Radioisotopes in Medicine
(Updated November 2016)
- Nuclear medicine uses radiation to provide diagnostic information about the functioning of a person's specific organs, or to treat them. Diagnostic procedures using radioisotopes are now routine.
- Radiotherapy can be used to treat some medical conditions, especially cancer, using radiation to weaken or destroy particular targeted cells.
- Over 40 million nuclear medicine procedures are performed each year, and demand for radioisotopes is increasing at up to 5% annually.
- Sterilisation of medical equipment is also an important use of radioisotopes.
This is a branch of medicine that uses radiation to provide information about the functioning of a person's specific organs or to treat disease. In most cases, the information is used by physicians to make a quick, accurate diagnosis of the patient's illness. The thyroid, bones, heart, liver and many other organs can be easily imaged, and disorders in their function revealed. In some cases radiation can be used to treat diseased organs, or tumours. Five Nobel Laureates have been intimately involved with the use of radioactive tracers in medicine.
Over 10,000 hospitals worldwide use radioisotopes in medicine, and about 90% of the procedures are for diagnosis. The most common radioisotope used in diagnosis is technetium-99, with some 35 million procedures per year (16.7 million in USA in 2012, 550,000 in Australia), accounting for about 80% of all nuclear medicine procedures worldwide.
In developed countries (26% of world population) the frequency of diagnostic nuclear medicine is 1.9% per year, and the frequency of therapy with radioisotopes is about one tenth of this. In the USA there are over 20 million nuclear medicine procedures per year among 311 million people, and in Europe about 10 million among 500 million people. In Australia there are about 560,000 per year among 21 million people, 470,000 of these using reactor isotopes. The use of radiopharmaceuticals in diagnosis is growing at over 10% per year.
The global radioisotope market was valued at $4.8 billion in 2012, with medical radioisotopes accounting for about 80% of this, and is poised to reach about $8 billion by 2017. North America is the dominant market for diagnostic radioisotopes with close to half of the market share, while Europe accounts for about 20%.
Nuclear medicine was developed in the 1950s by physicians with an endocrine emphasis, initially using iodine-131 to diagnose and then treat thyroid disease. In recent years specialists have also come from radiology, as dual CT/PET procedures have become established, increasing the role of accelerators in radioisotope production. However the main radioisotopes such as technetium cannot effectively be produced without reactors.*
* Some Tc-99m is produced in accelerators but it is of lower quality and at higher cost.
Computed X-ray tomography (CT) scans and nuclear medicine contribute 36% of the total radiation exposure and 75% of the medical exposure to the US population, according to a US National Council on Radiation Protection & Measurements report in 2009. The report showed that Americans’ average total yearly radiation exposure had increased from 3.6 millisievert to 6.2 mSv per year since the early 1980s, due to medical-related procedures. (Industrial radiation exposure, including that from nuclear power plants, is less than 0.1% of overall public radiation exposure.)
An important nuclear medicine procedure is Magnetic Resonance Imaging (MRI), which uses powerful magnets and radio waves to create cross-sectional images of organs and internal structures in the body. It does not use radioisotopes or ionizing radiation, but relies on nuclear magnetic resonance of hydrogen.
Diagnostic techniques in nuclear medicine
Diagnostic techniques in nuclear medicine use radioactive tracers which emit gamma rays from within the body. These tracers are generally short-lived isotopes linked to chemical compounds which permit specific physiological processes to be scrutinised. They can be given by injection, inhalation or orally. The first type are where single photons are detected by a gamma camera which can view organs from many different angles. The camera builds up an image from the points from which radiation is emitted; this image is enhanced by a computer and viewed by a physician on a monitor for indications of abnormal conditions.
A more recent development is Positron Emission Tomography (PET) which is a more precise and sophisticated technique using isotopes produced in a cyclotron. A positron-emitting radionuclide is introduced, usually by injection, and accumulates in the target tissue. As it decays it emits a positron, which promptly combines with a nearby electron resulting in the simultaneous emission of two identifiable gamma rays in opposite directions. These are detected by a PET camera and give very precise indication of their origin. PET's most important clinical role is in oncology, with fluorine-18 as the tracer, since it has proven to be the most accurate non-invasive method of detecting and evaluating most cancers. It is also well used in cardiac and brain imaging.
New procedures combine PET with computed X-ray tomography (CT) scans to give co-registration of the two images (PETCT), enabling 30% better diagnosis than with traditional gamma camera alone. It is a very powerful and significant tool which provides unique information on a wide variety of diseases from dementia to cardiovascular disease and cancer (oncology).
Positioning of the radiation source within the body makes the fundamental difference between nuclear medicine imaging and other imaging techniques such as x-rays. Gamma imaging by either method described provides a view of the position and concentration of the radioisotope within the body. Organ malfunction can be indicated if the isotope is either partially taken up in the organ (cold spot), or taken up in excess (hot spot). If a series of images is taken over a period of time, an unusual pattern or rate of isotope movement could indicate malfunction in the organ.
A distinct advantage of nuclear imaging over x-ray techniques is that both bone and soft tissue can be imaged very successfully. This has led to its common use in developed countries where the probability of anyone having such a test is about one in two and rising.
The mean effective dose is 4.6 mSv per diagnostic procedure.
Radionuclide therapy (RNT)
Rapidly dividing cells are particularly sensitive to damage by radiation. For this reason, some cancerous growths can be controlled or eliminated by irradiating the area containing the growth.
