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4 MORTALITY METHOD OF ISIS The testing of chemical agents in human subjects at B4gewood which began in 1955 continued for more than 20 ye. During that period, the volunteers participated in an average of 3.l tests each; 29% participated in only one test, and 2: participated in 10 or more tests. Because most of the volunteers participated in more than one test, the date of the most recent test was arbitrarily see as the date on which followup by the Medical Followup Agency of the National Research Council and the ascertainment of mortality began. Followup continued through December al, 1980. The period of followup ravaged from 4 to a maximum of 26 completed years. The experience of 6,620 men is examined here. One-hundred were excluded from the study because of erroneous identification or because some essential datum, such as date of birth, was unknot. Among those studied, there were 222 deaths. Deaths during followup were identified by matching the volunteers against a computerized file of veterans maintained by the Veterans' Administration (VA3, which includes the date of death of every veteran for whom the VA has received a claim for a burial allowance and other veteran death benefits. Both name and service number were uset for matching. If a death certificate showing the cause of death could not be found in the VA claim folder for a deceased veteran, a copy of the certificate was requested from the vital statistics office of the Jurisdiction where the death occurred. We underlying cause of death was coded for analysis. The 31 deaths for which death certificates had not been received by the cutoff date for the receipt of data for analysis--March 33-, 1982--have been classified as "cause of death unknown." These 31 deaths are distributed in similar proportions between the men who received potentially hazardous substances (15X of 134 deatha) and the men who did not (13X of 88 deatha). The groups of voJ-unteers cannot be compared for mortality solely on the basis of numbers of observed deaths. One must also take into account the number of years that each group has been followed and the ages of ache men being obeer~red. The volunteers in the early test years were about the came age as men used in tests conducted during the later years (Table 4-~. However, the men tested in the early years not only are under observation for a much longer period than men used in the most recent tests, but also have grow older and have had a lower followup. Consider two volunteers of the same age at testing, one whose followup began in 1955 and the other in 1970. The first man will have aged 15 yr by the time the second man is tested and will have been exposed to the risk of dying for an additional 15 yr at the end of follownp. Thus, the proportion of volunteers who die during followup will decrease for each succeeding t eat group, in the absence of any drug effect . The testing of drugs spanned a period of 21 ye. Bowever, Awe chemical agents were Bested earlier than others (Iable 4-2~. The testing of LSI) and derivatives was concentrated in the early years; more than half the total number of doses had been administered by 77

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the end of 1959. At the other extreme were the approved drugs, innocuous substances, and control substances, which were administered late in the testing period. One can therefore expect a much higher proportion of men in the LSI) tests to have died than of ehe men who received approved bugs, innocuous cheo~icala, or control substances, eared if LS~ and its derivatives have no adverse effects on survival. If one calculated the numbers of deaths expec ted among a test group of men, on the basis of their ages ant the numbers of years they were followed, one would have a yardstick for assessing the aignif icance of the number of deaths observed during followup. The ratio of observed deaths to expected deaths, the atandardized mortality ratio (SHR), can be used to compare the mortality experiences of two or more groups. Expected deaths by underlying cause were calculated on the assumption that the volunteers experienced-U.S. male, age-specific death rates for each calendar year of followup. RESULTS 7 Because most of the volunteers participated in two or more tests, an analytic problem arises: If one of the teat aubatancea, say Substance A, produced detectable adverse effects, such effects would also tend to appear among men who received Substance B if there were many men tested with both substances A and B. Accordingly, data on men who were tested with any particular substance are shown in two nonoverlapping groups: those who received 'only" that substance (whether once or more than once) and those who received "not only" that substance but other active aubatancea as well. Observed and expected numbers of deaths ant the ratios of observed to expected deaths, the SMRs, by underlying cause of death in volunteers who were exposed to chemicals of various types, are shown in Table 4-3. As noted above, a distinction has been mate between men who received only one type of chemical and those who were exposed to two or more type a (the "not only" groups). The SMR for the total experience, 0.81, indicates that obaerred mortality for all causes wee only 81Z of expectation. That reflects the requirement that a man meet minimal health standards to be accepted into the Army; the screening process results in a teeth rate that is lower than that of U.S. males in general, ant this effect peratats for many years. It is evident that men who were tested with active substances hat beer subjected to attitiocal screening, so these Den constituted an unusually fit group and eight be expected to have unusually low mortality for a number of Prearm. This phenomenon la identical with the "healthy~orker. effect that is seen in moat studies of occupational group. Hen who were exposes to two or more types of chemicals experienced lover SMRa than those exposed to only one type of compound, again because of selection, a man hat to be in exceptionally good health to participate in multiple tests. No all causes SMR exceeded 1 by an amount greater than can reasonably be attributed to chance. The high SMR, 1.11, representing an 1]Z excess of observed deaths, occurred in the no test" group-e who were not exposed to any chemical agent,

