TAB 5 Radiation: National Institutes of Health, "What We Know About Radiation" List of Attachments For Briefing Book Volume 1 Tab 5 Attachment I: Radiation: Henry D. Royal, "The Effects of Low Levels of Radiation. Attachment 2: Radiation: William R. Hendee, "Public Perception of Radiation Risks". What We Know About Radiation 1. What is radiation? We live in a sea of radiation. There are many different types of radiation, some of which are visible light, ultraviolet rays from the sun, infrared from a heat lamp, microwaves, radio waves and ionizing radiation. Radiation is said to be ionizing if it has sufficient energy to displace one or more of the electrons that are part Of an atom. This creates an electrically charged atom known as an ion. Common examples of ionizing radiation are x rays and their cousins, gamma rays, which are emitted by radioactive materials. Others include beta rays, which are also emitted from radioactive materials, and neutrons, which are emitted during the splitting (fission) of atoms in a nuclear reactor. 2. When do we encounter ionizing radiation in our daily lives? Everyone who lives on this planet is constantly exposed to naturally occurring ionizing radiation (background radiation). This has been true since the dawn of time. Sources of background radiation include cosmic rays from the sun and stars; naturally occurring radioactive materials in rocks and soil; and radioactive isotopes (unstable radioactive counterparts to naturally stable atoms) normally incorporated into our body's tissues; and radon and its products, which we inhale. Radon exists as a gas and is present in soil from which it seeps into the air. Radon gets trapped inside buildings, especially if the ventilation is poor. Levels of environmental radiation depend upon geology, how we construct our dwellings, and altitude. For example, radiation levels from cosmic rays are greater for people On airplanes and those living on the Colorado plateau. However, the risk of cancer has not been shown to vary consistently with the levels of background radiation. We are also exposed to ionizing radiation from man-made sources, mostly through medical procedures. On the average, doses from a diagnostic x ray are comparable to natural background radiation. Radiation therapy, however, can reach levels many times higher than background radiation but this is usually targeted only to the affected tissues. We are also exposed to ionizing radiation from color televisions, smoke detectors, building materials, mining and agricultural products, and coal-burning. People who smoke receive additional radiation from radioisotopes in tobacco smoke. 3. How do we know about the effects of high doses of ionizing radiation? The adverse effects of high doses radiation were seen shortly after the discovery of radioactivity and x rays in the 1890s. In 1902, skin cancers were reported in scientists who were studying radioactivity. Back then, no one took special precautions in working with radioactive materials because their effects were not yet fully recognized. The occupational hazards soon became apparent. For example, a 1931 report described cases of bone cancer in women who wet their brushes on their tongues to 1 get a good "point" for painting radium on watch dials. Radiation's role in causing leukemia in humans was first reported in 1944 in physicians and radiologists. Much of our data On the effects of high doses of radiation comes from survivors of the 1945 atomic bombs dropped on Hiroshima and Nagasaki and from other people who received high doses of radiation, usually for treatment. The National Cancer Institute (NCI), part of the National Institutes of Health (NIH), in collaboration with the Radiation Effects Research Foundation, an international group supported jointly by the U.S. Department of Energy and the Japanese Ministry of Health and Welfare, continues to study the long-term effects of radiation on the survivors of the bombs. Only about 12% of all the cancers that have developed among these survivors are estimated to be related to radiation; only about 9% of the fatal cancers in these people are estimated to be related to radiation. Uranium miners and those who lived near the Nevada nuclear weapons test sites used from 1951-1963 are also among those being monitored in order to learn more about the effects of high doses of ionizing radiation. NCI is also helping to set up studies of the people most affected by the Chernobyl nuclear power plant accident, especially the children who lived nearby and the workers who cleaned up the plant after the accident. The information from all these studies has been and will continue to be published--after rigorous review--in medical and scientific journals that are available to everyone. 4. What are some of the beneficial ways in which ionizing radiation is used in medicine and in medical research? The discovery of x rays in 1895 was a major turning point in diagnosing diseases because physicians finally had an easy way to "see" inside the body without having to operate. Newer x-ray technologies such as CT (computerized tomography) scans have revolutionized the diagnosis and treatment of diseases affecting almost every part of the body. Other sophisticated techniques have provided physicians with low-risk ways to diagnose heart disease. For example, doctors can now pinpoint cholesterol deposits that are narrowing or blocking coronary arteries, information essential for bypassing or unclogging them. Every major hospital in the United States has a nuclear medicine department, in which radioisotopes are used to diagnose and treat a wide variety of diseases more effectively and safely by "seeing" how the disease process alters the normal function of an organ. To obtain this information, a patient either swallows, inhales, or receives an injection of a tiny amount of a radioisotope. Special cameras reveal where the isotope accumulates briefly in the body, providing, for example, an image of the heart that shows normal and malfunctioning tissue. Radioisotopes are also used in laboratory tests to measure important substances in the body, such as thyroid hormone. Radioisotopes are used to effectively, treat thyroid diseases, including Graves disease--one of the most common forms of hyperthyroidism--and thyroid cancer. The use of ionizing radiation has led to major improvements in the diagnosis and treatment of patients with cancer. These innovations have resulted in increased survival rates and 2 improved quality of life. Mammography can detect breast cancer at an early stage when it may be curable. Needle biopsies are more safe, accurate, and informative.when guided by x-ray or other imaging techniques. Radiation is used in monitoring the response of tumors to treatment and in distinguishing malignant tumors from benign ones. Bone and liver scans can detect cancers that have spread. Half of all people with cancer are treated with radiation, and the number of those who have been cured continues to rise. There are now tens of thousands of individuals treated and cured from various cancers as a result of radiotherapy. In addition, there are many patients