External irradiation (sometimes called teletherapy) can be carried out using a gamma beam from a radioactive cobalt-60 source, though in developed countries the much more versatile linear accelerators are now being utilised as a high-energy x-ray source (gamma and X-rays are much the same). An external radiation procedure is known as the gamma knife radiosurgery, and involves focusing gamma radiation from 201 sources of cobalt-60 sources on a precise area of the brain with a cancerous tumour. Worldwide, over 30,000 patients are treated annually, generally as outpatients. Teletherapy is effective in the ablation of tumours rather than their removal; it is not finely tuned.
Internal radionuclide therapy is by administering or planting a small radiation source, usually a gamma or beta emitter, in the target area. Short-range radiotherapy is known as brachytherapy, and this is becoming the main means of treatment. Iodine-131 is commonly used to treat thyroid cancer, probably the most successful kind of cancer treatment. It is also used to treat non-malignant thyroid disorders. Iridium-192 implants are used especially in the head and breast. They are produced in wire form and are introduced through a catheter to the target area. After administering the correct dose, the implant wire is removed to shielded storage. Permanent implant seeds (40 to 100) of iodine-125 or palladium-103 are used in brachytherapy for early stage prostate cancer. Alternatively, needles with more-radioactive iridium-192 may be inserted for up to 15 minutes, two or three times. Brachytherapy procedures give less overall radiation to the body, are more localised to the target tumour and are cost-effective.
Treating leukaemia may involve a bone marrow transplant, in which case the defective bone marrow will first be killed off with a massive (and otherwise lethal) dose of radiation before being replaced with healthy bone marrow from a donor.
Many therapeutic procedures are palliative, usually to relieve pain. For instance, strontium-89 and (increasingly) samarium 153 are used for the relief of cancer-induced bone pain. Rhenium-186 is a newer product for this.
Lutetium-177 dotatate or octreotate is used to treat tumours such as neuroendocrine ones, and is effective where other treatments fail. A series of four treatments delivers 32 GBq. After about four to six hours, the exposure rate of the patient has fallen to less than 25 microsieverts per hour at one metre and the patients can be discharged from hospital. Lu-177 is essentially a low-energy beta-emitter (with some gamma) and the carrier attaches to the surface of the tumour.
A new field is targeted alpha therapy (TAT) or alpha radioimmunotherapy, especially for the control of dispersed cancers. The short range of very energetic alpha emissions in tissue means that a large fraction of that radiative energy goes into the targeted cancer cells, once a carrier such as a monoclonal antibody has taken the alpha-emitting radionuclide such as Bi-213 to exactly the right places. Clinical trials for leukaemia, cystic glioma and melanoma are under way. TAT using lead-212 is increasingly important for treating pancreatic, ovarian and melanoma cancers.
An experimental development of this is boron neutron capture therapy using boron-10 which concentrates in malignant brain tumours. The patient is then irradiated with thermal neutrons which are strongly absorbed by the boron, producing high-energy alpha particles which kill the cancer. This requires the patient to be brought to a nuclear reactor, rather than the radioisotopes being taken to the patient.
Radionuclide therapy has progressively become successful in treating persistent disease and doing so with low toxic side-effects. With any therapeutic procedure the aim is to confine the radiation to well-defined target volumes of the patient. The doses per therapeutic procedure are typically 20-60 Gy.
Treatment may involve significant radioactivity, e.g. 4.4 GBq is quoted as an average dose of iodine-131 for thyroid ablation, and up to 11 GBq for patients with advanced metastatic disease. According to US regulatory guidelines for I-131, the patient can be released if the activity is below 1.2 GBq, or 0.07 mSv/hr at 1 metre. Meanwhile a lot of I-131 is flushed down the hospital toilet and plumbing needs to be shielded accordingly.
It is very easy to detect the presence or absence of some radioactive materials even when they exist in very low concentrations. Radioisotopes can therefore be used to label molecules of biological samples in vitro (out of the body). Pathologists have devised hundreds of tests to determine the constituents of blood, serum, urine, hormones, antigens and many drugs by means of associated radioisotopes. These procedures are known as radioimmuno-assays and, although the biochemistry is complex, kits manufactured for laboratory use are very easy to use and give accurate results. In Europe some 15 million of these in vitro analyses are undertaken each year.
Gamma irradiation is widely used for sterilising medical products and supplies such as syringes, gloves, clothing and instruments, many of which would be damaged by heat sterilisation. Cobalt-60 is the main isotope used, since it is an energetic gamma emitter. Large-scale irradiation facilities for gamma sterilisation are in many countries. Smaller gamma irradiators, often with Cs-137, are used for treating blood for transfusions and for other medical applications.
Every organ in our bodies acts differently from a chemical point of view. Doctors and chemists have identified a number of chemicals which are absorbed by specific organs. The thyroid, for example, takes up iodine, the brain consumes quantities of glucose, and so on. With this knowledge, radiopharmacists are able to attach various radioisotopes to biologically active substances. Once a radioactive form of one of these substances enters the body, it is incorporated into the normal biological processes and excreted in the usual ways.
Diagnostic radiopharmaceuticals can be used to examine blood flow to the brain, functioning of the liver, lungs, heart or kidneys, to assess bone growth, and to confirm other diagnostic procedures. Another important use is to predict the effects of surgery and assess changes since treatment.
The amount of the radiopharmaceutical given to a patient is just sufficient to obtain the required information before its decay. The radiation dose received is medically insignificant. The patient experiences no discomfort during the test and after a short time there is no trace that the test was ever done. The non-invasive nature of this technology, together with the ability to observe an organ functioning from outside the body, makes this technique a powerful diagnostic tool.
