The vast majority of the public thinks that research reactors, such as the High Flux Reactor (HFR) in Petten, the Netherlands, are essential for the supply of medical radioisotopes. And indeed these nuclear reactors are currently producing the vast majority of the isotopes. The nuclear industries like to maintain this widespread misunderstanding to justify their right to exist. A brief look in the history of nuclear medicine learns that all medical radioisotopes were originally manufactured by another type of production. The first medical applications of radioisotopes paralleled the development of the nuclear physics instruments which all these isotopes produced: the (charged) particle accelerators. Currently, these instruments are mistakenly purely seen as tools in fundamental scientific research.
2.1 Original production of radioisotopes
Tracer principal
Radiopharmaceuticals are used as radioactive tracers for the diagnosis and treatment of patients. The Hungarian chemist George Charles de Hevesy, born as Hevesy György, published the first paper on the radioactive tracer concept in 1913. He coined the term radioindicator or radiotracer and introduced the tracer principle in biomedical sciences. An important characteristic of a tracer is that it can facilitate the study of components of a homeostatic system without disturbing their function. In 1924, the tracer concept paved the way for the use of radioisotopes as diagnostic tools. In 1927, the US physicians Hermann Blumgart and Soma Weiss injected solutions of bismuth-214 (214Bi) into the veins of men to study the velocity of blood.
Particle accelerator
After the discoveries of the cyclotron by Ernest Lawrence in 1931 and artificial radioactivity by Irène Curie and Jean-Frédéric Joliot in 1934, it was possible to make practically every imaginable radioisotope for use in diagnostics or in therapy. Isotopes such as iodine-131 (131I), phosphorus-32
(32P) and cobalt-60 (60Co) are already used in diagnostics and therapy since the mid-1930s.4 By bombarding an aluminum sheet with particles emitted by polonium Curie and Joliot created for the first time a radioactive element, which they baptized radio-phosphorus. Coupled with the Geiger counter’s detection capabilities, their discovery markedly expanded the range of possible radioisotopes for clinical tracer studies. Enrico Fermi produced a whole range of radioisotopes, including phosphorus-32 (32P). Soon 32P was employed for the first time to treat a patient with leukemia. Ernest Lawrence recognized the medical potential of radioisotopes. His brother, John, a hematologist, helped researched the field’s potential and established and administered the therapeutic procedures. In 1936 he treated a 28-year-old leukemia patient using 32P produced in one of his brother’s cyclotrons. It was for the first time that a radioisotope had been used in the treatment of a disease, marking the birth of nuclear medicine.
In 1938, Emilio Segre discovered technetium-99m (99mTc), and thyroid physiology was studied by using radioactive iodine. It was discovered that thyroid accumulated radioiodine (131I). Consequently it was soon realized that 131I could be used to study abnormal thyroid metabolism in patients with goiter and hyperthyroidism. More specifically, in patients with thyroid cancer, distant metastases were identified by scanning the whole body with the Geiger counter. The names radioisotope scanning and atomic medicine were introduced to describe the medical field’s use of radioisotopes for the purpose of diagnosis and therapy. Strontium-89 (89Sr), another compound that localizes in the bones is currently used to treat pain in patients whose cancer has spread to their bones, was first evaluated in 1939.5 All of these radioisotopes are now considered as ‘typical reactor-produced isotopes’
(The first successful cyclotron)
The first commercial medical cyclotron was installed in 1941 at Washington University, St. Louis, where radioactive isotopes of phosphorus, iron, arsenic and sulfur were produced. Soon there hadn’t been enough cyclotron capacity to fulfill the rising demand of isotopes. Civilian use of a military nuclear reactor provided relief to the producers of pharmaceuticals. The Manhattan Project – the US-led project to develop the first atomic bomb - resulted in an unprecedented expansion of radiation research and expertise, as well as its diagnostic and therapeutic application in nuclear medicine, including human experimentation. As a byproduct of nuclear reactor development, radioisotopes came to abound. As a result of this most radioisotopes of medical interest began to be produced in a nuclear reactor during World War II. Especially in the Oak Ridge reactor, which was constructed under the secrecy of the Manhattan Project. To protect this secrecy, the 32P produced by the reactor had to appear as if it had been produced by a cyclotron. Thus, 32P was sent from Oak Ridge to the cyclotron group at the University of California at Berkeley, from which it was distributed to the medical centers. The shortage of radioisotopes ended in 1945, when isotopes became widely available for research and medical use, including reactor-produced 131I from Oak Ridge. Globally, particle accelerators produced the vast majority of radioisotopes with medical applications until the 1950s when other countries followed the US by using reactor-based isotopes.
