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2 Enriched Stable Isotopes HISTORICAL PERSPECTIVE The discovery of stable ''isotopes" began with J. J. Thomson's identification of neon-22 in 1912 (Bievre et al., 1984). More than 90 naturally occurring elements have been identified on the earth; they exist as nearly 270 stable isotopes—that is, forms of the elements that do not decay or emit radiation—and hundreds of radioactive isotopes. The various isotopes of a given element differ from one another only in the number of neutrons in their atomic nucleus (the number of protons in the nucleus differentiates the elements from one another), and even highly purified samples of an element are generally a mixture of several isotopes. Pure silver, for example, is composed of nearly equal amounts of silver-107 and silver-109. Iron is mostly iron-56 (92 percent), but it contains small amounts of three other isotopes as well, and tin is a mixture of 10 stable isotopes, the most abundant of which makes up only 33 percent of the total. Enriched refers to material that consists largely or exclusively of a single isotope and is usually obtained by one of the separation techniques described later in this chapter. The use of enriched stable isotopes and their applications as they are presently known emerged from early work with metabolites labeled with deuterium (Schoenheimer and Rittenberg, 1935). Their extra mass made them traceable (usually by mass spectrometry of, for example, blood or urine) as they proceeded through various biochemical pathways. Similar labeling of nearly any compound is theoretically possible by synthesizing it with large quantities of an isotope that is relatively rare in nature. In the last two decades the use of enriched stable isotopes has offered substantial advantages to scientists and clinicians involved in the rapid growth of research on human body composition, energy balance, protein turnover, and fuel utilization (Whitehead and Prentice, 1991). Today,
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increased awareness of the role played by the elements in human health and as etiologic factors in diseases (osteoporosis, heart disease, cancer, diabetes, kidney disease) (National Research Council, 1989; U.S. Department of Health and Human Services, 1988) as well as diagnostic and therapeutic adjuncts (obesity, inborn errors of metabolism, heart disease) has created an explosion in the need for stable isotopes at a time when the production capacity is questionable. Although stable isotopes occur naturally, their utility can be greatly enhanced when they are isolated and enriched through processes such as electromagnetic separation, cryogenic distillation, thermal diffusion, or other physical and chemical processes. These enriched stable isotopes are used as target materials in the preparation of radioisotopes with particle accelerators and nuclear reactors and as biological tracers in biomedical research and clinical applications. In addition, they serve as probes for basic physics and chemistry studies. Table 1-1 in the previous chapter lists some of the many fields that use stable or radioactive isotopes. Selected biomedical research topics and potential clinical uses of stable isotopes are given in Table 2-1. Despite the pioneering role of the United States in this field, the country is rapidly becoming more dependent on sources in the former Soviet Union for many necessary isotopes. Serious debate is needed regarding the desirability of this dependence and the attendant possibility of the pernicious effects on U.S. science and technology of an isotope monopoly controlled by a single financially distressed foreign source. CURRENT APPLICATIONS IN MEDICINE AND PHYSICAL AND LIFE SCIENCES In many areas of research, the need for enriched stable isotopes is as vital as the need for pure chemicals (Friedlander and Wagner, 1982). Stable isotopes used primarily for research are usually purchased intermittently in relatively small amounts, from fractions of a gram to a few grams at a time. However, biomedical research often requires kilogram quantities (e.g., oxygen-18). The general approach to biomedical studies that use stable isotopes involves the same tracer methods used for radioactive isotopes. But since there is no radiation to detect, specialized analytical methods for detection of the specific stable isotopes are used. For example, after ingestion or injection of an isotope of zinc, the absorption of zinc by the human body can be determined by measuring the trace amounts that appear in the blood and urine over a period of days or weeks after ingestion or injection. The dilution of the stable isotope tracer gives information on the distribution of zinc in the body, and the rate of excretion gives information regarding how well a particular mineral is absorbed. The simultaneous use of two isotopes in two different foodstuffs can be used to determine how absorption of calcium, for example, might vary as a function of mode of intake. The major advantages of using enriched stable isotopes for biomedical re-
