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THE MEDICAL FOLLOW-UP STUDY
Men who are selected to serve in the Army are, in general, in
better physical and mental health than their peers. Because their
later health would also be expected to be better than average, it is
inappropriate to compare their health and life experiences with those
of the general U.S. male population. One option for this report would
be a purely descriptive presentation of the findings derived from hos-
pital records and a questionnaire. But the men exposed to the various
chemicals differed in several ways, such as in age and date of testing,
so a simple presentation of outcomes could be misleading. To permit
useful conclusions to be drawn about the experience of men in the
different chemical-group tests, comparative statistics were developed
on the basis of observed and expected life experiences of comparison
groups.
ANALYTIC PROBLEMS
_
The testing of chemical agents in human subjects at Edgewood began
in 1955 and continued for some 20 years. The main objective of these
tests was to determine effects of various chemical agents on the
ability of test subjects to function effectively in a military situa-
tion. It was not anticipated that any late effects would occur. In
fact, two characteristics of the testing program make the demonstration
of late effects extremely difficult:
· Selection Bias: The volunteers received careful physical and
mental screening examinations for contraindications to the planned
tests. The health of a volunteer helped to determine the type of test
in which he participated. The more healthy men were exposed to the
active chemicals, and the less healthy were used as controls and in
some cases tested equipment without being exposed to chemicals. Such
selection bias means that the men not exposed to chemicals would be
expected to have more illness; therefore, the likelihood of discovering
effects in them (whether early or late) due to the treatments would be
smaller.
o Multiplicitv of Chemical Exposures: For the sake of efficiency,
many volunteers were used in two or more tests. If a test substance
produced detectable long-term adverse effects in a man who was also ex-
posed to another substance, it could be difficult to ascribe the effect
to the first substance alone, especially if many men were tested with
both substances.
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The Committee had many discussions on how best to evaluate the
effects of the test chemicals, given the lack of suitable control
populations and the multiple exposures of some of the men. It was
decided that two comparison groups would be used. The first group
included the subjects who received no test chemicals--the
"no-chemical-test" (NCT) group. Although these men met the
requirements for military service, they did not meet the rigorous
standards demanded for exposure to chemicals. A second comparison
group consisted of subjects who were tested with chemicals other than
those being evaluated in a particular statistical comparison--the
"other-chemical-test" (OCT) group. Suggestions to use additional
comparison groups from other populations as surrogate controls were
quickly turned aside, because the factors involved in selecting sub-
jects for the Edgewood tests were not well understood and would
involve variables that were not available for analysis, such as race,
religion, socioeconomic status and characteristics related to subjects'
desire to volunteer for the tests.
Several other problems that make simple comparisons between exposed
and unexposed groups difficult are discussed below.
DIFFERENCES IN AGE AT FOLLOW-UP
Posttest experiences of groups of volunteers cannot be compared
solely by comparing numbers of events experienced; one must also take
age differences among the test groups into account. Volunteers in the
early test years were about the same age at the time of testing as men
tested later (Table 1~. By 1984, the participants in the early tests
had a much longer posttest period than the most recent participants;
men tested more recently are younger now than-men tested earlier.
Thus, those tested earlier are more likely to have had experiences that
are more frequent with advancing age, even in the absence of exposure.
The testing program spanned a period of some 20 years, and the
chemical agents tested changed with time (Table 2~. For example, the
testing of LSD derivatives was concentrated in the early years; more
than half the doses had been administered by the end of 1959. At the
other end of the testing period were tests of FDA-approved drugs,
innocuous chemicals, and control substances. One can therefore expect
health problems more common to the later years of life to have occurred
in a much higher proportion of men in the LSD tests than of men who
received approved drugs, innocuous chemicals, or control substances,
even if LSD and its derivatives do not promote such health problems.
Because of the age differences, comparisons between groups were
adjusted for current age.
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MAGNITUDE OF DETECTABLE EFFECTS OF CHEMICAL EXPOSURES
How small a real effect can one reasonably expect to detect? The
answer to this question depends on several factors:
· The number of subjects exposed to each chemical of interest.
This number is fixed for each chemical tested.
· The number of subjects available for comparison purposes.
· The proportion of members of each chemical-test group and
comparison groups on whom follow-up information is obtained.
· The level of significance at which the null hypothesis of "no
effect" will be rejected. The 5% level is proposed for screening
purposes. For this kind of examination, a one-sided test of signifi-
cance, directed solely at identifying adverse exposure effects, is
appropriate. (In making such a test of significance, it is assumed
that the chemical-test participants have not benefited from their
exposure.)
· The "power" of a study is the probability that a true effect of
a given size, or larger, will be detected in that study and labeled
"statistically significant." "Power" depends on how big the true
difference is (or is expected to be) and how many persons there are in
the exposed group and the comparison group. The larger the true
difference, the more likely it is to be detected, hence the greater
the power. Similarly, the larger the number of persons observed, the
more likely that a given difference will be found to be statistically
significant. In general, bigger true difference and larger study both
mean greater power.
Power calculations are shown in Tables 3 and 4 for comparison with
two base line groups of participants: the NCT group, consisting of
subjects who did not participate in any of the chemical tests (those
exposed only to FDA-approved drugs or placebo substances and those who
were exposed only to equipment); and the OCT group, consisting of
subjects who were not exposed to a chemical of interest, but were
exposed to other test chemicals. Like use of the NCT group, use of
the ACT group can decrease the probability of detecting effects of
exposure to specific chemicals. In both comparison groups, health
status, including fertility, might be lower than in a true control
population. That could be the case in the NCT group because the
selection process included volunteers who were less healthy. It could
be the case in the OCT group if exposure to chemicals other than those
of interest in a particular test had independent health effects on
those volunteers.