A radioisotope used for diagnosis must emit gamma rays of sufficient energy to escape from the body and it must have a half-life short enough for it to decay away soon after imaging is completed.
The radioisotope most widely used in medicine is technetium-99m, employed in some 80% of all nuclear medicine procedures – hence some 30 million per year, of which 6-7 million are in Europe, 15 million in North America, 6-8 million in Asia/Pacific (particularly Japan), and 0.5 million in other regions. It is an isotope of the artificially-produced element technetium and it has almost ideal characteristics for a nuclear medicine scan. These are:
- It has a half-life of six hours which is long enough to examine metabolic processes yet short enough to minimise the radiation dose to the patient.
- Technetium-99m decays by a process called "isomeric"; which emits gamma rays and low energy electrons. Since there is no high-energy beta emission the radiation dose to the patient is low.
- The low energy gamma rays it emits easily escape the human body and are accurately detected by a gamma camera. Once again the radiation dose to the patient is minimised.
- The chemistry of technetium is so versatile it can form tracers by being incorporated into a range of biologically-active substances to ensure that it concentrates in the tissue or organ of interest.
Its logistics also favour its use. Technetium generators, a lead pot enclosing a glass tube containing the radioisotope, are supplied to hospitals from the nuclear reactor where the isotopes are made. They contain molybdenum-99, with a half-life of 66 hours, which progressively decays to technetium-99. The Tc-99 is washed out of the lead pot by saline solution when it is required. After two weeks or less the generator is returned for recharging.
A similar generator system is used to produce rubidium-82 for PET imaging from strontium-82 - which has a half-life of 25 days.
Myocardial perfusion imaging (MPI) uses thallium-201 chloride or technetium-99m and is important for detection and prognosis of coronary artery disease.
Canadian 2006 data shows that 56% of Tc-99 use there is in myocardial ischemia perfusion, 17% in bone scans, 7% in liver/hepatobiliary, 4% respiratory, 3% renal, 3% thyroid.
For PET imaging, the main radiopharmaceutical is fluoro-deoxy glucose (FDG) incorporating F-18 – with a half-life of just under two hours – as a tracer. The FDG is readily incorporated into the cell without being broken down, and is a good indicator of cell metabolism.
In diagnostic medicine, there is a strong trend to using more cyclotron-produced isotopes such as F-18 as PET and CT/PET become more widely available. However, the procedure needs to be undertaken within two hours reach of a cyclotron, which limits their utility compared with Mo/Tc-99.
For some medical conditions, it is useful to destroy or weaken malfunctioning cells using radiation. The radioisotope that generates the radiation can be localised in the required organ in the same way it is used for diagnosis – through a radioactive element following its usual biological path, or through the element being attached to a suitable biological compound. In most cases, it is beta radiation which causes the destruction of the damaged cells. This is radionuclide therapy (RNT) or radiotherapy. Short-range radiotherapy is known as brachytherapy, and this is becoming the main means of treatment.
Although radiotherapy is less common than diagnostic use of radioactive material in medicine, it is nevertheless widespread, important and growing. An ideal therapeutic radioisotope is a strong beta emitter with just enough gamma to enable imaging, eg lutetium-177. This is prepared from ytterbium-176 which is irradiated to become Yb-177 which decays rapidly to Lu-177. Yttrium-90 is used for treatment of cancer, particularly non-Hodgkin's lymphoma and liver cancer, and it is being used more widely, including for arthritis treatment. Lu-177 and Y-90 are becoming the main RNT agents.
Iodine-131, samarium-153 and phosphorus-32 are also used for therapy. Iodine-131 is used to treat the thyroid for cancers and other abnormal conditions such as hyperthyroidism (over-active thyroid). In a disease called Polycythemia vera, an excess of red blood cells is produced in the bone marrow. Phosphorus-32 is used to control this excess.
Caesium-131, palladium-103 and radium-223 are also used for brachytherapy, all being Auger (soft) x-ray emitters, and having half-lives of 9.7 days, 17 days, and 11.4 days respectively, much less than the 60 days of iodine-125 which they replace.
A new and still experimental procedure uses boron-10, which concentrates in the tumour. The patient is then irradiated with neutrons which are strongly absorbed by the boron, to produce high-energy alpha particles which kill the cancer. This is boron neutron capture therapy.
For targeted alpha therapy (TAT), actinium-225 is readily available, from which the daughter bismuth-213 can be obtained (via three alpha decays) to label targeting molecules. The bismuth is obtained by elution from an Ac-225/Bi-213 generator similar to the Mo-99/Tc-99 one. Bi-213 has a 46-minute half-life. The actinium-225 (half-life 10 days) is formed from radioactive decay of radium-225, the decay product of long-lived thorium-229, which is obtained from decay of uranium-233, which is formed from Th-232 by neutron capture in a nuclear reactor.
Another radionuclide recovered from thorium-232, but by natural decay via Th-228, is lead-212, with half-life of 10.6 hours, which can be attached to monoclonal antibodies for cancer treatment by TAT. A Ra-224/Pb-212 generator system similar to the Mo-99/Tc-99 one is used to provide lead-212 from radium-224 (via Rn-220 and Po-216). Pb-212 has a half-life of 10.6 hours, and beta decays to bismuth-212 (1 hour half-life), then most beta decays to polonium-212. The alpha decays of Bi-212 and Po-212 are the active ones destroying cancer cells over a couple of hours. Stable Pb-208 results, via thallium-208 for the bismuth decay.
