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4 Accelerator-Produced Radionuclides and a National Biomedical Tracer Facility HISTORICAL PERSPECTIVE A decade before the first nuclear reactor, the invention of the cyclotron by Ernest Lawrence in 1931 made it possible to produce radioactive isotopes of a number of biologically important elements. In this machine and its close relative, the linear accelerator, powerful radiofrequency electric fields are employed to accelerate charged particles (such as protons, deuterons, or alpha particles) through an evacuated path into some target material. In the cyclotron this path is an ever-widening spiral, whereas in the linear accelerator, as the name implies, it is a long straight tube. When a suitably accelerated particle collides with the nucleus of a target atom a reaction occurs and a radioactive product is formed. Milestones in the use of these artificially produced radiotracers included experiments by Hamilton and Stone (1937), who used radioactive sodium clinically; Hertz et al., (1938), who used radioactive iodine in the study of thyroid physiology; and the investigations of Lawrence et al., (1940), who studied leukemia with radioactive phosphorus. In 1941, the first medical cyclotron was installed at Washington University in St. Louis, where radioactive isotopes of phosphorus, iron, arsenic, and sulfur were produced. With the exploitation of the fission process during World War II, most radioisotopes of medical interest began to be produced in nuclear reactors, (see Chapter 3). After the War, the widespread use of radioactive materials in medicine led to the establishment of the new field of what was then called atomic medicine, which was later called nuclear medicine. Although the first artificially produced radionuclides came from Lawrence's cyclotrons, it was another 30 years before accelerator-produced radionuclides began to play a major role in the production of medically important radio-
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pharmaceuticals. Many radionuclides produced in accelerators cannot be produced by neutron reactions. When they can be, the principal advantage of accelerator-produced radioisotopes is the higher specific activity (more disintegrations per mass of desired element) that can often be achieved than is the case with reactor products. Another not insignificant advantage is that a smaller amount of radioactive waste is generated from charged-particle reactions, especially at low (£30 million electron volts [MeV]) bombarding energies. Both commercial radionuclide producers and research institutions have added accelerators to their armamentaria. The machines have mostly been compact cyclotrons (Martin, 1979) for industrial use (more than 17 in North America alone) or medical use (Wolf, 1984; Wolf and Jones, 1983). The commercial suppliers of radionuclides each possess two or more cyclotrons for their production needs. The mix of radionuclides produced with these cyclotrons is market driven. As a result a number of radionuclides that are used extensively by the biomedical research community are not available from commercial suppliers because of management decisions associated with profitability. In addition, major North American accelerator installations such as the Brookhaven Linac Isotope Producer (BLIP) facility at Brookhaven National Laboratory (Mausner et al., 1986) and the Los Alamos Meson Physics Facility (LAMPF) at the Los Alamos National Laboratory (Grant et al., 1982) in the United States and the Tri-University Meson Facility (TRIUMF) in Canada (Pate, 1979) have significant radionuclide production programs serving both commercial and research clients. This chapter reviews the use of selected radionuclides and their availabilities from various sources and how this availability would be affected by an accelerator-based National Biomedical Tracer Facility (NBTF) of the sort suggested by previous advisory groups (Holmes), 1991; Kliewer and Green, 1992; McAfee, 1989; Moody and Peterson, 1989). CURRENT APPLICATIONS IN MEDICINE AND PHYSICAL AND LIFE SCIENCES As Table 4-1 illustrates, accelerator-produced radioisotopes, like the reactor-produced radioisotopes reviewed in the previous chapter, are both abundant and versatile. As with the reactor products, their uses fall into the general categories of tracer studies, of which imaging is a special and very important case, and radiotherapy. The general principles involved in the use of radioisotopes in the life sciences as well as some of the history and recent research directions were also provided in the previous chapter, so this section will be limited to a few recent successes. Perhaps the most widely used accelerator isotope in the medical field is thallium-201 (201Tl). 201Tl imaging of heart muscle is employed during exercise to detect and differentiate between diminished blood flow and tissue death from the loss of blood flow in patients with coronary artery disease. Overall, 201Tl is
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TABLE 4-1 Selected Accelerator-Produced Radionuclides and Their Uses Radioisotope Uses Beryllium-7 Berylliosis studies Magnesium-28 Magnesium tracer Scandium-47 Radioimmunotherapy Vanadium-48 Nutrition and environmental studies Iron-52 Iron tracer, positron emitter Iron-55 X-ray fluorescence source Cobalt-57 Calibration of imaging instruments Copper-61 Positron emitter for studies requiring longer time periods Copper-64 Positron emitter for studies requiring longer time periods; radioimmunotherapy Copper-67 Radioimmunotherapy Zinc-62 Parent in the generator system for producing the positron-emitting 62Cu Germanium-68 Parent in the generator system for producing the positron-emitting 68Ga; required in calibrating PET tomographs, potential antibody label Arsenic-74 A positron-emitting chemical analog of phosphorus Bromine-77 Radioimmunotherapy Bromine-80m Radioimmunotherapy Strontium-82 Parent in generator system for producing the positron-emitting 82Rb, a potassium analog Yttrium-88 Radioimmunotherapy Zirconium-89 Radioimmunotheraphy, positron emitter Ruthenium-97 Hepatobiliary function; tumor and inflammation localization Cadmium-109 To analyze metal alloys for checking stock, scrap sorting Indium-111 Radioimmunotherapy Iodine-123 SPECT brain-imaging agent Iodine-124 Radioimmunotherapy; positron emitter Xenon-122 Parent in generator system for producing the positron-emitting 122I Xenon-127 Used in lung ventilation studies Barium-128 Parent in generator system for producing the positron-emitting 128Cs, a potassium analog Cerium-139 Gamma-ray calibration source Tantalum-179 X-ray fluorescence source (substitute for the alpha-emitter 241Au which is used in cardiac studies) Tungsten-178 Parent in generator system for producing 178Ta, short-lived scanning agent Mercury-195m Parent in the generator system for producing 195mAu which is used in cardiac blood pool studies Thallium-201 Cardiac imaging agent Bismuth-205 Bismuth biological distribution Bismuth-206 Bismuth biological distribution used in about 13 percent of all nuclear medicine procedures, making it second only to technetium-99m in volume of use. A potassium analog, 201Tl is readily extracted in proportion to regional blood flow within heart muscle, and at equilibrium, its distribution provides an assessment of the amount and location of viable heart muscle. Single-photon emission computed tomography (SPECT) provides