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search lie in their ease of use on large patient populations in studies of nutrition, in children and adults in clinical studies of metabolic abnormalities of the digestive system, and in investigations of osteoporosis. The availability of several stable isotopes of the same element allows simultaneous investigation of nutrients within various body compartments. Some of the most important contemporary uses of enriched stable isotopes involve investigations of the human metabolism of calcium, zinc, magnesium, and other cations needed by humans. The minimum dietary requirements of metals needed in trace amounts (e.g., selenium, molybdenum, copper, and rubidium) require enriched stable isotopes for their determination. A major application is the study of calcium absorption from ingested foodstuffs and its subsequent turnover in bone in relation to osteoporosis. By using simultaneous oral and intravenous administration of two or more stable isotopes (e.g., calcium-42 and calcium-44), the absorption of various calcium supplements and food sources can be investigated. This is an area of great potential for metabolic research, particularly in the area of osteoporosis. Key tools for research on human metabolism relative to obesity, starvation, diabetes, and atherosclerosis are mass spectrometric or magnetic resonance measurement of carbon-13 (13C) levels in human subjects who have received substrates labeled with 13C, and mass spectrometry of the temporal course of excretion after ingestion of water labeled with both oxygen-18 and deuterium. Stable isotopes have been used to determine the metabolic and biochemical bases for familial hyperlipidemia and the kinetic parameters in apolipoprotein B metabolism. In these applications advances are needed to reduce the cost of these 13C compounds and the oxygen-18-labeled water that has been difficult to obtain in the past 3 years (oxygen-18 for double-labeled water studies currently costs about $1,000 per patient). The dearth of inexpensive methods for incorporation of the isotope into chemical compounds is also limiting their application. For example, 13C is usually shipped as the carbonate or as gaseous carbon dioxide. Calcium isotopes are available as the calcium carbonate. The costs of specialized tools for the study of metabolism in humans, for example, of [1-13C]glucose or calcium-42 or calcium-44 are so great that many investigations of major importance to health care are impeded or not possible. For example, the study of human glycogen synthesis by nuclear magnetic resonance (NMR) requires about 70 g of 1-13C-labeled glucose. The 1994 catalog cost is $10,000. A study of the pentose shunt with [2-13C]glucose requires about 40 g at $400/g and a total cost of $16,000 on the basis of 1994 catalog prices. A very important study of glutamine metabolism that would use nitrogen-15 and NMR would cost $30,000. The major element responsible for these costs is the incorporation of the stable isotopes into biologically important compounds, generally 10 times the cost of the production or separation of the stable isotope. The potential use of stable isotopes in diagnostic tests will clearly be limited without drastic reductions in these costs, no matter how useful
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TABLE 2-1 Selected Enriched Stable Isotopes Used in Biomedical Research Stable Isotope Uses Boron-10 • Extrinsic food label to determine boron metabolism Calcium-42, -44, -46, -48 • Calcium metabolism, bioavailability, and absorption parameters during physical stress, bed rest, and space flight • Osteoporosis research and bone turnover studies • Role of nutritional calcium in pregnancy, growth and development, and lactation • Bone changes associated with diseases such as diabetes and cystic fibrosis Carbon-13 • Fundamental reaction research in organic chemistry • Molecular structure studies • Fundamental metabolic pathway research, including inborn errors of metabolism • Noninvasive breath tests for metabolic research and diagnosis • Biological substrate oxidation and turnover • Elucidation of metabolic pathways in inborn errors of metabolism • Amino acid kinetics • Fatty acid metabolism • Air pollution and global climatic change effects on plant composition Chlorine-35, -37 • Environmental pollutant toxicity studies Chromium-53, -54 • Noninvasive studies of chromium metabolism and human requirements • Adult onset diabetes mechanisms Copper-63, -65 • Noninvasive studies of copper metabolism and requirements • Studies of congenital disorders and body kinetics in gastrointestinal diseases • Investigation of role in maintaining integrity of tissue such as myocardium Helium-3 • In vivo magnetic resonance studies Hydrogen-2 • Vitamin research • Chemical reaction mechanisms Iron-54, -57, -58 • Metabolism, energy expenditure studies • Conditions for effective iron absorption and excretion • Research to develop successful interventions for anemia • Metabolic tracer studies to identify genetic iron control mechanisms
