DISCLAIMER The following is a staff memorandum or other working document prepared for the members of the Advisory Committee on Human Radiation Experiments. It should not be construed as representing the final conclusions of fact or interpretation of the issues. All staff memoranda are subject to revision based on further information and analysis. For conclusions and recommendations of the Advisory Committee, readers are advised to consult the Final Report to be published in 1995. TAB F-4 þþþDRAFT þ FOR DISCUSSION PURPOSES ONLYþþþ MEMORANDUM TO: Members of the Advisory Committee on Human Radiation Experiments FROM: Advisory Committee Staff DATE: March 9, 1995 RE: Comments on UCSF Report The following are comments on the interim "Report of the UCSF Ad Hoc Fact Finding Committee," released by UCSF on February 23, 1995. As a general comment, the report tends to treat the three plutonium injections at UCSF as an isolated phenomenon, rather than as just one part of a complex and extended series of human experiments, beginning under Manhattan Engineer District (MED) auspices in 1943 and continuing with Atomic Energy Commission (AEC) support until at least 1949. In fact, the so-called Plutonium Project was only part of a broader and more comprehensive radioisotope research program involving human subjects. Although that program was temporarily halted in December 1946, it was resumed and even expanded by the AEC in April 1947. The plutonium injections in the cases of CAL-1, 2, and 3 appear to share common ground with the CAL-A americium injection in June 1947, the CAL-Z zirconium injection in January 1948, and as many as a half dozen human subjects injected with columbium [niobium] in 1948 and 1949.[CAL-1 was the designation given Albert Stevens, a 58-year-old house painter; CAL-2 was a four-year old Australian boy, Simeon Shaw; CAL-3 was Elmer Allen, a 36-year-old railroad porter; CAL-A was an Asian teenager. The identify of CAL-Z, a 55-year-old woman, and of the columbium patients has not yet been established.] All were done with AEC support as part of a larger Commission-funded research effort, and all were apparently carried out at UCSF by the same group of researchers holding joint appointments at University Hospital and UC Berkeley's Division of Medical Physics. The UCSF Ad Hoc committee considered two hypotheses concerning the plutonium injections. Hypothesis #1 was "All three UCSF patients participated in the MED-sponsored project to determine human excretion rates of plutonium." (p. 16) Hypothesis #2 was "Only CAL-1 was part of the MED-sponsored project while CAL-2, CAL-3, and CAL-4 [CAL-A] participated in a University-sponsored medical research program aimed at finding a new treatment for bone cancer." (p. 17) 1 Later in the report, however, the UCSF Ad Hoc committee observes that the differences between the three UC plutonium injections "probably arise from an attempt by [Joseph] Hamilton and colleagues to piggyback two experimental designs"--i.e., the AEC's Plutonium Project with their own search for radioisotopes that would be efficacious in cancer treatment. (p. 23) As the report notes: One satisfied the MED contract restrictions while the other satisfied their medical research interests. . . .It is likely that they attempted to embark on clinical research efforts (i.e., the discovery of a new treatment for bone cancer) while completing the tasks and adhering to the restrictions defined in their contracts. It is the opinion of Advisory Committee staff that this third, unidentified hypothesis--namely, that the CAL cases were so-called "dual-purpose" experiments, aimed at accomplishing the AEC's aims as well as furthering the physicians' own cancer-related research--is the most plausible and well-supported explanation of the plutonium injections as well as subsequent radioisotopes experiments at UCSF, for the following reasons. As was pointed out in a staff presentation at the October 1994 public meeting of the Advisory Committee, the search for a selectively localizing, radioisotope "magic bullet" for the treatment of cancer is an early and Bolero-like theme in the history of nuclear medicine. This was particularly the case at Berkeley, where Hamilton and his colleagues had pioneered the use of one such radioisotope, Iodine 131, in the 1930s, and were investigating another isotope for cancer therapy, Strontium 89, at the time of America's entry into the war. Indeed, it was exactly this area of Hamilton's expertise that attracted the interest of the MED. It is also clear from the documents that Hamilton and his colleagues at UCSF and Berkeley remained interested in the potential of selectively localizing isotopes for cancer treatment throughout the war and well into the postwar era.