed on extrapolation
from animal experimentation, and estimation of the LD1 is generally
unreliable.
Many other extrapolation techniques have been used in manipulation
of animal lethality data in an effort to generate a reasonable human
estimate. By taking a conservative approach with data on deaths at low
doses, one can derive estimates for man that are modest and in keeping
with clinical judgement. Such methods depend on procedures developed
and applied in toxicology.
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Representative terms from entire chapter:
highly toxic