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Stable Isotope Uses Krypton-78, -80, -82, -84, -86 • Diagnosis of pulmonary disease Lead-204, -206, -207 • Isotope dilution to measure lead levels in blood Lithium-6 • Sodium and renal physiology • Membrane transport • Psychiatric diseases Magnesium-25, -26 • Noninvasive studies of human nutrition requirements, metabolism, and absorption • Kinetic studies of heart disease and vascular problems Molybdenum-94, -96, -97, -100 • Extrinsic labeling of food for determination of human nutrition requirements Nickel-58, -60, -61, -64 • Noninvasive measurement of human consumption and absorption Nitrogen-15 • Large-scale uptake studies in plants • Whole body protein turnover, synthesis, and catabolism • Amino acid pool size and turnover • Metabolism of tissue and individual proteins Oxygen-17 • Studies in structural biology • Cataract research Oxygen-18 • Noninvasive, accurate, and prolonged measurement of energy expenditures during everyday human activity • Lean body mass measurements • Obesity research • Comparative zoology studies of energy metabolism Rubidium-85, -87 • Potassium metabolism tracer • Mental illness research Selenium-74, -76, -77, -78, -80, -82 • Bioavailability as an essential nutrient Sulfur-33, -34 • Human genome research and molecular studies • Nucleotide sequencing studies Vanadium-51 • Diabetes, bioavailability, and metabolism • Brain metabolism studies Xenon-129 • Magnetic resonance imaging Zinc-64, -67, -68, -70 • Noninvasive determination of human zinc requirements • Metabolic diseases, liver disease, and alcoholism • Nutritional requirements and utilization studies
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the results. These facts argue for a national initiative on efficient synthesis that could be facilitated through an overall national program on biomedical isotopes. Although the introduction of stable isotope tracers revolutionized the understanding of biological processes, the field relies heavily on sophisticated chemical techniques and analytical instrumentation not routinely available. Expensive measurement methods are also limiting applications. The instruments used to detect stable isotopes include mass spectrometers, accelerator mass spectrometers, and gas chromatographs, all with wide ranges of sophistication. The use of certain radionuclides for in vivo studies is likely to be increased with the widespread introduction of accelerator mass spectrometry (AMS) for their detection. AMS has been shown to be several orders of magnitude more sensitive than counting of radioactivity for the detection of certain long-lived radionuclides (Elmore et al., 1990; Felton et al., 1990). Of particular interest for tracer studies is the application of carbon-14 and calcium-41. It has been calculated that for experiments with carbon-14 in which the carbon-14 is detected by AMS, the radiation dose to human subjects can be as little as 0.003 millisieverts (mSv). This is only a small fraction of the amount of natural radiation received by humans in a year. The needs for detection systems for stable isotope applications are as great as the needs for reductions in the costs of incorporating stable isotopes into biomedical compounds. At present any substantial research study can require a dedicated analyst-technician and the acquisition of specialized instrumentation costing more than $100,000. Some solution for this bottleneck in stable isotope applications needs to be developed. The committee found this lack of detection instrumentation one of the most important impediments to the use of stable isotopes. A reliable supply of enriched stable isotopes is also essential for radioactive isotope production. These materials are used as targets in reactors and accelerators to produce radioisotopes for basic and clinical research (see Table 2-2 and Chapters 3 and 4), and they are the feedstock for the commercial production of radiopharmaceuticals that are used routinely in the clinic and clinical laboratory for diagnosis and therapy. Small quantities of a wide variety of stable isotopes are essential for maintaining the National Institute of Standards and Technology's widely used Standard Reference Materials. The application of stable isotopes in science and industry continues to be varied and widespread, but the production and sales of these tools are not large or lucrative businesses. The worldwide market for stable isotopes is estimated to be only in the range of $8 million to $10 million, more than half of which is accounted for by only four products: thallium-203, which accounts for one-quarter of all sales, and strontium-88, helium-3, and zinc-68, each of which makes up 10–12 percent of the total market. Overall, nearly 40 percent of the world's enriched stable isotope sales are small purchases for research purposes. Medicine, primarily radiopharmaceutical companies, accounts for about half of all purchases, and industrial users account for the remaining 10 percent.
