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William Moss and Roger Eckhardt
T
he human plutonium injection experiments carried out during
and after the Manhattan Project have received tremendous noto-
riety in the past year or so owing to the Pulitzer-prize winning
journalism of Eileen Welsome in the Albuquerque Tribune in 1993.
The purpose of those experiments was to develop a diagnostic tool that
could determine the uptake of plutonium in the body from the amount
excreted in the urine and feces. This tool was essential for the protec-
tion of workers who would produce and fashion plutonium metal for
use in the early atomic bombs. The idea was to remove a worker from
the job if and when it was determined that the he had received an inter-
nal dose that was close to or over the limit considered safe.
Although some of the results of the studies were declassified and re-
ported in the scientific literature in the early fifties (and further reports
appeared in the seventies), the names of the subjects were not dis-
closed. Investigative reporting by Welsome uncovered the identities of
five of the eighteen subjects and gave details about the circumstances
and lives of three of them. The secret nature of the studies and the
fact that the subjects may not have been informed about what was
being done to them has generated outrage and distrust in the general
pubic regarding the practices of the national laboratories. Why were
such experiments done? Who allowed them to happen? The Secre-
tary of Energy, Hazel O’Leary, equally disturbed, pledged an era of
openness in the Department, promising to make available to the public
all information that could be located that was pertinent to those and
Louis Hempelmann
similar radiation experi-
ments with humans.
This article is intended to tell the Los Alamos story of these experiments and their aftermath. The article is based on memos and other documents that were collected by one of the authors (Moss) and were released to the public as a result of Secretary O’Leary’s openness initiative. Los Alamos was not directly in- volved in choosing the subjects for the experiments nor in carry- ing out the clinical studies. Nev- ertheless, the motivation for the experiments arose at Los Alamos and scientists at Los Alamos were involved in planning the experi- mental protocols, preparing the ma- terial to be injected in the subjects, and analyzing the results. They were involved both at the time the experiments took place and years later when it became clear that re- analysis was appropriate.
Our intent in reviewing this story is to give enough scientific and quantitative details to bring out two areas that are usually not adequately addressed in the press and other popular reports. The first area is the purpose of the studies. What was to be learned, and how well did the experiments succeed in accom- plishing the stated goals? The second area is the significance of the results for the protection of plutonium workers. How have those results aided our cur- rent understanding of the uptake, distri- bution, and retention of plutonium, and how have the results helped us to mini- mize the risks of internal exposure from plutonium? We will, in fact, show a new analysis of the data from the 1940s that, coupled with a recent human plu- tonium injection study using plutonium- 237, strengthens our understanding of the manner in which plutonium, once it has reached the bloodstream, distributes itself in the body.
But first, we examine motivations and try to reconstruct why things were done
as they were. For that we need to go back to the atmosphere of World War
II and the enormous pressures attendant on using unknown and uncharacterized materials to build the first atomic weapons.
The Manhattan Project and
Its Need for Plutonium
In planning the development of the atomic bomb, scientists considered using two fissionable materials capable of sustaining a chain reaction—urani- um-235 and plutonium-239. Each pre- sented a different set of production and health-related problems.
Uranium-235 was present in natural uranium in small amounts (0.7 per cent). Scientists faced the daunting task of separating kilogram amounts of uranium-235 from the much more plen- tiful uranium-238 isotope by taking ad- vantage of the slight difference in the mass of the two isotopes. For example,
in the gaseous-diffusion method, gaseous compounds of the two isotopes diffuse through porous barriers or membranes at rates that differ by about 6 parts per thousand. Similarly, the elec- tromagnetic method passes a beam of ionized uranium through a magnetic field, and the two isotopes follow circu- lar paths that very gradually diverge.
In 1942, it was problematic whether enough uranium- 235 could be separated by such painstaking techniques to achieve the goal of hav- ing an atomic bomb by January 1945. It was deemed necessary to pur- sue plutonium-239 as an- other possible weapon ma- terial. Because plutonium is chemically different from uranium, it was thought that it could be produced in reactors through neutron absorption and then separated easily from its ura- nium parent and fission products by chemical means.
Scientists had created tiny amounts of plutonium with the cyclotron at the University of California Radiation Lab- oratory in 1941 and demonstrated its favorable nuclear properties (see “The Making of Plutonium-239”). The phys- ical properties and the chemistry of plu- tonium were determined using only mi- crogram (micro = 10-6^ ) quantities. Such small amounts and the fact that plutonium emits alpha radiation, which doesn’t penetrate the skin, meant the risk of handling plutonium, compared to gamma-emitting radionuclides, was not a major concern. In fact, the alpha activity of these small quantities was the only means to track and account for the material.
The discovery of plutonium led the Of- fice of Scientific Research and Devel- opment to inaugurate work on plutoni- um for a weapon design. The work
178 Los Alamos Science Number 23 1995
180 Los Alamos Science^ Number 23^1995
physiological effects of ionizing radia- tion was assembled under the direction of Robert S. Stone. The intention was to develop health-protection methods for workers involved in the production, purification, and fabrication of uranium and plutonium, including development of ways to monitor personnel for expo-
sures to ionizing radiation by blood tests. In September, research was start- ed to increase information about the toxicity of uranium compounds.
The chemical toxicity of uranium (its radiological risk was unknown) was identified with heavy-metal poisoning
related to deposits in the kidney and bone. Plutonium, on the other hand, was an unknown health-risk factor. If plutonium metal or compounds were in- haled or ingested, where would they de- posit in the body? What limits should be set on internal body burdens that would be safe? What tests would indi-
L E G E N D
Manhattan Project Sites Involved with
Human Plutonium Injection Experiments
Animal studies
Analysis of plutonium injection experiments
Injection of patients with plutonium
.
.