who have had their disease temporarily halted by radiotherapy. Radioisotopes are also being used to decrease or eliminate the pain associated with cancer- - such as that of the prostate or breast-- which has spread to the bone. Radioisotopes are a technological backbone for much of the biomedical research being done today. They are used in identifying and learning how genes work. Much of the research on AIDS is dependent upon the use of radioisotopes. Scientists are also "arming" monoclonal antibodies--that are produced in the laboratory and engineered to bind to a specific protein on a patient's tumor cells--with radioisotopes. When such "armed" antibodies are injected into a patient, they-bind to the tumor cells, which are then killed by the attached radioactivity, but the nearby normal cells are spared. So far, this approach has produced encouraging success in treating patients with leukemia. Most new drugs, before they are approved by the Food and Drug Administration, have undergone animal studies that use radioisotopes to learn how the body metabolizes them. Another clinical and research tool, PET scanning (positron emission' tomography), involves injecting a small amount of a radioisotope into a person to "see" the metabolic activity and circulation in a living brain. PET studies have enabled scientists to pinpoint the site of brain tumors or the source of epileptic activity, and to better understand many neurologic diseases. Researchers were able to learn how dopamine--the chemical messenger (neurotransmitter) that's involved in Parkinson's disease--is used by the brain. These are but a few of the many vital uses of ionizing radiation in medicine. About 70 to 80 percent of all research at the National Institutes of Health is performed using radiation and radioactive materials. NIH research has consistently produced results that have improved the health of the American people. 5. What are the adverse effects of ionizing radiation? Ionizing radiation can cause important changes in our cello by breaking the electron bonds that hold molecules together. For example, radiation can damage our genetic material (DNA) either directly by displacing electrons from the DNA molecule, or indirectly by displacing electrons from some other molecule in the cell, which then interacts with the DNA. A cell can be destroyed quickly or its growth or function may be altered through a change (or mutation) that may not be evident for many 3 years. However, the possibility of this inducing a clinically significant illness or other problem is quite remote at low radiation doses. Our cells, however, have several mechanisms to repair the damage done to DNA by radiation. The efficiency of these repair mechanisms differs among cells and depends on several things, including the type and dose of radiation. There also are biological factors that can greatly modify the cancer-causing effects of high doses of radiation. The severity of radiation's effects depends on many other factors such as the magnitude and duration of the dose; the area of the body exposed to it; and a person's sex, age, and physical condition. A huge dose of radiation to the whole body at one time can result in death. Exposure to high levels of radiation can increase the risk of developing cancer. Because a radiation- induced cancer is indistinguishable from cancer caused by other factors, it is very difficult to pinpoint radiation as the cause of cancer in a particular individual. Other effects of high doses of radiation include suppression of the immune system and cataracts. Certain tissues of a fetus, particularly the brain, are especially sensitive to radiation at, specific stages of development. An increased rate of severe mental retardation has been found in atomic bomb survivors whose mothers were 8-25 weeks pregnant when the bombs were dropped. However, the children and grandchildren of the atomic bomb survivors so far have shown no greater incidence of genetic problems than unexposed populations. It is very difficult to detect biologic effects in animals or people who are exposed to low-level radiation. Based on studies in animals and in people exposed to high doses of radiation such as the atomic bomb survivors, scientists have made conservative estimates of what might be the highest doses that would be reasonably safe for a person over a lifetime.' But these calculations are estimates only, based on mathematical models. Even so, the U.S. government uses these estimates to set the limits on all potential exposures to radiation for-workers in jobs that expose them to ionizing radiation. International experts and various scientific committees have, over the years, examined the massive body of knowledge about radiation effects in developing and refining radiation protection standards. 6. Should patients be concerned about the radiation they may receive from tests that their physicians have ordered? The doses involved in medical procedures have been decreasing over the past two decades as x-ray films and equipment have been improved. In addition, the ability to target radiation more precisely to one part of the body has resulted in less exposure to the rest of the body. It is always wise to avoid unnecessary radiation exposure. Physicians routinely compare the risks of radiation to the benefits derived from a diagnostic use of radiation to ensure that there is more benefit to the patient than risk. In many cases, such diagnostic tests enable doctors to treat the patient without invasive and life-threatening procedures. 4 Radiologists, health physicists, the National Council on Radiation Protection and Measurements--the Congressionally chartered independent advisory group that, among other things, recommends what the U.S. radiation standards should be--and other responsible parties are continually seeking ways of minimizing risk while retaining or improving the benefits from medical uses of radiation. 7. Should patients be concerned about the radiotherapy they undergo for cancer treatment? Radiation, surgery, and chemotherapy are the mainstays of cancer treatment and are used in combinations depending on the cancer. Certain tumors can be treated successfully with radiotherapy alone. The effectiveness of radiation in killing cancer cells--and, at the same time, the potential for harm to normal tissues--depends on several things. including the type of radiation used, the extent of the body that is treated, and the patient's age or other medical problems. Doctors try to avoid exposure of large parts of the body to radiation because this can cause serious side effects like cancer. However, only about 5% of all secondary cancers--ones that develop after treatment for the initial cancer- -have been linked to radiotherapy. The risk of leukemia after high doses of radiation to localized areas of the body often is surprisingly low, because the local effect is to kill cells that might, at lower doses, undergo transformation -- the changes that a normal cell undergoes as it becomes malignant --eventually leading to leukemia. Other side effects of radiotherapy range from mild to serious; many are temporary. With the development of better machines and the use of computers to plan the treatment, the safety and efficacy of radiotherapy has steadily improved. Radiologists make every attempt to minimize harmful effects to normal tissues. Thus, a patient's risks from exposure to radiation are far offset by the benefits from the treatment. 