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TABLE 2-2 Selected Enriched Stable Isotopes and Derived Radioisotopes Stable Isotope Target Radioisotope Producta Cadmium-112 Indium-111 Carbon-13 Nitrogen-13 Chromium-50 Chromium-51b Germanium-76 Arsenic-77b Lutetium-176 Lutetium-177b Nickel-58 Cobalt-57 Nitrogen-15 Oxygen-15 Oxygen-18 Fluorine-18 Palladium-102 Palladium-103b Platinum-198 Gold-199b Rhenium-185 Rhenium-186b Samarium-152 Samarium-153b Strontium-88 Strontium-89b Thallium-203 Thallium-201 Xenon-124 Iodine-123 Zinc-68 Gallium-67, Copper-67 a For specific examples of radioisotope applications, refers to Chapters 3 and 4. b Produced in a reactor; the others are produced in an accelerator. ISOTOPE SEPARATION IN THE UNITED STATES Since the late 1940s the dominant source of most of the enriched stable isotopes produced in the United States has been the calutrons (from California University cyclotron) at the Oak Ridge National Laboratory (ORNL). These large separators were originally developed to separate the isotopes of uranium in World War II. The technology that they employ, which has been relatively unchanged for the last 50 years, is based on the electromagnetic separation of elemental material into its constituent isotopes. The element, or a compound containing the element, is first converted to an ionized gas. A stream of these ions is then bent by a powerful magnetic field. The degree of curvature produced is dependent on the mass of the ion, so the ions with lighter isotopes are bent more than the heavier ones. Metal collector plates situated appropriately then intercept the separated beams of individual isotopes. Approximately 60 of these machines remain at ORNL today, 50 of which have been adapted for the enrichment of 225 stable isotopes of 58 elements (Collins, 1993). The calutrons represent a unique but aged resource for the production of enriched stable isotopes, and no other facility that could duplicate this capability exists in the United States. Operation of the calutrons requires a staff of 35, however (Collins, 1993), and it would cost about $5 million annually to produce a large spectrum of isotopes (Arthur Andersen & Co., 1993). Despite their age, the calutrons have been operated successfully in recent years through the skill and knowledge of longtime opera-
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tors. For reasons more fully discussed below, the calutrons are currently not being operated but are in a standby mode (at an annual cost of $2 million). Future operation of the calutrons appears to depend on the ability of the U.S. Department of Energy's (DOE's) Isotope Production and Distribution Program (IPDP) to obtain contracts with the private sector for substantial isotope purchases. The research community cannot afford the costs required to reactivate the calutrons to produce the generally small quantities of enriched stable isotopes required for their programs. Moreover, because many calutron operators have already or will soon be retiring, it seems unlikely that a new operations crew would be capable of restoring the calutrons to full operating efficiency without considerable expense and other difficulties. In addition to the calutrons, equipment for the plasma separation technique is in place at ORNL, but additional funding would be required before this enhancement of the ORNL isotope separation capabilities could be realized. Plasma separation could be used for the direct production of enriched stable isotopes or to enrich material as feedstock for the calutrons. The plasma separation process is only about half as efficient as the process performed by the calutrons in terms of product purity, but it is 300 times faster. The two processes could thus be used in series to enrich naturally rare isotopes more efficiently. Large amounts of enriched stable isotopes of the light elements such as carbon, nitrogen, and oxygen are particularly important for biomedical research (e.g., oxygen-18 as a source material for the fluorine-18 used in position emission tomography). The primary source of such isotopes in the United States today resides in the commercial sector. Examples include Isotec in Ohio and the Cambridge Isotope Laboratories in Massachusetts. Cryogenic distillation columns are employed by these companies to separate the light isotopes. At present, there appears to be an adequate supply of such light isotopes; however, researchers have complained about short supplies in the recent past that have forced them to foreign sources (e.g., Israel) and about costs that continue to limit their widespread use. DOE also has capability in this area: cryogenic columns are in place, but in a standby mode, at Los