[In a May 1946 report, Hamilton and colleague Robert Stone wrote: "Emphasis should be laid not upon the limited progress that has been made to date on the therapeutic application of the artificial radio-elements but rather in the implication of things that we can expect to come in the future. The fundamental fact has already [been] demonstrated that if a sufficient quantity of a radioactive material can be made to localize in a diseased structure of the body such as the thyroid gland, intense irradiation of that organ will take place without damage to adjoining normal tissues. The wide spread availability of adequate quantities of the artificial radio-elements will make possible a more rapid and effective search for radioactive compounds which may be localized in malignant tissues by virtue of the fact that the metabolism of cancer cells is as we already know, different in certain subtle ways from the metabolism of normal cells." Hamilton and Stone, May 31, 1946, "Medical Applications of the Radioactive Materials" ] 2 For example, in an October 1947 paper, "The Medical Applications of Radioactive Tracers," Hamilton wrote: The therapeutic applications of the artificial radioelements are based upon the fact that certain radioactive materials will selectively localize in pathological structures, thus subjecting such tissues to a greater degree of irradiation than to the surrounding normal area. Among the radioisotopes which Hamilton identified in the article as of current or potential usefulness in this application was phosphorous, iodine, strontium, zirconium, and yttrium.[Joseph Hamilton, BP-132, "The Medical Application of Radioactive Tracers" [unpub. draft, 10/31/47]] The MED, and later the AEC, remained equally interested in the same isotopes, but for very different reasons--not as promising therapeutic agents, but as environmental pollutants likely to be released in the event of a reactor accident or a nuclear war. Plutonium was only the most hazardous and hence the most prominent of such substances. In an August 1945 meeting of the MED's Health Division, Hamilton reported that he and his colleagues at Berkeley were "carrying on studies using cerium and yttrium," in an effort to discover an isotope that penetrated to "the salt part of the bone."["Reports of the Various Laboratories to the X-10 Projects Advisory Committee," August 21, 1945, p. 10.] The following month, Hamilton notified the MED that he was planning to inject the next human subject with "small quantities of radio-Yttrium, radio-Strontium and radio-Cerium," in addition to plutonium, so as "to compare in man the behavior of these three representative long-lived Fission Products with their metabolic properties in the rat," and "the differences in their behavior from that of Plutonium."[Joseph Hamilton, "Progress Report for Month of September 1945," September 14, 1945, p. 4.] Several months later, CAL-2 was injected with plutonium, yttrium, and cerium, in what appears to have been a classic dual-purpose experiment. The interest of the Berkeley-UCSF researchers in radioisotopes as possible candidates for cancer therapy continued after the war, closely paralleling the AEC's concerns with fission products as threats to worker safety and the environment. For example, a January 1947 AEC report on future Commission-supported work to be carried out by Hamilton at Berkeley focussed on the "metabolism of fission products, radium, actinium, protoactinium, uranium, neptunium, plutonium, americium and curium in animals and man."["Report of the 23-24 January 1947 Meeting of the Interim Medical Committee, U.S. Atomic Energy Commission," p. 10.] Similarly, a February 1948 report 3 by Hamilton's colleagues on their AEC-supported research noted: Considerable effort has gone into the problem of developing means of selectively localizing radioisotopes in specific tissues and study of irradiation effects thereby induced. (This work has been supported in part by the Atomic Energy Funds and in part by other laboratory funds.) Colloids of yttrium, zirconium, columbium, and uranium have been synthesized which on intravenous injection are selectively removed by the. . .liver and spleen, with minimal localization in all other tissues.["The Activities of the Division of Medical Physics on Atomic Energy Supported Work through February 1948," p. 9.] CAL-2, a four-year-old with bone cancer, had been injected with yttrium and cerium in April 1946. CAL-Z, a fifty-five-year-old woman with multiple cancers, was injected with zirconium at UCSF in January 1948. Evidence contained in a Hamilton file marked "Human Subjects" indicates that a thirty-day-old infant was given an intracranial injection of columbium [niobium] in December 1948, three days before her death. Injections of zirconium or columbium were also apparently given to at least seven cancer patients by Hamilton's colleagues between 1948 and 1949, according to documents located by DOE researchers at Berkeley but not yet examined by Advisory Committee staff. (Medical records have not yet been located on the zirconium or columbium cases.) The fact that CAL-2, CAL-3, and CAL-A were all primary bone cancer patients--a point cited by the UCSF committee as supportive of the "cancer research" hypothesis--also seems open to a different, equally plausible interpretation: That these patients were selected because amputations or rib resections, carried out as part of their treatment, provided evidence of where radioactive substances went in the bone--a matter of interest to the AEC and cancer researchers alike.