8. Should patients or normal volunteers be concerned about participating in medical research studies in which they may be exposed to some radiation? The U.S. government takes measures to protect the rights and welfare of everyone who participates in medical research studies. By law, studies involving humans and funded by the U.S. government must first be approved by the Institutional Review Board (IRB) of the hospital or university where the study will be conducted. The IRB, composed of a group of individuals with backgrounds in science, ethics, and other fields, must ensure that all risks to the participants are justified on the basis of potential benefits either to themselves or to society and that their rights will be protected. This regulation applies to all studies, including those in which the use of radiation is proposed. It is also the IRB's responsibility to ensure that patients or volunteers are fully and accurately informed of the risks and benefits of participation in the study, are not coerced in any way into participating, and are competent to make the decision to participate. (If the studies will be conducted in 5 children, then parental consent and assent by the child is required.) When the use of ionizing radiation is involved, nearly all such institutions also have a group of radiation health experts (the radiation safety committee) review the proposed research before it can be approved to proceed. 9. Should people be conceded about ionizing radiation? Most of the radiation that we are receiving is naturally occurring background radiation. Some level of exposure to radiation is unavoidable. It appears, however, that the cancer risk from very low-dose exposure is quite low. It is prudent to avoid unnecessary exposure, but not if one loses more--in money, time, convenience, or increased risks from other things--by avoiding radiation rather than ignoring it. The cancer risk associated with exposure to high-levels of ionizing radiation is among the best understood of any relationships involving environmental agents that cause cancer; this relationship continues to be studied and reevaluated. This knowledge is constantly used in evaluating the risks and benefits of the uses of radiation in medicine. In the overwhelming majority of cases where it is used, the benefits of medical radiation far outweigh the risks associated with it, but there is a tradeoff. In this sense, radiation is no different than any other diagnostic or therapeutic agent, except that we have more information than usual. Properly managed, radiation can be used for great benefit to humanity and with minimal risk, a risk comparable to or lower than those commonly accepted as an ordinary part of daily life such as driving to work. Prepared by the Office of Communications, OD, NIH April Il, 1994 6 TAB 5 Radiation: Henry D. Royal, "The Effects of Low Levels of Radiation" The Effects of Low Levels of Radiation Henry D. Royal, M.D. Associate Director of Nuclear Medicine Mallinckrodt Institute of Radiology Professor of Radiology Washington University School of Medicine St Louis, MO Radiation and its risks is a topic of considerable interest to both medical and nonmedical persons. Medical personnel work in an environment where radiation is frequently used for the diagnosis and treatment of patients. They are often asked questions about the risks of radiation by their patients. Nonmedical issues that have received great public attention include siting of low and high level waste facilities, the risk-benefit of nuclear power and the medical consequences of nuclear war. The public often turns to medical professionals for an assessment of the health risks of these various issues. Despite the relevance that knowledge of radiation and its effects has to the practice of medicine, most medical professionals are ill prepared to answer everyday questions patients have about radiation and its risks. The reasons for this poor preparation are complex. A review of most medical schools curriculum quickly will indicate that little, if any time is devoted to radiation biology. The cursory treatment given to radiation biology is due to several factors. The effects of low levels of radiation are difficult, if not impossible, to measure; the effects that can be detected take years to develop; no high technology diagnostic techniques are required and there is no specific treatment Accidents involving high doses of radiation that cause acute, sometimes lethal, effects occur infrequently. Since the early 1940's when we entered the nuclear age, approximately 100 fatalities due to the acute effects of accidental exposure to radiation have been recorded worldwide. This number includes the 29 acute radiation fatalities that occurred as a result of the April 1986 accident at the Chernobyl nuclear power station. In the United States, 32 radiation accident deaths have occurred during this period. To put these numbers into perspective it is useful to remember that approximately 45,000 fatalities occurred per year in the United States alone due to automobile accidents. These facts clearly do not give radiation and its effects a high priority in most modern medical school's curriculum that emphasize acute treatable illnesses. Myths About Radiation Many myths about radiation and its effects exist It is important to explicitly recognize these misconceptions exist if one is to credibly explain what is known about the risks of radiation to a patient. Numerous studies have shown that the public's perception of the risks of radiation is many times the actual risks. The misconceptions about radiation are perpetuated and often amplified by the fact that information available about radiation from lay sources is often very inaccurate. For example, when the nuclear reactor accident occurred in Chernobyl, it was reported that 2,000 people were killed within the first day or two following the start of the accident. Anyone knowledgeable about the acute effects of large doses of radiation would immediately recognize how implausible it would be for 2,000 fatalities to occur within a few days of a radiation accident. This "fact" was widely reported by the major newspapers Henry D. Royal. M.D. Low Levels of Radiation Effects April 12, 1994 and television networks. Deaths due to an acute high dose radiation exposure are much more likely to occur 2-5 weeks following the accident when the victims are at greatest risk due to severe bone marrow depression. In fact, except for two immediate deaths which were due to the mechanical effects of the explosion and thermal burns, the 29 radiation related deaths following the Chernobyl accident occurred 14 to 96 days after the accident. There are several reasons why misconceptions about radiation exist. First, radiation was discovered relatively recently by Wilhelm Conrad