2.2 The rise of reactor-produced radioisotopes
After the war, the US continued its atomic research in a series of national laboratories, among them Los Alamos and Oak Ridge. These labs were supervised by the then Atomic Energy Commission (AEC), a governmental agency to coordinate the military, economic, political, and scientific work in atomic energy. The main mission of the AEC was promoting the military use of nuclear material, but “giving atomic energy a peaceful, civilian image” was also part of it. Including the promotion of research, among which radiobiology and nuclear medicine. Immediately after the war, radioisotopes flooded the laboratories and hospitals. In 1946, as part of the Isotope Distribution Program of the AEC, the Oak Ridge Reactor (see archive picture below) began delivering radioisotopes to hospitals and universities nationwide. In 1948 isotopes for biomedical research, cancer diagnostics and therapy even became free of charge, which can be considered as an early forerunner of the Atoms for Peace Campaign in the early 1950s aimed to promote the ‘the peaceful use of nuclear energy’. The rest of the western world followed this change in isotopes production. Entirely prospectless the particle accelerators tasted defeat in the competition with the subsidized nuclear reactors.6
The cyclotron-based radioisotopes production for medical applications revived a little in the 1950s, after the discovery that thallium-201 (201Tl) could be used as an ideal tracer for detecting myocardial perfusion. Thallous chloride labeled with 201Tl remains the gold standard for measuring cardiac blood flow despite the availability of technetium-99m myocardial perfusion agents.
(Oak Ridge National Laboratory – early 1950s)
2.3 Nuclear imaging modalities
Gamma camera
The era of nuclear medicine, as a diagnostic specialty began following the discovery of the gamma camera based on the principle of scintillation counting, first introduced by Hal Anger in 1958. Since then, nuclear medicine has dramatically changed our view of looking at disease by providing images of regional radiotracer distributions and biochemical functions. Over the last five decades, a number of radiopharmaceuticals have also been designed and developed to image the structure and function of many organs and tissues.
Molybdenum-99/Technetium-99m (99Mo/99mTc) generators
In 1959 the U.S. Brookhaven National Laboratory (BNL) started to develop a generator to produce technetium-99m from the reactor fissionable product molybdenum-99, which has a much longer half-life. The first 99mTc radiotracers were developed at the University of Chicago in 1964. Between 1963 and 1966, the interest in technetium grew as its numerous applications as a radiotracer and diagnostic tool began to be described in publications. By 1966, BNL was unable to cope with the demand for 99Mo/99mTc generators. BNL withdrew from production and distribution in favor of commercial generators. The first commercial generator was produced by Nuclear Consultants, Inc. of St. Louis, later taken over by Mallinckrodt (Covidien), and Union Carbide Nuclear Corporation, New York.7
Computed Tomography (CT)
CT is a medical imaging method employing tomography created by computer processing. The CT-scan was originally known as the EMI-scan as it was developed at a research branch of EMI, a company best known today for its music and recording business. It was later known as computed axial tomography (CAT or CT scan) and body section röntgenography. Although the term computed tomography could be used to describe positron emission tomography and single photon emission computed tomography, in practice it usually refers to the computation of tomography from X-ray images. The initial use of CT for applications in radiological diagnostics during the 1970s sparked a revolution in the field of medical engineering. In 1972, the first EMI-Scanner was used to scan a patient’s brain. CT provided diagnostic radiology with better insight into the pathogenesis of the body, thereby increasing the chances of recovery.8
Positron Emission Tomography (PET)