Considerable medical research is being conducted worldwide into the use of radionuclides attached to highly specific biological chemicals such as immunoglobulin molecules (monoclonal antibodies). The eventual tagging of these cells with a therapeutic dose of radiation may lead to the regression – or even cure – of some diseases.
In 2006 Britain witnessed the murder of one of its newer citizens, Alexander Litvinenko, a former Russian intelligence official, by poisoning with radioactive polonium. His death was slow and excruciating.
Polonium has about 26 isotopes, all of which are radioactive. Webelements periodic table says that it is 250 billion times more toxic than hydrocyanic acid. It is readily soluble in weak acid. (It was the first element discovered by Marie Curie, in 1898, and named after her native Poland. Her daughter Irene was contaminated with polonium in a laboratory accident and died of leukemia at the age of 59.)
Polonium-210 is the penultimate decay product of U-238, before it alpha decays to become stable lead. It results from the beta decay of Pb-210 (in the U-238 decay series) to Bi-210 which rapidly beta decays to Po-210. This gives rise to its occurrence in nature, where uranium is ubiquitous. However, because of its short (138 day) half life, very little Po-210 would be found in uranium ore or mill tailings (Webelements suggests 0.1 mg/tonne). Po-210 levels in soil would be even less, but it is concentrated in tobacco and traces of it can be found in smokers' urine.
Po-210 can also be made by neutron irradiation of Bi-209, and that is most likely source of any significant quantity. Russia has used Po-210 as a heat source in short-life spacecraft and lunar rovers. It also operates reactors using lead-bismuth cooling, which becomes contaminated with Po-210 due to neutron bombardment.
Because its half-life is so short, a gram of Po-210 is about 5000 times as radioactive as a gram of radium – which sets the standard of activity. But at 138 days its half-life is long enough for it to be manufactured, transported and administered before it loses its potency. It would not put the carrier at much risk, since alpha radiation is only really a hazard inside the body – a layer of skin is protection. About 10 micrograms (2 GBq) was said to have been used, administered in a cup of tea (it would be warm due to the decay).
However, simply dosing someone with polonium might not have much effect if it simply went in one end and out the other in a day or two without being absorbed from the gut. It would probably need to be complexed on to an organic carrier which would enter the bloodstream and take it to vital organs where it would stay. (This is what happens with targeted alpha therapy (TAT) using very low levels of alpha-active radioisotopes: the carriers take them to dispersed cancerous tissues where they are needed.)
In Mr Litvinenko's case the intense alpha radiation was reportedly in vital organs and sufficient to destroy them over three weeks. It was apparently over one hundred times the dose used in TAT for cancer treatment and the Po-210 is much longer-lived than isotopes used for TAT. It could have been attached to something as simple as a sugar.
In 2003 an investigative journalist in Russia, Yuri Shchekochikhin was fatally poisoned, and in 2004 a St Petersburg businessman Romam Tsepov met a similar fate, his symptoms closely resembling those of Livinenko. Both are considered to have been radiologically poisoned.
Supplies of radioisotopes
The main world isotope suppliers are Mallinckrodt Pharmaceuticals (Ireland), MDS Nordion (Canada), IRE (Europe), NTP (South Africa), Isotop-NIIAR (Russia) and ANSTO (Australia).
Most medical radioisotopes made in nuclear reactors are sourced from relatively few research reactors, including:
- HFR at Petten in Netherlands (supplied via IRE and Mallinckrodt)
- BR-2 at Mol in Belgium (supplied via IRE and Mallinckrodt)
- Maria in Poland (supplied via Mallinckrodt)
- Orphee at Saclay in France (supplied via IRE)
- FRJ-2/ FRM-2 at Julich in Germany (supplied via IRE)
- LWR-15 at Rez in Czech Republic
- HFETR at Chengdu in China
- Safari in South Africa (supplied from NTP)
- OPAL in Australia (supplied from ANSTO to domestic market, exports from 2016)
- ETRR-2 in Egypt (forthcoming: supplied to domestic market)
- Dimitrovgrad in Russia (Isotop-NIIAR)
- NRU at Chalk River in Canada (supplied via MDS Nordion) ceased production in October 2016, though the capacity will remain on standby until the reactor closes in March 2018.
Of fission radioisotopes, the vast majority of demand is for of Mo-99 (for Tc-99m), and the world market is some US$ 550 million per year. About 40% of it is supplied by MDS Nordion, 25% from Mallinckrodt (formerly Covidien), 17% from IRE and 10% from NTP. Over half of the Mo-99 has been made in two reactors: NRU in Canada (30-40% but ceased production in October 2016) and HFR in Netherlands (30%). The rest is from BR-2 in Belgium (10%), Maria in Poland (5%), Safari-1 in South Africa (10-15%), Opal in Australia (increasing to 20% from mid-2016) and until the end of 2015, Osiris in France (5%). Output from each varies due to maintenance schedules.
Russia is keen to increase its share of world supply, and in 2012 some 66% of its radioisotope production was exported. For I-131, 75% is from IRE, 25% from NTP.
