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United States Atomic Energy Commission Division of Technical Information Library of Congress Catalog Card Number: 66-62749 1966

Radioisotopes in Medicine

INTRODUCTION

History

The history of the use of radioisotopes for medical purposes is filled with names of Nobel Prize winners. It is inspiring to read how great minds attacked puzzling phenomena, worked out the theoretical and practical implications of what they observed, and were rewarded by the highest honor in science.

A French physicist, Antoine Henri Becquerel, newly appointed to the chair of physics at the Ecole Polytechnique in Paris, saw that this discovery opened up a new field for research and set to work on some of its ramifications. One of the evident features of the production of X rays was the fact that while they were being created, the glass of the vacuum tube gave off a greenish phosphorescent glow. This suggested to several physicists that substances which become phosphorescent upon exposure to visible light might give off X rays along with the phosphorescence.

Becquerel experimented with this by exposing various crystals to sunlight and then placing each of them on a black paper envelope enclosing an unexposed photographic plate. If any X rays were thus produced, he reasoned, they would penetrate the wrapping and create a developable spot of exposure on the plate. To his delight, he indeed observed just this effect when he used a phosphorescent material, uranium potassium sulfate. Then he made a confusing discovery. For several days there was no sunshine, so he could not expose the phosphorescent material. For no particular reason Becquerel developed a plate that had been in contact with uranium material in a dark drawer, even though there had been no phosphorescence. The telltale black spot marking the position of the mineral nevertheless appeared on the developed plate! His conclusion was that uranium in its normal state gave off X rays or something similar.

At this point, Pierre Curie, a friend of Becquerel and also a professor of physics in Paris, suggested to one of his graduate students, his young bride, Marie, that she study this new phenomenon. She found that both uranium and thorium possessed this property of radioactivity, but also, surprisingly, that some uranium minerals were more radioactive than uranium itself. Through a tedious series of chemical separations, she obtained from pitchblende small amounts of two new elements, polonium and radium, and showed that they possessed far greater radioactivity than uranium itself. For this work Becquerel and the two Curies were jointly awarded the Nobel Prize in physics in 1903.

At the outset, Roentgen had noticed that although X rays passed through human tissue without causing any immediate sensation, they definitely affected the skin and underlying cells. Soon after exposure, it was evident that X rays could cause redness of the skin, blistering, and even ulceration, either in single doses or in repeated smaller doses. In spite of the hazards involved, early experimenters determined that X rays could destroy cancer tissues more rapidly than they affected healthy organs, so a basis was established quite soon for one of Medicine's few methods of curing or at least restraining cancer.

The work of the Curies in turn stimulated many studies of the effect of radioactivity. It was not long before experimenters learned that naturally radioactive elements--like radium--were also useful in cancer therapy. These elements emitted gamma rays, which are like X rays but usually are even more penetrating, and their application often could be controlled better than X rays. Slowly, over the years, reliable methods were developed for treatment with these radioactive sources, and instruments were designed for measuring the quantity of radiation received by the patient.

The next momentous advance was made by Frederic Joliot, a French chemist who married Irene Curie, daughter of Pierre and Marie Curie. He discovered in 1934 that when aluminum was bombarded with alpha particles from a radioactive source, emission of positrons was induced. Moreover, the emission continued long after the alpha source was removed. This was the first example of artificially induced radioactivity, and it stimulated a new flood of discoveries. Frederic and Irene Joliot-Curie won the Nobel Prize in chemistry in 1935 for this work.

Others who followed this discovery with the development of additional ways to create artificial radioactivity were two Americans, H. Richard Crane and C. C. Lauritsen, the British scientists, John Cockcroft and E. T. S. Walton, and an American, Robert J. Van de Graaff. Ernest O. Lawrence, an American physicist, invented the cyclotron , a powerful source of high-energy particles that induced radioactivity in whatever target materials they impinged upon. Enrico Fermi, an Italian physicist, seized upon the idea of using the newly discovered neutron and showed that bombardment with neutrons also could induce radioactivity in a target substance. Cockcroft and Walton, Lawrence, and Fermi all won Nobel Prizes for their work.

More persons are trained every year in methods of radioisotope use and more manufacturers are producing and packaging radioactive materials. This booklet tells some of the successes achieved with these materials for medical purposes.

What Is Radiation?

Radiation is the propagation of radiant energy in the form of waves or particles. It includes electromagnetic radiation ranging from radio waves, infrared heat waves, visible light, ultraviolet light, and X rays to gamma rays. It may also include beams of particles of which electrons, positrons, neutrons, protons, deuterons, and alpha particles are the best known.

What Is Radioactivity?

It took several years following the basic discovery by Becquerel, and the work of many investigators, to systematize the information about this phenomenon. Radioactivity is defined as the property, possessed by some materials, of spontaneously emitting alpha or beta particles or gamma rays as the unstable nuclei of their atoms disintegrate.

What Are Radioisotopes?

