 CHAPTER VII. RISK OF HARM AND NON-THERAPEUTIC RESEARCH WITH CHILDREN The 21 Case Examples During the 1944-1974 period, there was an explosion of interest in the use of radioisotopes in clinical medicine and medical research, including pediatrics. The 21 research projects we review here include only a small number of all those that were likely conducted. These 21 do include, however, every non-therapeutic study that was funded by the federal government and fell in our original group of 81 pediatric radiation experiments. The table that appears at the end of the chapter provides information about the number of children involved in each of the experiments, the radioisotopes used, and the risk estimates for cancer incidents. These 21 represent a subset of 81 studies identified in documents of the Atomic Energy Commission and a review of the medical literature that met the criteria described above. All 21 projects analyzed in detail involve the administration of radioisotopes to children in order to better understand child physiology or to develop better diagnostic tools for pediatric disease. In this respect, the studies supported by the federal government do not differ from those reviewed that had other funding sources. With the exception of the study at the Rentham School to evaluate protective measures for fallout, none of the 21 experiments reviewed was related to national defense concerns. Seventeen of the 21 experiments involved the use of I-99-131 for the evaluation of thyroid function. Three examples of research reviewed by the committee will help illustrate the nature of the experiments and the risks posed to children. In the first example, investigators at Johns Hopkins in 1953 injected iodine-131 into 34 children from ages two months to 15 years with hypothyroidism and an unknown number of healthy controlled children in order to better understand the cause of this disease. Iodine is normally taken up and used by the thyroid gland for hormone production. In this experiment, a radiation detector was placed over the thyroid to detect the amount of iodine-131 taken up. Most children with hypothyroidism have an underdeveloped thyroid gland, in which case only very low levels of iodine-131 uptake will occur. Indeed, this is what the investigators found in this experiment, which was one of the first projects to use iodine-131 uptake as a measure of thyroid function in children. Hypothyroidism is a relatively common condition, one per 4,000 births, that can cause profound mental retardation if untreated. Today, better diagnostic tools for thyroid function, including radio-immuno-assay and effective thyroid hormone replacement, have virtually eliminated hypothyroidism as a cause of mental retardation in the developed world. A second example of research reviewed by the committee is an experiment by investigators at the University of Minnesota in 1951, in which four children with nephrodic syndrome were injected with an amino acid labeled with sulfur-35, along with two controlled children hospitalized for other conditions. Nephrodic syndrome is a serious pediatric condition in which protein is excreted by the kidneys in large quantities. There was controversy at the time over whether children with nephrodic syndrome have low blood protein levels solely because of renal losses, or whether they also have impaired protein production. This experiment looked at the incorporation of the radioisotope-labeled amino acid into protein, and the results suggested that the protein production in children with nephrodic syndrome is normal. A third example of research reviewed by the committee is a study of iodine-125 and iodine-131 uptake by eight healthy children performed at the Los Alamos laboratory in 1963. The purpose of the study was to evaluate the use of radioisotopes in very small doses, nano-curie levels, as a measure of thyroid function. The study demonstrated that the technique was scientifically valid, and exposed the children to smaller radiation doses than earlier methods. How can the risks posed to children in these types of experiments be estimated? The primary risk posed by the administration of radioisotopes is the potential development of cancer years, even decades, after the exposure. As will be discussed further, the risk of cancer following external radiation exposure was not well documented until the late 1950s and the early 1960s. Thus the published reports of research projects prior to that time rarely discussed the issue of long-term risks. The principles of risk assessment for radioisotopes are laid out in the basics of radiation science at the end of introduction, the atomic century. To review, the increased risk of cancer is generally assumed to be proportional to the dose of radiation delivered to the various organs of the body. This dose depends upon a number of factors, including the amount of radioactivity administered, its chemical form, which determines which organs will be exposed, and how long it stays in the body, which in turn depends upon the radioactive decay rate and the body's normal excretion rate for that substance. For many radioisotopes, the overall personal dose can be derived by the effective dose method, in which the doses to the ten most sensitive organs are computed and added together, waiting the various organs in proportion to their radio sensitivity. Thus, this effective dose can be thought of as producing the same excess risk of cancer, all sites combined, as if the whole body had received that amount as a uniform dose. This risk is then computed by multiplying the effective dose by established risk estimates per unit dose for various ages. For this chapter, the advisory committee has adopted the effective doses and risk estimates tabulated by the International Commission on Radiation Protection and the National Council on Radiation Protection. The lifetime risk estimate used in this chapter is one-one-thousandth excess cancers per rem of effective dose for children and fetuses exposed to slowly delivered radiation doses, like those from radioactive tracers. The risks of thyroid cancer following exposure to radioactive iodine, generally I-131, represent a special case for three reasons. First, use of the effective dose method is inappropriate because the dose is much greater to the thyroid than for other organs, and the lifetime risk is therefore dominated by the thyroid cancer risk. Therefore, risk is best calculated using only the thyroid dose and its associated risk. Second, the thyroid cancer risk varies even more by age than for other cancers. Third, the risk for iodine-131 has not been measured directly, but several lines of evidence suggest that it may be substantially lower than that for external radiation. For this chapter, the advisory committee has adopted estimates provided by three follow-up studies of external irradiation of the thyroid by x-rays or gamma rays in childhood. Twenty-six hundred children who received x-ray treatment for enlarged thymus glands in the first year of life, eleven thousand children who were treated by x-rays in Israel for ringworm under age ten and Japanese atomic bomb survivors under age twenty. The risk estimates from these studies were divided by three to convert them to internal iodine-131 exposures. The estimates from these studies are for cancer incidents, for mortality we have divided them by ten, since ninety percent of thyroid cancers are curable. The resulting estimates are summarized in table one. These are the same estimates used by the Massachusetts Task Force, which investigated the Fernald and Rentham experiments. We can use data from the previously described Johns Hopkins Iodine-131 study as an example. In this study, the amount of radioactivity administered was 1.75 microcuries per kilogram body weight, equivalent to 44 microcuries in a seven-year-old child weighing 25 kilograms. Based on interpolation of the tables in ICRP-53, and assuming a 13 percent thyroid uptake, this would produce a thyroid dose of 115 rem to a child aged seven. In this age range, five to nine, the lifetime risk of developing thyroid cancer would be calculated by multiplying this dose by twenty per million person-rems to produce an estimate of 2.3 cases per 1,000 exposed individuals, or 0.23 percent for a particular child. The risk of dying of thyroid cancer would be one-tenth of this, or 0.023 percent. The 21 experiments subjected to the committee's detailed risk analysis included approximately 800 children. Eleven of the studies produced estimates of average risk of cancer incidence within the range of 1 and 0.1 percent. Eight studies ranged within 0.09 and 0.01 percent, and the remaining two studies produced average risk estimates of 0.001 percent. The maximum potential risk estimate was 2.3 percent, in a few children aged one to two years at the time of exposure. The average risk of cancer incidence for the phenoled radio iron and radicalsium studies were 0.03 percent and 0.001 percent respectively, and for the renthum fallout, iodine-131 study, 0.10 percent. All of the highest risk experiments involved iodine-131, and hence the risks of dying of cancer would be about ten times smaller. See table two at the end of this chapter for further details. Based on the average risk estimate for each of the 21 experiments, we would estimate an excess cancer incidence of 1.4 cases for the entire group of 792 subjects. However, given the uncertainties built into the risk analysis, it is also possible that no excess cases resulted. Furthermore, since most of that excess would have been thyroid cancer, it is particularly unlikely that any cancer deaths would have been caused. Finally, as thyroid cancer does occur in the general population, it would be difficult to attribute these cases to an individual's involvement in research. In addition, any cases of thyroid cancer among former subjects attributable to their participation in research conducted in the 1940s and 1950s are likely to have occurred already, although there is little long-term follow-up data to know for certain what the ultimate lifetime risk might be. Table one. Summary of risk estimates for thyroid cancer from iodine-131. Exposure at various ages. Lifetime risk of cancer incidence per million exposed per rim. Males. Age 0 to 4, 27. 