World demand for Mo-99 was 23,000 six-day TBq/yr* in 2012, but has apparently dropped back to about 19,500 since. Mo-99 is mostly produced by fission of U-235 targets in a nuclear research reactor, much of this (75% in 2016) using high-enriched uranium (HEU) targets. The targets are then processed to separate the Mo-99 and also to recover I-131. OPAL, Safari, and increasingly other reactors such as Maria use low-enriched uranium (LEU) targets, which adds about 20% to production costs. However, in medical imaging, the cost of Mo-99 itself is small relative to hospital costs. Mo-99 can also be made by bombarding Mo-98 with neutrons in a reactor. However, this activation Mo-99 has relatively low specific activity, with a maximum of 74 GBq/g (depending on the neutron flux available in the reactor), compared with 185 TBq/g or more for conventional fission-produced Mo-99.
Emerging supply constraints
A number of incidents in 2008 pointed up shortcomings and unreliability in the supply of medical isotopes, particular technetium. As indicated above, most of the world's supply of Mo-99 for this comes from only five reactors, all of them 43 to 52 years old (in mid-2010). The Canadian and Netherlands reactors required major repairs over 2009-10 and were out of action for some time. Osiris was due to shut down in 2015. NRU at Chalk River was re-licensed to October 2016 when it ceased production, though AECL is keeping it on standby to March 2018. A new 20 MW South Korean reactor at Busan is expected to be operating in 2016. An increasing supply shortfall of Tc-99 was forecast from 2010, and the IAEA is encouraging new producers. Also the processing and distribution of isotopes is complex and constrained, which can be critical when the isotopes concerned are short-lived. A need for increased production capacity and more reliable distribution is evident. The Mo-99 market is about $5 billion per year, according to NECSA.
In 2009 the NEA set up the High-level Group on the Security of Supply of Medical Radioisotopes (HLG-MR) to strengthen the reliability of Mo-99 and Tc-99 supply in the short, medium and long term. It reviewed the Mo-99 supply chain to identify the key areas of vulnerability, the issues that need to be addressed and the mechanisms that could be used to help resolve them. It requested an economic study of the supply chain, and this was published in 2010 by the NEA. The report identifies possible changes needed. The historical development of the market has an impact on the present economic situation, which is unsustainable. The supply chain’s economic structure therefore needs to be changed to attract additional investment in production capacity as well as the necessary reserve capacity, and all supply chain participants worldwide need to agree on and implement the changes needed.
The NEA report predicts supply shortages from 2016, not simply from reactors but due to processing limitations. Historically reactor irradiation prices have been too low to attract new investment, and full cost recovery is needed to encourage new infrastructure. This will have little impact on end prices since irradiation only accounts for about 1% of product cost. Transport regulation and denial of shipment impede reliable supply. HEU use needs to be minimised, though conversion to LEU targets will reduce capacity. Outage reserve capacity needs to be sourced, valued and paid for by the supply chain. Fission is the most efficient and reliable means of production, but Canada and Japan are developing better accelerator-based techniques.
This led in December 2014 to a NEA Joint Declaration on the Security of Supply of Medical Radioisotopes, focused on Mo-99, which is so far supported by 13 countries: Australia, Canada, France, Germany, Japan, the Netherlands, Poland, South Korea, Russia, South Africa, Spain, the UK and the USA.
US supply initiatives for Mo-99
The US Congress has called for all Mo-99 to be supplied by reactors running on low-enriched uranium (LEU), instead of high-enriched uranium (HEU). Also it has called for proposals for an LEU-based supply of Mo-99 for the US market, reaching 111 six-day TBq per week by mid-2013, a quarter of world demand. Tenders for this closed in June 2010, but evidently no immediate progress was made. In December 2012 Congress passed the American Medical Isotope Production Act of 2011 to establish a technology-neutral program to support the production of Mo-99 for medical uses in the USA by non-federal entities.
In mid-2013 Los Alamos National Laboratory announced that had recovered Mo-99 from low-enriched sulphate reactor fuel in solution, raising the prospect of this process becoming associated with commercial reprocessing plants as at La Hague in France.
In January 2009 Babcock & Wilcox (B&W) announced an agreement with international isotope supplier Covidien to produce Mo-99 sufficient for half of US demand, if a new process involving an innovative reactor and separation technology is successful. They planned to use Aqueous Homogeneous Reactor (AHR) technology with low-enriched uranium in small 100-200 kW units units where the fuel is mixed with the moderator and the U-235 forms both the fuel and the irradiation target.* A single production facility could have four such reactors. B&W and Covidien expected a five-year lead time to first production. B&W received $9 million towards this Medical Isotope Production System (MIPS) in 2010 from the US government and completed the R&D and conceptual design phase in 2012. However, in October 2012 Covidien pulled out of the joint venture with B&W “after learning that the time and cost involved with the project would be greater than originally expected.” Covidien said that it was "making significant long-term capital investment in a new Tc-99m generator facility at our US plant, and conversion from HEU- to LEU-based Mo-99 production at our processing plant in the Netherlands.” B&W appears to have dropped the MIPS.
In the USA, Northstar Medical Technologies founded in 2006 is using the University of Missouri research reactor (MURR) to irradiate Mo-98 targets with neutrons, producing activation Mo-99. Such Mo-99 has relatively low specific activity, and there are complications then in separating the Tc-99. The company received approval to begin routine production in August 2015, and aims eventually to meet half of US demand with 110 six-day TBq per week. Production was envisaged from mid-2014, rising to meet half of US demand. In November 2013 Northstar was awarded a $21.8 million cooperative agreement half-funded by NNSA to support its “non-uranium based Mo-99 production by neutron capture”. A further $5.2 million grant from NNSA was in November 2014. MURR runs on low-enriched uranium. Longer-term Northstar is considering a non-reactor approach – see below.
