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DISCUSSION
In a well-controlled study, subjects are randomly selected for
assignment to various test or control groups. In the Edgewood tests,
members of short-term control Grouts were later assigned to test
groups and thus were lost as long-term controls. There were two main
reasons for this procedure: the Edgewood studies were conducted to
determine immediate behavioral effects that might be important in a
military situation, and the later exposure of controls to experimental
chemicals enabled the experimenter to make multiple use of each volun-
teer. A need for evaluating long-term health effects was not fore-
seen.
_
One might therefore say that this arrangement precludes a proper
assessment of long-term effects of the Edgewood tests. Strictly
speaking, that is true. However, the present evaluation can support
many useful inferences. For example, the lack of excess malignancies
among a test population that has received a topical carcinogen would
be a significant finding. The lack of excess malignancies and other
debilitating diseases in the entire test population would be impor-
tant. Because of shortcomings in test design, this evaluation is not
likely or even intended to reveal minor health deficiencies that might
have resulted from the test experience. Only major problems that
occur in a large number of men are likely to be uncovered.
. ~ .
The subjects were not assigned to treatments in a formal ran-
_ _ _ ~
domized manner. To be eligible for exposure to the test chemicals,
the volunteers had to pass additional physical and mental tests that
would have selected the most fit men for chemical testing and the less
fit men for testing of equipment and relatively innocuous materials.
Nonetheless, two comparison groups could be constructed. The first
consisted of the NCT (no-chemical-test) men, and the second, of all
men tested with chemicals other than those of interest (the OCT, or
other-chemical-test, group).
Using the NCT men as a comparison group would tend to under-
estimate chemical effects, because the NCT men, having been less fit
at the outset, might be expected to have more illnesses than the men
tested with chemicals. Using the OCT men as a comparison group -
resolves this problem, but suffers from the possibility that, if more
than one chemical led to deleterious effects, we would be comparing
one potentially affected group with another potentially affected
group. However, because the a priori expectation of the kinds of
damage that might be anticipated from each class of chemical would
most likely be different, it is unlikely that this kind of loss of
information would occur.
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Suggestions to use additional comparison groups from other
populations as surrogate controls were quickly turned aside because
information on the composition of test groups needed to select com-
parable control groups (race, religion, socioeconomic status) was
available. Furthermore, the effects of the volunteers' desire to
participate in the Army studies could not be controlled for.
The Committee has already assessed the possibility of long-term
adverse health effects of short-term exposure to the chemical agents
tested at Edgewood in two reports (see Appendix A for their executive
summaries). The conclusions in those reports were based on a review
of literature reporting acute and chronic effects, on the dosages
administered to soldiers, and on immediate effects and acute findings
reported by clinician observers. The evaluations yielded almost no
significant positive findings.
The work reported here involved an evaluation, based on a ques-
tionnaire, of the current health status of subjects 10-30 years after
testing. The questionnaire asked 15 questions, the most important
specifically targeted at learning whether test subjects had experi-
enced higher prevalences of cancer, mental disorders, necrologic
disorders, or reproductive effects than members of comparison groups.
The results do not indicate that important effects were seen. Answers
to questions 4, 9, 11, 13, and 15 a and b were directly pertinent to
the current health status of the subjects. The health status of test
subjects does not appear to have been significantly altered, according
to responses to the questionnaire.
There are several reasons why this study might have low power to
detect some long-term effects (see Appendix C). Mail surveys always
miss some information and include potential bias; both flaws can
result from failure to locate some intended recipients or from failure
of recipients to respond. Some questions require the recall of health
status or job experience over several years; these kinds of questions
often lead to misreporting. Subtle effects on health usually can be
assessed only through physical examination and testing. The question-
naire used in this study was largely Invalidated, so its sensitivity
and specificity for particular health problems and life quality are
unknown. Some attempts at validation were made, however. A subset of
volunteers who reported having had three to five children were inter-
viewed by telephone to validate some questions for larger families.
But the questions regarding substance abuse and health effects were
not validated. Finally, the study had no true control groups. The
baseline groups used in this report for comparison, the NCT group and
possibly the OCT group, might be expected to have poorer health than a
true control group; if that were the case, the probability of detect-
ing some health effects would be decreased. Hence, the objective of
this study was to detect major, long-term health effects of the expo-
sures to chemicals.
