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Part II

Chapter 6


Origins of the AEC Radioisotope Distribution Program in the Manhattan Project

The AEC Assumes Responsibility for Radioisotope Distribution

Local Oversight: Radioisotope Committees

General Benefits of Radioisotope Research


Chapter 6: General Benefits of Radioisotope Research

The system for distribution of radioisotopes worked well and encouraged researchers to explore new applications. There are two striking aspects of the application of radioisotopes to medicine since World War II: rapid expansion and complexity. Practices that at the end of the war were limited to fewer than four dozen practitioners have now become mainstays of modern medicine.[89] The second major aspect of the field is its complexity. Just as nature at times is best regarded as a seamless web, not unconnected scientific fields, knowledge nurtured in one field often provides unexpected benefits in another. A few examples can illustrate how some of the hopes at the dawn of the atomic age have actually been realized.[90]

Improved Instrumentation to Detect Radiation

Improved instruments, the basic tools for all biological research using radioisotopes, were developed through the interaction of biology and medicine with physics and engineering. Improvements not only provide greater precision, they also allow the same amount of information to be gathered with lower doses of radiation, thereby reducing the risk.

Perhaps the best-known example is the application of the "whole-body counter" to biological problems. The device was originally developed as a tool for physics, enabling measurements of minute amounts of radiation by combining sensitive detectors with extensive shielding to eliminate extraneous radiation. The result was similar to placing a sensitive microphone in a sound-proofed room, allowing lower levels of radioactivity to be detected than was previously possible. For some research, no radioisotope at all was administered; the counters could measure naturally occurring radioisotopes. Whole-body counters also greatly simplified metabolic studies. In some studies, subjects who previously would have had to reside continuously in a metabolic ward could now schedule visits to the whole-body counter for their natural radioactivity to be measured on an outpatient basis.[91] This device was later adapted for whole-body counting after administration of tracer amounts of radioisotopes and is the basis for a number of fundamental nuclear medicine tests.

In the early 1970s, computerized tomographic scanning (CT) was introduced. This technique was first applied to x-ray imaging by taking multiple x-ray "slices" through a region of the body, then programming a computer to construct a three-dimensional image from the information. Thus, internal structures of the body may be imaged noninvasively. Newer types of tomographic scanning include positron emission tomography (PET), in which various metabolites or drugs are labeled with a very short half-life positron-emitting radioisotope, such as fluorine 18, and the passage of the labeled material is tracked throughout the body by taking multiple images over several minutes or hours.

Diagnostic Procedures

The first medical application of any radiation was the use of x rays for diagnostic purposes, such as locating broken bones inside the patient. Radioisotopes later opened another window into the body. The natural tendency of certain organs to preferentially absorb specific radioisotopes, coupled with ever-improving detection techniques, allowed radioisotopes to be used to increase the contrast between different parts of the body. X rays could distinguish between hard and soft tissues because of their different densities. Radioisotopes could go one step further and distinguish different kinds of tissues from one another based upon their metabolic function, not merely their physical density.

Radioisotopes also could go beyond detecting different types of tissues. Since they were distributed throughout the body by the body's own metabolism, their location provided a picture not only of structure, but also of processes. Tracing radioisotopes was a means of observing the body in action. The earliest success was using radioiodine to measure the activity of the thyroid. The gland cannot distinguish between radioactive and nonradioactive forms of iodine and therefore preferentially absorbs all isotopes of iodine. Thus, the activity of the gland can be assessed by observing its absorption of radioiodine. Largely as a result of these advances, the thyroid gland is arguably the best understood of all human endocrine organs, and its hormones the best understood of all endocrine secretions. Since the incidence of thyroid disease is second only to diabetes mellitus among human endocrine diseases, this understanding is basic to therapy in large numbers of patients.[92]

Because the brain is a crucial and delicate organ, techniques for diagnosing brain tumors without surgery were vital. In 1948 radioactive isotopes were applied to this task. Using radiotagged substances that were preferentially absorbed by brain tumors, physicians could more accurately detect and locate brain tumors, allowing better diagnosis and more precise surgery. Similar "scanning" techniques were later developed for the liver, spleen, gastrointestinal system, gall bladder, lymphomas, and bone.