In 2015 Northstar Medical Radioisotopes signed an agreement with Westinghouse to investigate production of Mo-99 in nuclear power reactors using its Incore Instrumentation System.
In 2014 another plan using the US University Reactor Network was announced. Northwest Medical Isotopes LLC (NWMI) plans to produce half of North America’s demand for Mo-99 from 2017, using LEU targets. It has licensed the process for small Triga reactors from Oregon State University, which operates one of the 35 in USA, a Triga MkII of 1.1 MW. It is setting up its 44,600 sq metre radioisotope production facility at the University of Missouri’s Research Park at Columbia, Missouri. It is not clear whether this involves the University of Missouri research reactor (MURR).
In February 2015 Nordion and its US parent Sterigenics International announced a new arrangement with the University of Missouri research reactor (MURR) and General Atomics to produce Mo-99 from LEU targets from 2017 using the 10 MW pool type reactor. This new medical isotope supply will be produced using General Atomics’ innovative Selective Gaseous Extraction (SGE) technology to extract the Mo from the targets.
In the USA Coquí Pharmaceuticals has signed a contract with Argentinian nuclear engineering company INVAP to build an open-pool reactor similar to Australia’s Opal, using LEU targets, and a Mo-99 production facility at Alachua county, Florida.
Russian supply initiatives for Mo-99
In Russia, the Research Institute of Atomic Reactors (NIIAR or RIAR, with three reactors for isotope production) and Trans-regional Izotop Association (becoming JSC Isotope in 2008) established a joint venture, Isotop-NIIAR to produce Mo-99 at Dimitrovgrad from 2010. Phase 1 of the Mo-99 production complex with capacity of 1700 TBq/yr was commissioned in December 2010, and Phase 2 was commissioned in June 2012 taking capacity to 1480 TBq/yr (evidently 6-day activity). Earlier reports quoted 4800 TBq/yr, and Rosatom aimed for 20% of the world Mo-99 market by 2014, supplied internationally through Nordion. In September 2010 JSC Isotope signed a framework agreement with MDS Nordion to explore commercial opportunities outside Russia on the basis of this Isotop-NIIAR JV, initially over ten years.
Since 2009, JSC Isotope has been authorized by Rosatom to control all isotope production and radiological devices such as RTGs in Russia. A second production facility is Karpov IPC. Its product portfolio includes more than 60 radioisotopes produced in cyclotrons, nuclear reactors by irradiation of targets, or recovered from spent nuclear fuel, as well as hundreds of types of ionizing radiation sources and compounds tagged with radioactive isotopes. It has more than 10,000 scientific and industrial customers for industrial isotopes in Russia.
At Russia's Kurchatov Institute the 20 kW ARGUS Aqueous Homogeneous Reactor (AHR) has operated since 1981, and R&D on producing Mo-99 from it is ongoing. (See process description above, re B&W and MIPS).
Other reactor supply initiatives for Mo-99
Australia's Opal reactor has the capacity to produce half the world supply of Mo-99, and with the ANSTO Nuclear Medicine Project will be able to supply at least one-quarter of world demand from 2019. ANSTO is building a substantial Mo-99 production facility to ramp up quickly to 130 six-day TBq per week (6500 per year), or 10 million Tc-99m doses per year, with exports to the USA, Japan, China and Korea. ANSTO increased production from 30 to 80 six-day TBq/wk (1500 to 4000 per year) from July 2016.
During the 2009-10 supply crisis, South Africa's (NECSA) Safari was able to supply over 25% of the world's Mo-99.
Technetium-99m or molybdenum-99 can also be produced in small quantities from cyclotrons and accelerators, in a cyclotron by bombarding a Mo-100 target with a proton beam to produce Tc-99m directly, or in a linear accelerator to generate Mo-99 by bombarding a Mo-100 target with high-energy X-rays. It is generally considered that non-reactor methods of producing large quantities of Tc-99 are some years away. At present the cost is at least three times and up to ten times that of the reactor route, and Mo-100 is available only from Russia. If Tc-99 is produced directly in a cyclotron, it needs to be used quickly, and the co-product isotopes are a problem.
In the USA, SHINE Medical Technologies is developing an advanced accelerator technology for the production of Mo-99 as a fission product. It was awarded a $3.2 million grant from NNSA in November 2014, and it has a $125 million debt financing package from healthcare investment firm Deerfield Management. A low-enriched uranium target solution is irradiated with low-energy neutrons in a subcritical assembly – not a nuclear reactor. SHINE is an acronym for Subcritical Hybrid Intense Neutron Emitter. A plant at Janesville, Wisconsin, is planned eventually to supply half of the US demand for Mo-99, and in February 2016 the NRC authorised a construction permit for the project. In June 2016 China's largest producer and distributor of medical radioisotopes, HTA, entered a strategic agreement for the supply of SHINE’s Mo-99.
In Canada the government has an Isotope Technology Acceleration Program (ITAP) to promote R&D on non-reactor based isotope production, particularly through the Medical Isotope Program (MIP). Canada Light Source Inc (CLS) in Saskatoon is using a linear accelerator to bombard Mo-100 targets with X-rays, and has produced some Mo-99 for MIP.
Northstar has long-term plans for producing Mo-99 from Mo-100 in an accelerator.
