Radiation Risk in Nuclear Medicine S. James Adelstein, MD, PhD Given the central roles that anatomical and functional imaging now play in medical practice, there have been concerns about the increasing levels of radiation exposure and their potential hazards. Despite incomplete quantitative knowledge of the risks, it is prudent to think of radiation, even at low doses, as a potential, albeit weak, carcinogen. Thus, we are obliged to minimize its dose and optimize its benefits. Hopefully, time will clarify our estimates of the dangers. Until then, we should educate and assure our patients, their families, and colleagues that the risks have been taken into account and are well balanced by the benefits. Semin Nucl Med 44:187-192 C 2014 Elsevier Inc. All rights reserved.



ractitioners of nuclear medicine should have knowledge not only of radiation effects but also of the potential hazards that may result from radiation exposure. There are several reasons such information is essential. First, specialists should ensure that the exposure of patients to radiation from diagnostic or therapeutic procedures is not excessive. Although most current radiopharmaceuticals deliver radiation doses within a readily acceptable range, such was not the case 40 years ago when the radionuclides employed were generally longer lived and emitted significant particulate radiation, for example, iodine-131 and strontium-87m. As a result, before 1970, radionuclides were generally administered only to pediatric patients with advanced neoplastic diseases. Today, as new agents are introduced, it is imperative to understand the details of their distribution and the resulting radiation doses delivered to various organs. Moreover, for those who participate in clinical trials with new radiolabeled agents, an estimation of the absorbed radiation dose is required by institutional review boards as is some assessment of the potential hazard. Second, patients and the parents of young patients are frequently concerned about the radiation risks associated with nuclear medical procedures. It is important to convey these potential risks clearly, placing them in the context of radiologic and other risks as well as the benefits to be gained from diagnostic accuracy.

Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. Address reprint requests to S. James Adelstein, MD, PhD., Harvard Medical School, 180A Longwood Ave - 207, Boston, MA 02115. E-mail: [email protected]

http://dx.doi.org/10.1053/j.semnuclmed.2014.03.003 0001-2998/& 2014 Elsevier Inc. All rights reserved.

Third, nuclear medical specialists are often asked for their advice about the potential harm that may result from nuclear accidents such as those at Three Mile Island, Chernobyl, and Fukushima. It serves the practitioner well to respond to such requests in an authoritative and intelligible fashion. The increased use of medical imaging procedures has sensitized the medical community to the concomitant increase in radiation exposure, particularly from CT examinations and from nuclear imaging studies, as well.1,2 In the interval between 1984 and 2008, the number of nuclear medical studies increased from 6-18 million. In the same interval, the number of CT scans expanded at the rate of 10% per year. This increase in imaging use raised the average individual radiation exposure in the United States from 3.5-6 mSv, approximately 50% of which is now owing to medical procedures; the background radiation having remained constant. In response to this, nation-wide programs aimed at reducing medical radiation exposure have been established: in children, Image Gently, www.imagegently.org, and in adults, Image Wisely, www.imagewisely.org. Of course, the distribution of doses is far from the average and is not distributed uniformly; some 30% of the US population receives none at all. On the contrary, more than 55% of men and more than 75% of women receive an annual effective dose between 40 and 20 mSv.2 Neither are the imaging procedures distributed uniformly by age groups, the greater number of examinations are performed in middle- and advanced-age.3 This review presents some of the observations that form the basis for risk estimates. How the radiation protection community thinks about the risks of low-dose and low-dose-rate exposure is considered. The final section discusses explanation of potential risks to others. 187

