The Medical Isotope Shortage

Thomas J. Ruth

With the most recent shut down of the NRU reactor in Chalk River, Canada, the supply of medical isotopes has dwindled to the point that it is impacting medical diagnoses worldwide.  How did we reach a situation  with supply  so fragile and  prospects for solutions so bleak? As with most stories the answer is complex and convoluted. In some respects the medical isotopes community is a victim of its own success.

Technetium-99m is the most widely used radionuclide in diagnostic medicine. Its use for imaging human disease has its roots in the US Atomic Energy Commission, the predecessor of today’s Department of Energy. Research at Brookhaven National Laboratory in the early 1960s resulted in the development of the generator for producing Tc-99m.

The parent element, molybdenum-99, can be produced through a number of nuclear reactions, but the fission of ²³⁵U with thermal neutrons provides for the most efficient, high-yield product with very high specific activity. Six per cent of the fission process results in the production of Mo-99.

After it is produced,  Mo-99  is sequestered on an inert column matrix to which the decay product, Tc-99m, is loosely bound and can be washed off with saline. With half-lives of 66 hours and 6 hours, respectively, the ⁹⁹Mo/⁹⁹mTc pair can be separated repeatedly over a week, with the Tc-99m fraction growing due to radioactive decay of the parent after each separation. Tc-99m is subsequently used for imaging studies such as bone scans or cardiac profusion. These scans are made possible by bonding the Tc-99m to an appropriate radiopharmaceutical that has the in vivo biological activity to be monitored. The gamma camera found in nearly every nuclear medicine department around the world has been designed for high efficiency for the 140 keV gamma ray emissions from the decay of Tc-99m to its ground state. Thus for more than 40 years Tc-99m has been the primary radionuclide used in nuclear medicine. Figure 1 shows a whole-body Tc-99m-based bone scan.

Currently, the world depends on five ageing research reactors that are located in Canada, The Netherlands, Belgium, France and South Africa.  The National Research Universal (NRU) reactor in Canada  and the High Flux Reactor (HFR) in The Netherlands together supply approximately 80% of the world’s Mo-99. The US uses approximately 50% of the world’s Mo-99 and gets 60% from the NRU and the remainder from the HFR. The other 3 reactors supply Europe and parts of Asia. They also serve as backups for when one of the major producers are off-line for maintenance.

The worldwide sales of generators are on the order of $300 million per year. Since these generators account for multiple studies using Tc-99m radiopharmaceuticals costing a few hundred dollars each, the Tc-99m business accounts for hundreds of billions of dollars annually.

In the mid 1990’s MDS Nordion (Ottawa, Canada) commissioned Atomic Energy of Canada Limited (AECL) to build two reactors, to be called Maple 1 and Maple 2, dedicated to the production of Mo-99. Each of these reactors  was to have the capacity to meet the world’s Mo-99 needs,  so that each would serve as a backup for  the other. With the prospect of the Maple reactors coming on line in early 2000, the community felt there was no need for additional supplies of Mo-99 and projects to have a US source through work at Los Alamos and then at Sandia National Labs never came to fruition. This has proven to be a serious mistake.  After technical problems caused delay after delay  and the Canadian Nuclear Safety Commission (CNSC) denied a license to operate the Maple reactors due to a positive reactivity coefficient, AECL suddenly cancelled the Maple Project in May 2008.

All of the today’s existing production reactors are 40 or more years old, and while they can have extended lives, there will inevitably be problems due to age.  In fact the problems that both the NRU and HFR reactors have had are not associated with the reactors themselves but in the infrastructure: leaking containment vessels and leaking pipes buried deep in shielding walls. Such problems are difficult to isolate and solve, resulting in prolonged shutdowns. These shutdowns cause major disruptions in the supply chain because the short half life of Mo-99 makes it impossible to stock for more than a few days. The smaller reactor operations can increase capacity somewhat but none of the other reactors has the capacity of the NRU or HFR.

The severity of this decision has become apparent through a series of unexpected shutdowns of the primary reactors producing Mo-99. The first was in the Fall of 2007 when the NRU was off line for maintenance and the regulator, CNSC, denied permission to restart due to a dispute over the installation of a backup emergency pump system. This shut down caused a shortage of Mo-99 that was felt world wide and the Canadian Government intervened to order the reactor restarted. Then in the Spring of 2008 a leak in one of the cooling systems was found in the HFR reactor in The Netherlands. This resulted in a two month shutdown for repairs, again causing a shortage. There were also a number of disruptions caused by a lack of coordination of the other producers having maintenance periods that overlapped. The next major problem occurred in May 2009 when a leak in the containment vessel of the NRU was discovered. At the time of the discovery the AECL stated that the NRU would be down for 3 months to access the extent of the leak and repair the vessel. Two months later the down time was revised to the end of the calendar year 2009. There are concerns within the community that it may never be put into operation again.