Table 3 summarizes power calculations based on 1,058 men in the
NCT group who responded to the questionnaire (discussed later), and
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Table 4 summarizes power calculations based on a typical number of
respondents in the OCT group.
As an example of how to use these tables, assume that 1,000
exposed respondents are being compared with the 1,058 NOT respondents
(Table 3~. Assume further that the background, or base line, risk
among the comparison subjects is 10% (0.100) and that we wish to
discover the true effect of exposure that results in an additional 1%
(0.010) above the background risk (the resulting risk in exposed
subjects is therefore 11%~. For 1,000 exposed (the NOT comparison
group), the intersection of the column representing the 10% base line
risk and the row representing a 1% risk increase due to exposure con-
tains the value 0.183, which signifies that there is an 18.3% chance
of reporting a significant increase among exposed respondents.
Table 4 is computed in the same manner as Table 3; however, the
size of the OCT comparison group is not constant, but increases as the
exposed group decreases, and by the same amount.
Tables 3 and 4 show that the probability of observing a signifi-
cant difference decreases with reduced numbers of exposed respondents
and with an increased base line risk. As might be expected, the
larger the true increase in risk, the larger the probability that the
increase will be detected and labeled statistically significant.
MULTIPLE COMPARISONS
Tests of statistical significance lead to statements concerning
the probability that some observed difference could have been due to
chance alone. Probabilities are computed as though only one signifi-
cance test, or comparison, had been conducted. However, one is seldom
faced with a single-comparison situation. As the number of compari-
sons increases, so does the probability that chance alone will lead to
finding "significant" differences.
In this report, the five chemical classes were analyzed separately
as seven groups; the psychochemical class was analyzed separately for
those exposed to LSD, Sernyl, and cannabinoids. Furthermore, the data
on the men who were exposed to chemicals of only one class were
analyzed separately from the data on those exposed to chemicals of
that class and later to chemicals of another class. Therefore, in the
following analyses, 14 chemical-test groups (seven with single
chemical-class exposures and seven with multiple chemical-class
exposures) are compared with two baseline groups on at least 27 end
points (outcomes), for a minimum of 756 comparisons (14 x 2 x 27 =
756~. In the absence of any real adverse chemical-test effect, it is
to be expected that several differences will be declared "significant"
at the O.01 level, and possibly even one at the O.001 level, assuming
that the end points are independent. Collateral data must therefore
be brought to bear before even findings that are statistically highly
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significant (i.e., ~ < 0.001) can be said to demonstrate that a true
effect exists. Some of these collateral data are based on determina-
tion of whether a dose-response relationship exists, whether the
association is biologically reasonable, and whether the effect can be
explained by peculiarities in or differences between the comparison
populations.
METHODS OF STUDY
This report is based on a follow-up of the 6,720 men who partici-
pated in experiments conducted by the Army at the Aberdeen Proving
Ground, Edgewood, Maryland, in 1955-1975. Follow-up information was
obtained from four sources:
· A tape file, provided by the Army, of admissions of partici-
pants to Army hospitals during calendar years 1958-1983. This file
made possible the examination of the hospital experiences of volun-
teers between the time of test participation and separation from the
service.
· A tape file, provided by the Veterans' Administration (Vi), of
admissions of participants to VA hospitals from 1963 to 1981. This
file was used to examine the use of VA hospital facilities after sepa-
ration from the service.
· Responses to a health questionnaire mailed to men who were
still living in 1984.
· Information obtained from men who initially did not respond to
the questionnaire, but provided interviews when asked to do so in
follow-up telephone calls.
OBTAINING ADDRESSES
The mail survey of health status was undertaken to obtain infor-
mation related to health, social adjustment, and lifestyle during the
posttest period. The survey was directed at 6,395 men for whom no
claim for a burial allowance had been received by VA (Table 5~.
Several sources of address information were used, including the VA
compensation and pension files, records at the St. Louis Military
Personnel Records Center, the National Institute for Occupational
Safety and Health (which can obtain current address information from
the Internal Revenue Service on persons with occupational exposure to
possible health risks), and a commercial tracing agency. Addresses of
5,620 volunteers, or 88% of those not known to be dead, were ob-
tained. Of these addresses, 624 (11%) were reported by the U.S.
Postal Service to be incorrect, leaving 4,996 persons who are believed
to have received the questionnaire; of these, 4,085 responded. The
information on the total group of volunteers participating in the
Edgewood studies follows:
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Total participants
Died before survey
Could not be located
Located, but failed to respond
Located and responded
No. TO
6,720 100.0
325 4.8
1,399 20.8
911 13.6
4,085 60.8
Table 5 shows the follow-up information on the persons in each
chemical-test group. Presumably correct addresses were obtained for
4,996 men, or 78% of all living volunteers; this varied from 70% of
men used in tests of LSD to 84% of those used in tests of the
anticholinergics and cholinesterase Deactivators. There was sub-
stantial uniformity from test group to test group in the proportion of
persons responding to the questionnaire, once the participants were
located. The response rate, 82% of all participants, was slightly
higher among the participants in the chemical tests (81-84%) than
among the NCT group (78%~.
The likelihood of obtaining an address for a volunteer was
greatest for those who participated in the most recent tests and
decreased as the time since test participation increased (Table 6~.