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possibly because of aloe health defect detected in the exaoItna~ion that preceded testing. The highest SMR, 1.20, occurred tn the small group of men exposed only to the cholinesterase reactivators and represents an excess over expectation of less than a single death. The only ocher SMR to exceed unity occurred in men who were exposes to the anticholinergic chemicals only. Men who were exposed to anticholinergic chemicals plus other chemicals (which sometimes included substances to counteract the effects of the anticholinergic chemicals) had an SMR, 0.56, which is significantly below unity. However, when 212 men exposed to low single doses and 319 to high single dotes were examined separately, no dose effect was apparent. Had the anticholinergic cheo~icala increased the risk of dying, one would have expected that increase to be larger in men with larger single exposures. No evidence of a deferred, drug-induced mortality increase was seen when the experiences of the first 10 and remaining 16 follow-up years were examined separately. Of the 14 categories of experimental chemicals studied, only two had an She exceeding unity during the last 16 follow-up years. One of these (cholinesterase Deactivator, only) was clearly due to small numbers, one observed death with 0. S deaths expected, while the other, 47 observed versus 39.7 expected deaths, was seen in the 1,719 volunteers who were cot exposed to any of the chemicals, the -no test" group. We can state with 95-percent certainty that the true SMR for these men during the first 10 years falls between 0.69 and 1.36, while the limits for the last 16 years are 0.83 and 1.54, respectively. Most of the experimental chemicals were administered to too few volunteers to be examined separately for an influence on mortality. However, a few were considered of sufficient interest to justify being examined in that way (Table 4-4~. The specific chemicals are grouped by type. The SMRs for these individual compounds range from a low of 0.80 (nine observed, Il.3 expected deatha) for the Den tested with sarin only, to a high of 2.50 (five observed, two expected) for scopolamine only. Atropine, a therapeutic anticholinergic similar to scopolamine, had the next highest She, 1.76 (three observed, I.7 expected). Of the eight deaths of men who received one or the other of these two therapeutically similar compounds, three were attributed to trauma (one accident, one suicide, and one other trauma), and one was due to cancer; the causes of the other four will Doe be known until ehe death cert if icates are obtained. The SMRs become much more erratic when attention is directed to the underlying causes of death, because of the small expected number. If 0.5 deaths are expected, the SHR will be 0.0, 2.0, or 4. 0, if only zero, one, or two deaths are observed. Trauma was the underlying cause of 86 deaths, compared with 128.2 expected, for an SMR of 0.67. These volunteers had a significantly lower death rate from injury than that experienced by U.S. males in general. This tendency is seen in every category of test chemical, with two exceptions--the 570 men who received anticholinergic agents only (10 observed, 10.0 expected, SHR ~ 1.00) and the 607 men who received cholineseerase Deactivators (~l observed, ll.O expected, SMR - lOO). In each lostance, deaths due t o home Aide contri bused to the excess ~ It would be difficult to at tribute an increase in deaths due to trauma to effects of the two types of chemicals, because the excess is not seen among all 79