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images of a series of sections through the heart, and these images provide an overall sensitivity of up to 90 percent for the detection of coronary artery disease (Berman et al., 1993). In addition to 201Tl for heart studies, significant quantities of iodine-123 and gallium-67 are used for thyroid imaging and for the localization of tumors and infections, respectively. Accelerator-produced isotopes are also well-represented among the newest efforts at disease-specific imaging via monoclonal antibodies and peptides. The Food and Drug Administration (FDA has already approved an indium-111-labeled monoclonal antibody for radioimmunoscintigraphy of colorectal and ovarian carcinomas (Cytogen's Oncoscint) and is thought to be close to approving the first peptide-based radiopharmaceutical, a Sandoz/Mallinckrodt indium-111-labeled somatostatin agent (Octreoscan) for imaging small cell carcinoma of the lung and neuroendocrine tumors. Accelerator-produced isotopes are also the basis of positron emission tomography (PET). Most of the important radionuclides in PET have such short half-lives that they must be generated on-site, that is, within a few seconds or minutes of administration. Nearly all of the 60 to 70 PET centers in the United States have their own cyclotrons, with which they produce carbon-(11C), nitrogen-(13N), oxygen-(15O), and fluorine-(18F), for incorporation into metabolically important molecules. A computer uses the radiation emitted to create images reflecting different functions of the body and specific organs. Some of these molecules are very simple, like 11CO2 and H215O, which are used for blood flow studies. More complex compounds, for example, 18F-labeled fluorodeoxyglucose, allow for the visualization and quantification of regional glucose metabolism. Other labeled ligands can be used to measure amino acid utilization and receptor binding of neurotransmitters in living human patients. Still largely a research tool, PET already promises to have important clinical applications to heart disease, cancer detection, and cerebral dysfunctions caused by ischemic, degenerative, convulsive, and psychiatric disorders, as well as the detection of metastatic tumors. SUPPLIES AND SUPPLIERS The issue of accelerator-produced radioisotope availability has been subdivided into three categories, recognizing that there are essentially three sources: commercial radioisotope and radiopharmaceutical companies, site-specific cyclotrons that produce short-lived PET radionuclides for immediate use, and several large government accelerator facilities where isotope production for both industry and research is ''piggybacked" onto other missions. Commercially Available Radioisotopes Currently, three major companies in the United States operate cyclotrons for the commercial production and distribution of radionuclides with half-lives in the
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range of a few hours to a few days. The committee heard statements from representatives of all three: Roy Brown of Mallinckrodt Medical, Inc., Carl Seidel of DuPond Merck Pharmaceutical Co., and John Kuranz of Medi-Physics. These radiopharmaceutical companies each operate at least three cyclotrons, each typically with 30-MeV protons or less. Medi-Physics also operates a 70-MeV cyclotron in Arlington Heights, Ill. Relatively few isotopes are routinely produced by these companies, the main ones being gallium-67 (half-life, 78 hours), indium-111 (half-life, 68 hours), iodine-123 (half-life, 13 hours), and thallium-201 (half-life, 73 hours). To ensure continuous supplies of these radioisotopes to their customers in case of production difficulties, backup agreements between these companies are in place to maintain the supply in case of breakdown or other events that force a halt to accelerator operations. These companies readily made it clear that their product lines are profit driven and that they introduce new products only when market studies predict an attractive return. Their research and development efforts are largely devoted to new carrier molecules for well-studied radionuclides, and they are all in favor of an NBTF, which would help to develop and open new markets. They also see an important educational role for NBTF in training scientists and technicians in the use and handling of radioisotopes and radiolabeled compounds, but they do not expect that an NBTF would compete with them in the commercial market. These commercially important isotopes are also available through the Canadian company Nordion (see below under the section TRIUMF). Overall, the reliability of supplies of these short-lived, accelerator-produced (profitable) radionuclides does not seem to be in question. Table 4-2 gives the estimated quantities of commercial radioisotopes used in the years 1982 and 1990, as well as estimates of 1992 revenues to the producers of the isotopes (not the end products). TABLE 4-2 Main Commercial Radionuclides Used in 1982, 1990 and 1992 Estimated Life Science Retail Use (~Ci/year, time of end use) Nuclide Half-Life 1982a 1990b Wholesale Market in 1992 ($ millions) Thallium-201 73 h 500 6,000 >30c Iodine-123 13.2 h 75 3,100 1–5c Indium-111 68 h 150 185 1–5c Gallium-67 78.3 h 800 820 1.5d Strontium-82 25 days NAe 12d 1.2d Xenon-127 36.4 days 100 100 81 a SOURCE: Ruth et al., 1989. b SOURCE: J. Porter, Nordion International, Inc., personal communication, February 1994. c SOURCE: Evans, 1993. d SOURCE: Holmes, 1991. e NA, not available.