With the NRU shut down that left the remaining reactors to try and fill the gap; however the capacity is not there and thus the patient community has been severely affected by these shortages. Many procedures have been delayed or cancelled. While there are some alternatives such as using PET scanning or CT scanning with contrast agents, these measures cannot match the demand.

To compound the situation further, the HFR will be off line for at least a month during the August/September 2009 period. In addition, the HFR is due for a major maintenance period lasting six months in early 2010.

What alternatives exist?

There are two reactors proposed or being built in Europe. The Jules Horowitz multipurpose reactor (France) is due to come on line by 2015 and the replacement of the HFR, the PALLAS reactor, has yet to sited. The Missouri University Research Reactor (MURR) and the McMaster University reactor in Hamilton, Ontario, are probably the only reactors in North America that can be used to lessen the crisis. However, both are using highly enriched uranium (HEU) cores and have not been converted to use low enriched uranium (LEU) targets, compounding the problems associated with using them. Also, both are more than 40 years old. The problem with HEU is that it is weapons grade uranium and represents a major security issue. The US National Nuclear Safety Administration and the IAEA have been working for decades to remove HEU from civilian use.

There are plans to convert the MURR reactor to use LEU targets and build processing facilities to handle Mo-99 production, both of which will take approximately five years. Upgrades of MURR and the McMaster reactor have been proposed and each has received some funding to proceed. Does the push for LEU get put on the back burner until the crisis period is over, or do these reactors hold sufficient promise so that they should be converted to Mo-99 production in the process of upgrading them?  This is a political question yet to be determined.

The Australian OPAL reactor is supposed to come on line later in 2009 and there is growing pressure to fast track the approval process for it. However it is not clear whether it can provide more than 10% of the US needs. Babcock and Wilcox is planning to build a reactor where fission of U-235 in solution will continuously produce Mo-99 which can be periodically extracted as needed during the production cycle. This approach represents an interesting concept but it is not clear how difficult it will be to engineer and how much can be expected to be promised in a single reactor. This proposed reactor being built in Lynchburg, Virginia probably will not be available for at least 5 years.

There have been discussions about operating the Maple reactors at lower power to mitigate the safety issues while still producing some Mo-99. While this may be worth considering, it does not address the HEU target problem. One possibility is that one could operate one reactor while the other is modified to deal with LEU targets.

The recent announcement in the Canadian press (CBC.CA) from the Canadian government that they were getting out of the “isotope” business caught the world by surprise. This statement basically indicated that the government would no long subsidize production of Mo-99.  All of the present producers are located at government facilities. The infrastructure thus provided represents a significant subsidy. The Canadian government has assured the world that they will proceed with the repair of the NRU reactor and keep it in operation through the expected expiration of its safety license in 2016. However with the recent announcement that the NRU will not restart before the end of 2009 there is growing concern that it may never operate again.

Where do we go from here?

The alternatives are somewhat limited in the near term, while the mid- to long-term allows other options. But for these to have a chance of making an impact on the Mo-99 supply, decisions will have to be made very soon.

If there are no reactor-based solutions in the near term, can accelerators be used to help in this problem? While the idea of using high-energy accelerators to recreate neutrons through spallation has been proposed a number of times, such an approach cannot compete with reactors for efficiency of neutron production. [Spallation involves the collision of high energy projectiles with the target nuclei with enough energy (>200 MeV, 1mA) to produce a very large array of products.] There has also been discussion of using a spallation device to generate neutrons for direct fission of U-235 in a blanket surrounding the spallation target.

 What are the possibilities of using low energy cyclotrons? Takács et al (2002, 2003) explored the production of Mo-99 from the ¹⁰⁰Mo(p,pn)⁹⁹Mo reaction. However the production cross section for Mo-99 from proton reactions is too low to be of practical use. Their results indicated a thick target yield (40-45 MeV) of 3.8 mCi/μAh. The daily production for a cyclotron operating at 500 mA would be about 50 Ci; at this rate about 100 cyclotrons would be required to meet US demand for Mo-99. The other approach would be the direct spallation of a target to produce Mo-99. The production rate of Mo-99 from most reasonable target materials would be at best many orders of magnitude lower than the reactor methods and two orders of magnitude lower than the above accelerator reaction and thus not a viable approach.