S.J. Adelstein


A Little Radiation Biology The most significant consequence of low-level radiation exposure of animals and humans is cancer. Other outcomes have also been observed: In animals, irradiation of germ cells can lead to inheritable diseases, but none, so far, have been observed in humans. However, in humans, premature cardiac atherosclerosis has been found, albeit at a lower frequency than cancer for equivalent doses. There are no exact cell culture models of cancer, although mutagenesis and neoplastic transformation have been suggested as surrogates. Recent findings at low doses (bystander effects, genomic instability, and adaptive responses) may have implications for carcinogenesis induced by medical exposures, but how they affect human risk estimates is not clear (see article by Brooks and Dauer in this issue).4,5 Efficient mutagenesis can be induced in cultured cells by radionuclides as well as by external radiation sources.6 Radiation-induced transformation has also been observed. For the latter, dose-rate delivery seems to be important with less transformation found at lower rates.7 Exposure of rodents and other animals to increasing doses of radiation leads to an increased incidence of cancers and genetic abnormalities in offspring. In the case of cancers, the incidence rises with dose to reach a maximum at approximately 300500 cGy. Lowering the dose rate reduces the incidence of animal cancer with its potential relevance to internally deposited radionuclides.8 On the contrary, when cancer of the liver was induced in rats from a combination of radiation with a carcinogenic chemical, no dose-rate effect could be discerned when comparing external x-rays with internal irradiation from 113m In and 198Au colloid.9 In addition, there is experimental evidence that low doses of radiation do produce paradoxical biological effects, but whether they are detrimental is a matter of contention. Chronic, low-dose exposure (1 mSv per week for mice; 0.8 mSv per day for rats) increases the life span of rodents, an effect that has been ascribed to enhanced immune responsiveness.10 This increase in life span has been challenged.11 Similarly, a decreased incidence of thymic lymphoma has been found in mice because of chronic, fractionated low-dose total-body x-irradiation.12 Furthermore, exposure of some cells and organisms to low-dose radiation produces an adaptive response to higher doses of radiation, that is, certain biological changes occur with less frequency at higher levels of radiation exposure than are found in previously unexposed cells.13 These changes include survival, chromosome aberrations, and gene mutations. The increased radiation resistance has been ascribed to radical scavenging, stimulated DNA repair mechanisms, or the production of protective stress proteins. In dogs, inhalation of beta-gamma–emitting radionuclides produced lung tumors whose frequency strongly depended on dose rate. Short-lived 90Y was 8 times as effective in inducing tumors as the longer-lived 90Sr.14 Thus, animal experiments suggest that a dose-rate factor may be operative from radionuclide exposure but its existence or magnitude or both in humans remain unknown.

The main source of genetic information about the effects of radiation on the germ cells of mammals comes from experiments with mice. Increasing rates of mutation are found with increasing doses. Again, a reduction in dose rate has a significant effect on mutational frequency. In the male mouse, radiation sensitivity is reduced by a factor of 3 when the dose rate goes from 1000 to 10 mGy per minute, whereas in the female mouse low dose rates produce few if any mutations. From these experiments, the doubling dose (i.e., that quantity of radiation required to double the mutation rate to twice its spontaneous value) is estimated to be approximately 1000 mGy. As no direct information on the production of radiation-induced, inheritable human disorders is available, risk estimates are based on mouse experiments.15 The children of persons exposed acutely to radiation in Hiroshima and Nagasaki have been carefully examined, and no evidence for genetic change above the baseline has been found. Hence, it has been assumed that humans are no more sensitive to inheritable mutations than mice, and in the case of chronic irradiation, may be considerably less so.16

The Epidemiologic Record In a number of instances, exposure to ionizing radiation has produced cancer in humans. Early radiologists who performed fluoroscopic examinations with bare hands and high-dose sources developed skin cancers. Radium-dial painters who pointed brushes with their tongues leading to ingestion of the radionuclide developed sarcomas of the bone. Patients receiving thorium by injection to make the liver opaque to x-rays developed liver tumors. These observations alerted the medical community to the proposition that high-dose exposure could produce human cancer later. Studies that are more recent have been concerned with quantifying the dose-response relationship in populations exposed to various doses of radiation in the range of 100-2000 mSv. These populations include survivors of the atomic bomb detonations in Japan, patients treated by x-rays for ankylosing spondylitis, patients with tuberculosis and thoracoplasties who were followed up for long periods with multiple fluoroscopic examinations, patients treated with radiation for mastitis, and children who underwent