Roentgen in 1895. This invisible, odorless, intangible force which allowed scientist and physicians to see through clothes and skin was understandably regarded as a mysterious power. Use of the mysterious power of radiation was certainly exploited by charlatans soon after its discovery. One only has to tune in the Saturday morning cartoons to see that the mysterious powers of radiation are still being exploited. Many superheroes, aliens, arch villains and mutants obtained their unusual powers from radiation. Spiderman was a normal human being until bitten by a radioactive spider. The hulk owes his phenomenal stature and strength to exposure to radiation when an experiment went awry. Given the early incessant exposure to these myths about radiation, it is no wonder that patients' perception of the risks of radiation are often much greater than the actual risks. Second, radiation is strongly linked to the ultimate human catastrophe, nuclear war. This linkage has had a significant effect on the efforts to educate the public about the effects of radiation. Understandably, the horrors of nuclear war serve as a strong motivating force to get people to become politically active to do what they can to prevent this unthinkable disaster. In the minds of some, the more horrible the consequences. the stronger the motivating force. There has been a tendency to try to outdo each other in graphic accounts of the medical consequences of nuclear war. Caught up in this horror are the effects of radiation. Only the most extreme effects of radiation are presented further re- enforcing the public 's fear of radiation. Any attempt to present a more complete description of radiation effects is sometimes misconstrued as an attempt to undermine efforts intended to prevent nuclear war. The opposition to nuclear war has evolved into opposition to nuclear everything. An example of the profound effect that the anti-nuclear movement has had is that the word "nuclear" was quickly dropped from nuclear magnetic resonance imaging lest this word interfere with the acceptance of this new imaging tool. Some activists believe that one way to avoid nuclear war is to cripple the nuclear industry. Anti-nuclear activists have used this tactic very effectively and created an environment in which it is difficult to educate the public about the facts of radiation. The final reason that misconceptions about radiation exist is that radiation biology is a complex field unto itself. As with any scientific discipline it has its own jargon which can be bewildering to those outside the field. Because the effects of low levels of radiation are small and difficult to measure directly, they must be inferred from mathematical models and/or statistical analysis. Neither of these approaches are very satisfying to most individuals. RADIATION VOCABULARY There are several important commonly used words to describe radiation related concepts that health professionals must master. The vocabulary is particularly confusing because many of the words have a similar appearance yet can have subtle but important differences in meaning. Henry D. Royal, M.D. Low Levels of Radiation Effects April 12. 1994 Even the word, radiation, has subtle nuances that are important to understand. In its most general sense, radiation refers to particles or waves that transport energy. Non- particulate radiation includes x-rays, y-rays (gamma rays), light, radiowaves and microwaves. All of these forms of non-particulate radiation are part of the electromagnetic spectrum. The emissions in the electromagnetic spectrum are often divided into those that are less energetic and those that are more energetic (non-ionizing and ionizing radiation, respectively). This division by energy is important since the major mechanism by which ionizing radiation causes its biological effect is by stripping electrons from atoms (ionization) making them chemically very reactive. X-rays and Y- rays are the most frequently used ionizing radiation in medicine. The only difference between x-rays and y-rays is their source. X- rays are emitted by excited electrons whereas y-rays are emitted by excited nuclei. Once x-rays or y-rays are produced they are indistinguishable. Particulate forms of radiation include alpha and beta rays. positrons, protons and deuterons. Unlike x-rays and y-rays, these forms of radiation have mass and an electrical charge. Therefore, they interact (collide) with matter much more readily. These rapid interactions prevent this type of radiation from traveling very far. For this reason, particulate radiation that has an electrical charge is often referred to as non-penetrating radiation. Particulate radiation with no electrical charge (neutrons) can readily penetrate matter. Alpha rays consist of two protons and two neutrons. The large mass of this particle and its positive charge prevent it from even penetrating the dead layers of the skin. Radionuclides which exclusively emit alpha rays (plutonium) are only a biological hazard when they are inhaled, ingested or absorbed through an area of damaged skin. Beta rays consist of a negatively charged particle with the mass of an electron. Beta rays are able to penetrate several centimeters of the body therefore they are potentially an external as well as an internal hazard. The radiation injuries to the firemen at Chernobyl consisted of both beta burns to the skin due to nonpenetrating radiation and whole body exposure due to penetrating radiation. This combination of injuries proved to be particularly lethal. Large doses of whole body radiation reduced the body's defenses against infections and the skin injuries greatly increased the portal for entry of infections. The words radiation and radioactive are often confused. Radioactive refers to an element which spontaneously emits ionizing radiation. Radionuclides used in nuclear medicine spontaneously emit radiation and are therefore radioactive. An x-ray machine does not spontaneously emit x-rays therefore, it is not radioactive. X- ray machines use electricity to excite electrons to produce x-rays. Radioactivity is often used to describe the radiation produced by a radioactive substance. Radionuclide, radioisotope and radioactive element are used synonymously by most people. The distinction between radiation and radioactive is an important one. Patients who have a diagnostic x-fay or even patients who have received radiation therapy are not radioactive. Once the source of radiation is turned off the radiation stops. On the other hand, patients who have radioactive materials injected as part of a nuclear medicine study are mildly radioactive even after the study is completed. Patients who ingest large amounts -3 - Henry D. Royal. M.D. Low Levels of Radiation Effects April 12, 1994 of radioactive materials or have radioactive sources locally implanted for treatment of cancer (e.g., radium implants for the treatment of cervical cancer) can be a significant hazard to others unless proper precautions are taken. The potentially harmful effects of radiation are proportional to the amount of radiation. Failure to understand the significance of the amount