As mentioned, a recently developed technique is PET scanning, which is especially helpful in studying the human brain in action. Glucose is the primary food for the brain; by tagging a glucose analog with fluorine 18, investigators can identify the actively metabolizing portions of the brain and relate that to function. This technique has opened a new era of studies of the brain. Outwardly observable functions, such as language, object recognition, and fine motor coordination can now be linked with increased activities in specific areas of the brain.

Radioisotopes allow investigators to increase the sensitivity for analyzing biological samples, such as tissue and blood components, especially when separating out the material of interest using chemical processes would be difficult. Because instruments to measure radioactivity are so sensitive, radioisotopes are frequently used in tests to detect particular hormones, drugs, vitamins, enzymes, proteins, or viruses.

Therapeutic Techniques

Radioisotopes are energy sources that emit one or more types of radiation as they decay. If radioisotopes are deposited in body tissues, the radiation they emit can kill cells within their range. This may be harmful to the individual if the exposed cells are healthy. However, this same process may be beneficial if the exposed cells are abnormal (cancer cells, for example).

The potential for radiation to treat cancer had been recognized in the early days of work with radiation, but after World War II the effort to develop radiation therapy for cancer increased. Iodine 131 treatment for thyroid cancer was recognized as an effective alternative to surgery, both at the primary and metastatic sites. Cancer is not the only malady susceptible to therapy using radioisotopes. The use of radioiodine to treat hyperthyroidism is perhaps the most widespread example. It illustrates the progression from using a radioisotope to measure a process (thyroid activity) to actually correcting an abnormal process (hyperthyroidism).[93]

Not all experimental applications of radioisotopes are successful. Some experiments end in blind alleys, an important result because this prevents widespread application of useless or even harmful treatments. Negative results also help researchers to redirect their efforts to more promising areas. The importance of negative results is sometimes not appreciated because they do not lead to effective treatments. Negative results may range from simply not obtaining an anticipated beneficial effect to the development of severe side effects. Such side effects may or may not have been anticipated; they may occur simultaneously with beneficial effects, such as the killing of cancer cells. Occasionally negative results include earlier-than-anticipated deaths of severely ill subjects. An example is the experimental use of gallium 72 in the early 1950s on patients diagnosed with malignant bone tumors.[94]

Another radioisotope, cobalt 60, has been used successfully to irradiate malignant tumors, but in this case the radioisotope is not administered internally to the patient; rather, the cobalt 60 forms the core of an external irradiator, and the gamma radiation emanating from the radioisotope source is focused on the patient's tumor. Although cobalt 60 irradiators have been largely replaced by linear accelerators, they were developed under AEC sponsorship and were responsible for many advances in radiation therapy.

Recent efforts to utilize radioisotopes in cancer diagnosis and treatment are based on the ability of antibodies to recognize and bind to specific molecules on the surface of cancer cells and the ability of biomedical scientists to custom-design and manufacture antibodies, thus improving their specificity. These fields are now contributing to a hybrid technique: cloning antibodies and tagging them with radioactive isotopes. As the antibody selectively binds to its target on the surface of the cancer cell, the radioactive isotopes attached to the antibody can either tag the cell for detection and diagnosis or deliver a fatal dose of radiation to the cancer cell. The Food and Drug Administration recently approved the first radiolabeled antibody, to be used to diagnose colorectal and ovarian cancers.[95]

Even in the case of widespread metastases where cure is no longer possible, radiation treatments will often produce tumor regression and ease the pain caused by cancer. Phosphorus 32 has been used to ease (palliate) the bone pain caused by metastatic prostate and breast cancers. Recently, the FDA approved the use of strontium 89 for similar uses.[96]

Metabolic Studies

Studies of the basic processes within the body may not have any immediate application in diagnosis or therapy, but they can indirectly lead to practical applications. One example is in the study of the metabolism of iron in the body. Iron is an important part of hemoglobin, which carries oxygen from the lungs to all cells in the body. Studies using radioactive iron established the pathway iron takes, from its ingestion in food to its use in the blood's hemoglobin and its eventual elimination from the body; these studies had practical applications in blood disease, nutrition, and the importance of iron metabolism during pregnancy.