Figure 1 Actual and predicted time course of radiation-induced diseases in the Japanese life span study; 1945-2028. (Reprinted with permission from Douple et al.18)

Radiation risk in nuclear medicine

Figure 2 Dose response for radiation-induced leukemia from life span study of atomic bomb survivors. (Reprinted from Hsu et al.19)

irradiation of the scalp and thymus with consequent irradiation of the thyroid. All of these studies have shown an increase in cancer incidence with increasing doses of radiation for a number of organs including bone marrow, breast, thyroid gland, lung, stomach, colon, and ovary. Although among these studies there are some variations in the dose-response relationship, several generalities have emerged:17

189 sensitive to radiation carcinogenesis. In the HiroshimaNagasaki life span study, breast and bladder were more so, whereas rectum, pancreas, and uterus less. 2. Children are more susceptible than adults are.20 Moreover, there seems to be an increase in childhood cancers, particularly leukemia, of the same magnitude in children exposed in utero. The incidence of additional cancer cases increases with age in parallel with the increase in cancer of solid organs seen in an unexposed population. 3. The incidence of solid cancer is also gender dependent, with women having a higher relative risk than men do. From the life span study from Japan, this seems particularly so for breast, lung, and bladder cancers.21 4. Exposure of the thyroid gland to external radiation results in an increased incidence of thyroid nodules and thyroid cancer, as would be expected.22 Childhood thyroid cancer has increased early and markedly in areas subject to radioiodine fallout from the Chernobyl nuclear accident.23 The marked sensitivity and rapid onset may be due to the relative iodine deficiency in these areas. Notwithstanding, this observation suggests that caution should be used in treating children and young adolescents before the age of 15 with iodine-131. Moderate to high doses of radiation also produce developmental defects and functional losses in certain organs. Unlike carcinogenesis, these responses have a clear threshold above the levels provided by most nuclear medical procedures. For this reason, they are not described here but can be found in a number of sources.24 As for inheritable diseases following radiation of gametes, so far none have been observed in humans at low doses and are, therefore, not considered to be of significance.16

1. The response of bone marrow differs significantly from that of solid organs. Leukemias appear earlier after exposure than do other cancers; they reach a peak incidence within 5-10 years and decline slowly thereafter (Fig. 1).18 Childhood forms, such as acute lymphocytic leukemia, differ from adult forms, such as acute and chronic myelogenous leukemias. The dose-response curve for leukemia appears to be linear quadratic in shape with a possible threshold (Fig. 2).19 For solid tumors there is a latent period of at least 10 years, and the dose-response curves appear to be approximated by straight lines (Fig. 3).20 Not all tissues are equally

Most nuclear medical exposures and most nonoccupational accidental radiation exposures lead to equivalent doses in the

Figure 3 Dose response for radiation-induced solid cancers from life span study of atomic bomb survivors. (Reprinted from Ozasa et al.20)

Figure 4 Radiation-induced cancer risk estimation for 10-mSv exposure as a function of age. (Reprinted from Sodickson et al.31)

