39K and ⁴¹K are stable isotopes and together constitute 99.99% of potassium.

Although only present in the low concentration of 0.01%, in contrast to the other potassium isotopes, ⁴⁰K emits radiation and therefore must be considered as a radioisotope of potassium.

The relative abundances of the three isotopes of potassium are constant, regardless of source. Therefore, as a consequence of there being 150 to 200 grams of potassium in the adult human body, some 15 to 20 milligrams of it must always exist as the radioisotope ⁴⁰K.

Another source of natural radioactivity is the air we breathe.

Bombarded by radiation from the Sun and outer space, atmospheric nitrogen undergoes nuclear reactions to produce the carbon radioisotope, carbon-14 (¹⁴C) and radioactive hydrogen (tritium, ³H).

In the form of carbon dioxide, ¹⁴C enters the Earth's carbon pool is fixed by photosynthesis in green plants, which are then consumed by herbivores. Of course, at the head of this food chain is the human animal, which sustains itself by consuming ¹⁴C of both vegetable and animal origin.

During our lifetime we participate in natural processes involving ¹⁴C absorption and excretion and, as a result, the ¹⁴C in our tissues gradually increases to an equilibrium level. On a much longer time scale, the levels of ¹⁴C in our tissues decrease due to radioactive decay. Because the half-life of ¹⁴C is 5730 years, the effect of decay is not noticeable while we are alive. Only after we are dead and have stopped assimilating the radioisotope is an age effect measurable. Then an accurate measure of the residual ¹⁴C becomes a very sensitive gauge of the age of an object that was once alive.

The technique of measuring ¹⁴C content is possibly the most important tool available to archaeologists for dating historical artefacts. Tandem Accelerator

The most significant of the naturally occurring radioisotopes are radon-222 (²²²Rn) and radon-220 (²²⁰Rn). These radioactive gases seep out from rocks containing uranium and thorium to be responsible for between 50 and 80% of the background radiation exposure.

The concentration of radon in air is highest in localities where igneous rocks are prevalent. It can be trapped in poorly ventilated buildings. The sedimentary nature of the underlying rocks and the outdoor life-style contribute to the Australian exposure to radon being relatively low.

Much higher levels of natural radioactivity have existed throughout the history of the Earth. Fortunately, the planet is old enough to have allowed the original intense radioactivity to all but disappear.

However, we should not lose sight of the fact that all species of plants and animals have evolved to their present life-forms in this radiation environment. No plant or animal species has ever known absolute protection from radiation.

Artificial Radioactivity

Many practical applications for radioisotopes in scientific research had already been demonstrated in the period 1920 to the early 1930s. However, the few naturally occurring radioisotopes that were available severely limited the scope of what was possible. The full potential was not realised until radioisotopes could be produced artificially.

The first major advance occurred in 1934 with the invention of the cyclotron by Ernest Lawrence in Berkeley, California. With this electrical machine being used to accelerate DEUTERONS (ions of the stable hydrogen isotope, ²H) to very high speeds, it became possible to create the nuclear instability that we now know is a pre-requisite of radioactivity.

By directing a beam of the fast-moving deuterons at a carbon target, Lawrence induced a reaction which resulted in the formation of a radioisotope with a half life of 10 minutes.

Radioactivity had been created by disturbing the natural balance of 6 protons and 6 neutrons in the nucleus of the carbon atom with the insertion of another proton.

The product atom now had 7 protons in its nucleus, was no longer carbon and, in fact, had been changed to a nitrogen species. The neutron count in the nucleus of the product atom, however, stayed at 6; this was insufficient to stabilise the 7 protons that were now present in the nucleus.

The overall effect of bombarding carbon with deuterons in the cyclotron was not only to convert the carbon to nitrogen, but also to ensure that the new species was radioactive.

Following this experiment, the path was opened to the discovery and production of many more radioisotopes from the cyclotron.

In the same year as Lawrence experimented with the cyclotron, Enrico Fermi in Rome started systematically exposing the elements in the Periodic Table to beams of neutrons.

In the course of this work, Fermi identified around 40 new radio-active species and thus was able to show how neutrons that had been slowed down prior to interacting with the targets gave rise to much higher levels of radioactivity.

