 Section 30 of Final Report of the Advisory Committee on Human Radiation Experiments. This is a LibriVox recording. All LibriVox recordings are in the public domain. For more information or to volunteer, please visit LibriVox.org. Recording by Patrick McAfee, Evanston. Final Report of the Advisory Committee on Human Radiation Experiments. Case Studies, Chapter 5, Part 4. Human experimentation continues. In March 1947, just as he was declaring that, quote, public relations and, quote, required the reclassification of plutonium data, Medical Division Chief Major Brundage approved a 1947-48, quote, research program and budget, end quote, for Rochester that provided for metabolism studies with polonium, plutonium, uranium, thorium, radio lead, and radium. The program was put on hold by the AEC soon after. The future of the metabolism work at Rochester apparently was decided when Shields Warren was named the first chief of the AEC's division of biology and medicine in fall 1947. In his private diary for December 30, 1947, Warren tersely noted, quote, ordered abandonment of human isotope program at Rochester, end quote. The program at the University of California at Berkeley, however, continued. On December 4, 1947, Shields Warren had met with Hamilton and Stone. The decision to allow the program to continue clearly was not a hasty one. A 1974 recollection of Shields Warren indicates that his decision to allow the program to continue may have been due to Hamilton's assertion in December 1947 that it had been the University of California's practice to obtain some form of undocumented consent. According to Warren, Hamilton had said that subjects were told, quote, they would receive an injection of a new substance that was too new to say what it might do, but that it had some properties like other substances that had been used to control growth processes in patients or something of that general sort, end quote. Warren went on to observe that, quote, you could not call it informed consent because they did not know what it was, but they knew that it was a new and to them unknown substance, end quote. Warren's observation does not go far enough, however. If Warren's second-hand account is accurate, and this is indeed what the patient subjects at the University of California were told, then they were more misled than informed. Analogizing plutonium to substances that, quote, control growth processes in patients, end quote, even in prospect might reasonably lead patients to believe that they would be receiving a substance with some hope of treating their cancer. Certainly such a remark would not communicate to patients that the experiment to be performed was not for their own benefit. It would have been appropriate that these patients be told that their participation might benefit future patients with the same conditions. It would have been crucial to distinguish, however, between this legitimate explanation of potential benefit to future cancer patients and misleading the patient into believing the experiment might benefit him or her. Human experimentation continues at the University of California. By the summer of 1947, human experimentation had resumed at the University of California under AEC contract. In June, Cal A, a teenage Asian American bone cancer patient at Chinese Hospital in San Francisco, was injected with americium. An instruction in the patient's file by one of Hamilton's assistants specifies that, quote, we will use the same procedure as with Mr. S, end quote. Evidently, a reference to Albert Stevens. Dr. Durbin, Hamilton's associate, believes that Cal A's guardian was informed of the procedure followed in that case. The advisory committee received incomplete records for Cal A that contained no evidence of disclosure or consent. UCSF has told the committee that records at Chinese Hospital from the 1950s and earlier have been destroyed. A 36-year-old African-American railroad porter named Elmer Allen, codenamed Cal 3, was believed to be suffering from bone cancer and was injected with plutonium at the University of California in July 1947. His left leg was amputated shortly thereafter. There is a note in his medical chart signed by two physicians stating that the experimental nature was, quote, explained to the patient who agreed to the procedure, end quote, and that, quote, the patient was in fully oriented and insane mind, end quote. It is likely that this note was intended to fulfill one of the April 1947 conditions for human experimentation, which allowed for such a procedure as documentation of having obtained the patient's subject's consent. It is not clear from the note, however, whether in explaining about the experimental nature of the procedure, the physicians told the patient about the potential effects of the injection as required by the Wilson letter or that the injection was not intended to be of medical benefit to the patient. On this second point, the injection was in violation of the Wilson letter, which also required that there be an, quote, expectation that it may have therapeutic effect, end quote. As acknowledged by the February 1995 UCSF report, there was never any expectation on the part of the experimenters that the injection would be of therapeutic benefit to Mr. Allen. Mr. Allen lived until 1991. According to UCSF's 1995 review of patient subjects medical charts, upon biopsy of his tumor, a pathologic diagnosis was made of chondrosarcoma, a type of malignant bone tumor. UCSF reported that patients with this type of tumor, quote, frequently survive many years beyond diagnosis if there is complete excision of the primary tumor, end quote. This pathology finding suggests that Mr. Allen was a long term cancer survivor. A note in his patient chart recorded that the tumor was, quote, malignant but slow growing and late to metastasize, prognosis therefore moderately good, end quote. On March 15, 1995, Elmarine Whitfield Bell, the daughter of Elmar Allen, told the advisory committee in Washington, D.C. that she, quote, continues to be appalled by the apparent attempts at coverups, the inferences that the nature of the times, the 1940s, allowed scientists to conduct experiments without getting a patient's consent or without mentioning risks. We contend that my father was not an informed participant in the plutonium experiment. He was asked to sign his name several times while a patient at the University of California Hospital in San Francisco. Why was he not asked to sign his name permitting scientists to inject him with plutonium? Why was his wife, who was college trained, not consulted in this matter, end quote. On January 5, 1948, a 55 year old woman with cancer was injected with zirconium at the University of California. The patient record for this case has not yet been located, nor have any other documents that might bear on whether this experiment was conducted in compliance with the consent requirements of the Wilson letters. We do know that the injection of zirconium was not expected to benefit the subject herself. A secret report on the zirconium injection was reviewed by the AEC in light of public relations and liability concerns. In August of that year, the report was denied declassification with the approval of Shields Warren, who wrote, quote, this document should not be declassified for general medical publication, and it would be very difficult to rewrite it in an acceptable manner, end quote. Warren was responding to a memorandum from Albert H. Holland Jr., Medical Advisor at Oak Ridge, which specified that the concern about rewriting had to do with public relations and the fact that the report, quote, specifically involves experimental human therapeutics, end quote. Follow-up of the patient subjects at Rochester. The investigators at Rochester and the AEC were interested in obtaining long term data from surviving subjects on excretion levels and the distribution of plutonium in various tissues. Follow-up studies at Rochester continued at least through 1953 with two of the subjects in the HP series, Eda Charlton and John Musso. We have already noted Wright Langhams' 1950 instruction to the physicians at Rochester, suggesting that they were not to give these patients any indication of the true purpose of the follow-up studies. In addition, Langhams sought help in early 1950 to locate Ebb Cade, the man injected at Oak Ridge Hospital, for follow-up excretion studies. Langham asked Dr. Albert Holland at Oak Ridge to try to locate Mr. Cade and to keep his, quote, eyes open for a possible autopsy, end quote. It is unclear to the committee whether follow-up of any kind was ever done with Mr. Cade. On June 8, 1953, Eda Charlton's rib was removed during exploratory surgery for cancer and analyzed for plutonium. Lewis Hempelman, who by that time had moved from Los Alamos to Strong Memorial Hospital at Rochester, wrote to Charles Dunham of the AEC's Division of Biology and Medicine in advance of the procedure, quote. The patient in question was brought in for a skeletal survey and turned out to have a coin-like lesion inside the chest wall. It is undoubtedly an incidental finding, but she must be explored by the chest surgeon here at Strong. In the course of the operation, he will remove a rib which we can analyze. Her films show the same type of minimal indefinite change in the bone that the others have had, end quote. It was standard practice at the time to remove a section of rib, incidental, to lung surgery. It is clear that the patient was still being followed for long-term effects of plutonium and that some subclinical bone changes of unclear significance had already been observed by this time. Therefore, the examination of this rib segment would