Valid current addresses were obtained for 83% of living men involved
in tests conducted in 1970 or later, compared with 81% of men who
participated in 1960-1964. For the men involved during the earliest
years, before the replacement of the Army Service Number with the
Social Security Number, the address yield fell to 57%. Knowledge of a
person's Social Security Number is very important for successful
tracing. The Internal Revenue Service failed to locate in its files
only 171 (3%) of the 5,680 men whose Social Security Numbers were sent
for tracing (Table 7~. The earliest test groups, Sernyl and LSD, had
the highest proportions of "no record of SSN" responses; however, IRS
still found in its files more than 95XO of the persons whose Social
Security Numbers were known. The proportionate yield of good addresses
of the living among the various chemical-test groups varied from 70% for
LSD-tested subjects (early tests) to 84% of men exposed to anticholin-
ergic chemicals (recent tests), as shown in Table 5. Addresses were
obtained for 7670 of living subjects in the several test categories
that constitute the NCT comparison group.
CONTACTING BY MAIL
Up to three mailings, 6 weeks apart, were made to a man at a given
address. The first mailing contained the questionnaire and an explan-
atory letter (Appendix E, Exhibit A). The second and third mailings
included supplemental letters (Appendix E, Exhibits B and C) emphasi-
zing the importance of a reply. An addressed, postage-paid envelope
was enclosed with each mailing. The third mailing to a given address
was sent by certified mail with return receipt requested as proof of
delivery, and the enclosed letter invited the man to telephone the
study director, reversing the charges, if he wished to inquire further
concerning the survey. A mailgram (Appendix E, Exhibit D) was sent at
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the time of the third mailing, advising the subject that the third
request was on its way, in the hope of convincing him that the letter
should not be treated as discardable mail. The mailing sequence ended
on receipt of a completed questionnaire or a refusal. If the Postal
Service returned a letter marked "address incorrect," another mailing
sequence, to the next most likely address on file, was started. The
priority for the use of addresses was (1) that obtained from the IRS,
(2) that obtained from the VA compensation and pension file, (3) that
obtained from service records, and (4) commercial tracing.
The cutoff date for receipt of questionnaires to be included in
the analysis was February 1, 1985. Questionnaires were received from
4,085 men, 64% of survivors (Table 8~. The response rate for men who
were correctly located was 82~; 2Yo of located men declared their
unwillingness to participate, and 16% of those located failed to
respond. Those who failed to respond were telephoned, and when
necessary visited, to determine the reasons for their not responding.*
A total of 657 (74%) of the 891 nonrespondents were interviewed. The
results of the interviews are discussed later.
COMPARISON GROUPS
The chemical tests were conducted by the Army for the sole purpose
of studying immediate effects. The tests in which a volunteer parti-
cipated were therefore determined by the tests being conducted at a
given time. Volunteers participated in an average of 3.3 tests. Some
were tested more than once with the same material, and some were
tested with several materials. Only 43% of respondents in any
chemical-test group were exposed to only a single class of chemicals.
That is, most of the men were exposed to multiple chemicals from
different chemical groups. Thus, comparisons of importance to the
search for late effects
are those between men who participated in tests involving a single
class of chemicals and the 1,058 volunteers in the NOT comparison
group. The NCT group includes:
· 907 respondents who were not exposed to drugs (used mostly in
tests of equipment).
· 93 respondents who were exposed to FDA-approved drugs (58 dif-
ferent).
· 17 respondents who were exposed to relatively innocuous sub-
stances (alcohol, caffeine, etc.~.
· 39 respondents who were exposed to control substances (water,
saline, bicarbonate of soda).
· 2 respondents who were exposed to two of the above.
* This survey of nonrespondents was conducted by the Research
Triangle Institute, Research Triangle Park, N.C. 27709.
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Evidence that the NOT group was composed of the less healthy
volunteers dictated that other comparison groups be defined--groups
less likely to have a built-in health bias. These groups, the OCT
groups, consisted of all volunteers who participated in chemical tests
other than those under immediate evaluation. Members of the OCT
groups had received one or more of the chemicals. By definition, the
OCT groups were likely to yield underestimates of possible effects of
exposure to specific chemicals, because its members were exposed to
other chemicals. Although the possibility of adverse effects due to
other exposures must be considered, no such effects were noted when
the OCT groups were compared.
Table 9 is a sample of the computer tables used in the preliminary
screening of the data. Multiple test-group comparisons (described
below) were considered in deciding whether a given category of chem-
ical appeared to have had an adverse effect on exposed volunteers.
The categories shown in Table 9 are those used in the study of men
exposed to anticholinesterase chemicals. Similar groups were defined
for the other categories of chemicals. The column definitions are as
follows:
· A ALN (Alone): Persons who participated in tests of the category
of chemical named in the table heading and no others (in this example,
the anticholinesterases)O
· A AND: Persons who participated in tests of the category named
and in tests of at least one other category.
· TTL A: The sum of A ALN and A AND (i.e., all persons exposed to
the category named).
· CNTRL: The no-chemical-test (NCT) comparison group defined
earlier.
· OTHER: All subjects in chemical tests except those involving
the category named, i.e., the other-chemical-test (OCT) comparison
group.
· NOT A: All subjects (including the NOT group) minus volunteers
who participated in tests involving the named category (i.e., the sum
of CNTRL and OTHER).
· TOTAL: All respondents (i.e., the sum of TTL A and NOT A).
Each computer table consists of several panels representing cur-
rent age categories in 1984 (the survey year) and a "total" panel
representing the sum of all age groups. The responses to the various
questions of the questionnaire are defined by the labels in the left
margin. Table 9 deals with whether the volunteers requested informa-
tion about the results of the study. The percentages are based on
column totals for a given panel.
