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APPENDIX A EXECUTIVE SUMMARIES OF VOLUMES 1 AND 2 EXECUTIVE SUMMARY OF VOLUME 1 In response to a request from the Department of the Army, the Committee on Toxicology (COT) of the National Research Council Assembly of Life Sciences conducted a study to evaluate the possi bility of long-term or delayed adverse health effects of chemical agents tested on military volunteers during the 1960s and 1970s. The task was begun about 2 years ago, with interviews of key people who had been associated with the soldier-volunteer test program of the Army Chemical Center (Edgewood Arsenal), Maryland. Initial efforts included a thorough review of the Army's laboratory and clini- cal records and of reports in the scientific literature. Some 6,720 soldiers took part in the Edgewood program as test subjects in about 1958-1975, and 24 chemicals were administered in an experimental setting. The chemicals were divided into eight major pharmacologic classes and organized within each class according to structure. The most extensively studied classes are the anticholinergic and the anti- cholinesterase chemicals, and these are the subjects of this report; the other classes will be reported on later. Panels were then formed to study these two main classes. The chairmen were selected for expertise in some aspect of the review of the pharmacologic class in question. The anticholinesterases are generally organophosphates; these are nerve agents resembling parathion. Major symptoms of low-level anti- cholinesterase exposure include salivation, increased sweating, con- tracted pupils, and bronchospasm. The anticholinergics are generally "glycolates," (substituted glycolic and tropic acid esters) of which the representative and best-known member is atropine. Major symptoms of low-level atropinization include dry mouth, dilated pupils, and tachycardia. There were 24 anticholinergics tested on about 1,800 subjects. There were 15 anticholinesterases tested on about 1,400 subjects. These two classes are readily paired, in that members of each are used as treatment for overexposure to members of the other. The next step involved organization of Edgewood data and reports. Some of this material had to be declassified before use by the panels. Digests of the entire available literature, classified and -67-

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unclassified, were prepared by consultant pharmacologists, and various documents were made available to the panels for use in investigating the possibility that the Edgewood test experience resulted in persis- tent adverse effects. The panels met several times, beginning in June 1980. The specific charge to the two panels was to determine: Whether the data available are sufficient to estimate the like- lihood that the test chemicals have long-term health effects or delay- ed sequelae. Whether the involved chemicals, as tested, are likely to pro- duce long-term adverse health effects or delayed sequelae in the test subjects. ANTICHOLINESTERASE CHEMICALS The panel concludes that although no evidence has been developed (to date) that any of the anticholinesterase test compounds surveyed carries long-range adverse human health effects in the doses used, the results of an ongoing NAS/NRC morbidity study may shed further light on this issue. The panel therefore is unable to rule out the possi- bility that some anti-ChE agents produced long-term adverse health effects in some individuals. Exposures to low doses of OF compounds have been reported (but not confirmed) to produce subtle changes in BEG, sleep state, and behavior that persist for at least a year. Whether the subjects at Edgewood incurred these changes and to what extent they might now show these effects are not known. If such changes occurred and persisted, they would be difficult to detect now. They could be determined scientifically only by a new study in which EEG, sleep state, and psychologic-test scores were compared with those from the NCT group. -[his might be considered, if reasonable suspicion develops, based on responses obtained in the ref- erenced morbidity study, that selected subjects experienced behavioral changes traceable in onset to experimental exposure to the anti-ChE agents. ANTICHOLINERGIC CHEMICALS No firm evidence has been seen that any of the anticholinergic test compounds surveyed produced long-range adverse human health effects in the doses used at Edgewood Arsenal. More intensive study is required to confirm this conclusion. The high frequency of uncon- trolled variables makes evaluation of behavioral effects difficult. On the basis of available data, in the judgment of the panel, it is unlikely that administration of these anticholinergic compounds will have long-term toxicity effects or delayed sequelae. An ongoing -68-

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morbidity study should provide more definitive information once it is completed. MORTALITY Standardized mortality ratios were derived from mortality data for the soldiers (all males) who participated in the Edgewood tests and from U.S. mortality rates. For each class of chemicals, the mortality rates among the soldiers were not significantly higher than the rates of the U.S. population, categorized by age and calendar year. MORBIDITY An ongoing morbidity study among the test subjects is expected to provide a more complete understanding of the long-term consequences of exposure to anticholinergic and anticholinesterase chemicals. EXECUTIVE SUMMARY OF VOLUME 2 In 1980 the Board on Toxicology and Environmental Health Hazards of the National Research Council's Commission on Life Sciences began a program to evaluate the long-term health effects of chemical agents administered to military volunteers at the Army Chemical Center, Edgewood, Md., during the 1950s, 1960s, and 1970s. This work was conducted at the request of the Department of the Army. The tests were conducted to find out how various potential chemical warfare agents affect human performance. It was felt that animal tests were inadequate for this type of evaluation and that only humans could pro- vide definitive information. The first report (Volume l) reviewed data on 15 anticholinesterase and 24 anticholinergic agents, to which almost half of some 6,700 sub- jects were exposed at Edgewood. The current report, prepared by three panels of the Board's Committee on Toxicology, evaluates possible delayed health effects of three additional classes of compounds that were tested on most of the remaining volunteer subjects: cholinesterase Deactivators, psychochem- icals, and irritants and vesicants (blistering chemicals). The cholinesterase Deactivators, of which there are four, are used as antidotes for anticholinesterase poisoning. The psychochemicals include phencyclidine, an anesthetic with substantial disorienting effects that is also available (with impurities) as the street drug POP, and 10 related dibenzopyrans that are central nervous system depressants capable of producing orthostatic hypotension. The irritants include the well-known lacrimatory chemical ON, the riot- control agent CS, and other ocular and respiratory irritants. Mustard gas was the vesicant whose effects were studied. -69-