have included special tests to determine whether plutonium was present. On August 31, 1950, an internal DBM memorandum recorded the understanding of some AEC officials that Wright Langham and Rochester doctors were engaged in follow-up studies. In a 1974 interview, however, Shields Warren recalled that he had no knowledge that the patients were the subjects of follow-up studies. Quote, I did not learn of this continuing contact while I was in office at AEC. I had assumed because I had been told they were incurable patients that they all had died by the time we talked, end quote. Additional follow-up studies in the Argonne Exhumation Project. In 1968, Dr. Patricia Durbin undertook an investigation of the plutonium injection subjects, which included a reevaluation of the original plutonium data. Her goal was to pursue, quote, some elusive information on PU in man and the information or assumptions about physiology needed to create a believable PU model for man, end quote. She, quote, decided to look at all the old PU patients as individuals rather than in a lump, end quote. Durbin was surprised to find in her search for the original experimental data that the University of California data were drawn from three subjects who received plutonium and one who received americium. The data from only one plutonium subject from California had previously been reported in the open scientific literature. Durbin asked the original researchers why these data had not been analyzed. She wrote, quote, I understand from Wright Langham that this problem has been discussed before and discarded as too messy, end quote. In 1972, after the classified report on the experiments had been downcrated to official use only, she went on to publish, quote, plutonium in man, a new look at the old data, end quote. A landmark paper in the plutonium story. This was the first review in the open literature to analyze Langham's results in light of the actual medical conditions of the patient subjects. Because of the prolonged secrecy surrounding the experiments, it was generally not known that two of the three University of California cases had been omitted from the 1950 analysis. The report also revealed in retrospect that all the patients were not hopelessly or terminally ill, as had been suggested in Langham's later public references, that some were still alive and that some had been misdiagnosed. In December 1972, Argonne National Laboratories Center for Human Radiobiology, CHR, to whom Durbin had provided the names of surviving subjects, began a review of the data from all 18 people who were injected with plutonium between 1945 and 1947. CHR was the national center designated by the AEC to do long term follow up of individuals with internally deposited radionuclides, primarily the radium dial painters. Argonne's follow up plan for the plutonium experiments was to uncover the post injection medical histories of all the subjects, obtain biological material from those still living, and exume and study the bodies of those deceased in order to, quote, provide data on the organ contents at long times after acquisition of plutonium, end quote. In 1973, three patients, Eda Charlton, John Musso, and Elmer Allen, were admitted to the University of Rochester's metabolic ward for more excretion studies paid for by CHR. Elmer Allen had first been brought to Argonne where an unsuccessful attempt had been made to detect plutonium by external counting techniques. In the course of his examination, however, CHR found subclinical bone changes that an Argonne radiologist characterized as, quote, suggestive of damage due to radiation, end quote. Again, there was no disclosure to the subjects that they were now being followed because they had been subjects of an experiment that had been unrelated to their medical care, an experiment in which there was continuing scientific interest. The 1974 AEC investigation concluded that, in the case of the surviving Rochester subjects, Dr. Waterhouse, who conducted the follow-up studies with these patients for Argonne, had not told them the purpose of the studies in 1973 because she believed, quote, that disclosure might be harmful to them in view of their advanced age and ill health, end quote. This suggests that Dr. Waterhouse had well-intentioned motivations for not being straightforward with the Rochester subjects. It also suggests that these subjects had not been told the truth about the experiments at the time the injections occurred or that they had forgotten. According to Dr. Waterhouse, the studies were feasible without the subjects' knowledge of the true purpose of the research since these two patients, quote, were accustomed to participating in clinical studies unrelated to this matter involving the collection of excretion specimens, end quote. Elmer Allen's physician was told by CHR that the purpose of bringing Mr. Allen to Argonne's CHR and the University of Rochester for follow-up was interest in the treatment he received at the University of California in 1947 for his cancer. This use of the term treatment in the information provided Mr. Allen's physician, which he presumably relayed to Mr. Allen and his family, was deceptive and manipulative. It implied that the injection Mr. Allen received had been given as therapy for his benefit. The second component of this follow-up study was research on the exhumed bodies of deceased subjects. The 1974 AEC investigation concluded that the families were not informed that plutonium had been injected. Instead, they were told that, quote, the purpose of exhumation was to examine the remains in order to determine the microscopic distribution of residual radioactivity from past medical treatment, end quote, and that the subjects had received an unknown mixture of radioactive isotopes. The investigation concluded that such disclosure, quote, could be judged misleading in that the radioactive isotopes were represented as having been injected as an experimental treatment for the patient's disease, end quote. Thus, the families of the deceased subjects, as well as those subjects still surviving, were deceived by officials of the AEC. A December 1972 intra-laboratory memorandum, written by an argon investigator, instructs that, quote, outside of CHR we will never use the word plutonium in regard to these cases. These individuals are of interest to us because they may have received a radioactive material at some time is the kind of statement to be made if we need to say anything at all, end quote. Robert E. Rowland, the author of this memorandum, told advisory committee staff in 1995 that he had written this after he had been instructed earlier that month by Dr. James Liverman, director of the AEC's division of biomedical and environmental research, that, quote, I could not tell the individuals that they were given plutonium. I protested that they must be given a reason for our interest in them, and I was told to tell them that they had received an unknown mixture of radioisotopes in the past and that we wanted to determine if it was still in their bodies. Further, we were not to divulge the names of the institutions where they received this unknown mixture, end quote. Dr. Rowland said he had received these instructions during a trip to Washington DC to obtain approval and funding for the study. Dr. Liverman told advisory committee staff that he has, quote, no recollection of discussions with anyone in which some stricture would have been placed on what could be discussed with the patients. That is a medical ethics issue which would have been left to the physicians, end quote. This study was not brought to the attention of the Argonne Human Use Committee until November 1973, even though it had been established in January 1973. C Chapter 6 for a Discussion of Human Use Committees. In a briefing for the 1974 AEC investigation, Dr. Liverman attributed this failure to bring the study before the Human Use Committee to the following factors, quote, Argonne's opinion that the studies came under the scope of a protocol approved by that committee in 1971. Two, the nature of the studies was to be suppressed to avoid embarrassing publicity for AEC, end quote. In 1974, the AEC informed at least two of the four subjects, Ida Charlton and John Musso, of the plutonium injections and had them sign documents to this effect. These documents did not provide any information on possible effects of the injections, although they did describe the purpose as having been, quote, to determine how plutonium, a man-made radioactive material, is deposited and excreted in the human body, end quote. One living patient, Jan Statt, was not told because it was her attending physician's opinion that her condition was precarious and that disclosure in this case would be, quote, medically indefensible, end quote. This judgment, like that of Dr. Waterhouse's, exemplifies how physicians of the time commonly manage the information they shared with their patients. Physicians typically told patients only what they thought it was helpful for them to know. If, in the physician's judgment, information might cause the patient to become upset or distressed, this was often considered reason enough to withhold it. The judgment also suggests that Ms. Statt, like Ms. Charlton and Mr. Musso, had not been told the truth about the experiments at the time the injections occurred or that she had forgotten. The AEC recommended that exhumations continue, but only with full disclosure to the subjects next of Kent. The Boston Project Uranium Injections Human experiments conducted to measure the excretion and distribution of atomic weapons materials did not stop with the last of the injections at the University of