Los Alamos
(Site Y)
First atomic bomb
Joseph Hamilton
Director of Berkeley
animal and human
plutonium studies
Louis Hempelmann
Director of Los
Alamos Health
Group
Wright Langham
Biochemist who
analyzed Oak
Ridge and
Rochester pluto-
nium experiments
Berkeley
Discovery of plutonium
Birth of nuclear medicine
Hanford
(Site W)
Plutonium production
reactors
Number 23 1995 Los Alamos Science 181
cate when these body-tolerance limits were being approached? As a result of such concerns, efforts in health protec- tion paralleled the growth of the nu- clear weapons research (see “The Med- ical Researchers”).
A contract was issued in October 1942
by the Met Lab to the University of California Radiation Laboratory at Berkeley to study the metabolism of the radioactive materials that would re- sult from the fission process in natural uranium piles. These studies, directed by Joseph G. Hamilton, would initially be limited to the metabolism in rats of
small quantities of cyclotron-produced fission products (their radioactivity would “trace” their course through the body). As larger quantities of the transuranics became available from the Clinton pilot reactor in 1944, the stud- ies would focus on the assimilation, distribution, retention, and excretion in
.
Chicago
(Met Lab)
Plutonium Project
First nuclear chain
reaction
.
Oak Ridge
(Site X)
Pilot reactor
for plutonium
production
Rochester
Rochester Medical
Project
Robert Stone
Director of Met Lab
Health Division
Stafford W arren
Medical Director of
the Manhattan Project
The development of atomic weapons by the Manhattan Project was carried out during World War II at a number of universities and secret laboratory sites across the country. The icons represent facets of the plutonium injection studies carried out at each site, including both ani- mal studies (no background) and human studies (red circle in back- ground).
Number 23 1995 Los Alamos Science 183
Stafford Warren was educated at the University of California at Berkeley from 1918 to 1922 and re- ceived his M.D. from the University of California Medical School at San Francisco in 1922. In 1925, he was appointed as an assistant pro- fessor of radiology at the University of Rochester School of Medicine and Dentistry, eventually serving there as the Department of Radiol- ogy Chairman. In April 1943, War- ren was appointed a consultant to the Manhattan Project to establish the Rochester site. By November, persuaded partly by management at Eastman Kodak, who were run- ning the uranium processing plant at Oak Ridge, Warren was made the medical director of the Manhat- tan Project with headquarters at Oak Ridge, Tennessee, and was commissioned as a colonel in the Army Medical Corps.
In the mid-thirties, Robert Stone, a radiologist, and Joseph Hamilton, an intern with a degree in chem- istry, were recruited by Ernest Lawrence from the University of California Medical School in San Francisco (at that time, part of the UC, Berkeley system) to develop biomedical applications for the Berkeley cyclotron. One applica- tion was the direct treatment of cancer, and Stone pioneered the use of cyclotron radiation for exper- imental treatment of human cancer patients. A second application was to use the cyclotron to produce ra- dionuclides for the internal ra- diotreatment of disease. By the late thirties, Hamilton and Stone were involved with human metabol- ic and clinical studies using sodi- um-24, a short-lived radioisotope. They hoped sodium-24 could re-
place the long-lived radium iso- topes for the internal radiotreatment of certain illnesses. Their studies would involve using human volun- teers—patients with leukemia, or other illnesses, and normal healthy subjects—to acquire comparative data and to test for toxic responses and evidence of cures. The
amounts of the radioisotope admin- istered to the patients were always well below what were considered toxic levels relative to the then rec- ognized risks from external expo- sures to x rays and internal expo- sures to radium (from the use of soluble radium salts to treat a wide range of illnesses).
Louis Hempelmann’s medical train- ing was at Washington University in St. Louis, followed by a residency in Boston at the Peter Bent Brigham Hospital. A fellowship
brought him to the Radiation Labo- ratory at Berkeley in 1941, where he studied radiobiology with Stone and John Lawrence (Ernest Lawrence’s brother) and worked on the use of cyclotron-produced neu- trons for therapeutic treatment of cancer. At that time, Hamilton was doing other research with a variety
of radioisotopes, including the cy- clotron-produced fission product io- dine-131. Many of those studies used both normal human subjects who had volunteered and patients who were then tested for evidence of responses that could lead to medical treatments of illnesses, in- cluding cures. In a 1942 article, Hempelmann said that “if the cy- clotron finds no place in medicine other than to provide ‘tagged atoms’ for medical studies, the medical profession will owe Ernest Lawrence an everlasting debt.” n
A Radiotracer Experiment in the 1930s. Joseph Hamilton (left) performs a tracer experiment in which the volunteer drinks a solution containing radioactive sodium with his hand (out of sight) inside a shielded counter that will detect the arrival of the radioisotope in that part of his body.
The Medical Researchers
generated in reactors at Argonne (twen- ty miles southwest of Chicago) and later at Clinton, Tennessee, and that material would be processed into metal at the Chicago Met Lab before being sent to Los Alamos. However, in May 1943, a committee appointed by Groves reviewed the use of plutonium pro- duced by cyclotrons and reactors and decided it was necessary to locate the final production steps for weapons ma- terial at the same site that would assem- ble the bombs. Thus, Los Alamos was assigned the responsibility of the final purification and production of the pluto- nium metal, starting with the Clinton product in 1944 and, later, with large quantities of the Hanford product (which was sent to Los Alamos in the form of a plutonium-nitrate slurry). The Met Lab would also continue its innovative research for Los Alamos on the physical and chemical properties of plutonium using, in 1944, milligram quantities of the Clinton product.
The new assignment resulted in an in- crease in personnel in the Chemistry and Metallurgy Division at Los Alamos from about twenty in June 1943 to about four hundred by 1945. It also created an important difference in the type of work at the two sites—the Met Lab research was mainly “wet chem- istry,” whereas the Los Alamos produc- tion effort involved a considerable amount of “dry chemistry,” resulting in different types of health hazards, and in particular, exposure to the airborne dust of plutonium and its compounds.