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Whether a class of chemicals might have had an adverse effect on
exposed subjects was based first on inspection of the percentages of
subjects with similar responses in each of the first five columns
named above. This inspection was performed separately for each age
group. If it appeared that the responses of those who were exposed to
the chemical group of interest alone or in combination differed from
the responses of the NCT group (control) or the OCT comparison group
(other), the pooled data were compared with a more rigorous analysis
that included adjustment for age differences and testing for statis-
tical significance. Age was adjusted for by calculating the expected
number of the given response for each age group. Expected numbers
were based on the proportion of NCT subjects who responded in similar
fashion. This proportion was then multiplied by the number of sub-
jects in the exposed group to find the expected number of the given
response for that age group. The expected numbers were then summed
for all age groups to get a total expected number, which was compared
with the total observed number of responses. A similar adjustment was
made with the OCT comparison group.
For assessment of fertility and other relevant variables, current
marital status was also adjusted for. In these cases, the data were
adjusted for age and marital status concurrently. That is, the popu-
lation was divided into age groups, which in turn were divided into
marital-status groups for purposes of determining expected values.
Significance testing was performed with observed data for both the
exposed and comparison groups. Each group was subdivided into age-
specific groups, and the Mantel-Haenszel chi-square test procedure was
used. 6 This procedure tests for differences between exposed and
comparison groups by combining tests performed for each age group.
For this purpose, the responses were reclassified in some cases into
only two categories, i.e., dichotomized. For example, the total num-
ber of children of each man was reclassified into no children and at
least one child.
In some instances, particularly with respect to occurrence of
specific disorders, the total numbers of events were very small. For
these comparisons, a Fisher exact test was used to generate the prob-
ability of observing the number of events actually reported by the
respondents, given the numbers observed in each of the two comparison
groups. For example, assume that 10 of the respondents reported a
particular disability, including 4 exposed subjects and 6 who were not
exposed. The exact test provides the probability that the 10 reported
events would include 4 or more exposed subjects (an excess as great as
or greater than that observed).
The response of interest in Table 9 is whether the volunteers
asked to be informed about the results of the study. It is apparent
that more men who were involved in tests of anticholinesterases asked
to be informed of the results of the studies than NCT subjects. Of
all the groups studied, the NCT group showed the least interest in the
results.
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RESULTS
A total of 27 outcome variables (Table 10) related to the health,
social adjustment, and reproductive experiences of the Edgewood
participants were examined for each of the seven classes of chemicals
tested. That led to 189 possible decisions concerning the existence
of a chemical effect--27 decisions for each of the seven chemical
groups. Only a few of these decisions were judged to have possibly a
significant association between exposure and the outcome variable.
The evidence leading to those judgments is presented in this chapter.
In addition, detailed comparisons were made where there was some
biologic reason to anticipate a specific response, even though
preliminary examination of the data did not suggest an effect.
ADMISSIONS TO HOSPITALS
Admissions to Army Hospitals
The Army provided a tape file of admissions of volunteers to Army
hospitals in calendar years 1958-1983. This file does not cover the
early test years, but the loss of information is limited to the early
posttest years and to men who participated during the first 3 years of
Army testing. The numbers of volunteers under observation during each
posttest year were counted for each of the chemical groups of volun-
teers; separation from the service terminated observation. 3 Follow-
up of volunteers began at the time of testing, or in 1958 for those
tested earlier, and numbers of person-years of observation were summed
over successive posttest intervals. Rates of hospital admissions were
estimated per l,OOO person-years of observation. Percentages of men
hospitalized were based on the mean numbers of men being followed.
Army hospital admission rates after test participation are shown
separately for men exposed to a single class of chemicals (Table 11)
and for men exposed to more than one class of chemicals at Edgewood
(Table 12~; the two groups are mutually exclusive. These data, and
those on the VA hospital admissions that follow, are reported for all
volunteers, not only those who returned the questionnaire. For each
class of volunteers, the need for Army hospital admission was greatest
during the first 5 years of follow-up and decreased over succeeding
intervals. However, neither table shows that the men in any of the
chemical-exposure groups appear to have had more hospital care than
did the NOT group.
Hospital admission rates were more sensitive to the frequency of
hospital care than were the percentages of men hospitalized. Numbers
of men admitted to Army hospitals were compared for men exposed to
only one chemical group (Table 13) and for men exposed to chemicals in
more than one group, including the group of interest (Table 14~. The
percentages of hospitalized men in each chemical-test group seldom
exceeded that of NOT subjects more than trivially. No pattered of
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excess hospital use was shown for any chemical group when the one-
class and multiple-class exposure groups were compared.
The medical conditions responsible for admissions were examined in
broad categories based on the Eighth Revision International Classifi-
cation of Diseases (1967-1969), 26 referred to as ICD 8. Among the
more frequently encountered diagnostic categories for all volunteers
are respiratory disease (359 admissions, 16.1% of total), digestive
disorders (260, 11.7%), infectious and parasitic diseases (202, 9.1%),
musculoskeletal and connective tissue problems (178, 8.0%), and
symptoms, ICD 8, codes 780-796 (162, 7.3YO). These five categories
account for over half the 2,231 recorded Army hospital admissions of
these volunteers since testing. Furthermore, these medical conditions
are common in Army life. Conditions that might have resulted from the
various chemical exposures resulted in few admissions, with rates
similar to those for the NCT subjects. The medical conditions that
might have resulted from exposures include malignant neoplasms; benign
and unspecified neoplasms; -endocrine, nutritional, and metabolic
diseases; diseases of the blood and blood-forming organs; mental
disorders; diseases of the nervous system and sense organs; and
diseases of the circulatory system. Several of these groups of
disorders are examined separately below.