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Short-Lived Radioisotopes for PET Because of the very short half-lives of 18F, 11C, 13N, and 15O (110, 20, 10, and 2 minutes, respectively), an NBTF would be unlikely to have a direct effect on the use of these radionuclides. They will generally continue to be prepared with small, on-site accelerators. An important concern related to these radionuclides is the availability of enriched stable target material, especially stable 15N and 18O. This question has been discussed in the section on stable isotopes. (Chapter 2). There is some chance that the 18F, with a half-life of 110 minutes, could be shipped from an NBTF in a major city to facilities in the vicinity (Syncor, Inc., and Mallinckrodt Medical, Inc., have recently established four regional radiopharmacies that produced their own 18F-labeled 2-fluoro-2-deoxyglucose and ship it to nearby hospitals), but the major application of NBTF to these short-lived radionuclides would probably be in the development of high-beam-current targets for the low-energy accelerators that are being proposed. This will be discussed in Chapter 5. PET could expand beyond the large medical center and become a truly routine clinical tool if some additional sources of positron-emitting radionuclides could be found. One possibility is the supply of medium half-life radionuclides from an NBTF. Candidate radionuclides that have been discussed in the literature (Anderson et al., 1992; Welch and Kilbourn, 1988) include zirconium-89 (half-life, 78.4 hours), bromine-76 (half-life, 16.1 hours), iodine-124 (half-life, 4.2 days), and copper-64 (half-life, 12.7 hrs). Another possibility for an additional source of positron-emitting radionuclide is a "generator" system, similar to the molybdenum-99/technetium-99m generator described in the previous chapter. Such a generator consists of a parent radionuclide absorbed on a column from which a shorter-lived, positron-emitting decay product is eluted by passing a suitable solvent through the column. Table 4-3 lists some candidate parent-daugh TABLE 4-3 Candidate Parent-Daughter Systems for Positron Emission Tomography Parent Isotope Parent Half-Life Daughter Isotope Daughter Half-Life Daughter Positron Yield (%) Germanium-68 271 days Gallium-68 68.1 min 90 Strontium-82 25.4 days Rubidium-82 75 sec 96 Zinc-62 9.2 h Copper-62 9.73 min 98 Iron-52 8.27 h Manganese-52m 21.1 min 98 Xenon-122 20.1 h Iodine-122 3.6 min 77 Tellurium-118 6.0 days Antimony-118 3.6 min 83 Barium-128 2.43 days Cesium-128 3.6 min 61 Selenium-72 8.4 days Arsenic-72 26 h 77 Titanium-44 47 yr Scandium-44 3.9 h 95 SOURCE: Welch, 1992.