In January 1944, at the same time the first milligrams of reactor-produced plutonium were being shipped from Clinton, Seaborg and others at the Met Lab began thinking seriously about the fact that more and more people would soon be working with gram quantities of plutonium—perhaps thousands of people at Hanford alone. Hamilton had probably informed Seaborg of a 1943 paper by Robley Evans about the dan- gers of radium and the deaths of radi- um-dial painters in the 1920s, in this
way alerting Seaborg to a potentially similar situation with plutonium. The Evans paper estimated that as little as 1 or 2 micrograms of radium retained in a person’s skeleton could cause cancer, a latent radiation effect. It also ex- plained the reasoning behind the occu- pational tolerance limit of 0.1 micro- grams for radium retained in the body (see “Radium—the Benchmark for In- ternal Alpha Emitters” on page 224 for a fuller discussion of the radium toler- ance levels).
Similarities with radium. That the health risks for the intake and retention of plutonium might be as dangerous as those of radium was apparent from a comparison of their chemical and nu- clear properties. Both elements were heavy metals that were expected to de- posit in bone. Both had long half- lives—1,600 years for radium-226 and 24,000 years for plutonium-239—and both decayed by alpha emission. A comparison of their specific activities ( microcurie per microgram for radium- 226 and 0.06 microcuries per micro- gram for plutonium-239) and the ener- gies of their alpha particles, including those of the daughters of radium, im- plied that plutonium might be a factor of 50 times less effective than radium at causing physiological damage. But because of the tragic deaths of the radi- um-dial painters (dating from the use of radium in 1917 to1918), it was impera- tive to obtain metabolic data on pluto- nium so that a safe tolerance limit could be established for the Manhattan Project workers.
On January 5, 1944, Seaborg sent a memo to Stone, expressing his con- cerns. He offered to help set up safety measures for handling plutonium and suggested that “a program to trace the course of plutonium in the body be ini- tiated as soon as possible.” Stone replied by explaining Hamilton’s planned tracer studies at Berkeley, which would determine the metabolic distribution of plutonium in animals, and Hamilton’s need for milligram
amounts. Hamilton had apparently been offered microgram quantities of plutonium-239 prior to 1944, but he had informed Stone that “the studies can be much more accurate and much more quickly done” when milligram quantities were available (see “Detec- tion of Internal Plutonium”). He pre- ferred to wait until then to do the pluto- nium metabolic studies, undoubtedly fearing that experiments with smaller amounts would lead to questionable re- sults that would have to be repeated.
On January 15, Seaborg sent a second memo to Stone.
I am seriously worried about the health of the people in my section, for which I am responsible, since they will soon handle such relatively large amounts of plutonium. I won- der whether some plutonium should be made available to Dr. Hamilton for his distribution studies sooner than the couple of months or more indicated in your memorandum.... The problem of health hazards as- sumes even greater importance for Site Y [Los Alamos] where so much plutonium will be handled in so large a variety of operations. It is, of course, also important in connec- tion with the operations which will go on at Site W [Hanford], particu- larly those involved in its final isolation there.
In response to those concerns, manage- ment at the Met Lab initiated discus- sions about plutonium and its potential for toxicity, beginning with a meeting of the Project Council at the Clinton Laboratory in Tennessee on January 19,
- Compton summarized the deliv- ery schedule for plutonium from the Clinton reactor as 0.5 grams that month, 3 grams in February, and 3 to 4 grams in March and indicated that the Plutonium Project was “still in the lead” in the race with the uranium iso- tope separation effort.
Tolerance limits. According to the
184 Los Alamos Science Number 23 1995
continued from page 182
as
plutonium
nitrate. One-and-a-half milligrams of plutonium went to the Chicago Met Lab on January 6, and six
milligrams went to Los Alamos on Jan- uary 17. The quantity shipped to Los Alamos was ten times larger than the previous 650 micrograms and was large
enough, in its glass vial, for Weisskopf to remark in his memoirs: “I held on the palm of my hand the first little grain any of us had ever seen. (I should not have done it, I suppose, because of its radioactivity, but it was such a tiny quantity that it didn’t have any detrimental effect.)”* Increasing
amounts of plutonium followed in sub- sequent months.
At the Met Lab, they implemented safe- guards for plutonium work by putting linoleum on all the floors and having their people use filter masks, rubber
gloves, and outer protection cloth- ing. Eating in the laboratories was stopped. Methods were developed to monitor the air in the labs for evidence of plutonium dust conta- mination. Similar safety proce- dures were adopted at Los Alamos at the beginning of March 1944.
Nose swipes. By the end of April, the Met Lab proposed a plutonium air tolerance limit of 5 3 10210 micrograms per cubic centimeter of air (arrived at by estimating the build-up of pluto- nium in the lungs over a two- year period for a worker breathing the air 300 days a year). A procedure to detect the inhalation of plutonium dust using nose swipes had al- ready been initiated. A moist filter-paper swab was inserted into the nostril and rotated, then the swab was spread out, dried, and read in an alpha detector. A reading of 100 counts per minute or higher was considered evidence of an exposure.
It was realized early with this procedure that the nose-swipe could easily be contaminated with plutoni- um from the worker’s hand. Steps were included to help eliminate such contamination, and the procedure was changed so that individ- ual counts were taken from each nostril to serve as a check. (Nose swipes are still used for plutonium workers. Nose- swipe counts and air monitoring are the criteria used to decide when medical treatment for the worker, including prompt collection of urine samples and the initiation of chelation therapy, is necessary.)
