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 G Part 2 þþþDRAFT þ FOR DISCUSSION PURPOSESþþþ MEMORANDUM TO: Members of the Advisory Committee on Human Radiation Experiments FROM: Advisory Committee Staff DATE: October 18, 1994 RE: Historical Background on the Plutonium Injections The injection of plutonium in human subjects during the years 1945-1947 was part of a government-led effort to determine the metabolic fate and toxicity of internal radiation emitters in workers accidentally exposed to these materials while building the atomic bomb. [There is some lack of clarity in the documents as to whether the intent of the experiments was to determine the metabolic fate of plutonium in the body or its toxicity, or both. In a 1958 Los Alamos report, "Human Experiences with Plutonium," Wright Langham and Payner Harris wrote that the studies were "initiated. . .to determine whether small doses of plutonium were acutely toxic and to establish the urinary excretion rate to provide a more accurate base line from which to determine the body burden of exposed workers." In a 1962 Health Physics article on the injection, Langham and his co-authors wrote: "Although no acute toxic effects were expected from such small doses, clinical laboratory observations were carried out, especially with regard to hematological changes and liver and kidney functions. No acute subjective or objective clinical effects were observed." Langham et. al, "The Los Alamos Scientific Laboratory's Experience with Plutonium in Man," Health Physics, 1962, Vol. 8, pp. 753-760.] Plutonium was, in fact, only one of the radioactive materials of concern to health physicists working for the Army's Manhattan Project. Polonium, used in the bomb's initiator, was administered to five human subjects starting in 1943; uranium, used as the fuel in one type of atomic bomb, was injected in six human subjects in 1946-47. The particular interest in plutonium toxicity stems from a January 5, 1944, letter by Glenn Seaborg, a co-discoverer of the element, warning "that the physiological hazards of working with plutonium and its compounds may be very great". Within weeks, Dr. Stafford Warren, director of the Manhattan Project's Medical Section, advised the Army: "New biological problems are presented as fission products and [plutonium] become available. Information on the biological effects of these materials is urgently needed and these materials are now available in suitable quantity for experimental work." By August 1944, Warren and other Army representatives had outlined a research program, which included "[t]racer experiments on humans to determine the percentage of plutonium excreted daily". The program was delayed, however, "awaiting the development of a more satisfactory method of administration of product [plutonium] than is now available," wrote one researcher. 1 By March 1945, the Los Alamos Laboratory had arranged with the Army's Medical Section "for a human tracer experiment to determine the percentage of plutonium excreted daily in the urine and feces. It is suggested that a hospital patient at either Rochester or Chicago be chosen for injection of from one to ten micrograms of material and that the excreta be sent to [Los Alamos] for analysis". In early April 1945, Wright Langham of the Los Alamos Health Group sent Hymer Friedell, associate director of the Manhattan Project's Medical Division at Oak Ridge, five micrograms of plutonium, along with detailed instructions for preparing the injection, and a "Protocol of Clinical Experiment". [This document was one of some 250 uncovered in the AEC's 1974 investigation of the plutonium experiments. This collection has thus far not been found by DOE.] On April 10, 1945, the first human subject, an automobile accident victim, was injected with plutonium at the Army's hospital in Oak Ridge. In an undated letter to Los Alamos, Friedell wrote, "Everything went smoothly. . . . I think we will have access to considerable clinical material here and we hope to do a number of subjects. . . ." Subsequently, seventeen other human subjects were injected with plutonium as part of this Army-funded research project; three at Chicago; eleven at Rochester; and three at the University of California, San Francisco. Since the UCSF subjects were the last to be injected, and are perhaps the best documented, they have been chosen for the following case studies. I. Case Studies: Subject Selection As early as January 1945, Dr. Joseph Hamilton--a UCSF neurologist with a joint appointment at Berkeley's Radiation Laboratory, who was working on the plutonium project under contract to the Manhattan Project--confirmed to the Army his plan "to undertake, on a limited scale, a series of metabolic studies with [plutonium] using human subjects." Since October 1942, Hamilton had been exposing rats to plutonium and other radioactive materials as part of his government contract. The purpose of this work, Hamilton wrote, "was to evaluate the possible hazards. . .to humans who might be exposed to them, either in the course of the operation of the [Chicago] pile or in the event of possible enemy action against the military and civilian population." On May 10, in a progress report to the Manhattan District, Hamilton advised that he was awaiting "a suitable patient" for the plutonium experiment. Four days later, a fifty-eight-year-old white male, designated CAL-1, became the first human subject in the UCSF portion of the project when he was injected with plutonium. 2 According to an oral history interview by the Advisory Committee staff with Dr. Patricia Durbin, one of Hamilton's colleagues, CAL-1 was chosen in the belief that he was suffering from advanced stomach cancer, and hence had as little as six months to live. [Durbin's remark is confirmed by independent evidence. According to Wright Langham's summary of the plutonium experiments, "Life expectancy of the individual was considered as the basis of selection of subjects for study. As a rule, those chosen were past forty-five years of age and suffering from chronic disorders (other than of the kidneys) such that survival for ten years was highly improbable. By adhering to these criteria, the possibility of late radiation effects developing would be negligible. Furthermore, the possibility of obtaining post mortem material within a few months, or at most a few years, would be much greater." Langham and Payner Harris, "Human Experiences with Plutonium," Los Alamos Scientific Laboratory, 1953.] Shortly after the injection, however, a biopsy revealed the suspected cancer to be a benign gastric ulcer. For a period of a year and a half, excreta was collected daily from CAL-1. The results of the investigation were reported monthly by Hamilton to the Manhattan Project's Medical Division. [It was one of these progress reports that led the Army, in November 1946, to temporarily suspend its support of the human plutonium experiments.] CAL-1 died of heart disease in January 1966. On April 26, 1946, CAL-2, a four-year-old white Australian boy suffering from bone cancer, became the second human subject injected at UCSF. The solution injected consisted of plutonium, cerium, and yttrium. Details of CAL-2's selection remain undocumented, though the story of the boy's travel to the United States on a U.S. Army transport plane was described as a "dramatic race against death" in a local newspaper of the time. CAL-2 returned to Australia in June. He died in January 1947. Unlike CAL-1, there was little if any medical follow-up of CAL-2. The third and final plutonium experiment at UCSF involved a thirty-six-year-old black male believed to be suffering from bone cancer, who was injected on July 18, 1947. CAL-3's left leg was amputated shortly after the injection. He died of respiratory failure in June 1991. [A fourth human subject at UCSF, CAL-A, a teenage Asian male with bone cancer, was injected with americium on June 10, 1947. A fifth subject, a 55-year-old female cancer patient, was injected with zirconium-95 on January 5, 1948.] Although the exact procedure for selecting the subjects in the plutonium experiments at UCSF, as elsewhere, remain unknown, two of the human subjects in San Francisco, CAL-1 and CAL-3, were almost certainly chosen by physicians at the Medical Center, several of whom had joint appointments with Berkeley's Radiation Laboratory. Reportedly, CAL-2 came to the U.S. under the auspices of the U.S. Army and the Red Cross. [According to one contemporary press account, a physician in Sidney referred CAL-2's parents to UCSF. CAL-2's mother is quoted in the article: "Inside of one hour, American Army officers and Red Cross workers had arranged priorities for us as paying passengers" onboard a military transport flight to San Francisco.] 3 II. Case Studies: Consent In the AEC Inspector General's 1974 investigation of the plutonium story, Dr. Shields Warren recalled a December 1947 discussion with Dr. Hamilton, in which the latter indicated that "he had explained to the patients 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." [Patricia Durbin, Hamilton's associate, believes the "other" substance referred to was strontium, which was administered to eight cancer patients at UCSF between September 1941 and October 1944 as a palliative.] Hamilton, according to Warren, also noted at this time that there "were very rigid restrictions on the use of the word plutonium and the handling of the material and letting anyone know that there was any such