Radioisotopes are isotopes that are unstable, or radioactive, and give off radiation spontaneously. Many radioisotopes are produced by bombarding suitable targets with neutrons now readily available inside atomic reactors. Some of them, however, are more satisfactorily created by the action of protons, deuterons, or other subatomic particles that have been given high velocities in a cyclotron or similar accelerator.

Radioactivity is a process that is practically uninfluenced by any of the factors, such as temperature and pressure, that are used to control the rate of chemical reactions. The rate of radioactive decay appears to be affected only by the structure of the unstable nucleus. Each radioisotope has its own half-life, which is the time it takes for one half the number of atoms present to decay. These half-lives vary from fractions of a second to millions of years, depending only upon the atom. We shall see that the half-life is one factor considered in choosing a particular isotope for certain uses.

Percent of 100 50 25 12.5 6.75 Radioactivity Beginning 1 2 3 4 of Life Half-life Half-lives Half-lives Half-lives 28 years 56 years 84 years 112 years

Most artificially made radioisotopes have relatively short half-lives. This makes them useful in two ways. First, it means that very little material is needed to obtain a significant number of disintegrations. It should be evident that, with any given number of radioactive atoms, the number of disintegrations per second will be inversely proportional to the half-life. Second, by the time 10 half-lives have elapsed, the number of disintegrations per second will have dwindled to ?/???? the original number, and the amount of radioactive material is so small it is usually no longer significant.

How Are Radioisotopes Used?

A radioisotope may be used either as a source of radiation energy , or as a tracer: an identifying and readily detectable marker material. The location of this material during a given treatment can be determined with a suitable instrument even though an unweighably small amount of it is present in a mixture with other materials. On the following pages we will discuss medical uses of individual radioisotopes--first those used as tracers and then those used for their energy. In general, tracers are used for analysis and diagnosis, and radiant-energy emitters are used for treatment .

Radioisotopes offer two advantages. First, they can be used in extremely small amounts. As little as one-billionth of a gram can be measured with suitable apparatus. Secondly, they can be directed to various definitely known parts of the body. For example, radioactive sodium iodide behaves in the body just the same as normal sodium iodide found in the iodized salt used in many homes. The iodine concentrates in the thyroid gland where it is converted to the hormone thyroxin. Other radioactive, or "tagged", atoms can be routed to bone marrow, red blood cells, the liver, the kidneys, or made to remain in the blood stream, where they are measured using suitable instruments.

Of the three types of radiation, alpha particles are of such low penetrating power that they cannot be used for measurement from outside the body. Beta particles have a moderate penetrating power, therefore they produce useful therapeutic results in the vicinity of their release, and they can be detected by sensitive counting devices. Gamma rays are highly energetic, and they can be readily detected by counters--radiation measurement devices--used outside the body.

For comparison, a sheet of paper stops alpha particles, a block of wood stops beta particles, and a thick concrete wall stops gamma rays.

In one way or another, the key to the usefulness of radioisotopes lies in the energy of the radiation. When radiation is used for treatment, the energy absorbed by the body is used either to destroy tissue, particularly cancer, or to suppress some function of the body. Properly calculated and applied doses of radiation can be used to produce the desired effect with minimum side reactions. Expressed in terms of the usual work or heat units, ergs or calories, the amount of energy associated with a radiation dose is small. The significance lies in the fact that this energy is released in such a way as to produce important changes in the molecular composition of individual cells within the body.

What Do We Mean by Tracer Atoms?

When a radioisotope is used as a tracer, the energy of the radiation triggers the counting device, and the exact amount of energy from each disintegrating atom is measured. This differentiates the substance being traced from other materials naturally present.

With one conspicuous exception, it is impossible for a chemist to distinguish any one atom of an element from another. Once ordinary salt gets into the blood stream, for example, it normally has no characteristic by which anyone can decide what its source was, or which sodium atoms were added to the blood and which were already present. The exception to this is the case in which some of the atoms are "tagged" by being made radioactive. Then the radioactive atoms are readily identified and their quantity can be measured with a counting device.

A radioactive tracer, it is apparent, corresponds in chemical nature and behavior to the thing it traces. It is a true part of it, and the body treats the tagged and untagged material in the same way. A molecule of hemoglobin carrying a radioactive iron atom is still hemoglobin, and the body processes affect it just as they do an untagged hemoglobin molecule. The difference is that a scientist can use counting devices to follow the tracer molecules wherever they go.

DIAGNOSIS

Pinpointing Disease

Mr. Peters, 35-year-old father of four and a resident of Chicago's northwest side, went to a Chicago hospital one winter day after persistent headaches had made his life miserable. Routine examinations showed nothing amiss and his doctor ordered a "brain scan" in the hospital's department of nuclear medicine.

Thirty minutes before "scan time", Mr. Peters was given, by intravenous injection, a minute amount of radioactive technetium. This radiochemical had been structured so that, if there were a tumor in his cranium, the radioisotopes would be attracted to it. Then he was positioned so an instrument called a scanner could pass close to his head.