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volunteers exposed to them. No excess te seen in the anticholinergic -cot only" group or in the cholinesterase Deactivator "only. group. Three dlaessea were reapoDatble for more deaths than expected among all volunteers: cancer of the respiratory tract, 1eULeDia and aleukemia, ant reDa1 dicesee. All three renal-tisesse deaths were to the no-teat group; the excess he clearly cot a drug effect. The excess of reapiratory-cancer teethe derives in part from the control and no-teat groups; that auggesta that the esceca is general, Not trug-related. Deathe due to respiratory cancer were reapo~alble for an SMR of 1.11 to a group of world War II and Korean Coofllct veterans (13. It is possible that the proportion of clgarette-a~okera is higher among veterans than to the U.S. male population in general. me third disease causing more deaths than expected is leukemia and aleukemia (four observer 2.8 expected, SMR - 1.43). One death occurred in the innocuoua-cheeical and-control group. Of the other three who died of leukemia or aleukeots, two had received antlcholinesterase agents, two choliDestereae reactivatora, and one each lrritanta, cannabis, and an uDslasalfled chemical (included under total experience in Table 4-3)~ Then the total volunteer experience is divided into the 1,984 aeD who did not receive potentially hazardous chemicals and the 4,636 men who did, the average annual death rates from leukemia are aiailar ~3.4 aDd 4.0 per 100,000 peraon-yr of obaervatlon, respectively. What is the chance that an increeacd risk of death will actually be detected? After choosing a level of significance at which the null hypothesia (no increased rlsk3 will be rejected (P .05, say), the power of a comparison is the probability that, in fact, the number of deaths observed will be large enough to constitute a significant escesa over the number expected if there were DO increased risk. Power can be large if the relative risk is large or if the sample is sufficiently large. If the ample la amall, then only fairly large relative risks will be detected with high probability. In particular, if 10 or more deaths would be expected on the null hypothesia, a relative rick of 2.0 would be detected in more than 80 percent of trials (power greater than 0.80). The came power is achieved if three deaths are expected only if the relative rick is at least 3.0, and if only two deaths are expected at U.S. population rates, the relative rick would have to be at least 4.0 to achieve power of 0.80. Then the Dumber of men esposed to ~ given cheeic-1 are small enough or the condition at increased risk rare enough to produce an expected value of only 0.1 deaths, failure to demonstrate a significant increase would mean only that the relative rick is lesa than 30. From a statistical point of view, the experience being studied is incapable of demonatrating risks of dying increased lesa than three- or four-fold. It can be concluded that, over the time span examined here, there is no evidence that volunteer participation in the testing programs had any long-ten. adverse effect OD mortality. 80

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Table 1 N~bere of Men Tested by Year of Birth and Year of Beginning of Follo~p 1955- 1960- I965- Year of Birth 1959 1964 1969 1970- Total = ~ ~ ~ -. _ , .. .. No. Men: Be fore 1920 35 17 52 1920-1924 55 22 2 79 1925-1929 118 78 1 197 1930-1934 417 139 17 573 1935-1939 491 837 77 17 1,422 1940-1944 47 978 805~ 69 1,899 1945-1949 31 1,191 571 1,793 l9SO-1954 18 516 534 Af ter 1954 1 70 71 Tota 1 1, 163 2, 102 2, 112 1 ,243 6 ,620 Mean Year of Birth: 1934 1939 1945 1950 1942 He an Age at Beginning of Followup, I. 23.9 23.5 22.4 81 .. . 22.8 23.1

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Table 2 }median Years in Which Categories of Chemicals were Administered Category An ~ ichol ines terases Aneichol inergice Cholinesterase deactivators Irritants Cannabis LSD derive t ive s Approved drugs Innocuous chemicals and controls 82 Yeas 1962 1968 1968 1967 1965 1959 1971 1971

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Table 4 Obeenred and Expected Dcathe long Test Subjects by Chceica1 ~ministcred - No. Eesths Chemical No 5ubjecta Obeesved Expected DUE Aneicholinesterase only 507 21 29.2 0c72 Sarin only 149 9 11.3 0.80 VX only 281 12 14.5 0.83 Remainder of group 77 0 3~3 O.O Anticholinergic only 570 19 18.0 1.06 BE only 136 6 6.9 0.87 EA 3443 only 28 1 1.l 0.91 EA 3580 only 45 0 1.4 0.0 Scopolamine only 85 5 2.0 2.50 Atropine only 62 3 1.7 1.76 EA 3834 only 64 1 t.2 0.83 Remainder of group lSO 3 3.8 0.79 Irritant only 885 18 31.0 0.58 Musters only 68 3 3~0 1~00 Remainder of group 817 15 28.0 0.54 86

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REFERENCE 1. Reehn, R. J., 1980: Follo~up Studies of World War II ant Korean Conflict Prisoners. III. Mortality to 1 January 1976, Am. J. Epidemiol. Ill: 194-211. 87

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