Alamos National Laboratory (LANL). Finally, additional capability for stable isotope separation exists at DOE's Mound Facility in Ohio, which uses thermal diffusion to provide DOE laboratories with isotopes of the halogens and the noble gases. FUTURE SUPPLIES Although a substantial capability for the production of enriched stable isotopes exists in the United States—both in the private sector and within the infrastructure of DOE—many of the operations located within DOE must be considered to be in jeopardy. Two recent and unrelated events have resulted in the inability or unwillingness of both private-and public-sector groups to pay DOE's going rate for isotopes and are driving these groups to non-U.S. suppliers. These
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events, the passage of the Energy and Water Development Appropriations Act of 1990 (Public Law 101-101) and the emergence of the Republics of the former Soviet Union as a major force in the isotope market, are detailed in the following paragraphs. From its beginnings in the Manhattan Project, the U.S. government's enriched stable isotope program operated with modest federal subsidy (approximately $2 million annually in the late 1980s) in support of research deemed to be of programmatic interest to DOE. In 1989, IPDP was established within the Office of Nuclear Energy of DOE to oversee all federal isotope production. Public Law 101-101 incorporated this reorganization into law and, in addition, decreed that, henceforth, isotope production and distribution were to be self-supporting (i.e., fees for isotopes and related services were to provide for full cost recovery, including administrative expenses and the depreciation of equipment). IPDP has not become self-sustaining, and its problems have been the subject of congressional subcommittee hearings, a U.S. General Accounting Office report (1992), and a management study by the consulting firm of Arthur Andersen & Co., 1993). Those studies point to high operating costs, which are largely beyond the control of IPDP; unrealistic capitalization for equipment; and, even less susceptible to remedy, the aggressive entry into the isotope market of the Republics of the former Soviet Union as matters of concern. The Cold War arms race spawned the expanded development and use of electromagnetic separators and gas centrifuges in the Soviet Union as well as the United States. The functional state of this former Soviet equipment is not known, but many of these facilities have not hesitated in making the leap into a market economy. Although anecdotal information about Russian inventories is abundant, the extent of these supplies is unknown, but it is estimated to be many times that of U.S. inventories (Arthur Andersen & Co., 1993) and priorities for future production in Russia appear to be dominated by the quest for hard currency. Aggressive Russian marketing cut DOE's share of the world stable isotope market from roughly 90 percent in 1990 to less than 60 percent in 1992 (Arthur Andersen & Co., 1993). DOE sales of thallium-203, the stable isotope with the largest world demand, fell from $2.5 million in 1990 to less than $350,000 in 1992. This decline is expected to continue, because Russian suppliers are still setting their prices as a percentage of the IPDP price, and this decline could become precipitous if the Russia or other former Soviet republics set up an efficient distribution system. The committee was informed by a U.S.-based representative of one Russian laboratory as recently as March 1994 that the laboratory was too poor to publish a catalog but that prices would be "about half of those in the Oak Ridge catalog." It seems likely that prices would rise sharply in the absence of at least potential competition from Oak Ridge, but most if not all of the major radiopharmaceutical companies have turned to the former Soviet Union, some with long-term contracts. Industry representatives (Brown, 1993; Seidel, 1993) reported to the committee that, at least for fairly large repeat orders, they