California. The Boston Project Human Uranium Injection Experiments were conducted from 1953 to 1957 at Massachusetts General Hospital, MGH, as part of a cooperative project between the hospital and the Health Physics Division of Oak Ridge National Laboratory. Eleven patients with terminal conditions were injected with uranium, although data obtained from three of these subjects were never published. The ORNL and the AEC undertook the Boston Project to obtain better data for the development of worker safety standards. One of the investigators wrote that the Boston Project would provide, quote, a wonderful opportunity to secure human data for the analysis and interpretation of industrial exposures, end quote. The occupational standards for uranium at the time were based on animal data and on the experiment conducted at Rochester in the 1940s. No autopsy data were obtained from this earlier experiment at Rochester, however, since none of the patients had terminal diseases. Thus wrote a Boston Project investigator, quote, the uncertainty insofar as the distribution of uranium was concerned was not reduced by the Rochester experiment or could not even be determined, end quote. The Boston Project involved a second purpose, the search for a radioisotope that would localize in a certain type of brain tumor called glioblastomas and destroy them when activated by a beam of neutrons. This had long been the research interest of Dr. William Sweet at MGH. At the time, these tumors were clearly diagnosable and 100% fatal, and there was no effective treatment. This research involved many radioisotopes over the years, most notably isotopes of boron and phosphorus. It is unclear whether Dr. Sweet would have tested uranium without ORNL's involvement or whether it would have been made available to him by the AEC. Dr. Sweet has indicated to the committee that he was interested in the potential of uranium as a therapeutic agent prior to being approached by the AEC about the possibility of conducting a joint project. The Boston Project produced data on the distribution of uranium in the human body that the earlier Manhattan District uranium studies had not provided. The data obtained indicated that uranium, at least at the dose levels used in the Boston Project, localized in the human kidney at higher concentrations than small animal data had predicted and that therefore the maximum permissible levels for uranium in water and air might be unsafe. Recommendations made by the investigators of the Boston Project for more conservative occupational standards were apparently not heated, however. The accepted occupational levels for uranium became less rather than more conservative over the years, despite the findings of the Boston Project. Hopes that uranium would localize sufficiently in brain tumors to be of potential therapeutic use were unfulfilled. In a 1979 interview, Robert Bernard, one of the health physicists at ORNL, most intimately involved with the study, was asked if during the experiment uranium was showing any promise as a treatment. No, it concentrated in the kidney just like Rochester said back in the 40s. They got brain tumor samples. There was very little uranium present, but sweet was still wondering. Maybe it was not a high enough dose. In a 1995 interview, Carl Morgan, head of the Health Physics Division of ORNL at the time of the Boston Project, indicated that the project was ultimately discontinued in 1957 because of the concerns of an ORNL health physicist. He felt that the patients were given very large doses of uranium, which our data had indicated, that is, the data we collected at ORNL, in setting permissible doses would be very harmful. I immediately canceled our participation in the program. Apparently they were given doses that were many times the permissible body burden. In their application to their radioisotope committee, MGH investigators clearly recorded that the proposed dose of 2.12 REM per week, quote, exceeds maximum permissible exposure rate of 0.3 REM per week, but patients are terminal, end quote. At least one of the subjects was selected for the distribution part of the study only. Reports describe the patients as, quote, virtually all, end quote, having malignant brain tumors. Newly available documents indicate that at least one patient injected with uranium did not have a brain tumor at all. An unidentified male, identity and age still unknown at the time of his death, became Boston Project subject, Roman numeral 6, when he, quote, was brought to the emergency ward after being found unconscious. No other information was obtainable, end quote. According to his autopsy report, this patient was suffering from a subdural hematoma, a severe hemorrhage on his brain. There was clearly no benefit intended for this patient from the injection of uranium, but there is evidence of harm attributable to the injection. His autopsy report records clinical evidence of mild kidney failure and pathological evidence of nephrosis damaged to the kidney tubules from the chemical toxicity of uranium metal. The report also records that, quote, the liver, spleen, kidneys and bone marrow showed evidence of radiation, end quote. Even for the patient subjects with brain cancer, there was no expectation on the part of investigators that the experiment would benefit the subjects themselves. The object of the experiment was to test whether uranium would localize sufficiently in brain tumors to be of therapeutic value in the future. In order for uranium to have had therapeutic potential for patient subjects, exposure to a reactor's neutron beam would have been necessary to then activate the uranium, if it had localized sufficiently in the tumors, which it did not. There was, however, no plan to expose these patients to a neutron beam. The goal was to see whether the concentration would justify further research that would involve exposure to a neutron beam. Most of the subjects were already comatose, end quote, in the terminal phase of severe irreversible central nervous system disease, end quote. The doses used in the Boston Project were high. The lowest dose was comparable to the highest used in the earlier Rochester uranium experiment, a dose that had caused detectable kidney damage in one of the Rochester subjects. One document records that at least two Boston Project subjects, in addition to subject Roman numeral 6, had kidney damage at the time of death, although this document does not directly link this damage to the uranium injections. There is no discussion of consent in any of the Boston Project reports. It appears that ORNL left such considerations to Dr. Sweet and MGH. In an interim report, ORNL discusses the division of responsibility in the experiment, quote. It was agreed that the Y-12 Health Physics Department at Oak Ridge would prepare injection solutions and perform the analytical work associated with this joint effort. Massachusetts General Hospital agreed to select the patients, perform the injections, and care for the patients during the period of study, end quote. Dr. Sweet told the advisory committee in 1995 that it was his practice to obtain consent from patients or from their families, end quote, scrupulously to give a patient all the information we had ourselves, end quote. The committee has not been able to locate any documents that bear on questions of disclosure or consent for this experiment. The case of the Boston Project subject who was brought into the hospital after being found unconscious and who, according to his autopsy report, was never identified and never regained consciousness indicates that this rule was not applied universally. End of Section 30. Recording by Patrick McAfee, Evanston. Section 31 of final report of the advisory committee on human radiation experiments. This is a LibriVox recording. All LibriVox recordings are in the public domain. For more information or to volunteer, please visit LibriVox.org. Recording by Patrick McAfee, Evanston. Final report of the advisory committee on human radiation experiments. Case studies, Chapter 5, Part 5. Conclusion. From 1945 through 1947, Manhattan Project researchers injected 18 human subjects with plutonium, 5 human subjects with polonium, and 6 human subjects with uranium to obtain metabolic data related to the safety of those working on the production of nuclear weapons. All of these subjects were patients hospitalized at facilities affiliated with the universities of Rochester, California, and Chicago, or at Oak Ridge. Another set of experiments took place between 1953 and 1957 at Massachusetts General Hospital, in which human subjects were injected with uranium. In no case was there any expectation that these patient subjects would benefit medically from the injections. At 50 years removed, it is in some respects remarkable that so much information has survived that bears on the question of what the patient subjects and their families were told. Particularly for the Manhattan Project plutonium experiments, information is available in large part because of the 1974 AEC inquiry in which interviews with principles of these experiments were conducted and records of these interviews maintained. At the same time, however, there are significant gaps in the record for all the experiments. Particularly where the evidence is skimpy, it is possible that some of the patient subjects agreed to be used in non-therapeutic experiments, but the picture that emerges suggests otherwise. This picture is bolstered by the historical context. As we discussed in Chapter 2, it was not uncommon in the 1940s and 1950s for physician investigators to experiment on patients without their knowledge or consent, even where the patients