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1 INTROD UCT ION H ISTORY OF THE EDGEWOOD TESTING PROGRAM Human experimentation appears to have been an integral part of the history of the U.S. Amy chemical warfare (COO) research efforts until its suspension in 1975. On June 2B, 1918, the President directed the establishment of the Chemical Warfare Service . (BUS) . Four years later, in October 1922, the CWS created a Medical Research Di~rislon to conduct research directed at pro~riding a defense against chemical agents. No matter how exhaustively an agent was tested in animals, it was felt that its efficacy in humans also had to be s tudied . In early 1941, the threat of war increased the urgency of the development of protection against CW agents and, consequently, engendered a need for a larger source of volunteers. Formal authority to recruit ant use volunteer subjects in CW experiments was initiated in 1942. The Secre tary of War was asked to rule on the permissibility of using enlisted men for testing agents of the mustard-gas type. In July 1943, the CONS was assigned responsibility for all medical research relates to CW. This extension of the CWS mission included toxicologic research and the study of hazard s to the health of personne 1 in the CWS . The i ssue of the use of human volunteers was considered by the Armed Forces Medical Policy Council during the early 1950' s. The Council concluded that essential data could not be obtained unless human volunteers were used, and the use of humans in medical research was author) zed . By 1954, the Chemical Corps ~ formerly CUS ) had established a framework within which to conduct human experimentation, but i t lacked an adequate pool of volunteers. In 19 55, i ~ was decided that the most practical source of volunteers would be enlisted men stationed at Army installations in the vicinity of Edgewood Arsenal. It was emphasized Chat voluntary consent of each human subject was absolutely essential. It was also stated that, in all experiments involving volunteer subjects, the subjects would be thoroughly inf orbed of all procedures and of what might be expected as a result of each tent. Furthermore, each volunteer would be free to determine whether he desired to participate in a given experiment. In October 1959, approval wee granted for the conduct of research on voluneeera to investigate defense against incapacitating CH agents. The search for incapacitating agents intensified when the Kennedy administration took office. The involvement with incapacitating agents represented a departure from an earlier period, begun in 1946, when inters st in highly toxic (acute) anticholinesterase chemicals resulted from their development in Germany during World War Il. The basic purpose of a military incapacitating agent is to produce temporary ineffectiveness without permanent injury or death. Incapacitating agents (anticholinergic chemicals) and highly toxic (acute) anticholinesterase chemicals produce functional and structural effects on the nervous system which cause rapid or delayed effects on an individual's performance and behavior. 1

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PROCEDURES USED AT THE EDGEWOOD CHEMICAL TESTING PROGARM A fairly extensive diacussion of the procedures used is provided in the Inspector General's report, Use of Yolunteera in chemical Agent Research, prepared by Colenel James R. Taylor and MaJor William H. Johnson ant dated March 1976 (listed in Appendixes C,D). RECRUITMENT OF VOLUNTEERS Recruiting teams (initially a/ministrative officers, but later often including military physicians from the Edgewood laboratory) visited Army installations where a briefing, usually with a film and handouts, was presented to a large number of enlisted men. Generally 10 to 20 percent of the audience expressed interest and these men were asked to complete a personal history. which included medical and psychologic items and the Minnesota Mule~phasic Personality Inventory (MMPI). It was not unusual for 400-600 men to request aasignment in the course of a tour of Seven to ten inatallations. Of these' no more than 100 were selected and eventually assigned for a 1- to 2- month period of temporary duty at Edgewoot Arsenal. The incentivea for volunteering consisted of a small monetary allowance (approximately gI.SO a-day for temporary duty), the assignment of only light duties while at Etgewood, ant almost every weekend free. Some volunteers were genuinely interested in the scientific and experimental aspects; however, if curiosity or the desire to "test one ~ s self " seemed too Stool, the applicant was usually not accepted. As a group, the volunteers were above average in physical and mental quallflcations, with a mean IQ near 110, good behavior records, and "normal" Maps with profiles generally within two standard deviations of the population mean on all scales. GUIDELINES FOLLOWED IN THE PROTECTION OF SUBJECTS . . . The Nuremberg and Helsinki guidelines were regarded by the investigators ant their supervisors as appropriate constraints in studies performed on volunteere, although this was not clearly articulated in official memoranda until the seit-1960s. The provision of accurate, luformatlve explanations of what was planned ant what might be expecter was regarded as essential to the continuance of the program. Written consents, witnessed by medical staff members, were required from the outset ant became more elaborate with time. However, minutes of hearings conducted by the U.S. Senate Subcommittee on Health ant Subcommittee on Administrative Practice ant Procedure, September 10-12, 1975, atatet that the consent information wee inadequate by current standards. INVESTIGATORS . , When BZ studies were begun in 1960, the need for a psychiatrist with biologic training and interest was recognized, ant one was assigned tO the program in January 1961. Physicians trained in internal medicine, anesthesiology, cardiology, surgery, dermatology, ophthalmology, neurology, and other specialties were assigned as the program proceeded. Many were research-orientet and have since gained excellent reputations in academic medicine at leading universities. 2

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SELECT ION OF 00 SES FOR HU.~*AN TESTS . . Subchreshold doses based on estimates from animal potency studies were used in the first few subjects. For example, the earliest exposures to BE, one of the antichollnergic test compounds, were at doses between 0.1 and 0.5 ~g/kg, which was less than one-tenth the incapacitating dose (ID) ultimately established at approximately 5.5. g/kg. The intravenous route was preferred initially, but other routes of administration were also used. Inhalation studies were sometimes undertaken after a compound had been thoroughly studied by one of these parenteral routes. Oral ant percutaneous studies were performed when effectiveness via these routes was of interest. As the program developed, it became customary to test agents at dose Increments of 40 percent, once the approximate effects of the lower doses were known. Placebos were used in some studies, but the cost with respect to subject confinement time, staff workload, and delay in achieving estimates of potency made this impractical except in special cases (e.g., evaluation of antagonists). Instead, low and high doses were assigned in a randomized manner by someone not involved in an experiment. Placebo responses were minimal. Signs of drug effects at all but the lowest doses were significant and made the value of placebo or no treatment inconsequential. RANGE 0E DOSES _ ,. Rarely did the intramuscular or intravenous doses exceed 1.5 times the incapacitating dose. Inhalation doses were higher, but potencies were lower by this route (usually about 60 percent of that by the intravenous or intramuscular route). Compared with doses described in the scientific literature on atropine coma therapy (18-23) or scopolamine therapy (19), the BZ doses to which volunteers were exposed appear modest. As much as 20 times the IDso of atropine and 30-40 times the IDso of scopolamine have been administered in the past by clinicians--often to older and less robust patients. Many patients received multiple exposures of this magnitude over a period of days or weeks. these therapeutic procedures, reported several decades ago in refereed journals, actually stressed and advocated the benefits of such treatment, despite occasional deaths (most of which appear to have been caused by hyperthermia). SAFETY MARGIN The safety margin of a drug is defined as the ratio of the lethal dose (LD) to the effective dose (ED). Sometimes, ratio of the LDso to ED,o is used, although a more conservative approach favors the use of the ratio of LD1 to EDgg (standard margin of safety). In the case of incapacltatlug agents, much reliance is placed on extrapolation from animal experimentation, and estimation of the LD1 is generally unreliable. Many other extrapolation techniques have been used in manipulation of animal lethality data in an effort to generate a reasonable human estimate. By taking a conservative approach with data on deaths at low doses, one can derive estimates for man that are modest and in keeping with clinical judgement. Such methods depend on procedures developed and applied in toxicology. 3

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