of radiation is one of the greatest contributors to misunderstandings regarding radiation. All living things evolved and currently live in a sea of naturally occurring low level radiation. Since radiation is present everywhere, it is not enough, when attempting to assess the risk from radiation, to say that radiation was present. Unless the amount of radiation is known and understood, no risk assessment can be made No one would hazard to answer a patient who asked "Is it safe to jump?" without first determining the height that the patient had in mind. Although jumping off a curb entails some risk, jumping off the roof of a three 'story building entails a risk that is several orders of magnitude greater. This simple fact is often ignored in discussions of the risk of radiation. The word radiation" can be so frightening that no consideration of amount is given. Three terms, roentgen, rad, and rem are used to describe the amount of radiation. The roentgen is the term the physicist is likely to use to describe the amount of radiation produced by an x- ray machine. Under standard condition, the physicist exposes air to the output of a machine that produces radiation and measures the number ion pairs produced per gram of air. A roentgen is equal to the amount of radiation necessary to produce 2.08 x 10 9 ion pairs per cc of air (2.38 x 10 coul/kg). The rad is a term that the biologist uses to describe the amount of energy absorbed from radiation by a living organism. The rad, an acronym for "roentgen absorbed dose", is a measure of how much potentially damaging energy from radiation is absorbed by the body. The amount of radiation absorbed depends on the amount of radiation, (measured by the roentgen) and the size, shape and density of the body. A standard 70 kg man exposed to 1 roentgen of radiation will absorb a skin dose of about I rad of radiation. The dose to his other organs will decrease with depth. One rad is equal to 100 ergs/gm of tissue (the amount of energy deposited per unit mass of tissue). The biological effect of the radiation depends not only on the amount of energy absorbed, (i.e., rad) but also on how the energy was deposited. Some forms of radiation, x-rays and y-rays (gamma rays) deposited their energy more uniformly than other kinds of radiation such as alpha rays. Because alpha rays deposit their energy less uniformly they cause more damage per amount of energy deposited per gram of tissue (rad) than x-rays and y-rays. Note that alpha rays are only more damaging if they reach living tissue. Since they penetrate matter so poorly, an alpha emitting radionuclide needs to be absorbed or inhaled in order for it to have a biological effect. The term rem (roentgen equivalent in man) adjusts for the different biological effects of different forms of radiation in man by using a "quality factor". For x-rays and y-rays the quality factor is 1 therefore rads and rems are equivalent For alpha-rays, the quality factor is 10-20. Alpha-rays have 10-20 times the biological effect as x-rays or y-rays per amount of energy deposited per gram of tissue. Therefore, 1 rad of alpha-rays equals 10-20 rems of alpha-rays. -4- Henry D. Royal. M.D. Low Levels of Radiation Effects April 12, 1994 The terminology for describing the amount of radiation has been further complicated by the introduction of two new terms, the Gray (100 rads) and the Sievert (100 rems), that are intended to replace the rad and the rem respectively. These terms have been widely adopted in other countries, however, they have not been widely adopted in the United States. When dealing with radioactive materials, the amount of radiation is usually measured in curies. A Curie is a measurement of the number of radioactive atoms that are disintegrating per unit time. A Curie is equal to 3.7x1010 disintegrations per second. This is approximately equal to the number of disintegrations per second in a gram of radium The Becquerel is the new 51 unit to replace the curie. A Becquerel is equal to 1 disintegration per second therefore 1 curie = 3.7x1010 Becquerels. A curie is a fairly large amount of radioactive material. For diagnostic scans, mCi amount (1000 mCi = 1 curie) are normally injected. In order to calculate the radiation dose from a radioactive substance within the body it is necessary to know 1) the amount of he radionuclide (curies); 2) the physical halflife of the radionuclide; 3) the mixture of radiation (alpha, beta, gamma rays) emitted; 4) the biodistribution (fraction of the substance in each organ of the body); 5) the biological halflife (how long the substance remains in each organ of the body). Biological Effects of Radiation The effects of high dose radiation (acute radiation syndrome) can be measured directly. In this context, high dose means greater than 20 rems received over a period of less than a few. hours. Because of the importance of this topic to the military. the effects of high dose radiation has been extensively studied in animals. The LD 50/60 is the lethal dose of radiation that will kill 50% of the exposed individuals in 60 days. The LD 50/60 assumes no treatment For obvious reason, the LD 50/60 has not been well studied in man. With treatment, the LD 50/60 for man is likely to be between 600-800 rems. There are three major long term adverse effects of high doses of radiation that are of great concern: carcinogenesis, teratogenesis, and mutagenesis. Although all three of these effects have been seen in plant and animal models, it has been difficult to demonstrate mutagenesis in man. The survivors of Nagasaki and Hiroshima have been extensively studied for genetically transmitted abnormalities. None have been definitively found. On the other hand, the carcinogenic and teratogenic effects of acute high doses (>20 rems) of radiation have been well documented in the atomic bomb survivors and in other populations (e.g.. radium watch painters). The effects of low levels of radiations have been impossible to measure directly in man despite the fact that they have been extensively searched for. With low doses of radiation it has been impossible to directly measure the carcinogenic effect of radiation for several reasons. First, spontaneously occurring cancer is common, accounting for 22% of all deaths. Second, there is considerable natural variation the cancer rate. Third, any cancers induced by radiation are not evident until years after the exposure and the radiation induced cancers are indistinguishable from naturally occurring cancers. Since the carcinogenic effect of low doses of radiation can not be measured directly, the effect at high doses has been extrapolated to low doses. This extrapolation outside the range of the observed data has the potential for serious error. The most commonly used estimate of the carcinogenic effects of low doses of radiation is that approximately 400 fatal -5- Henry D. Royal. M.D. Low Levels of Radiation Effects April 12, 1994 radiation induced cancers occurs for every 1,000,000 individuals who are exposed to 1 rem of radiation. This estimate of the carcinogenic effect of low levels of radiation assumes that there is no threshold that