could not benefit medically from the experimental procedures. This context is referenced in a 1946 letter about the University of California injections. These doctors state that the injections would probably be made without the knowledge of the patient. Such injections were not divergent from the normal experimental method in the hospital. Here we present our conclusions about the ethics of these experiments. First for the set of experiments conducted between 1945 and 1947, and then for the experiment conducted from 1953 to 1957. Because the facts appear to be different in the different institutions at which these experiments took place, we summarize what we have learned about risk, disclosure, and consent at each location. We also analyze the ethical issues the experiments raise in common. In our analysis we focus on whether the subjects consented to being used in experiments from which they could not benefit medically, and the extent to which the subjects were exposed to risk of harm. We also focus on the particular ethical considerations raised when research is conducted on patients at the end of their lives. All but one member of the advisory committee believe that what follows is the most plausible interpretation of the available evidence in light of the historical context. In any exception, the historical record suggests that these patients' subjects were not told that they were to be used in experiments for which there was no expectation they would benefit medically, and as a consequence it is unlikely they consented to this use of their person. In the case of the plutonium experiments, there was no reason to think that the injections would cause any acute effects in the subjects. This was not true, however, in the case of the Rochester uranium experiments. Both the plutonium and the Rochester uranium experiments put the subjects at risk of developing cancer in 10 or 20 years time. In some cases this risk was eliminated by the selection of subjects who were likely to die in the near future. The selection of subjects with chronic illnesses was also an apparent strategy to contain this long-term risk of cancer. However, some of these subjects lived far longer than 10 years, and some were misdiagnosed altogether. On the basis of available evidence, we could not conclude that any individual was or was not physically harmed as a result of the plutonium injections. There is some evidence that there were observable subclinical bone changes of unclear significance in at least two surviving subjects who were followed up in 1953 and 1973 and in one deceased subject who was exhumed in 1973. The uranium injections at Rochester were designed to produce minimal detectable harm. That was the end point of the experiment. Such minimal damage is reported to have occurred in the sixth patient of the series. In the case of Mr. Cade at Oak Ridge, a physician claiming to have injected Mr. Cade reported that his consent was not obtained. An apparently healthy man in his early fifties, Mr. Cade was put at some probably small risk of cancer by the plutonium injection. At the University of Chicago, the only evidence that bears on disclosure and consent comes from an interview with a Chicago investigator conducted as part of the AEC's 1974 inquiry. The investigator was recorded as saying that in obtaining consent, patients were told that the radioactive substance to be injected, quote, was not necessarily for the benefit of the patients but might help other people, end quote. This statement is misleading. It suggests that there was some chance these patient subjects might benefit when there was no such expectation. At the same time, however, this statement suggests that the subjects at Chicago were told something. These subjects also were all apparently terminally ill and thus at no risk of developing plutonium-induced cancer. At least two of the three were known to have died within one year of the injection. Misleading language was purportedly also used with subjects at the University of California, where a second hand account suggests that subjects were told they were to be injected with a new substance that, quote, had some properties like other substances that had been used to control growth processes in patients, end quote. Language in a 1946 letter suggests that at least some of the injections at the University of California may have occurred altogether without the knowledge of the patients. In the case of Mr. Allen, one of the California subjects, two physicians attested that the experimental nature of the procedure had been explained to Mr. Allen and that he had consented. And yet Mr. Allen's physician was subsequently informed that the follow-up studies were in relation to treatment Mr. Allen had received at the University of California. This suggests that while Mr. Allen may have been told the procedure was experimental, it is not likely he was told that the procedure was part of an experiment in which there was no expectation that he would benefit medically. Both Mr. Allen and Mr. Stevens survived long enough after injection to be at risk of plutonium-induced cancer. All the available evidence suggests that none of the subjects injected with either plutonium or uranium at Rochester knew or consented to their being used as subjects in experiments from which they could not benefit. This evidence comes from recollections of some of the individuals who were involved with the plutonium injections as well as documents about seminars and follow-up studies in the early 1950s suggesting that information about the experiments should be concealed from the subjects. Most of the subjects at Rochester had serious chronic illnesses. It is unclear how likely it was at the time that these patients would not survive more than 10 years. A few of these subjects were still alive more than 20 years after the injections. None of the plutonium subjects but all of the uranium subjects were put at risk of acute effects from the experiment. The purpose of the 1973 follow-up studies was withheld from two surviving subjects. Also, both Elmer Allen's physician and family members of deceased subjects were misled by AEC officials about the purpose of the follow-up studies. They were told that the follow-up was in relation to past medical treatment, which was not true. It is unlikely that AEC officials would have lied about or otherwise attempted to conceal the purpose of the follow-up studies if at the outset the subjects had known and agreed to their being used as subjects in non-therapeutic experiments. It is also relevant that when the Atomic Energy Commission succeeded the Manhattan Project on January 1, 1947, officials decided to keep the plutonium injections secret. It appears that this decision was based on concerns about legal liability and adverse public reaction, not national security. The documents show that the AEC responded to the possibility that consent was not obtained in the plutonium experiments, as well as their lack of therapeutic benefit by stating requirements for informed consent and therapeutic benefit for future research while still keeping the experiments secret. As a result of the decision to keep the injections secret, the subjects and their families, as well as the general public, were denied information about these experiments until the 1970s. The one likely exception to this picture of patients not knowing that they were used as subjects in experiments that would not benefit them is the plutonium experiment conducted at Rochester. This is the one instance in which the patient subjects are said to have volunteered after being told about, quote, the general problem, end quote. Although there is no direct evidence that these subjects were told that the experiment was not for their benefit, the language of volunteering suggests a more forthright disclosure was made, more in keeping with the conventions in non-therapeutic research with healthy subjects than in research with patients C Chapter 2. We cannot reconcile the account of the plutonium experiment with the historical record on the other injections. The advisory committee has persuaded that these experiments were motivated by a concern for national security and worker safety and that particularly in the case of the plutonium injections, they produced results that continue to benefit workers in the nuclear industry today. However, with the possible exception of the plutonium experiments, we believe that these experiments were unethical. In the conduct of these experiments, two basic moral principles were violated. That one ought not to use people as a mere means to the ends of others, and that one ought not to deceive others in the absence of any morally acceptable justification for such conduct. National security considerations may have required keeping secret the names of classified substances, but they would not have required using people as subjects in experiments without their knowledge, or giving people the false impression that they or their family members had been given treatment when instead they had been given a substance that was not intended to be of benefit. The egregiousness of the disrespectful way in which the subjects of the injection experiments and their families were treated is heightened by the fact that the subjects were hospitalized patients. Their being ill and institutionalized left them vulnerable to exploitation. As patients, it would have been reasonable for them to assume that their physicians were acting in their best interests, even if they were being given experimental interventions. Instead, the physicians violated their fiduciary responsibilities by giving the patients substances from which there was no