The new procedure quickly bore re- sults, because on May 30, the Los Alamos Safety Committee informed Kennedy that Ted Magel, one of the
186 Los Alamos Science Number 23 1995
*Victor Weisskopf. 1991. The Joy of Insight: Passions of a Physicist. BasicBooks.
workers making the first plutonium metal-reduction runs, had a nose swipe of 11,372 alpha counts per minute. They felt it was apparent that safety rules had been violated, and Magel was instructed to follow those rules in the future. Apparently, in his desire to make sure that a metal-reduction exper- iment was being set up correctly, Magel had lifted the lid of a crucible contain- ing plutonium without first putting on his respirator and so exposed himself to plutonium dust particles. Magel contin- ued to work with plutonium until he left Los Alamos a couple of months later in August 1944. (A positive urine assay of a sample obtained from Magel in 1945 confirmed the nose-swipe evi- dence of exposure.)
By the end of August, Los Alamos had received 51 grams of plutonium, and scientists had used the material in over 2,500 different experiments. In a memo to Groves, Oppenheimer stated that “the overall loss per experiment has been about 1 per cent,” and that 36 grams remained. One group at the Laboratory was dedicated solely to re- covery (and repurification) of the pre- cious metal both from laboratory acci- dents and from completed experiments. Because they could never be sure what substances or chemicals the plutonium would be mixed with (for example, as- phalt floor tiles in a laboratory spill or a mass of burned material from a furnace in a metal-reduction experiment), they had worked out a flow chart for sepa- rating plutonium from every other ele- ment in the periodic table. In his memo, Oppenheimer continued: “We are now in a position to carry through the operations necessary for final fabri- cation with a very high yield (99%) and to recover almost all that is not includ- ed in the yield.” He felt that the loss of 15 grams of plutonium “will be paid for many times over by the effectiveness with which we can deal with produc- tion lots when they become available.”
There was, of course, great concern about the lost material. In September,
Kennedy wrote a memo expressing that concern to the people in his division working with plutonium. Among other things, he said, “the suspicion that sev- eral grams of 49 are scattered some- where in building D is not pleasant. In addition to its great value, this material constitutes a definite hazard to health.” He went on to describe efforts to im- prove handling and recovery.
Plutonium Animal Studies
The quickest way to obtain more realis- tic information about the toxicity of plutonium was with animal studies. It was hoped that such studies would an- swer a lengthy series of questions, in- cluding how the amount of plutonium taken into the body would depend on the exposure mode (for example, oral ingestion, inhalation, or absorption through the skin), how retention would
depend on the chemical, physical, or valence state of the plutonium, and how much of the plutonium that had become internal would be excreted and how rapidly. It was also unknown what fraction of internal plutonium would become “fixed” in tissue in the body (see Figure 1) and how it would be dis- tributed among the various organs.
When Hamilton started his series of an- imal experiments, his guess was that a plutonium tolerance dose of even 10 micrograms was “very conservative.” His reasoning was most likely based on the known excretion behavior of radi- um, which was very high at first (more than 20 per cent of radium administered as a soluble salt was eliminated in hu- mans the first day) but eventually be- came very low (less than 1 per cent by the tenth day and less than 0.3 per cent by the twenty-first day). It was thought that the high elimination rate occurred
Number 23 1995 Los Alamos Science 187
Figure 1. Daily Urinary Excretion for an Internal Exposure When a person or animal gets a quantity of a metal compound, such as those of pluto- nium, radium, or zirconium, into their blood, the material may initially circulate in a rela- tively “free” form. Eventually, however, material that isn’t rapidly excreted—within a few minutes, hours, or days—may deposit and become “fixed” in the tissue of various organs and be less available to the blood stream. As a result, a lesser amount will be filtered out by the kidneys and excreted. The two phases (the initial-intake phase and the metabolized phase) will be evident in urine excretion curves as regions with differ- ent slopes. The duration and excretion rate of the two phases for a given element will depend on that element’s chemical nature and biochemical affinities. The figure shows a theoretical excretion curve.
Days after injection
Fraction excreted
Metal free in blood
Metal fixed in tissue
which meant the assumptions about rapid initial elimination and slow “fix- ing” of plutonium in the tissue were not accurate. After roughly 20 to 30 days, the excretion rate appeared to become constant, but again, at much lower rates (about 0.01 per cent in urine). The total excretion rate (urinary and fecal) at 21 days was about 10 times less than that of radium.
The discovery that absorption of solu- ble compounds of plutonium through the gastrointestinal tract was very low and essentially no absorption occurred through the skin meant that the main routes to internal deposition were ab- sorption from contaminated wounds or inhalation of dust particles. Such con- siderations led Hamilton, on May 5, 1944, to suggest treatment for puncture wounds.
Hamilton informed Stone that in acci- dents involving intramuscular injec- tion—such as might occur if closed systems at high temperatures exploded and shards punctured the worker’s skin—absorption of plutonium would be slow. Hamilton felt that “only a few percent [of soluble product] would be
expected to be taken up within a matter of an hour or so.” He realized “that analogies are frequently dangerous for the purposes of comparison, but the su- perficial similarities... to snake bite come to mind.” As a result, he sug- gested a treatment that included, when possible, the use of a tourniquet, which “facilitates the washing out of the mate- rial by bleeding and at the same time retards absorption.”
Acute effects. By the end of 1945, studies with rodents and dogs had shown that the acute radiation effects of plutonium were less “toxic” than highly toxic chemicals (such as curare, strych- nine, and botulinus toxin) but far ex- ceeded any known chemical hazard of heavy metals. The clinical picture of acute plutonium toxicity in dogs was, superficially at least, quite similar to the effect of a single lethal dose of total- body x rays. Although the initial vom- iting and depression seen with x rays were absent, weight loss and refusal of food and water in the first days were followed, around the tenth day, by the final “shock” phase that included a rise in body temperature, pulse rate, labored breathing, and various hemorrhages.
Changes occurred in the blood as well, including drops in white and red cell counts. However, other animal species showed certain dissimilarities between acute plutonium toxicity and total-body x rays.
