Chronological Summary -- Defense Atomic Support Agency/DNA Reports (from Saenger's Uccm Human Radiation Experiments - Both Grant Submissions + Progress Reports)

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a. Dr. Saenger submitted ten reports to DASA/DNA from 1961 through 1972 in accordance with the terms of his contract. research‘s scope, increased sophistication of techniques, and ambitiousness of future plans: The reports were similar in that they stated the purpose of and criteria for the research, research structure and techniques, how the work was conducted, the results of the experiments, observations and analysis of the data, plans for future study, and individual case histories of patients observed during the reporting period. 2. General information about DoD sponsorship of radiation experiments at the University of Cincinnati 1960-1971. b. The reports provide a means to trace the expansion of the 1958 In September, 1958 Dr. Saenger submitted an unsolicited research application to the Research and Development Division of the Army Surgeon General’s Office. The application proposed to research metabolic changes in humans following total body radiation for the purpose of determining whether the presence of amino-acidura in humans after radiation would provide a reliable biological marker of radiation exposure. Dr. Saenger requested approximately $25,000 for the first year and $21,000 for two subsequent years. Over the next year the proposal was reviewed within the Defense Department and a contract negotiated. Available documentation reveals that at least four Army Medical Corps and one Medical Service Corps officer reviewed the proposal. They recommended the contract application be approved. In October, 1959 the Defense Atomic Support Agency’s (DTGA) Deputy Chief of Staff, Weapons Effects and Test requested, thru the Chief, DASA, the Contract Management Branch, Directorate of Logistics negotiate a contract with the University of Cincinnati for the study of the metabolic changes in humans following total body radiation. In early 1960 a contract (DA-49-146-XZ-029, dated 1 January 1960) was signed between DASA and the University of Cincinnati Board of Directors. The contract provided $25,085 for the study. This contract, with supplements and modifications,

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funded the study through February, 1964. The first contract stated the technical scope of the research was "to study the phenomen of aminoacidura following irradiation, a condition which has been reported in humans and animals, to clarify some of the mechanisms responsible for amino-acidura and to determine whether it is a practical biological test of radiation exposure." The search for a biological marker of radiation exposure was one constant of Dr. Saenger's research effort over the next decade. On 28 February 1961 the Cincinnati project's contract was modified for the first time. The contract was modified to establish a new date for work completion to provide additional time for research on amino-aciduria following irradiation; amended the technical scope of the work to meet additional objectives of the government; provided additional funds to meet research requirements under the amended scope of work; altered portions of the contract to bring the contract in accordance with Armed Services Procurement Regulations that became effective subsequent to the signing of the original contract. The contract amount increased almost $30,000 from $25,000 to $54,000 and the length of the project was extended from February, 1961 to April, 1962. The scope of the work was expanded by three requirements: a breakdown of desoxyribonucleic acid and is derivatives in patients receiving total body radiation; DNA studies on patients who received partial irradiation and radiomimetic chemotherapeutic agents; and preliminary determination of appropriate psychometric tests. In June, 1961 the contract was modified for the second time. A n additional $650 was allocated to use the technical services of a French authority on radiobiology at a Whole Body Radiation Conference to be held by DASA at the University of Cincinnati in October, 1961. In April, 1962 the project's contract was modified for the third time. The contract total was increased approximately $39,000 to $94,400. The project completion date was extended to April 30, 1963. The scope of work was also further Additional studies were to be made of--increasing the upper range of radiation dose to 150-200 rad, Three additional objectives were added.