expectation they would benefit and whose effects were uncertain. This is clearest at Rochester, where at least the uranium subjects and perhaps the plutonium subjects were apparently the personal patients of the principal investigator. Concern for minimizing risk of harm to subjects is evident in several of the planning documents relating to the experiments, an obligation that many of those involved apparently took seriously. At Chicago, for example, where the highest doses of plutonium were used, care was taken to ensure that all the subjects had terminal illnesses. In those cases where this concern for risk was less evident and subjects were exposed to more troubling risks, the moral wrong done in the experiments was greater. Where it was not reasonable to assume that subjects would be dead before a cancer risk had a chance to materialize, or in the case of the uranium injections at Rochester, where acute effects were sought, the experiments are morally offensive. Consideration for the basic moral principle that people not be put at risk of harm is apparently what animated the decision to give higher doses to only terminal patients who could not survive long enough for harms to materialize. A person who is dying may have fewer interests in the future than a person who is not. This does not mean, however, that a dying person is owed less respect and may be used like an object as a mere means to the ends of others. There are many moral questions about research on patients who are dying. The desperation of their circumstances leaves them vulnerable to exploitation. At a minimum, non-therapeutic research on a dying patient without the patient's consent or the authorization of an appropriate family member is clearly unethical. Uranium was also injected in 11 patients with terminal conditions at Massachusetts General Hospital in an experiment conducted jointly by the Hospital and Oak Ridge National Laboratory from 1953 to 1957. ORNL's purpose was to obtain data for setting nuclear worker safety standards. A second purpose was to identify a radioisotope that would localize in brain tumors and destroy them when activated by a neutron beam. Although all but one of the patient subjects had brain cancer, the limited purpose of the experiment to establish whether uranium would localize sufficiently meant that there was no expectation that patient subjects might benefit medically from the uranium injections. The uranium doses in the Boston experiment were comparable to or higher than the one that caused measurable physical harm in the Rochester subject. Boston subjects were apparently subjected to brain biopsies, presumably solely for scientific purposes. At least three Boston subjects showed kidney damage at the time of death. In one of these cases, a trauma victim who was found unconscious, the autopsy report recorded clinical evidence of some amount of kidney failure and pathological evidence of kidney damage due to the chemical toxicity of uranium. The only evidence available about what the Boston subjects were told comes from 1995 testimony of one of the investigators, Dr. William Sweet, who said it was his practice to, quote, give a patient all the information we had ourselves, end quote. Presumably, this would have included that the injections had no prospect of benefiting the patient. The Boston project was an instance in which high doses were given to dying patients. Some of these patients were comatose or otherwise suffering from severe irreversible central nervous system disease. Unless these patients or the families of comatose or incompetent patients understood that the injections were not for their benefit and still agreed to the injections, this experiment also was unethical. There was no justification for using dying patients as mere means to the ends of the investigators and the AEC. In at least one case, this disrespectful treatment clearly occurred. The trauma victim who arrived at the hospital unconscious was used as a subject, despite the fact that his identity was never known. Presumably, he was not accompanied by any family or friends who might have authorized such a use of his body. Only extraordinary circumstances can justify deception and the use of people as mere means by government officials and physicians in the conduct of research involving human subjects. In the case of the injection experiments, we see no reason that the laudable goals of the research could not have been pursued in a morally acceptable fashion. There is no reason to think that people would not have been willing to serve as subjects of radiation research for altruistic reasons, and indeed there is evidence of people writing to the AEC to volunteer themselves for just such efforts. That people are not likely to live long enough to be harmed does not justify failing to respect them as people. Concerns about adverse public relations and legal liability do not justify deceiving subjects, their families, and the public. Insofar as basic moral principles were violated in the conduct of the injection experiments, the Manhattan Engineer District, the AEC, the responsible officials of these agencies, and the medical professionals responsible for the injections are accountable for the moral wrongs that were done. End of section 31. Recording by Patrick McAfee, Evanston. Case studies, chapter 6, part 1. The AEC program of radioisotope distribution. At the dawn of the atomic age, many people hoped for dramatic advances in medicine, akin to the new miracle drug penicillin. Many of these hopes have been fulfilled. Radioisotopes have become remarkable tools in three areas. First, as their travels within the body are traced, radioisotopes provide a map of the body's normal metabolic functions. Second, building on tracer research, diagnostic techniques distinguish between normal and abnormal functioning. Finally, radioisotopes carried by the body's own processes to abnormal or cancerous cells can deliver a lethal dose of radiation to those undesirable cells. By supplying radioisotopes and supporting their use, the Atomic Energy Commission, AEC, actively promoted the research needed to achieve this progress. The growth in the applications of radioisotopes involve thousands of experiments using radioisotopes. No feasible method was found to review in detail the vast number of individual radioisotope experiments in the advisory committee's database. This was due not only to the large number of experiments, but also to the scarcity of information about many of the individual experiments. Both consent and exact dose levels were often not discussed in public work. No federal repository was found that had collected records documenting these aspects of experiments. Given the decentralized structure of American medicine, it is not surprising that the committee found that records on consent and exact dose, if they exist, would still be at the local institutions conducting research, or perhaps even in the private papers of physicians and scientists. Even when records were found at the local level, there was little documentation about consent. Thus for the largest group of human radiation experiments, little documentation remains, and a meaningful examination of all such experiments was not possible. The committee instead chose to focus its energies in two directions, examining the overall system of oversight created by the federal government, and examining small subsets of radioisotope experiments that posed significant ethical issues. The first effort led to this chapter, an overview of the system created by the federal government to monitor radioisotope experiments. The second effort led to the case study on experiments involving children. Chapter 7. Since those raised questions about additional biological risk and justification for doing non-therapeutic research on minors. The AEC's isotope distribution program was faced with three essential ethical questions. The most immediate question concerned the allocation of a scarce resource. Given the likelihood that demand for radioisotopes would exceed supply, how should priorities be set? The question involved not simply the choice among competing proposals for human uses, including experimentation, treatment of disease and diagnosis, but between human uses and other kinds of uses, for example basic scientific research or industrial uses. Another immediate question was the safety with which this new material would be used. Since the government was actively promoting the use of radioactive isotopes, it had an obligation to ensure their safe use. Harm to patients, physicians and others involved could arise from inexperienced and untrained users of radioisotopes. When properly used in trace amounts, radioisotopes posed risks well below those deemed acceptable in occupational settings. Balancing risks versus benefits and seeking means to decrease risks and increase benefits as the field developed was a major ethical obligation. Finally, there was the question of the relationship between researcher and subject, or precisely the question of the authorization for use in humans and the process of disclosure and consent, if any, to be followed. These uses can be divided into one, therapeutic diagnostic uses, two, therapeutic diagnostic research, and three, non-therapeutic research. As we shall see, great attention was paid initially to the question of resource allocation, but supplies soon proved far greater than expected, and the need for this attention evaporated. The control of the risk posed by the use of AEC provided radioisotopes was also a source of intense focus from the outset and remained so as the program grew. By contrast, notwithstanding the 1947 decorations by AEC