Additional information on admissions to Army and VA hospitals was
available. The data on admissions during the whole period after
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exposure were evaluated. The data on Army hospital admissions would
give some indication of severe, short-term effects, and the data on VA
hospital admissions would provide information on possible severe,
long-term effects in men who continued to use the VA system. However,
the probability of detecting long-term effects was decreased by the
low rate of use of the VA system among men discharged from the service.
Again, therefore, the comparisons would detect only major health effects
of exposure.
Because so many comparisons (more than 756) were included in this
study, it is almost certain that at least one chance difference would
be declared "significant" at the O.O1 level. To rule out such chance
occurrences, attempts were made to develop corroborating evidence,
such as evidence of a dose-response relationship or biologic plausi-
bility. In addition, comparisons were made after controlling or stan-
dardizing for known confounding factors.
Another statistical consideration that is relevant to the inter-
pretation of the findings of this study is that the sampling errors
are large for the outcomes, because of the nature of the response
rates and the nature of the data collected. "Sampling error" refers
to the notion that accurate estimation of the range of outcomes
requires extremely large numbers of responses. Because many of the
groups in this study are small, the ability to detect a true effect
(i.e., power) is low. Tables 3 and 4 demonstrate the need for very
large populations.
ANTICHOLINESTERASE CHEMICALS
The primary health concern regarding subjects tested with
anticholinesterases\was that long-term health effects might occur in
the form of subtle changes in EEG, sleep pattern, and behavior--such
as increased irritability, inability to concentrate and depression--
that could persist for more than a year (Appendix A). However, if
these changes occurred and persisted, they might be difficult to
detect. They might have been identified by the subjects as general
health problems or, in severe instances, identified by physicians as
mental disorders. In fact, answers from subjects who received
anticholinesterases compared favorably with answers from NOT
subjects.
Posttest admissions to Army or VA hospitals for mental disorders
did not appear to be significantly increased (Table 18), either during
the years immediately after testing or later. The responses to ques-
tions about current health status by subjects exposed to anticholines-
terases suggest that, as a group, these subjects were no different
from the NCT comparison group or from the remainder of the test sub-
Jects. If subtle changes occurred, they were not revealed by the
subjects' answers about their current health status.
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There was a borderline significant increase in malignant neoplasms
among soldiers who were admitted to VA hospitals (but not Army
hospitals) and were exposed to anticholinesterases, compared with
those who received no chemical testing. The neoplasms occurred at
various sites, and no consistent pattern was seen. Current animal
studies show that this pharmacologic class is unlikely to have induced
malignancies among the Edgewood subjects; that conclusion is based on
a review of NCI-sponsored lifetime studies of animal bioassay for car-
cinogenesis at maximal tolerated doses of ten anticholinesterase
organophosphate pesticides. \6 - 25
ANTICHOLINERGIC CHEMICALS
According to the published literature, the primary health concern
for subjects tested with anticholinergics might be short-term cardio-
vascular effects. No clear indication of such effects over a long
period was found. No evidence of differences between these subjects
and others was found, with respect to current health status or first
admission to a military hospital. All the chemical-test groups showed
a trend toward increased rates of admission to Army hospitals per
person-year for the first 5 years after testing (Table 12~. However,
the rate was greatest among the volunteers exposed to anticholiner-
gics. After the first 5 years, there was no evidence of a higher rate
among these volunteers than among the others.
An apparent difference in fertility was noted between these
subjects and the NCT subjects or OCT subjects (Tables 26 and 27~.
However, the exposures to anticholinergics occurred relatively late in
the series of tests (Table 2~. Current age and marital status were
taken into account in the estimation of expected values in Tables 26
and 27, but other cohort and social differences might account for the
smaller family sizes. There has been a trend toward lower birth rates
and greater ages at conception during the last decade.15 The men
exposed to the anticholinergics have the lowest average current age in
this population (Table 24), and their lower fertility might reflect
these trends in our society. When the appropriate adjustments were
performed to take cohort differences into account, the apparent dif-
ference between observed and expected fertility rates disappeared
(Table 28~. It was therefore concluded that there was no evidence of
an effect of the anticholinergics on fertility among the exposed
men.
There remained, however, a reduction in numbers of male children
among the total number of children born after exposure. This re-
duction was of borderline significance (p = 0.04~. It was not seen in
comparison of males and females among first children born after expo-
sure. Statistics describing proportions of children by sex, such as
percentages of male children or sex ratios, are made unreliable by
small sample sizes. \2 This small size might have contributed to
the finding. No published reports were found of human or animal
exposures to anticholinergic chemicals that affected the sex of
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offspring. Isolated reports of exposures and later distortions of the
proportion of male children have been published in connection with
uranium,8 2 7 dibromochloropropane (DBCP), 2 ~ ~ anesthetic
gases, 7 and air pollution containing metals.4 5 The decrease
in the proportion of male children in the present study was judged to
be a random finding and was to be expected, because so many
comparisons were evaluated.