Main Mo-99 Production Reactors
Planned Mo-99 Production Capacity
||133+ (111 export)
* Six-day TBq/week
Source: Annex 1, 2 & 3, Supply of Medical Radioisotopes, March 2103, OECD/NEA
Other medical radioisotopes
Cobalt-60 has mostly come from Candu power reactors by irradiation of Co-59 in special rods for up to three years, and production is being expanded. Production sites include: Bruce B and Pickering in Canada (70% of world supply, expanding to Bruce A and Darlington); Embalse in Argentina; Qinshan Phase III units 1 and 2 in China; Wolsong 1 and 2 in South Korea (all Candu); and Leningrad 1 in Russia (RBMK). These were to be joined by the Clinton and Hope Creek BWRs in USA from 2012. Most of this Co-60 is for sterilization, with high-specific-activity (HSA) Co-60 for cancer treatment being made in Canada’s NRU at Chalk River, and in the Bruce B nuclear power plant.
Areva Med built a small plant at Bessines-sur-Gartempe in France to provide lead-212 from irradiated thorium, and this came on line in 2013. A second plant has been built at Plano in Texas, operating from 2016, and a new industrial-scale plant is planned for Caen in France. A radium-224/Pb-212 generator similar to the Mo-99/Tc-99 one enables the Pb-212 to be eluted as required for targeted alpha therapy (TAT). Ra-224 is a natural decay product of Th-228, and indirectly, of Th-232.
Nuclear medicine wastes
The use of radioisotopes for medical diagnosis and treatments results in the generation of mainly low-level waste (LLW). This waste includes paper, rags, tools, clothing and filters, which contain small amounts of mostly short-lived radioactivity. These types of waste often undergo decay storage for periods of months to a few years before being disposed of at urban land-fill sites.
When radiography sources have decayed to a point where they are no longer emitting enough penetrating radiation for use in treatments, they are considered as radioactive waste. Sources such as Co-60 are treated as short-lived intermediate-level wastes (ILW). Other sources such as Radium-226, used in cancer therapy, will however require long-term storage and geological disposal as ILW, as a result of their higher level of long-lived radioactivity.
ANSTO Nuclear Medicine Project in Australia involves developing a co-located Synroc treatment plant for its wastes from Mo-99 production. It will treat legacy acid wastes as well as alkaline ones from ongoing production, and construction is due to start in 2017. The final storage volume with Synroc will be 1% of the same wastes cemented for disposal.
Isotopes used in medicine
Many radioisotopes are made in nuclear reactors, some in cyclotrons. Generally neutron-rich ones and those resulting from nuclear fission need to be made in reactors, neutron-depleted ones are made in cyclotrons. There are about 40 activation product radioisotopes and five fission product ones made in reactors.
Bismuth-213 (46 min):
Used for targeted alpha therapy (TAT), especially cancers, as it has a high energy (8.4 MeV).
Caesium-131 (9.7 d):
Used for brachytherapy, emits soft x-rays.
Caesium-137 (30 yr):
Used for low-intensity sterilisation of blood.
Chromium-51 (28 d):
Used to label red blood cells for monitoring, and to quantify gastro-intestinal protein loss or bleeding.
Cobalt-60 (5.27 yr):
Formerly used for external beam radiotherapy, now almost universally used for sterilising. High-specific-activity (HSA) Co-60 is used for brain cancer treatment.
Dysprosium-165 (2 h):
Used as an aggregated hydroxide for synovectomy treatment of arthritis.
Erbium-169 (9.4 d):
Used for relieving arthritis pain in synovial joints.
Holmium-166 (26 h):
Being developed for diagnosis and treatment of liver tumours.
Iodine-125 (60 d):
Used in cancer brachytherapy (prostate and brain), also diagnostically to evaluate the filtration rate of kidneys and to diagnose deep vein thrombosis in the leg. It is also widely used in radioimmuno-assays to show the presence of hormones in tiny quantities.
Iodine-131 (8 d)*:
Widely used in treating thyroid cancer and in imaging the thyroid; also in diagnosis of abnormal liver function, renal (kidney) blood flow and urinary tract obstruction. A strong gamma emitter, but used for beta therapy.
Iridium-192 (74 d): Supplied in wire form for use as an internal radiotherapy source for cancer treatment (used then removed), eg for prostate cancer. Strong beta emitter.
Iron-59 (46 d):
Used in studies of iron metabolism in the spleen.
Lead-212 (10.6 h):
Used in TAT for cancers or alpha radioimmunotherapy, with decay products Bi-212 (1 h) and Po-212 delivering the alpha particles. Used especially for melanoma, breast cancer and ovarian cancer. Demand is increasing.
Lutetium-177 (6.7 d):
Lu-177 is increasingly important as it emits just enough gamma for imaging while the beta radiation does the therapy on small (eg endocrine) tumours. Its half-life is long enough to allow sophisticated preparation for use. It is usually produced by neutron activation of natural or enriched lutetium-176 targets.
Molybdenum-99 (66 h)*:
Used as the 'parent' in a generator to produce technetium-99m.
Palladium-103 (17 d):
Used to make brachytherapy permanent implant seeds for early stage prostate cancer. Emits soft x-rays.
Phosphorus-32 (14 d):
Used in the treatment of polycythemia vera (excess red blood cells). Beta emitter.
Potassium-42 (12 h):
Used for the determination of exchangeable potassium in coronary blood flow.
Radium-223 (11.4 d):
Used for brachytherapy, emits soft x-rays.
Rhenium-186 (3.8 d):
Used for pain relief in bone cancer. Beta emitter with weak gamma for imaging.
Rhenium-188 (17 h):
Used to beta irradiate coronary arteries from an angioplasty balloon.