General Manager Carol Wilson on the importance of consent, the matter of consent received only limited attention in the early years of the program. Origins of the AEC Radioisotope Distribution Program in the Manhattan Project The medical importance of radioisotopes was recognized before World War II, but distribution was unregulated by government. The post-war program for distributing radioisotopes grew out of the part of the Manhattan Project that had developed the greatest technical expertise during the war, the isotopes division of the research division at Oak Ridge. Production of useful radioisotopes required extensive planning for both their physical creation and their chemical separation from other materials. Plans to distribute radioisotopes to medical researchers outside the Manhattan Project were developed in the final year of the project. In June 1946, the Manhattan Project publicly announced its program for distributing radioactive isotopes. The new world of radioisotope research was to be shared with all. Most research would be unclassified. In enthusiastic science magazine reported, production of tracer and therapeutic radioisotopes has been heralded as one of the great peacetime contributions of the uranium chain-reacting pile. This use of the pile will unquestionably be rich in scientific, medical and technological applications. An article in the New York Times magazine told readers that properly chosen atoms can become a powerful and highly selected weapon for the destruction of certain types of cancer. Until now, the doctors and biologists have had to plea for samples of isotope material from their brothers in the cyclotron laboratories. Now the picture has changed in a revolutionary way. The government has adapted one of the Oak Ridge uranium piles to the mass production of radioactive, byproduct material. Extensive planning led up to this public announcement. Although the initial expectations were that basic research would proceed extensive medical applications from the very beginning, official plan for clinical investigation with humans. In doing so, they recognized that the administration to humans places extreme demands, both moral and legal, upon the specifications and timing of the radioisotope material supplied. The recognition of special moral and legal aspects of human experimentation and reliance on the professional competency of those administering radioisotopes formed the cornerstones of the radioisotope distribution systems over side of experiments. Significantly, however, the system was not designed to oversee consent from subjects prior to the administration of radioisotopes. Radioisotopes could not simply be ordered from the Manhattan engineered district. Each purchase had to be reviewed and approved. For human applications, each application was reviewed by a special group of experts. The advisory subcommittee on human application of the interim advisory committee on isotope distribution policy of the Manhattan Project. According to one of the initial planners, the chief reason for setting this group up as a separate entity from the research group, another subcommittee, is that of medical legal responsibility involved in the use or treatment of humans experimentally or otherwise. When the AEC began its work, this subcommittee continued but was renamed the subcommittee on human applications of the committee on isotope distribution of the AEC. In 1959, it was absorbed into the advisory committee on medical uses of isotopes. In 1974, the AEC's responsibilities were transferred to the Nuclear Regulatory Commission. Coupled with this review was a requirement that those wishing to purchase radioisotopes demonstrate the special competence required for working with radioactive materials. This mechanism for centralized nationwide review was unusual at the time it was begun. The breadth of the subcommittee's purview can be seen in the range of proposals examined. Although the advisory committee is concerned primarily with medical research, the AEC's subcommittee review extended well beyond this realm. Apparently the subcommittee reviewed all proposed uses for radioisotopes that might result in the exposure of humans to radiation. These included, for example, using Cobalt-60 in nails and wooden survey stakes, probably to assist in later locating them. Sulphur-35 in firing underground coal mines and E-trium-90 as a tracer gasoline in simulated airplane crashes. Its jurisdiction was limited to byproduct material, however, and did not extend a fissionable material such as plutonium and uranium. Soon after the Manhattan Project's public announcement, both the radioisotope distribution system and its oversight structure began operation. On June 28, 1946, the subcommittee on human applications held its first meeting. Attending as members were Dr. Andrew Dowdy, chairman and biophysicist Giocino Faila. Dowdy was director of the University of Rochester's Manhattan Project division, while Faila was a professor at Columbia University and consultant to the meturgical laboratory in Chicago. Not attending was the third member of the subcommittee, Dr. Heimer Friedel, executive officer of the Manhattan Project's medical section. Attending as non-voting secretary was Paul Aversold in charge of the production of radioisotopes at Oak Ridge, later to head the AEC's isotope division. His efforts to promote the use of radioisotopes later earned him the nickname Mr. Isotope. Also attending as advisors from Oak Ridge were W. E. Cohn, the author of the original memorandum proposing a system for distributing radioisotopes, and Carl Morgan, director of health physics at Oak Ridge, who would over the years become a leading figure in the establishment of occupational exposure limits for radioisotopes. Although the primary task of the subcommittee was to oversee safety at the time, many expected a shortage of radioisotopes, thus much of this first meeting was taken up with a discussion of priorities for allocation. As it happened, supply exceeded demand within one year. It was in the context of this discussion of allocation, not a discussion of safety or ethics, that a system of local committees was suggested. Each local committee, also called local isotope committee at this meeting, would include A. a physician well versed in the physiology and pathology of the blood-forming organs. B. a physician well versed in metabolism and metabolic disorders. C. a competent biophysicist, radiologist, or radiation physiologist, qualified in the techniques of radioisotopes. The main advantage of a system of local committees were administrative efficiency and delegation of prioritization for scarce isotopes. The primary functions of each local isotope committee were coordination, allocation, and safety. Evidently no mention was made of overseeing subject consent. At this first meeting, the subcommittee had before it no actual request to evaluate. Even so, members did agree on the general principles on which they would deny a request. A. the requesters are not sufficiently qualified to guarantee a safe and trustworthy investigation. B. insufficient knowledge exists to permit a safe application of the material and the proposed human cases. There was no elaboration of crucial terms such as qualified, safe, and trustworthy, insufficient knowledge, and safe application. Although no standards of adequate consent were mentioned, this degree of oversight was unusual in medical research during this time, and even later. Although it had no specific request before it, the subcommittee did consider the anticipated uses of some isotopes. The uses of some isotopes were apparently rejected, not only because of the hazards of radiation, but also because of chemical toxicity and the availability of less hazardous alternatives. For others, specific limits were set. For example, the subcommittee was especially cautious concerning isotopes of strontium because it concentrated in bone, as did radium, which was known to be hazardous from the pre-war experience of the dial painters. The subcommittee set a specific exposure limit, the SR90 and Y90 daughter, should not contribute in excess of 1% to the total rate of beta disintegration. Such general guidelines have little effect unless a procedure is established for their implementation. At its first meeting the subcommittee set out in detail the mechanism for its own future operation. What the subcommittee would be reviewing were requests to purchase isotopes for any use in human beings. Only after the subcommittee approved a request would the isotope be sold and shipped to the researcher. The need for speed in responding to requests for human uses was recognized. Details of the procedure for purchasing isotopes were disseminated to potential users through a brochure issued in October 1946 by the isotopes branch at Oak Ridge. Most of the brochure concerned the paperwork, which, among other things, ensure that the subcommittee on human applications would actually be notified of all applications for human use. The last stage of the purchase procedure indicates the underlying concern with legal liability. Although Manhattan Project approval was required, the actual purchase was from the private contractor operator of the Clinton Laboratories, later designated the Oak Ridge National Laboratory in Oak Ridge, at that time Monsanto Chemical Company. The final purchase agreement contained a clause relieving both the government and the private contractor for many responsibility for injury to persons or other living material or for any damage to property in the handling or application of this material. The Manhattan Project also required the purchaser to file with the isotopes office, a