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Medical Isotope Production without Highly Enriched Uranium MEDICAL ISOTOPE PRODUCTION WITHOUT HIGHLY ENRICHED URANIUM Committee on Medical Isotope Production Without Highly Enriched Uranium Nuclear and Radiation Studies Board Division of Earth and Life Studies NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu
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Medical Isotope Production without Highly Enriched Uranium THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This study was supported by Contract/Grant No. DE-AM01-04PI45013 between the National Academy of Sciences and the U.S. Department of Energy. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the views of the organizations or agencies that provided support for the project. International Standard Book Number-13: 978-0-309-13039-4 International Standard Book Number-10: 0-309-13039-5 Cover: Image generated from a brain perfusion scan using technetium-99m (courtesy of Satoshi Minoshima, University of Washington). Overlay: Photograph of the University of Missouri Research Reactor (MURR) core (courtesy of the University of Missouri). Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. Copyright 2009 by the National Academy of Sciences. All rights reserved. Printed in the United States of America
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Medical Isotope Production without Highly Enriched Uranium THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and Medicine The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org
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Medical Isotope Production without Highly Enriched Uranium COMMITTEE ON MEDICAL ISOTOPE PRODUCTION WITHOUT HIGHLY ENRICHED URANIUM CHRIS WHIPPLE (Chair), ENVIRON International Corporation, Emeryville, California STEVE M. LARSON (Vice Chair), Memorial Sloan-Kettering Cancer Center, New York, New York CYNTHIA ATKINS-DUFFIN, Lawrence Livermore National Laboratory, Livermore, California ANTHONY E. BOARDMAN, University of British Columbia, Vancouver D. JEFFREY BOSTOCK, Lockheed Martin Energy Systems (retired), Seabrook Island, South Carolina G. BRIAN ESTES, U.S. Navy (retired), Williamsburg, Virginia MILTON LEVENSON, Bechtel International (retired vice president), Menlo Park, California IRVIN W. OSBORNE-LEE, Prairie View A&M University, Prairie View, Texas EUGENE J. PETERSON, Los Alamos National Laboratory, Los Alamos, New Mexico RICHARD C. REBA, Georgetown University, Washington, DC, and the National Institutes of Health, Bethesda, Maryland IAIN G. RITCHIE, International Atomic Energy Agency (retired), Victoria, British Columbia THOMAS J. RUTH, TRI-University Meson Facility, Vancouver, British Columbia JASMINA VUJIC, University of California, Berkeley RAYMOND G. WYMER, Oak Ridge National Laboratory (retired), Oak Ridge, Tennessee Staff KEVIN D. CROWLEY, Study Director NAOKO ISHIBE, Program Officer DANIELA STRICKLIN, Program Officer COURTNEY GIBBS, Senior Program Assistant SHAUNTEÉ WHETSTONE, Senior Program Assistant
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Medical Isotope Production without Highly Enriched Uranium NUCLEAR AND RADIATION STUDIES BOARD RICHARD A. MESERVE (Chair), Carnegie Institution, Washington, DC S. JAMES ADELSTEIN (Vice Chair), Harvard Medical School, Boston, Massachusetts JOONHONG AHN, University of California, Berkeley JOEL S. BEDFORD, Colorado State University, Fort Collins SUE B. CLARK, Washington State University, Pullman ALLEN G. CROFF, Oak Ridge National Laboratory (retired), St. Augustine, Florida PATRICIA J. CULLIGAN, Columbia University, New York, New York SARAH C. DARBY, Clinical Trial Service Unit, Oxford, United Kingdom JAY DAVIS, Lawrence Livermore National Laboratory (retired), Livermore, California ROGER L. HAGENGRUBER, University of New Mexico, Albuquerque DAVID G. HOEL, Medical University of South Carolina, Charleston HEDVIG HRICAK, Memorial Sloan-Kettering Cancer Center, New York, New York THOMAS H. ISAACS, Lawrence Livermore National Laboratory, Livermore, California PAUL A. LOCKE, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland BORIS F. MYASOEDOV, Russian Academy of Sciences, Moscow JOHN C. VILLFORTH, Food and Drug Law Institute (retired), Gaithersburg, Maryland RAYMOND G. WYMER, Oak Ridge National Laboratory (retired), Oak Ridge, Tennessee PAUL L. ZIEMER, Purdue University (retired), West Lafayette, Indiana Staff KEVIN D. CROWLEY, Director MICAH D. LOWENTHAL, Senior Program Officer JOHN R. WILEY, Senior Program Officer DANIELA STRICKLIN, Program Officer TONI GREENLEAF, Administrative and Financial Associate LAURA D. LLANOS, Administrative and Financial Associate MANDI M. BOYKIN, Senior Program Assistant SHAUNTEÉ WHETSTONE, Senior Program Assistant JAMES YATES, JR., Office Assistant
