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The US Transuranium and Uranium Registries (USTUR)

A Five-Decade Follow-Up Of Plutonium and Uranium Workers

Kathren, Ronald L.; Tolmachev, Sergei Y.1

doi: 10.1097/HP.0000000000000963
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Dedication: The research of the US Transuranium and Uranium Registries relies heavily upon postmortem autopsy findings and radiochemical analysis of tissues. The enormous debt owed to those now-deceased registrants who unselfishly voluntarily participated in the US Transuranium and Uranium Registries program through postmortem donation of their tissues and to those still-living registrants who have volunteered to be future postmortem tissue donors is hereby acknowledged with gratitude. The scientific findings derived from postmortem analysis of these tissues have been instrumental in advancing our understanding of the actinide elements in humans and have led to refinement, validation, and confidence in safety standards for those who work with these elements as well as for the general public. To these generous and anonymous persons who made this ultimate contribution, this paper is dedicated with great thanks and admiration.

1US Transuranium and Uranium Registries, Washington State University, 1845 Terminal Drive, Suite 201, Richland, WA 99354.

The authors declare no conflicts of interest.

For correspondence contact Ronald L. Kathren, 137 Spring Street, Richland, WA 99354, or email at kathren@bmi.net.

(Manuscript accepted 30 July 2018)

Online date: November 28, 2018

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INTRODUCTION

Realization of the hazards of plutonium

FROM THE outset of the Manhattan Engineering District (MED), safety and in particular, radiological safety, have been important considerations. Although human experience with element 92 uranium, which is ubiquitous in nature, spanned centuries (the metal itself had been identified in 1789), the situation with element 94 was quite different. Element 94 was a new element, artificially created and “discovered” on 25 February 1941 and named plutonium (Hewlett and Anderson 1962; Kathren et al. 1994; Seaborg 1946). Because plutonium is not found in nature, there was no human experience with it, but vast quantities would be produced by the MED. Because of the similarities with radium, the necessity for biological study of both plutonium and uranium was quickly understood, spurred in large measure by the recent tragic experience of the radium dial painters. Historian Barton Hacker summed the plutonium problem up well, noting “everyone expected plutonium to be a major hazard” (Hacker 1987).

MED director General Leslie R. Groves noted in his memoir that the most urgent problem of the medical department was to determine the toxicity of uranium and plutonium (Groves 1962), and Glenn Seaborg, Nobel Prize-winning discoverer of plutonium, expressed concern about the potential health hazards of plutonium and the need for haste in studying them. Even before meaningful quantities of plutonium could be made, Seaborg, then in charge of MED plutonium chemistry research, wrote in a memo to Robert Stone, MED medical director:

“In addition to helping to set up safety measures in handling so as to prevent the occurrence of such accidents I would like to suggest that a program to trace the course of plutonium in the body be initiated as soon as possible. In my opinion, such a program should have the very highest priority.” (Memo, Seaborg to Stone dated 4 January 1944, reprinted in Kathren et al. 1994).

Accordingly, when the plutonium became available a month later, 11 mg (2.2% of the total amount then in existence) were sent to Joseph Hamilton for biological studies (Kathren et al. 1994).

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First human studies with plutonium: the plutonium injection cases

The earliest human studies of plutonium, conducted at a time when ethical concerns were very much relaxed relative to today, were carried out primarily to resolve conflicting animal data, for extrapolation from animals, and for the development of appropriate biokinetic models and human safety limits on radionuclide intake. The scientific aspects of the initial studies have been well documented and summarized in the monumental classic history of radiation and health by J. Newell Stannard (1988) and in considerable detail by Durbin (1972), Moss and Eckhardt (1995), and others. In an effort to study the biokinetics and toxicity of plutonium, for which human data were not available, 18 patients—13 male and 5 female—ranging in age from 4 to 68 y, suffering from a variety of conditions, and thought to be terminally ill, were injected with various amounts and compounds of 238Pu or 239Pu between 1945 and 1947 (Durbin 1972; Stannard 1988). All but four were in so-called hospital metabolic wards where their ailments required excreta collection and measurement of food and fluid intake. Urinary and fecal excretion of plutonium were followed for 138 d.

Despite some problems with the study design, including the fact that not all of the patients were terminally ill, some surviving decades after receiving the plutonium injection with no apparent ill effect, several important conclusions could be drawn from the study (Stannard 1988). With the exception of the liver, there were no major differences in tissue distribution of plutonium between laboratory animals and humans. Liver uptake in humans was estimated at 20 to 40% of injected activity, compared to less than 10% in rats, and retention half-time was significantly greater as well. The whole-body retention half-time in humans ranged from 84 to 175 y with an average of 118 y, considerably greater than had been observed in laboratory animals. The human excretion pattern differed from animals, and by extrapolation of the 138‐d excretion data with excretion data from plutonium workers at Los Alamos, a power function model of human urinary excretion out to 5 y postexposure was derived (Langham et al. 1950). Although errors were later discovered in this model (Moss and Gautier 1985), it nonetheless served for decades as the basis for permissible exposure standards for intake of plutonium and for determining intakes and body burden in plutonium workers.

While considerable scientific knowledge, highly useful in developing protection standards for plutonium, was gained from the plutonium injection study, it raised serious ethical concerns and has provoked much controversy and criticism over the years. Informed consent was essentially ignored and the participating patients were, for security reasons, not told with what they were being injected. Numerous investigations of the injection study have been done over the years, and criticisms and discussions have appeared in the media and elsewhere. Efforts were made to keep the experiments secret and classified, but ultimately public pressure won out and some years later, attempts were made to obtain informed consent from those patients still living or from the next of kin of those who had died. The study has been well documented in the report of the President’s Advisory Committee on Human Radiation Experiments (ACHRE 1995).

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Pre-US Transuranium and Uranium Registries tissue studies

In 1949, what has been described as “a modest program of postmortem tissue sampling at autopsy…” was begun at the US Atomic Energy Commission (AEC) Hanford plutonium production site in Washington state. The purposes of the program were twofold: (1) to assist pathologists in evaluating the possible contribution to disease states identified at autopsy by providing them with information regarding the concentration and doses from plutonium in the tissues at the time of death, and (2) to assess the effectiveness of occupational and environmental plutonium containment measures at the Hanford plutonium production site (Bruner 1968; Nelson et al. 1972; Newton et al. 1968).