needs to be exceeded for the carcinogenic effect of radiation to be expressed. Age also affects the risk estimates. Young people are 2-3 times more sensitive to the carcinogenic effects of radiation. Most authorities believe that risk estimates used for radiation protection should be conservative (overestimate the risk). Cancers, especially solid tumors, that are induced by radiation have a long latency period. The increase in the leukemia rates seen in the survivors of Nagasaki/Hiroshima were first noted in a few years after their radiation exposure. The maximum increase in the leukemia rates was noted from 7 to 12 years after the radiation exposure. By 30 years after the exposure, the leukemia rates returned to normal. In contrast to the experience with leukemias, an increased incidence of solid tumors was not noted until 15 years after the exposure. The increased incidence of solid tumors has persisted until the present time. A brief review of some 01 the data from Hiroshima/Nagasaki will help to point out some of the obstacles which make an accurate assessment of the risk of cancer from radiation difficult There were over 280,000 survivors from Hiroshima/Nagasaki. 120,132 of these survivors have been followed extensively. By the mid 1980's, 39,84() of the 120,132 survivors had died. Statistical analysis reveals that there have been between 400-500 excess cancer deaths. This excess in cancer deaths has been attributed to the radiation exposure, although other factors (e.g.. chemical carcinogens produced in the firestorm; malnutrition) may have contributed to the excess in cancer deaths. Statistically, approximately, 7,800 cancer deaths from natural causes is was expected ill this population. The average radiation dose of the survivors is 20 rads. This large group of individuals, exposed to large amounts of radiation, experienced only a 7% increase in overall cancer rates. The amount of radiation that we are exposed to from natural sources (average in the US - 300 mrems/year) varies greatly. Studies of populations that live in high background regions (2-3 times the radiation in the low background regions) have not shown that there is any relationship between cancer rates and the amount of naturally occurring radiation. Radon has received a great deal of publicity as a potential naturally occurring carcinogen in our homes. Only the alpha rays of radon and its daughter are of concern. Since alpha rays can not penetrate the dead layers of the skin, radon is only a hazard to our lungs. Inhaled radon and its daughter come into contact with the living cells lining the lungs. Its only known health risk is to cause lung cancer. Although it is clear the miners exposed to high doses of radon have an increased risk of lung cancer, it is unclear if lung cancer will be induced by the lower levels of radon found in homes. Approximately 130,000 cases of lung cancer occur each year. The great majority of these cases (110 120,000) occur in smokers and could be prevented. Estimates of the number of cancers cause by radon range from 0-30,000 lung cancers per year. It is likely that only a few hundred of these deaths would be preventable by testing and taking remedial action for radon. Many more lung cancers could be prevented by programs to encourage people to stop smoking. Despite the fact that the adverse health effects from radon are controversial, radon certainly is the greatest source of exposure to radiation. If the public is concerned about the carcinogenic effect of radiation, their efforts should be focused on efforts to decrease their -6- Henry D. Royal, M.D. Low Levels of Radiation Effects April 12, 1994 dose from radon. The dose to the general population from radon is hundreds to thousands of times greater than their dose from the nuclear industry. SELECTED REFERENCES 1. Weart, SR: Nuclear Fear: A History of Images. Harvard University Press, Cambridge MA, 1988. 2. Chapter 11: Perception and acceptance of risk IN: Mettler FA. Moseley RD: Medical Effects of Ionizing Radiation Grune and Stratton, Inc. Orlando, FL, 1985. pp 247-255 3. Hendee WR: Real and perceived risks of medical radiation exposure. Western Journal of Medicine 138:380-386, 1983. 4. Fairbank JI: Radiation and health. Western Journal of Medicine 138:387-390, 1983. 5. NCRP Report No 93: Ionizing Radiation Exposure of the Population of the United States. Bethesda MD, 1987. 6. Frigerio NA, Stowe RS: Carcinogenic and genetic hazard from background radiation. IN: Biological and environmental effects of low-level radiation. Vol 2. Vienna IAEA 1976 pp 385-393. 7. High Background Radiation Research Group. China Health survey in high background radiation areas in China Science 209:877- 880, 1980. 8. BEIR IV: Health Risks of Radon and other internally deposited alpha emitters. National Academy Press, Washington D.C., 1988. 9. Low level radiation effects: A fact book. Society of Nuclear medicine, New York, 1985. 10. Neel JV, Satoh C, Goriki K, Asahawa J. Fajitia M, Takahashi N, Kageoka T Hayama R: Search for mutations altering protein charge or function in children of atomic bomb survivors: Final report. Am J Hum Genet 42: 663-76, 1988. 11. Preston DL, Kato H, Kopecky K. Fujitia S: Studies of the mortality of A-bomb survivors: Cancer mortality, 1950-1982. Radiat Res 111:151-78 1987. 12. Cancer Induction and Dose Response Models IN: Mettler FA, Mosely RD, eds, Medical Effects of Ionizing Radiation, Grune and Stratton. Inc., Orlando FL, 1985, pp 74-92. 13. Maruyama T. Kumamoto Y, Noda Y: Reassessment of gamma doses from the atomic bombs in Hiroshima and Nagasaki. Radiat Res. 113:1-14 1988. 14. Fry RJ, Sinclair WK: New dosimetry of atomic bomb radiations. Lancet 2:845-8. -7- Henry D. Royal, M.D. Low Levels of Radiation Effects April 12, 1994 15. Ichikawa Y. Nagatomo T, Hoshi M. Kondo S: Thermoluminescence Dosimetry of y-Rays from the Hiroshima Atomic Bomb at Distances of 1.27 to 1.46 Kilometers from the Hypocenter. Health Physics 52:43-451, 1987. 16. Kerr RA: Indoor Radon The Deadliest Pollutant Science 240:606, 1988. 17. ICRP Publication 50: Lung Cancer Risk From Indoor Exposure to Radon Daughters. Pergamon Press, Oxford, England. 1986. 18. Council on Scientific Affairs: Radon in Home Interior. JAMA 258:L668-672, 1987. 19. Shore RE: Electromagnetic radiations and cancer: Cause and prevention. Cancer 62: 1747- 1754. 1988. 