Admissions to VA Hospitals
Data on admissions to VA hospitals have been obtained from the VA
for the years 1963-1981. Because only 15% of veterans' hospital-care
needs are provided by VA,1 the rates of postseparation admission
of men exposed to a single chemical group (Table 15) and to more than
one group (Table 16) grossly underestimate hospital use by these par-
ticipants. However, there is no a priori reason to suspect that those
exposed to one chemical group are more likely to depend on VA for their
hospital needs than another group. Thus, the rates shown for the sev-
eral chemical groups are assumed to be comparable.
Admission rates for various postseparation intervals show consid-
erable variation between chemical groups. Although there are excep-
tions, the NCT subjects generally experienced the highest admission
rates. This relationship is seen clearly when the postseparation
period is examined as one unit. The procedures used by the Army to
select NCT subjects apparently had the effect of identifying, on the
average, men more likely to use or require hospital care after dis-
charge.
In Table 16, the exposure group with the highest admission rate is
the Sernyl group, but comparison with Table 15 shows that 38 of the 39
admissions were of men exposed to other chemicals, as well as Sernyl.
The admission rate among those exposed to several chemicals including
Sernyl was 57.0 per 1,000 person-years. However, because the total
number of men, and consequently of person-years of observation, is so
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small for this group, the increase could easily be due to chance,
rather than to exposure to Sernyl. Most of the increase occurred 5-14
years after exposure to the chemicals.
Admissions for Selected Disorders
Hospital admission rates constitute a good index of the need of
the test participants for hospital care, but they can be distorted by
the repeated admission of a few persons for a given condition. This
problem can be eliminated by examining the numbers of men admitted to
hospitals for selected conditions. Three categories of illness of
particular interest for possible relationship with the chemical agents
tested are malignant neoplasms (ICD-8, codes 140-239), mental dis-
orders (ICD-8, codes 290-315), and diseases of the nervous system and
sense organs (ICD-8, codes 320-389~. The numbers of men admitted to
Army hospitals and to VA hospitals for these conditions for each
chemical-test group are shown in Tables 17, 18, and 19. Two counts of
"expected" admissions are also shown: those based on the experience of
participants exposed to chemicals other than the group being considered
for a specific comparison, the OCT group; and those based on the NCT
group experience.
Seven volunteers were admitted to Army hospitals for malignant
neoplasms during their posttest period of service, of whom three were
NCT subjects and four were participants in chemical tests (Table 17~.
Chemical-test participants as a group experienced fewer admissions
than were expected on the basis of the NCT experience. When each
chemical-test group was compared with all other groups combined, the
differences between observed and expected admissions for malignant
neoplasm were in general no greater than might be expected owing to
chance. All six cases of malignant neoplasms treated in VA hospitals,
however, occurred among participants in chemical tests. Three
chemical-test groups had more cases than expected: anticholines-
terases, anticholinergics, and cholinesterase Deactivators. There is
duplication among the cases associated with these three groups,
because some of the subjects had been exposed to more than one
chemical. Hence, the sum, nine admissions, is greater than the
admissions to VA hospitals. The number of neoplasms among the
anticholinesterase-exposed men was not significantly increased over
the OCT expected number. When an exact test was performed with the
four cases in the anticholinesterase group and no cases in the NCT
group, the results were barely significant. An examination of the
admission diagnoses revealed no consistent pattern of site involve-
ment. There were two cases of cancer of the trachea or lung; one each
of cancer of the lip, skin, and lymphoid tissues; and one myeloma.
Mental disorders (Table 18) led to admission of 56 participants to
Army hospitals and 109 participants to VA hospitals after separation
Both the Army and the VA experiences clearly indicate that NCT subjects
were more likely to have mental disorders requiring hospitalization
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than were the chemical-test participants and indicates that this group
was not as fit as those who were given experimental chemicals.
Because of the increased frequency of mental disorders among the NCT
group, a more useful comparison for the chemical groups is obtained by
using men tested with other chemicals to compute expected values. For
no specific chemical group were more men admitted to Army or VA hos-
pitals than expected on the basis of the NCT comparison group. In
comparison with expectation that was computed from the OCT comparison
group, there were slight excesses in four of 14 categories, but in no
case was the excess statistically significant.
Diseases of the nervous system and sense organs resulted in the
admission of 43 participants to Army hospitals and 16 to VA hospitals
(Table lay. Consistently more chemical-test participants were hos-
pitalized for diseases of the nervous system than would be expected
from the NCT experience, both while in the Army and after separation.
The numbers of admissions for these disorders were significantly
higher than three of the four expected values for the men exposed to
LSD. Among the LSD-exposed volunteers, three were hospitalized for
otitis media, two for diseases of the retina (not detachments), one
for a cataract, and one for deafness. No Sernyl participants were
admitted for this group of illnesses; Sernyl-exposed men constituted
the only group with fewer participants admitted than expected on the
basis of the NCT experience. Half the men admitted to Army hospitals
for diseases of the nervous system and sense organs were first admitted
within 5 years of testing, whether they were in chemical-test groups
or the NCT group. When the distributions of specific diagnoses are
compared among the test groups, no consistent pattern is seen that
suggests that any of them can be attributed to the testing program.
MAIL SURVEY
Response Bias
As noted earlier (Table 5), responses were received from 4,085
participants--64% of the 6,395 men who were believed to be living when
the mail survey was conducted and 82% of the 4,996 men who were
located. Because responses to the questionnaire survey were not
obtained from all living men, it is necessary to compare the health of
respondents with the health of those who were located but did not
respond and of those who could not be located. The current health
status of the three groups could not be evaluated directly, but it has
been possible to examine the percentages of men still in the Army at
successive intervals since testing and the percentages that were
hospitalized during each interval (Table 20~. The upper panel of
Table 20 shows the mean annual numbers of men who were still in the
service during successive 5-year posttest intervals. The center panel
shows the numbers of these men who were hospitalized by the Army, and
the lower panel shows the percentages of hospitalized men among those
still in service.