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The Committee established three panels to identify and assess evidence on the possible long-term health effects or delayed sequelae of the chemicals tested. As in the work that led to Volume 1, the chairman of each panel was selected from the Committee on Toxicology. The specific charges to each panel were as follows: To determine whether there was sufficient evidence to assess the likelihood that the test chemicals had had long-term health effects or delayed sequelae. To determine on the basis of this evidence whether the chem- icals, as administered, are likely to have produced such adverse effects in the test subjects. The conclusions in this volume are based on available epidemio- logic, toxicologic, and mortality data that were reported in Volume 1. They also rely on a review of test-subject exposure data obtained from Edgewood, all of which were available to panel members. Long- term clinical follow-up was not conducted. The subjects tested were healthier than the control subjects with whom they were compared, and both groups were healthier than the general population, reflecting the better health status of those in military service. The analyses presented here necessarily reflect the limitations of the available data. These conclusions might change in the light of information gained through a study of morbidity, which will be based on a questionnaire and an analysis of admissions to Army and Veterans' Administration hospitals (to be reported in Volume 3~. CHOLINESTERASE REACTIVATORS On the basis of an examination of toxicologic literature, case reports from Edgewood volunteers, and a review of mortality data conducted by the National Research Council Medical Follow-up Agency, the Committee found no evidence of chronic disease in animals or humans associated with single or repeated doses of the cholinesterase Deactivators (oxides). The lack of follow-up data on volunteers prevents certainty in predicting occurrence or absence of delayed effects. The compounds are eliminated very rapidly from the body, but they produce a variety of acute effects that are short-lived and reversible, such as gastrointestinal distress after oral adminis- tration, pain at an injection site, dizziness, headache, and ocular discomfort. The Committee found no conclusive studies of carcino- genicity, mutagenicity, teratogenicity, or reproductive anomalies associated with the four oximes and therefore did not reach a conclu- sion in this regard. PSYCHOCHEMICALS The Committee found the evidence on the long-term health effects of the tested psychochemicals to be sparse. The target organs that -70-

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may be involved in prolonged or delayed effects of phencyclidine are the brain and cardiovascular system. Target mental or cardiovascular effects did not take place within a week of exposure to the drug. No case reports have identified long-term effects or mental or c~rdiovas- cular effects soon after first exposure. ~ The margin of safety of a tested chemical is sometimes estimated by considering the ratio of the lethal dose to the pharmacologically effective dose (the dose at which some detectable biologic effect occurs). On the basis of animal data on the psychochemicals tested, the margin of safety for short-term effects is large for acute intra- venous, intragastric, intraperitoneal, and subcutaneous administration and somewhat smaller for inhalation of thy aerosolized form. On the basis of the scientific literature alone, it is not pos- sible to predict whether any long-term effects would be associated with the small exposures used. However, evaluation of this toxicity literature and the Edgewood studies led this Committee to conclude that, at the doses and frequencies of phencyclidine used at Edgewood in a small number of test subjects, it is unlikely that detectable long-term or delayed effects have occurred or will occur. Acute administration of the dibenzopyrans (dimethylheptylpyran and congeners) produced various degrees of physical incapacitation in Edgewood subjects, mainly because of moderate to marked and prolonged orthostatic hypotension. The duration and intensity of effects varied among most doses and subjects. Despite the variations, there is a large pharmacologic margin of safety in the use of these compounds in animals. The dibenzopyrans produced more potent long-lasting ortho- static hypotension and weaker (but otherwise similar) psychologic effects than A-9-tetrahydrocannabinol during the Edgewood experi- ments. There is no information on chronic effects of dibenzopyrans. IRRITANTS AND VESICANTS The Committee analyzed published studies describing the in viva and in vitro properties of the agents used and reviewed short-term data collected by the U.S. Army on volunteers. The ability to provide definitive answers to the questions raised by the charge to the Committee was limited by the absence of long-term follow-up studies of the soldiers and by the sparseness of chronic effects studies of these compounds in animals or in humans after industrial exposure. In general, the Committee found insufficient evidence to evaluate these chemicals, except mustard gas. Mustard gas is an experimental mutagen and human carcinogen at high doses. Data on the irritants are insufficient to evaluate their mutagenicity, carcinogenicity, or other long-term effects. Tests of all these chemicals involved few expo- sures and low doses. -71-