stuff." CAL-1, therefore, was almost certainly never informed that plutonium was the material being used in his experiment. Nor, according to Hamilton's assistant, Kenneth Scott, was CAL-1 subsequently informed of the reason for the continued interest and follow-up in his case. Nonetheless, Hamilton and Scott petitioned the Army for funds to be paid CAL-1 in order to persuade him to remain in the area, as "an experimental subject." [The Army denied the request. Instead, a subsidy of $1.50 per "biological specimen" was agreed to be paid to CAL-1 out of the Army's contract with the Radiation Laboratory, in an arrangement brokered by the lab's attorney. The follow-up on CAL-1 ended, according to Hamilton's assistant, when "the Laboratory wouldn't pay for his feces anymore." Transcript of oral history interview with Mr. Kenneth Scott, Bancroft Library, UC Berkeley.] Although even the word "plutonium" remained classified at the time of CAL-1's injection, and for the remainder of the war, its existence and its characteristics were no longer secret after mid-August 1945, and the publication of the so-called Smyth Report. At the time of the injection of CAL-2 and CAL-3, plutonium and its application in the atomic bomb were a matter of public record. Details on the degree or type of consent sought from CAL-2 remains presently unknown. However, the AEC's 1974 investigation cites a note by a medical student on CAL-2's chart "to the effect that the family was anxious for the patient to be started on plutonium treatment." After CAL-2 returned to Australia, only one follow-up contact with the parents was made by the physicians at UCSF, in 1949, inquiring about the patient's condition. The injection of CAL-3 occurred after the transfer of responsibility for the plutonium experiments from the Army to the civilian Atomic Energy Commission, and in the midst of the AEC's imposition of new standards governing human subject research, including standards for consent. 4 Internal AEC documents indicate that the Commission's Legal Division, in January or February 1947, urged "that it be susceptible of proof that any individual patient, prior to treatment, was in an understanding state of mind and that the nature of the treatment and possible risk involved be explained very clearly and that the patient express his willingness to receive the treatment." The Legal Division accordingly recommended that, in the future, the patient's consent be obtained directly, and in writing. However, following a telephone call from Stafford Warren on March 7, 1947, the Legal Division and the AEC's General Manager acceded to Warren's request that the requirement for the subject's written consent be omitted, though the AEC continued to urge "that in every case at least two doctors certify in writing to the patient's state of mind to the explanation furnished him and to his acceptance of the treatment. [The question of signed consent by the patient evidently remained in contention between the AEC and the Interim Medical Advisory Committee, headed by Stafford Warren, as evidenced by an April 30, 1947, letter to Warren from AEC General Manager Carroll Wilson: "The Commission does not intend to influence in any way the exercise of judgment by the doctor as to the administration of any particular treatment authorized under the approved program. Indeed, from the discussion at the meetings [of the Interim Medical Advisory Committee] of April 3-5, it seemed evident to me that doctors would not allow their judgment on this matter to be influenced by anyone." The letter concludes: "In view of your recommendation, the Commission does not request that written releases be obtained in such cases. . . ."] The "two-physician" rule, using this same language, was codified in the General Manager's instructions to AEC contractors the following April; and was, in fact, followed in the specific example of CAL-3, whose medical chart has the signature of three physicians attesting to the patient's understanding of and consent to the procedure. The physicians' statement appended to CAL-3's medical chart reads: "The experimental nature of the intramuscular injection of the radioactive tracer sample was explained to the patient, who agreed on the procedure. The pat. was in fully oriented and in sane mind." [This statement was signed by Miss Mary Wootten, R.N.; Dr. Donald F. Bellamy; Dr. Ray Mullen; and Dr. B.V. Low-Beer, all presumedly on the staff of the Medical Center at UCSF. Dr. Bertram Low-Beer was one of Hamilton's colleague's at UCSF, and likewise had a joint appointment at Berkeley's Radiation Laboratory.] Exactly what the patient was told by the physicians, however, necessarily remains a matter of conjecture, as the AEC's 1974 investigation noted. 5