Based on what had been observed with laboratory animals, the autopsy protocol called for collection of samples of bone, lung, liver, and occasionally tissues from other organs from both Hanford workers and other nonoccupationally exposed residents of the nearby city of Richland where most site workers resided. Once collected, the tissue samples were subjected to destructive radiochemical analysis and the results evaluated. The results of this study over its two-decade lifetime demonstrated that plutonium workers did not acquire appreciable burdens of plutonium from occupational exposure and that, among those sampled at autopsy after 1962, the predominant source of exposure was not from occupational exposure but likely from fallout from nuclear weapons tests (Newton et al. 1968; Nelson et al. 1993).

A similar study of plutonium in tissues from the general population from across the country was initiated at Los Alamos Scientific (now National) Laboratory (LANL) in 1959 (Campbell et al. 1969; McInroy et al. 1979) and by the US Public Health Service in the early 1960s (Magno et al. 1969) to examine plutonium deposition from weapons testing. Also during the 1960s, a program of limited postmortem sampling and analysis was begun at the AEC Rocky Flats Facility near Denver (Lagerquist et al. 1969). Limited postmortem tissue sampling and analysis may have been performed at LANL and elsewhere incidental to autopsy. Although only peripherally related to tissue studies per se, LANL has followed the health of plutonium workers over the years and formally instituted an extensive long-term health monitoring follow-up study of 27 workers with high intakes of plutonium during 1945 and 1946, collecting excretion data and regularly performing medical examinations at 5‐y intervals, and recruiting several of the participants for voluntary postmortem tissue donation. Recognizing the frequent urine sampling done, this group of 27 was informally known as the UPPU Club, an acronym derived from “you pee Pu.” The volunteered postmortem tissue from members of this cohort will be of inestimable value in adding to understanding and control of plutonium hazards (Hempelmann et al. 1973; Voelz et al. 1997).

The results from the Hanford study as reported at the Seventh Annual Hanford Symposium on Biology were in the main similar to those from the other studies mentioned above. Not unexpectedly, measurable low levels of plutonium had been found in the tissues of both site workers and unexposed residents, and was largely attributable to fallout from nuclear weapons tests (Newton et al. 1968). Liver concentrations were typically greater than those in the lung, with the greatest concentrations observed in lymph nodes associated with the respiratory tract in workers. Lung burdens in radiation workers were estimated to be 40 times greater than the estimated burden from post‐1962 weapons test fallout. Based on their observations, the investigators concluded that work in a plutonium facility could be carried out without incurring appreciable depositions of plutonium and that they planned to continue the Hanford autopsy tissue sampling and analysis program indefinitely (Newton et al. 1968).

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HANFORD ENVIRONMENTAL HEALTH FOUNDATION

Birth and early activities: US Transuranium Registry

In July 1966, the AEC held a meeting on plutonium contamination in man at the Rocky Flats Facility that was attended by a number of outside experts (Fig. 1). It was at this meeting that the idea of a plutonium registry was floated and began to gain impetus. Further impetus was given the following year at the Hanford Biology Symposium. In addition to the types of activities that the Hanford group was doing, director H.D. Brunner of the AEC Division of Biology and Medicine outlined progress toward the establishment of a National Plutonium Registry to correlate data from accidental intakes of plutonium with the subsequent health record of the exposed individual, presciently noting that such a registry should include consideration of other transuranium elements as well (Bruner 1968). Thus, in August 1968, the progenitor of what is now the US Transuranium Registry (USTUR) was formally established with the name National Plutonium Registry by the Hanford Environmental Health Foundation (HEHF) under contract to the AEC (Kathren 2000).

Fig. 1

Fig. 1

Even before the contract had been finalized, HEHF Medical Director Phillip A. Fuqua, who had been one of the key physicians on the MED Plutonium Project, established a blue ribbon Advisory Committee for the soon-to-be-created registry. The initial six-member committee included three physicians: pathologist Clarence C. Lushbaugh, Oak Ridge Associated Universities; Thomas F. Mancuso, retired head of the Pennsylvania state Occupational Health Program and a member of the University of Pittsburgh faculty; and occupational physician James H. Sterner from the University of Texas Medical School. The remainder of the group included two physicists: Robley D. Evans, renowned for his studies of the radium dial painters and as the author of the widely used textbook The Atomic Nucleus, and Herbert M. Parker, the British-American medical and health physicist, former director of the Hanford Research Laboratories, and codeveloper of the widely used system of radium therapy dosimetry bearing his name; and chemist Lloyd M. Joshel, the general manager of the AEC Rocky Flats Facility. The following year the committee was joined by LANL Biomedical Division Associate Director Wright Langham, who many acknowledged as “Mr. Plutonium” for his pioneering seminal studies of plutonium in humans.

HEHF physician W. Daggett Norwood, a colorful figure known by his nickname “Dag” and for traversing the lower 48 states on foot in the 1930s, was appointed the initial director on a half-time basis. Norwood was an excellent choice, for in addition to his medical qualifications, he also had earned an undergraduate degree in electrical engineering and thus had a relatively strong physical science background. Scientific support was provided by half-time board-certified health physicist Carlos E. Newton, Jr., on loan from Battelle-Northwest (now Pacific Northwest National Laboratory) who carried the title of consultant and directed the health physics aspects of the program. Dorothy Potter served as general administrative assistant. The stated primary purpose of the registry, as indicated in the original proposal to the AEC, was “to protect the interests of workers, employees, and the public by serving as a national focal point for the acquisition and preservation of the latest and most precise information about the effects of the transuranic elements on man” (Norwood and Newton 1974), and the new registry went right to work.

The Advisory Committee met for the first time on 30 and 31 October 1968 in Richland, electing Sterner and Evans as chairman and vice chairman, respectively. Attendees at the first Advisory Committee meeting are shown in Fig. 2. The committee provided guidance through a thorough and detailed discussion of the scope and planned activities for the registry. By the end of its first year, the registry had established its basic operational protocols, including developing forms for collection of medical and health physics data. Study populations were identified and active recruitment of registrants begun with three signing up that first year. Cooperative working agreements were sought with 45 facilities, mostly AEC contractors. By June 1974, a total of 5,343 transuranium workers had been identified, of whom 3,880 had signed medical and health physics releases and 819 had given autopsy authority. Forty-five autopsies had been carried out, two-thirds by or from Rocky Flats, which by agreement maintained this responsibility for cases from Rocky Flats.