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ter systems for PET. It is difficult to predict at this point which of these will prove to be most useful in the future, but given a reliable year-round supply of the parent nuclides, generators could certainly relieve some potential PET users of the substantial burden imposed by an in-house accelerator (Budinger, 1988). However, none of the generator systems will produce isotopes of carbon, nitrogen, and oxygen for incorporation into physiologically active molecules. Thus, the principal advantage of generator-produced positron emitters lies in the ability of PET technology to provide quantitative mapping of certain functions. Radionuclides Currently Produced at DOE Facilities For most of the previous postwar decades the U.S. Department of Energy (DOE) facilities at Brookhaven National Laboratory (BLIP) and Los Alamos National Laboratory (LAMPF) have served as the primary sources for most of the accelerator-produced radionuclides used in research in the United States. A brief description of these facilities will be given, along with a description of the TRIUMF facility in Vancouver, British Columbia, Canada, since its radioisotope production capabilities could, and do, supplement the DOE-sponsored effort. Table 4-4 provides a summary of the characteristics of the accelerator at each of these sites. BLIP Although BLIP is the acronym for the Brookhaven Linac Isotope Producer, it refers to the infrastructure including the linear accelerator (linac) source for the alternating-gradient synchrotron (AGS), the BLIP building (where the targets are irradiated), and the building where the hot cells are located for processing the targets (Building 801). Building 801 is located about 2 km from the BLIP building, so targets must be transferred in shielded vessels from the point of irradiation to the location of processing. The linac produces 40-microamp (40µA) beams of 200-MeV protons. The target area is immersed in water, and a series of up to 10 targets is irradiated simultaneously, the downstream targets being exposed to beams of lower energy and intensity because of upstream target absorption and attenuation. The processing cells are more than over 40 years old. The Radionuclide and Radiopharmaceutical Program at Brookhaven National Laboratory is supported by the Isotope Production and Distribution Program, within the Office of Nuclear Energy of DOE, and the Office of Health and Environmental Research (OHER), within the Office of Energy Research of DOE. The program at Brookhaven National Laboratory is a longstanding research program, and the isotope production efforts are supposed to be self-supporting through outside sales. For a variety of reasons, including the perception by the staff that isotope sales is a secondary mission, isotope production has not broken even financially.
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TABLE 4-4 High-Energy Accelerator Facilities for North American Radioisotope Production Accelerator Type Particle Energy (MeV) Current (µA) Comments TRIUMF Beamline 1A Cyclotron H- 520 150 Twelve spallation targets Beamline 2C Cyclotron H- 50—120 10—100 Four targets TISOL Cyclotron H- 200—520 1—10 On-line isotope separator BLIP Linac H+, H- 200 40 Ten targets; 20 weeks/year BLIP upgraded Linac H+, H- 200 150 46 weeks/year? LAMPF Linac H+, H- 800 1,000 Expensive; 1996 closing proposed
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BLIP operating time and costs are strongly dependent on the use of AGS by the high-energy-physics researchers at Brookhaven National Laboratory. When AGS is in use, it uses pulses of protons from the linac. The latter operates at 5 Hertz (Hz), and AGS uses, on average, only 4 pulses in 13. The remaining pulses are diverted to BLIP, which is charged at a rate of $12,000 per week (all cost estimates were provided by BLIP staff during a site visit by committee members in November 1993). AGS occasionally uses heavy ions from another source rather than protons from the linac. BLIP then gets all 5 pulses per second,, but operating costs to BLIP escalate to $35,000 per week. In a third scenario, the AGS is not operating at all. Linac operation in this case costs BLIP $55,000 per week. The magnitude and unpredictable variation in these costs, largely salaries and power consumption, have made both year-round operation and predictable isotope pricing impossible. In recent years BLIP has been in operation an average of only 16 weeks per year. Isotope production in fiscal year 1993 is summarized in Table 4-5. LAMPF At present, six products represent the major production efforts at the LAMPF (copper-67, germanium-68, strontium-82, aluminum-26, arsenic-73, and cadmium-109). However, another dozen or so radioisotopes are available either in stock or as by-products from routine production. These radioisotopes are extracted from targets irradiated in the LAMPF beam dump area. The maximum energy of the 0.6-mile (1-km) long accelerator is 800 MeV, and its beam current TABLE 4-5 Radionuclides Distributed by BLIP and LAMPF in Fiscal Year 1993 BLIP LAMPF Radionuclide Quantity (mCi) Income (thousands of $) Quantity (mCi) Income (thousands of $) Beryllium-7 12 3 4 0.9 Sodium-22 — — 1,645 82 Aluminum-26 — — 0.0006 18 Silicon-32 — — 0.03 39 Copper-67 382 25 — — Germanium-68 398 100 1,428 336 Rubidium-83 — — 19 4 Strontium-82 3,753 376 4,611 415 Technetium-96 30 4 — — Ruthenium-97 100 6 — — Cadmium-109 — — 3,500 175 Xenon-127 65 2 — —
