Conclusion

Chapter 5: Human Experimentation Continues

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: "Ordered abandonment of human isotope program at Rochester."[119] The program at the University of California at Berkeley, however, continued. On December 4, 1947, Shields Warren had met with Hamilton and Stone;[120] 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.[121]

According to Warren, Hamilton had said that subjects were told "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."[122] Warren went on to observe that "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."[123] Warren's observation does not go far enough, however. If Warren's secondhand 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 "control growth processes in patients," 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

A thirty-six-year-old African-American railroad porter named Elmer Allen, code-named 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 "explained to the patient, who agreed to the procedure" and that "the patient was in fully oriented and in sane mind."[127] 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-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 "expectation that it may have therapeutic effect."[128] 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 "frequently surviv[e] many years beyond diagnosis if there is complete excision of the primary tumor."[129] This pathology finding suggests that Mr. Allen was a long-term cancer survivor. A note in his patient chart recorded that the tumor was "malignant but slow growing and late to metastasize. Prognosis therefore moderately good."[130]

On March 15, 1995, Elmerine Whitfield Bell, the daughter of Elmer Allen, told the Advisory Committee in Washington, D.C., that she

continue[s] to be appalled by the apparent attempts at cover-ups, 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?

On January 5, 1948, a fifty-five-year-old woman with cancer was injected with zirconium at the University of California.[131] 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.[132]

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, "This document should not be declassified for general medical publication [and] it would be very difficult to rewrite it in an acceptable manner."[133] Warren was responding to a memorandum from Albert H. Holland, Jr., medical adviser at Oak Ridge, which specified that the concern about rewriting had to do with public relations and the fact that the report "specifically involves experimental human therapeutics."[134]

Follow-up of the Patient-Subjects at Rochester

On June 8, 1953, Eda Charlton's rib was removed during exploratory surgery for cancer and analyzed for plutonium. Louis Hempelmann, 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:

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.[137]

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.[138] In a 1974 interview, however, Shields Warren recalled that he had no knowledge that the patients were the subjects of follow-up studies: "I did not learn of this continuing contact while I was in office at AEC. . . . I had assumed because I had been told that they were incurable patients that they all had died by the time we talked."[139]

Additional Follow-up Studies and the Argonne Exhumation Project

In 1972, after the classified report on the experiments had been downgraded to "Official Use Only," she went on to publish "Plutonium in Man: A New Look at the Old Data," a landmark paper in the plutonium story.[143] 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 Laboratory's Center for Human Radiobiology (CHR), to whom Durbin had provided the names of surviving subjects, began a review of the data from all eighteen 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 postinjection medical histories of all the subjects, obtain biological material from those still living, and exhume and study the bodies of those deceased in order to "provide data on the organ contents at long times after acquisition of plutonium."[144]

In 1973, three patients--Eda Charlton, John Mousso, 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 "suggestive of damage due to radiation."[145]

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 "that disclosure might be harmful to them in view of their advanced age and ill health."[146] 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 "were accustomed to participating in clinical studies, unrelated to this matter, involving the collection of excretion specimens."[147] 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.[148] 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 "the purpose of exhumation was to examine the remains in order to determine the microscopic distribution of residual radioactivity from past medical treatment" and that the subjects had received an "unknown" mixture of radioactive isotopes.[149] The investigation concluded that such disclosure "could be judged misleading in that the radioactive isotopes were represented as having been injected as an experimental treatment for the patient's disease."[150] Thus, the families of the deceased subjects as well as those subjects still surviving were deceived by officials of the AEC.

A December 1972 intralaboratory memorandum, written by an Argonne investigator, instructs that "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."[151] 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 "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."[152] Dr. Rowland said he had received these instructions during a trip to Washington, D.C., to obtain approval and funding for the study.[153] Dr. Liverman told Advisory Committee staff that he has "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."[154]

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. (See 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: "(1) [Argonne's] opinion that the studies came under the scope of a protocol approved by that Committee in 1971. (2) The nature of the studies was to be suppressed to avoid embarrassing publicity for AEC."[155]

In 1974 the AEC informed at least two of the four living subjects--Eda Charlton and John Mousso--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 "to determine how plutonium, a man-made radioactive material, is deposited and excreted in the human body."[156] One living patient, Jan Stadt, was not told, because it was her attending physician's opinion that her condition was precarious and that disclosure in this case would be "medically indefensible."[157] This judgment, like that of Dr. Waterhouse's, exemplifies how physicians of the time commonly managed 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.[158] The judgment also suggests that Ms. Stadt, like Ms. Charlton and Mr. Mousso, 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 kin.

The Boston Project Uranium Injections

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 percent 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.[162]

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 heeded, however. The accepted occupational levels for uranium became less rather than more conservative over the years, despite the findings of the Boston Project.[163]

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 '40's. . . . They got brain tumor samples. There was very little uranium present, but Sweet was still wondering: maybe [it was] not a high enough dose."[164]

In a 1995 interview, Karl 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[165] 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 cancelled our participation in the program. Apparently, they were given doses that were many times the . . . permissible body burden.[166]

In their application to their radioisotope committee, MGH investigators clearly recorded that the proposed dose of 2.12 rem per week "exceeds maximum permissible exposure rate of 0.3 rem/week but [patients] are terminal."[167]

At least one of the subjects was selected for the distribution part of the study only. Reports describe the patients as "virtually all" 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 VI when he "was brought to the Emergency Ward after being found unconscious. . . . No other information was obtainable."[168] 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[169] and pathological evidence of kidney nephrosis (damage to the kidney tubules) from the chemical toxicity of uranium metal.[170] The report also records that "the liver, spleen, kidneys and bone marrow showed evidence of radiation."[171]

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 particular patient-subjects 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 and "in the terminal phase of severe irreversible central nervous system disease."[172]

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 VI, had kidney damage at the time of death, although this document does not directly link this damage to the uranium injections.[173]

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: "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."[174]

Dr. Sweet told the Advisory Committee in 1995 that it was his practice to obtain consent from patients or from their families and "scrupulously to give a patient all the information we had ourselves."[175] The Committee has not been able to locate any documents that bear on questions of disclosure or consent for this experiment.[176] 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.