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were generally satisfied with the speed and reliability of delivery as well as the quality of isotopes from their Russian sources. Not surprisingly, the result has been that DOE has suspended its production of enriched stable isotopes. Enriched stable isotopes may still be purchased from IPDP, which has a substantial inventory of some isotopes still on hand. Although prices have risen sharply, IPDP is the only alternative for researchers without a Russian connection or for scientists needing only small quantities of a variety of isotopes at irregular intervals (for which Russian sources have been unreliable or nonexistent). In addition, stable isotopes may be leased for nondestructive, nonconsumptive, scientific investigation. Prior to the establishment of IPDP, materials from a circumscribed "loan pool" known as the Research Materials Collection, were reserved for loan to researchers for nondestructive uses; however, this policy has been abandoned, and all materials controlled by IPDP are available for purchase, resulting in a steady depletion of this invaluable collection. The ORNL calutrons have been in standby mode since August 1991. The committee sees no point in recommending the resumption of production without the promise of substantial sales, something that is unlikely to occur as long as DOE prices must cover the full costs of calutron operations and the Russians continue to deliver isotopes to the major buyers at cut-rate prices. The calutrons are now more than 50 years old. Newer, more efficient technologies could supplant them and provide a buffer against an uncertain Eastern European supply. For this reason, the committee heard reports from a number of DOE-funded scientists exploring alternative separation processes. NEW AND ALTERNATIVE SEPARATION TECHNOLOGIES As noted above, the calutrons have been the sources of more than half of the enriched stable isotopes, but they are based on 50-year-old technology and old equipment. Over the last decade or so, considerable effort has been invested by the U.S. government, sometimes in collaboration with industry, in new technologies for producing enriched stable isotopes for a variety of purposes. Some of these new technologies hold the promise of producing research-grade isotopes at reduced costs, in large quantities (grams or even kilograms), and at high levels of enrichment. Although many of these technologies are still in the research and development stage—even, in some cases, in a conceptual stage—they should be studied and developed as potential contributors to the future supply of enriched stable isotopes that will be needed by the research community in the United States and elsewhere. During the November 1993 meeting of the committee, several of these new technologies were described in the public portion of the meeting, although none are yet in a position to replace current methods, and it is difficult to assess how much additional development will be required. These advances are briefly described below. It is important to recognize, however, that these examples by no means represent all of the technologies being studied.
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Three of the new techniques described at the November 1993 meeting—the vacuum arc centrifuge (VAC), the solitron, and atomic vapor laser isotope separation (AVLIS) (Krishnan, 1993; Schwager, 1993; Stern, 1993)—require the use of strong electric and magnetic fields to facilitate the process leading to stable isotope separation. In VAC, separation is achieved via the interaction between an ion beam (composed of the isotopes to be separated) with a suitable magnetic field, with the separation factor between any two isotopes depending on the difference in their masses and the rotation frequency of the plasma. This technique is under development by scientists at the Science Research Laboratory under a grant from DOE. They envision it as a low-cost (ca. $1 million to build and $500,000 a year to operate), modular enrichment tool that could supply a large range of stable isotopes (carbon-13 to heavy elements such as thallium-203) in gram to kilogram quantities (Krishnan, 1993). The solitron is a device under development at the Lawrence Livermore National Laboratory (LLNL). The goal is to provide an inexpensive (same range as the VAC) and compact (portable) device that can be used to produce a variety of stable isotopes for research applications. Isotope separation is achieved through the selectivity provided by a solitary, traveling electric-field wave imposed on an ion beam. Prototype work is being carried out to demonstrate its feasibility and to understand the scaling properties to a larger device. Like the VAC, products produced in the solitron could readily be switched by changing the ion source. Eventually, the LLNL group hopes to achieve an eight-beam solitron that could separate isotopes at a substantial cost reduction over existing techniques (Schwager, 1993). The final technique discussed here, AVLIS, was developed at LLNL to provide a uranium enrichment capability for the United States. This goal has been accomplished through a large-scale demonstration project, and any future deployment of this technology for uranium production is now under the control of the newly established U.S. Enrichment Corporation. Both