statement required by Section 505A of the Federal Food, Drug and Cosmetic Act. However, the advisory committee found no evidence of direct involvement by the FDA at that time in the planning or operation of the radio isotope distribution program. By October 1946 the distribution program was well underway, 217 requests had been received, of these 211 had been approved, human use requests totaled 94 of which 90 had been approved. The AEC assumes responsibility for radio isotope distribution. When the AEC took over responsibility for the program on January 1, 1947, the structure of the radio isotopes distribution system remained intact. The subcommittee on allocation and the subcommittee on human applications remained as standing subcommittees of the interim committee on isotopes distribution policy, which became known as the advisory committee on isotope distribution policy. The forms developed by the Manhattan Project were reissued as AEC forms without substantial revision. The system of application from private users, review, purchase and distribution continued to operate. At first there appears to have been some confusion over the responsibility of the AEC for its own research program and for its program to distribute radio isotopes to private researchers. As discussed in Chapter 1, two 1947 letters from AEC General Manager Carol Wilson describe strong consent requirements. The April letter to Stafford Warren was expressly directed to the terms on which research conducted by AEC contractors, including universities, would be approved. The November letter was sent to Robert Stone. As we have discussed those clear statements to contract, researchers do not seem to have been made to those applying for radio isotopes. This confusion about the relationship between contract research and isotope distribution is discussed in a September 26, 1947 memorandum from J. C. Franklin, Manager of Oak Ridge Operations, to Carol Wilson. Other correspondence also indicates confusion over whether the AEC's own labs, which were themselves often operated by contractors, were to follow the procedures for the radio isotope distribution program, which would have placed their human use requests before the subcommittee on human applications. Initially requests for by-product materials from within the AEC used to form that did not specify whether the radio isotope was to be used on humans. By August 1949, Shields Warren, Director of the AEC's Division on Biology and Medicine, had directed that human use by AEC laboratories be subject to review by the subcommittee on human applications. However, when regulations governing radio isotope distribution were first promulgated, AEC-owned facilities were specifically exempted from all such regulations. Warren's goal was achieved instead by a memorandum from Carol Wilson in July 1950. This memorandum discontinued use of the earlier form, and directed that all requests used the same form used by outside purchasers, which directed human use requests to the subcommittee on human applications. End of Section 32 Section 33 of Final Report of the Advisory Committee on Human Radiation Experiments This is a LibriVox recording. All LibriVox recordings are in the public domain. For more information or to volunteer, please visit LibriVox.org. Final Report of the Advisory Committee on Human Radiation Experiments Case Studies, Chapter 6, Part 2 The AEC Subcommittee on Human Applications At the heart of overseeing the expansion of the use of radioisotopes was the Subcommittee on Human Applications of the AEC's Advisory Committee on Isotope Distribution. Applications had to have been approved by a local isotope committee before even being considered by the subcommittee. The subcommittee itself conducted most of its reviews by mail. Unfortunately, only fragmentary records of this correspondence have been found. The subcommittee formally met only once a year to discuss general issues. By its second meeting, in March 1948, membership had grown to four. Dowdy was no longer on the subcommittee. Joseph Hamilton and A. H. Holland had been added. Hamilton was, as described in Chapter 5, a physician investigator with the University of California's Radiation Laboratory in Berkeley. Holland was a physician investigator who became medical director at the AEC's Oak Ridge Operations in late 1947. As we shall see in Chapter 13, he played a central role in the question of the declassification of secret experiments. As the subcommittee continued to examine each case on its own merits, it began to generate principles for general guidance. In doing so, it began to categorize experiments apparently according to the degree of hazard posed. One category was tracer studies in normal adult humans using beta and gamma emitters with half-lives of twenty days or fewer. Applications needed to include information on biodistribution and biological half-life of the radioisotope, based either on animal studies or references to the literature. A second category was studies in normal children. In 1948 the subcommittee did not issue detailed guidelines, but instead simply stated that such applications would be given special scrutiny by the subcommittee on human applications. In 1949 it issued more detailed guidelines, which indicate that the concern was with minimizing risk, not requiring or overseeing consent. In general, the use of radioisotopes in normal children should be discouraged. However, the subcommittee will consider proposals for use in important researches, provided the problem cannot be studied properly by other methods, and provided the radiation dosage level in any tissue is low enough to be considered harmless. It should be noted that in general the amount of radioactive material per kilogram of body weight must be smaller in children than that required for similar studies in adults. Coupled with the children's category in 1949 were studies on pregnant women. The use of radioactive materials in all normal pregnancies should be directly discouraged where no therapeutic benefit is to be derived. Although not specifically mentioned in the minutes, such a policy may, like research in normal children, have been waived for important researches that could not otherwise be undertaken. One recurring difficulty was the problem of deciding when an application could be considered safe. There was no simple mechanical process for making such a judgment. This can be seen in the subcommittees detailed consideration of an application for Phosphorus 32 to be used in a blood volume study of children. The amount of radioactivity proposed ranged from one fourth to one microcurie per kilogram of body weight. Initially three of the four members approved the application and the allocation was made. However the fourth member, replying late, reopened the question. Following reconsideration by the entire subcommittee three of the four members concluded the original application for use on children should be turned down and the investigator was asked to revise the application to state the importance of making the study in children and to keep the amount of activity less than one half microcurie per kilogram. The reduction in the allowable amount of activity illustrates both the diligence with which the subcommittee pursued its task and the inherent difficulties in making judgments about what constituted safe practices in a rapidly developing field of research. The subcommittee's task was made a bit easier when considering applications with adults where it could draw upon occupational guidelines. Requests for long-lived radioisotopes were placed in a third category defined as those with a biological half-life greater than twenty days. In contrast with experiments on children here the subcommittee was willing to set a general dose limit. The dosage in the critical tissue should be such as to conform to the limitation stated by the National Committee on Radiation Protection. The NCRP, now the National Council on Radiation Protection and Measurements, is an independent organization that publishes occupational radiation protection guidelines based on expert reviews of contemporary scientific knowledge. As with children such applications must be reviewed separately. The subcommittee did not wish this limit to be ironclad. In special cases, however, the subcommittee on human applications may permit the use of radioisotopes in higher dosages. At this point the subcommittee appears to have been establishing general principles. No specific radioisotopes or particular research proposals are mentioned. A final category was applications using radioisotopes with long half-lives in patients with short life expectancies. The term moribund was used in correspondence by Paul Ebersold prior to the second meeting of the subcommittee in March 1948. He wrote to the subcommittee members explaining that the item was on the agenda because requests for such work had been received. He referred to a written request from a physician at Massachusetts General Hospital to use Calcium 45 and an oral request from a staff member at Presbyterian Hospital in Chicago to use testosterone labeled with Carbon 14. Ebersold did not provide any details as to the purposes of the proposed research. The issue was what policy to adopt when the patients were predicted not to live long enough for long-term hazards to develop. Ebersold told the subcommittee that this office feels that such requests should be allowed if a satisfactory mechanism for determining the moribundness of the patients in question is established. We believe that this question should be decided by a group of doctors and written evidence signed by the group filed with the isotopes division prior to the use