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The overall use of hospitals was highest during the 5-year period
immediately after test participation. The proportion of participants
hospitalized beyond the fifth posttest year was greatest among men who
responded to the questionnaire, somewhat lower among men who failed to
respond, and lowest among men who could not be located. These percen-
tages suggest that men who could be the most likely to have health
problems were most likely to respond. If a response bias exists, ~
therefore, it is in the direction of overestimation of current health
problems of the living volunteers.
Survey of Nonrespondents
An attempt was made to interview the current nonrespondents (in
person or by telephone) to answer four basic questions:
~ Did the man participate in the Edgewood testing program'
· If sordid he receive any of the mailings addressed to him?
.
If so, did he respond to the questionnaire?
· If not, why not?
An arrangement was made with Research Triangle Institute (RTI),
Research Triangle Park, North Carolina, to attempt to interview the
891 men who had not responded (20 of the nonrespondents were not
identified in time to be included in the survey). The survey
instrument used is shown in Exhibit E of Appendix E.
Interviews were obtained with 657 nonrespondents, 74% of the total
(Table 21~. The proportion of men interviewed from among the chemical-
test groups varied from 71% for the irritant or vesicant group to 91%
for the Sernyl group. Thirty-six nonrespondents (4%) refused to be
interviewed--from none of the Sernyl group to 7% of the LSD group.
RTI was unable to contact the remaining 198 (22%) of the nonrespon-
dents (from 9% of the Sernyl group to 24% of the anticholinesterase
group and irritant and vesicant group). These 198 included 74
participants who could not be located.
The identification of participants among the nonrespondents was
reasonably good; 643 (98%) of persons interviewed confirmed their
having been on special assignment to the Aberdeen Proving Ground. Of
the 643, 102 (16%) could not recall having received any of the three
mailings (Table 22~. It is reasonably certain that the third letter
was delivered, inasmuch as certified-mail receipts of delivery were
returned for the nonrespondents. The letters probably were simply
discarded after receipt.
Of the 541 participants who remembered receiving the questionnaire,
62 (11%) claimed to have completed and returned it (Table 23~. Only 13
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questionnaires were eventually received from these 62 men, including
seven received after the cutoff (February 1, 1985~. The three most
frequently reported reasons for not responding were lack of health
problems to report (337 participants, 62%), concern about confiden-
tiality (135, 25%), and judgment that the questionnaire was too
personal (114, 21%~. There is no evidence that the men exposed to
different chemical groups differed in their reasons for not
responding, particularly where current health was concerned.
Mail Survey Findings
Age of Respondents. Although the ages of participants at the time of
testing were similar among the exposed to the various chemical groups
(Table 2), differences in the periods during which the different
classes of chemicals were being tested are reflected in the ages of
questionnaire respondents in 1984 (Table 24~. The mean age of the
respondents in 1984 was 42.4 years, with a 9-year spread between the
anticholinergic test group (mean age, 40.4 years) and the Sernyl test
group (mean age, 49.1 years).
Education of Respondents. The level of education of respondents
varied little among those exposed to the various chemical groups
(Table 25~. Median reported years of education, 13.3 for all
respondents, ranged from 12.7 years for the Sernyl group to 13.7 years
for the anticholinergic group; 2% of respondents failed to report
their education.
Family Relationships. Social status, living habits, and family
composition of the various test groups were similar to those of both
comparison groups. With one exception, the small observed differences
disappeared when the results were adjusted for current age. The
exception involves the reproductive experience of men who participated
in tests of anticholinergics. Volunteers exposed only to
anticholinergics and volunteers exposed to anticholinergics and other
chemicals both reported having had significantly fewer liveborn
children (stillbirths were not reported) after test exposure.
In comparisons of numbers of children, men who did not respond to
the question on children were assumed to have had no children. Most
men who failed to respond to this item had never been married. Table
26 shows the numbers of children reported by men tested only with
anticholinergics and with anticholinergics and other chemicals. The
deficits in numbers of children of those exposed only to anticholiner-
gics and those exposed to anticholinergics and other chemicals were
the same: 1.81 children per respondent compared with an expectation of
2.01 children per respondent, based on the age-specific NCT-group
reproduction rates. The expected number of men with given family
sizes was also estimated on the basis of the age-specific reproduction
—1
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histories of the participants in tests of all other chemical groups--a
mean of 1.95 offspring were expected per respondent. The deficiency
of offspring among the anticholinergic test subjects increased when
allowance was made for differences in current marital status (Table 27~.
However, data were not available to control for duration of marriage
after exposure. Allowance for age and education differences reduced
the expectation to 1.93 children. An examination of the ratios of
observed to expected numbers of men indicates that the anticholinergic-
test subjects were less likely to report larger families (three or more
children) than were the OCT subjects.
The above analyses were performed with the total family sizes of
the men, i.e., including children born before and born after the
chemical tests. Approximately 16% of the children were born before
testing or within a year after testing. Later analyses therefore used
only children born later than a year after exposure. To estimate
expected values, the rates were corrected for the ages of the men at
the time of testing. That is, a man aged 20 at the time of testing
could be expected to have more children born after testing than a man
who was 35 at the time of testing. This would be true even if their
current ages were the same.