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is rated at 1 milliamp (mA). These operating parameters enable thick targets to be irradiated for long periods of time. Like at Brookhaven National Laboratory, operation is dictated by physics research, and although this has occasionally allowed operation for 6 months in a year, it has been operating for only 16 weeks in recent years. Only careful scheduling in conjunction with BLIP has enabled DOE to provide short-lived radionuclides for as many as 30 weeks a year. The accelerator target area at LAMPF is located about a 10-minute drive from the processing area. To transfer the irradiated targets to the processing unit, the irradiated targets must be placed in a heavily shielded container and this container must be loaded onto a flatbed truck for transport to the laboratories with the hot cells. Because Los Alamos National Laboratory is distributed over a wide geographic area connected by public roadway and the shielded container does not meet current U.S. Department of Transportation standards for public transit, this shipment demands extensive coordination and requires about 24 hours from the time of removal of the targets to their arrival at the processing unit. The LAMPF facility is scheduled to be shut down in fiscal year 1995 (the President's budget request). Political action may keep LAMPF open for an additional year or so, but the long-term prospects for LAMPF are in doubt, despite some proposed options (e.g., upgrade and continuation of the Neutron Scattering Center by the Defense Programs division of DOE) that could keep its isotope production capability in place. At $60 million per year for its operation this accelerator is clearly too big to be devoted solely to isotope production. Table 4-5 provides a summary of isotope production in fiscal year 1993. TRIUMF TRIUMF is a Canadian national laboratory located on the campus of the University of British Columbia and operated by four local universities (the University of British Columbia, University of Alberta, University of Victoria, and Simon Fraser University). As a national laboratory it is supported by the National Research Council of Canada, which provides more than $30 million a year in core support. TRIUMF not only operates the world's largest cyclotron and conducts an extensive program of research in nuclear and particle physics but also has a strong program in technology transfer associated with its Applied Science Program. Biomedical isotopes and the small cyclotrons that produce them are the key components of the transfer program, along with superfast microchips, devices for detecting hidden plastic explosives and removing undesirable components from smokestack emissions, PET software, and pion and proton cancer therapy. Royalties from the sale of these products by commercial partners provide TRIUMF with an additional $1 million per year. Nordion International Inc., whose exclusive contract for packaging and distributing reactor isotopes from the Chalk River reactor was discussed in the previous chapter, also has a 30-year technical support agreement with TRIUMF,
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making Nordion the sole commercial source of isotopes produced on the 520-MeV cyclotron, and in turn making TRIUMF the sole supplier of accelerator isotopes to Nordion. Nordion also owns and operates two compact cyclotrons, CP-42 (42MeV) and a TR-30 (30 MeV), on-site in the Chemistry Annex. The structure was built by Nordion and is shared with TRIUMF staff. These cyclotrons are used to make thallium-201, iodine-123, indium-111, gallium-67, cobalt-57, and germanium-68. Nordion also uses the main TRIUMF cyclotron to make longer-lived isotopes during the two 13-week periods during which it operates each year. This machine can simultaneously bombard 12 solid targets with 520-MeV protons and has been used in the past to make copper-67, cadmium-109, xenon-127, and germanium-68. It is currently being used to make strontium-82 from natural molybdenum by spallation. This cyclotron also has a variable-energy extractor on one of its many beam lines that can irradiate multiple targets at 65 to 120 MeV. Nordion currently uses a solid target station on that line to make strontium-82 from natural rubidium. A fourth cyclotron, TR-13 (13 MeV), designed by TRIUMF and recently completed by another of TRIUMF's industrial partners, EBCO, will be dedicated to isotope production, primarily for PET research at TRIUMF. The TRIUMF long range plan requests some $700,000 for a new, highly automated Radiochemistry/Isotope/Pharmaceutical Laboratory for the separation of radiochemicals from targets, the preparation of new radiochemicals that mimic chemicals used in metabolism, and experiments, including animal tissue preparations, that indicate the suitability of these chemicals and associated pharmaceuticals. The justification offered for this laboratory is a desire to continue the isotope research that has been so successfully brought to market by Nordion. Further evidence of this desire was the report of a TRIUMF staff member that he had just returned from a 5-week trip to Moscow. He visited a newly completed accelerator facility (160 MeV; 100µA now, 500 µA later) and arranged a full-blown collaboration that will make strontium-82 and some other long-life isotopes in Russia. The committee is of the opinion that the relation between TRIUMF and Nordion is beneficial to both partners and to the user community and that the arrangement is one that might serve as a model for a public-private partnership in the United States. This is explored further in Chapter 5. Future Production Proposed NBTF NBTF proposed previously (Holmes, 1991; Kliewer and Green, 1992; Moody and Peterson, 1989) would serve the United States as a national resource dedicated to the production of radionuclides using a particle accelerator. This $40 million-plus facility (five potential sites recently awarded Project Definition Phase
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TABLE 4-7 Time Required for Production of Selected Radionuclides at NBTF with a 500-µA Accelerator Radionuclide Half-Life Projected Demanda (mCi/yr) Energy Required (MeV) Time on NBTF per Table 4-6 (alternate demand time estimate) Arsenic-73 80.3 days 100 11 1 day Beryllium-7 53.3 days 15 20 12 min Copper-67 61.9 h 8,700 (24,000)b 40 40 days (100 days) Germanium-68 271 days 2,700 (12,000)b 30 9 days (35 days) Magnesium-28 21 h 2 70 30 min Strontium-82 25.6 days 30,000 (60,000)b 70 15 days (30 days) Tantalum-179 1.8 yr 10,000 22 170 days Technetium-96 4.3 days 100 20 A few hours Xenon-122 20.1 h 100,000 (200,000)c 70 2.5 days (5 days) Xenon-127 36.4 days 330 (3,000)b 20 1 day (4 days) Yttrium-88 106 days 100 20 8 h a Projected demand taken from Cole (1992), except as noted. b Values in parentheses are the projected demands taken from Holmes (1991). c The value in parentheses is the projected demand based on 20 PET centers requiring one shipment (two shipments) per week (T. Budinger, Lawrence Berkeley Laboratory, University of California, Berkeley, personal communication, 