of the material. The subcommittee had no objection to the basic principle of applying larger doses to patients with short life expectancies, but its language was more oblique than Ebersold's letter. It is recognized that there may be instances in which the disease from which the patient is suffering permits the administration of larger doses for investigative purposes. Safeguards were to be provided by reliance on the judgment of local physicians, not on a precise definition of moribund. Indeed the subcommittee did not even use that term. Applications would be approved providing, one, full responsibility for conduct of the work is assumed by a special committee of at least three competent physicians in the institution in which the work is to be done. This will not necessarily be the local radioisotope committee. Two, the subject has given his consent to the procedure. Three, there is no reasonable likelihood of producing manifest injury by the radioisotope to be employed. No further explanation was given of how the second requirement, giving consent, would be fulfilled by a moribund patient, nor was additional guidance provided to clarify the third criterion. One instance in which this policy was applied took place at the Walter E. Fernald State School in Massachusetts, C.7. Correspondence between the researchers and the AEC indicates that the AEC allowed the administration of 50 microcuries of calcium 45, 50 times the amount the AEC allowed the researchers to administer to other subjects in the study, to a ten-year-old patient with a life expectancy of a few months, suffering from Hurler-Hunter syndrome, a degenerative disease of the nervous system. In applying for the radioisotope, Dr. Clemens Benda, the researcher, noted that permission for the use of higher doses administered to moribund patients has been granted by you to other investigators. This subject was part of a study of calcium metabolism approved by the superintendent of the school. Students had been described as voluntarily participating in a letter sent earlier to the parents, asking if they objected, but that did not mention the use of radioactive tracers. Lack of response from a parent was presumed to be approval. The subject with Hurler-Hunter syndrome was found to have abnormal calcium metabolism, but died before the study could be completed. Even as it developed procedures for unusual cases, the subcommittee recognized that some existing uses were becoming routine and did not need to be continuously reviewed by the subcommittee itself. The subcommittee delegated the review of such requests to the isotopes division, setting out the criteria to be applied. Such applications should be justified by A. a commensurate increase in patient load, B. an expanded research program, C. provision of adequate storage and handling facilities, D. assurance that personnel protection and supervision are adequate for the larger amounts requested. An additional simplification occurred with the introduction in 1951 of General Authorizations, which delegated more authority to the local radioisotope committees of approved institutions. These authorizations enabled research institutions to obtain some radioisotopes for approved purposes after filing a single application each year, therefore eliminating the need to file a separate application for each radioisotope order. As such they also reduced the oversight of the AEC's subcommittee on human applications, as each order was no longer reviewed individually. However, at first the General Authorizations did not apply to human use, and when they were expanded to human use in 1952 they were limited to certain radioisotopes for clinical use and excluded radioisotopes in cancer research, therapy and diagnosis. Both the AEC and the subcommittee reacted strongly when proper bureaucratic procedures were not followed. One example was a private industrial lab that used iodine-131 for a human study that had not been properly reviewed. Even though no one was harmed, the AEC threatened to suspend shipments of all radioisotopes, not just iodine-131. Such an action would have put the company out of business. Abersold, at the direction of the committee, notified the company president that while the incident did not lead to any unfortunate results from the standpoint of radiation hazard, a recurrence of this type of violation should result in cessation of all shipment of radioactive materials to Tracer Lab Incorporated. For his part the company president reacted by notifying employees that such action would be grounds for automatic dismissal. Thus, as it proceeded in its work of evaluating individual applications, the subcommittee developed more general principles such as categories of human use based upon risk and updating of criteria based upon developing knowledge. The goal, as the AEC's director of research K. S. Pitzer stated in 1950, was to make radioisotopes as nearly as possible ordinary items of commerce in the technical world. For example, cancer researchers initially received radioisotopes at no charge. The free program was changed to an 80% discount program in 1952 and ended in July 1961. AEC regulations and published guidelines. An important step towards making the use of radioisotopes a component of medical practice routine was formally enacting regulations governing the use of isotopes. The first regulations were enacted in 1951. These early regulations essentially promulgated facility and personnel requirements without establishing dose limits or mentioning the consent requirement established in 1949 for administering larger doses to very sick patients. Throughout the 1950s changes in the regulations dealt with administrative procedures, other concerns about radioisotope use, such as consent requirements, were disseminated through circulars, brochures, and guides of the isotopes division. In 1948 the circular describing medical applications was only three pages long. By 1956 it had been replaced by a 24-page guide that provided detailed requirements for many different applications of isotopes. This greater precision can be seen, for example, in the guidelines for terminal patients. By the time of the 1956 guide, the use of radioisotopes with half-lives greater than 30 days ordinarily would not be permitted without prior animal studies establishing metabolic properties unless patients had a short life expectancy. The judgment of local physicians was now to be guided by a more exact definition. Exceptions would be limited to patients suffering from diseased conditions of such a nature, life expectancy of one year or less, that there is no reasonable probability of the radioactivity employed producing manifest injury. However, while a more precise definition of terminal was now provided, there was no longer an explicit mention of a specific requirement for consent from these patient subjects as had been made earlier. Consent was required, though, in the section of the 1956 guide on the use of radioisotopes in normal subjects for experimental purposes. Presumably normal here means healthy. This section included the earlier provisions that the tracer dose does not exceed the permissible body burden, and that such experiments not normally be conducted on infants or pregnant women. It also, however, included a new provision that such experiments were to be limited to volunteers to whom the intent of the study and the effects of radiation have been outlined. The term volunteer would seem to imply a requirement that consent be obtained following a disclosure of information to potential subjects. The disclosure requirement does not include, however, all of the elements of information that today are included in duties to obtain informed consent. The 1956 consent requirement now governed all radioisotope experiments in normal subjects, a substantial expansion of the earlier requirement of consent only from terminal patients receiving larger than usual doses. It also explicitly required that both the purpose and effects of radiation be explained. It is unclear whether the failure to mention consent in the section on terminal patients was an oversight in drafting or a deliberate distinction between patients and normal subjects. The advisory committee has not found documents revealing the history of this provision nor any explanation of the choice to limit the broad consent requirement to normal subjects. This broad requirement continued over the next decade as part of AEC policy. In 1965 the AEC published the Guide for the Preparation of Applications for the Medical Use of Radioisotopes. The guide described the application process and specific policies for the non-routine medical uses of by-product material. This policy statement reiterated the exclusion of pregnant women and required that subject characteristics and selection criteria be clearly delineated in the application. Another requirement stated that applications should include confirmation that consent of human subjects or their representatives will be obtained to participate in the investigation, except where this is not feasible or in the investigator's professional judgment is contrary to the best interests of the subjects. During the 1960s the entire system of oversight of radioisotope research began to change as the Food and Drug Administration began developing a more active role in supervising the development of radiopharmaceuticals. The regulatory history of this shift in authority is complex and beyond the scope of this report. Suffice it to say that by the mid-1960s the regulation of radioisotope research was beginning to merge with the regulation of pharmaceutical research in general. End of Section 33, Recording by Maria Kasper