Fig. 2

Fig. 2

Given the rather broad scope of the stated primary purpose, the name was changed in 1970 to US Transuranium Registry (USTR) to reflect the broader programmatic interest in all the transuranium elements. Carlos Newton was appointed associate director. The basic operating plan was to sign up fully informed volunteer persons with the potential for occupational exposure who worked in facilities that handled transuranium elements. Upon notification of death of a registrant, the registry would arrange to have an autopsy performed by an independent board-certified pathologist who would also harvest samples of various tissue, primarily bone, liver, lungs, and respiratory tract lymph nodes, according to an established USTR protocol. The tissue samples were subjected to radiochemical analysis, which initially was performed by Battelle, Pacific Northwest Laboratories (now Pacific Northwest National Laboratory, PNNL), except for samples from the AEC Rocky Flats Facility, which performed radiochemical analysis for cases originating there.

Plutonium tissue analysis for the first 14 registry cases was reported at the 12th Hanford Biology Symposium and revealed some significant preliminary findings (Norwood et al. 1973). Perhaps most significant and heartening was that measured postmortem tissue depositions were much lower than estimates made on the basis of urinalyses performed during life. This was a clear indication that operational radiation safety practices were more than achieving the sought-after measure of control of plutonium intakes. While comforting in that it revealed a large degree of conservatism and indeed a cushion of safety, as it were, it also indicated that the accepted biokinetic models (e.g., ICRP 1960; Langham et al. 1980) used to calculate the body burden overestimated deposition and were in need of revision. The results from these 14 cases also revealed that plutonium distribution in tissues differed from the generally accepted and standard model that had been put forth by the International Commission on Radiological Protection (ICRP 1960).

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Controversy and change

In 1975, a follow-up paper containing data from the initial 30 autopsies appeared in the peer-reviewed literature (Norwood and Newton 1975). This publication reemphasized and buttressed the previous finding that estimates of systemic plutonium deposition using urinalysis data and accepted biokinetic models were in fact greater than those determined by postmortem radiochemical analysis of tissues. In addition, it concluded that deposition of plutonium in the human body is generalized throughout the tissues and that knowledge of the biokinetics of the specific physical and chemical forms of plutonium was necessary to ascertain concentrations in many different organs at specific times following intake. Lastly, it included the causes of death in these 30 cases, concluding “the usual causes of death were encountered” (Norwood and Newton 1975).

The causes of death for these 30 cases was independently evaluated by physician Sidney Wolfe of the Ralph Nader Health Research Group. Wolfe concluded that the 11 solid tumor and leukemia deaths in this small cohort of 30 was approximately double the expectation of 6 for white males, and largely on this basis he recommended a 1,000‐fold reduction in the generally accepted maximum permissible body burden for plutonium as put forth by ICRP. Wolfe’s conclusions were released to the media, appearing in the New York Times and elsewhere in the public media, creating a bit of a firestorm. Although there was a sidebar by Edsall (1976) to the effect that Wolfe’s interpretation of the mortality data had been submitted as a letter to Lancet, there is apparently no publication by Wolfe on this topic in any peer-reviewed scientific journal. In a letter to the editor Norwood (1976) responded, noting that the registry population was biased by selection factors inherent in the autopsy, making a comparison of the registrant causes of death with those in the general population inappropriate. Norwood’s letter was followed by a brief paragraph from Edsall which stated in part: “I agree that the 30 autopsies at the US Transuranium registry provide no significant evidence concerning the toxicity of plutonium in man in view of the biased character of the sample. The epidemiological study described by Dr. Norwood is obviously of great importance and is to be welcomed.” The same issue of the Bulletin of Atomic Scientists also included critical comments from two other scientists plus a response by Edsall (Cohen 1976; Hutchins 1976).

Although refuted by a number of scientists, the claims by Wolfe proved more than a passing embarrassment. It brought into focus the conduct of epidemiologic studies, responsibility for which had been included in the original registry research proposal, and that LANL had an independent charter from AEC to conduct epidemiologic studies of transuranic workers. Clearly, there were overlapping and conflicting responsibilities, which led to restructuring of the USTR Advisory Committee with the stated need to expand and develop new areas of involvement and to resolve questions of overlap. The newly appointed committee included four holdovers from the previous committee—Sterner (as chair), Evans (as vice chair), Lushbaugh, and Parker, plus four new members: Charles W. Mays, health physicist and University of Utah radiobiology researcher; health physicist John M. Poston, Georgia Institute of Technology professor; University of Washington and Fred Hutchinson Cancer Research Institution biostatistician Donovan J. Thompson; and physician George L. Voelz, LANL, who was conducting the follow-up study of the 27 early workers with depositions of plutonium. At its first meeting, the new USTR Advisory Committee recommended that both LANL and the USTR review their programs and recommended that Voelz and recently appointed half-time USTR director Bryce D. Breitenstein meet to resolve the questions about who was doing and should do what and report back to the committee (Breitenstein et al. 1978).

The ultimate result was a clear change in function of the USTR, narrowing it and better defining the objectives. In the minutes of its 1979 meeting, the Advisory Committee listed the objectives of the USTR; epidemiology was not among them. Epidemiology was covered in the following item, which stated in strong, unequivocal language: “It is to be emphasized that the present USTR is not an epidemiology study,” further stating that the epidemiological follow-up of transuranic workers was being done at LANL under the direction of physician Voelz. The committee noted that the major effort of the USTR was its autopsy program and evinced strong support for the USTR tissue studies.

And because of the negative publicity engendered by misinterpretation of cause-of-death information by the Nader group, for many years there was essentially no evaluation or reporting of morbidity or mortality within the USTR cohort, which by the end of its first decade in 1978 had an identified population of more than 15,000 transuranium workers with more than 1,000 enrolled as volunteer donors in the autopsy program. A total of 83 autopsies had been performed, and in addition to annual reports, seven papers had been published in the open peer-reviewed scientific literature.