The acute lethal dose for animals ap- peared to be somewhere in the range from 400 to 4000 micrograms of pluto- nium per kilogram of body weight, de
pending on the species and, to a lesser extent, on the chemical form of the plu- tonium. Damage tended to occur more specifically in the liver, kidneys, and spleen and to red blood-cell production in the bone marrow. In rats, about 60 per cent of the retained plutonium ended up in the skeleton and 18 per cent in the liver.
At that time, very little of the experi- mental work extended over a period of more than six or seven months, so the picture of chronic plutonium toxicity was essentially a guess. A few bone tumors and one instance of bone thin- ning had been observed in rats and mice. It was not at all certain whether the various effects, including those to the blood, were progressive or whether they could be extrapolated to lower doses.
Certainly, extrapolating the results of animal studies to humans had to be done with caution. Experiments with other toxic substances had shown in- stances of dramatic differences between animals and humans. Rats, for exam- ple, will tolerate quantities of deposited radium per unit of body weight that would be lethal to humans, and various inbred mice are capable of surviving huge doses of external gamma radiation compared to humans. Likewise, any study involving skin was particularly suspect because of the very great differ- ences between human skin and those of animals. Thus, the animal studies could only be suggestive of what was expected to happen in humans.
Number 23 1995 Los Alamos Science 189
Table 1. The Metabolic Behavior of Radium and Plutonium in Animals
Property Radium Plutonium
Initial excretion (rats) urinary (first day) ~15 % ~0.7 % fecal (first day) ~16 % ~2.3 %
Total excretion in 25 days (rats) urinary ~23 % ~2.5 % fecal ~32 % ~25.0 %
Overall deposition bone 99 % ~50 % liver — ~30 %(at first)
Bone deposition within the surface of mineralized bone “active” bone
Planning for the Human
Injection Studies
By August 1944, despite the efforts of a full-time chemist at Los Alamos and another at Chicago, no satisfactory method of analyzing excreta that could consistently detect 1-microgram body burdens had yet been devised (assum- ing the 0.01-per-cent urinary excretion rate suggested by the animal experi- ments). An ion-exchange method de- veloped by the Met Lab was satisfacto- ry at the 5-microgram level, but Hempelmann was convinced it was im- portant to achieve even lower levels of detectablility (see “Detection of Internal Plutonium”).
People in the Chemistry Division at Los Alamos were concerned “about the inability of the Medical Group to detect dangerous amounts of plutonium in the body.” They had already had instances of significant inhalation exposures and one accident in which a chemist inad- vertently swallowed an unknown, but small amount of plutonium solution (see “A Swallow of Plutonium”). In addition, there had been five accidents involving wound exposures. They could not afford to continue using guesswork as the basis for transferring skilled workers who had experienced plutonium exposures away from priority work.
As a result, on August 16, 1944, Hempelmann proposed a new research program to Oppenheimer. The first order of business would be “develop- ment of methods of detection of pluto- nium in the excreta.” Hempelmann also stressed the importance of deter- mining “the factor by which the amount of plutonium in the excreta must be multiplied to ascertain the amount in the body” and of developing “methods of detection of plutonium in the lung.”
Oppenheimer authorized work on the detection of plutonium in both excreta and lungs, but he was concerned about balancing priorities. He said, “in view
of the many urgent problems facing the laboratory, it should be carried out with as small an investment of personnel as possible... fewer than ten people.” In the same vein, he continued: “As for the biological sides of the work, which may involve animal or even human ex- perimentation... it is desirable if these can in any way be handled elsewhere not to undertake them here.” Los Alamos lacked the appropriate medical research facilities, and Oppenheimer suggested that Hempelmann and he “discuss the biological questions with
Colonel Warren at a very early date.” Warren, of course, had by now been in charge of the medical programs for the Manhattan Project for over a year. It was logical that biological research should be carried out at a site, such as Rochester, which housed the appropri- ate staff and facilities.
A three-part plan. Groves, informed of the plutonium exposure problems, apparently made sure that Warren was in Los Alamos about a week later. On August 29, Hempelmann summarized
190 Los Alamos Science Number 23 1995
A Swallow of Plutonium
On August 1, 1944, a sealed tube containing plutonium chloride solution ejected part of its contents while being opened.* Gases had built up, most likely from the dissociation of water by the alpha radiation, and some of the solution shot through the narrow tube out against the wall when the pres- sure was released and the gases “boiled.” Don Mastick, the young chemist working with the plutonium, realized from the taste of acid in his mouth that part of the solution must have bounced off the wall into his mouth.
It was estimated that about 10 milligrams of the material was lost, mostly on the walls of the room, with some on Mastick’s face and some swallowed. Although his face was thoroughly scrubbed, the skin remained contaminated with about a microgram of plutonium. His mouth was also thoroughly washed, but for many days afterwards, he could blow at an open-faced ion- ization chamber across the room and cause the needle to go off-scale—the level of contamination estimated to be about 10 micrograms. (This last fact suggests that the plutonium solution may have had other radioactive conta- minants in it since it was later found not to be possible to detect plutonium deposited in the lungs through ionized air molecules.)
Hempelmann pumped out Mastick’s stomach to retrieve much of what had been swallowed (analysis of the contents for plutonium registered 4098 counts per minute, which corresponds to only about 60 nanograms). Since very little would have been absorbed through his gastrointestinal tract, Ma- stick ended up with only a barely measurable body burden. His initial 24- hour urine assays, when the excretion rate was highest, were only 5 to 7 counts per minute, which translates to well below a 1-microgram body bur- den. Some plutonium was absorbed, of course, and improved assay meth- ods available in the early seventies were able to detect small amounts of plutonium in his urine thirty years later (hundredths of counts per minute).
*The 10 milligrams that were ejected in the accident were not “Los Alamos’ entire supply of pluto- nium,” as reported elsewhere (for example, by Eileen Welsome in her 1993 articles in the Albu- querque Tribune and in the October 1995 Final Report of the President’s Advisory Committee on Human Radiation Experiments). In March the first 1-gram reduction of plutonium to metal had been performed at Los Alamos, and by the end of August, the Laboratory was working with over 50 grams of plutonium (5000 times more than the amount sprayed at the wall).