The anticholinergics (median year of testing, 1968) were among the
chemicals more recently tested (see Table 2~. Because the mean ages
of the men at testing were approximately the same for each chemical
group, the current mean age of the anticholinergic-test group was the
lowest (see Table 24~. There has been a general trend in the U.S.
population toward lower birth rates and higher ages at conception.~5
Therefore, the apparent decrease in fertility could reflect this trend.
Adjusting for the age of the respondent at time of testing does not
adjust for such trends. The expected values presented in Table 28 are
adjusted for age of respondents at time of testing and year during
which the last testing was conducted. With these adjustments, the
differences between observed and expected fertilities were sharply
reduced when the OCT group was used as the comparison group. However,
a deficit in the number of male children born after testing did not
disappear after the corrections. When the NOT group was used as the
comparison group, the findings were similar, i.e., no significant
overall fertility difference and the deficit in number of male births
remained significant (see Appendix D). Other information that might
be related to the fertility of these men--duration of marriage after
exposure, use of oral contraceptives, race, and socioeconomic status,
etc.--was not available.
A telephone survey of 50 fathers who reported having had three to
five children was made to determine whether reporting had been accu-
rate or whether men with large families underreported family size.
Two additional liveborn children were discovered by the survey; a boy
"pronounced dead at birth" and a girl born before test participation
and therefore intentionally omitted from the questionnaire by the
respondent. Six of the 163 reported children, two boys and four
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girls, lived only a few hours. Thus, the telephone survey strongly
supported the conclusion that the reporting of liveborn children was
accurate.
Sex of First Child. The sexes of all the children born to the volun-
teers exposed to anticholinergics and the children born to the OCT -
group are shown in Table 28. There appears to be a decrease in male
children born to the anticholinergic group. However, to evaluate the
impact of an exposure on the sex of liveborn children, it is believed
more appropriate to consider only the first child conceived by the -
volunteer after exposure, hereafter referred to as the first postex-
posure child. These are the first children born at least 1 year after
exposure. If an effect exists, it should be strongest in the first
postexposure child. Restricting these comparisons to the first post-
exposure child born within a given period after the test--say, 1 or 2
years--would have yielded too few children for useful comparisons. A
further reason for considering the first postexposure child, rather
than all postexposure children, is that some epidemiologists feel that
cultural and societal expectations might influence the proportion of
children who are male in a completed family. (However, a mathematical
"modeling of this phenomenon shows that it would have only a minor
effect.)
Among the first postexposure children born to men exposed to
anticholinergics, 445 (48.7% ~ 1.7%) were males and 469 females. Of
the first postexposure children of the OCT group, 714 (49.8% ~ 13
were males and 720 females. These values are not significantly
different.
Among the first postexposure children of the NCT group, 445 (54.9%
1~7Yo) were males, 370 females. This value is significantly differ-
ent from both the anticholinergic-exposed group and the OCT comparison
group. A national survey found that 51.2% of offspring were males.13 i5
For outcome characteristics, such as health, that are strongly affected
by the selection of healthy volunteers at a given time, it is clear
that comparing these volunteers withy U.S. male population is
inappropriate. However, there is no reason why selection for general
health at one time should affect the proportion of later children who
are male. Therefore, it is appropriate to compare the NCT comparison
group, which received no exposure, with this general population. The
NCT has a significantly increased proportion of male children
(p < 0.005), when compared with the national population. But the
OCT group does not differ significantly in this regard. Because there
is no a priori reason for the NCT group to differ from the national
population, sampling errors might explain this extremely high propor-
tion of males. Therefore, it was concluded that there was no clear
indication that exposure to anticholinergics would affect the sex of
later offspring in a significant way and that there were no animal or
laboratory data to support such a finding.
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Respondents' Health. Several questionnaire items were aimed at deter-
mining the respondents' health status. These ranged from a simple
self-assessment of health on a four-point scale (excellent, good,
fair, and poor) to the recording of illnesses requiring medical care
over the preceding 5 years, confinements to bed for illness or injury
during the preceding month, and impairments limiting ability to work
and care for oneself. Responses to these items were strongly related
to the respondents' ages, so adjustment for current age was particu-
larly important.
Of the 4,085 respondents, 25% reported their health to be excel-
lent, 54% good, and 17Xo fair. Only 3% of respondents considered their
health poor, and 1% failed to respond. None of the chemical-test
groups, either alone or in combination with other groups, differed
from either comparison group.
When asked whether they had ever been told by health professionals
that health problems they were experiencing were due to exposure to a
toxic substance, 316 (7.7%) of the 4,085 respondents answered "yes."
Only the men exposed to irritants and vesicants had a response pattern
that showed a significant increase over either comparison group
(Mantel-Haenszel test of "yes" versus "no" responses, ~ = 0.05~. The
538 men exposed to irritants and vesicants alone responded as follows:
Reported health problem Observed
due to toxic exposure No. %
Expected
No * %
.
No 464 86.2 485.3 90.2
Yes 47 8.7 37.4 7.0
Unknown 27 5.0 15.3 2.8
Total 538 538.0
* Based on the age-specific no-chemical-test experience.
Much of the difference is due to an increase in "unknown" responses.
But a review of the nature of the exposures of the volunteers exposed
to irritants and vesicants and of a sample of NOT subjects who
responded "yes" to this question clearly indicates that acute effects,
mainly erythema and blistering during the immediate posttest period,
were responsible for the difference. The irritants-vesicants class of
chemicals produced no demonstrable excess of late effects. (Long-term
health effects of men who experienced acute erythema and blistering
are discussed later.)
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Half the respondents reported having sought medical care for a
disease or illness during the preceding 5 years. There is no evidence
that any of the chemical-test groups experienced an increased use of
medical care. The irritants-vesicants group, the only one that
differed significantly (n < 0.05) from either comparison group,
reported a reduction in later use of medical care.