The other reaction that has been explored is the direct production of Tc-99m from the ¹⁰⁰Mo(p,2n)⁹⁹mTc. The biggest disadvantage with this approach is that the final product (the one used in nuclear medicine procedures) is directly produced and has a short half life (6 hours). Thus, its usefulness will be greatly hampered if it needed to be shipped great distances to the end users. Even a network of suppliers would face a challenge. Takács, et al. report that the cross section for the direct production of Tc-99m from enriched Mo-100 would be approximately 17 mCi/μAh. At this level even with a very high beam-current facility (500μA protons) and irradiation periods of a day (i.e., 24 hours), the most that could be produced in a single facility would be < 200 Ci per day. Meeting US needs would require more than 25 cyclotrons dedicated to this process, not accounting for the losses associated with transport and chemical efficiencies for separating the Tc-99m from the target matrix. A single site might be able to become self sufficient but this would not help the larger community.

TRIUMF, Canada’s National Laboratory for Nuclear and Particle Physics, has proposed the use of photo-fission of U-238 for the production of Mo-99. It turns out that the fission yield distribution for on U-238 is almost identical to that of (n,f) on U-235. However, the photon process is several orders of magnitude less efficient and would necessitate a very high photon flux. To generate such a high flux TRIUMF is proposing the use of a very high power (5 MW) electron linear accelerator. A workshop in the Fall of 2008 concluded that this approach held promise with the biggest outstanding issue being the converter required to produce the photons from the electron beam. With this approach, the product is identical to that produced in the present reactors and the HEU/ LEU issue is not a factor—both strong pluses. The downside is that even at 5 MW there would have to be several machines to meet US demand. TRIUMF is proposing to perform the demonstration experiment and to let market forces decide if this is a viable solution. With the recent announcement of funding for the e-linac (summer 2009) a demonstration is possible by 2012.

Concluding Remarks

This medical crisis is clearly a mix of technical and political issues. From this analysis, it appears that there are few viable alternative approaches to the supply of Mo-99 or Tc-99m for widespread distribution.

In the meantime, production of research radionuclides has been transferred within the DOE from the Nuclear Energy program to the Nuclear Physics (NP) program. As part of that process NP organized a workshop and assembled an Advisory committee to help them outline a path forward. Obviously the Mo-99 was the elephant in the room because of its overriding consequences to the field of Nuclear Medicine. While no part of the charge to the committee dealt with options for producing Mo-99, the discussions for producing research radionuclides often included possible solutions for Mo-99 including some of the approaches discussed here. The report from NSAC Isotopes report is due to be published during the summer of 2009.

With the termination of the Maple project, alternative approaches need to be explored in comparison to the cost of constructing and commissioning a new reactor facility, in particular the possibility of using photon-induced fission of U-238.

The interesting political situation here is that the US is considering supporting upgrading the MURR. Traditionally, the US has not been in favor of subsidizing industry while Canada has not shied away from this approach: the historical roles may be reversed. Nevertheless, the question is really an issue of supporting the public good in health care.

References:

CBC.CA: Canada getting out of medical isotope production: PM

Takács S., Z. Szűcs, F. Tárkányi, A. Hermanne, and M. Sonck. 2003. Evaluation of proton induced reactions on ¹⁰⁰Mo: New cross sections for production of ^99mTc and ⁹⁹Mo. Radioanal. Nucl. Chem. 257(1):195-210.

Takács S., F. Tárkányi, M. Sonck, and A. Hermanne. 2002. Investigation of the ^natMo(p,x)^96m,gTc nuclear reaction to monitor proton beams: New measurements and consequences on the earlier reported data. Nucl. Inst. Method. in Phy. Res. B 198:183- 196.

Thomas Ruth is a senior research scientist at TRIUMF and senior scientist at the British Columbia Cancer Research Centre. His research for the past 35 years has centered on the production and use of radiotracers for the physical and biological sciences. He has published more than 200 peer-reviewed articles in this area. He serves on numerous national and international committees dealing with radioisotopes, most recently on National Academy of Sciences panels dealing with the status of Nuclear Medicine in the US and the production of medical isotopes without highly enriched uranium, and on the US Department of Energy committee on isotope availability.

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This contribution has not been peer refereed. It represents solely the view(s) of the author(s) and not necessarily the views of APS.