5 to 9, 13. 10 to 14, 6.7. 15 to 19, 1.9. Females. Age 0 to 4, 53. 5 to 9, 27. 10 to 14, 13. 15 to 19, 3.7. Both. Ages 0 to 4, 40. 5 to 9, 20. 10 to 14, 10. 15 to 19, 2.8. Lifetime risk of cancer mortality per million exposed per rim. Males. Ages 0 to 4, 2.7. 5 to 9, 1.3. 10 to 14, 0.7. 15 to 19, 0.2. Females. Age 0 to 4, 5.3. 5 to 9, 2.7. 10 to 14, 1.3. 15 to 19, 0.4. Both. Ages 0 to 4, 4.0. 5 to 9, 2.0. 10 to 14, 1.0. 15 to 19, 0.3. How do these risk figures compare with what is acceptable in non-therapeutic research today? As noted in this chapter, the contemporary regulatory standard permits children to be involved in non-therapeutic research if the research poses no more than minimal risk to the subjects. Minimal risk is defined by analogy only. A risk is minimal where the probability and magnitude of harm or discomfort anticipated in the proposed research are not greater, in and of themselves, as those ordinarily encountered in daily life or during the performance of routine physical or psychological tests. The regulations also allow for non-therapeutic research with children that does present more than minimal risk but only if the risk represents a minor increase over minimal risk. The procedures involved are commensurate with the general life experiences of subjects and the research is likely to yield knowledge of vital importance about the subject's disorder or condition. The regulations do not specify what would count as a minor increase over minimal risk. With this general guidance, it is the obligation of individual institutional review boards, IRBs, to determine whether a non-therapeutic study involving children is acceptable. It is likely that a cancer risk of greater than 1 per 1,000 subjects would be considered by most, if not all IRBs, to be unacceptable by a minimal risk standard, even for non-fatal cancers. It is less clear whether this risk would be considered unacceptable by the minor increase over minimal risk standard, assuming the research satisfied the vital importance condition. The difficulty of establishing an acceptable level of risk in non-therapeutic radiation research with children is currently being debated in the medical literature, a debate that will likely continue at least until federal guidelines become more specific. What was known at the time about risk in children? Assuming that any study that posed risks of greater than one excess case of cancer per 1,000 subjects would be judged to be more than minimal risk, eleven of the twenty-one research projects reviewed by the committee exposed children to higher risk than is acceptable today for non-therapeutic experiments. From a moral perspective, a crucial question is whether investigators at the time could or should have known that they were putting their pediatric subjects at greater than minimal risk. If they could have known, then arguably these investigators were not conforming to the AEC's requirement, permitting non-therapeutic research in children, provided that the radiation dosage level in any tissue is low enough to be considered harmless. It is clear that the medical community's understanding of the nature and magnitude of risks posed to children by radiation exposure is not what it is today. Researchers did not positively associate prior exposure to external radiation with an increased risk of cancer until the mid-to-late 1950s. In 1950 Duffy and Fitzgerald raised the question as to whether there might be cause to investigate a possible association between therapeutic thymic irradiation during childhood and subsequent development of thyroid or thymic cancers. To pose a cause-and-effect relationship between thymic irradiation and the development of cancer would be quite unjustified on the basis of data at hand when one considers the large number of children who have had irradiation of an enlarged thymus. However, the potential carcinogenic effects of irradiation are becoming increasingly apparent and such relationships as those of thymic irradiation in early life and the subsequent development of thyroid or thymic tumors might be profitably explored. By 1959 several studies had reported an association between radiation exposure and the subsequent development of leukemia. Sanger, at all, performed an epidemiologic study of several thousand children in 1960 to evaluate the association between radiation exposure and cancer. They stated, The question of whether or not radiation can be indicted as the principal causative factor in the induction of neoplasia following radiation exposure for either diagnostic or therapeutic purposes has been of increased interest over the past several years. In completing their analysis they concluded, it remains a fact, indisputable in all respects, that the rate of thyroid cancers in the irradiated group is disproportionately high. In 1961 Beech and Dolphin prepared a detailed analysis of the literature on the relationship between radiation and thyroid cancer in children. They reported, The thyroid has always been considered to be an organ comparatively radio-resistant to alteration and subsequent tumor development. Although no definite development of radiogenic tumor has been reported in adults after therapeutic administration of iodine-131, Jellif and Jones, 1960, discuss a total of ten cases of thyroid cancer reported in the literature in persons treated early in life by x-ray irradiation in the neck region. The total of malignant thyroid tumors which develop in children given a dose of x-radiation to the thyroid, that is of the same order of magnitude as the incidence estimated for other tumors if a linear dose response relationship is assumed. No biologic significance is attached to this point apart from noting the fact that the child's thyroid appears to be more radio-sensitive than the adults but not more sensitive than some adult tissues. This lack of appreciation for the potential long-term effects of radiation in children is further reflected in institutional policy development for use of radioisotopes at the time. The Massachusetts General Hospital developed standards for tracer doses of radioisotopes in May, 1949. Dr. Shields Warren, director of the AEC Division of Biology and Medicine assisted in the development of the MGH standard. Tracer doses in humans will always be kept to the absolute minimum required to make the observation. Adult humans who are ill and who are expected to benefit from the procedure shall not receive tracer doses of radioactive material giving off radiation in excess of a total of four rep. Children, all patients below 15 years of age shall not receive more than a total of 0.8 rep. In any other cases, tracer doses will be limited to radioactive material giving off radiation in an amount less than a total of one rep. In the case of iodine, the thyroid, which retains most of the radioactivity, is radio-resistant. In this case, the permitted dosage may be increased by a factor of 100. Despite the cautious tone of this document, the policy illustrates the complete lack of understanding of the true radio-sensitivity of the thyroid gland, especially in the pediatric population. Further allowances must be made with regard to what was known about the distribution of radioisotopes in children at the time. It is evident that investigators using radioisotopes in children were not employing available information on organ weights in children to calculate tissue exposures at least until the mid-1960s. When standard man assumptions were used to calculate pediatric exposures before pediatric standards were developed, investigators may have significantly and systematically underestimated effective tissue doses in children. It is notable that the highest levels of risk posed in the experiments reviewed were to infants administered iodine-131. Iodine-131 was routinely used for diagnostic procedures in the pediatric population until the 1980s, when it was replaced by I-123, a newly available radioisotope with a significantly shorter half-life, which reduced the thyroid dose markedly. The Rentham fallout study performed in 1961 employed doses of iodine-131 that resulted in an average dose of 44 rad to the gland, slightly less than the dose that would have been received for a diagnostic thyroid scan during this time. Although the doses of radioisotopes subsequently declined during these years for both therapeutic medicine and non-therapeutic research, these guidelines were not based on long-term outcome studies of exposed individuals, but rather on conservative extrapolations from high-dose studies and on the dosages necessary to enable detection with the available equipment. The debate over the potential risks of low-dose exposure continues today, as epidemiological studies of thyroid