However, the significance of his most important experiment initially eluded him. That was when uranium was exposed to neutrons and several new radioactive species were produced as a consequence.

Accounting for the multiplicity of products induced by the neutron bombardment of uranium occupied many brilliant minds for the next four years.

Repeating Fermi's experiments, Otto Hahn, Lise Meitner and Fritz Strassman in Berlin concluded that the only explanation was nuclear fission - a process in which uranium nuclei are split into barium, krypton and smaller amounts of other highly radioactive disintegration products, all accompanied by the release of enormous amounts of energy.

The possibility that nuclear fission could be developed into a bomb of enormous power was not overlooked.

Mindful of the perils this latest scientific discovery imposed on world peace, Meitner secretly slipped out of Germany to Sweden where she explained nuclear fission. The discovery was published in Nature in January 1939.

In view of the darkening war clouds in Europe, Fermi, who by now was resident in the USA, was moved to draft a letter (with the collaboration of Leo Szilard and Eugene Wigner), which was signed by Albert Einstein and then delivered on 11 October 1939 to US President Roosevelt to alert him to the danger.

The President reacted immediately to initiate the Manhattan Project which ultimately led to the creation of the first nuclear reactor then to the nuclear weapons that brought World War II to a conclusion.

The development of the cyclotron had provided the scientific world with a prolific source of artificial radioisotopes from which were facilitated enormous advances in the field of biochemistry.

However, the nuclear reactor's capability of producing copious quantities of radioisotopes completely eclipsed the cyclotron.

Once the war was over, the US authorities lost little time in making radioisotopes available "for peaceful and humanitarian ends".

Radioisotopes in Nuclear Medicine

In NUCLEAR MEDICINE a radio-isotope is administered to a patient either to aid the diagnosis of disease or for the treatment of disease.

The radioisotopes used in DIAGNOSTIC nuclear medicine are selected on the basis of their ability to provide useful clinical information (usually by providing an image of an internal structure in the human body or by visualising various stages in the function of an organ) while exposing the patient to only minimal radiation.

To ensure this, certain selection criteria are applied :-

For example the radioisotope should -

• possess a short half-life(hours) which is commensurate with the duration of the investigative procedure
• not emit alpha or beta radiation, because these particles would be trapped in the patient's tissues and not be detected externally
• emit gamma radiation of an energy which will allow its origin to be efficiently assessed
• be available in the highest possible specific activity, so that it will not invoke either a toxic or pharmacological response in the patient.

On the other hand, in THERAPEUTIC nuclear medicine, a different set of criteria apply :-

• the half life should not be the cause of an extended stay in hospital for the patient
• the radioisotope should emit particulate (alpha or beta) radiation of sufficient energy to penetrate to all parts of the lesion
• it should, in addition, emit gamma rays to facilitate the assessment that the appropriate region of the body has been targeted.

From a possible population of more than 2300, only a handful of radioisotopes come close to satisfying the selection criteria for use as a diagnostic agent. Of these, reactor-produced technetium-99m (^99mTc) is pre-eminent, being used in more than 80% of the estimated 100,000 patient studies that are performed world-wide each day.

After (^99mTc), a series of cyclotron produced radioisotopes, such as thallium-201(²⁰¹Tl), gallium-67 (⁶⁷Ga), indium-111(¹¹¹In) and iodine-123(¹²³I), are the next most popular.

A different group of radioisotopes is used for therapeutic purposes.

Well-established examples are iodine-131 (¹³¹I), phosphorus-32 (³²P) and yttrium-90 (⁹⁰Y) but several others are being investigated for possible application.

Examples of these are samarium-153 (¹⁵³Sm), rhenium-186 and rhenium-188 (¹⁸⁶Re, ¹⁸⁸Re), dysprosium-165 (¹⁶⁵Dy) and holmium-166 (¹⁶⁶Ho).

The various radioactive substances found naturally in terrestrial materials are very ancient remnants of the time when the Earth was formed. None of them satisfy the nuclear medicine selection rules and consequently are not used clinically.

Reactors and Cyclotrons

A popular misconception, which has been particularly evident in the public debate that has continued since the reactor disaster at Chernobyl, is that the cyclotron is an alternative to the nuclear reactor for the production of artificial radioisotopes.