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and single doses of nitrogen mustard or other radiomimetic drug using .4mg/kilo. The following tests were to be conducted for 9 days posttreatment--urinary taurine for correlation with leukocyte count, BAIBA in urine, Kynurenic and xanthurenic acids, deoxycytidine, DNA fragments in urine, et al, xanthine and hypoxanthine in urine, urinary phosphate, and glutathione. The test were to be done over a 30 day period--routine quantitative precipitin studies, serum urea nitrogen and/or serum creatine once weekly, urinalysis once weekly and as needed, routine hematology, and completion of the manuscript of the DASA Conference on Total Body Irradiation of On April 1, 1963 the contract was modified for the fourth time. The contract was extended through April 30, 1964. Funding was increased $40,000 to $134,56. The scope of the work was further amended. Teswto be conducted over a 30 day period between March 1, 1962 and February 28, 1963 were to be: (1) routine electrophesis, (2) immunoelectrophesis, (3) quantitative precipitin studies, (4) serum urea nitrogen and/or serum creatine once weekly, (5) urinalysis once weekly or as needed, and (6) routine hematology. During the same year the following tests were to be conducted over a 42 day period included 3,4,,5,6 and chromosome cultures of peripheral blood. Contract DA-49-146-XZ-315came into effect and funded the research from February, 1964 to April, Ralph C. Rursiek and Dr. Eugene L. Saenger wrote a letter, dated May 17, 1965, to Director, Defense Atomic Support Agency, ATTN: STMD requesting that NWER No. 03.009 be funded at an estimated cost of $45,000 for FY65. The overall objective was to study various phenomena of desoxyribonucleic acid breakdown and other abnormalities following whole or partial body irradiation of human beings. Fifteen patients were to be studied. The project intended to study patients for 5-14 days prior to irradiation and for as long as possible after to evaluate clinical hematological and psychological changes. Investigation of the metabolism and urinary excretion of deoxycytidine was to be continued. Bone marrow was also to be stored prior to

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irradiation. All serum was to be sent to Dr. Luzzio at Fort Knox. In 1967 a member of the University of Cincinnati research team, Dr. James G. Kereiakes, attended an Atomic Energy Commission sponsored conference at Oak Ridge, Tennessee. A purpose of the conference was to refine the dosimetric aspects of whole and partial body irradiations being used by the medical community to treat leukemia and widely disseminated cancers. The aim of the conference was to standardize the dosimetry being used to report patient dose. Information developed at the conference revealed 1,835 patients at about 35 institutions had received whole or partial body irradiations for the palliation or treatment of cancers. The use of radiation was widely spread and acknowledged as an effective modality. The final contract (DASA-01-69-C-0131),effective May, 1969 funded the research until March, 1972 when the University of Cincinnati refused DASA's offer for additional contract funding. Dr. Eugene L. Saenger wrote a letter, March 22, 1971, to Dr. Robert Loind, DASA, Attn: STMD. The cover letter with attachments forwarded the projects proposal for FY 73. The proposal requested $70,000 for a study entitled "An Appraisal of Human Studies In Radiobiological Aspects of Weapons Effects". description of the study's philosophy, the role of future human research in relation to the remainder of the radiobiology program, specific areas of effects, behavioral effects, dose response studies, partial body studies, prognosis, therapeutic methods, use of healthy volunteers), and future plans regarding funding. Through 1971 DoD ultimately spent over $650,000 on Dr. Saenger's endeavors which treated 85 adults with localized Ewing's tumor were also treated provided for laboratory, psychological and psychiatric tests to assess the effects of varying doses of whole and partial body irradiation. No funds were paid to the University of Cincinnati for direct patient care.

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1960-1961 The report for the first research period (February 19, 1960 to October 31, 1961) was DASA 1422 Supplement, which was entitled Metabolic Chancres title was used for the reports through 1967. The report provides a detailed itemization of the investigations and study projects. The aim of the studies was "to obtain new information about the metabolic effects of total body and partial body irradiation so as to have a better understanding of the acute and subacute effects of irradiation in the human." During this period ten patients received total body irradiation in doses that ranged from 16 to 150 rads. Patients were selected for the study were those with "proven metastatic nutritional status, i.e., able to maintain their body weight .... [andl have normal hematological values." An explanation of one of the study's technique stated "the patient is told that he is to receive treatment to help his sickness. There is no discussion of subjective reactions resulting from the treatment. Other physicians, nurses and ward personnel are instructed not to discuss these aspects with the patient." report discussed on-going studies, clinical observations, dosimetry, and other study techniques supplemented with tables and patient The remainder of The second report, DASA 1422 reported on the research from November, 1961 to April, 1963. Ten patients were treated with total body radiation in doses that ranged from 150-200 rad during the report period. The study's statement of aims was identical to that of the previous report except that it was expanded. The added aim stated "This information is necessary to provide knowledge of combat effectiveness of troops and to develop additional methods of diagnosis, prognosis, prophylaxis and treatment of these injuries." patient selection criteria was more refined. In addition to those already stated new criteria was excluded. . . Patients with solid neoplasms not radiosensitive are sought." The technique reported previously remained in use. Verbal consent of the patients was obtained prior to involved complications in trying to determine the One of the issues the researchers encountered