cancer incidents, subsequent Iodine-131 administration in both the diagnostic as well as therapeutic dose range, have been largely negative. Risks as a result of Iodine-131 exposure are still unclear, and risk analyses for exposure to radioisotopes are thus based on extrapolations from studies involving external irradiation. In summary, during the period in which children were exposed to the highest levels of risk from non-therapeutic research involving radioisotopes, investigators had a limited understanding of the potential long-term risks of low-dose radiation and of methods to accurately calculate the tissue doses in children. Today, we cautiously assume that any exposure to radiation likely produces some small increase in cancer risk so that no exposure is absolutely harmless. Instead, the concept of minimal or acceptable risk is commonly used, as discussed earlier. Some of the studies during this period involved risks that would be judged as minimal even today, whereas others would be clearly viewed as unacceptable today. Should the investigators then have viewed any of these studies as harmless? Though an understanding of the association between exposure to external radiation and subsequent development of cancer was emerging during this time, a similar association had not been made for exposure to low-dose levels of radioisotopes. In addition, the relative radio sensitivity of many pediatric tissues, including thyroid, had not been established, and most researchers during this period subscribed to the threshold theory of risk, which assumed that sufficiently low doses were probably harmless. In the face of such widespread factual ignorance, it is difficult to hold these investigators culpable for imposing risks on their subjects that were not appreciated at the time. End of Section 38 Section 39 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 7, Part 4 Beyond Risk Other Dimensions of the Ethics of Non-therapeutic Research on Children The level of risk to which children are exposed is critical in evaluating the ethics of non-therapeutic research on children. Also important, however, is whether and how the authorization of parents was solicited and also which children were selected to be so used. For nineteen of the twenty-one studies reviewed by the committee we know almost nothing about whether the permission of parents was sought or what the parents were told about their children's involvement. Two of the studies conducted at the Fernald School were the exceptions, as a result of extensive historical and archival research by the Massachusetts Task Force on Human Subjects Research. There is a reference to parents in the published literature on only one of the remaining nineteen studies, a 1954 iodine uptake experiment at the University of Tennessee. This paper included the following line. The procedure was described to the mothers of the infant studied and the mothers gave consent for the study before the tests were made. The inclusion of this line is noteworthy, for it suggests that at least some investigators thought parental permission was worth mentioning in published reports of their research. If the committee had devoted extensive investigatory resources to these nineteen studies it is likely we would have learned more about whether or how parental authorization was obtained in at least some cases. It is also almost certain that even the deepest archival digging would have produced no useful information about parental authorization for some of these experiments. The recent experience of the Massachusetts Task Force demonstrates the possibility of both outcomes. For some of the experiments conducted at the Fernald School the Task Force's diligent historical research uncovered a variety of documents that shed important light on what both parents and children were told. For the experiments at Rentham similar efforts did not produce any significant information on questions of parental authorization. Again with the exception of the experiments conducted at Fernald and Rentham we know almost nothing about who the children were who served as subjects in these experiments. The journal articles on these remaining studies do not describe the sociodemographic characteristics of the subjects. They do sometimes mention whether the subjects had relevant medical conditions and usually that the children including the control subjects were hospitalized patients. In some of the experiments reviewed by the committee the scientific research questions of interest could have been pursued only in children who were ill and hospitalized. In other instances however the hospitalized children were likely samples of convenience. This is particularly plausible in the case of control subjects when a sample of healthy, non-hospitalized children might have made a better control group from a scientific perspective. As we saw in Chapter 2 hospitalized patients were often viewed by physician investigators as a convenient source of research subjects. Because so little is known the committee cannot draw conclusions about the ethics of most of the non-therapeutic studies involving children we reviewed apart from the important issue of risk of harm to the children involved. We turn now to an analysis of the studies where relevant information about parental authorization, disclosure, and subject selection is available. The studies conducted at the Fernald School. The Studies at the Fernald School Researchers from the Massachusetts Institute of Technology working in cooperation with senior members of the Fernald staff carried out non-therapeutic nutritional studies with radioisotopes at the state school in the late 1940s and early 1950s. The subjects of these nutritional research studies were young male residents of Fernald who were members of the school's Science Club. In 1946 one study exposed 17 subjects to radioactive iron. The second study, which involved a series of 17 related sub-experiments, exposed 57 subjects to radioactive calcium between 1950 and 1953. It is clear that the doses involved were low and that it is extremely unlikely that any of the children who were used as subjects were harmed as a consequence. These studies remain morally troubling, however, for several reasons. First, although parents or guardians were asked for their permission to have their children involved in the research, the available evidence suggests that the information provided was, at best, incomplete. Second, there is the question of the fairness of selecting institutionalized children at all, children whose life circumstances were by any standard already heavily burdened. Parental Authorization The Massachusetts Task Force found two letters sent to parents describing the nutrition studies and seeking their permission. The first letter, a form letter signed by the superintendent of the school, is dated November 1949. The letter refers to a project in which children at the school will receive a special diet rich in various cereals, iron, and vitamins, and for which it will be necessary to make some blood tests at stated intervals, similar to those to which our patients are already accustomed and which will cause no discomfort or change in their physical condition other than possibly improvement. The letter makes no mention of any risks or the use of a radioisotope. Parents or guardians are asked to indicate that they have no objection to their son's participation in the project by signing an enclosed form. The second letter, dated May 1953, we quote in its entirety. Dear Parent In previous years we have done some examinations in connection with the nutritional department of the Massachusetts Institute of Technology with the purposes of helping to improve the nutrition of our children and to help them in general more efficiently than before. For the checking up of the children we occasionally need to take some blood samples which are then analyzed. The blood samples are often after one test meal which consists of a special breakfast meal containing a certain amount of calcium. We have asked for volunteers to give a sample of blood once a month for three months and your son has agreed to volunteer because the boys who belong to the Science Club have many additional privileges. They get a quart of milk daily during that time into a baseball game, to the beach, and to some outside dinners, and they enjoy it greatly. I hope that you have no objection that your son is voluntarily participating in this study. The first study will start on Monday, June 8, and if you have not expressed any objections we will assume that your son may participate. Sincerely yours, Clemens E. Benda, M.D. for Nald Clinical Director. Approved, Malcolm J. Farrell, M.D. for Nald Superintendent. Again, there is no mention of any risks or the use of a radioisotope. It was believed then that the risks were minimal as indeed they appear to have been and as a consequence school administrators and the investigators may have thought it unnecessary to raise the issue of risks with the parents. There was no basis, however, for the implication in both letters that the project was intended for children's benefit or improvement. This was simply not true. The conclusion of the Massachusetts Task Force was that these experiments were conducted in violation of the fundamental human rights of the subjects. This conclusion is based, in part, on the Task Force's assessment of these letters. Specifically, the Task Force found that the researchers failed to satisfactorily