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Medical Isotope Production without Highly Enriched Uranium Preface This study was motivated by a conflict between the nonproliferation objectives of the Energy Policy Act of 1992, which created increasing pressures to phase out U.S. exports of highly enriched uranium (HEU) for medical isotope production, and the Energy Policy Act of 2005, which sought to increase the reliability of medical isotope supply by lifting the requirements of the 1992 Act for HEU exports to Canada, the Netherlands, Belgium, France, and Germany for medical isotope production.1 At no time during the study were these dual objectives of securing HEU and providing a reliable supply of medical isotopes questioned by the committee—both objectives are obviously important. The question we pursued was the feasibility of achieving both. All of the U.S. supply of the most widely used medical isotope, technetium-99m (Tc-99m), is produced by irradiating HEU targets in a reactor, extracting molybdenum-99 (Mo-99) from the targets, and collecting the Tc-99m that is produced when Mo-99 decays. No Mo-99 is currently produced domestically for medical use. The two main sources of Mo-99 for use in the United States are the National Research Universal (NRU) Reactor operated by Atomic Energy of Canada, Ltd. (AECL) at its Chalk River, Ontario, site and the High Flux Reactor (HFR) operated by the Nuclear Research and Consultancy Group at the Petten, Netherlands, site. Both reactors are over 40 years old. 1 See Sidebar 1.3 for a discussion of these congressional amendments.
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Medical Isotope Production without Highly Enriched Uranium The Committee was tasked with evaluating the feasibility of converting medical isotope production of Mo-99 from HEU to low enriched uranium (LEU). For reasons discussed in Chapter 3, the report focuses on the feasibility of producing Mo-99 with LEU. In Section 630 of the Energy Policy Act of 2005, Congress defines feasibility to include consideration of cost, specifically, that “the average anticipated total cost increase from production of medical isotopes in such facilities without use of highly enriched uranium is less than 10 percent.” That Mo-99 can be produced in a reactor without using HEU is not in doubt; Argentina has been producing Mo-99 with an all-LEU system since 2002. An Argentine-designed and built reactor near Sydney, Australia, will likely produce Mo-99 with LEU fuel and targets in the near future, and an Argentine company is completing construction of a Mo-99 processing facility at an all-LEU reactor near Cairo, Egypt. As the committee began to assess the technology of isotope production and the system of production and distribution, it quickly came to understand that the system that supplies and distributes medical isotopes involves more than just cost considerations. We found that the medical community that uses Tc-99m and the industry that provides it greatly value the reliability of supply. During the study, there were three significant medical isotope outages in the United States and one currently ongoing in Europe. The first, from November 2005 through April 2006, was the result of a Tc-99m generator supply disruption when a U.S.-based technetium generator producer, Mallinckrodt, shut down production because of a product recall. The second outage was the result of a safety-related shutdown of the NRU Reactor in Canada that began in late November 2007 and lasted about a month. The third outage was the result of the shutdown of HFR in the Netherlands that began in August 2008 and is expected to last through the middle of February 2009. At about the same time, a Mo-99 processing facility in Belgium was also shut down after radioactive iodine was inadvertently vented to the environment. The global production of Mo-99 was inadequate to meet demand during these outages, and some hospitals and clinics were forced to postpone or cancel diagnostic imaging procedures. At the time of our study’s first meeting in February 2007, AECL was working to complete two new reactors, Maple I and Maple II, which were to be dedicated to medical isotope production, and a new Mo-99 processing facility. The reactors and their associated processing facilities would have had the capacity to supply essentially all of the Mo-99 needed to meet worldwide demand if necessary and would have provided redundancy to ensure reliability. However, for reasons described in Chapter 10, AECL discontinued work on the Maple reactors in May 2008. Planning is underway in Europe for a replacement for HFR in the Netherlands, but construction has not begun. Construction of a new