192 Los Alamos Science Number 23 1995
Met Lab procedure to analyze urine samples of four Los Alamos workers who had already experienced instances of high readings from their nose swipes failed to detect concentrations of pluto- nium alpha activity consistent with the high nose-count records.
As it turned out, one problem with the Chicago procedure was that running a complete 24-hour urine sample (1 to 2 liters) through the column overloaded the resin with organic material. A drop in resin performance altered results and nullified the expected increases in sen- sitivity. The Chicago method worked well with 100-milliliter aliquots at the activity level of excreted plutonium- 239 expected for 5-microgram body burdens. But detection of body bur- dens of 1-microgram or less would re- quire an analytical procedure that used a 24-hour urine sample and eliminated the organic material and urine salts.
Concerns were heightened by an acci- dent in August in which part of a plu- tonium-chloride solution sprayed into the mouth of Don Mastick, a young chemist (see “A Swallow of Plutoni- um”). How much of the plutonium had been absorbed by his gastrointestinal tract? What fraction of a serious dose did the absorbed plutonium represent? Was it safe for him to go back to work at his old job and possibly be exposed again? In fact, to avoid further expo- sures, Mastick was transferred tem- porarily to Hempelmann’s group “to work on the problem of detection of plutonium in the excreta.”
The research team at Los Alamos that attacked the problem of detection meth- ods included Perley, who continued to investigate the Chicago procedure, Robert Fryxell, who studied a method of separating plutonium from urine that used cupferron as the main complexing agent, and Mastick, who investigated various ether extractions. The analyti- cal procedure for isolating plutonium from one liter of urine (a 24-hour sam- ple) was outlined by Arthur Wahl. In
September, Roger Kleinschmidt joined the team to investigate methods of iso- lating plutonium from urine ash samples using a lanthanum-fluoride carrier to precipitate plutonium from the dissolved ash. He would also direct the plating and measurement of the final precipitate with a goal of 90-per-cent chemical re- covery of spiked urine samples.
Fryxell consulted with Wright Lang- ham on the cupferron technique for plutonium isolation. Langham was a biochemist who had been transferred to Los Alamos in July 1944. Previously, he had spent a short period at the Met Lab in the analytical chemistry group where he’d been involved in plutonium purification research. Before long, Wright Langham would become one of the major names associated with the detection, analysis, and evaluation of plutonium in humans.
Cupferron extraction. By late 1944, Hempelmann’s team had devised a sat- isfactory technique, using cupferron ex- traction, for analysis of urine contain- ing tenths of a nanogram of plutonium. After collection, the samples underwent a multistep preparation that included evaporation to dryness, treatement with
acid and peroxide to remove organic matter, and the cupferron extraction step. Eventually, the plutonium was carried out of solution as a co-precipi- tate with lanthanum fluoride, and this final precipitate was transferred to a platinum disc. The activity of the plat- ed sample was measured by placing the disc in an alpha counter.
However, analyzing spiked urine sam- ples—or even samples taken from ani- mals—in a laboratory environment was one thing. Analyzing samples from people working with plutonium on a daily basis was another thing entirely. Early assays of workers yielded surpris- ingly high results, indicating that if the 0.01-per-cent-per-day excretion rate de- rived from the animal data were applic- able to humans, then these workers had significant levels (greater than micro- gram amounts) of deposited plutonium.
Sample contamination. An analysis technique sensitive enough to detect tenths of nanograms would easily de- tect tiny particles of plutonium dust or contaminated skin that, say, dropped from a worker’s hand into the sampling flask. As a result, a collection proce- dure was set up in which the worker to
Estimates of the Detection Regime
Plutonium-239 has a specific activity of 0.06 curies per gram, which means that a nanogram of the substance undergoes about 130 disintegrations per minute ((0.06 Ci/g) (10-9^ g/ng) (3.7 x 10^10 d/s/Ci) (60 s/min) < 130 d/min/ng). However, the Hanford “product” contained small quantities of other plutonium isotopes (at the time, it was commonly referred to as 239-240 Pu), and ac- counting for such impurities increases the rate to about 140 disintegrations per minute per nanogram. If we want to detect a tolerance limit of 5 micro- grams of “product” in the body and only 0.01 per cent of the plutonium is being excreted per day (several weeks after the initial exposure), then a 1- liter, 24-hour sample of urine will contain 0.5 nanograms of plutonium. If only 100 milliliters (10 per cent) is analyzed, the test must be capable of de- tecting 0.05 nanograms of plutonium. A sample at this level emits about 7 alpha particles per minute (0.05 ng 3 140 d/m/ng), which, in an alpha counter with 50 per cent efficiency, corresponds to a reading of 3 or 4 counts per minute. If we want to detect a lower tolerance limit of 1 microgram—one-fifth as large—the counting rate drops to less than 1 count per minute.
Number 23 1995 Los Alamos Science 193
be tested was removed from the work- place for forty-eight hours and asked to “wear freshly laundered clothing... and to bathe and wash their hands fre- quently.” After this period, the worker was admitted to the hospital, asked to shower, placed in a special room (the “health pass ward”), and checked for contamination. He was instructed to wash his hands and wear white cotton gloves each time he urinated, and the flask and funnel were placed so they didn’t have to be touched.
A trial run with plutonium workers vividly demonstrated the need for such care: the average counts per minute when the samples were collected by the workers at home was 20, whereas the average for samples collected using the above procedure was only 2.2 counts per minute! Thus, external contami- nates picked up at work made the plu- tonium excretion rate appear ten times larger than it actually was.