Low-Dose and Low-Dose-Rate Exposure

S.J. Adelstein

190 range of 5-25 mSv. Ideally, estimates of the risk would be derived from definitive epidemiologic studies performed in this dose range. Although there are many such studies, none are conclusive. Several populations have been examined: atom bomb survivors, persons exposed to nuclear sources such as fallout from weapons tests, those exposed as workers in nuclear facilities, medically irradiated populations, and persons who have lived in high background areas. Some studies have shown increases in cancer incidence with low doses, and others have not; a few have indicated a decrease in cancer incidence with doses slightly above background levels. All have suffered from small sample size, inadequate controls, incomplete dosimetry, or a range of confounding factors. As the statistical restraints on studies of small populations are so much greater than those on large ones, it is easy to see why these investigations shed little light on the question of a threshold for radiation effects and provide no definitive quantitative estimate of radiation risks at low doses. On the contrary, a number of recent reports suggest that medical exposure, particularly in childhood, leads to an increase in cancer. A retrospective cohort study from Great Britain has found that CT scans with cumulative doses of 5060 mGy seem to have tripled the risk of leukemia and brain cancer. Because of the relative rarity of these tumors, only 1 excess case of each was found per 10,000 CT examinations.25 An Australian investigation followed up 10.9 million people between the ages of 10 and 19 years. In a mean duration of 9.5 years following CT exposure, an increased incidence of cancer was found that was dose dependent.26 With time, such epidemiologic cohort studies may help clarify the actual risks after diagnostic medical exposures. In view of the uncertainty, national and international bodies, taking a prudent approach, have adopted the stance that all radiation exposure is potentially harmful, with even the lowest doses producing some damage at the molecular and cellular levels.27,28 Thus, considerable effort has been expended in estimating the risks at low doses and low dose rate by extrapolation from moderate- and high-dose epidemiologic data. The principal arguments have focused on the correct form for the dose-response curve.29 The curve for leukemia, which appears to be of the linear-quadratic form (Fig. 2), agrees with the shape of responses across a wide variety of biological end points. In the case of solid organs, extrapolation has proved more difficult; the data fit a linear relationship, but there is considerable uncertainty at low doses and a linear-

quadratic fit is as likely as a linear one (Fig. 3). To take into account this possibility and the fact that progressively lowering the dose rate incrementally reduces the slope of the doseresponse curve in experimental systems, a dose and dose-rate effectiveness factor has been introduced to approximate the limiting slopes at low dose rate. The value of this factor has been estimated to be 1.5-10, but most agencies have used a value of approximately 2 to be on the conservative side. From all these adjustments, the carcinogenic and inheritable risk from 10 mSv exposure is estimated at  5 in 10,000 for adults and about 10 in 10,000 for children. Given these assumptions, it is incumbent on practitioners to minimize the risks without compromising clinical care. Three general approaches can be employed: first, minimize the dose from imaging procedures using ionizing radiation without compromising image fidelity; second, replace procedures based on ionizing radiation (e.g., CT and nuclear studies) with those that are not (e.g., MRI and ultrasound) when appropriate; and third, order CT and nuclear images only when indicated by clinical decision rules and appropriateness criteria. When such guidelines have been followed, significant reduction in radiation exposure has been observed. The “Image Gently” and “Image Wisely” campaigns have taken the lead in promoting these, and much useful information for patients, families, and medical practitioners can be found on their websites.

Explaining the Risks to Others Patients and Their Families When providing information to patients who are to undergo a diagnostic nuclear medical procedure or to those inadvertently exposed to radiation releases, as well as to their families, the goal should be to reduce anxiety by conveying a realistic and comprehensible estimate of the projected harm. This is not always an easy task. As described previously, the long-term consequences of radiation exposure are frightening in their potential prospect: cancers and genetic defects. Moreover, the perception of risk is often contextual, with the fear of radiation exposure from a nuclear accident being greater than that from medical and natural sources.30 There are several ways to facilitate the discussion of these matters with patients. First, the time course for the late effects of radiation can be described with the help of a diagram such as

Table 1 Lifetime Risk of Death From Everyday Activities Compared With Medical Radiation Exposures; For Example 1 of 304 Americans Will Die Because of an Accident While Riding in a Car During His or Her Lifetime Activity




Riding in car Crossing street Choking Drowning Falling on stairs Riding bike Airplane crash Hit by lightning

304 652 894 1127 2024 4734 7058 84,388

CT abdomen (10 y old) CT abdomen (40 y old) 18 FDG-PET (10 y old) 18 FDG-PET (40 y old) 99m Tc-MDP (10 y old) 99m Tc-MDP (40 y old)