20. BEIR V: Health Effects of Exposure to Low Levels of Ionizing Radiation. National Academy Press, Washington, D.C., 1990. -8- RSNA Refresher Course Course No: 811 Title: Effects Of Low Level Radiation: Scientific, Political, and Social Views Day, Date, and Time: Friday December 3, 1993 at 8:30 AM Room: M-4 Henry D. Royal, M.D. Associate Director, Division of Nuclear Medicine Mallinckrodt Institute of Radiology Professor of Radiology Washington University School of Medicine St Louis, MO 63110 Mailing Address: Division of Nuclear Medicine Mallinckrodt Institute of Radiology 510 S. Kingshighway Blvd. St Louis, MO 63110 (314) 362-2809 Course No: 811 Effects of Low Level Radiation Page 2 Introduction: In January 1990, the committee on the biological effects of ionizing radiation released the latest in a series of updates on the health effects of exposure to ionizing radiation (BEIR V). The cancer risk estimates presented by the committee are approximately three times larger for solid cancers and about four times larger for leukemia than the risk estimates presented in the BEIR III report (BEIR V, page 6). The purpose of this review is to summarize the major findings in BEIR V. The effects of low level radiation will be emphasized since every member of society is exposed to low levels (--380 mrem/year average U.S. per capita dose) of radiation. Unintended exposure to high levels of radiation (>10 rems/yr) is rare and not a significant public health issue. The three effects of low level radiation that are of greatest concern are mutagenesis, teratogenesis and carcinogenesis. The carcinogenic effect of low level radiation is the dominant risk and will be discussed in greatest detall. Other effects include the induction of cataracts and sterility. Since the latter effects occur only at high doses, they will not be discussed further. Although there are several sources of data from which the risks from low levels of radiation can be estimated (table 1), by far the greatest human data is derived from the survivors of the atomic bombings of Hiroshima and Nagasaki. Because of their importance, the strengths and weaknesses of these data will be discussed in detail. Genetic Effects In the past, there was considerably more concern about the genetic effects of radiation. This concern was prompted by fruit fly and mouse experiments which clearly demonstrated radiation's ability to increase the mutation rate. Despite this concern, genetic effects have yet to be demonstrated in humans. The largest human experience is based on studies of the children of the survivors of Hiroshima and Nagasaki. In a study of 75,000 births of which 38,000 had at least one parent who was exposed to radiation prior to conception (BEIR V, page 94), Neel et al was unable to find a significant effect on the number of still births, birth weight, congenital abnormalities, infant mortality, childhood mortality, leukemia, or sex ratio. More recent studies looking for rare electrophoretic variants of 28 proteins of the blood and plasma and erythrocytes have been carried out Among the children of exposed patients, three probable mutations have been found in 667,404 genetic loci. In a control population of unexposed children, three probable mutations have been found 466,881 genetic loci. Although the estimated mutation rate in the control population was greater than in the exposed population, the difference was not significant (BEIR V, page 95). Since mutations have not been observed in humans, the BEIR V estimate of the genetic risks of radiation (doubling dose = 100 rems) is based on the minimum possible doubling dose (95% confidence) consistent with failure to be able to detect an effect The BEIR V estimate is in agreement with previous estimates (UNSCEAR 1988). Teratogenic Effects The major teratogenic effects that have been demonstrated in man are effects on the central nervous system. The incidence of small head size and severe mental retardation were related to the radiation dose and the gestational age at the time of exposure (BEIR V, Figure 62). In a study of 1598 individuals who were exposed in uro, 30 children were found to have severe mental retardation. CNS development is most rapid during 8-15 weeks of gestation and this is the period of greatest vulnerability. BEIR V calculates the risk of severe mental retardation to be 0.43% per rad during this period. Of great importance is that a threshold may exist in the range of 20 to 40 rads. Excess cases of severe mental retardation were also observed when the exposure occurred during the 15-25 week of gestation but the risk was approximately one quarter (0.1% per rad) of that for the 8-15 week period. No excess cases of severe mental retardation were observed when the exposure occurred before the 8th week or after the 25th week. Course No: 811 Effects of Low Level Radiation Page 3 Intelligence scores of individuals who were exposed prenatally at Hiroshima and Nagasaki have been analyzed. As shown in Figure 6-3, (page 360) there is not a statistically significant change in I.Q. scores in individuals exposed during the 0-7 week period of time or during week 26 or greater. Children exposed 8-15 and 16-25 weeks after conception, however, show a progressive shift downward in individual scores with increasing exposure. The decrease in intelligence score is 0.3.I.Q. points per rad. No statistically significant decrease in IQ can be shown below 204() rads. Carcinogenic Effect The carcinogenic effect of radiation exposure has been demonstrated in several large groups of patients (Table 1). Of note is the fact that the population of atomic bomb survivors, by far represents the largest human data set available for model fitting. It is also the primary source of data for site specific risk estimates. Although each of the data sets listed in table have their limitations, the risk estimates obtained from animal studies and multiple human experiences are in reasonable agreement. The leukemia risk estimate calculated by BEIR V is four times greater than the risk estimate calculated by BEIR III; the non- leukemia risk estimate is three times greater than that of BEIR III. There are three major reasons for the increase in the risk estimates. First, the estimated dose to the survivors of Hiroshima and Nagasaki has been revised. Recent analysis suggests the previous estimates (T65D) of the neutron exposure at Hiroshima had been overestimated. In addition, the gamma radiation dose in Nagasaki had also been overestimated. The new dosimetry estimates are 50% of the prior estimates for Hiroshima and 65% of the prior estimate for Nagasaki. The neutron dose is now too small to be able to estimate the risk from neutrons. Second, BEIR III used a linear quadratic model to estimate the non- leukemia cancer risk whereas the BEIR V uses a linear model. This change in the risk model increases the risk by a factor of approximately 2.5. Third, excess solid cancers continue to be observed. As a result, the cancer excess is more consistent with "relative" risk estimates than with the "absolute" risk estimates favored by BEIR Ill. "Absolute" risk estimates assume that the number of excess cancer that occur will be a function of the dose and that this excess will be added to the baseline cancer rate observed in unexposed persons. This behavior was observed for leukemias that occurred in the Hiroshima-Nagasaki survivors. Excess leukemias were noted within 5 years of the exposure. By 30 years post-exposure the leukemia incidence returned to near normal. "Relative" risk estimates assume that excess cancer due to radiation exposure will be a constant per cent increase over the baseline cancer incidence. Since the baseline cancer incidence continues to increase with age, the number of excess cancers observed continues to increase with time. Acceptance of the "relative" risk model also increases the estimates of the cancer risk.BEIR V calculates the best estimates of the