Isotopes for Medicine and the Life Sciences (1995)

This report has emphasized the importance of an adequate and reliable supply of stable and radioactive isotopes for biomedical and other purposes. In particular, it has focused on the 13 million diagnostic nuclear medicine procedures and the 50,000 therapeutic uses of radioisotopes in the United States each year. Current requirements and future opportunities require a stable infrastructure that will secure the chain of production from starting material to finished radio-pharmaceuticals brought to the clinic and laboratory. Such an infrastructure must include sources for enriched stable isotopes as well as reactor-produced and accelerator-produced radionuclides; it must also include related facilities and resources for research, development, and pre- and postdoctoral education and training. The report makes specific recommendations as to how these objectives should be achieved, recognizing that the goals are most likely to be met by a carefully crafted partnership among industry, universities, and the national laboratories.

To recapitulate:

1. Enriched stable isotopes are critical starting materials for the production of many radionuclides; they are also unique research and diagnostic tools in their own right. Major current sources for some of these are in Russia and other former Soviet Republics, but the reliabilities of these sources in the future are unknown. Hence, to secure a continuing and dependable supply of enriched stable isotopes, the United States should maintain the electromagnetic separation facilities (calutrons) at Oak Ridge National Laboratory in a state of readiness until they can be supplanted by new separation technologies or until substantial sales become likely because of rising foreign prices or a breakdown in the distribution of these products from Russia and the other former Soviet Republics.

2. Reactor-produced radionuclides are central to clinical practice ad biomedical research. They currently can be divided naturally into three categories:

1. molybdenum-99 for generators of technetium-99m, the workhorse of diagnostic nuclear medicine;

2. radionuclides used routinely in medicine (phosphorus-32, phosphorus-33, chromium-51, cobalt-58, cobalt-60, yttrium-90, iodine-131, xenon-133, cesium-137, iridium-192, gold-198) and in research laboratories (hydrogen-3, carbon-14, sulfur-35, phosphorus-32, phosphorus-33, iodine-125); and

3. radionuclides for research that promise to be of clinical use in the near future.

   It appears that current Canadian supplies of molybdenum-99 backed up by supplies from Western European facilities should be more than adequate to meet U.S. requirements. An additional backup source for this critical radionuclide could be from the reprocessing of spent fuel from the University of Missouri Research Reactor (MURR) and other research and test reactors.

   With the closing of many government-run reactors, it is essential that one or more reactors be maintained for isotope production and other uses as well. The research reactor at the University of Missouri is already engaged in this activity and should be supported by federal funds.

   Because reactors have finite lifetimes, the committee also recommends that plans for the Advanced Neutron Source at Oak Ridge National Laboratory include a radionuclide production capability.

3. Accelerator-produced radionuclides play an important role in current nuclear medicine practice and promise to play a greater one in the future. As with reactor-produced isotopes, these, too, can be divided into three categories:

1. Short-lived, positron-emitting radionuclides (carbon-11, nitrogen-13, oxygen-15, and fluorine-18) produced by hospital cyclotrons that are the cornerstone of current positron emission tomography (PET) activity. An important concern to PET facilities is the continued and adequate supply of stable nitrogen-15 and oxygen-18 required for the production of oxygen-15 and fluorine-18, respectively.

2. Radionuclides that are routinely used in clinical practice and that can be produced by accelerators operating at 30 million electron volts (MeV) or less (gallium-67, indium-111, iodine-123, and thallium-201). All of the major commercial radiopharmaceutical suppliers own and operate such accelerators, and they back each other up in emergencies.

3. Research radionuclides that can be produced by accelerators operating at greater than 70 MeV with appropriate beam currents. Experience has shown that radionuclides and pharmaceuticals found to be promising in research can be transferred to clinical practice only when a reliable and adequate source can be assured. For this reason the committee strongly recommends the creation of a facility dedicated to the production of ac-

celerator-produced radionuclides. The accelerator could operate at 80 MeV with 750 microams (µA) of beam current. It should be dedicated because experience has proven that isotope production facilities that are piggybacked onto those created primarily for physics research or other activities are generally not available for the year-round isotope production required for medical purposes. A dedicated facility is also not subject to the vagaries of funding that attach to a parasitic relationship and prevent long-term budget planning. In addition to the accelerator, the facility must have a staff and infrastructure capable of providing target handling, isotope separation, and packaging and shipping at high efficiency. Until the new facility is established, the needs of the community should be met temporarily by an upgraded Brookhaven Linac Isotope Producer (BLIP) supplemented by an additional processing and distribution unit and sufficient operating funds for year-round operation.