1994). and Environmental Physics (OHER) and $3 million from High Energy Physics) was allocated to upgrade the BLIP linac and other BLIP facilities. The $3 million upgrade goals for the linac are to increase its beam current its present 40 µA to something approaching the design specifications of 150 µA, to provide energy variability from 66 to 200 MeV in 21-MeV steps, and to add to the production capabilities that three isotopes are currently only available from LAMPF. The $6 million upgrade to the BLIP facilities covers the construction costs involved in the upgrade and expansion of Building 801 hot cells, a structural addition to the BLIP target irradiation building, and modifications of the linac to enhance reliability at high currents. No additional operating costs have been provided to date, but they have been requested for the years following the completion of upgrade construction to increase operations to 46 weeks per year. Table 4-8 compares one prediction of the capability of such an upgraded facility, running for 40 or more weeks annually, with the proposed capability of an NBTF accelerator (Holmes, 1991) and with the current capability of the TRIUMF facility. It is apparent from Table 4-8 that an upgraded BLIP, the proposed NBTF, and TRIUMF all would have sufficient energies and currents to meet the projected demands by the research community in the near future. However, there have been a number of serious impediments to the attempts of present DOE facilities to serve as satisfactory sources for the radionuclides used in the bio-
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TABLE 4-8 Hypothetical Production of Radioisotopes at Three Facilities Production (mCi) at Isotope BLIPa (Normal) BLIPa (Upgrade) Time Required Production (mCi) at TRIUMFb Time Required Production (mCi) at NBTFc Time Required Strontium-82 4,000 18,900 40 days 12,000 30 days 30,000 15 days Germanium-68 1,100 2,700 50 days 2,700 50 days 2,700 9 days Copper-67 1,550 7,000 100 days 7,000 180 days 8,700 40 days Xenon-127 250 330 4 days 330 4 days 330 1 day Cobalt-55 75 75 1 day 75 1 day 75 1 min Technetium-96 45 90 3 days 90 3 days 100 Few h Beryllium-7 10 15 1 day 15 1 h 15 1 min Magnesium-28 1 2 1 day 2 1 day 2 30 min Yttrium-88 0 100 3 days 100 3 days 100 8 h Cadmium-109 0 5,000 60 days 5,000 60 days 5,000 20 days Sodium-22 0 1,500 1 yr 1,500 1 yr 1,500 150 days Arsenic-73 0 60 5 days 60 5 days 60 1 day a SOURCE: Cole, 1993. b Estimates calculated from present operating parameters. c Assumes 500-µA current. NBTF could produce many other isotopes as well.
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sciences, none of which will automatically disappear with the completion of the BLIP upgrade now under way. Most serious are the limited operating schedules of the accelerators at Brookhaven and Los Alamos National Laboratories; the age and design of the linacs (meant for physics research, they are more expensive to operate than a new machine designed for isotope production, and target insertion and removal are so inconvenient that making very short lived radionuclides is impractical); the requirement that the production facilities be self-supporting (Public Law 101-101), in concert with DOE policy forbidding competition with the commercial sector; the perception of isotope sales and distribution as second-class activities for a major research laboratory; the relative isolation of these two laboratories from major shipping centers. The committee also believes that no DOE accelerator facility could both pay for itself the sales of isotopes not available from a domestic commercial supplier and satisfactorily meet the requirements of U.S. research scientists. Thus, although the national laboratories have a number of attractive features, including a potentially substantial one in waste management (see Appendix A), the very nature of the mission of DOE accelerators and the resulting lack of flexibility would make it impossible to meet the various mixtures and frequencies of radioisotopes deliveries that the research community desires. Recognition of these problems has led the committee to accept the necessity for a facility whose primary mission is the production and distribution of small amounts of a wide range of radionuclides to research scientists and the medical community: NBTF. In the original NBTF document (Holmes, 1991) a basic parameter list indicating a proton beam current of 750 µA and an energy maximum of 100 MeV were suggested as appropriate design goals to meet the objectives of NBTF. Although a number of accelerating structures can be used to realize these parameters, attention in the future will probably focus on cyclotrons and linacs, with which there is considerable experience and expertise in both the private and the public sectors. Detailed considerations of the appropriate choice of accelerator technology will not be discussed here. These discussions will develop as NBTF moves from a conceptual design phase through to a final design that will be thoroughly reviewed. At present, upper energies of 70 to 100 MeV appear to be needed for NBTF. The costs for both cyclotrons and linacs vary approximately linearly with energy above about 50 MeV. Other considerations, such as overall operating costs, shielding requirements, and ability to access accelerator and target areas, must be answered before a final choice of accelerator technology is determined. No single solution appears to be favored at this time, but the requirements appear to be well within the reach of present technology. In-House Research and Education at the NBTF The committee believes that the field will best be served if the primary focus of research at the upgraded BLIP, the proposed NBTF, and the University of