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Medical Isotope Production without Highly Enriched Uranium research reactor, the Jules Horowitz, has just begun in France, and it is scheduled to begin operation in 2014. As discussed in Chapter 3, other supplies could come online that could contribute to U.S. Mo-99 supply, including supplies from domestic producers. The supply of Mo-99 in the United States is likely to be unreliable until newer production sources come online. The reliability of the current supply system is an important medical isotope concern; as noted in Chapter 10, the committee has concluded that achieving a cost difference of less than 10 percent in facilities that will need to convert from HEU- to LEU-based Mo-99 production is much less important than is reliability of supply. Chris Whipple, Chair Steve Larson, Vice Chair
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Medical Isotope Production without Highly Enriched Uranium Acknowledgments At the start of this study, the committee had much to learn about all aspects of the radiopharmaceutical market, including the technologies involved in radiopharmaceutical production, distribution, medical application, and regulation. The cooperation we received from radioisotope producers and associated organizations was complicated by their responsibilities to protect proprietary technologies and business plans. Despite this complication, the information and cooperation that the committee received from these organizations was critical to the success of this study. This report could not have been written without the support of the people listed below who made presentations to the committee and/or met with small groups of committee members during site visits. The committee acknowledges the excellent support it received from the project sponsor, the U.S. Department of Energy, National Nuclear Security Administration. The committee is especially grateful for the support it received from Andrew Bieniawski, Nicole Nelson-Jean, Parrish Staples, and Edward Fei. The committee gratefully acknowledges the following people who made presentations at its information-gathering sessions: Henri Bonet, Institut National des Radioéléments (IRE) Roy Brown, Council on Radionuclides and Radiopharmaceuticals (CORAR) Ralph Butler, Missouri University Research Reactor (MURR) Jack Coffey, Cardinal Health
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Medical Isotope Production without Highly Enriched Uranium Pablo Cristini, Comisión Nactional de Energía Atómica (CNEA) Stephen Dembek, U.S. Nuclear Regulatory Commission Therese Donlevy, Australian Nuclear Science and Technology Organization (ANSTO) Edward Fei, U.S. Department of Energy, National Nuclear Security Administration (DOE-NNSA) Ira Goldman, International Atomic Energy Agency (IAEA) Ed Lyman, Union of Concerned Scientists Peter Lyons, U.S. Nuclear Regulatory Commission Grant Malkoske, MDS-Nordion Brian McGee, Atomic Energy of Canada Limited (AECL) Nicole Nelson-Jean, DOE-NNSA Adrian Nunn, Bracco Research Evans Reynolds, Babcock & Wilcox (B&W) Richard Roberts, Mallinckrodt Marcelo Salvatore, Investigaciones Aplicadas Sociedad del Estado (INVAP) Dale Simpson, Mallinckrodt Parrish Staples, DOE-NNSA Orhan Suleiman, U.S. Food and Drug Administration George Vandegrift, Argonne National Laboratory Frank von Hippel, Princeton University Small groups of committee members visited several facilities during this study to obtain first-hand information about the medical isotope production process (see Appendix C). We gratefully acknowledge the following organizations and individuals for supporting these visits: AECL Chalk River Laboratories (Chalk River, Ontario, Canada), Brian McGee ANSTO (Lucas Heights, Australia), Ian Smith and Ian Turner CNEA and INVAP (Buenos Aires, Argentina), Gabriel Norberto Barcelo, National Atomic Energy Commission, Pablo Cristini, CNEA, and Juan José Gil Gerbino, Marcelo Salvatore and Daniel Amaya, INVAP Compagnie pour l’ Etude et la Réalisation de Combustibles Atomiques (CERCA; Romans, France), Henri Sztark and Laurent Hallé High Flux Reactor (Petten, the Netherlands), Rob Stol and Fred Wjitsma, Nuclear Research and Consultancy Group IRE (Fleurus, Belgium), Henri Bonet Mallinckrodt (Maryland Heights, MO, and Petten, the Netherlands), Dale Simpson
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Medical Isotope Production without Highly Enriched Uranium MDS Nordion (Ottawa, Ontario, Canada), Grant Malkoske. Mr. Malkoske retired toward the end of the study; the committee’s point of contact after his retirement was Jill Chitra MURR (Columbia, MO), Ralph Butler and Charlie Allen The committee is also grateful for the excellent assistance provided by the National Research Council staff in preparing this report. Staff members who contributed to this effort are Kevin Crowley, study director and director of the Nuclear and Radiation Studies Board, Naoko Ishibe (program officer), Daniela Stricklin (program officer), Courtney Gibbs (senior program assistant), and Shaunteé Whetstone (senior program assistant). The expertise needed to cover the areas within our scope was remarkably broad, and the committee membership reflected this diversity. The expertise of the committee members included nuclear medicine, radiopharmaceutical production, nuclear reactor design and operations, fabrication and chemical processing of uranium targets, waste management, nuclear nonproliferation, security for facilities with highly enriched uranium, economics, construction management, and risk assessment. A consequence of such diversity is that the study was an excellent learning experience for all involved. I thank the members of the committee for their dedicated efforts throughout the development of this report. Chris Whipple, Chair
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Medical Isotope Production without Highly Enriched Uranium Reviewers This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making the published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The content of the review comments and draft manuscript remains confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their participation in the review of this report: Mr. Pablo Adelfang, International Atomic Energy Agency Dr. Jim Adelstein, Harvard Medical School Dr. Carolyn Anderson, Washington University Dr. Frank Bengel, Johns Hopkins School of Medicine Dr. Sue Clark, Washington State University Mr. Allen Croff, Oak Ridge National Laboratory (retired) Dr. Jay Davis, Lawrence Livermore National Laboratory (retired) Dr. Chris T. Hendrickson, Carnegie Mellon University Dr. Kevin Kao, Buddhist Tzu Chi General Hospital Dr. Alan Packard, Children’s Hospital Boston Dr. Geoffrey Rothwell, Stanford University Dr. A.A. Sameh, Consultant
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Medical Isotope Production without Highly Enriched Uranium Dr. Armando Travelli, Argonne National Laboratory (retired) Dr. Frank von Hippel, Princeton University Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by Dr. Harold Forsen, Bechtel Corporation, and Dr. John Bailar, University of Chicago. Appointed by the National Research Council, they were responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the National Research Council.
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Medical Isotope Production without Highly Enriched Uranium Contents Summary 1 1 Background and Study Task 7 2 Molybdenum-99/Technetium-99m Production and Use 16 3 Molybdenum-99/Technetium-99m Supply 31 4 Molybdenum-99/Technetium-99m Supply Reliability 55 5 Molybdenum-99/Technetium-99m Demand 66 6 Molybdenum-99/Technetium-99m Production Costs 80 7 Conversion to LEU-Based Production of Molybdenum-99: Technical Considerations 90 8 Conversion to LEU-Based Production of Molybdenum-99: Regulatory Considerations 101 9 Conversion to LEU-Based Production of Molybdenum-99: General Approaches and Timing 108
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Medical Isotope Production without Highly Enriched Uranium 10 Conversion to LEU-Based Production of Molybdenum-99: Prospects and Feasibility 114 11 Progress in Eliminating HEU Use 142 References 163 Appendixes A Section 630 of the Energy Policy Act of 2005 169 B Biographical Sketches of Committee Members 173 C Presentations and Visits 181 D Alternative Molybdenum-99 Production Processes 184 E Correspondence with Atomic Energy of Canada Limited 190 F Present Value Calculation 194 G Glossary 196 H Acronyms 200