1600 2900 1515 2700 2560 4760

Reprinted with permission from Fahey et al.30

Radiation risk in nuclear medicine


that shown in Figure 1. The risk of leukemia starts after a latent period of 2 years, peaks at 6-7 years, and is generally exhausted after 25 years. The risk of a solid tumor begins after 10 years and may peak after 40 years. The lifetime attributable risks of a 10-mSv exposure are shown in Figure 4.31 One way of expressing this risk is to compare it with the ordinary risk of dying of cancer—a probability of approximately 20%. The incremental risks are small and, with appropriate usage, are outweighed by the benefits. Another approach is to compare these risks with other hazards of everyday living. With an average fatal accident rate of 6 per 10,000 per year, over a 50-year period, this risk is approximately 3%, or the equivalent of an exposure to 600 mSv or 120 average nuclear medical procedures. Fatal accidents also provide a useful spectrum of risks (Table 1). The analogy, however, can be faulted, as these accidents are generally immediately fatal in comparison with the long-term consequences of radiation exposure. In contrast, the frightening aspects of radiation risk are the uncertainty of outcome and relatively long period of latency. A similar approach can be taken for inheritable genetic risks. It is important to convey that the uncertainty is greater in this instance because estimates are based on animal data, although we are fairly certain that humans are less sensitive than mice. In humans, the natural probability of an offspring having a genetic abnormality, which includes genetic and chromosomal diseases as well as constitutional diseases and anomalies, is approximately 6%. Following a radiation exposure of 10 mSv, it is projected that there is an additional probability of 0.0004%, so the total probability becomes 6.0004%, hardly a significant increment. No conversations with patients and families concerning the risks of exposure from imaging studies should omit their benefits. This should include the reasons for the study, be it for diagnostic accuracy, its effect on decisions as to treatment and hospitalization, or to measure therapeutic response. The discussion should make it clear that the decision to employ a nuclear or CT study is based on a benefit that exceeds any potential risk. Although most patients and parents generally assume such logic, it is reassuring for them to hear that those caring for the health of children do so as well.

Table 2 Effective Doses of Selected Radiographic and Nuclear Imaging Procedures Procedure

Average Effective Dose (mSv)

P/A and lateral chest radiogram 99m Tc-radionuclide cystogram Head CT 99m Tc-MAG3 renal scan 99m Tc-sestamibi cardiac perfusion scan Chest CT 18 F-FDG-PET scan Abdominal CT

0.1 0.1 2.0 2.7 6.7 7.0 7.4 8.0

Reprinted in part with permission from Fahey et al.30

Institutional Review Boards The institutional review process that is required at clinical research institutions before new or experimental procedures are introduced is greatly facilitated by having a uniform radiation risk standard with which the new procedures may be compared. Of course, review boards are also interested in the relative benefit and effectiveness of the new procedure in relation to its hazard; introduction of the procedure to the clinic, after all, is based on efficacy. In pediatric nuclear medicine, these questions are especially important as many new procedures and agents are first tested in adult patients and then extended to children on a trial basis. We have found that a good comparison is with equivalent doses from well-established radiologic and nuclear medical procedures. (Keep in mind that the background equivalent dose is approximately 3 mSv per year.) Some representative equivalent doses are shown in Table 2.

Conclusion Practitioners of nuclear medicine should have a firm understanding of the risks of radiation, particularly for low doses and low dose rates. We have an obligation to look at the absorbed doses from standard procedures with these risks in mind and to convey the risks of new ones in a fashion that compares them with the risks of other medical tests. We must be able to present these risks to patients and their families in a manner that allows them to appreciate the hazards and benefits in a realistic way and in relation to the risks of other activities.