Radioisotopes have also been used to study how the weightlessness of space travel affects the human body. Radioisotopes have allowed more precise observation of effects of space travel on blood plasma volume, total body water, extracellular fluid, red cell mass, red cell half-life, and bone and muscle tissue turnover rates.

Other uses of radioisotopes are in studies of the transport and metabolism of drugs through the body. New drugs for any clinical application, whether diagnostic or therapeutic, must be understood in detail before the FDA will approve them for general use. One method for readily determining how a drug moves through the blood to various tissues, and is metabolically changed in structure, is to incorporate a radioactive isotope into the structure of the drug.

Unexpected results from an experiment can at times have widespread consequences. An example is how the work of Rosalyn Yalow and Solomon Berson of the Bronx VA Medical Center opened up the field of radioimmunoassay. In the early 1950s, it was discovered that adult diabetics had both pancreatic and circulating insulin. This appeared odd; previously, it had been believed that all diabetics lacked insulin. To explain the presence of diabetes in people with pancreatic insulin, Yalow and Berson decided to study how rapidly insulin disappeared from the blood of diabetics. To do this, they synthesized radioiodine-labeled insulin. This would act as a radioactive tag, making it much easier to measure the presence of insulin in blood. To their surprise, they found that insulin disappeared more slowly from diabetic patients than from nondiabetic people.[97]

Their work had an impact beyond the study of diabetes, however. In the process of studying the plasma of patients who had been injected with insulin, they discovered that the radioactively tagged insulin was bound to an antibody, a defensive molecule that had been produced by the patient's body and custom-designed to attach itself to the foreign insulin molecule. This was a surprise, since prevalent doctrine held that the body did not produce antibodies to attack small molecules such as insulin. To study the maximum binding capacity of the antibodies, they did saturation tests, using fixed amounts of radiolabeled insulin and of antibody to measure graded concentrations of insulin. With this technique Yalow and Berson realized they could measure with great precision the quantities of insulin in unknown samples. They thus developed the first radioimmunoassay. This technique, for which Rosalyn Yalow was awarded the Nobel Prize in Medicine in 1977, has become a basic tool in many areas of research. Radioimmunoassay revolutionized the ability of scientists to detect and quantify minute levels of tissue components, such as hormones, enzymes, or serum proteins, by measuring the component's ability to bind to an antibody or other protein in competition with a standard amount of the same component that had been radioactively tagged in the laboratory. This technique has permitted the diagnosis of many human conditions without directly exposing patients to radioactivity.

No discussion of the impact of radioisotopes on biomedical science would be complete without a recognition of their fundamental importance in basic biological investigations. The ability of radioisotopically labeled metabolites to act like, and therefore trace, their nonradioactive counterparts has allowed scientists to follow virtually every aspect of metabolism in cells of bacteria, yeasts, insects, plants, and animals, including human cells. Among the benefits of such studies are (a) an understanding of the similarities in metabolism of organisms throughout the evolutionary scale, (b) identification of sometimes subtle differences in cell structure and function between organisms and thus the ability of drugs to kill bacteria, fungi, or insects without harming humans, and (c) elucidation of the fundamental properties of genetic material (DNA). The last of these examples has important implications today, as the human genes controlling many important bodily functions are being identified and cloned and gene therapy is just beginning to find its way into clinical application. Many benefits of understanding the human genetic code have already been realized, and others will likely accrue in the next few years. These benefits are the result of fundamental advances in genetics and molecular biology of the past half century, which in turn depended heavily on studies with lower organisms and with radioisotopically labeled materials. Thus, human health is benefiting from both human and nonhuman research with radioisotopes.

The grandest dream of the early pioneers--a simple and complete cure for cancer--remains unfulfilled. Promising paths at times proved to be dead ends. However, the AEC's widespread provision of radioisotopes, coupled with support for new techniques to apply them, laid the foundation stones for much of modern medicine and biology. This section has only skimmed the field of nuclear medicine, with its vast array of diagnostic and therapeutic techniques, and the use of radioisotopes in many areas of basic research.