inform the subjects and their families that the nutritional research studies were non-therapeutic, that is, that the research studies were never intended to benefit the human subjects as individuals but were intended to enhance the body of scientific knowledge concerning nutrition. The letter in which consent from family members was requested, which was drafted by the former Frenald Superintendent, failed to provide information that was reasonably necessary for an informed decision to be made. Fairness and the use of institutionalized children The Frenald experiments also raise quite starkly the particular ethical difficulties associated with conducting research on members of institutionalized populations, especially where some of the residents have mental impairments. Living conditions in most of these institutions, including Frenald and Rentham, have improved considerably in recent years and sensitivity toward people with cognitive impairments has likewise increased. As Fred Boyce, a subject in one of those experiments, has put it, Frenald is a much better place today and in no way does it operate like it did then. That's very important to know that. The Massachusetts Task Force describes conditions in state-operated facilities like Frenald, particularly as they bear on human experimentation, as follows. Until the 1970s, the buildings were dirty and in disrepair. Staff shortages were constant, brutality was often accepted, and programs were inadequate or nonexistent. There were no human rights committees or institutional review boards. If the superintendent, in those days required to be a medical doctor, cooperated in an experiment and allowed residents to be subjects, few knew and no one protested. If nothing concerning the experiments appeared in the resident's medical records, if requests for consent letters were less than forthright, or if no consent was obtained, there was no one in a position of authority to halt or challenge such procedures. Although public attitudes toward people who are institutionalized are admittedly different today than they were 50 years ago, it is likely that this state of affairs would have been troubling to most Americans even then. Historian Susan Letterer has revealed several episodes of experimentation with institutionalized children in America that caused considerable public outcry even before 1940, presaging the concern generated by Willowbrook when this research became a public issue in the 1960s. The LMRI staff reported in the early 1960s that the pediatric researchers whom they had gathered agreed, in principle, that the convenience of conducting research on institutionalized children did not outweigh the moral problems associated with this practice. Several investigators spoke about the practical advantages of using institutionalized children who are already assembled in one location and living within a standard controlled environment. But the conferees agreed that there should be no differential recruitment of ward patients rather than private patients, of institutionalized children rather than children living in private homes or of handicapped rather than healthy children. A particularly poignant dimension of the unfairness of using institutionalized children as subjects of research is that it permits investigators to secure cooperation by offering as special treats what other non-institutionalized children would find far less exceptional. The extra attention of a science club, a quart of milk, and an occasional outing were for the boys at Fernald extraordinary opportunities. As Mr. Boyce put it, I won't tell you now about the severe physical and mental abuse, but I can assure you it was no boys' town. The idea of getting consent for experiments under these conditions was not only cruel but hypocritical. They bribed us by offering us special privileges, knowing that we had so little that we would do practically anything for attention, and to say, I quote, this is their debt to society, end quote, as if we were worth no more than laboratory mice, is unforgivable. Even when a child was able to resist the offers of special attention and refused to participate in the experiment, the investigators seemed to have been unwilling to respect the child's decision. One MIT researcher, Robert S. Harris, explicitly noted that it seemed to him that the three subjects who objected to being included in the study could be induced to change their minds. Harris believed that the recalcitrant children could be induced to join in the study by emphasizing the Fernald Science Club angle of our work. From the perspective of the science, it was considered important to conduct the research in an environment in which the diet of the children's subjects could be easily controlled. From this standpoint, the institutional setting of Fernald was ideal. The institutional settings of the boarding schools in the Boston area, however, would have offered much the same opportunity. Although the risks were small, the children of the elite were rarely, if ever, selected for such research. It is not likely that these children would have been willing to submit to blood tests for extra milk or the chance to go to the beach. The question of what is ethical in the context of unfair background conditions is always difficult. Perhaps the investigators who were not responsible for the poor conditions at Fernald believed that the opportunities provided to the members of the Science Club brightened the lives of these children, if only briefly. Reasoning of this sort, however, can all too easily lead to unjustifiable disregard of the equal worth of all people and to unfair treatment. Today, fifty years after the Fernald experiments, there are still no federal regulations protecting institutionalized children from unfair treatment in research involving human subjects. The committee strongly urges the federal government to fill this policy void by providing additional protections for institutionalized children. Conclusion If an ethical evaluation of human experiments depended solely upon an assessment of the risks to subjects that would reasonably be anticipated at the time, the radiation experiments conducted on children reviewed in this chapter would be relatively unproblematic. During this time the association between radiation exposure and the subsequent development of cancer was not well understood and in particular little was known about iodine-131 and the risk of thyroid cancer. Both researchers and policymakers appear to have been alert to considerations of harm and concerned about exposing children to an unacceptable level of risk. At the same time, however, the scientific community's experience with radionuclides in humans was limited and this approach to medical investigation was new. Although the available data about human risk were encouraging and the biological susceptibility of children to the effects of radiation was not appreciated, we are left with the lingering question whether investigators and agency officials were sufficiently cautious as they began their work with children. This is a difficult judgment to make at any point in the development of a field of human research. It is particularly difficult to make at 40 or 50 years' remove. Investigators and officials had to make decisions under conditions of considerable uncertainty. This is commonplace in science and in medicine. Although the biological susceptibility of children was not then known, investigators and officials held the view that children should be accorded extra protection in the conduct of human research and they made what they thought were appropriate adjustments when using children as subjects. If human research never proceeded in the face of uncertainty there would be no such experiments. How little uncertainty is acceptable in research involving children is a question that remains unresolved. Today we continue to debate what constitutes minimal risk to children in radiation and in other areas of research. The regulations governing research on children offer little in the way of guidance either with respect to conditions of uncertainty about risk or when risks are known. As best as we can determine in 11 of the 21 experiments we reviewed the risks were in a range that would today be likely to be considered as more than minimal and thus is unacceptable in non-therapeutic research with children according to current federal regulations. It is possible, however, that four of the 11 might be considered acceptable by the minor increase over minimal risk standard. In these four experiments the average risk estimates were between one and two per thousand. The studies were directed at the subject's medical conditions and they may well have had the potential to obtain information of vital importance. Physical risk to subjects is not the only ethically relevant consideration in evaluating human experiments. With the exception of the studies at Fernald we know almost nothing about whether or how parental authorization for the remaining 19 experiments we reviewed was obtained. And with the exception of the Fernald studies and the experiment at Rentham we know very little about the children who were selected to be the subjects of this research. Therefore we cannot comment on the general ethics of these other experiments. The experiments at Fernald and at the Rentham School unfairly burdened children who were already disadvantaged children whose interests were less well protected than those children living with their parents