Research and training needs vital to the national program can be substantially implemented at the new accelerator facility, the National Biomedical Tracer Facility (NBTF), and the designated isotope production reactor (MURR). The research emphasis, perforce, should differ from the basic and disease-oriented research of the universities and academic health centers; rather it should focus on vital areas or critical needs in isotope technology development.

The educational programs of the accelerator and reactor production facilities should also be used to ease the current shortage of nuclear science professionals. In particular, a cadre of scientists trained in accelerator physics, nuclear engineering, and nuclear chemistry and radiopharmaceutical chemistry will be required. Because DOE has the legislative authority as well as a mandate to support education and training in the nuclear and related sciences, only commitment and the appropriate allocation of resources are needed. Forms of support should include pre- and postdoctoral fellowships, incentives for establishing new faculty positions, as well as faculty scholarships that involve collaborations with university departments of chemistry, physics, nuclear engineering, nuclear medicine, and radiopharmaceutical chemistry. The production facilities themselves should be used as training sites.

Rational planning, management, and budgeting can occur only if the various programs of isotope production (stable, reactor-produced, accelerator-produced) and associated activities in research, development, and education are well coordinated. At present, these various activities are spread throughout the DOE organization. The Isotope Production and Distribution Program (IPDP) is imbedded in the Office of Nuclear Energy; the BLIP and Los Alamos Meson Physics Facility receive much of their operations money from the Office of High Energy and Nuclear Physics in the Office of Energy Research of DOE; and the proposed NBTF effort and BLIP upgrade are projected to be funded from the Medical Application and Biophysical Research Division of the Office of Health and Envi-

ronmental Research, also in the Office of Energy Research of DOE. A coherent, rational isotope policy could best be developed and administered if the various elements can be gathered into a single office. Because the committee has suggested that the federal role in isotope production be focused on research and the needs of researchers rather than commerce, that office should be placed among the science and technology programs of DOE. Its head should report directly to the director of the Office of Energy Research, rather than, for example, the director of the Office of Nuclear Energy. Without sufficient autonomy, it is not likely to fulfill its mission or have the ability to form partnerships with private-sector industries and universities. In addition, the broad-based nature of the program suggests that it should be connected to other agencies such as the U.S. Department of Health and Human Services (especially the National Institutes of Health), the National Science Foundation, and the U.S. Department of Commerce. To expedite the coordinated development of new diagnostic and therapeutic agents, DOE representatives should meet with National Institutes of Health review committees concerned with nuclear medicine, such as the Diagnostic Radiology and Radiation Study Sections. In addition, DOE should establish a mechanism by which the National Science Foundation could keep DOE informed of the developments in physics, chemistry, and the life sciences requiring the production of new radioactive and stable isotopes.

A National Isotope Program (NIP) should have responsibility for ensuring adequate radionuclide production by charged particles and neutrons and for the production of stable isotopes. The three production capabilities do not need to be at the same location, but their activities must be well coordinated. Research, education, and training, not only at these sites but at academic and commercial grant sites throughout the nation should be integral parts of the program.

A national committee must be formed to advise the NIP director. It could well have subcommittees for the various aspects of the program. At the reactor and accelerator facilities, this national advisory committee should assist the management in choosing among applicants wishing to use the facilities or obtain their products for research. The matter of which research isotopes should be manufactured will be a central strategic issue at all locations. This NIP Advisory Committee should assist in prioritizing vital areas of critical needs in technology development, performing at the national level a function which is what a number of user organizations now perform at individual laboratories. It should also provide advice on the development and execution of the several educational programs.

1. On the basis of its congressional mandate, its historic role, and its technical expertise and resources, DOE has important roles to play in all aspects of isotope production, research, and education.

2. Although the full cost recovery provision of Public Law 101-101 has

hindered rather than helped DOE in promoting isotope research and application, the concept of centralized management is not without merit. The important research, development, and education activities associated with isotope production and distribution are, however, still spread throughout DOE.

1. A National Isotope Program, reporting directly to the director of the Office of Energy Research of DOE, should be created to consolidate the administration of all biomedical isotope-related activities: production and distribution, research and development, and education and training.

2. A national advisory committee should be formed to assist the National Isotope Program Director in prioritizing critical needs in technology development and in choosing among applicants wishing to use the reactor and accelerator isotope production facilities or obtain their products. This National Isotope Program Advisory Committee should also provide advice on the development and execution of the several educational programs associated with isotope production and use.