the technology and the $500 million prototype facility at LLNL now have the potential of being applied to production of very large quantities of other isotopes for applied and basic research (e.g., kilogram levels for lanthanides and actinides have been achieved). A wide range of elements can potentially be separated by AVLIS. The process may be capable of providing enriched stable isotopes for more than half of the elements of the periodic table, although annual operating costs for the LLNL plant might be as high as $20 million to $30 million (Stern, 1993). AVLIS achieves isotope separation by the use of intense laser beams tuned to selectively ionize specific isotopes. A two-laser system that dissociates formaldehyde in an isotopically selective manner was also described as a potential high volume system for enrichment of large quantities of carbon-13 and oxygen-18, light isotopes of particular importance to biomedical research. Such large quantities would open up new areas of research with biomedical applications. Other researchers (Stevenson et al., 1993) have recently reported on the
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observation of isotopic substitution in electron self-exchange equilibrium in chemical reactions. It has been conjectured that this may form the basis for a highly efficient, new technology for separating selected isotopes. A chemical exchange technique involving gas-liquid, liquid-liquid, and solid-liquid systems is in the research and development stage at DOE's Mound Facility in Ohio and may hold special importance for the separation of calcium isotopes (Eppley, 1993). Other work there involves a thermal diffusion approach that can be applied to both gases (e.g., xenon-124 and xenon-126) and liquids. This process is closer to the production stage and may be especially applicable to isotopes with lower masses. This brief discussion has drawn attention to new technologies that are being developed and that can be applied to the stable isotope supply question. For a new technology to achieve wide acceptance it will have to provide cost savings over present-day methods. Whether any of these new technologies will become commercially viable is uncertain. But it is absolutely clear that the United States must have a steady supply of enriched stable isotopes for both its applied and basic research programs in the biomedical and physical sciences. The support of promising technologies for stable isotope production is a critical national need, and it is appropriate that the federal government take the lead in this activity. CONCLUSIONS Enriched stable isotopes are important research and diagnostic tools, and they offer a number of unique applications. Enriched stable isotopes are critical starting materials in the production of many widely used radioisotopes. An adequate supply of enriched stable isotopes currently exists for the production of most biomedically significant radionuclides, but DOE inventory of enriched stable isotopes is being depleted through sales without replacement. The pool of isotopes formerly available only on a lease basis for nondestructive uses no longer exists. Moreover, a number of enriched stable isotopes that are crucial for research and other applications are not available or are priced beyond the means of researchers. Some research communities—for example, biological, physical, and earth sciences—frequently require only small quantities, but a great variety of enriched stable isotopes. These research isotopes are seldom viable as commercial products. Since the electromagnetic isotope separators, the calutrons, at ORNL are currently in the standby mode, U.S. production of the majority of enriched stable isotopes is at a standstill. Future separations are planned only to replace high retail volume isotopes or as specific contracts are negotiated. The use of enriched stable light isotopes—for example, carbon-13, oxygen-18, and the stable calcium isotopes—will likely increase, if they can be
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produced more cheaply and in large quantities. Research opportunities and applications will be promoted by offering greater amounts of isotopes at reduced costs. The extent of inventories in the Republics of the former Soviet Union is unknown, but they are estimated to greatly exceed the U.S. supplies for most enriched stable isotopes. New technologies that may provide more cost-effective separation methods within 3 to 5 years are being developed. RECOMMENDATIONS A dependable supply of enriched stable isotopes controlled by the United States is crucial for research, therapy, diagnosis, and other applications. In the near term this means that the electromagnetic