or children who were socially privileged. At the Fernald School where more is known there was some attempt to solicit the permission of parents but the information provided was incomplete and misleading. The investigators successfully secured the cooperation of the children with offers of extra milk and an occasional outing. Incentives that would not likely have induced children who were less starved for attention to willingly submit to repeated blood tests. One researcher speaking almost 35 years ago set out the fundamental moral issue with particular frankness and clarity. We are talking here about first and second class citizens. This is a concept none of our consciences will allow us to live with. The thing we must all avoid is two types of citizenry. It might have been common for researchers to take advantage of the convenience of experimenting on institutionalized children but the committee does not believe the convenience offsets the moral problems associated with employing these vulnerable children as research subjects now or decades ago. End of section 39. Section 40 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 7. Part 5. The Vanderbilt Study. In an exceptionally large study at Vanderbilt University in the 1940s, approximately 820 poor, pregnant, Caucasian women were administered tracer doses of radioactive iron. Vanderbilt worked with the Tennessee State Department of Health and the research was partly funded by the Public Health Service. Today most women take iron supplements during pregnancy. This experiment provided the scientific data needed to determine the nutritional requirements for iron during pregnancy. The radio iron portion of the nutrition study directed by Dr. Paul Hahn was designed to study iron absorption during pregnancy. The women, who were anywhere from less than 10 weeks to more than 35 weeks pregnant, were administered a single dose of radioactive iron, FE-59, during their second prenatal visit, before receiving their routine dose of therapeutic iron. On their third prenatal visit, blood was drawn and tests performed to determine the percentage of iron absorbed by the mother. The infant's blood was then examined at birth to determine the percentage of radio iron absorbed by the fetus. The doses to the women were estimated in the study article, using crude dose estimation methods available at the time, to be from 200,000 to 1,000,000 countable counts per minute. Although the investigators did not estimate doses to the fetuses in the original study, Dr. Hahn later estimated fetal doses to be between 5 and 15 rad. This estimate, however, has been questioned. There is at least some indication that the women neither gave their consent nor were aware they were participating in an experiment. Vanderbilt's study subjects, expressing bitterness at the way they believed they had been treated, testified in an advisory committee meeting that the proffered drink, called a cocktail to the fetuses, was offered with no mention of its contents. I remember taking a cocktail, one woman said simply. I don't remember what it was, and I was not told what it was. Although it is not clear what, if anything, the subjects were told, information about the Vanderbilt experiment was available to the general public. In late 1946, news reports appeared in the Nashville Press. The actual risk to the fetuses in the Vanderbilt experiment has long been a matter of study. In 1963 to 1964, a group of researchers at Vanderbilt found no significant differences in malignancy rates between the exposed and non-exposed mothers. However, they did identify a higher number of malignancies among the exposed offspring. Four cases in the exposed group, acute lymphatic leukemia, synovial sarcoma, lymphosarcoma, and primary liver carcinoma, which was discounted as a rare familial form of cancer. No cases were found in a control group of similar size, and approximately 0.65 cases would have been expected on Tennessee's state rates, compared to which the three observed cases is a marginally significant excess. This led the researchers to conclude that the data suggested a causal relationship between the prenatal exposure to FE-59 and the cancer. The investigators also concluded that Dr. Hahn's estimate of fetal exposure was an underestimation of the fetal-absorbed dose. A 1969 study, funded by the AEC, and conducted by one of the investigators from the 1963-1964 study, attempted to reconstruct the doses of FE-59 to the fetuses in the original Vanderbilt study. The investigators observed that the one case of leukemia might have been due to radiation damage, but that the doses in the other two cases were low. Therefore, the relationship between the radiation exposure and the cancer in those cases might not have been causal. However, the researchers also noted that due to incomplete data they could not estimate the dose absorbed by the fetus with confidence, and that no definitive conclusions could be drawn from this study as to whether these exposures resulted in damage to the fetus. The Vanderbilt study raises many of the same ethical issues as the experiments reviewed in this chapter. Like these experiments, the Vanderbilt study offered no prospect of medical benefit to the pregnant women or their offspring, raising the question of the conditions under which it is acceptable to put children at risk for the benefit of others, whether before or after birth. What could the investigators reasonably have been expected to know about the risks to which they put their subjects? Did they exercise appropriate caution in exposing fetuses to radiation? What were the pregnant women told, if anything, and was their permission sought? Who were these women? And how were they positioned relative to pregnant women, generally? The committee did not have the resources to pursue these questions in both research in which children were the subjects and research in which children were exposed as fetuses. We did establish that the Vanderbilt study was not the only experiment during this period to expose fetuses in research that offered no prospect of medical benefit to them or their mothers. While the committee did not conduct an exhaustive review of the scientific literature, we did find twenty-seven human radiation studies that included pregnant or nursing women as subjects between 1944 and 1974. Of these studies, eight were considered therapeutic and nineteen offered no prospect of benefit to the subject. Most of the nineteen were tracer experiments. These studies were performed in order to examine human physiology during pregnancy or to study the uptake of radioactive substances by fetuses or nursing infants. They generally addressed valid scientific questions that could not be investigated in other populations. Knowledge of fetal exposure to radioiodine, for example, was relevant to issues such as potential harm to the fetus or internal uptake of radioiodine in diagnostic tests or to estimate the potential effects of environmental exposure to radioiodine on the human fetus. In other studies, radioactive iron was administered to better understand the physiology of maternal and fetal intake of iron during pregnancy. Nasopharyngeal Irradiation Nasopharyngeal Irradiation, produced by S. J. Crowe and J. W. Baylor of the Otological Research Laboratory at the Johns Hopkins University, was employed from 1924 on as a means of shrinking lymphoid tissue at the entrance to the eustachian tubes to treat middle-ear obstructions, infections, and deafness. For this treatment intranasal radium applicators sealed ampules containing radium salt were inserted. At least three insertions per treatment cycle into the nasopharyngeal area for 12-minute periods. The therapeutic effect of the treatments resulted from the penetrating radiation emitted from the radium source, gamma and beta rays, not from the internal deposition of radium itself. Crowe and his colleagues reported that under this treatment the lymphoid tissue around the tubal orifices gradually disappeared, marked improvement or complete return of the hearing followed, and in many the bluish discoloration of the tympanic membrane also disappeared. This method was used for more than a quarter century as a prophylaxis against deafness for relieving children with recurrent adenoid tissue following tonsillectomy and adenoidectomy, and for children with chronic ear infections. Cosmatic children with frequent upper respiratory infections were also often considered for this type of irradiation. An average of 150 patients a month, mostly children, were given the treatment at the Johns Hopkins Clinic over a period of several years. Many children received the treatment more than once as recurrent lymphoid tissue was considered an indication for treatment. Crowe and his colleagues reported that the results following irradiation of the nasopharynx alone were not only as good as, but often better than, those following removal of tonsils and adenoids. In review articles they noted that approximately 85% of treated patients responded with decreased numbers of infections and or improved hearing when treated at young ages. They also concluded that it is effective, safe, painless, inexpensive, and has proved particularly valuable for prevention of certain ear, sinus, and bronchial condition in children. Although early articles by Crowe and colleagues indicate that nasopharyngeal radium treatments were accepted as standard procedure for the prevention of childhood deafness, these treatments, like most standard interventions in medicine, had not been subjected to formal scientific evaluation. A controlled study was conducted from 1948 to 1953 by Crowe and his colleagues to determine the feasibility of irradiation of the nasopharynx as a method for controlling hearing impairment in large groups of children associated with lymphoid hypoplasia in the nasopharynx to draw conclusions concerning the per capita cost of such an undertaking as a public health measure. Crowe, at all, wrote in an NIH notice of research that the procedure of treatment is not new as an individual measure. This is the first adequately controlled experiment of sufficient size for accurate statistical analysis. This work was funded by NIH for the entire period of study. As recorded in an NIH grant application the study involved approximately 7,000 children screened for hearing impairment. Of those screened, approximately 50% were selected for further study based on the chosen criteria for hearing loss. Half of this study group was irradiated with radium while the other half served as a control group. Crowe and colleagues reportedly concluded from this study, published in 1955, that the radium treatments did shrink swelling of lymphoid tissue and improve hearing. This type of therapy was ultimately discontinued because of newly available antibiotics and the use of transtympanic drainage tubes as well as awareness of the potential risks of radiation treatment. In addition to the targeted lymphoid tissue the brain and other tissues in the head and neck region including the perinazle sinuses, salivary glands, thyroid and parathyroid glands are also exposed to significant doses of radiation in the radium treatments, prompting concern that these treated individuals might have been placed at increased risk for radiation induced cancers at these sites. Dale P. Sandler, at all, in their 1982 study of the effects of nasopharyngeal irradiation on excess cancer risk for children treated at the Johns Hopkins Clinic, found a statistically significant overall excess of malignant neoplasms of the head and neck along exposed subjects, based, however, on only four cases in comparison with 0.57 expected. This excess was accounted for mainly by three brain tumors that occurred in the irradiation subjects. One other malignant tumor, a cancer of the soft palate, was also reported. The Department of Epidemiology at the Johns Hopkins University has undertaken a further follow-up study by the Crow et al. cohort of children irradiated there, previously studied by Sandler et al. Verdoin et al. in their 1989 study of cancer mortality risk for those individuals, mostly children, treated by nasopharyngeal irradiation with Radium-226 in the Netherlands, reported that the present study has found no excess of cancer mortality at any site associated with radium exposure to pro and Baylor therapy. Specifically, the finding of Sandler et al. of an excess of head and neck cancer was not found in this study group. Among the Japanese atomic bomb survivors, no excess of brain tumors was found. However, several studies have noted an increased risk of both benign and malignant brain tumors following therapeutic doses of radiation to the head and neck region during childhood. From the committee's own limited risk analysis of these experiments, we concluded that the brain and surrounding head and neck tissues would be put at highest risk and estimated the lifetime risk at approximately 4.35 per thousand and an increased relative risk of 62%. The Hopkins nasopharyngeal study raises different ethical issues than those posed by the other experiments reviewed in this chapter, all of which offered no prospect of medical benefit to the children who served as subjects. By contrast, the nasopharyngeal irradiation experiment was designed to determine whether children at risk for hearing loss would be better off receiving radiation treatments or not receiving such treatments. A central issue here was whether it was permissible to withhold this intervention from at-risk children. The application of radium was at this point a common but scientifically unproven treatment for children at risk of hearing loss. The risks of the treatment were not well characterized. If it was really unknown which was better for children receiving radium or no intervention then the medical interests of the children were best served by being subjects in the research because as a consequence they would have a 50% chance of receiving the better approach. The nasopharyngeal experiment thus belongs to a class of research the committee did not investigate therapeutic research with children. End of Section 40 Section 41 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 8, Part 1 Total Body Irradiation Problems when treatment and research are intertwined In the fall of 1971 the public controversy erupted about the ethics of a research project at the University of Cincinnati College of Medicine funded for more than a decade by the Department of Defense, DoD. In this research the subjects were cancer patients who underwent external Total Body Irradiation, TBI. The DoD was funding post-irradiation research on the biological effects of this type of exposure to radiation. Critics of the research charged that the physician investigators were exposing unknowing patients to potentially lethal doses of TBI not to treat their cancer but to collect data on the effects of nuclear war for the military and that numerous patients had died or seriously suffered from the radiation. Defenders asserted that the TBI was reasonable medical treatment for people with incurable cancer and that this treatment was performed in accordance with contemporary professional ethics. Over the next four months the research was reviewed favorably by ad hoc committees of physicians appointed by the American College of Radiology, ACR, the preeminent professional organization of radiologists, and by University of Cincinnati officials but critically by an ad hoc committee of junior non-medical faculty members at the university. Following these reports the university president rejected further Defense Department funding for the post-treatment data collection program and the use of TBI was suspended. When news reports about human radiation experiments appeared in late 1993 journalists and investigators again focused on this Cincinnati project. Critics charged that the reviews commissioned by the university and the ACR were biased and had been whitewashes. Supporters countered that the Cincinnati research had been conducted in the open had been thoroughly and favorably reviewed by the medical community and was old news. In addition, patients were identified publicly for the first time leading a number of their family members to file a lawsuit against the university, the physicians, and other parties in federal court. The family members also formed an advocacy group called the Cincinnati Families of Radiation Victims Organization. The University of Cincinnati was only the last in a line of institutions that received funds to provide data to the government on the effects of total body irradiation on humans. In this chapter we review 30 years of research supported by the Manhattan Project, the Department of Defense, and the AEC aimed at gathering data on the effects of radiation on hospitalized patients who were medically exposed to total body irradiation. Much of the record is incomplete and some of it is contradictory. We cannot and do not resolve all the inconsistencies and uncertainties in the record. We do, however, focus on the ethical issues that emerged in this research, some of which are still with us today. The history of TBI research is important to the committee for several reasons. First, in the other case studies conducted by the committee, there was never any expectation or any claim that subjects, even if they were patients, would benefit medically from their being involved in experiments. By contrast, in the TBI research, the TBI itself was recommended as treatment for incurable cancer for which the expectation of benefit was low, although possible. Chemotherapy, which would be considered standard today, was not well established until the mid to late 1960s. The post-radiation effects studies sponsored by the DOD, however, were not intended to benefit the patients. As we noted in chapter 4, the presence of an intent to benefit that intent is both genuine and reasonable, alters the ethics of the situation. An intent to benefit the patient subject does not, however, ensure that an experiment is ethically acceptable. Many perplexing questions about the ethics of research involving human subjects that we face today occur at the bedside with patient subjects who may or may not benefit medically by their participation. The TBI story, thus foreshadows important issues we discuss in part 3 of this report when we focus on contemporary research involving human subjects, much of which involves patient subjects and the prospect of medical benefit. The core of the ethical problem is straightforward. Whenever the treatment of a patient is intertwined with the conduct of research, the potential emerges for a conflict between the interests of science and the interests of the patient. The patient may, for example, be exposed to additional risk or discomfort as a consequence. At the same time, for some patients, participation in research may offer the only chance or the best chance of improving their medical condition. The second reason the history of TBI research is important to the committee is that although the research was conducted on cancer patients, the government's interest in the research was not to advance the treatment of cancer, but to find answers to problems facing the military in the development and use of atomic weapons and nuclear-powered aircraft. It is this disparity that raised questions, both in 1971 and today, about the motivations behind treatment of these patient subjects with TBI. Whether it matters morally that the government pursued its interests in the effects of TBI on patient subjects depends in large measure on whether the government's objectives in supporting this research inappropriately compromised the medical care the patient subjects received. We have just noted that the conjoining of research with medical care necessarily creates a potential for conflict between the interests of the research and the interests of the patient. This is true even where the objective of the research is to find a treatment for the condition from which the patient suffers. A central issue in the case of the TBI research is whether this conflict was exacerbated by the nature of the gap between the interests of the patient and the objectives of the research. A complicating feature of the TBI story is that the DOD did not pay directly for the patients to be administered TBI. The funding by these agencies was restricted to the costs associated with the physiological and psychological measurements taken in conjunction with the TBI rather than the costs of the TBI itself. The committee was also struck with how well the history of TBI research illustrates two very contemporary problems, how to draw boundaries between medical care and medical research, and how to draw boundaries between research with patient subjects that is therapeutic and research that is non-therapeutic. Was the administration of TBI always an instance of medical research? Was it ever standard care? Was it sometimes administered as a departure from standard care outside of research? When TBI was administered in the context of research, was there a basis for believing that there was a reasonable prospect that patients could benefit? Or was it the kind of research from which patients could not benefit medically? Because of conflicting and incomplete evidence, these were questions that we could not always answer, but that guided our inquiry. The committee began our review by seeking to track down TBI research identified in a retrospective study of TBI exposures conducted in the mid-1960s by the Oak Ridge Associated Universities on behalf of the National Aeronautics and Space Administration, NASA, which collected records on more than 2,000 TBI exposures on both radio-sensitive and radio-resistant cancers from 45 U.S. and Canadian institutions. The committee then focused on approximately 20 research studies that were published between 1940 and 1974 on the use of TBI in the United States. Nine of these 20 studies involved at least some patients with radio-resistant cancers. Eight of the nine institutions that conducted the studies received funding from either the Manhattan Project or the DOD. The Atomic Energy Commission sponsored one of the studies involving radio-sensitive cancers at the Oak Ridge Institute of Nuclear Studies, ORINs. In addition, the committee found only one instance in which non-government-funded TBI research involved patients with radio-resistant cancers. In this chapter we begin with the definition of TBI, including a discussion of the then contemporary distinction between the use of TBI to treat radio-sensitive and radio-resistant tumors. The distinction is important to what follows because patients with radio-sensitive cancers for which TBI was considered most promising medically were less useful subjects for obtaining the type of information that the military sought, information on the acute effects of radiation on healthy soldiers or citizens during the course of atomic warfare-related activities. In these patients it would be less clear whether signs such as nausea, vomiting or other acute effects were due to rapid destruction of cancer cells by the radiation or due to the radiation acting on normal tissue such as normal blood cells. Similarly, patients with radio-sensitive cancers were less useful for research intended to find biological measures of radiation doses, biological dosimeters, because this research depended on measuring various cell products in the blood or urine that could also be released by tumor cells Patients with radio-resistant tumors were more desirable because it was more likely that the effects seen were related to radiation effects on normal tissue rather than rapid destruction of their tumor cells. Following a discussion of TBI itself we turn to a chronological history of government sponsorship of research related to the effects of TBI with radio-resistant tumors. This research began during the Manhattan Project. In 1949 and 1950, as we next discuss, DOD and AEC experts and officials met to consider the need for further BMI human experiments in order to gain information needed in the development of the nuclear-powered airplane. When the decision was made not to proceed with human experiments involving healthy subjects the military began to fund research on the effects of TBI on patients undergoing treatment for cancer. As we discuss, this program began in 1950 at the M.D. Anderson Hospital for Cancer Research in Houston and continued through the end of the Cincinnati research in the early 1970s. We conclude our review with a discussion of the AEC-funded TBI research conducted at Oak Ridge between 1957 and 1974 which focused on patients with radio-sensitive cancers. What is TBI? Medically administered total-body irradiation, also known as whole-body radiation, involves the use of external radiation sources that produce penetrating rays of energy to deliver a relatively uniform amount of radiation to the entire body. Total-body irradiation was used as a medical treatment long before the 1944 to 1974 experiments and it continues to be used today. Soon after doctors began to experiment with radiation they recognized that radiation had different effects on different types of cancers. They thus began to distinguish between radio-sensitive cancers which generally responded to the radiation treatment and radio-resistant cancers which most often did not respond. By the 1940s TBI was recognized as an acceptable treatment for certain radio-sensitive cancers that are widely disseminated throughout the body such as leukemia and lymphoma, a cancer whose origin is in the lymphoid tissue. By the late 1950s TBI was also being used to assist in conjunction with research on bone marrow transplantations for radio-sensitive cancers. During this period TBI was also explored as a possible palliative treatment providing relief but not cure for disseminated radio-resistant cancers such as carcinomas of the breast, lung, colon and other organs. Carcinoma is a cancer that originates from the cells lining these organs. However TBI alone did not prove to be of value in treating these cancers because without support measures to maintain bone marrow function the doses needed to significantly shrink the tumors were potentially lethal to the patient. In the 1950s there were few effective methods for treating radio-resistant cancers. Chemotherapy was just being developed. It was risky to use and only marginally effective. With no better alternatives interest in TBI continued. In addition the development in the 1950s of high energy sources of radiation cobalt 60, cesium 137 and megavolt x-ray sources represented a significant advance in technology. These new teletherapy units allowed high energy radiation to penetrate deeper into the body without damaging the overlying skin and soft tissues. Thus higher absorbed marrow doses in rad could be delivered than with previous equipment. The advent of this new teletherapy encouraged researchers to retest TBI on patients with radio-resistant cancers even though prior TBI techniques with older x-ray therapy machines had failed. By the late 1960s however chemotherapy began to be recognized as more effective and interest in TBI waned. During the 1970s researchers explored the effectiveness of administering TBI without bone marrow transplant through multiple exposures at lower doses that is 10 to 30 rad known as fractionated radiation to achieve cumulative total body doses of 150 to 300 rad rather than single exposures of an equivalent total body dose. They also focused much more extensively on partial body irradiation because the risk of patient bone marrow failure was lower. Since the 1980s TBI has again been used to treat certain widely disseminated radio-resistant carcinomas at doses as high as 1,575 rad in conjunction with effective bone marrow transplantation which became routinely available in the late 1970s. TBI can cause acute health effects during the first six weeks following an acute single exposure. The type and severity of these effects depend among other things on the dose, the dose rate and the individual's sensitivity to radiation. The most serious side effects seen during this period are related to radiation-induced depression of the bone marrow which can cause a decrease in the number of circulating platelets and white blood cells which in turn can result in small hemorrhages and infections possibly leading to death. Moderate bone marrow depression results with doses of about 125 rad. The following