CHOLINESTERASE REACTIVATORS
A review of the literature disclosed no long-term effects of
cholinesterase deactivators (Appendix A). They are eliminated rapidly
and produce a variety of short-term, reversible acute effects. These
short-term effects might explain in part the slightly increased
(nonsignificant) rates of admission to Army hospitals during the first
5 years after testing (Table 12~. However, there was no evidence of a
difference in current health status between these subjects and the
other subjects. Nor was there evidence of differences in the current
social functioning of these subjects, e.g., in employment, marital
status, and family life.
PSYCHOCHEMICALS
A variety of psychochemicals were tested, including Sernyl
(phencyclidine) and dibenzopyrans (dimethylheptylpyran and related
compounds). A review of the literature found only sparse evidence of
the long-term health effects of these chemicals (Appendix A). The
target organs of these substances are the brain and cardiovascular
system. However, target mental or cardiovascular effects did not
persist beyond a week of exposure to the drugs. It was concluded
that, at the dosages used, detectable long-term or delayed effects
were unlikely. The data supplied by the soldiers in response to the
questionnaire and the patterns of admissions of these soldiers to
military hospitals did not contradict these conclusions with regard to
specific health effects.
Of particular interest were the 86 soldiers who were exposed to
some form of Sernyl, a purified form of phencyclidine. (The impure
street form is reported to have undesirable properties; see Vol. 2 of
this series.) Of these soldiers, six were known to have died since
testing. A total of 48 soldiers returned the questionnaire. The
proportion of volunteers ever hospitalized was lowest among those
exposed to Sernyl (Table 14~. The primary health concern for these
subjects was mental disorder. Because few subjects were tested with
this compound, the expected number of such admissions was low; in
fact, the observed first admissions to Army and VA hospitals for
mental disorders were not significantly higher than expected values
(Table 18~. Similarly, the expected numbers of admissions for malig-
nant neoplasms and diseases of the nervous system were low among this
group; no such admissions were observed--an indication that there was
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no apparent increase in these health effects among these volunteers.
In general, most reported few or no problems and little or no need for
health care.
The primary short-term health effects of the dibenzopyrans were
moderate to marked and included prolonged orthostatic hypotension.
However, there was no indication from the responses on the question-
naire that the current health of exposed subjects was affected.
Of 254 soldiers who were exposed to cannabinoids, 161 returned the
questionnaire. This group, as a whole, had the lowest rate of admis-
sions to Army or VA hospitals (Table 15~. They did not appear to
differ from the other groups in any way assessed by the questionnaire.
IRRITANTS AND VESICANTS
Mustard gas has been shown experimentally to be mutagenic and
carcinogenic. Other possible long-term effects, specifically
blindness and skin tumors, were expected to be related to local
toxicity (Appendix A). However, the soldiers who participated in the
Edgewood studies were exposed to mustard gas only at low doses and
were wearing gas masks and impregnated clothing. Thirty-eight
volunteers had skin damage and erythema after exposure to mustard
gas. All these subjects returned the questionnaires; no tumors were
associated with skin sites affected as a result of the exposure.
In general, there appeared to be no significant differences in
current health status, functioning, or previous hospital admissions
between subjects exposed to any of the irritants or vesicants and the
rest of the subjects.
LSD DERIVATIVES
Of 571 soldiers exposed to LSD, 317 returned completed question-
naires. This group did not differ from the NOT or OCT subjects in
total hospital admissions, admissions for malignant neoplasms or
mental disorders, or current health. The soldiers exposed to LSD did,
however, have an increased number of first admissions for nervous
system and sense organ disorders. There was prestudy concern about a
possible increase in suicide rate or epilepsy rate that might result
from exposure to LSD. There was no evidence of such effects in the
data collected. But the soldiers did report more use of controlled
substances. In particular, they reported rates of LSD use higher than
expected rates, according to age-specific reported use either by the
NOT subjects or by the OCT subjects (Table 30~. It is thought that
there is underreporting of use of controlled substances, even in
self-reporting questionnaires. However, before the testing period,
the soldiers were informed as to the substances they might be exposed
to; perhaps those who knew that they had been exposed to LSD were more
willing to report later use of LSD.
l
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Representative terms from entire chapter:
health status