Some 29% of respondents reported having been hospitalized during
the preceding 5 years. The test volunteers as a group reported fewer
hospital admissions than either comparison group. Hospital admissions
of the anticholinergics group were significantly (p < 0.05) less
than those of NCT subjects.
Bed confinements of 1 day or more during the preceding month were
reported by 20% of respondents. The experience reported by chemical-
test participants tended to be more favorable than that of the NCT
comparison group. None of the test-group differences from either
comparison group was statistically significant.
Health problems or impairments prevented 337 (8%) of the respon-
dents from working and limited the type of work engagement for an
additional 492 men (12%~. One test group, subjects exposed to anti-
cholinergics alone (consisting of 353 men), reported significantly
(p < 0.05) more men with work limitations, as shown below:
Observed
Ability to work No. %
Expected (NCT group)
No. %
No limitations 259 73.4 279.7 79.2
Limits work 50 14.2 38.2 10.8
Prevents work 33 9.3 27.1 7.7
Unknown 11 3.1 8.0 2.3
Total 353 353 ~ 0
A review of the responses of anticholinergic-test and NCT men
reporting work limitations indicates that no particular type of
impairment was involved. Furthermore, there was no difference between
the men exposed to anticholinergics and the OCT comparison group. No
relationship to specific chemical type, route of administration, or
dose was seen. The excess of reported work impairments among men
exposed to anticholinergics most likely can be attributed to chance.
Problems in performing household chores were reported by 376 (9%~:
159 (4%) reported that performance was "prevented," and 217 (5%) that
it was "limited." None of the test groups differed significantly from
either comparison group, nor were the directions of differences
consistent.
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Problems in personal care were reported by eight respondents, and
an additional 27 required help with their daily routines. No differ-
ences between test groups and either comparison group were noted.
Substance Use and Abuse. Four questions were related to the use and
abuse of tobacco, alcoholic beverages, and drugs. Nearly one-third of
the respondents never used tobacco regularly. The vast majority of
those who smoked on a regular basis were currently smoking cigarettes;
1,493 respondents (37%) smoked at least one pack per day, and 167
cigar smokers and 130 pipe smokers smoked at least one cigar or one
pipeful per day. Of the 2~,779 respondents who reported ever having
smoked regularly (more than occasionally), 1,438 (52%) reported that
they no longer smoked. None of the chemical-test groups differed from
either comparison group in smoking experience, in terms of the number
with a history of regular smoking or current smoking patterns.
The drinking of alcoholic beverages daily was reported by 3,147
(77%) of the respondents; 68% drank beer, 44% wine, and 54% whiskey or
other hard liquor. These figures are not different from that reported
by adult males in a national survey, i.e., 69%.15 A total of 231
men (5.7%) reported having had drinking problems that required treat-
ment. Similar drinking experiences were reported by the chemical-test
groups and by the NCT group.
Table 29 shows the reported use of selected substances of
potential abuse. Most frequently reported was marijuana (37% of
respondents), followed by "other narcotics, opiates" (34%), tran-
quilizers (29%), amphetamines and other stimulants (18%), LSD (12%),
barbiturates and other depressants (lOYo) ~ cocaine (10%), phencyclidine
(3%), and heroin (2%~.
With one exception, the use of the various substances shows no
relationship to chemical-test group. The one exception is the LSD-
test group (Table 30~. LSD-test subjects reported much more frequent
use of the substance than the NCT group or the appropriate OCT group.
Most of the excess use of LSD was among those who used it one to nine
times, so much of the reported excess might have been due to the
reporting of test exposures. However, nine subjects (2.8% of the
total) reported having used LSD 10 or more times, compared with 1.2
subjects expected on the basis of the NCT group experience and 2.2
subjects expected on the basis of the OCT group experience. A few of
the LSD-test subjects, therefore, appear to have continued to use LSD,
inasmuch as no participant received more than four test exposures (or
six test exposures, depending on the source of information). Perhaps
continued substance abuse by the LSD-test group of soldiers explains
in part their somewhat higher rate of questionnaire refusal to respond
to the questionnaire for reasons of concern about confidentiality
(Table 23).
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Groups of Special Interest. The responses of all 38 soldiers who
experienced erythema or blisters as a result of exposure to mustard
gas were examined in detail, because of the carcinogenic and mutagenic
potential of this chemical (see Appendix A). None of the 38 mentioned
cancer in response to the question of whether any health professional
attributed a health problem to exposure (question 9) or the question
of whether any disease or hospitalization had occurred in the preceding
5 years (question 13~. One person mentioned cellulitis as a recent
health problem, but his physician had not attributed this to the expo-
sure. The mustard-damaged skin site (shoulder) was in a different
location from the cellulitis (lower leg).
;
A second group of special interest consisted of subjects exposed
to Sernyl, a purified form of phencyclidine. The primary focus for
this group was whether any general health problems or mental disorders
had developed as a result of exposure to this chemical. The follow-up
responses of 48 men were received; this sample represented 60% of the
80 exposed men who were known to be alive at the time of the survey.
In response to the question regarding their "overall health"
(question 4), 35 men (73%) reported good to excellent health. The
remaining 13 men reported health problems that bore no relation to
their test experience in the Army. For example, five men reported
"low back pain," three reported "hernias," and three others reported
"prostate problems."
No questions were explicitly related to the psychologic status of
these men. However, there were only two reports of treatment for
alcoholism, infrequent reports of drug use, and no unusual reports
regarding employment, marital, and family status. There is no basis
to infer above-average frequency or intensity of psychologic problems
among these men.
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Representative terms from entire chapter:
children born