There were other important changes in the operation of the USTR as well. Tissue radiochemical analysis was transferred from PNNL to Los Alamos Scientific Laboratory (LASL). The Advisory Committee, now chaired by health physicist Mays, had but a single physician member, Voelz, in addition to five prominent health physics research scientists. The Advisory Committee had created a three-member Dosimetry Subcommittee, which functioned primarily to analyze data and direct the scientific operations of the USTR, acting in many respects more like management and staff than advisors. Indeed, until about 1985, the scientific mission of the USTR was largely carried out by the Dosimetry Subcommittee, which took the lead in performing such basic tasks as data analysis. Since the committee met only annually, and the registry staff included only the half-time director and a half-time scientist, progress was necessarily slow.

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US Uranium Registry

Although the USTR had originally been formed to study plutonium in humans and quickly extended to include the other transuranic elements, uranium itself was not included, and despite the long human history with uranium, there was still much to be learned about this element. Plutonium, of course, was synthesized from neutron bombardment of uranium, and various enrichments of uranium used for nuclear reactors and explosives had different toxicologic properties. Studies in the MED had shown that natural and low enrichments of uranium were primarily a chemical toxin, while at higher enrichments the radiotoxicity predominated. The idea of a separate uranium registry had been discussed, and in 1978 became a reality when the Energy Research and Development Administration (ERDA) established a parallel but administratively separate US Uranium Registry (USUR) (Marks 1981). The USUR was considered to apply only to the front end of the uranium fuel cycle and its initial activities were threefold: (1) survey of facilities and operations to determine workers’ exposure to both radiologic and nonradiologic hazards; (2) literature survey of the health effects in workers exposed to uranium with an eye towards determining if epidemiologic studies were warranted; and (3) tissue studies patterned after those of USTR.

The USUR was organized along the same lines as USTR, and indeed with the exception of the director, the registries shared staff and facilities but zealously maintained administrative separation. Robert H. Moore, an occupational physician with a background in pathology, was named half-time director. Scientific support was provided by Kenneth R. Heid who had replaced Carlos E. Newton in USTR upon his retirement and now would support both registries, a task he carried out until 1985 when he was replaced by Ronald L. Kathren, board certified in both health physics and medical health physics. Despite the large number of uranium workers in industry and the government weapons programs, recruitment of registrants was slow—painfully slow. By 1992, there were only 32 living registrants, but tissues from 12 autopsies and 1 surgical sample had been obtained. The USUR was not idle, however, issuing four technical reports that characterized uranium and its hazards in the United States in addition to coauthoring a study on 210Pb in uranium workers (Palmer et al. 1984) and sponsoring a national colloquium on uranium biokinetics (Moore 1984). The USUR also located and followed up a worker who had incurred a massive inhalation intake of uranium hexafluoride (UF6) some 38 years previously (Kathren and Moore 1986), a paper that assumed considerable importance years later to those studying uranium biokinetics (Avtandilashvili et al. 2015).

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USTR + USUR = USTUR

In early 1989, USUR Director Moore retired and USTR Director Margery J. Swint, who had replaced Breitenstein upon his promotion in 1982, temporarily assumed the directorship of both registries, which still remained administratively separate but within a short time were de facto operating as one with a combined Advisory Committee. The following year, Kathren was appointed director of both registries in her place and the name was initially, albeit informally, changed to US Transuranium and Uranium Registries (USTUR). Kathren, board certified in both health and medical physics, was the first nonphysician to direct the registries. He had initially joined the registries in 1984 as a 2‐hour-per-week scientific consultant from PNNL to augment the scientific capabilities of the program.

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Interlude: the halfway point

By the end of 1991, the approximate midpoint of the registries’ existence, USTUR staff had authored or contributed to more than 60 papers in the peer-reviewed scientific literature, only 9 of which had been contributed in the first decade for an average of about 3 per year overall. However, by the year 2000, USTUR raised the overall average to 5 papers per year (Fig. 3). The dramatic increase in publications can be attributed to several factors. The most important of these was the increasing number of donations to the registries not only from partial-body donations (routine autopsy) but more significantly from five whole-body donations. A second reason was the increased analytical laboratory throughput that had occurred following the transfer of radiochemistry responsibilities from PNNL to LANL in the mid‐1970s. That part of the program was ably managed by chemist James F. McInroy and health physicist Kathren, who had complementary scientific skills and developed a close professional working relationship that proved to be most productive, despite the geographic distance between their two facilities. A third reason was the transfer from HEHF under a contract with US Department of Energy (DOE) to a grant at Washington State University (WSU) at Tri-Cities. Other factors included increased efficiencies associated with the combined registries, a lessening of the activities of the Dosimetry Subcommittee with respect to data collection and analysis, and the experience gained during the initial years of operation. Key among these was receipt of the first whole-body donation USTUR case 0102.

Fig. 3

Fig. 3

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Some registries’ landmarks

First whole body: USTUR case 0102

The first whole-body donation to the registries was in 1979. This individual was a chemist with known exposure to transuranium elements, primarily 241Am. In many ways, this was overwhelming, for the analysis of this case required far greater resources than the registries, with only two half-time professional staff, could hope to provide, and it necessitated development of procedures for the treatment of the body as well as collaborative arrangements with other investigators—in particular with the radiochemistry operation now at LANL. Autopsy, dissection, and tissue analysis of a whole body were new challenges, well met but not without a few missteps, none of which proved significant from a scientific standpoint. The evaluation of this case resulted in a USTUR special issue of Health Physics consisting of five scientific papers (Roessler 1985). Especially significant were the findings with respect to biokinetics, which revealed significant differences from ICRP and the need for revisions in their widely accepted model for americium (Durbin and Schmidt 1985), and the outstanding detailed description of the techniques used for preparation and radiochemical analysis results of the tissues and bones (McInroy et al. 1985). Only half of the skeleton had been analyzed, and the remaining half was used to make in vivo calibration phantoms of head, torso, arm, and leg, which have been made available to other experimenters and used worldwide (Kramer et al. 2011; Nogueira et al. 2015).