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Missouri Research Reactor remains production rather than development of further applications, which is being done quite well on a decentralized basis via the peer-reviewed grant process. The development of target and targets cooling systems capable of withstanding the high temperatures induced by high-current particle beams are essential research and development activities at any radionuclide production facility. Support for this work should be an essential element in the core funding (i.e., noncompetitive) of NBTF. Research into the target choice for any radionuclide might begin with cross-section measurements on feasible target materials. Encapsulation in the accelerator beam, cooling methods, the desired physical phase radiation effects, the optimal thickness, and the optimal density must be determined and tested. Also vitally important are the methods available for the recovery and purification of the desired product(s). The post-irradiation physical and chemical states of both the target and the radionuclides produced must be known for cost-effective and efficient separation to ensure not only pure, high-specific-activity radionuclides but also maximum reuse of often expensive enriched target material. Some well-known radionuclide production targets could be improved substantially by focused engineering research. In some cases, this type of research has required the reallocation of funds from scientific applications programs, and generally, this type of engineering and chemistry development is not seen as a high-priority investment, even though it could significantly reduce the cost of radiopharmaceuticals. An example is the development of a target for the production of xenon-122, which is the precursor of iodine-122 (a positron emitter with a 3.5 minute half-life). There is a high degree of potential that a xenon-122/iodine-122 generator system (Lagunas-Solar et al., 1986) can be used for economical studies of brain and heart blood flow because this system obviates the need for a local cyclotron to produce 15O-labeled water or 13N-labeled ammonia for similar studies. The target must be developed and married to a particular beam line at an appropriate accelerator facility (e.g., TRIUMF; Crocker Laboratory, Davis, California; BLIP; Medi-Physics, Arlington Heights, III). The development of targets has always been based on contemporary needs such as the production of fluorine-18 or carbon-11 monoxide and carbon-11 dioxide. No effective mechanism exists for the development of new targets on the basis of an interest in a radionuclide but without knowledge of obvious and widespread applications once it is developed. Without having the radionuclide, the investigator cannot show clinical or research applications, but without some demonstration of successful applications, an investigator cannot obtain funds to develop the target to make the radionuclide in the first place. Thus, new ideas for radionuclides and radionuclide generators do not get tested. Target technology involves mechanical, materials, and systems engineering, including automation for safe loading and unloading. Target reliability under high currents (e.g., 500 µA) and varying beam optics is an essential area that
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requires a significant investment in engineering time. Target development for a particular accelerator can cost hundreds of thousands of dollars, particularly if more than one chemical compound is synthesized. This category of targeted research is an area of focus highly appropriate for a national facility such as NBTF. Certain work involving the efficiency and/or safety of the facility's accelerator should also be included in core support, as should very early labeling work establishing feasibility. Further labeling work and other application-oriented research should be funded only by peer-reviewed grants, though it should be possible to assign projects to the facility that have been identified by DOE as important but neglected. As with any high-quality research institution, NBTF scientists would be encouraged to apply for peer-reviewed research grants from government agencies as well as industry. Affiliation with and proximity to a major research university could also expand potential NBTF research by providing access to animal and tissue testing resources as well as patients and individuals with clinical research expertise. Education in the nuclear sciences plays an essential role in all aspects of the infrastructure involved in the production, separation, development, use and application of isotopes, including the safe operation and maintenance of accelerator and reactor facilities. Without this activity, none of the major discoveries involving the use of isotopes and none of the daily uses and applications of isotopes mentioned in earlier chapters would be possible. There is, however, a sense from people working in various fields of nuclear science that there is a critical shortage of undergraduate and graduate students and a great dependence on foreign-trained scientists to fill existing needs (Holmes, 1993; Choppin and Welch, 1988; Yates, 1993). DOE has substantial legislative authority to support university research and related education. The Department of Energy Science Education Enhancement Act of 1990, Section 3161 et seq., amends the basic Department of Energy Organization Act of 1977 to include support for education as one of the major missions of the department and to authorize the development of research and educational partnerships between DOE laboratories and educational institutions at all levels. Although the National Science Foundation (NSF) has traditionally been the federal government's primary source of support for science education, NSF has usually deferred to DOE as far as nuclear science is concerned, arguing that it is DOE that has the expertise necessary to best direct such programs. A persistent difficulty with this arrangement has been that support for nuclear science education, because it covers a very broad spectrum, has been spread widely throughout various departments within DOE, none of which feels responsible for the entire program and all of which give it a relatively low priority. Between 1989 and 1993, congressionally mandated support was provided through the University and Science Education Program, which provided funds for nuclear education-