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192 12. Ishii K, Hosoi Y, Yamada S, et al.: Decreased incidence of thymic lymphoma in AKR mice as a result of chronic, fractionated low-dose total-body  irradiation. Radiat Res 1996;146:582-585 13. Johansson L: Hormesis: An update of the present position. Eur J Nuc Med Mol Imaging 2003;30:921-933 14. Brooks AL, Eberlein PE, Couch LA, et al.: The role of dose-rate on risk from internally-deposited radionuclides and the potential need to separate dose-rate effectiveness factor (DREF) from the dose and dose-rate effectiveness factor (DDREF). Health Phys 2009;97:458-469 15. Sankaranarayanan K: Estimation of the hereditary risks of exposure to ionizing radiation: Current status, and emerging perspectives. Health Phys 2001;80:363-369 16. Tatsukawa Y, Cologne JB, Hsu W-L, et al.: Radiation risk of individual multifactorial diseases in offspring of the atomic-bomb survivors: A clinical health study. J Radiol Prot 2013;33:281-293 17. Boice JD Jr.: Lauriston Taylor Lecture: Radiation epidemiology—the golden age and future challenges. Health Phys 2011;100:59-76 18. Douple EB, Mabuchi K, Cullings HM, et al.: Long-term radiation-related health effects in a unique human population: Lessons learned from the atomic bomb survivors of Hiroshima and Nagasaki. Disaster Med Public Health Preparedness 2011;5(suppl 1):S122-S133 19. Hsu W-L, Preston DL, Soda M, et al.: The incidence of leukemia, lymphoma and multiple myeloma among atomic bomb survivors: 19502001. Radiat Res 2013;179:361-382 20. Ozasa K, Shimizu Y, Suyama A, et al.: Studies of the mortality of atomic bomb survivors, report 14, 1950-2003: An overview of cancer and noncancer diseases. Radiat Res 2012;177:229-243 21. Preston DL, Ron E, Tokuoka S, et al.: Solid cancer incidence in atomic bomb survivors: 1958-1998. Radiat Res 2007;168:1-64

S.J. Adelstein 22. Ron E, Lubin JH, Shore RE, et al.: Thyroid cancer after exposure to external radiation: A pooled analysis of seven studies. Radiat Res 1995;141:259-277 23. United Nations Scientific Committee on the effects of atomic radiation: Sources and effects of ionizing radiations. UNSCEAR 2000 Report to the General Assembly with scientific annexes. Vol. II: Effects. New York: United Nations, 2000 24. Schull WJ, Otake M: Cognitive function and prenatal exposure to ionizing radiation. Teratology 1999;59:222-226 25. Pearce MS, Salotti JA, Little MP, et al.: Radiation exposure from CT scans in childhood and subsequent risk of leukemia and brain tumors: A retrospective cohort study. Lancet 2012;380:499-505 26. Mathews JD, Forsythe AV, Brady Z, et al.: Cancer risk in 680,000 people exposed to computed tomography scans in childhood or adolescence: Data linkage study of 11 million Australians. Br Med J 2013;346:f2360 27. National Research Council of the National Academies. Health Risks From Exposure to Low Level of Ionizing Radiation: BEIR VII, Phase 2. Washington, DC: The National Academies Press; 2006 28. ICRP 99. Low-dose extrapolation of radiation-related cancer risk. Ann ICRP 2005;35:1-142 29. Little MP, Wakeford R, Tawn EJ, et al.: Risks associated with low doses and low dose rates of ionizing radiation: Why linearity may be (almost) the best we can do. Radiology 2009;251:6-12 30. Fahey FH, Treves ST, Adelstein SJ: Minimizing and communicating radiation risk in pediatric nuclear medicine. J Nucl Med 2011;52:1240-1251 31. Sodickson A, Baeyens PF, Andriole KP, et al.: Recurrent CT, cumulative radiation exposure, and associated radiation-induce cancer risks from CT of adults. Radiology 2009;251:175-184

Radiation risk in nuclear medicine.

Given the central roles that anatomical and functional imaging now play in medical practice, there have been concerns about the increasing levels of r...
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