Based on peer-reviewed publications, the latter half of the 1980s decade through the year 2000 was notably productive. Two cases of particular note are discussed in more detail below. Some others worthy of mention include a report of the analysis of six whole-body donations (McInroy et al. 1989), which provided important data useful for refining models; specific studies of distribution in skeleton (Kathren et al. 1987) and comparisons of plutonium and americium distribution in man, baboon, and monkey (Lynch et al. 1989), the latter providing validation of the extrapolation of animal data; and a study that compared biokinetic models used to determine plutonium in urine with what was observed postmortem in whole-body cases (Kathren and McInroy 1991), which clearly demonstrated that the models used for operational health physics purposes overestimated, sometimes by several fold, in vivo plutonium estimates as compared with what was found at autopsy, clearly showing conservatism and erring on the side of safety. Many more could be cited but practicalities of time and space do not permit mention of more than these few.

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The atomic man: USTUR case 0246

In 1976, a chemical explosion occurred in a glove box containing americium, showering the face, neck, and upper torso of the operator with glass shards, nitric acid, and gram quantities of 241Am. The initial description of the accident and follow-up case management including medical management was published as the special issue of Health Physics in October 1983 (Thompson 1983). This issue included two papers by the registries dealing with medical aspects and chelation therapy (Breitenstein 1983) as well as initial 241Am deposition estimates (Robinson et al. 1983). So heavily contaminated both internally and externally was the victim that this case has attracted great attention among scientists, physicians, the media, and members of the public. The victim was given the name “The Atomic Man” by the media. He had been heavily chelated and medically followed until the time of his death 11 y later from heart disease. The USTUR role in this case was confined to postmortem findings in the case, although the physician (Breitenstein) under whose care he was is a former director of the USTR.

After his death, the registries obtained a number of tissue samples obtained at autopsy through the kind generosity of his widow, and he was designated as USTUR case 0246. The initial postmortem findings in this case, carried out in conjunction with collaborators, were published as five separate papers in a single issue of Health Physics (Filipy et al. 1995; McInroy et al. 1995; Priest et al. 1995; Schlenker et al. 1995; Toohey and Kathren 1995).

Radiochemical analysis of the tissue samples revealed a total body burden of 241Am estimated to be 540 kBq, 90% of which was in the skeleton. This finding corroborated earlier studies with registry cases in which similar observations had been made, showing that the skeletal fraction estimated by the ICRP model was far too small. Other measurements showed that the 241Am was largely deposited on the bone surfaces, consistent with a lack of bone remodeling and which could have been at least in part age related. The estimated dose to the bone was 360 Sv and 10,400 Sv to the bone surfaces. Despite these truly prodigious doses, there was no indication of cancer in the skeleton or in any other site.

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Thorotrast study: USTUR case 1001

An extraordinary opportunity was presented to the registries with the offer of a whole-body donation from a woman who was medically exposed to Thorotrast. The donor was a Caucasian female who died at age 72 y, 36 y after an injection of Thorotrast. In the decade preceding her death, she developed three recognized Thorotrast-related morbidities, and three others likely linked to Thorotrast (Tauber 1992). Cause of death was myelodysplastic syndrome and refractory anemia with excess blasts marked by destruction of platelets, complicated by gastric hemorrhage that ultimately led to her death (Graham et al. 1992).

Although Thorotrast had been extensively studied, its distribution had never been evaluated in all tissues from a single individual. There were as yet many unanswered questions not only regarding thorium but also more generally applicable to alpha emitters in the body. Interest in this case, which offered a holistic approach not only to tissue concentrations and modeling but also to the biokinetics and cancer risk of Thorotrast, was high particularly among European researchers and led to collaborative research with a number of scientists at more than a half dozen other institutions including National Naval Medical Center, National Cancer Institute, and three national laboratories. The results from this case did not disappoint and led to a special workshop held at the National Cancer Institute that was reported in Health Physics, Volume 63(1). This issue was dedicated to the memory of Charles W. Mays, Jr., of the National Cancer Institute and a member of the USTUR Advisory Committee, who in addition to finding this individual had contributed so much to the evaluation and publication of the results before his untimely death (Mays and Guilmette 1992).

External counting of selected tissues was carried out prior to radiochemical analysis to determine relative activity of specific members of the 232Th decay chain and the degree of radioactive disequilibrium among the daughter products, information of potential value for in vivo counting and modeling. External counting revealed that the spleen, which on postmortem examination was observed to be nearly totally ablated with a weight of 25 g as compared with the reference man value of 180 g, and the hepatic lymph nodes had the highest concentrations of 232Th. Radioactive disequilibrium was found in the spleen, liver, kidney, and erythrocytes while secular equilibrium was observed in the bone, pancreas, larynx, esophagus, and breast tissues (Mays and Guilmette 1992).

The radiochemical results indicated that essentially all of the injected Thorotrast remained in the body 36 y after the injection and that approximately 60% of the 228Ra progeny had been excreted from the body. Around 45% of the total activity from 232Th and decay products were in the liver, 33% in the skeleton, and 13% in the very-much-reduced-in-size spleen. The remainder was found in the soft tissues and 3% in a thorotrastoma at the injection site. The remaining 228Ra and its second progeny 228Th were in approximate equilibrium throughout the body (McInroy et al. 1992). Lifetime absorbed doses from the 232Th series were massive and estimated as 2,420 Sv to the spleen, 300 Sv to the liver, and 80 Sv to the skeleton (Kathren and Hill 1992).

Examination of bone marrow samples revealed Thorotrast to be largely restricted to areas of cellular (red) bone marrow with no significant deposits in the fatty (yellow) bone marrow (Priest et al. 1992). DNA samples from six different tissues were analyzed genomically. None of the tissue samples revealed alteration of the c-mos gene, but an alteration of the c-fms gene was noted in the blood sample (Collart et al. 1992).

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The registries under siege

Although scientific progress was certainly being made by the registries, all was not sweetness and light. The 1980s and 1990s were marked by numerous allegations regarding the legality and ethics of the registries’ activities by individuals and groups, including the media, US General Accounting Office, and President’s Commission on Human Radiation Experiments, and by threats of law suits. None of the latter ever materialized although USUR was named for a time in a case alleging that tissues obtained from a coroner that were sent for analysis for uranium were improperly solicited and obtained. The court dropped USUR from the case noting that the coroner who had requested the analysis was charged under the law with determining the cause(s) of death and thus had every right to request the uranium analysis from an impartial body like USUR since he did not have the capability to perform the requested analysis.