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effects of radiation. T h e report stated "Physicians assess patient to be certain that the underlying disease can be evaluated. Thus, there was difficulty in selection of patients for assessment of radiation effects because of underlying disease. Patients previously treated by radiation or chemotherapy were excluded because previous treatment confounded the response to radiation in several early patients." Throughout the narrative and near the conclusion with the researchers thoughts on "Human Several of their observations included: "Marked hematological changes occur generally between the 25th and 35th day following exposure. Maximum recovery to be obtained generally requires about 100 days." "Human beings recover slowly and are quite sensitive to radiation with multi-system I'Prodromal acute effects such a nausea, vomiting, anorexia, and lassitude are of the duration hours. Intermediate effects such as hematologic complications are to be conceived of "A previous dose of radiation does influence the incidence of acute effects. will be significantly increased on re-exposure of "...individuals with previous exposure to radiation will be less tolerant of subsequent exposures. #ence troops previously exposed to 150-300r of whole body radiation will tend to show more combat ineffectiveness in the prodromal period than will those who are unexposed." "This field of investigation has obvious important implications. Breakdown of DNA has long been implicated as the fundamental biochemical change of radiation and there is an impressive cited above of decrease of DOC after the administration of protective agents indicates the possibility of the use of specific prophylactic agents for the protection of humans in nuclear

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A final observation was offered on future study: "It is our opinion that human radiation studies need to be expanded. We propose to establish facilities for withdrawal, storage, and reinfusion of autologous bone marrow. As indicated elsewhere in this report we have encountered significant hematological difficulties with a dose range of 200-325r. Therefore, to proceed with higher doses, we feel the need to protect our patients even if we might sacrifice their value for hematological evaluation after 2-3 weeks since the hematological effects are well documented. Once this technique has been developed as a support procedure we then anticipate increasing doses to Tables, figures and case histories rounded out the report. 1963-1964 DASA 1633 was the report submitted for the period May 1, 1963 to February 29, 1964 during which six patients were treated with total body radiation doses between 100 to 150 rad. The aims of the study remained as previously reported. "Normal renal function' was added to patient selection criteria. The technique to limit subjective reactions treatment was unchanged. Proposals for human study expanded on the previous report's discussion of autologous bone marrow reinfusion. The report stated: marrow will be accomplished in the facility which storage and reinfusion is to protect subjects who receive doses in excess of 150 rad in the event of bone marrow failure. We hope to utilize doses Tables and case histories once again "Storage and reinfusion of autologous bone accompanied the report. 1964-1966 DASA 1844 covered not only the study years 1964 to 1966 but also provided a summary of the first six years of the experiment. decade the aims of the project were stated as: Midway through the "This program is designed to obtain new

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information regarding the metabolic, physiologic, immunologic, hematologic, and biochemical effects of TBR and PBR in human beings. It will then be possible to understand better the influence of radiation on combat effectiveness of troops and to develop more suitable methods of diagnosis, prognosis, prophylaxis and treatment of radiation injuries. It is our belief that information concerning radiation effects in the human being can be determined as well or better in these subjects as in the laboratory animal even though the characteristic of cancer must be kept in mind in the evaluation of the data." On page 2 the aims were once again addressed " A major objective of these studies has been in terms of the original scope of the study: a search for a suitable biological indicator of urinary excretion of deoxycytidine seems to be promising as a biological indicator." Another aim was stated on pages 2 and 3 . "Psychological and psychiatric testing has been started in 14 patients ....This approach will provide information on another important parameter of combat effectiveness of troops.'I Later in the report an aspect of the psychiatric evaluation is further discussed. "One of the most difficult aspects of radiation injury requiring evaluation is that of performance decrement. This term is loosely used but in our laboratory it is defined as any decrease in ability to carry out assigned tasks." Patient selection criteria was more specific: "Patients with metastatic or incurable neoplasms are given whole partial body radiation for palliative treatment of their disease. patients for the studies described in this report are selected from patients treated as described above providing that they satisfy the following 1. The patients have solid tumors. 2. Relatively good nutritional status Patients with lymphoma are excluded.

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(ability to maintain weight). 3. Normal renal function 4. Stable hemogram in the control Twenty three additional patients were treated during the research period between 1964 and 1966. Of these patients 13 received total body radiation treatments with dosages between 25 and 150 rads. Partial body radiation doses between 100 and 300 rads were used in the treatment of 10 patients. discussions of subjective reactions …