[Thus, Project 48A--the so-called "plutonium project" at the University of California--was not only interested in identifying where isotopes and fission products went in the body, but also methods and chemical agents ("chelating agents") to remove them.] It is also worth noting that some cancer research experiments under an AEC contract would have been explicitly sanctioned by the so-called 20% clause, which specified that an amount equal to that portion of a contract could be reserved for "pursuing lines of research which appear fruitful to [researchers], even though not immediately related to specific items in the approved program for the particular project."[Carroll Wilson to Stafford Warren, April 30, 1947] 4 While both direct and inferential evidence support the contention that the plutonium injections, as well as subsequent experiments at UCSF, were dual-purpose, Advisory Committee staff have seen no evidence to support a claim that the primary purpose of the experiments was "therapeutic research," understood here as research intended to advance knowledge about the potential effects of radioactive substances on bone cancers. It should be noted that the UCSF report concludes that the injections in the CAL cases were not intended to be of therapeutic benefit to the individual patient: "The injections of plutonium were not expected to be, nor were they, therapeutic or of medical benefit to the patients." (p.27). This corresponds with the evidence of a letter, written by Hamilton in July 1946, three months after the injection of CAL-2, to the author of an article on the peacetime implications of wartime medical discoveries: To date no fission products, aside from radioactive iodine, have been employed for any therapeutic purposes. There is a possibility that one or more of the long list of radioactive elements produced by uranium fission may be of practical therapeutic value. At the present time, however, we can do no more than speculate.[Hamilton to Dr. John Fulton, 19 July 1946] Thus, regardless of whether the plutonium injections were conducted to determine human excretion rates of plutonium, discover a new treatment for bone cancer, or both, these subjects were used merely as means towards the ends of others and not to further the subjects' own interests or welfare. Only the express and valid consent of the subject or an appropriate surrogate would make such a use morally acceptable. Moreover, it is not clear that there are any moral differences that bear on the ethics of research with human subjects between the goal of seeking a cure or treatment for cancer and the goal of seeking measures to protect the health of workers. On the issue of consent, Advisory Committee staff agree with the UCSF report that "regardless of the type of experiment..., consent was necessary." (p.23). We also concur with the conclusion of the UCSF report that "[w]e do not know, and cannot know, exactly what was told to the research subjects or what they understood regarding the nature of the radioactive injection or its risks." (p. 34) Only in one case, that of CAL-3, is there is any direct written evidence bearing on the question of consent--the signatures of two physicians attesting to the subject's understanding of and consent to the procedure, found in CAL-3's medical record. (UCSF has not yet been able to locate the patient records of CAL-Z, whom Advisory Committee staff regard as a primary "test case" of whether AEC regulations were adhered to after CAL-3.) 5 The evidence of consent in all the other cases rests upon the 1974 recollection by former AEC official Shields Warren of comments made by Hamilton in 1947 regarding what was told to the subjects injected with plutonium. According to Warren's recollection, Hamilton told the subjects: that 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 those of other substances that had been used to help control growth processes in patients, or something of that general sort.["Interview with Shields Warren - 4/9/74", AEC Office of the Inspector General, p. 11.] Pat Durbin, who later worked with Hamilton, has stated that the "other substances" referred to in this case was almost certainly strontium, which was injected in eight patients at UCSF between 1941 and 1944 as an experimental therapeutic treatment or for palliation of pain. If Durbin is correct, Hamilton's remarks fell far short of aiming at obtaining a valid consent, and could even be regarded as "disinformed" consent--since the statement might logically lead the patient to believe that he would be receiving a substance with some hope of treating his cancer, despite the fact that the experiments were not expected to be of therapeutic or medical benefit to him. Documentary evidence suggesting that at least some UCSF subjects were not informed of the nature or purpose of the injections was not in the possession of the UCSF committee when it made its report. Such evidence is contained in a December 30, 1946 memorandum from T.S. Chapman to the Berkeley Area Engineer, a copy of which was sent by Advisory Committee staff to Berkeley's DOE researchers and was included in the Advisory Committee's December 1994 Briefing Book. 6