There were a number of stories in the media and an appearance by both Kathren and McInroy on the television program 60 Minutes and interviews for articles in such publications as Mother Jones and various newspapers. Specific charges included body snatching, false reporting of results, failure to obtain releases for medical and exposure records, and failure to follow the Nuremburg Code. However, no investigation, official or unofficial, has ever found any evidence of the registries’ noncompliance with legal or ethical requirements or indeed any ethical violation or evidence of wrongdoing, willful or accidental.

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WATERSHED: THE MOVE TO WSU

Partly in response to allegations of impropriety and an undercurrent within the scientific community that the registries were slow to publish and were withholding data, coupled with an increasingly unsupportive climate for research at HEHF, the USTUR moved to WSU on 14 February 1992, under provisions of a $3,760,000 3‐y grant from the US DOE. Replacement of the contract with a grant gave greater flexibility and independence from sponsor control while at the same time formally imposing requirements related to human subjects. Along with the move, the two registries were officially and formally combined under the name US Transuranium and Uranium Registries (USTUR). Kathren was named director of the renamed body and was appointed a full professor in the WSU College of Pharmacy. The Advisory Committee membership was altered to include a representative from the university, an ethicist, and a representative from the labor union whose members included many transuranium and uranium workers. The Dosimetry Subcommittee was no longer involved in the direct operation of the registries but reverted to a more appropriate advisory role before ultimately disbanding entirely.

The move to WSU provided a number of advantages, not the least of which was increased credibility from association with a major university; allegations of impropriety and inappropriate behavior on the part of the registries virtually ceased. Library facilities and the availability of a broad-based faculty with expertise in areas related to USTUR research, along with the availability of student workers, were additional benefits, as was a fully supportive dean of the College of Pharmacy, M. M. Abdel-Monem, who himself was a noted medicinal chemist.

Immediately following the move to WSU, a complete review of every registrant case file was made to ensure that appropriate permissions and medical and health physics records were on file. An intensive effort was made with the assistance of student helpers to trace lost registrants, to reestablish contact with them, and to remove from the active roll individuals who had volunteered to participate early in the program but whose occupational history did not indicate any likelihood of exposure to transuranics or uranium or who no longer wished to participate. Out of 862 registrants, a total 439 were moved to inactive status. Many early registrants had not been contacted in more than 20 y and were seemingly lost to contact, but the location of essentially every individual was ultimately determined. Those still living were offered the opportunity to continue to be enrolled with the program, assuming they met the criteria for acceptance, i.e., documented intake or likely potential for exposure to uranium or transuranics. A formal policy of contacting active registrants annually and validating their status every 5 y was established. The entire database, including every document in every registrant file, was microfilmed, and a backup copy of the microfilmed files was placed in the library under proper controls to ensure privacy, thus fulfilling a recommendation made by the Advisory Committee two decades previously. Electronic database capability was upgraded, and the large collection of pathology slides and blocks that had been obtained from registrants over the years was organized. Administrative procedures and policies were formalized and documented, and in many cases, developed and written; current versions are available today on the USTUR website. After a suitable laboratory intercomparison study, the registries also assumed responsibilities for the radiochemistry operations from LANL, thus putting the entire program under one roof, so to speak (Fig. 4).

Fig. 4

Fig. 4

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National Human Radiobiology Tissue Repository

Shortly after the move to WSU, USTUR acquired frozen and other tissue materials from the radium dial painter study, which was being closed out at Argonne National Laboratory (ANL) (Rowland 1995). John J. Russell, a radiobiologist at ANL who had supervised the final phases of the closeout and was well acquainted with the materials, joined the USTUR faculty as the collection curator personally overseeing the move from Illinois to Washington and contributing to other areas of the USTUR program as well. The registries’ collection, which included frozen tissues and individual solutions from analysis of registrant tissues, were acquired from LANL and together with the radium dial painter materials (Rowland 1995), were used to create the National Human Radiobiology Tissue Repository (NHRTR), which made these unique materials available to others for legitimate research and collaboration. In 1996, the registries acquired, from PNNL, the National Radiobiology Archives (NRA)—a library of original laboratory notebooks, documents, pathology blocks, slides, and similar materials from animal studies. In 2010, NRA was transferred to Northwestern University where it now resides as a part of the Northwestern University Radiation Archives (NURA).

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Publications and citations

During the WSU era, which basically covers the second half of the five-decade lifetime of the registries, scientific efforts continued and expanded, particularly with respect to biokinetic modeling, enhanced by the greater availability of tissue materials, the findings of the first half decade, and a shift in the operations of the Advisory Committee away from doing the work of staff into their more proper advisory role. One widely used metric for research productivity is peer-reviewed publications, which in turn are dependent on other factors, including funding, scientific personnel, and available facilities, which are often beyond the control of the researchers.

Fig. 3 shows the number of peer-reviewed journal articles and abstracts, books and book sections, and conference papers and editorial notes published as of the end of 2016. It shows quite clearly a peak in publication output following the move to WSU. Productivity and breadth of study areas increased by the addition of adjunct faculty and graduate students or, to paraphrase a common vernacular expression, more bang for no more bucks! Collaborations with other researchers both in the United States and across the world were encouraged. Close international collaborations and working relationships were expanded by two recent directors, Anthony C. James (2005 to 2010) and current director Sergei Y. Tolmachev (2010 to date), which increased the number of USTUR’s research publications. Since the move to WSU, the average cost per peer-reviewed publication has been slightly less than $100,000, expressed in 2016 dollars, comparing quite favorably with most scientific research costs.

Perhaps a more significant metric is the number of citations a publication receives. By the end of 2016, USTUR had published 300 papers, of which 208 had received citations based on Web of Science online scientific citation indexing service. The average number of citations was 13.6, and the h-index (Hirsch 2005) was a respectable 28 considering the highly specialized, narrow field of USTUR research.