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related engineering, graduate, undergraduate, and precollege programs is nuclear technology as well as merit-reviewed nuclear science and engineering research projects (Riggs, 1993). Without a similar congressional mandate in fiscal year 1994, funding for educational activities has declined sharply, resulting in stipend reductions for current students and a reduction in the number of new students admitted. Five programs are being considered for significant cuts in faculty (Kunze, 1994). These programs are at major research universities and train about 30 percent of radiation-based science and technology students. Similarly, among the important statistics compiled in the National Research Council (1988) report on requirements for nuclear chemists was a 60 percent decrease in radiochemistry faculty and 57 percent decline in nuclear and radiochemistry courses offered in Ph.D.-granting departments between 1978 and 1987, despite a clear and growing need for scientists thoroughly trained in radiochemistry. Figure 4-1 shows the steady decline in the number of doctoral degrees granted in nuclear chemistry over the last two decades (Oak Ridge Institute for Science and Education, 1993). Within nuclear medicine the primary areas of need are in radiochemistry (analysis and synthesis), training in the use of instrumentation, the design of new radionuclide generators, optimization of radionuclide production at accelerators, and development of new applications. The committee envisions the NBTF playing a large role in training in all of these areas, albeit only with the cooperation with one or more universities. As the Society for Nuclear Medicine report (Holmes, 1991) suggests, the educational program would be similar to those at the NSF Center of Excellence. Whether sited at a university or not, NBTF must have a close association with a university and a scientific staff with university appointments. NBTF could then be an invaluable location for graduate students as well as postdoctoral fellows and visiting scientists to learn state-of-the-art radiochemical research and production techniques. An association with established research programs in nuclear medicine, radiopharmacy, or radiochemistry at an affiliated university would in turn provide NBTF with continuing sources of extramural collaborations, inexpensive labor, and intellectual stimulation. Pre- and postdoctoral fellowships, faculty scholarships, and incentives for new faculty positions should thus be part of DOE's core support for NBTF, supplemented by industry and government (DOE and others) grants to both university and NBTF staff. CONCLUSIONS In the short term there does not appear to be any problem with the availability of commercial radionuclides produced on accelerators with energies of about 30 to 40 MeV. There is, however, a clear need for a higher-energy machine to provide researcher with radionuclides for new applications. Brookhaven National Labo-
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FIGURE 4-1 Doctoral degrees in nuclear chemistry awarded by U.S. universities, 1970–1991. SOURCE: Adapted from Oak Ridge Institute of Science and Education, 1993. ratory (BLIP) and Los Alamos National Laboratory (LAMPF), as the primary domestic sources of these radionuclides, have been unreliable because of scheduling and costs. There is also concern about each of these facilities because of their ages and the changing missions for which they were constructed. The future outlook for LAMPF is not clear, and the expertise that has been assemble there over the year will be lost when the accelerator facility is shut down. The linac
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that BLIP uses will continue to operate in the future since it is one of the injectors that the Relativistic Heavy Ion Collider will use when it starts operating in 1999. It is unclear how available it will be for radioisotope production, assuming that operating funds are also available. The present processing facilities at BLIP are inadequate, outdated, and poorly maintained, in part, because of their ages. In the short term an upgraded BLIP facility, including an extended operating time, and the TRIUMF facility can meet many of the radiotracer needs of the research community. However, both facilities have a mandate to operate as basic physics accelerators and cannot meet the full demand for research radionuclides in their present modes of operation. Base on the production reactions presented in Table 4-7, all of the radionuclides envisioned for current and future use can be prepared on an accelerator with an energy of 80 MeV. The choice between cyclotron and linac is beyond the scope and expertise of this committee report, but a high beam current (750 µA or more) is required to ensure production of large quantities of a few commercially viable isotopes and allow multiple target irradiations that will produce small quantities of experimental radionuclides. RECOMMENDATIONS DOE should create a dedicated, reliable source for research radionuclides that has stable core support for the production of radioisotopes that are not available from the commercial suppliers. An NBTF that can incorporate the production facilities with the necessary infrastructure for research and training in isotope production and related activities is essential for the United States to maintain continued leadership in biomedical research using radiotracers. Until such a facility is established, the needs of the isotope user community should be met by an upgraded BLIP supplemented by additional operating funds to allow for an extended operating period and a processing and distribution section that is similar to that at the University of Missouri Research Reactor. Implementation of this recommendation should alter the current basic research environment and attitude at the BLIP facility and put isotope production and distribution on equal footing with in-house medical research. The cooperative arrangement between government and industry at Canada's TRIUMF facility has lead to successful technology transfer to the private sector and should be emulated in the United States. DOE should explore the utility of such models for coupling commercial production and research (see Chapter 5). A national advisory committee should be established to assist in monitoring the operation of and in setting priorities for the operation of both the upgraded BLIP and NBTF (see Chapter 6).
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TRIUMF 500-MeV clyclotron lower magnet pole face during construction. SOURCE: Tri-University Meson Facility.
Representative terms from entire chapter: