It is often claimed by the nuclear industries that reactor-produced radionuclides can be only made by research reactors. A closer look at the production methods, however, learns that this assertion is not tenable. This chapter discusses the production of reactor-based isotopes with particle accelerators, cyclotron-produced isotopes as an alternative for reactor-produced isotopes and other alternatives. The last paragraph highlights the advantages of cyclotrons.
The most commonly used reactor produced isotopes in medical applications are technetium-99m (99mTc)[decay product of the fission product molybdenum- 99 (99Mo)], iodine-131 (131I), phosphorus-32 (32P), chromium-51 (51Cr), strontium-89 (89Sr), samarium- 153 (153Sm), rhenium-186 (186Re) and lutetium-177 (177Lu). Therefore these radioisotopes and some other isotopes are discussed here. About 20% of medical applications use radioisotopes such as such as the cyclotron-based 201Tl, 111In, 67Ga, 123 I, 81mKr [parent isotope: 81Rb], and reactor-based 131I and 133Xe. The use of 201Tl for cardiac studies and 123 I for thyroid studies is widespread.40
4.1 Accelerator production methods for commonly used reactor-based radioisotopes
After the continued disruptions in the supply of technetium-99m and other radioisotopes in the past years, Canada commissioned a group of experts to find ways for a more secure supply of radioisotopes. This Expert Review Panel on Medical Isotope Production presented its findings at the end of November 2009. Different methods of isotopes production with accelerators, for the production of 99Mo and direct production of 99mTc, are currently being investigated in Canada. The Expert Review Panel considers direct production of 99mTc with cyclotrons as the most promising technique and recommends to support a research and development program for cyclotron-based 99mTc production. The two linear accelerator options for the production of 99mTc have limited prospects for multi-purpose use, according to the experts. Nonetheless, as a hedge against the risk of failure of other options, the panel recommends a modest R&D investment in the linac technology based on molybdenum-100 transmutation since the projected economics appear better, and it largely avoids nuclear waste management issues. In addition the panel recommends “investments in PET technology to reduce the demand for 99mTc now and over the longer term, which would reduce the impact of future shortages of reactor-produced isotopes.”
The panel’s preferred cyclotron option is based on bombarding enriched 100Mo targets with protons to produce 99mTc according to the charged particle reaction 100Mo(p,2n)99mTc. This is the only option in which 99mTc is produced directly without first generating 99Mo. The cyclotron option is considered to be the timeliest option. The panel expects that commercial production of 99mTc could begin between 2011 and 2014.41
Despite the panel’s reserved attitude regarding the use of linacs, earlier tests with the linac method they have chosen show good results. In 1998, researchers from Kharkov, Ukraine, published their results on 99Mo production by targeting 100Mo with an energetic electron beam produced by the linac according to the charged particle reaction 100Mo(γ,n)99Mo. They concluded: “[..] the proposed technique has the promise of returning very high profits in a not too-distant future.”42
Canada’s accelerator laboratory TRIUMF has formed a consortium with the Canadian medical isotope supplier MDS Nordion to study the feasibility of making 99Mo in a linear accelerator. This method include irradiating a natural uranium target by a highly intense photon beam to create 99Mo. Construction of the facility at TRIUMF is scheduled to start in 2010 with tests slated for 2013. MDS Nordion and TRIUMF already collaborate on the production of other medical isotopes using cyclotron accelerators.43
Another non-reactor method under development is the proton-driven fission neutron source for the production of fission 99Mo as proposed by IBA, a Belgian producer of cyclotrons and one of the market leaders. The IBA proposal is based on a 150 MeV, up to 2 mA cyclotron driving a sub-critical intense neutron source, generating thermal neutron fluxes similar in intensity to those of nuclear reactors used for the production of 99Mo.44 Such accelerator-driven systems (ADS) can be used in the transition to charged particle accelerator-based isotopes production. The sub-critical ADS produces less waste than critical (research) reactors. Linacs and cyclotrons, however, produce much less waste than ADS. By making a choice for non-reactor production of radioisotopes the use of ADS is temporarily needed to fill the gap in the transition to the production of medical isotopes with charged particle accelerators.
Seaborg and Jack Livingood bombarded tellurium with deuterons in the Berkeley Lab's 37-inch cyclotron, creating 131I in the 1930s. Currently most of the 131I is produced by a reactor. Just like 99Mo it is a fission product of uranium-235. In states such as India 131I is still routinely made with cyclotrons by irradiating tellurium (Te), either as metallic or tellurium dioxide (TeO2). A recent publication describes a new and simple method of separation of 131I from Te material, generating no or little amount of liquid radioactive waste as compared to the wet distillation technique where a large volume of radioactive and toxic waste generates.45 Apart from that iodine-123 (123I) appears to be a better diagnostic imaging agent than 131I for diagnosis of thyroid function.46 The cyclotron produced 123I is therefore increasingly used in thyroid therapy. Studies have shown that 99mTc is a better option than the use of 131I for the treatment of various renal disorders.47 A radiopharmaceutical of 123I has better results in therapy for relapsed neuroblastoma than 131I.48 In addition PET isotopes will replace the use of 131I more and more.
32P was one of the first radioisotopes produced with cyclotrons, before the production of reactor-produced isotopes. The 32P was prepared in substantial amounts in the cyclotron of Berkeley Laboratory by bombardment of red phosphorus with deuterons.49 Besides production with a cyclotron, it can be also produced by linacs.50
89Sr is just like 32P one of the first radioisotopes used in nuclear medicine. It was produced at the cyclotron and already in 1940 applied to cure prostate metastases in bone. It is still used in palliative therapy of bone metastases.51 A number of publications show that cyclotron-produced 89Sr can be made in large amounts with a cyclotron.52 Samarium-153 (153Sm)
153Sm can be also made with alfa-beam irradiation in a cyclotron according to the charged particle reaction 150Nd(α,n)153Sm. In a 2007 publication researchers concluded that the reaction would lead to sufficient yield of the no-carrier-added product, provided a highly enriched target is used.53
186Re is a newer product for the relief of cancer-induced bone pain and is used as an alternative for 153Sm.54 It can be also produced by a cyclotron according to the charged particle reaction 186W(p,n) 186Re. It is one of the two important therapeutic isotopes of rhenium. The advantage over 188Re is the longer half-life, the advantage over the reactor based 185Re(n,γ)186Re process is the carrier free quality. Reaction with deuteron appeared to produce higher purity of 186Re (> 99%).55 The alternative 188Re, by the way, can be also produced with cyclotrons. In the Shanghai Institute of Nuclear Research Academia Sinica, a 30 MeV proton cyclotron was imported from IBA (Belgium) in 1997 to produce among others 89Sr, 188W and 188Re.56 Tungsten-188 also serves as the parent isotope for the production of 188Re, like 99Mo is for the production of 99mTc.
192Ir, used in high-dose rate brachytherapy, can be also made with cyclotrons. In 2005 researchers produced 192Ir according to the reaction
192Os(p,n)192Ir. They concluded: “In terms of yield and purity of 192Ir the reactor method appears to be superior; the only advantage of the cyclotron method could be the higher specific activity of the product.” Two years later other researchers made 192Ir according to the reaction 192Os(d,2n)192Ir with a substantial better yield and purity.57
As noticed in Chapter 4 177Lu is projected to become as important as iodine-131 (131I), the second most used medical radioisotope. Several countries have already begun or are planning medium to large scale production of this radioisotope. Currently this β-emitter is mainly produced in a nuclear reactor in a mixed form of two different states: 177mLu and 127gLu. The first one is a long-lived radionuclidic impurity and the second one is used in radiotherapy. Deuteron irradiation on very highly enriched 176Lu target or deuteron induced reactions on 176Yb in a cyclotron is leading to a significant amounts of a very high radionuclidic purity 177gLu, not contaminated by the long-lived metastable level 177mLu.58
4.2 Cyclotron-produced isotopes as an alternative for reactor-produced isotopes
213Bi is not a necessary medical isotope. For example a recent study shows that thorium-226 (226Th), a cyclotron produced radionuclide, has a higher efficiency in overcoming chemo- and radioresistance in myeloid leukemia cells compared to 213Bi.59
51Cr is also not a necessary medical isotope. Many publications in the 1970s and 1980s show that indium-111 (111In), a cyclotron-produced isotope, is a better labeling agent for blood cells than 51Cr.60 More recent studies confirm that 111In is superior as a radiolabel for platelet scintigraphy when compared with 51Cr or 99mTc.61
133Xe is one of the fission products of a research reactor. Until the 1990s 127Xe was the preferred alternative. Except by the reactor, this isotope is produced solely by high-energy accelerators, such as the Brookhaven Linac Isotope Producer, which do not operate year round. This circumstance contributed to the decision by Mallinckrodt Medical Inc. (Covidien), the only commercial supplier in the United States, to withdraw the isotope from the market. Nowadays, 127Xe is made by a reactor. However, it isn’t necessary if a number of linacs are operating for the continue supply of these rarely used medical isotopes.62
4.3 ADS alternatives for reactor-produced isotopes
According to 2007 IAEA data “there is a large demand for yttrium-90 for radionuclide therapy and consequently there is increasing interest in the isolation and purification of the
parent radionuclide 90Sr from spent fuel.”63 There is, however, an alternative method to the fission product based on the 90Sr/90Y generator. By activating zirconium-90 (90Zr) with neutrons, generated through (p,xn) reactions during 33 MeV proton irradiation of natural tungsten or other targets, 90Y can be produced according to the 90Zr(n,p)90Y reaction or the
93Nb(n,α)90Y reaction. These methods can produce two states of 90Y: 90gY and 90mY in significant amounts. 90gY radiopharmaceuticals have been used together with 111In radiopharmaceuticals for cancer therapy and 90mY for imaging (diagnosis). 90Y radiopharmaceuticals containing 90mY could solve long-standing problems associated with the use of reactor-produced 90gY together with 111In for imaging.64
4.4 Other alternatives for reactor-produced isotopes
60Co sources provide relatively high energy gamma rays for radiotherapy which are suited for treatment of head and neck cancers and tumors like breast cancers and soft tissue sarcomas of extremities. However, they are not adequate for the treatment of other tumors and another disadvantage is that they have to be replaced within 5-7 years. Disposal of decayed source is another major concern. High energy Linacs for external radiation therapy are expensive, a 6 MV Linac, however, compares favorably in terms of costs with a Cobalt 60Co unit.65
117Lu is a rather recently introduced isotope, currently mainly produced by a nuclear reactor. The energy emitted by 177Lu, however, is comparable with the energy emitted by the cyclotron-produced scandium- 47 (47Sc). Before and during the introduction of 177Lu pharmaceuticals experts noted that similar results could be made with 47Sc. This example is illustrative for many reactor-produced isotopes. One can always find analogue cyclotron-produced isotopes, provided that there is the willingness to invest in the production of these isotopes and their medical applications.66
4.5 Advantages of the cyclotron
According to a 2007 survey of the International Atomic Energy Agency it is estimated that there are about 350 cyclotrons available with many dedicated to the production of positron emission tomography (PET) isotopes.67 In 2009, the IAEA stated: “The production capacity of radioisotopes using cyclotrons has increased. [..] In response to growing demand for fluorodeoxyglucose (FDG), tabletop cyclotrons (~7.5 MeV), [..] are under development and are expected to be adopted by major hospitals worldwide.68
The contrast between a nuclear reactor and a cyclotron is startling. Reactors are huge complex machines in running 24 hours a day, surrounded by layer upon layer of security and shutdown systems, and with radioactive waste that will last for millennia. The typical medical cyclotron is varying from tabletop format to a big metal box in a room that measures about 8 by 10 meters.
Cyclotrons have a number of advantages over nuclear reactors for radioisotope production, such as safety, cheaper operating and decommissioning costs. Because cyclotrons are powered by electricity rather than the uranium fission reaction of a nuclear reactor, they generate far less than 10% of the waste of research reactors. In addition, cyclotron-produced radwaste is far less hazardous than radwaste produced by a research reactor. All cyclotron produced radwaste, including contaminated decommissioning parts, is treated as low level radioactive waste and stored in an authorized storage area.69 In the US this waste is classified as naturally occurring and accelerator produced radioactive material (NARM).70 Finally, cyclotrons pose no risk in relation to nuclear weapons proliferation since they do not use high-enriched uranium (HEU) targets, as used in research reactors, and there is no need for controlled chain reactions producing bomb-grade nuclear material.
40 Beneficial Uses and Production of Radioisotopes, 2004 Update. NEA/IAEA Joint Publication. OECD 2005. Industrial Applications and Chemisty Section Areas of Activities in Radioisotopes and Radiation Technology, IAEA. http://www-naweb.iaea.org/napc/iachem/areas_of_activities.asp
41 Report of the Canadian Expert Review Panel on Medical Isotope Production, 30 November 2009. http://nrcan.gc.ca/eneene/sources/uranuc/pdf/panrep-rapexp-eng.pdf
42Uvarov, V.L. et al.; Electron Accelerator's Production Of Technetium-99m for Nuclear Medicine National Science Center Kharkov Institute of Physics & Technology, Kharkov, 1998, Ukraine. http://accelconf.web.cern.ch/accelconf/pac97/papers/pdf/7 P112.PDF
43 Accelerator lab targets medical isotopes, 28 April 2009: http://physicsworld.com/cws/article/news/38860
44 Cohilis, P. and Jongen, Y.; High Beam Intensities for Cyclotron-based Radioisotope Production Ion Beam Applications s.a. (IBA), Chemin du Cyclotron 3, B-1348 Louvain-la-Neuve, Belgium (paper from 1996) www.cern.ch/accelconf/e96/PAPERS/THPG/THP075G.PDF
45 Chattopadhyay, Sankha; A new method of separation of I-131 from tellurium material using a charcoal column. J Nucl Med. 2009; 50 (Supplement 2):1886 http://jnumedmtg.snmjournals.org/cgi/content/meeting_abs tract/50/2_MeetingAbstracts/1886
46 Andó, L.; Pure iodine-123 production by small cyclotron for medical use. Journal of Radioanalytical and Nuclear Chemistry. Volume 146, Number 3 / October, 1990
http://www.springerlink.com/content/u061101072522wx0/Mandel, S.J. et al.; Superiority of iodine-123 compared with iodine-131 scanning for thyroid remnants in patients with differentiated thyroid cancer. Clin Nucl Med. 2001 Jan;26(1):6-9. http://www.ncbi.nlm.nih.gov/pubmed/11139058 Urhan, M.; Iodine-123 as a diagnostic imaging agent in differentiated thyroid carcinoma: a comparison with iodine-131 post-treatment scanning and serum thyroglobulin measurement. Eur J Nucl Med Mol Imaging - 01-JUL-2007; 34(7): 1012-7
http://www.mdconsult.com/das/citation/body/170946602- 2/jorg=journal&source=MI&sp=19963034&sid=0/N/1996 3034/1.html?issn=
47 Kabasakal, L.; Clinical comparison of Technetium- 99m-EC, Technetium-99m-MAG3 and iodine-131-OIH in renal disorders. The Journal of nuclear medicine. 1995, vol. 36, no2, pp. 224-228 (32 ref.)
48 Taggart, Denah R. et al; Comparison of Iodine-123 Metaiodobenzylguanidine (MIBG) Scan and
[18F]Fluorodeoxyglucose Positron Emission Tomography to Evaluate Response After Iodine-131 MIBG Therapy for Relapsed Neuroblastoma. Journal of Clinical Oncology, Vol 27, No 32 (November 10), 2009: pp. 5343-5349 Veenendaal, Liesbeth M. et al.; Liver metastases of neuroendocrine tumours; early reduction of tumour load to improve life expectancy. World Journal of Surgical Oncology 2006, 4:35
49 Cohn, Waldo E.; The Early Use of Artificial Radioactive Isotopes. J. Biol. Chem. 123, 185–198 (1938) www.jbc.org/content/277/45/e33.full.pdf
50 Proceedings of EPAC 2000, Vienna, Austria: Linear Electron Accelerator For the Medical Isotopes Production. Kharkov 2 GeV Linac Team, Kharkov, Ukraine accelconf.web.cern.ch/AccelConf/e00/PAPERS/WEP2B1 2.pdf
51 Adloff, P. et al.; One Hundred Years after the Discovery of Radioactivity. R. Oldenbourg Verlag, München, 1996. p.250 Nair, Narendra; Relative Efficacy of 32Pand 89Sr in Palliation in Skeletal Metastases. The Journal Of Nuclear Medicine Vol. 40 No. 2 February 1999. http://jnm.snmjournals.org/cgi/reprint/40/2/256.pdf
52 Petrusenko, Yu.T. et al.; Analysis Of Data Arrays On Cyclotron Production Of Medical Radioisotopes. Problems OF Atomic Science Aan Technology, 2009. Series: Nuclear Physics Investigations (51), p.82-88. http://vant.kipt.kharkov.ua/ARTICLE/VANT_2009_3/arti cle_2009_3_82.pdf Yuzheng Lin; Applications Of Low Energy Accelerators In China. Tsinghua University, Beijing, 100084, China. Proceedings of the Second Asian Particle Accelerator Conference, Beijing, China, 2001 http://epaper.kek.jp/a01/PDF/FRAM01.pdf
53 Spahn, I.et al.; New nuclear data for production of 73As, 88Y and 153Sm: important radionuclides for environmental and medical applications. International Conference on Nuclear Data for Science and Technology 2007. nd2007.edpsciences.org/articles/ndata/pdf/2007/01/ndata0 7351.pdf
54 Radioisotopes in Medicine. Nuclear Issues Briefing Paper 26, May 2004. albert-cordova.com/ans/medical-radiso.pdf
55 Persico, Dr. Elisa; Cyclotron Production of rhenium-186 for metabolic radiotherapy, by proton and deuteron cyclotron irradiation. wwwgir.mi.infn.it/Presentazioni/riassunto_tesi_persico.pdf Beyer, Gerd-Jürgen; Radioisotopes in Medicine: The potential of accelerators. Cyclotron Unit University Hospital of Geneva, Switzerland; PowerPoint presentation XXXV European Cyclotron Progress Meeting, Nice, France, 1-4 November 2006. www.aima.fr/ecpm2006/talks/Beyer_ECPM06.ppt Solin, L.; Cyclotron Yields of Rhenium-186. 5th International Conference on Isotopes, Brussels, 25-29 April, 2005. http://citeseerx.ist.psu.edu/viewdoc/download;jsessionid=4 ABFA45B1F2A9D04A9D4CC40482380CD?doi=10.1.1.9 6.2868&rep=rep1&type=pdf
56 Lin, Yuzheng (Tsinghua University, Beijing, China); Applications of Low Energy Accelerators in China. Proceedings of the Second Asian Particle Accelerator Conference, Beijing, 2001cern.ch/AccelConf/a01/PDF/FRAM01.pdf
57 Tárkányia, F. et al.; Study of the 192Os(d,2n) reaction for production of the therapeutic radionuclide 192Ir in no-carrier added form. Applied Radiation and Isotopes Volume 65, Issue 11, November 2007, Pages 1215-1220. Hermanne, A.; Production of medically relevant radionuclides with medium energy deuterons (paper). International Conference on Nuclear Data for Science and Technology 2007.
58 Bonardi, M.L.; Deuteron cyclotron production of high specific activity NCA Lu-117g for metabolic radiotherapy, as a competitive method to neutron activation in nuclear reactor. (paper) NRC7 - Seventh International Conference On Nuclear And Radiochemistry. Budapest, Hungary 24- 29 August 2008 http://www.nrc7.mke.org.hu/pdf/presentations/abstract249. pdf Hermanne, A. et al.; Deuteron-induced reactions on Yb: Measured cross sections and rationale for production pathways of carrier-free, medically relevant radionuclides. Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms Volume 247, Issue 2, June 2006, pp. 223-231.
59 Friesen,C. et al.; Radioimmunotherapy Using Anti-CD33 Antibodies Radiolabeled With Thorium-226 Or Bismuth-213 Overcome Chemo- And Radioresistance In Myeloid Leukemia Cells. Haematologica 2009;
94[suppl.2]:329 abs. 0816
60 Palestine, Alan G. et al; Lymphocyte Migration in the Adoptive Transfer of EAU. Investigative Ophtalmology & Visual Science. Vol. 27. April 1986. p.614
61 Kinuya, Keiko et al.; Scintigraphic prediction of therapeutic outcomes of splenectomy in patients with thrombocytopenia. Annals of Nuclear Medicine Vol. 17, No. 2, 161–164, 2003. p.163
62 The Journal of Nuclear Medicine Vol. 33 No. 2 February 1992
63 Nuclear Technology Review 2007, International Atomic Energy Agency, Vienna, 2007. p.29
64 Necsoiu, D. et al.; Monte Carlo simulations and experimental studies of yttrium-90 production using a 33 MeV linac. Applied Radiation and Isotopes Volume 57, Issue 4, October 2002, Pages 509-515 Nagia, Yasuki; Production of an Isomeric State of 90Y by Fast Neutrons for Nuclear Diagnostics. Journal of the Physical Society of Japan 78(11), p.113201_1-
113201_4(2009); (JAEA-J 06647).
65 Reddy, K.S.; Choice of a Teletherapy Unit: Cobalt-60 vs Linear Accelerator - 50 Years of Cancer Control in India, 1997. mohfw.nic.in/pg87to95.pdf
66 Haddad, Ferid; ARRONAX, a high-energy and high-intensity cyclotron for nuclear medicine. European Journal of Nuclear Medicine and Molecular Imaging; 1619-7070 (Print) 1619-7089 (Online), Volume 35, Number 7. Springer Berlin / Heidelberg, July 2008 Grignon, C.; Nuclear medical imaging using β+γ coincidences from 44Sc radio-nuclide with liquid xenon as detection medium. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment. Volume 571, Issues 1-2, 1 February 2007, Pages 142-145. Proceedings of the 1st International Conference on Molecular Imaging Technology - EuroMedIm 2006 www-subatech.in2p3.fr/~incade/LXePET_ARRONAX_ISC.pdf Majkowska, Agnieszka et al.; Complexes of low energy beta emitters 47Sc and 177Lu with zoledronic acid for bone pain therapy. Applied Radiation and Isotopes, Volume 67, Issue 1, January 2009, Pages 11-13 linkinghub.elsevier.com/retrieve/pii/S0969804308004363
67 Nuclear Technology Review 2007, IAEA p29
68 Nuclear Technology Review 2009, IAEA p43
69 Calandrino, R.; Decommissioning procedures for an 11 MeV self-shielded medical cyclotron after 16 years of working time. Health physics vol. 90, no6, 2006 pp. 588-596
http://cat.inist.fr/?aModele=afficheN&cpsidt=17787604 Green, Jim; WISE News Communique 16 Feb 2001: Australians battle nuclear reactor plan.
70 Federal Register (Volume 72, Number 189), 1 Oct. 2007: NRC Publishes Requirements for Expanded Definition of Byproduct Material - Final NARM Rule. http://www.snm.org/index.cfm?PageID=6836&RPID=277 &Archive=1