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Mustard Gas (H) Mustard gas is highly reactive and has vesicant and systemic toxic effects. It is an alkylating agent that is mutagenic in various lab- oratory test systems, including mammalian germ cells, but data are inadequate to predict the extent of its genetic risk in humans. Mus- tard gas is also carcinogenic in experimental animals and humans. Other possible long-term effects of mustard gas are related to its local toxicity; specifically, it can cause blindness, possible skin tumors from some cases of permanent scarring of the skin, and chronic bronchitis. Reported instances of long-term injury, such as carcino- genesis in workers in a Japanese mustard production plant, were asso- ciated with exposure at high, long-term dosages. Information is insufficient to project risks associated with smaller exposures to mustard gas, however, serious long-term adverse effects in the small number of soldiers who received one or a few low-dose exposures at Edgewood seem unlikely (except for possible skin tumors and some cases of permanent scarring). Some of those exposed at Edgewood suffered skin injuries that took several weeks to resolve. However, in view of the small number of persons tested (about 150 healthy men) and the very low dosages involved, it is unlikely that a statistically signi- ficant increase in the risk of cancer or other chronic disease can be detected in those exposed to mustard gas at Edgewood. When exposed, the Edgewood subjects were wearing gas masks and impregnated clothing--an ensemble being tested for efficacy against toxic contamination. o-Chlorobenz~lidene Malononitrile (CS) Results of experimental studies in microorganisms and short-term experiments in laboratory animals suggest that long-term medical abnormalities in soldiers exposed to CS are unlikely. Acute tissue changes produced in animals and humans seem reversible and not likely to become chronic in the absence of recurrent exposures. Follow-up information on the long-term state of health of exposed soldiers is not available, but no reports indicate that Edgewood subjects have experienced any long-term sequelae. Chloroacetophenone (CN) CN, a moderately toxic irritant, has immediate effects on the eyes, skin, and respiratory tract. CN is a strong skin-sensitizing agent, but is rarely lethal. The Committee found no evidence of lasting ocular or respiratory effects in 99 volunteers exposed experimentally at Edgewood between 1958 and 1972 when subjects were evaluated 2 wk after cutaneous administration or inhalation of aerosol. Allergic contact dermatitis or hypersensitivity in these volunteers on re-exposure to CN is possible. There has been no systematic study of the=possible mutagenic and neoplasm-promoting effects of CN with current scientific methods. -72-

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DibenzRb,fl r 1,4loxazepine (CR) CR, a mild lacrimatory irritant, manifests less acute toxicity than CN and CS. At low doses, it causes transient effects. There are a few studies on long-term health effects, including potential muta- genicity and teratogenicity. The available data are insufficient to predict long-term health effects. The small number of exposures and the small number of subjects exposed to CR at low doses at Edgewood make the occurrence of demonstrable effects in these subjects unlikely. chloropicrin (PS ? PS is acutely toxic and has a variety of sensory effects in animals. It has not been evaluated thoroughly for mutagenicity or carcinogenicity. Like those exposed to mustard gas, the subjects exposed to PS were wearing gas masks, and small numbers of soldiers were exposed to small doses. PS is unlikely to have produced detec- table long-term health effects in volunteers exposed at Edgewood. BrombenzY1 CYanide (CA), DiphenYlaminochlorarsine (DM), and 1-Methoxv-1,3,5-cYcloheptatriene (CHT) CA, DM, and CHT are unlikely to have produced measurable long-term health effects in volunteers exposed at Edgewood. But there are no specific toxicologic data on the mutagenicity and carcinogenicity of these compounds. CHT is less toxic than CN or DM when administered acutely. Nonanovl Mornhol; do The Committee does not expect long-term health effects in volunteers tested with nonanoyl morpholide at the dosages used at Edgewood. As with CA, DM, and CHT, specific toxicologic data regarding its potential in this regard are not available. 123 Irritant Chemicals A total of 123 irritant chemicals were tested on only two subj ects each. There are no data on their mutagenicity, carcinogenicity, or other long-term health effects. However, because the exposures were small, detectable adverse effects seem unlikely. OVERVIEW The Army's studies on human subjects were designed entirely to evaluate short-term physiologic and pharmacologic effects. A review -73-

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of all available data reveals that these data are inadequate to provide definitive answers regarding the likelihood that the test chemicals produced or did not produce long-term health effects or delayed sequelae. Information on long-term health effects of the test chemicals on animals or humans is lacking, as is follow-up information on the current health status of the subjects. It therefore cannot be determined whether some subjects may have sustained long-term or delayed effects. Analysis of a questionnaire and of admissions to Army and Veterans' Administration hospitals (Volume 3) may provide further information on the current health status of these subjects. -74-