An Example of Hopes Unfulfilled: The Gallium 72 Experiments

Human experiments with gallium 72, as discussed in the section titled "General Benefits of Radioisotope Research," were conducted at the Oak Ridge Institute of Nuclear Studies in the early 1950s. The experiments used gallium 72 because of its short half-life (14.3 hours) and because an earlier animal study indicated it concentrated in new bone, making it useful as a tumor marker and possibly for therapy.[a] The 1953 published report stated that the purpose of the study was "to investigate the therapeutic possibilities in human tumors involving the skeletal system."[b] In 1995 one of the original researchers stated to Advisory Committee staff a somewhat broader purpose: "to exploit to the fullest possible extent any possible use of this isotope as a bone seeking element rather than to seek a cure for a specific malignant bone tumor, such as osteogenic sarcoma. . . . While the Gallium-72 studies did include osteogenic sarcomas, they only represented less than half (9/21), 43%, of all the other primary and metastatic skeletal malignancies studied."[c]

Patients were chosen who had been diagnosed with "ultimately fatal neoplasms not amenable to curative surgery or radiotherapy."[d] The diagnosis later proved to be accurate in all but one of the fifty-five subjects.[e] In one part of the study, thirty-four patients were given trace amounts of gallium. Both external radiation measurements and a variety of excreta, blood, and tissue samples were analyzed to determine the localization of gallium. In another part of the study, twenty-one other patients were given doses that the researchers hoped would be in the therapeutic range. Total doses ranged from 50 to 777 microcuries.[f] The gallium was administered in fractionated doses biweekly. According to the medical investigators, these patients "were, in general, in a more advanced stage of disease and were completely beyond even palliation from conventional forms of therapy."[g] For these patients, "doses which were believed to be moderate were given and gradually increased to toxic level."[h] The conclusion of the report notes that "most of the patients in whom gallium therapy was attempted were given maximum amounts of the isotope. Only the hopelessness of their prognoses justified a trial of doses so damaging to the hematopoietic tissues."[i]

A major difficulty was lack of knowledge about both the chemical toxicity of stable (that is, nonradioactive) gallium and the radiation toxicity of gallium 72. Calculations and small animal studies indicated that dosimetry techniques used for other radioisotopes would "be of little value."[j] During the study, close monitoring was done of many bodily functions to observe toxic effects as soon as they began to appear. Blood tests revealed changes that "were prominent and were usually of primary importance in determining when the treatments should be discontinued."[k] Other effects included drowsiness, then anorexia, nausea, vomiting, and skin rash.

One problem was determining whether these effects were due to chemical toxicity, radiation toxicity, or a combination. Due to technical difficulties in separating out pure gallium 72, the radioactive gallium was injected with larger amounts of stable gallium, so both chemical and radiation effects could be present. To distinguish them, one patient was administered an amount of stable gallium equal to a therapeutic dose, but with only an insignificant amount of radioactive tracer (to determine localization). Observed toxic effects in this patient did not include bone marrow depression. The researchers concluded, therefore, that the "profound bone marrow depression is characteristic of radiation damage and is probably chiefly caused by radiation, though an element of stable metal toxicity may also be contributory."[l]

Bone marrow depression gradually ended after gallium injections were stopped. While it lasted, bone marrow depression led to greater susceptibility to infection and bleeding. Two subjects died sooner than anticipated, one from infection and bleeding and the other from infection, while their bone marrow was still depressed. "These two patients died in spite of antibiotics, blood transfusions, and toluidine-blue therapy."[m] The researchers reported that "in two patients our estimates of safe dosage limits were in error and radiogallium is believed to have hastened death."[n] One researcher, writing in 1995, stated that "since 'safe dosage' levels were only estimates and seven other patients had survived with even higher dosages, our choice of language [citing the preceding quotation] was unfortunate. It must be emphasized that this portion of the study must be likened to a current clinical Phase I trial where in a limited fashion [a] broad range of toxicity levels may at best be only estimated."[o]

The major conclusion of the experiment was that hopes for gallium therapy were unfulfilled. Even though the maximum tolerated doses had been administered, the researchers reported that "we were impressed with the almost complete lack of any clinical improvement following gallium treatment, even in patients who showed evidence of striking differential localization of gallium in tumor tissue."[p]