Other problems solved by people at the Met Lab and at Los Alamos were the maintenance of a laboratory free from alpha contamination (including the reagents used in the analysis), the de- velopment of a method capable of han- dling large volumes of urine (1-liter rather than 100-milliliter samples), and the development at Chicago of alpha- counting instruments capable of detect- ing less than 1 alpha count per minute.
By February 1945, which coincided with delivery of multi-gram amounts of plutonium from Hanford, the urinalysis procedure appeared capable of detecting 0.02 nanogram of plutonium-239 alpha activity in a 24-hour urine sample. If the human urinary excretion rate was equal to the animal rate of 0.01 per cent per day, the method could detect a body burden of less than 1 microgram with 95 per cent confidence.
The method was tested on thirty-six workers at Los Alamos. Fourteen of these people had evidence of previous inhalations of plutonium dust because
of at least one high nose-swipe count. These fourteen people had an average of 1.2 counts per minute in their 24- hour urine samples. The urine samples of the other twenty-two people, who had never shown a high nose-swipe count, averaged 0.2 counts per minute. The five most highly exposed people had urine samples with an average of 2.2 counts per minute. Such correla- tions were strong evidence that devel- opment of a sensitive analytical proce- dure had succeeded at Los Alamos.
TTA extraction. The method devel- oped at Berkeley for analyzing urine samples used extraction with thio- phenyltrifluoracetone (TTA). After the sample was ashed, a lanthanum-fluoride precipitation was performed, followed by the TTA extraction step. This method resulted in a negligible sample mass and low background counts.
One of the main sources of alpha conta- mination in the Berkeley and Los Alamos methods was the lanthanum- fluoride reagent. The Los Alamos pro- cedure ended with the lanthanum-fluo- ride precipitation step, which introduced alpha contaminants and lim- ited the sensitivity of the technique be- cause of a count-per-minute back- ground. In the Berkeley procedure, the lanthanum-fluoride-precipitation step preceded the extraction step, and the alpha contaminants were left behind, which yielded a background of only 0. counts per minute.
Each of the three techniques had its ad- vantages and disadvantages, as well as its proponents and detractors, but the Los Alamos, Chicago, and Berkeley sites were each able to acquire highly satisfactory data using their particular method. n
The Los Alamos Urine Analysis Method
The method developed in 1945 at Los Alamos for the plutonium analysis of urine started by evaporating a 24-hour urine specimen almost to dryness. (It was recommended that people being tested keep their intake of liquids to a minimum—one cup of liquid per meal and little or no liquids in between—to expedite this step.) The residue was then wet-ashed (by repeated additions of concentrated acids and hydrogen peroxide) until a white solid almost com- pletely free of organic matter remained. The solid was dissolved in hy- drochloric acid and precipitated as hydroxide. After redissolving the precipi- tate in hydrochloric acid and adjusting the pH, ferric iron was added as a carrier, and the dissolved plutonium was complexed with cupferron (an or- ganic compound that forms a soluble complex with iron). Choroform was then used to extract the cupferron complex, separating it from other dis- solved materials in the aqueous solution. (One of the most critical steps in the process was using a separatory flask to draw off exactly the chloroform layer.) After the chloroform was evaporated, the cupferron residue was di- gested with nitric and perchloric acids. Finally, the plutonium was carried out of this solution as part of a lanthanum fluoride precipitate, leaving the iron behind. The final precipitate was transferred to a platinum foil, dried, and counted in an alpha-particle detector for thirty minutes. The main rea- son for these various steps was to concentrate the plutonium while minimiz- ing material that would deposit on the foil and absorb part of the alpha radia- tion. Control urine samples spiked with plutonium analyzed concurrently with regular samples demonstrated an average chemical recovery of 88 per cent ( 6 11 per cent one standard deviation) and a reagent-contaminate back- ground of 1 count per minute.
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Other human experiments involved var- ious toxic heavy-metal radioisotopes that were either materials important for the development of the atomic weapons (polonium and uranium) or were part of a comparative evaluation of health haz- ards (radium). The polonium studies helped to develop techniques for the similar but later studies with plutonium (see “Polonium Human-Injection Experiments”). One of the main problems in the polo- nium studies was contamination. Working with the material could easily contaminate laboratory equipment used in the analysis, which, in turn, could bias results or even contaminate sam- ples related to other studies. It was thus anticipated that analysis procedures for plutonium would require laborato- ries that were absolutely free of alpha contamination. A “clean laboratory” was established at Los Alamos in Feb- ruary 1945 in the Medical Labs Build- ing, and the responsibilities in the plu- tonium study were split. The Medical Corps or the Rochester Project would handle the clinical work, and Los Alamos would analyze the resulting biological samples.
The First Human Experiments
with Plutonium
Reports issued in 1945 show that three human plutonium-injection studies were authorized in April 1945—a study by the Chicago Met Lab Health Group, an- other by Hamilton’s group in Berkeley and San Francisco, and a third study to be done jointly by Warren at the Army Medical Corp Hospital in Oak Ridge (clinical) and the Los Alamos Health Group (analytical). The three ap- proaches would allow using plutonium in two different valence states (+4 and +6), two different chemical forms (cit- rate and nitrate), and two different iso- topes (plutonium-239 and plutonium- 238). Each group would be responsible for analysis of excreta samples using their own plutonium analysis technique developed for that purpose (the cupfer-
ron-extraction method at Los Alamos, the cation-exchange method at Chicago, and the thiophenyltrifluoroacetone ex- traction method at Berkeley).
The plutonium-239 dose decided on for the Oak Ridge-Los Alamos and the
Chicago studies was 5 micrograms. That quantity would enable the Chicago group to detect plutonium accurately using 100-milliliter urine-sample aliquots of 24-hour collections and would provide appropriate activity lev- els for the Los Alamos method, which used full 24-hour urine samples. The
Berkeley site, however, would use a different isotope, plutonium-238, at a different dose level; the injected mass would only be 0.2 microgram, but be- cause of a much higher specific acti- tivy, it would have 10 times the ra- dioactivity. As a result, the excreta samples at Berkeley would also be ex- pected to have more than ten times the activity of corresponding samples from the other two studies, increasing the accuracy and precision of the alpha measurements on the excreta samples.