leukemia risk for males and females in the general population to be 110 and 80 excess cancer deaths per million person-rem (10,000 person-Sievert), respectively (Table 2). The corresponding solid cancer risks are 660 and 730 excess cancers deaths per million person-rem. According to the BEIR V estimates, the cancer risk varies greatly with age. The total lifetime cancer risk is 2-3 times greater under the age of 15-20 than the risk over the age of 35. The rise in cancer risk under the age of 35 is partly due to the fact that the cancer risk is expressed for a longer period of time. The risk estimates for the under 35 age group have greater uncertainty than for the older age group. These individuals are only now reaching the age where the baseline cancer rate is increasing. The current risk estimates are based on the relative risk model (cancer risk is equal to a percent increase over the baseline cancer rate). In a few more decades, the cancer risk will be based on the observed increase in cancer deaths rather than a model of increased risk. It is possible that the observed increase will be different than the increase predicted by the model. Course No: 811 Effects of Low Level Radiation Page 4 Leukemia is a type of cancer that is strongly associated with radiation because. the relative risk (excess number of leukemia deaths due to radiation / number of naturally occurring leukemia deaths is high. Leukemia is also strongly associated with radiation because its latency period is short; therefore, it was one of the first malignancies noted to occur in excess in an exposed population. Despite the strong association of radiation exposure with leukemia, it is important to remember, based on the risk estimates cited above, it is on average seven times more likely that an exposed individual will develop a solid radiogenic tumor than a radiogenic leukemia. Limitations Of Risk Estimation The increase in cancer risk estimates by BEIR V is consistent with the continued observation of the Hiroshima and Nagasaki survivors, further refinement of dosimetry estimates and the use of more sophisticated statistical techniques. There has been a monotonous increase in the cancer risk estimates by all organizations over the last decade. Organizations charged with estimating the risk of low level radiation are faced with a most difficult problem; they must provide an estimate of a risk that is too small to measure directly. Historically, the risks at high levels and high dose rates have been measured and have been extrapolated to low levels and low dose rates. The mathematical basis for the extrapolation is based on radiobiological experiments in simple cellular models. These simple cellular models do not account for many of the important confounding biological variables that are known to be important for cancer development in a complex organism. The attractiveness of current mathematical methods of extrapolation are their simplicity. When the data upon which to base a model is lacking, it makes good sense to choose simple models. The dangers of extrapolating results are well known to the scientific community. The story of the survivors of Hiroshima and Nagasaki is remarkable and is surprisingly unknown. A population of approximately 75,000 survivors has been comprehensively followed for a lifetime. As of 1985, the best estimate of the number of excess cancer deaths was about 350. In the exposed group there has been an 8% increase in the cancer rate. The change in the cancer rate in Hiroshima and Nagasaki is considerably less than regional changes in the cancer rate. Executing a long-term epidemiological study such as the follow-up of the survivors of Hiroshima and Nagasaki is subject to many pitfalls. First, a control group must be selected to estimate the expected incidence of cancer. Since there are considerable variations in the regional cancer rate, careful selection of the control group is essential. In Hiroshima and Nagasaki, the control group consisted of residents of Hiroshima and Nagasaki that were not in the city at the time of the bombings. This control group may be different from the exposed group in many ways. For example, healthy young male were more likely to be outside the cities and industrial workers were more likely to be in the city. The fact that cancer rates are higher in urban industrial areas is well known. Second, radiation was not the only carcinogen that the exposed population was exposed to. Presumably other carcinogens were created in the fire-storm caused by the bombing. These smoke- borne carcinogens were likely inhaled and ultimately 213 of the inhaled carcinogens were swallowed in the GI tract The greatest excess in cancers in the exposed survivors has been in the GI tract All of these excess cancers have been attributed to the radiation exposure alone. Third, the role of malnutrition, anxiety, and other injuries in the observed excess of cancers is unknown. Fourth, another potential bias of long-term epidemiology studies is that exposed patients are more motivated to seek comprehensive medical attention. Work-up bias may cause more cancers to be discovered and recorded in this group. On the other hand, earlier discovery of cancers due to more comprehensive medical care may decrease the mortality rates. Because of the difficulties of uncontrolled experiments the scientific method squires that the results of experiments be reproducible. As stated previously, the Hiroshima/Nagasaki data is unique not only because of its magnitude but also because it is the only study of Course No: 811 Effects of Low Level Radiation Page 5 external exposure in an otherwise healthy population. Some scientist arc hopeful that the accident at the Chernobyl nuclear power station will help to confirm or refute the conclusion based on the Hiroshima/Nagasaki population. Unfortunately the dosimetry at Chernobyl is much more complicated than the dosimetry at Hiroshima and Nagasaki. At Hiroshima/Nagasaki it was only necessary to know the location of an individual at the time of the nuclear explosion. The dose was instantaneous since fallout contributed only a some fraction of the total dose. At Chernobyl, the radiation dose was spatially, temporally and mechanistically much more complex Radionuclides were released from the reactor over a ten day period. The distribution of the radionuclides was complex and determined by the weather (wind direction and precipitation). In the early days of the accident, inhalation and external exposure were the dominant mechanism of exposure. Later ingestion and external exposure from contaminated soil were most important Radiation dose also was affected by interventions that were recommended such as stable iodine prophylaxis and prohibition of local food. References 1. National Research Council. Health effects of exposure to low levels of ionizing radiation. BEIR V. Washington, DC: National Academy Press; 1990. 2. United Nations Scientific Committee on the Effects of Atomic Radiation. Ionizing Radiation: Sources and Biological Effects. New York; United Nations; 1988. TAB 5 Radiation: William R. Hendee, "Public Perception of Radiation Risks"