Another major breakthrough in the history of nuclear medicine arrived with the preparation of fluorodeoxyglucose (FDG) labeled with fluorine-18 (18F) in the mid-1970s. Use of 18F-FDG for studying the glucose metabolism lead to the development of the imaging modality positron emission tomography (PET). The use of 18F-FDG in combination with a PET-camera produced images of an excellent quality of the brains and the heart for studying aberrations, and the detection of metastases of tumors. Subsequently a large number of other 18F-labeled radiopharmaceuticals were developed and the use of new isotopes grows fast. PET scans are performed to detect cancer; determine whether a cancer has spread in the body; assess the effectiveness of a treatment plan, such as cancer therapy; determine if a cancer has returned after treatment; determine blood flow to the heart muscle; determine the effects of a heart attack, or myocardial infarction, on areas of the heart; identify areas of the heart muscle that would benefit from a procedure such as angioplasty or coronary artery bypass surgery (in combination with a myocardial perfusion scan); evaluate brain abnormalities, such as tumors, memory disorders and seizures and other central nervous system disorders; and to map normal human brain and heart function.9
Single Photon Emission Computed Tomography (SPECT)
At the end of the 1970s single photon emission tomography (SPECT) was introduced. Its development parallels the development of PET. SPECT images are produced from multiple 2D projections by rotating one or more gamma cameras around the body. Reconstruction using methods similar to those used in X-ray CT provides 3D data sets allowing the tracer biodistribution to be displayed in orthogonal planes. SPECT uses gamma-emitting radioisotopes, such as 99mTc and the cyclotron-produced indium-111 (111In) and iodine- 123 (123I). The advantages of SPECT over planar scintigraphy can be seen in the improvement of contrast between regions of different function, better spatial localisation, improved detection of abnormal function and, importantly, greatly improved quantification.10
Hybrids of CT, PET, SPECT and MRI
The last decade has seen the development of hybrid imaging technologies. PET or SPECT are combined with X-ray computed tomography (CT). Experts agree that PET/CT and SPECT/CT are superior techniques over stand-alone PET and SPECT in terms of diagnostic accuracy. Insiders expect that these hybrid imaging technologies will become the gold standard for conventional scintigraphy. Hybrid cameras combining PET and MRI have already been introduced. They also prospect the development of new hybrid forms for a certain organ or body part. These systems will offer the virtually unlimited potential of simultaneously acquiring morphologic, functional, and molecular information about the living human body.11
2.4 Drawbacks of using PET, SPECT and especially (devices combined with) CT
Despite the major improvements in nuclear medicine by using modalities such as CT, PET and SPECT, investigations in the US uncovered that 20 to 50% of these high-tech scans have been unnecessary, because they offer no support by making a diagnosis.12 The U.S. National Cancer Institute reports alarming figures on the high radiation exposure of patients. It projects 29,000 excess cancers from the 72 million CT scans that Americans got in 2007 alone. Nearly 15,000 of those cancers could be fatal.13
An investigation by the US National Council for Radiation Protection and Measurements shows that frequent use of radioisotopes at one patient can result in a too high radiations exposure. It uncovered that the average dose has been increased from 3,6 millisievert (mSv) in the early 1980s to 6,2 mSv in 2006. The average dose per person is an average over the population of the United States.14 Apparently the enthusiasm to use these modern modalities has gone too far, which reminds to the widespread use of X-ray equipment in the 1950s.
By the end of February 2010, the U.S. Food and Drug Administration announced a federal program to prevent unnecessary radiation exposure from nuclear imaging devices and new safety requirements for manufacturers of CT scans. Medical doctors are urged to think twice before ordering such scans in order to weigh the risk and the benefit. According to estimates of David Brenner, director of Columbia University's Center for Radiological Research in New York, 20 million adults and one million children are being irradiated unnecessarily and up to 2% of all cancers in the U.S. at present may be caused by radiation from CT scans.15 The American Society for Radiation Oncology (ASTRO) issued a six-point plan that has to improve safety and quality in using CT and other nuclear imaging modalities and reduce the chances of medical errors.16 So far, there are no figures known about the situation in Europe.
Though CT produces images with far greater clarity and detail than regular X-ray exams, it has been estimated that the average radiation dose of one CT scan is equal to roughly 500 chest X-rays. An international study, conducted by the IAEA and published in April 2010 has shown that some countries are over-exposing children to radiation when performing CT scans. These children are receiving adult-sized radiation doses, although experts have warned against the practice for over a decade. An additional problem in developing countries is that the available CT machines are older models without the automatic exposure controls found in modern equipment. This function can detect the thickness of the section of the patient´s body that is being scanned and can therefore optimize the level of radiation dose, avoiding unnecessary exposure. The IAEA has started a program to reduce unnecessary child radiation doses.17
Meanwhile newer CT technology has been developed to reduce a patient’s exposure to excess radiation. Patients who got a type of heart CT scan called coronary angiography received 91% less radiation than those who were scanned with a traditional CT scanner. Although in the U.S. heart CTs only accounted for 2.3 million out of 65 to 70 million CT scans performed in 2006, they are worrisome because they deliver high radiation doses.18
2.5 Methods in radiotherapy
Brachytherapy is used for primary cancer treatment, for bone pain palliation, and for radiosynovectomy, used for patients that are suffering from joint pain. In cancer treatment the radionuclides are placed very close to or inside the tumor. During the therapy, controlled doses of high-energy radiation, usually X-rays, destroy cancer cells in the affected area. The radiation source is usually sealed in a small holder called an implant. Implants may be in the form of thin wires, plastic tubes called catheters, ribbons, capsules, or seeds. The implant is put directly into the body. Brachytherapy dates back to the time before the discovery of the cyclotron when natural radioisotopes, such as radium-226 (226Ra), were used in the treatment. Currently, common radionuclides are iridium-192 (192Ir), yttrium-90 (90Y), iodine-125 (125I) and palladium-103 (103Pd).19
(accelerator used in fundamental scientific research)
4. From Radioisotopes to Medical Imaging, History of Nuclear Medicine Written at Berkeley, 9 September 1996. http://www.lbl.gov/Science-Articles/Archive/nuclear-med-history.html Lawrence And His Laboratory - A Historian's View of the Lawrence Years: Ch2 The Headmaster and His School. Lawrence Berkeley National Laboratory, 1981. http://www.lbl.gov/Science-Articles/Research-Review/Magazine/1981/81fchp...
5. Chemistry Explained - Nuclear Medicine: http://www.chemistryexplained.com/Ne-Nu/Nuclear-Medicine.html
6. Rheinberger, Hans-Jörg; Putting Isotopes To Work: Liquid Scintillation Counters, 1950-1970. Max-Planck-Institut für Wissenschaftsgeschichte, Berlin 1999. pp.4-5 http://edoc.mpg.de/get.epl?fid=3199&did=46724&ver=0
7 The Technetium-99m Generator: http://www.bnl.gov/bnlweb/history/tc-99m.asp
8 Bartlett, Christopher A.; EMI and the CT Scanner [A] and B] www.blackwellpublishing.com/grant/docs/10EMI.pdf
9 Positron Emission Tomography – Computed Tomography (PET/CT); Radiology Info http://www.radiologyinfo.org/en/info.cfm?PG=pet
10 What is SPECT?: http://www.spect.net/: Nuclear Technology Review 2007, IAEA. p.61
11 Nuclear Medicine 2020: What Will the Landscape Look Like? http://www.molecularimaging.net/index.php?option=com_ articles&view=article&id=17661:nuclear-medicine-2020-what-will-the-landscape-look-like
12 Where Can $700 Billion In Waste Be Cut Annually From The U.S. Healthcare System? Robert Kelley, Thomson Reuters, October 2009. http://www.ncrponline.org/PDFs/Thomson_Reuters_White _Paper_on_Healthcare_Waste.pdf
13 Radiation From CT Scans May Raise Cancer Risk, 15 December 2009 http://www.npr.org/templates/story/story.php?storyId=121 436092&ft=1&f=1007
14 Medical Radiation Exposure of the U.S. Population Greatly Increased Since the Early 1980s, NCRP Press Release, 3 March 2009. http://www.ncrponline.org/Press_Rel/Rept_160_Press_Rel ease.pdf
People Exposed to More Radiation from Medical Exams, Health Physics Society, 9 March 2009. http://hps.org/media/documents/NCRP_Report-People_Exposed_to_More_Radiat... ms_9Mar.pdf
15 Radiation Risks Prompt Push to Curb CT Scans. Wall Street Journal, 2 March 2010. http://online.wsj.com/article/SB100014240527487042998 04575095502744095926.html
16 Medical Group Urges New Rules on Radiation. New York Times, February 4, 2010. http://www.nytimes.com/2010/02/05/health/05radiation- .html
17 IAEA Aims to Reduce Unnecessary Child Radiation Doses - New Study Shows Global Variation in Dose Levels for Child CT Scans. IAEA, 23 April 2010: http://www.iaea.org/NewsCenter/News/2010/childcts cans.html
18 Newer heart CTs deliver far less radiation. Reuters, 24 February 2010
19 Flynn A et al. (2005). “Isotopes and delivery systems for brachytherapy”. in Hoskin P, Coyle C. Radiotherapy in practice: brachytherapy. New York: Oxford University Press.