Oak Ridge. The first human plutonium injection occurred on April 10, 1945, barely two weeks after the meeting in Los Alamos between Friedell, Hempel- mann, and others. The person chosen for the experiment was a 55-year old man and a patient at the Manhattan Project Army Hospital in Oak Ridge. (Although the man was the first patient injected with plutonium, he was later grouped in reports with other patients injected at the Rochester site and was identified as HP-12.)* He had been hospitalized because of injuries in an automobile accident, and bones in his right forearm, left thigh, and right knee were broken. Some of the fractures were “in poor position,” which meant an operation to properly set the bones would be necessary. Except for those injuries and “a chronic urethral dis- charge which he has had for 10- years [his clinical record states this may have been due to chronic gonorrhea],” HP-12 had always been employed as a cement mixer and was generally in good health (“well developed, well nourished”).
In a report for a conference on plutoni- um, held May 14 and 15, 1945, Wright Langham stated that “the person was an elderly male whose age and general health was such that there is little or no possibility that the injection can have
At the present time the hazards of workers at Site Y are probably very much more serious than those at any other branch of the Project.... it would be appropriate that the med- ical program of the Man- hattan District consider some of our problems rather more intensely than they have in the past.
*Many of the names of the people who were in- jected with plutonium have been published else- where. However, we did not want to intrude fur- ther on the families of those people and so will only identify the patients by case number.
any effect on the normal course of his life.” HP-12 was 53 at the time of the injection and lived another 8 years be- fore dying, in 1953, of heart failure. Late radiation effects, such as cancer, were not expected to develop for ten to fifteen years, if at all. For example, the induction period in humans for radium- induced cancer, especially malignancy of the bones, was about 10 to 30 years after exposure. Despite Langham’s statement, we cannot, of course, dis- count the fact that HP-12 might have lived 20 or more years; although in 1945, fifty years of age was considered to be fairly advanced. On the other hand, the GIs at Los Alamos who were heavily exposed to plutonium in 1945 while working in D Building under poor industrial hygiene conditions (see “On the Front Lines” on page 124) were in their early twenties and were at greater risk of developing late radiation effects than was HP-12.
HP-12 was injected with 4.7 micro- grams of plutonium (0.29 microcuries) in the chemical form of the +4 citrate salt. The material had been sent to Dr. Friedell at Oak Ridge by Wright Lang- ham, along with directions for its use on a human subject. Langham stated that citrate was chosen “to produce the maximum deposition in the bone... [so as to] produce an excretion rate comparable to that of a worker having absorbed the material at a slow rate.” Urine samples were collected almost continuously for the first 42 days, and then intermittently until the 89th day after injection. Regular stool samples were collected as well over a 46-day period. In accordance with the plan, the Manhattan District Medical Office conducted the clinical part of the exper- iment, and the urine and fecal samples were sent to Los Alamos for analysis.
Langham also reported at the May con- ference that “the excretion during the first day was surprisingly low [0.1 per cent in the urine] and... the leveling off of the excretion rate was much slower than with rats.” Langham sug-
196 Los Alamos Science Number 23 1995
Polonium Human-Injection Experiments
In 1944, in response to concerns for the risk associated with occupational exposures to polonium, the Army Medical Corps authorized Rochester to un- dertake a study of the biological behavior of that element. The program was started in August 1944 with animals, and by November, studies with humans had begun. Eventually, tracer amounts of radioactive polonium-210 were in- jected into four hospitalized humans and ingested by a fifth.
Polonium, the first element isolated by Marie and Pierre Curie from pitch- blende in 1898, is an alpha emitter. When alpha particles from polonium- 210 collide with beryllium atoms, neutrons are ejected, and polonium-berylli- um combinations had already served physicists as a convenient source of neutrons. During the Manhattan Project, it was decided to use that neutron source as an initiator of the chain reaction in the atomic bombs, thus making polonium (and beryllium) an occupational health hazard for the people who needed to develop and build the initiators.
In the Rochester work, the subjects of the excretion studies were volunteers. The problem had been outlined to patients at the Rochester Hospital, who were told that it would involve the intake of tracer amounts of a radioactive substance followed by analysis of their excreta. Because polonium was not classified at that time,* the doctors may have even told the patients what substance they would be injected with. From the group of volunteers, four men and one woman were selected for the studies. They ranged in age from the early thirties to the early forties and were being treated for a variety of cancers (lymphosarcoma and various leukemias). One patient died from his cancer six days after the injection.
Four of the volunteers were injected with doses of polonium in a soluble form that ranged from 0.17 to 0.3 microcurie per kilogram of body weight. The fifth patient drank water containing 18.5 microcuries of polonium chlo- ride, equivalent to 0.19 microcuries per kilogram of body weight. The amount of polonium excreted in urine and feces were analyzed, and blood samples were taken to determine the amount freely circulating in the blood. Autopsy tissue samples were taken from the patient who died to determine the distribution of polonium throughout the body.
Polonium-210 has a short half-life (138 days) and very high activity (4, microcuries per microgram). The high activity meant very small quantities (of the order of nanograms, a factor of 1000 less than for plutonium) could be administered and detected, so concerns of chemical toxicity were mini- mal. The short half-life meant the substance would not remain in the body so that concerns about long-term radiation effects were also minimized. In 1945, urine assays corresponding to the tolerance limits were 7 counts per minute for plutonium-239 but 1500 counts per minute for polonium-210.
Such metabolic studies were possible at Rochester University in 1944 be- cause polonium was available at that time. The research yielded important information for the Manhattan Project on the hazards of polonium and helped develop techniques for the similar but later studies of plutonium. *Polonium was classified in July 1945 and given the code name “postum.”