A small sampling of the large number of USTUR peer-reviewed publications in the open scientific literature published since 1992 when the registries moved to WSU will give some indication of the breadth and depth of the postmortem research carried on at WSU and these publications’ applicability to operational radiation protection as well as radiation biology and analytical chemistry.

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Scientific activities

Until 1992, USTUR operated under the belief that, with the exception of some minor interest on the part of the British, it was the only formal national study of actinides in human tissues (House of Commons 2010). However, there was some interest on the part of other nations in establishing their own national actinide registries. Accordingly, in 1992 the International Atomic Energy Agency (IAEA) convened a technical committee to explore the establishment of national registries for actinides in humans and provided a 10‐step protocol to achieve this purpose (IAEA 1996). Then in 1993 at the Workshop on Intakes of Radionuclides held in Bath, UK (Stather et al. 1994), the registries learned about the existence of a similar research program in Russia—the Dosimetry Registry of the Mayak Industrial Association (DRMIA) and the associated Radiobiological Human Tissue Repository (Khokhryakov et al. 1994; Muksinova et al. 2006). Dialog between USTUR and DRMIA was immediately opened and resulted in long-term and successful collaboration (Filipy et al. 1998; Khokhryakov et al. 2000; Suslova et al. 1996, 2017).

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Plutonium studies

The USTUR studied distribution of plutonium and americium in the lungs and associated lymph nodes. About 80% of the 239Pu and 241Am activities were found in the lungs and only 20% in the lymph nodes, but the concentration activity ratio of lymph-node-to-lung was about an order of magnitude higher. Smokers were found to have 40% of 239Pu in the lung compared with 70% of 241Am and a correspondently lower concentration ratio in lung and lymph nodes, indicative of impaired clearance from lung to lymph node (Kathren et al. 1993).

The registries analyzed donated placental tissues obtained at birth from a mother who had a known (albeit very small) deposition of plutonium, as well as donated placental tissues from an unexposed control. This was the first, and as yet the only, study of placental transfer in humans, clearly applicable to studies of environmental plutonium exposures from weapons tests. The results revealed that plutonium did not cross the placental barrier in humans (Russell et al. 2003).

James et al. (2003) examined the applicability of the current ICRP models with respect to behavior of inhaled 238Pu in highly insoluble ceramic form. They found that the ICRP models provided a good representation of the total plutonium in the worker’s body, as well as an adequate estimate of the overall effective dose when used in conjunction with individual-specific transfer-rate constants and other parameters.

Jacobson (2005) studied incidence of cataracts among USTUR registrants. Analysis of data from 97 retired nuclear workers revealed 37.5% incidence of posterior subcapsular cataracts in the 24 cases with lifetime effective doses of greater than 200 mSv. This was significantly higher compared to 15.1% incidence among the remaining 73 cases with doses lower than 200 mSv.

Avtandilashvili et al. (2012, 2013) studied long-term lung retention and biokinetics of inhaled refractory plutonium oxide (239PuO2) particles. This study demonstrated that substantial modification of the ICRP 66 human respiratory tract model (HRTM) structure and parameters was required to explain the data. Findings strongly supported the necessity of respiratory tract model revision. An updated HRTM was recently published by ICRP in the occupational intakes of radionuclides series (ICRP 2015).

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Uranium studies

Concern for uranium chemical toxicity led to an effort to examine whether chronic, low-level, occupational exposures to uranium would induce kidney changes detectable upon postmortem histological examination. The independent pathologist who examined the unidentified slides was unable to reliably discriminate between the exposed workers and controls (Russell et al. 1996).

Uranium was measured in tissues from a whole-body donor with a documented occupational exposure. For the first time, all tissues from a single human body were analyzed. Contrary to the generally accepted uranium systemic biokinetic model, no long-term retention was observed in the kidneys, and the uranium concentration in the thyroid was elevated compared with other soft tissues (Russell and Kathren 2004).

To study distribution of natural uranium in the human body, uranium content was measured in tissues from three whole-body donors who had no documented occupational exposure to uranium (i.e., natural background exposures only). A remarkable agreement in uranium distribution was found among all three cases. Similarly to occupationally exposed cases, there was no evidence of a long-term uranium depot in the kidneys, and in two cases concentration of uranium in thyroid was higher compared to other soft tissues. Uranium content in kidneys was found to be 20‐fold lower than that for reference man. Most significantly from a biokinetics standpoint was that the residence half-time of uranium in the skeleton was found to be significantly longer than reported by ICRP, 13.6 y as compared with 4.1 y, and the systemic uranium fraction transferred from blood to skeleton was found to be 0.14 (Kathren and Tolmachev 2015).

Follow-up of a case exposed to a massive amount of UF6 65 y previously combined postmortem tissue analysis results with historical postaccident urinalysis data, analyzing them together with ICRP respiratory tract and uranium systemic models using maximum likelihood and Bayesian inference to estimate intake and model parameters that best describe the data, as well as to evaluate their effect on dose assessment. The analysis also suggested that the ICRP systemic model may not adequately describe kidney content at very late times after exposure (Avtandilashvili et al. 2015).

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Analytical methods

A number of publications dealt with analytical methods, often done with an eye not only to improved capability but also to reduced costs, particularly in the years after 2000 when funding was reduced. A fission-track analysis method to determine the 239Pu/240Pu atom ratio in tissues was developed to use in lieu of mass spectrometry, which was not conveniently available to USTUR at the time (Love et al. 1998). Several papers describing improved methods of analysis for uranium provide examples of this area of activity. Kinetic phosphorescence analysis (KPA) and recovery-corrected KPA for determination of natural uranium were compared and showed the benefit of recovery correction for elemental analysis (Elliston et al. 2005). Measurement of 236U in human tissue samples was a needed capability, and a method to achieve this was accomplished by using solid-phase extraction coupled to inductively coupled plasma mass spectrometry (ICP-MS; Li et al. 2010;Tolmachev et al. 2011). Thermal ionization mass spectrometry (TIMS) was evaluated and found to be a useful method for uranium isotopic analysis (Li et al. 2011).

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SO WHERE ARE WE GOING? A LOOK IN THE CRYSTAL BALL

Through the years, the registries have served to piece together the biokinetic puzzle of uranium and the transuranics. The USTUR research will continue to focus on biokinetic modeling of the actinides, development of a plutonium chelation model, analysis of uncertainties in organ dose estimates, and study of actinide distribution in the human body. Several groups of individual cases have been identified to study biokinetics and tissue dosimetry for specific radionuclides, exposure scenarios, and materials, as well as effects of decorporation treatment (Table 1).

Table 1

Table 1

An important aspect of USTUR is the operation of NHRTR, a specialized collection of human tissues, histopathology slides, and related materials. The USTUR will promote wide use of the USTUR/NHRTR as a scientific resource. The NHRTR materials will be increasingly valuable for biokinetic, toxicologic, ecologic, and even possible archeologic and geologic studies of other elements. This has already begun in the registries on a modestly small scale with beryllium (Lariviere et al. 2012). The tissue materials in NHRTR and associated case descriptions in USTUR files represent a remarkable, underutilized resource for cytogenetic studies to more specifically look for radiation biomarkers (Goans et al. 2019) and to determine disease origins and possible oncogenes triggered by radiation exposure to Thorotrast (Collart et al. 1992;Travis et al. 2003) and radium (Hardwick et al. 1989). It is also not at all far-fetched to note that such work could even make a major contribution to understanding the dose-response relationship at low doses and to assuring that dose limits and exposure criteria provide the desired measure of personnel protection for workers. Such work would, of course, be carried out jointly with and in support of other investigators with suitable qualifications and expertise. Further expansion and utilization of NHRTR tissue banks to provide additional support to researchers, decision makers, and forensics seems to hold great promise in the foreseeable future.

Finally, the registries could be in the forefront of training future health physicists, radiation biologists, radiopharmacists, and radiochemists, professions that have predicted growth potential, symbiotically providing research topics for theses and doctoral dissertations and helping to fill the needs for qualified personnel in these areas.

Fig. 5

Fig. 5

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Acknowledgments

The support and assistance of the USTUR staff (Fig. 5) in making available files, photographs, references, editorial, and secretarial assistance for this oral presentation is hereby acknowledged with great appreciation. So too are conversations with my (RLK) predecessors as USTUR directors, Bryce D. Breitenstein and Margery J. Swint, and my colleagues James F. McInroy and Robert W. Bistline. And especially noteworthy is the assistance and collaborative effort provided by my successor director, Sergei Tolmachev, who shares with me the authorship of this written version. This keynote history could not have been accomplished without your help and encouragement.

The USTUR is funded by US Department of Energy, Office of Domestic and International Health Studies (AU‐13), under grant award no. DE-HS0000073.

Author’s (RLK) note: It is indeed an honor to have been invited, along with my good friends and colleagues Eugene Carbaugh and Sergei Tolmachev, to be a keynote speaker at this full-day special scientific session devoted to USTUR. In preparing this written version of the keynote presentation at the 61st Annual Scientific Meeting of the Health Physics Society held in Spokane, Washington, I have attempted to remain faithful to the oral version using the same basic organization and virtually all of the slide headings as topic headings in the written version. I have also attempted to fully document by referring to the refereed literature wherever reasonable and practicable to do so, making only minor changes to the oral presentation and adding some material that by necessity of time constraints could not be included in the oral presentation. Regrettably, this historical presentation is of necessity incomplete, and the author assumes full responsibility for errors and omissions. Finally, those who know me will likely appreciate that only the jokes from the oral presentation have been omitted.

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APPENDIX

List of attendees at the US AEC Division of Biology and Medicine meeting on “Plutonium Contamination in Man,” 25–26 July 1966; Denver (Rocky Flats Plant). See Fig. 1.

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Front row (left to right)

Dr. H.D. Bruner (US AEC, Headquarters, Division of Biology and Medicine), Dr. Wright H. Langham (Los Alamos Scientific Laboratory), Dr. William J. Bair (Battelle Memorial Institute, Northwest Laboratories), Lloyd M. Grow (US AEC, Rocky Flats Area Office), Dr. Roy C. Thompson (Battelle Memorial Institute, Northwest Laboratories), Hodge Wasson (US AEC, Headquarters, Division of Biology and Medicine).

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Second row (left to right)

Dr. Walter S. Snyder (Oak Ridge National Laboratory), Dr. Donald Ross (US AEC, Headquarters; Division of Occupational Safety), Dr. Marcia W. Rosenthal (Argonne National Laboratory), Herbert Meyer (Monsanto; Mound Laboratory), Dr. Luis J. Casarett (University of Rochester).

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Third row (left to right)

John W. Cable (US AEC, Headquarters, Division of Biology and Medicine), Dr. W.D. Norwood (Hanford Occupational Health Foundation), Dr. Steven V. Guzak (Dow, Rocky Flats), Dr. Austine M. Brues (Argonne National Laboratory), Clair C. Palmiter (Federal Radiation Council).

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Standing (left to right)

Clarence W Piltingsrud (Dow, Rocky Flats), Dr. Dale B. Hylton (Dow, Rocky Flats), Dr. Roger O. McClellan (US AEC, Headquarters, Division of Biology and Medicine), Carlos E. Newton (Battelle Memorial Institute; Northwest Laboratories), Valens P. Johnson (Dow, Rocky Flats), Robert Bistline (Dow, Rocky Flats), Dr. Charles W. Mays (University of Utah), Phil Dean (Los Alamos Scientific Laboratory), Stanley E. Hammond (Dow, Rocky Flats), Dr. David R. Atherton (University of Utah), Edward A. Putzier (Dow, Rocky Flats), Claude E. Davis (US AEC, Albuquerque Operations Office, Division of Occupational Safety), John R. Mann (Dow, Rocky Flats), Dr. Allen Lough (US AEC, Headquarters, Division of Biology and Medicine), Robert A. Kirchner (Dow, Rocky Flats), Wilbur D. Kittinger (Dow, Rocky Flats), Dr. J.T. Bryne (Dow, Rocky Flats), Bruce J. Owen (Dow, Rocky Flats), Clayton R. Lagerquist (Dow, Rocky Flats).

Not in photo: Vincent C. Vespe (US AEC, Albuquerque Operations Office, Division of Occupational Safety).

Keywords:

biokinetics; plutonium; US Transuranium and Uranium Registries; uranium

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