Concerning patient consent, the published study says nothing, which was normal for scientific articles at that time. Near the end of the Advisory Committee's deliberations, ORINS reportedly found consent forms signed by subjects in the gallium study.[q] One of the researchers in 1995 did offer his recollections regarding consent to the Committee:

Forty-five years ago all of our patients and their families were given a booklet of information explaining how radioisotopes were used in medicine and more specific information about their own involvement including the possible known risks. Signed applications for admission and waiver and release forms were demanded for all patients. When, as in the ongoing gallium studies, toxicity or enhanced risks were encountered, these were immediately made clear to the patients and their families if they were known in that time frame. Very often toxicity is only apparent after review of the clinical data. In the gallium studies, when on review of the data it was determined that no therapeutic benefit had occurred, the study was immediately terminated.[r]

a . Herbert D. Kerman, M.D., FACR, to Dan Guttman, Executive Director, Advisory Committee on Human Radiation Experiments, 19 May 1995 ("It has come to my attention . . ."), 2. Dr. Kerman cites as the preceding study: H. C. Dudley and G. E. Maddox, "Deposition of radiogallium (Ga-72) in skeletal tissues," Journal of Pharmacology and Experimental Therapeutics 96 (July 1949): 224-227.

b . Gould A. Andrews, M.D., Samuel W. Root, M.D., and Herbert D. Kerman, M.D., "Clinical Studies with Gallium-72," 570, in Marshall Brucer, M.D. (ed.), Gould Andrews, M.D., and H. D. Bruner, M.D., "Clinical Studies with Gallium-72," Radiology 66 (1953): 534-613.

c . Kerman to Guttman, 19 May 1995, 2. Dr. Kerman presumably was referring to the twenty-one subjects who received doses in the therapeutic range, not the thirty-four who received trace doses.

d . Andrews, Root, and Kerman, "Clinical Studies with Gallium-72," 570.

e . A patient was diagnosed with osteogenic sarcoma in his leg, which was amputated. X rays also revealed dense nodules in his lung, which were diagnosed as inoperable but typical pulmonary metastases. He was discharged after the gallium study. When he later returned to the hospital, an operation revealed that the nodules were not typical metastases, but unidentifiable lesions "not characteristic of any specific lesion." This could not have been known prior to the study, when only x rays were available for diagnosis. Ibid., 585.

f . The researchers reported that these doses were equivalent to 8.5-89.2 mg/kg of body weight. Ibid., 574-577.

g . Ibid., 570.

h . Ibid., 571.

i . Ibid., 587.

j . The investigators wrote that "[n]ormal tissue and whole-body tolerances for amounts of radiogallium necessary to produce a significant effect upon malignant tissues were unknown. Preliminary calculations and small animal experiments had indicated that accepted radiation dosimetry as applied to other isotopes would be of little value in calculating radiation dosage to tissues. It was therefore necessary to utilize the hematologic picture to assess the damaging effects of whole-body irradiation, and clinical and roentgenographic experience in evaluating a therapeutic response." Ibid., 571.

k . Ibid., 573.

l . Ibid., 575.

m . Ibid., 573. Neither had suffered from osteogenic sarcoma; one had suffered from adenocarcinoma of the kidney with lytic bone metastases and another from cancer of the prostate with metastatic skeletal involvement. Kerman to Guttman, 19 May 1995, 3.

n . Andrews, Root, and Kerman, "Clinical Studies with Gallium-72," 571.

o . Ibid.

p . Ibid., 587. Researchers reported evidence of concentration in tumors as being one of the following: "no data," "none," "little," "moderate," or "pronounced." Ibid., 574.

q . Dr. Shirley Fry, telephone interview with Dan Guttman (ACHRE), 30 August 1995, 1. The Advisory Committee did not have enough time to review the forms and related file materials once they were identified, which, because ORINS deemed them privacy-protected material, would have required review at Oak Ridge.

r . Kerman to Guttman, 19 May 1995, 3. The booklet, "ORINS Patient Information Booklet" (circa May 1950), is discussed in chapter 1. ORINS hospital was known to be dedicated to experimental work with radiation and radioisotopes. Patients were admitted to the hospital only if they were willing to be experimental subjects. It is not as clear, however, whether the details of any particular experiment were always explained adequately to patients.

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