As the motor-driven scanner passed back and forth, it picked up the gamma rays being emitted by the radioactive technetium, much as a Geiger counter detects other radiation. These rays were recorded as black blocks on sensitized film inside the scanner. The result was a piece of exposed film that, when developed, bore an architectural likeness or image of Mr. Peters' cranium.

Mr. Peters, who admitted to no pain or other adverse reaction from the scanning, was photographed by the scanner from the front and both sides. The procedure took less than an hour. The developed film showed that the technetium had concentrated in one spot, indicating definitely that a tumor was present. Comparison of front and side views made it possible to pinpoint the location exactly.

Surgery followed to remove the tumor. Today, thanks to sound and early diagnosis, Mr. Peters is well and back on the job. His case is an example of how radioisotopes are used in hospitals and medical centers for diagnosis.

In one representative hospital, 17 different kinds of radioisotope measurements are available to aid physicians in making their diagnoses. All the methods use tracer quantities of materials. Other hospitals may use only a few of them, some may use even more. In any case they are merely tools to augment the doctors' skill. Examples of measurements that can be made include blood volume, blood circulation rate, red blood cell turnover, glandular activity, location of cancerous tissue, and rates of formation of bone tissue or blood cells.

Of the more than 100 different radioisotopes that have been used by doctors during the past 30 years, five have received by far the greatest attention. These are iodine-131, phosphorus-32, gold-198, chromium-51, and iron-59. Some others have important uses, too, but have been less widely employed than these five. The use of individual radioisotopes in making important diagnostic tests makes a fascinating story. Typical instances will be described in the following pages.

Arsenic-74

Brain tumors tend to concentrate certain ions . When these ions are gamma-ray emitters, it is possible to take advantage of the penetrating power of their gamma rays to locate the tumor with a scanning device located outside the skull.

The electrical circuitry in the scanner is such that only those gamma rays are counted that impinge simultaneously on both counters. This procedure eliminates most of the "noise", or scattered and background radiation.

Chromium-51

Because chromium, in the molecule sodium chromate, attaches itself to red blood cells, it is useful in several kinds of tests. The procedures are slightly complicated, but yield useful information. In one, a sample of the patient's blood is withdrawn, stabilized with heparin and incubated with a tracer of radioactive sodium chromate. Excess chromate that is not taken up by the cells is reduced and washed away. Then the radioactivity of the cells is measured, just before injection into the patient. After a suitable time to permit thorough mixing of the added material throughout the blood stream, a new blood sample is taken and its radioactivity is measured. The total volume of red blood cells then can be calculated by dividing the total radioactivity of the injected sample by the activity per milliliter of the second sample.

In certain types of anemia the patient's red blood cells die before completing the usual red-cell lifetime of about 120 days. To diagnose this, red cells are tagged with chromium-51 in the manner just described. Then some of them are injected back into the patient and an identical sample is injected into a compatible normal individual. If the tracer shows that the cells' survival time is too short in both recipients to the same degree, the conclusion is that the red cells themselves must be abnormal. On the other hand, if the cell-survival time is normal in the normal individual and too short in the patient, the diagnosis is that the patient's blood contains some substance that destroys the red cells.

When chromium trichloride, CrCl?, is used as the tagging agent, the chromium is bound almost exclusively to plasma proteins, rather than the red cells. Chromium-51 may thus be used for estimating the volume of plasma circulating in the heart and blood vessels. The same type of computation is carried on for red cells . This procedure is easy to carry out because the radioactive chromium chloride is injected directly into a vein.

An ingenious automatic device has been devised for computing a patient's total blood volume using the ??Cr measurement of the red blood cell volume as its basis. This determination of total blood volume is of course necessary in deciding whether blood or plasma transfusions are needed in cases involving bleeding, burns, or surgical shock. This ??Cr procedure was used during the Korean War to determine how much blood had been lost by wounded patients, and helped to save many, many lives.

For several years, iodine-131 has been used as a tracer in determining cardiac output, which is the rate of blood flow from the heart. It has appeared recently that red blood cells tagged with ??Cr are more satisfactory for this measurement than iodine-labeled albumin in the blood serum. It is obvious that the blood-flow rate is an extremely important physiological quantity, and a doctor must know it to treat either heart ailments or circulatory disturbances.

In contrast to the iodine-131 procedure, which requires that an artery be punctured and blood samples be removed regularly for measurement, chromium labeling merely requires that a radiation counter be mounted on the outside of the chest over the aorta . A sample of labeled red blood cells is introduced into a vein, and the recording device counts the radioactivity appearing in the aorta as a function of time. Eventually, of course, the counting rate levels off when the indicator sample has become mixed uniformly in the blood stream. From the shape of the curve on which the data are recorded during the measurements taken before that time, the operator calculates the heart output per second.

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