Samarium-153 (47 h):
Sm-153 is very effective in relieving the pain of secondary cancers lodged in the bone, sold as Quadramet. Also very effective for prostate and breast cancer. Beta emitter.
Selenium-75 (120 d):
Used in the form of seleno-methionine to study the production of digestive enzymes.
Sodium-24 (15 h):
For studies of electrolytes within the body.
Strontium-89 (50 d)*:
Very effective in reducing the pain of prostate and bone cancer. Beta emitter.
Technetium-99m (6 h):
Used in to image the skeleton and heart muscle in particular, but also for brain, thyroid, lungs (perfusion and ventilation), liver, spleen, kidney (structure and filtration rate), gall bladder, bone marrow, salivary and lacrimal glands, heart blood pool, infection and numerous specialised medical studies. Produced from Mo-99 in a generator. The most common radioisotope for diagnosis, accounting for over 80% of scans.
Xenon-133 (5 d)*:
Used for pulmonary (lung) ventilation studies.
Ytterbium-169 (32 d):
Used for cerebrospinal fluid studies in the brain.
Ytterbium-177 (1.9 h):
Progenitor of Lu-177.
Yttrium-90 (64 h)*:
Used for cancer brachytherapy and as silicate colloid for the relieving the pain of arthritis in larger synovial joints. Pure beta emitter and of growing significance in therapy, especially liver cancer.
Radioisotopes of gold and ruthenium are also used in brachytherapy.
* fission product
Carbon-11, Nitrogen-13, Oxygen-15, Fluorine-18:
These are positron emitters used in PET for studying brain physiology and pathology, in particular for localising epileptic focus, and in dementia, psychiatry and neuropharmacology studies. They also have a significant role in cardiology. F-18 in FDG (fluorodeoxyglucose) has become very important in detection of cancers and the monitoring of progress in their treatment, using PET.
Cobalt-57 (272 d):
Used as a marker to estimate organ size and for in-vitro diagnostic kits.
Copper-64 (13 h):
Used to study genetic diseases affecting copper metabolism, such as Wilson's and Menke's diseases, for PET imaging of tumours, and also cancer therapy.
Copper-67 (2.6 d):
Beta emitter, used in therapy.
Fluorine-18 (110 min) as FLT (fluorothymidine), F-miso (fluoromisonidazole), 18F-choline:
It decays with positron emission, so used as tracer with PET, for imaging malignant tumours.
Gallium-67 (78 h):
Used for tumour imaging and locating inflammatory lesions (infections).
Gallium-68 (68 min):
Positron emitter used in PET and PET-CT units. Derived from germanium-68 in a generator.
Germanium-68 (271 d):
Used as the 'parent' in a generator to produce Ga-68.
Indium-111 (2.8 d):
Used for specialist diagnostic studies, e.g. brain studies, infection and colon transit studies. Also for locating blood clots, inflammation and rare cancers.
Iodine-123 (13 h):
Increasingly used for diagnosis of thyroid function, it is a gamma emitter without the beta radiation of I-131.
Iodine-124 (4.2 d):
Tracer, with longer life than F-18, one-quarter of decays are positron emission so used with PET. Also used to image the thyroid using PET.
Krypton-81m (13 sec) from Rubidium-81 (4.6 h):
Kr-81m gas can yield functional images of pulmonary ventilation, e.g. in asthmatic patients, and for the early diagnosis of lung diseases and function.
Rubidium-82 (1.26 min):
Convenient PET agent in myocardial perfusion imaging.
Strontium-82 (25 d):
Used as the 'parent' in a generator to produce Rb-82.
Thallium-201 (73 h):
Used for diagnosis of coronary artery disease other heart conditions such as heart muscle death and for location of low-grade lymphomas. It is the most commonly used substitute for technetium-99 in cardiac-stress tests.
OECD/NEA 2012, A Supply & Demand Update of the Mo-99 Market
IAEA 2015, Feasibility of Producing Molybdenum-99 on a Small Scale Using Fission of Low Enriched Uranium or Neutron Activation of Natural Molybdenum, Technical reports series #478
What are radioisotopes?
Many of the chemical elements have a number of isotopes. The isotopes of an element have the same number of protons in their atoms (atomic number) but different masses due to different numbers of neutrons. In an atom in the neutral state, the number of external electrons also equals the atomic number. These electrons determine the chemistry of the atom. The atomic mass is the sum of the protons and neutrons. There are 82 stable elements and about 275 stable isotopes of these elements.
When a combination of neutrons and protons, which does not already exist in nature, is produced artificially, the atom will be unstable and is called a radioactive isotope or radioisotope. There are also a number of unstable natural isotopes arising from the decay of primordial uranium and thorium. Overall there are some 1800 radioisotopes.
At present there are up to 200 radioisotopes used on a regular basis, and most must be produced artificially.
Radioisotopes can be manufactured in several ways. The most common is by neutron activation in a nuclear reactor. This involves the capture of a neutron by the nucleus of an atom resulting in an excess of neutrons (neutron rich). Some radioisotopes are manufactured in a cyclotron in which protons are introduced to the nucleus resulting in a deficiency of neutrons (proton rich).
The nucleus of a radioisotope usually becomes stable by emitting an alpha and/or beta particle (or positron). These particles may be accompanied by the emission of energy in the form of electromagnetic radiation known as gamma rays. This process is known as radioactive decay.
Radioactive products which are used in medicine are referred to as radiopharmaceuticals.