Like most other misconceptions, this one also contains an element of truth.

It is important in promoting the benefits that radioisotopes have to offer society, that the respective roles of the reactor and the cyclotron are known and properly understood.

For the vast majority of radioisotopes, including almost all those used medically, the cyclotron complements the reactor - it does not replace it.

As described earlier, radioactivity is the end-result from disturbing the balance between neutrons and protons in the atomic nucleus.

In theory, radioactivity can be achieved by :-

1. adding a neutron to the nucleus, or
2. removing a proton from the nucleus,or
3. removing a neutron from the nucleus,or
4. adding a proton to the nucleus.

In practice, effects (1) and (2) can be achieved through reactions only available via a nuclear reactor - giving rise to a family of radioisotopes which are described as neutron rich.

On the other hand, effects (3) and (4), leading to the neutron deficient family of radioisotopes, are achievable only in a cyclotron.

Therefore the decision on which nuclear effect to exploit will direct whether a reactor or a cyclotron must be used.

Hence the cyclotron is complementary to the reactor, providing the producer with access to an even greater variety of radioisotope products.

Rarely do circumstances exist which allow either a reactor or a cyclotron to be used to produce the same radioisotope. The prime example is ^99mTc.

As indicated above, this radioisotope has the greatest impact on our welfare since it is used in more than 80% of nuclear medicine studies.

Those interested in minimising the use of nuclear reactors, strongly promote the cyclotron alternative for^99mTc. However, for this goal to be achieved a number of severe practical difficulties must be overcome.

For example, the cyclotron method is totally dependent on the availability of a rare and expensive starting material, a highly enriched stable isotope of molybdenum,¹⁰⁰Mo. Cyclotron production inevitably gives rise to impurities in the ^99mTc which increase the radiation exposure of each patient and could be responsible for inferior clinical images. It is also probable that cyclotron produced ^99mTc would be considerably more expensive than its reactor produced counterpart. Finally, current pharmaceutical regulations, specifying minimum drug quality, would prohibit the use of cyclotron ^99mTc in humans.

Research continues in an attempt to ameliorate these problems.

Meanwhile, around the world, ^99mTc is exclusively produced in nuclear reactors where there exists the option of two different technologies.

Most commonly, ^99mTc is obtained as the result of the fission of uranium(²³⁵U). From this rather complex process ^99mTc is produced in a highly purified state and at a reasonable price. There are, however, difficult waste products to be contended with.

Radiopharmaceuticals

Every developed nation needs access to one or more sources of artificially produced radioisotopes in order to provide its community with what has come to be expected as the full range of medical services.

When a radioisotope is designed for use in a medical application, it is usual for it to be presented in a form which directs in which part of the body it will concentrate.

This type of presentation is usually referred to as a RADIOPHARMACEUTICAL.

One particular radioisotope may be presented in a number of active forms, each designed to target specific tissues in the human body.

It is implicit in the formulation of a radiopharmaceutical that it possesses all the necessary attributes of purity, stability and safety.

Like any other drug, it must be proved safe and clinically effective through a series of clinical trials.

A radiopharmaceutical is the end-product of extensive chemical processing of a substance after it has been irradiated in a cyclotron or nuclear reactor.

Most commonly, the preparation of a radio-pharmaceutical involves :-

• extracting the radioisotope from the bulk of the target substance
• purification from undesirable chemical and radioisotopic impurities
• chemical conversion to a biologically specific form (may be more than one active form, each targeting specific groups of tissues in the human body)
• making the preparation suitable for administration to patients
• testing the quality of the final product.

While radiopharmaceuticals must comply with the normal requirements of drugs, their production must also contend with the special problems of radiation safety and short half-lives.

In Australia, radiopharmaceuticals have been routinely produced by the Australian Nuclear Science and Technology Organisation (ANSTO) for over a quarter of a century. ANSTO uses both its reactor, at Lucas Heights, and its cyclotron, located on the campus of Royal Prince Alfred Hospital, to create a range of artificial radioisotopes for a domestic and export market.

Special laboratory facilities exist to ensure that the products from these two major nuclear resources are processed into medical products essential to the continued well-being of the Australian community.

© ANSTO August 1996