table describes the general acute effects that are likely to occur to healthy persons from a single exposure. These effects can be exaggerated and prolonged for people who are ill or who have had prior radiation treatments. As with an ordinary diagnostic X-ray the patient feels nothing during the radiation exposure itself. In addition, TBI, like most other forms of radiation exposure can potentially have long-term effects such as cancer induction. However, most patients who receive TBI do not live long enough to experience most long-term effects. Midline tissue dose of 50 to 100 rad symptoms nausea, percentage 5 to 30%, time post-exposure, 3 to 20 hours. Midline tissue dose 100 to 200 rad symptoms nausea, 30 to 70%, within 4 to 30 hours, vomiting, 20 to 50%, within 5 to 24 hours, death in less than 5% within 5 to 6 weeks. Dose 200 to 350 rad symptom nausea, 70 to 90%, within 1 to 48 hours, vomiting in 50 to 80%, within 3 to 24 hours, death in 5 to 50% within 4 to 6 weeks. Dose 350 to 500 rad symptom nausea in 90 to 100% within 1 to 72 hours, vomiting in 80 to 100% within 3 to 24 hours, death in 50 to 99% within 4 to 6 weeks. Dose 550 to 750 rad symptom death in 100% within 2 to 3 weeks. Early use of TBI for radio-resistant tumors, the Manhattan Project Experiments on Patients, and the subsequent AEC Review. In the early 1930s, researchers at Memorial Hospital in New York, a major cancer research center, now known as the Memorial Sloan Kettering Cancer Research Institute, engaged in an extensive study on the medical effects of total body irradiation. As a part of this study, the researchers attempted to treat a few radio-resistant carcinomas. When they published their results in 1942, they noted that except for transient relief of pain in a few cases, the results in generalized carcinoma cases were discouraging. The reason for this is quickly apparent. Carcinomas are much more radio-resistant than the lymphomatoid tumors, and by total body irradiation the dose cannot be nearly large enough to alter these tumors appreciably. They cautioned that a cancer-killing dose will produce deleterious reactions in the bone marrow and general metabolism, which may prove lethal to the patient. The equipment used to deliver the TBI during this time was suboptimal because most of the radiation was deposited in superficial structures such as the skin and other soft tissues. During World War II, Memorial Hospital was one of three medical institutions chosen by the Health Division of the Manhattan Projects Metallurgical Project to conduct TBI experiments in order to help understand the effects of radiation. The other two were the Chicago Tumor Institute and the University of California Hospital. All three studies focused on individuals with radio-resistant diseases. From the limited records that are currently available, it appears that these three studies achieved little if any medical benefit to the subjects. In addition, the interest of the military in these studies was classified and kept secret from the patients in order not to reveal the ongoing atomic bomb project. The first experiment was carried out from 1942 to 1946 at the University of California Hospital in San Francisco to study the effects of total body irradiation with X-rays of varying energy on hematologically normal individuals. Twenty-nine patients were treated with total dosages ranging from 100 to 300R using a 250KV machine. The investigators noted that the treatments were administered as part of the normal therapy of these patients and reported that advantage was taken of the fact that patients were receiving such treatment by making numerous blood studies for the Manhattan Project. Little is known for this and the other two studies about the treatment of patients or the issue of patient consent. A number of the patients in the University of California study had rheumatoid arthritis and the use of TBI for that disease was severely criticized after the war by the Advisory Committee for Biology and Medicine of the newly formed Atomic Energy Commission, see below. In 1948 Dr. Robert Stone, Chief of the Manhattan Project's Metallurgical Laboratory Health Division, noted that although no signed consent was received from the patient the treatment was explained to them by the physicians and they, in full knowledge of the facts, accepted the treatments. At the same time, however, it was admitted that the fact that Manhattan District was interested in the effects of total body irradiation was kept a secret. A second Manhattan Project experiment was performed from December 1942 to August 1944 at Memorial Hospital in New York by one of the researchers who had previously written that they were discouraged by the use of TBI for radio-resistant cancers, Dr. L. F. Craver. Despite his earlier negative results, eight patients were given a total of 300R using a 250KV machine at various dose rates in order to yield some detectable effects on the blood count and to serve as a guide to the clinical tolerance for whole body irradiation. The patients had to have metastatic cancer of such an extent and distribution as to render their cases totally unsuitable for any accepted method of surgical or radiological treatment, yet be in good enough general condition so that they might be expected not only to tolerate the exposure to 300R of total body irradiation in a period of ten to thirty days, but also to survive the combined effects of their disease and the irradiation for at least six months in order that some conclusions might be drawn as to the later effects of the irradiation. The report on this experiment makes clear that the primary purpose of this TBI was to obtain data for the military. Dr. Craver essentially acknowledged that there was little prospect of actual medical benefit to the patients in light of the previous failure using the same procedure. A third TBI study involving fourteen people was performed at the Chicago Tumor Clinic from March 1943 to November 1944. Doses up to 120R were given with a 250KV machine. None of these individuals had radio-sensitive cancers. The use of TBI was justified by the investigators because there were no known treatments for their illnesses and therefore X-ray exposures that were given were as likely to benefit the patient as any other known type of treatment or perhaps even more likely than any other. The study appears to be the only TBI study that included healthy subjects. Three normals were each given three doses of 7R. After the war Dr. Stone took on the task of editing an official history of the experiments done for the Plutonium Project. At one point he complained to Dr. Shields Warren, Chief of the AEC's Division of Biology and Medicine, DBM, that declassifiers were withholding the report of the Chicago TBI experiment on grounds that its release would cause adverse publicity and even encourage litigation. Stone proposed to solve the problems by carefully re-wording the report. The report would make clear that the patients were suffering from incurable illnesses for which radiation was as good if not better than any other known treatment. Stone then proposed to deflect the likelihood of adverse publicity or litigation by deleting identifying information so that the patients could never connect themselves up with the report. The study was declassified and published in the form that Stone proposed. At about the same time in the fall of 1948 Dr. Alan Gregg, Chairman of the AEC's Advisory Committee for Biology and Medicine, ACBM, engaged Stone in an exchange regarding the Manhattan Project TBI experiment on the arthritic patients in the University of California Hospital. Stone, who by this time had returned to the staff of the U.C. hospital, had requested funding to monitor these arthritic patients. Gregg told Stone that I think that I do not misrepresent the opinion of the Advisory Committee for Biology and Medicine in saying that we agree with those who believe the X-ray treatment of arthritic patients that you have been giving patients is not justified. Despite Dr. Gregg's concerns, the role of TBI in the treatment of benign autoimmune diseases such as rheumatoid arthritis continues to be explored today. Gregg stated that the AEC had an obligation to provide a check on overly enthusiastic researchers, while admitting that a conservative consensus against certain treatments was not always correct. Gregg cautioned that there is plenty of experience that shows that some forms of therapy attract enthusiastic supporters only to be discarded later as unsafe or unjustified. In response Stone acknowledged that the military's need for worker safety information during the war was a primary motivation for choosing patients with non-radiosensitive carcinomas and some benign disorders such as arthritis. At that time I was confronted with the problem of building up the morale of the workers on the new atomic bomb project, many of whom were seriously worried about the effects of prolonged whole-body irradiation. But he countered that he and the other researchers did believe that total body irradiation would be therapeutic. Moreover, Stone retorted, Gregg's statements threatened researcher and doctor freedom. Wittingly or otherwise you have dictated how I should treat patients even outside of the Atomic Energy Commission's supported activities. Stone's declaration marked a boundary that government officials, including Stone's fellow medical researchers, would not be eager to cross. End of Section 41, Recording by Maria Casper.