separation capabilities of the Oak Ridge National Laboratory calutrons should be maintained in standby mode until a more cost-effective source of enriched stable isotopes can be developed, or external sources fail to meet demand. If more cost effective technology does not emerge within 5 years, subsidized operation of the calutrons should be resumed. The development of new separation technologies or improvements in existing ones, must be encouraged and supported, and the most promising of these must be evaluated for their commercial viability. This should include efforts for the efficient, cost-effective production of large amounts of enriched stable isotopes—including kilogram quantities of light isotopes. The expanded application of enriched stable isotopes into new research areas should be encouraged. A national policy of providing a subsidy for enriched stable isotopes used in small quantities for research purposes should be adopted. REFERENCES Arthur Andersen & Co. 1993. U.S. Department of Energy Isotope Production and Distribution Program Management Study. Washington, D.C. Bievre, P. D., M. Gallet, N. E. Holden, and I. L. Barnes. 1984. Isotopic Abundances and Atomic Weights of the Elements. Journal of Physical Chemistry Reference Data 13(3):809–891. Brown, R. W. 1993. Untitled presentation to the Biomedical Isotopes Committee, Institute of Medicine, National Academy of Sciences, Washington, D.C., November 19, 1993. Collins, E. D. 1993. Capabilities for Isotope Enrichment at Oak Ridge National Laboratory—Calutrons, Plasma Separation Process, Gas Centrifuges. Presentation to the Biomedical Isotopes Committee, Institute of Medicine, National Academy of Sciences, Washington, D.C., November 19, 1993. Elmore, D., M. H. Bhattacharyya, N. Sacco-Gibson, D. P. Peterson. 1990. Calcium-41 as a Long Term Biological Tracer for Bone Absorption. Nuclear Instrumentation Methods in Physics Research. B52:531–535. Eppley, R. E., 1993. EG&G Mound Applied Technologies: Chemical Exchange and Thermal Diffusion Processes. Presentation to the Biomedical Isotopes Committee, Institute of Medicine, National Academy of Sciences, Washington, D.C., November 19, 1993.
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Felton, J. S., K. W. Turteltaub, J. S. Vogel, R. Balhorn, B. L. Glendhill, J. R. Southan, M. W. Daffee, R. C. Finkel, D. E. Nelson, I. D. Proctor, J. C. Davis. 1990. Accelerator Mass Spectrometry in the Biomedical Sciences: Applications in Low Exposure and Environmental Dosimetry. Nuclear Instrumentation Methods in Physics Research. B52:517–523. Friedlander, G. and H. N. Wagner. 1982. Separated Isotopes: Vital Tools for Science and Medicine. Washington, D.C.: National Academy Press. Krishnan, K. 1993. The Vacuum Arc Centrifuge. Presentation to the Biomedical Isotopes Committee, Institute of Medicine, National Academy of Sciences, Washington, D.C. November 19, 1993. National Research Council. 1989. Diet and Health: Implications for Reducing Chronic Disease Risk. Committee on Diet and Health, Food and Nutrition Board . Washington, D.C.: National Academy Press. Schoenheimer R. S. and E. J. Rittenberg. 1935. Deuterium as an Indicator of Intermediary Metabolism. II. Methods. Journal of Biological Chemistry 111:163–192. Schwager, L. A. 1993. The Solitron. Presentation to the Biomedical Isotopes Committee, Institute of Medicine, National Academy of Sciences, Washington, D.C., November 19, 1993. Seidel, C. 1993. Untitled presentation to the Biomedical Isotopes Committee, Institute of Medicine, National Academy of Sciences, Washington, D.C., November 19, 1993. Stern, R. C. 1993. Atomic Vapor Laser Isotope Separation. Presentation to the Biomedical Isotopes Committee, Institute of Medicine, National Academy of Sciences, Washington, D.C., November 19, 1993. Stevenson, C. D., T. D. Halvorsen, D. E. Kage, R. C. Reiter, and D. J. McElheny. 1993. Free Energies of Electron Transfer from Ketyls to Isotopically Substituted Ketones. Journal of Organic Chemistry 58(17):4634–4638. U.S. General Accounting Office. 1992. DOE's Self-Supporting Isotope Program Is Experiencing Problems. GAO/RCED-92-122FS. Washington, D.C. Whitehead, R. G., and A. Prentice, eds. 1991. New Techniques in Nutrition Research. San Diego, Calif.: Academic Press.
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A view of the typical high-radiation-level hot cells at Brookhaven National Laboratory. These hot cells are utilized for the remote handling and processing of large quantities of radioactive isotopes produced at the Brookhaven Linac Isotope Producer or the High-Flux Beam Reactor at Brookhaven National Laboratory. SOURCE: Brookhaven National Laboratory.
Representative terms from entire chapter: