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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2 7 Medical Radiation Studies INTRODUCTION Studies of patients irradiated for the treatment or diagnosis of diseases have provided considerable information for the understanding of radiation risks, particularly for specific cancer types, including thyroid and breast cancer (IARC 2000; UNSCEAR 2000b). Today, approximately 50% of cancer patients are treated using radiation (Ron 1998), and several million cancer survivors are alive in the United States, emphasizing the importance of investigating the long-term consequences of radiotherapy and examining the features of epidemiologic studies of medical radiation. Large cohorts of radiation-treated patients who have been followed for long periods are available, allowing evaluation of cancer and other late effects. Population-based cancer registries in many countries have been used to identify these patients and to facilitate patient enrollment, thus allowing investigators to determine the risks of a second primary cancer after treatment with radiation for a primary cancer (Boice and others 1985). The characteristically detailed radiotherapy records for cancer patients and patients treated for nonmalignant conditions allow precise quantification of the doses to the organs of individuals, which in turn facilitates the evaluation of dose-response relationships. Frequently, patients with the same initial condition that receive treatments other than radiation are available for comparison, although the clinical indications for treatment may differ. In most cases, patients received high doses of radiation on the order of 40–60 Gy to the targeted region, aimed at producing cell killing. These “high” doses would decrease with distance from the target tissue, and some tissues might receive doses that are referred to in this report as “low dose” (100 mGy or less). The use of such studies to estimate the effect of low-dose exposures raises a number of questions. The exposures were generally only partial-body exposures in persons who were ill, possibly resulting in a different risk than an equivalent whole-body uniform exposure. Because of their disease, patients may have a different sensitivity to radiation-induced disease than persons who do not have the disease. However, these studies are valuable and will likely become more important in the next decade, both for radiation protection of patients and for radiation protection in general because they provide a unique opportunity to address the following issues: Effects of different radiation types Risk of specific tumor types Effects of potential risk modifiers, including sex, age, and exposure fractionation Possible genetic susceptibility to radiation-induced cancer In addition to studies of cancer survivors, long-term studies of patients who received radiation therapy for benign conditions such as enlarged tonsils and tinea capitis have also provided important information about radiation-induced cancer risk (UNSCEAR 2000b). These patients are particularly important in the evaluation of radiation risks in the absence of the possibly confounding effects of the malignant disease being treated and/or of concomitant therapy for cancer. Diagnostic radiation procedures, in contrast, generally result in small doses to target organs, and most studies of such exposure provide little information about radiation risks. A number of procedures, however, in particular repeated examinations of air collapse therapy for tuberculosis and of spine curvature for scoliosis, have resulted in sizable doses to specific tissues, and studies of patients who have undergone these examinations provide valuable information on radiation risks (UNSCEAR 2000b). It is noted that, although no informative studies are available, the recent use of computed tomography (CT) can deliver sizable doses, typically of the order of tens of millisieverts per examination (Brenner and Elliston 2004); UNSCEAR (2000b) reports cumulative doses of the order of 100 mSv for children. As in the other review chapters in this report, studies were judged to be informative for the purpose of radiation risk
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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2 estimation if (1) the study design was adequate (see Chapter 5 concerning informative study designs and limitations); (2) individual quantitative estimates of radiation dose to the organ of interest were available for the study subjects; (3) if so, the details of the dose reconstruction approach were evaluated; and (4) a quantitative estimate of disease risk in relation to radiation dose—in the form of an estimated relative risk (ERR) or excess absolute risk (EAR) per gray—was provided. Overall, more than 100 studies of patients receiving diagnostic or therapeutic radiation have evaluated the association between exposure to radiation and risk of cancer at multiple sites (IARC 2000; UNSCEAR 2000b). Studies that provide information about the size of radiation cancer risks are reviewed in detail in this chapter. Articles included in this chapter were identified principally from searching the PubMed database of published articles from 1990 through December 2004. Searches were restricted to human studies and were broadly defined: key words included radiation; neoplasms; cancers; radiation-induced; medical exposures; radiotherapy; diagnostic radiation; and iodine-131. Articles were also identified from UNSCEAR (2000b), from the references cited in papers reviewed, and from direct contacts with some of the main scientists who have been involved with studies of medical exposures in recent years. The data and confidence intervals are those given in the cited papers. MEDICAL USES OF RADIATION Medical use of radiation usually occurs under three circumstances: (1) treatment of benign disease, (2) diagnostic examination, and (3) treatment of malignant disease (Table 7-1). Diagnostic imaging using X-rays goes back to the time of Roentgen’s discovery in 1896. Diagnostic procedures, particularly the widespread use of X-rays, continue to be the most common application of radiation in medicine, even as non-ionizing radiation methods—ultrasound and magnetic resonance imaging—have become more generally accepted. Approximately 400 million diagnostic medical examinations and 150 million dental X-ray examinations are performed annually in the United States (Mettler and others 1996). On average, each person receives at least two examinations per year. The annual individual and collective effective doses from diagnostic medical X-rays have been estimated as 0.5 mSv and 130,000 person-Sv (UNSCEAR 2000b). The range of X-ray techniques used includes radiography, fluoroscopy, CT, interventional radiology, and bone densitometry. These procedures are intended to provide diagnostic information and in principle are conducted with the lowest practicable levels of patient dose to meet clinical objectives. Ranges of typical doses from various medical diagnostic exposures are shown in Table 7-1. TABLE 7-1 Estimated Range of Effective Doses from Diagnostic Radiation Exposures Procedure Type of Examination Range of Doses Conventional simple X-rays Chest films X-rays of bones and skull X-ray of abdomen 0.02–10 mGy Conventional complex X-rays GI series Barium enema Intravenous urogram 3–10 mGy Computed tomography (CT) Head injuries Whole-body examinations 5–15 mGy Spiral CT Head injuries Whole-body examinations 10–20 mGy Angiography Coronary, aortic, peripheral, carotid, abdominal 10–200 mGy Interventional procedures Angioplasties with stent placement Percutaneous dilatations, closures, biopsy procedures 10–300 mGy Internal emitters Radioisotope studies 3–14 mSv Although doses of single procedures are typically low, there is concern that populations of pediatric patients who may need repeated exams over time to evaluate their pulmonary, cardiac, urinary, or orthopedic conditions may receive relatively high cumulative doses. Similarly, adult patients may also require repeated examinations to evaluate fracture healing, or progression of pulmonary disease, or the regression or progression of neoplastic lesions. In contrast, therapeutic exposures are less frequent, and the dose levels are higher in view of the different purpose. Currently, radiotherapy is used mainly for the treatment of cancer, where the intention is to deliver a lethal dose to malignant tissue within a well-defined target volume, while minimizing the irradiation of surrounding healthy tissue. In the past, high doses of radiation have also been used for the treatment of a number of benign conditions, such as enlarged thymus and ringworm of the scalp (tinea capitis). Doses from radiotherapy to the target organs are generally above 1 Gy (and typically in the range of 50–60 Gy for the treatment of malignant diseases). Radiotherapy involves mainly partial-body irradiation, however; hence very different doses are delivered to different organs or tissues of the body. Doses to distant organs are generally considerably lower (of the order of fractions of a gray), and studies of cancer risk in these organs are therefore potentially informative for the assessment of risks associated with low-level exposure. Further, many of the patients treated with radiotherapy received frac-
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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2 tionated doses, and studies of these patients provide the potential to study the effects of exposure fractionation and protraction. Radiotherapy for Malignant Disease Studies of second cancer following radiotherapy have generally focused on patients treated for cervical cancer, breast cancer, Hodgkin’s disease (HD), and childhood cancers (i.e., patients that generally have a favorable long-term prognosis). Survivors of these cancers may live long enough to develop a second, treatment-related malignancy. It should be noted that chemotherapy and/or hormonal therapy used in the treatment of cancers is a potential confounding factor in investigations of the risk of a second primary cancer. Cervical Cancer The treatment of cervical cancer involves external beam radiotherapy or radium or cesium in applicators to deliver high local doses of X-rays and gamma rays to the cervix uteri and adjacent organs in the abdomen and pelvic area. Treatment is usually successful, and patients survive for years after radiotherapy. Although doses to the cervix are very high (typically 40–150 Gy), doses to distant organs are significantly lower: of the order of 0.1 Gy to the thyroid, 0.3 Gy to the breast and the lung, 2 Gy to the stomach, and 7 Gy to the active bone marrow (Kleinerman and others 1995). Most of the information on second cancers following radiotherapy for cervical cancer comes from an international cohort study of approximately 200,000 women treated for cervical cancer. The study involved the follow-up, based on 15 cancer registries in eight countries (Canada, Denmark, Finland, Norway, Sweden, the United Kingdom, the United States, and Yugoslavia [Slovenia]), of a multinational cohort of nearly 200,000 women patients treated for cancer of the cervix after 1960. In 1985, Boice and colleagues reported on 5146 second cancers that were diagnosed in this cohort up to 1980 and showed an increased risk of cancer following radiotherapy at a number of sites (Boice and others 1985). Kleinerman and coworkers (1995) extended the follow-up of this cohort, adding an additional 10 years of incident cases. Several registries from the original study were retained, and other registries were added to increase the number of nonexposed comparison subjects. A total of 7543 cases were included. This study confirmed earlier findings of increased risk of malignancies following radiotherapy and the persistence of increased risk over time. Case-control studies of specific cancer types, nested within this cohort, allowed the reconstruction of individual doses to specific organs and the estimation of site-specific cancer risks (Boice and others 1987, 1988, 1989). These studies are based on incidence data; the numbers of exposed and unexposed patients were large; there was long and complete follow-up (hundreds of cases and controls, with followup of 10–20 years or more); chemotherapy was rarely used; and the existence of radiotherapy records facilitated the development of a comprehensive dose reconstruction system to estimate individual doses. In an expanded case-control study nested within this international cohort (Boice and others 1988), radiation doses for selected organs were reconstructed from original radiotherapy records. Very high doses, of the order of several hundred grays delivered to the cervix, significantly increased the risks for cancers of the bladder, rectum, and vagina and possibly bone, uterine corpus, cecum, and non-Hodgkin’s lymphoma (NHL). Doses of several grays increased the risks for stomach cancer and for leukemia. The ERR1 for stomach cancer was 0.54 Gy−1 (90% CI 0.05, 1.5), with an excess attributable risk of 3.16 per 104 person-years (PY) per gray (0.05, 10.4), based on 348 cases and 658 controls. A nonsignificant twofold increase in the risk of thyroid cancer was observed, with an average dose of 0.11 Gy (43 cases and 81 controls). More detailed dose-response investigations were carried out for leukemia and breast cancer after treatment for cervical cancer. The case-control study of leukemia risk (Boice and others 1987) included 195 cases and 745 controls, of whom 181 and 672, respectively, had received radiotherapy. Radiation dose to the active bone marrow was estimated from detailed radiotherapy records of the subjects. Radiation exposure did not affect the risk of chronic lymphocytic leukemia (CLL; 52 cases). For other forms of leukemia taken together (143 cases), there was a significant twofold increase in risk associated with radiotherapy; the risk increased with increasing dose up to about 4 Gy and then decreased at higher doses and was modeled adequately by a linear-exponential function. The linear term of this model for leukemia other than CLL provides an estimate of the ERR per gray in the low-dose range, where cell killing is negligible; this estimate is 0.88 Gy−1 (standard error = 0.69). The case-control study of breast cancer included 953 cases and 1806 controls (Boice and others 1989). Radiation doses to the breast (average 0.31 Gy) and ovaries (average 32 Gy) were reconstructed from original radiotherapy records. Overall, there was no association between radiotherapy and risk of breast cancer. Among women with intact ovaries (561 cases), radiotherapy was associated with a significant reduction of risk, probably attributable to cessation of ovarian function. Among women with no ovaries, there was a slight increase in breast cancer risk and a suggestion of a dose-response with a relative risk (RR)2 of 1.0, 0.7, 1.5, and 3.1, respectively, for the dose groups 0, 0.01–0.24, 0.25–0.49, and 0.5 + Gy. From these data, UNSCEAR (2000b) 1 ERR is the rate of disease in an exposed population divided by the rate of disease in an unexposed population minus 1.0. 2 RR is the rate of disease in an exposed population divided by the rate of disease in an unexposed population.
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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2 estimated an ERR per gray of 0.33 (< −0.2, 5.8) for women with no ovaries and of −0.2 (< −0.2, 0.3) overall. A cohort study of second cancer risk following radiation therapy for cancer of the uterine cervix was also carried out in Japan among 11,855 patients (Arai and others 1991). Significant excesses of leukemia and of cancers of the rectum, bladder, and lung were observed. No estimation of organ dose is available. Hodgkin’s Disease The large radiation therapy fields used to treat HD and the young age and long survival of patients provide an opportunity to study the risk of second cancer after exposure to ionizing radiation. Most patients, however, in the past 20 years, have been treated with a combination of radiotherapy and chemotherapy. Following a first report by Arseneau and collaborators (1972), a number of authors have studied the risk of second cancer following treatment for HD (Boivin and others 1984). Initial reports focused mainly on the risk of leukemia following this treatment, but as longer follow-up periods were considered, an excess risk of a number of solid cancers (in particular breast and lung) became apparent. The results of the first multinational study were published in 1987 by Kaldor and collaborators. The study involved the follow-up (based on 11 cancer registries in seven countries: Denmark, Finland, Norway, Sweden, Slovenia, Canada, and the United Kingdom) of a cohort of 28,462 patients treated for HD between 1950 (in the earliest countries) and 1984. Increases in the risk of NHL, leukemia, lung, bladder, and breast cancer were reported in this cohort. No treatment information was available in this study, and no information is provided on radiation risks. Nested case-control studies of leukemia and of lung cancer were carried out, allowing reconstruction of individual doses for the subjects and estimation of site-specific cancer risks (Kaldor and others 1990a, 1992). The case-control study of leukemia included 163 cases and 455 controls. Radiation dose to the active bone marrow was estimated for subjects who had undergone radiotherapy, and doses were classified into three categories (<10, 10–20, and 20+ Gy). Among patients who did not receive chemotherapy, a significant increase in the risk of leukemia was seen at doses of more than 20 Gy (Kaldor and others 1990a). Another case-control study from the same collaborative group involved 98 cases of lung cancer occurring between 1960 and 1987 and 259 matched controls (Kaldor and others 1992). Radiation dose to the lung as a whole was estimated for the 60 cases and 275 controls who had undergone radiotherapy, and doses were classified into three categories (<1, 1–2.5, and 2.5+ Gy). Among patients treated with radiotherapy alone, there was a nonsignificant increase in risk in relation to radiation dose level. It is noted that the follow-up was short in this study, with three-quarters of the lung cancer cases having been diagnosed within 10 years of their initial disease (Kaldor and others 1992). In 1995, Boivin and collaborators published results of a joint Canada-U.S. study of second cancer risk among 10,472 patients treated for HD between 1940 and 1987. A total of 122 leukemia and 438 solid tumors were found, and nested case-control studies were carried out. Significant increases in the risk of cancers of the respiratory system, intrathoracic organs, and female genital system were observed among patients followed for 10 years or more after surgery. Estimates of organ doses were not available, and analyses by level of radiation dose are not shown. Van Leeuwen and collaborators (1995) conducted a case-control study of lung cancer nested in a cohort of 1939 patients treated for HD between 1966 and 1986 in the Netherlands. Radiation dose to the parenchyma, bronchi, and trachea were estimated for patients who had received radiotherapy (30 cases and 82 controls). A statistically significant increase in the risk of lung cancer was observed, with an RR of 9.6 (95% CI 0.93, 98.0) for patients who had received 9 Gy or more compared to patients who had received less than 1 Gy. The increase was greater among those who either continued smoking or started smoking after diagnosis, and a multiplicative interaction was observed between radiation dose and tobacco smoking. Swerdlow and collaborators (2001) carried out a nested case-control study of lung cancer in a cohort of 5519 patients with HD treated in Britain between 1963 and 1993. The study included 88 cases and 176 controls for whom treatment and other risk factor information was abstracted from medical records. An increased risk of lung cancer following radiotherapy was observed. No individual reconstruction of dose to the lung was carried out. Travis and colleagues (2002) carried out a case-control study of lung cancer nested within a multinational cohort of 19,046 HD patients diagnosed between 1965 and 1994 and reported to population-based cancer registries in Connecticut, Iowa, Denmark, Finland, the Netherlands, Sweden, and Canada (Ontario). The study included 222 cases and 444 matched controls. Nineteen of the cases were included in the previous case-control study by Kaldor and coworkers (1992). Dose to the specific location of the lung where the tumor had developed (and to a comparable location for matched controls) was calculated from radiotherapy records. The mean dose was 27.2 Gy in cases and 21.8 Gy in controls. In subjects who had not undergone chemotherapy, a significantly increased risk of lung cancer was observed (odds ratio [OR]3 5.9; 95% CI 2.7, 13.5) for a dose of 5 Gy or more. A significant trend in risk was observed with increasing dose. In a follow-up to this study, Gilbert and colleagues (2003) analyzed radiation effects among 227 lung cancer cases and 3 OR is the odds of being exposed among diseased persons divided by the odds of being exposed among nondiseased persons.
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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2 455 controls (the 199 cases and 393 controls from the Travis 2002 study who had adequate radiation dose information and 28 cases and 62 controls from the Dutch study of van Leeuwen and others 1995). Doses to the lung ranged from zero to more than 60 Gy; the distribution of doses was bimodal, with most subjects having received doses of less than 5 or more than 30 Gy. To account for a possible latent period between radiation exposure and lung cancer resulting from that radiation exposure, only doses received more than 5 years in the past were considered. Among the 146 cases and 271 controls who had received radiotherapy more than 5 years in the past, a significant association was seen between radiation dose and risk of lung cancer, with an ERR per gray of 0.15 (95% CI 0.06, 0.39). There was little evidence for nonlinearity of the dose-response, despite the fact that the majority of patients received doses to the lung in excess of 30 Gy. Information about smoking and radiotherapy was available for the study subjects. A multiplicative interaction was seen between radiation dose and tobacco smoking and an additive interaction with chemotherapy. The ERRs for men and women were respectively 0.18 (0.063, 0.52) and 0.044 (−0.009, 0.53); the difference between the sexes was not statistically significant. Breast cancer following treatment for Hodgkin’s disease has also been studied in a number of cohorts. Travis and collegues (2003) carried out a nested case-control study of breast cancer in a cohort of 3817 one-year survivors of HD diagnosed at age 30 years or younger between 1965 and 1994 and included in cancer registries in Iowa, Denmark, Finland, Sweden, the Netherlands, and Ontario, Canada. Individual doses to the area of the breast from which the tumor arose were reconstructed using detailed radiotherapy records and results of experiments with phantoms. Mean dose delivered to the location of the breast where cancer developed was 25.1 Gy (range: 12.0–61.3 Gy) in cases and 21.1 Gy (range 0–56.0 Gy) in controls. The study included 105 cases and 266 controls. A significant increase in the risk of breast cancer was seen following doses of 4 Gy or more (OR 3.2; 95% CI 1.4, 8.2); the increase remained significant even following very high doses (OR 8, 95%; CI 1.6, 26.4, of 40 Gy or more). No significant association between age at exposure or reproductive history was seen in this study, but the risk was lowered among women who received 5 Gy or more to the ovaries or who were also treated with alkylating agents. The estimated ERR per gray for women who did not receive alkylating agent chemotherapy or high radiation doses to their ovaries was 0.15 (95% CI 0.04, 0.74). Van Leeuwen and colleagues (2003) also studied the risk of breast cancer among female survivors of HD treated in the Netherlands. The study included 48 cases who developed breast cancer 5 years or more after HD diagnosis and 175 matched controls. It should be noted that 40 of the 48 cases in the study of van Leeuwen and colleagues were also included in the study by Travis and coworkers (2003). The object of the study was to evaluate the joint roles of radiation dose, chemotherapy, and hormonal factors in breast cancer following HD. As in the Travis study, the risk of breast cancer increased with radiation dose up to at least 40 Gy. A substantial risk reduction was associated with chemotherapy, which affects menopausal age, suggesting that ovarian hormones promote tumorigenesis after radiation-induced initiation. No estimate of ERR or EAR4 per gray is given. Little if any increased risk was seen for patients treated after age 30. Most recently, Dores and colleagues (2002) studied the risk of second cancers in general among 32,581 HD patients (including 1111 25-year survivors of HD) registered in 16 population-based cancer registries in North America and Europe. A total of 2153 second cancers were observed between 1935 and 1994. As before, significant increases in the risk of a number of second malignancies were observed. Although the elevated risks of cancers of the stomach, breast, and uterine cervix appeared to persist for 25 years or more, an apparent decrease in the risk of other solid tumors is suggested. These cohort studies, although they provide important information concerning treatment-related second neoplasms and their patterns of risk over time, do not provide quantitative information on the risk of radiation-induced cancer because of the absence of individual dose estimates. The risks of breast, thyroid, and gastrointestinal cancers were also investigated in patients treated for HD at Stanford University Medical Center (Hancock and others 1991, 1993a; Birdwell and others 1997). Increases in these diseases were observed, but no dose estimates were available. Hancock and colleagues (1993b) also investigated mortality from heart disease following treatment for HD in a cohort of 2232 patients treated from 1960 to 1991 with an average follow-up of 9.5 years. The RR for mortality due to heart diseases was 3.5 (95% CI 2.7, 4.3) among those who received mediastinal radiation doses of more than 30 Gy. The increased risk was highest for exposures that occurred before the age of 20 and increased with time since exposure. No increased risk was observed among subjects who received doses lower than 30 Gy. In a separate study, Heidenreich and coworkers (2003) found a high prevalence of asymptomatic heart disease—specifically aortic valvular disease—following mediastinal irradiation. Breast Cancer Leukemia, lung cancer, soft tissue sarcoma, and contralateral breast cancer have been studied in patients receiving radiotherapy for breast cancer. A case-control study of leukemia (excluding CLL) was carried out nested within a cohort of 82,700 women with breast cancer in the United States. A total of 90 cases and 264 controls were included with individual estimates of dose 4 EAR is the rate of disease in an exposed population minus the rate of disease in an unexposed population.
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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2 to the active bone marrow. A significant dose-response was seen for acute nonlymphocytic leukemia after adjustment for the amount of chemotherapy, with an RR of 2.4 among those who received radiotherapy alone (Curtis and others 1992). No information was provided on the magnitude of the risk per gray or on the risk of other forms of leukemia. A case-control study of contralateral breast cancer was carried out nested within a cohort of 41,109 women in Connecticut diagnosed with breast cancer between 1935 and 1982. A total of 655 cases and 1189 controls were included. The average dose to the contralateral breast was 2.8 Gy. A significant increased risk was seen only among women who received radiotherapy before age 45 (RR 1.59; 95% CI 1.07, 2.36, based on 78 exposed cases); a significant dose-response was observed in this group (Boice and others 1992). No excess risk of contralateral breast cancer was seen in a cohort of 14,000 women treated between 1946 and 1982 in Denmark (Basco and others 1985). The study included 194 cases with individual dose estimates (mean doses ranging from 1.4 to 3.3 depending on the type of radiotherapy and the field considered). The RR per 100 cGy was 0.99 (95% CI 0.76, 1.30); little difference was seen for those diagnosed 5–10 years or more after their first tumor. A case-control study of contralateral breast cancer was conducted among women with primary breast cancer entered in the Danish Cancer Registry from 1943 to 1978 (Storm and others 1992). A total of 529 cases and 529 controls were included, and individual doses to the contralateral breast were estimated from detailed radiotherapy records for all subjects who had received radiotherapy. The mean dose to the contralateral breast was estimated to be 2.5 Gy. There was no significantly increased risk of contralateral breast cancer in this study (RR = 1.04; 95% CI 0.74, 1.46). A case-control study of lung cancer was conducted based on the Connecticut Tumor Registry (Inskip and others 1994). The study included 61 cases of lung cancer and 120 controls. Cases were diagnosed between 1945 and 1981 among women who had been treated for invasive breast cancer between 1935 and 1971 and survived at least 10 years. Individual radiation dose to different segments of the lung was estimated from detailed radiotherapy records. Average dose to the lung was 15.2 Gy to the ipsilateral lung and 4.6 Gy to the contralateral lung. Patients who received radiotherapy had a 1.8 times higher risk of developing lung cancer than those who did not (95% CI 0.8, 3.8). The risk increased with time since exposure and appeared to be higher among women exposed under age of 45, although this was not significant. The risk was highest for the ipsilateral lung. The ERR was estimated to be 0.2 Gy−1 to the affected lung (95% CI −0.62, 1.03), based on 15 exposed cases. A nested case-control study of second malignant neoplasms was carried out for a cohort of 7771 women initially treated for breast cancer between 1954 and 1983 at the Institut Gustave Roussy near Paris, France (Rubino and others 2003). Individual doses to the location of the second tumor were estimated from detailed radiotherapy records. More than 40% of the irradiated patients received a local dose of less than 1 Gy. A significant quadratic dose-response was found in this study, with an excess risk of all second malignant neoplasms combined of 0.2% (95% CI 0.05, 0.5%) at 1 Gy. Darby and coworkers (2003) studied cardiovascular mortality in a cohort of 89,407 Swedish women identified from the Swedish cancer registry as having had unilateral breast cancer at the ages of 18 to 79 years between 1970 and 1996. Mortality from cardiovascular disease was higher in women who had left-sided tumors (OR 1.10; 95% CI 1.03, 1.18) 10 years or more after the diagnosis of breast cancer; for ischemic heart disease, the OR was 1.13 (95% CI 1.03, 1.25). No dose estimates were available in this record linkage study, but the fact that the increase was restricted to women with tumors in the left breast and that no increase in mortality from other causes (except breast cancer) was seen in this population lends plausibility to the hypothesis of a radiation effect on the risk of heart disease. Ovarian Cancer A case-control study of leukemia within an international cohort of 99,113 survivors of ovarian cancer showed no significant excess risk for leukemia associated with radiotherapy alone (Kaldor and others 1990b). A more recent case-control study was carried out, nested within an international cohort of 28,971 patients in whom ovarian cancer was diagnosed between 1980 and 1993 (Travis and others 1999). The study included 96 leukemia cases and 272 controls. Individual dose to the active bone marrow was estimated for the 26 cases and 79 controls who had received radiotherapy. The median dose to the bone marrow was 18.4 Gy. Radiotherapy increased the risk of leukemia following platinum-based chemotherapy. No increased risk of leukemia was observed in subjects who had radiotherapy alone; the data are sparse: one exposed case and 36 exposed controls. Testicular Cancer Travis and colleages (1997) studied second cancer incidence in a multinational cohort of 28,843 men who had been diagnosed with testicular cancer between 1935 and 1993 in the United States, Denmark, Finland, the Netherlands, Sweden, and Canada (Ontario). Cases of second cancers occurring between 1965 and 1994 in this cohort were identified from population-based cancer registries in these countries. Significantly increased risks of second cancers in general, as well as of leukemia (64 cases) and stomach cancer (93 cases), were observed among patients who had received radiotherapy 5 years or more in the past. No individual doses were available. Travis and colleagues (2000) conducted a case-control study of leukemia nested within a multinational cohort of 18,567 patients diagnosed with testicular cancer between
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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2 1970 and 1993 and registered in cancer registries in Iowa, Connecticut, New Jersey, Canada (Ontario), Denmark, Finland, the Netherlands, and Sweden. The study included 36 cases and 106 matched controls. Individual radiation dose to the active bone marrow was estimated from detailed radiotherapy records. In men who did not receive chemotherapy (mean radiation dose to 12.6 Gy), a 3.1-fold elevation of leukemia risk was observed (95% CI 0.7, 22). The risk increased with radiation dose to the active bone marrow, with an OR of 19.7 (95% CI 1.5, 59) for doses of 20 Gy or more (based on four exposed cases). No estimate of ERR or EAR per gray is given. Thyroid Cancer A cohort of 834 thyroid cancer patients treated with iodine-131 and of 1121 thyroid cancer patients treated by other means in Sweden between 1950 and 1975 was followed for cancer occurrence (Hall and others 1991). The average 131I cumulative activity administered was 4.55 GBq. The average duration of follow-up was 14 years. A total of 99 second cancers were found 2 years or more after 131I therapy among those treated with this modality and 122 among those treated by other means. The incidence of second malignancy was higher among those treated with 131I. Among women, the overall standardized incidence ratio (SIR)5 was 1.45 (95% CI 1.14, 1.83), and significantly elevated SIRs were found for tumors of the salivary glands, genital organs, kidney, and adrenal gland. A significant trend was seen with increasing 131I activity, with a SIR of 1.80 (95% CI 1.20, 2.58) for administered activities of 3.66 GBq and above. A cohort of 1771 patients treated with 131I for thyroid cancer was followed up for incidence of second cancers (de Vathaire and others 1997). The average 131I cumulative activity administered was 7.2 GBq, resulting in an estimated average dose of 0.34 Sv to the bone marrow and 0.80 Sv to the whole body. After a mean follow-up of 10 years, no case of leukemia was seen. Eighty patients developed a secondary solid cancer, including 13 colorectal cancers. The risk of colorectal cancer was related to the total activity administered (ERR = 0.47 GBq−1; 95% CI 0.1, 1.6). The overall ERR for solid tumors in this study was 0.38 per estimated effective sievert (95% CI −0.22, 1.2); when tumors of the digestive track were excluded, the ERR was reduced to −0.15 Sv−1 (95% CI −0.35, 0.22). Childhood Cancers The treatment for childhood cancers, often a combination of both radiotherapy and chemotherapy, has prolonged the life expectancy of children with cancer and increased the chance of development of second cancers. Since childhood cancer is rare, national and international groups such as the Late Effects Study Group (Tucker and others 1987a, 1987b, 1991) and several groups in the United Kingdom (Hawkins and others 1987) and France (de Vathaire and others 1989, 1999) have combined their data to evaluate risks. Results from these cohort studies have indicated that the risk for developing a second cancer in the 25 years after the diagnosis of the first cancer was as high as 12% (Tucker and others 1991). Further, genetic predisposition appears to have a substantial impact on risk of subsequent cancers. Among patients treated for hereditary retinoblastoma, the risk of developing a second cancer in the 50 years after the initial diagnosis was as high as 51% (Wong and others 1997b). Three nested case-control studies including 64 cases of bone cancer and 209 controls (Tucker and others 1987a), 23 cases of thyroid cancer and 89 controls (Tucker and others 1991), and 25 cases of leukemia and 90 controls (Tucker and others 1987b) were conducted from the Late Effects Study Group cohort of 9170 children who developed a second malignant tumor at least 2 years after diagnosis of the first tumor. A significant increased risk of bone cancer was found among patients who received radiation therapy (RR 2.7; 95% CI 1.0, 7.7), with a sharp dose-response gradient reaching a fortyfold risk following doses to the bone of more than 60 Gy. A significant increased risk of thyroid cancer was also found among patients who had received radiation therapy; most of the increase was among those who had received doses of 2 Gy or more. There was no evidence of a dose-response relationship for leukemia. In a U.K. cohort of 10,106 3-year survivors of childhood cancer, Hawkins and colleages (1987; Hawkins 1990) reported an excess of second tumors among subjects who had received radiotherapy in comparison with the general population. In addition, two nested case-control studies of 59 cases of second bone cancer and 220 controls (Hawkins and others 1996) and 26 cases of second leukemia and 96 controls (Hawkins and others 1992) were conducted within this cohort, with individual dose reconstruction to the organs of interest. The risk of bone cancer increased substantially with increased cumulative radiation dose to the bone (p < .001), although a decline in risk was seen at doses equal to or greater than 50 Gy. A nonsignificant increased risk of leukemia was observed among those who had received radiotherapy (RR 8.4; 95% CI 0.9, 81.0 based on seven exposed cases). A significant dose-response relationship was observed. In a cohort study of 634 children treated for childhood cancer from 1942 and 1969 in the Institut Gustave Roussy in Paris, a twofold increase in the risk of second malignancy was seen after doses from radiotherapy of more than 25 Gy, based on two exposed cases (de Vathaire and others 1989). A nonsignificant dose-response was seen based on 13 cases who had received radiotherapy alone. 5 SIR is the ratio of the incidence rate of a disease in the population being studied divided by the comparable rate in a standard population. The ratio is similar to an RR times 100.
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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2 In a French-British cohort study (de Vathaire and others 1999) that overlapped partially with the Late Effects Study, the French study, and British studies, described above, an excess of second cancers was seen among 1045 children who received radiotherapy alone (based on 31 second malignant neoplasms, including 8 brain cancers). Fourteen cases of thyroid carcinoma were identified in the entire cohort of 4096 3-year survivors of childhood cancers. All 14 had received radiotherapy. The average dose to the thyroid in this study was 7 Gy. A significant dose-response was observed for thyroid cancer in this study—RRs were 4.0 (90% CI 0.7, 44), 11.0 (90% CI 2.3, 123), 13.0 (90% CI 2.2, 141), and 26.0 (90% CI 3.4, 308) for doses within the ranges of 0.25 to <1 Gy (3 cases), 1.0 to <10 Gy (5 cases), 10 to <30 Gy (3 cases), and 30+ Gy (2 cases), respectively. In a joint analysis of data from childhood cancer survivor cohorts from France, Britain, and Nordic countries, a nested case-control study of melanoma was carried out. Radiotherapy appeared to increase the risk of melanoma for local doses greater than 15 Gy (OR 13.0; 95% CI 0.94, 174.0), based on three exposed cases; the ORs for doses less than 1 Gy and of 1–15 Gy were 1.4 (95% CI 0.28, 7.0) and 3.2 (95% CI 0.37, 27) based on very small numbers of exposed cases—five and two, respectively (Guerin and others 2003). A partially nested case-control study of soft tissue sarcoma (STS) was carried within the French-U.K. cohort of 4400 3-year survivors of childhood cancer survivors; 25 cases and 121 controls were included. Individual dose to the site of STS development was calculated. A significant increase in the risk of STS was seen among those who received radiotherapy (OR 19.0; 95% CI 3.0, 60.0). The risk increased with the square of the radiation dose and was independent of chemotherapy (Menu-Branthomme and others 2004). Other Cancers The health effects of radiotherapy for a number of other cancer types have also been considered in single studies. Travis and colleagues (1991) studied the risk of second cancers among 29,153 patients diagnosed with NHL between 1973 and 1987 in nine areas of the United States. Radiation therapy appeared to increase the risk of acute nonlymphocytic leukemia and possibly of cancers of the lung, bladder, and bone. No estimate of radiation dose was available. Curtis and coworkers (1994) studied the risk of leukemia following cancer of the uterine corpus in a cohort of 110,000 women assembled from nine population-based cancer registries in the United States, Canada, Denmark, Finland, and Norway. Radiation doses were computed to 17 sections of the active bone marrow for 218 women who developed leukemia and 775 matched controls. There was no association between radiation dose and risk of CLL (RR 0.90; 95% CI 0.4, 1.9). For all leukemia excluding CLL, however, the RR was 1.92 (95% CI 1.3, 2.9). There appeared to be no association with age at exposure in this study. A complex dose-response was observed, with a relative risk of 1.8 (95% CI 1.1, 2.8) following continuous exposures from brachytherapy6 at comparatively low doses and low dose rates (mean total dose 1.7 Gy). The risk was of the same order (RR 2.3; 95% CI 1.4, 3.7) after fractionated exposures at much higher doses and dose rates from external beam treatment (mean total dose 9.9 Gy). Summary Studies of second cancer following radiotherapy have generally focused on patients treated for malignant diseases with a favorable long-term prognosis, such as cervical cancer, breast cancer, HD, and childhood cancers. Because many survivors of these cancers live long enough to develop a second, treatment-related malignancy, these studies have provided valuable information on the magnitude of risk following radiation exposure. The cohort studies generally do not provide quantitative information on the risk of radiation-induced cancer because of the absence of individual dose estimates. Case-control studies of specific cancer types have been carried out, nested within cohorts of cancer survivors. In allowing the reconstruction of individual doses to specific organs for the subjects, they have provided important information for the estimation of site-specific cancer, even if the average doses to the target organs have generally been high. Studies of patients treated for HD have provided quantitative estimates of the risk of cancers of the lung and breast—organs that generally received fairly high doses (of the order of 20 Gy on average) from the radiotherapy. Studies of patients treated for cancer of the cervix have provided estimates of the risk of breast cancer, leukemia, and stomach cancer (at average doses of 0.2, 7, and 2 Gy, respectively). Studies of women treated for a first breast cancer have provided quantitative estimates of the risk of lung cancer, at average doses of the order of 5–15 Gy. These estimates are reviewed in detail, and compared with risk estimates derived from other medical exposure studies, in the section “Evaluation of Risk for Specific Cancer Sites.” Radiotherapy for Benign Disease Among Adults In the past, radiotherapy has been used in different countries for the treatment of a number of benign conditions in children (skin hemangioma, tinea capitis, enlarged thymus) and adults (e.g., benign breast and gynecological disease, ankylosing spondylitis, peptic ulcer). Studies of patients treated with radiation (X-rays and gamma rays) for benign disease provide valuable information about the carcinogenicity of low-LET (linear energy transfer) radiation. Doses 6 Radiation therapy in which a radioactive material sealed in needles, or wires, or other small delivery devices is placed directly into or near a tumor.
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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2 used in the treatment of benign conditions were generally not as high as those used to treat malignant disease so that cell-killing effects do not predominate, survival after treatment is good because the conditions treated were generally not life-threatening, and there is minimal confounding from concomitant treatment. Benign Breast Disease A U.S. cohort of 601 women treated with radiotherapy for acute postpartum mastitis and 1239 women treated by other means between 1940 and 1957 was followed for 29 years. The average dose to the breasts was 3.8 Gy. A significant increase in the risk of breast cancer was seen among women who had received radiotherapy, based on 51 exposed breasts with cancer. Using a linear multiplicative model the risk increased by 0.4% per rad (ERR per Gy 0.4; 90% CI 0.2, 0.7). A dose-response curve that appeared to be essentially linear up to about 7 Gy was demonstrated, and an increased risk for breast cancer was observed based on 56 cases (Shore and others 1986). A Swedish cohort of 1216 women treated for benign breast disease with radiotherapy and 1874 women treated by other means from 1925 to 1954 was followed for an average of 27 years for development of a subsequent cancer. Mean absorbed doses to the breast were determined from detailed radiotherapy records and experiments with phantoms. The average dose to the breast was 5.8 Gy (range 0–50): 278 cases of breast cancer were diagnosed; 183 of these cases had received radiotherapy. A significant linear dose-response relationship was seen, with a downturn at approximately 10 Gy and higher. The estimated ERR for breast cancer was 1.63 Gy−1 (95% CI 0.77, 2.89, based on 47 exposed cases) among subjects with less than 3 Gy and 1.31 Gy−1 (95% CI 0.79, 2.04, based on 75 exposed cases) among subjects with less than 5 Gy (Mattsson and others 1995). Mattsson and colleagues (1997) also studied the risk of malignancies other than breast cancer. Average doses were estimated to 14 organs. A significant increase in the risk of all cancers combined (excluding breast) was observed. A significant linear dose-response was seen for stomach cancer: ERR per Gy 1.3 (95% CI 0.0, 4.4), based on 14 exposed cases and a mean dose to the stomach of 0.66 Gy (range 0–5.4). No significantly increased risk was seen for any other cancer site, including leukemia, based on a small number of exposed cases (Mattsson and others 1997). The estimated ERR for lung cancer was 0.38 (95% CI <0, 0.6), based on 10 exposed cases and a mean lung dose of 0.75 (range 0–9.0). Peptic Ulcer Cancer mortality up to 1985 was studied in a U.S. cohort consisting of 1831 patients irradiated between 1937 and 1965 for the treatment of peptic ulcer and 1778 who were not (Griem and others 1994). An elevated risk of circulatory disease mortality was observed among those who received radiotherapy compared to those who did not. Overall, a 50% increase in the risk of all cancers combined was observed. Significant increases were seen for cancers of the stomach, pancreas, and lung; the average doses to the organs were estimated to be 15, 13, and 1.7 Gy, respectively. For stomach cancer, a threefold increase in risk was observed in this study; the RR at 1 Gy was estimated to be 1.15, and the absolute risk was 4.19 per 104 PY per gray. The estimated RR of lung cancer was 1.66 at 1 Gy. In an updated follow-up of this cohort up until 1997 (average follow-up 25 years), Carr and colleagues (2002) also reported significant exposure-related increases in the risk of cancers of the stomach, pancreas, and lung among 1859 patients treated with radiotherapy. For stomach cancer, the ERR was estimated to be 0.20 Gy−1 (95% CI 0, 0.73), based on analyses restricted to subjects who had received doses to the stomach of 10 Gy or less (mean dose to the stomach 8.9 Gy; number of exposed cases 11). The corresponding estimate for cancer of the pancreas was 0.34 Gy−1 (95% CI 0.09, 0.89), with a mean dose of 8.2 Gy and 14 exposed cancer cases. For lung cancer, the ERR was estimated to be 0.43 Gy−1 (95% CI 0.12, 1.35) among subjects in the lowest-dose quartile (<1.4 Gy—mean dose 1.1 Gy), based on 21 deaths from lung cancer. Although the risk of pancreatic cancer decreased with increasing age at exposure, no association with age at exposure was observed for stomach and lung cancer. Benign Gynecological Diseases A U.S. cohort of 4153 women treated with intrauterine 226Ra between 1925 and 1965 for uterine bleeding disorders was followed for an average of 27 years up to 1983 (Inskip and others 1990b). Individual organ doses were estimated based on detailed radiotherapy records and simulation of pelvic irradiation treatments on phantoms. A significantly increased standardized mortality ratio (SMR)7 for death from all cancers was seen in this population compared to the general population. In addition, significant increases were observed for deaths from colon and uterine cancer, cancers of the female genital organs, and leukemia. Estimated ERR per Gy were 0.006 (90% CI −0.01, 0.05) for cancer of the uterus, 0.41 (90% CI −0.69, 1.51) for other genital organs, 0.51 (90% CI −0.08, 5.61) for colon cancer, and 0.20 (90% CI 0.08, 0.35) for bladder cancer. Inskip and colleagues (1990a) studied the risk of leukemia in relation to radiation dose among 4483 of these women. Individual doses to various sections of the red bone marrow were calculated from detailed radiotherapy records. The median dose to red bone marrow was 0.53 Gy. A significant excess of leukemia was observed; the risk was highest 2–5 years after treatment (SMR 8.1; 95% CI 2.6, 18.8, 7 SMR is the ratio of the mortality rate from a disease in the population being studied divided by the comparable rate in a standard population. Often the ratio is multiplied by 100.
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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2 compared to the general population) and among women over 55 years at irradiation (SMR 5.8; 95% CI 2.5, 11.3). The average ERR in this study was 0.19 Gy−1 (95% CI 0.08, 0.32) for intrauterine 226Ra exposure, and the average absolute excess mortality from leukemia was 2.6 per 104 PY per gray. The risk of leukemia, lymphoma, and multiple myeloma was studied in an expanded cohort of 12,955 women treated for benign gynecological disorders at one of 17 hospitals in Massachusetts, Connecticut, Rhode Island, or New York State between 1925 and 1965 (Inskip and others 1993). Of these women, 9770 were treated with radiation (either intracavitary 226Ra or external beam X-rays), while the rest were treated by other methods. The average age at treatment was 46.5 years, and the average dose to active bone marrow in exposed women was 1.2 Gy. The RR for all cancers of hematopoietic and lymphatic tissue was 1.3 (95% CI 1.2, 1.5) for irradiated women, compared to nonirradiated. The risk of lymphomas, multiple myeloma, and nonacute lymphocytic leukemia was similar between irradiated and nonirradiated women. The RRs for acute lymphocytic leukemia and for myeloid leukemia were elevated, however: RR 3.7 (95% CI 1.3, 16) and 3.7 (95% CI 0.9, 36), respectively. For acute lymphocytic and nonlymphocytic leukemia, the SMRs were similar for women treated with radium only and with both modalities, and were smallest for X-ray patients (difference not statistically significant). The ERR per Gy was 0.29 overall; 0.37 Gy−1 (95% CI <0, 1.5) for treatment with radium only; 0.05 per Gy (95% CI −0.06, 0.33) for X-rays only; and ERR 0.21 per Gy (95% CI 0.05, 0.83) for the combination of both modalities. Average doses for the different treatment types were 0.6, 2.3, and 2.0 Gy, respectively, indicating a complex dose-response relationship. A cohort of 2067 women who received radiotherapy for metropathia hemorrhagica (uterine bleeding disorders) in Scotland between 1940 and 1960 was followed until the end of 1990 (Darby and others 1994). The average follow-up was 28 years. Absorbed doses to the active bone marrow and to 20 solid organs or anatomical sites were estimated from treatment records. Overall, 331 deaths from cancer were observed, and significantly elevated SMRs were observed for cancers at heavily irradiated sites (average local dose >1 Gy): cancer of pelvic sites, particularly urinary bladder cancer (mean dose 5.2 Gy); colon cancer (mean dose 3.2 Gy); leukemia, and multiple myeloma (mean total active bone marrow dose 1.3 Gy). A deficit of breast cancer mortality was also observed in this cohort, due mainly to a large deficit in women who had received doses to the ovary of 5 Gy or more. No estimate of risk per unit dose was presented. A Swedish cohort study included 2007 women treated for metropathia hemorrhagica between 1912 and 1977. Of these, 788 received radiotherapy for this condition. The population was followed up for cancer mortality and incidence from 1958 to 1982, with a mean follow-up period of 28 years (Ryberg and others 1990). A total of 107 cancers were observed among irradiated women. The SIR for cancer was 1.22 among irradiated women and 1.09 among nonirradiated. A significant increase in the SIR for cancers at heavily irradiated sites in the pelvic area was only observed 30 years or more after irradiation. A decreased risk for breast cancer was also observed in this cohort, except for women treated at the age of 50 or more. No estimate of risk per unit dose was presented. Hormonal Infertility A U.S. cohort of 816 women who received X-ray therapy to the ovaries and/or pituitary gland for refractory hormonal infertility and amenorrhea between 1925 and 1961 was followed up until the end of 1990 (Ron and others 1994). The average duration of follow-up was 35 years. Individual organ doses were estimated from radiotherapy records. Average doses were 0.01 Gy to the breast, 0.9 Gy to the ovary, and 1.0 Gy to the sigmoid colon. Seventy-eight deaths from cancer occurred in this cohort. No increase in mortality rates was found for leukemia or sites directly exposed to radiation, such as the ovary or brain, based on a very small number of deaths (two leukemia, three ovary, and one brain cancer death). The SMRs were significantly elevated, however, for cancer of the colon (15 deaths) and for NHL (6 deaths). No estimate of risk per unit dose was presented. Ankylosing Spondylitis A U.K. cohort consisting of 15,577 patients diagnosed with ankylosing spondylitis between 1935 and 1957 was followed for mortality up to the end of 1991 (Weiss and others 1994). The average duration of follow-up was 25 years. Of these subjects, 14,566 had received X-ray treatment for their disease. Radiation doses to various organs were calculated for a sample of patients, and average estimated doses from all treatment courses occurring within 5 years of the initial treatment courses were attributed to all patients. The mean total body dose was estimated to be 2.6 Gy. Irradiated patients had a significantly greater mortality rate from cancer than expected from the national rates for England and Wales, and significant increases were seen for leukemia, NHL, multiple myeloma, and cancers of the esophagus, colon, pancreas, lung, bones, connective and soft tissue, prostate, bladder, and kidney. A linear dose-response model for all cancers except leukemia gave an ERR of 0.18 Gy−1 (95% CI 0.10, 0.27) 5–24 years after treatment (based on 741 deaths), decreasing significantly to 0.11 Gy−1 25 years or more (based on 845 deaths) after treatment. For lung cancer, the ERR was 0.09 Gy−1 (95% CI 0.03, 0.15) 5–24 years after treatment, based on 282 deaths and an average dose to the bronchi of 8.88 Gy. For stomach cancer, the ERR was −0.004 Gy−1 (95% CI −0.05, 0.05) 5–24 years after treatment, based on 127 deaths and an average stomach dose of 3.21 Gy. There was no increased risk in breast cancer in
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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2 this population, based on 84 deaths (ERR 0.08 Gy−1; 95% CI − 0.30, 0.65); this may result from the fact that the average dose the ovaries was high—5.5 Gy). The risk of leukemia mortality in this cohort was studied further by Weiss and colleagues (1995), using a case-subcohort approach. A total of 60 leukemia deaths were observed during the follow-up period. Radiotherapy records were obtained for all but six of the deaths from leukemia excluding CLL, and individual doses to the red bone marrow were estimated as in the previous study; estimated doses were also available for the subcohort, as described in Weiss and colleagues (1994). The average dose to the total red bone marrow was estimated to be 4.44 Gy, but doses were nonuniform, with the heaviest dose to the lower spine. A linear-exponential model (in which the exponential term allows for cell sterilization in heavily exposed parts of the bone marrow), varying with time since exposure, provided a good description of the risk for non-CLL. The estimated ERR per Gy was 12.4 (95% CI 2.3, 52.1) 10 years after exposure; 1–25 years after exposure, the average ERR per Gy was estimated to be 7.0, based on 35 cases. A Swedish cohort of 20,024 patients who received X-ray therapy between 1950 and 1964 for painful benign conditions of the locomotor system (including arthrosis and spondylosis) was followed for cancer incidence and mortality until the end of 1988 (Damber and others 1995). The average length of follow-up was 25 years. Average conversion factors between surface dose and mean absorbed dose in the red bone marrow were estimated by treatment site (for six sites), based on the treatment records of random samples of 30 subjects drawn from the cohort (Damber and others 1995). The conversion factors were applied to the entire cohort and used for stratification of subjects in different levels of exposure. The average absorbed dose to the red bone marrow was estimated to be 0.39 Gy. A total of 116 leukemia cases (115 deaths) were observed during the study period. The SIR and SMR for subjects with mean absorbed doses of 0.5 Gy or more were 1.40 (95% CI 1.00, 1.92) and 1.50 (95% CI 1.05, 2.04), respectively. No estimate of risk per unit dose was presented. Thyroid Diseases Iodine-131 is currently the treatment of choice for hyperthyroidism, largely because no serious side effects are known. Concerns remain, however, about the subsequent risk of cancer. Several studies of patients treated with 131I for hyperthyroidism have been carried out in the United States, Sweden, and the United Kingdom. The occurrence of leukemia and of thyroid neoplasms (both benign and malignant) was studied among 36,050 patients treated for hyperthyroidism between 1946 and 1968 and included in the Cooperative Thyrotoxicosis Therapy Follow-up Study (Saenger and others 1968; Dobyns and others 1974). Approximately 20,000 subjects had been treated with 131I. The follow-up was active, with an average duration of 8 years. No excess of leukemia or thyroid cancer was observed among patients treated with 131I. In a follow-up to this study, Hoffman (1984) studied cancer risk up to 1979 in the subgroup of 3696 women who had been treated at the Mayo Clinic, one of the original participating centers. Among these, 1005 had received 131I therapy alone and 2141 had been treated with surgery alone. A total of 527 cancer cases were identified in these two study groups; 175 were excluded because they occurred within a year of treatment. The mean observation period was 15 years for patients treated with 131I. The average whole-body dose is estimated to be of the order of 0.06–0.4 Gy in this cohort. There was no increased cancer risk among those treated with 131I and no indication of a relation with 131I activity delivered. Nonsignificant increased risks were seen for cancers in the two most exposed organs (thyroid and salivary glands, based on three and two cases, respectively). Goldman and colleagues (1988) reported on an extended follow-up of 1762 women, included in the Cooperative Thyrotoxicosis Therapy Follow-up Study, who were treated at the Massachusetts General Hospital between 1946 and 1964. A total of 1406 had been treated with 131I. No dose estimation was conducted. The average follow-up duration was 17.2 years. An elevated SMR was noted in this cohort (SMR 1.3; 95% CI 1.2, 1.4) for all causes of death but not for all cancers (SMR 0.9; 95% CI 0.7, 1.1). A nonsignificantly increased SMR was noted for breast cancer (SMR 1.2; 95% CI 0.9, 1.5); no association with 131I activity was found. Ron and colleagues (1998a) reported on mortality to the end of 1990 in the Cooperative Thyrotoxicosis Therapy Follow-up Study. The cohort included 35,593 hyperthyroid patients, 91% of whom had been diagnosed with Grave’s disease. Fewer than 500 subjects were less than 15 years of age at the time of treatment. The mean length of follow-up was 21 years, and 51% of the subjects had died during the study period. Doses from 131I to 17 organs (other than the thyroid) were estimated for each study subject by multiplying the amount of administered activity by the age-specific dose factor and 24-h thyroid uptake provided for each organ by the International Commission on Radiological Protection (ICRP 1988). Treatment with 131I was not related to all cancer mortality (SMR 1.02; 95% CI 0.98, 1.07) or to mortality from any specific cancer, with the exception of thyroid cancer (SMR 3.94; 95% CI 2.52, 5.86, based on 27 cases). A nonsignificant increase in mortality from thyroid cancer was seen with increasing 131I administered activity—when deaths occurring in the first 5 years after treatment were excluded, there was no evidence of a relationship with total activity; it is therefore likely that the underlying thyroid disease played a role in the observed cancer increase. Cancer incidence was also studied in 4557 patients who received 131I therapy for hyperthyroidism in Sweden between 1950 and 1975 at Radiumhemmet, Sweden (Holm 1984). Information on thyroid disease and treatment was abstracted
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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2 FIGURE 7-2 Distributions of study-specific estimates of ERR and EAR for breast cancer according to level of average dose to the breast.
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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2
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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2 FIGURE 7-3 Distribution of study-specific estimates of ERR/Gy for breast cancer according to average age at exposure. Protraction of low-dose-rate exposure in the hemangioma cohort may account for the reduced risk following exposures in infancy in this cohort, although analyses within this study do not indicate a significant association. Preston and colleagues (2002b) carried out a pooled analysis of eight cohorts to estimate radiation-induced breast cancer risk and evaluate the role of modifying factors. The analyses included studies of the following populations: Japanese atomic bomb survivors (Thompson and others 1994), the original and extended Massachusetts TB fluoroscopy cohorts (Boice and others 1991b), the New York acute post partum mastitis cohort (Shore and others 1986), the Rochester infant thymic irradiation cohort (Hildreth and others 1989), the Swedish benign breast disease cohort (Mattsson and others 1993), and the Gothenburg and Stockholm skin hemangioma cohorts (Lindberg and others 1995). The analyses included 1502 breast cancer cases among 77,527 women, about half of whom were exposed to radiation, with 1.8 million person-years of follow-up. No simple unified summary model adequately described the excess risk in all of these studies. The excess risks for the thymus, tuberculosis, and atomic bomb survivor cohorts showed similar temporal trends, depending on attained age in the ERR model and on both age at exposure and attained age in the EAR model. The excess rates appeared to be similar in these cohorts, with a combined EAR estimate of 9.9 per 104 PY per gray (95% CI 7.1, 1.4) at age 50, suggesting similarity of risks following acute and fractionated low-dose-rate exposure. The ERR/Gy was greater among Japanese atomic bomb survivors; this difference may be partly attributed to the lower background rates of breast cancer in Japan. The excess rates were higher for the mastitis and benign breast disease cohorts with EAR estimates of 15 (95% CI 7.7, 24) and 32 (95% CI 21, 47) per 104 PY per gray, respectively, suggesting that women with some benign breast conditions may be at an elevated risk of radiation-induced breast cancer. The hemangioma cohorts showed lower risks (EAR: 5.1 per 104 PY per gray; 95% CI 1.3, 11), suggesting a reduction of risks following protracted low-dose-rate exposures. Thyroid Cancer Thyroid cancer is one of the less common forms of cancer. Its incidence is relatively high before age 40, it increases
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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2 comparatively slowly with age, and it is about three times higher in women than men. Ionizing radiation is a well-documented cause of thyroid cancer (UNSCEAR 2000b). Of all the studies reviewed in the medical uses of radiation section above, only six provide dose-specific estimates of ERR and/or EAR. Table 7-4 and Figure 7-4 summarize the results from these studies. In Figure 7-4, results are shown for all studies as well as restricted to studies in which the average dose to the thyroid was less than 1 Gy. All of the studies shown are studies of children who received radiotherapy for benign conditions. All results relate to thyroid cancer incidence. Because of the relatively good prognosis of most papillary thyroid cancers, studies of thyroid cancer mortality add little information about radiation risks. In studies of external radiation exposure, the ERR/Gy ranges from 3 Gy−1 in children exposed for enlarged tonsils and other benign head and neck disorders to 30 Gy−1 among those exposed in Israel for the treatment of tinea capitis. Similarly, the estimates of EAR vary from 0.9 per 104 PY per gray in the hemangioma study to 13 in the tinea capitis study. Although risk estimates from these studies vary considerably, the confidence intervals tend to be large; it is likely that the estimates shown are statistically compatible. Ron and colleagues (1995a) conducted combined analyses of data from seven studies including five cohort studies—the atomic bomb survivors study, the Rochester thymic irradiation study (Shore and others 1993a), the Israeli tinea capitis study (Ron and others 1989), and the Michael Reese and Boston enlarged tonsil studies (Pottern and others 1990; Schneider and others 1993)—as well as two case-control studies of thyroid cancer nested respectively within the International Cervical Cancer Survivor Study (Boice and others 1988) and the International Childhood Cancer Survivor Study (Tucker and others 1991). The analyses included a total of 707 cases, the majority of which (apart from the A-bomb and cervical cancer survivors) were below age 15 at time of exposure. For subjects exposed below age 15, a linear dose-response was seen with a leveling or decrease in risk at the higher doses used for cancer therapy. The pooled ERR was 7.7 Gy−1 (95% CI 2.1, 28.7), based on a random effects model that took into account the heterogeneity of risk across studies. The EAR was estimated to be 4.4 per 104 PY per gray (95% CI 1.9, 10.1). Both of these estimates were significantly affected by age at exposure, with a strong decrease in risk with increasing age at exposure and little apparent risk for exposures after age 20. The ERR appeared to decline over time TABLE 7-4 Risk Estimates for Cancer Incidence and Mortality from Studies of Radiation Exposure: Thyroid Cancer Reference Study Radiation Type Average Dose (Gy) Dose Range Cases Controls/Population ERR/Gy 95% CI EAR/104 PY/Gy LB UB Comments Incidence Ron and others (1989) Tinea capitis External 0.09 98 10,834 30.0 13.0 X-ray Shore (1992) Meta-analysis of hyperthyroidism studies 131I 88 2 602 0.30 (0, 0.9)a 0.1 (0.0, 0.2)a Schneider and others (1993) Benign head and neck External 0.6 309 234 3.00 Overall X-ray 0.6 109 9.20 Before 1974 and screening program 0.6 200 1.80 After 1974 Shore and others (1993a) Enlarged thymus External 1.36 0.03–10 37 2,657 9.00 (4, 24)a 2.9 (2.1, 3.9)a X-ray Lundell and others (1994) Hemangioma Mostly 1.07 <0.01–4.34 17 14,351 4.92 (1.26, 10.2) 0.9 Ra Lindberg and others (1995) Hemangioma 226Ra 0.12 15 11,807 7.50 (0.4, 18.1) 1.6 Ron and others (1995a) Pooled analysis of 7 studies External 700 58,000 7.7 (2.1, 28.7) 4.4 (1.0, 10.1) X-ray NOTE: The number of cases and controls (or population size in cohort studies), as well as the mean dose and range, relate to exposed persons only. Empty cells indicate data not available from publication. LB = lower bound; UB = upper bound of CI. a90% CI.
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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2 FIGURE 7-4 Distribution of study-specific estimates of ERR/Gy for thyroid cancer according to level of average thyroid dose. NOTE: The estimate from populations exposed to 131I is excluded. about 30 years after exposure but was still elevated at 40 years. Three studies provided data on exposure protraction or fractionation (thymus, tinea capitis, and Michael Reese); analyses indicate that a small nonsignificant decrease in risk may be related to exposure fractionation in these studies. A meta-analysis of hyperthyroidism studies provides a risk estimate of thyroid cancer in relation to 131I exposure in childhood (Shore 1992). The ERR estimate from that study is 0.3 Gy−1, lower than that from studies of external exposures, but based on only two exposed cases. This study therefore provides little information about the risk of thyroid cancer in relation to exposure to this nuclide. Studies of the effects of 131I exposure later in life are reviewed in the preceding section, although no dose-related estimate of risks have been provided. These studies, taken together, provide little evidence of an increased risk of thyroid cancer following 131I exposure after childhood.
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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2 Leukemia Leukemia is one of the less common malignancies, but substantial epidemiologic and experimental information exists on the leukemogenic effects of ionizing radiation (UNSCEAR 2000b). Of all the studies reviewed in the “Medical Uses of Radiation” section, six provide dose-specific estimates of ERR and/or EAR. Table 7-5 and Figure 7-5 summarize the results from these studies. In the figure, results are shown for all studies as well as restricted to studies in which the average dose to the active bone marrow was less than 1 Gy. Results shown are for leukemia excluding CLL in all studies except the tinea capitis and uterine bleeding studies. The ERRs/Gy shown in Table 7-5 range from 0.88 Gy−1 in women who received an average dose to the active bone marrow of 7 Gy from radiotherapy for cervical cancer to 12.4 Gy−1 in subjects treated for ankylosing spondylitis (average dose 4.4 Gy). All other estimates, from studies with average doses ranging from 0.1 to 2 Gy, are relatively close, in the range 1.9 to 5 Gy−1, and are statistically compatible. Three studies have provided estimates of EAR per 104 PY per gray. Risk estimates between these studies are relatively close, ranging from 1 to 2.6. In most of the studies included here, the majority of subjects were adults at the time of exposure (with average ages at exposure between 45 and 52 years in the uterine bleeding, benign breast disease, and cervical cancer survivor studies). Only the tinea capitis and hemangioma studies provide information about exposures in childhood. In the hemangioma study—where all subjects were irradiated in infancy—the overall ERR/Gy is similar to that seen in other studies; it is notable, however, that this is driven mainly by a higher ERR for childhood leukemia; the ERR for adult leukemia in this study was very close to zero. In the tinea capitis study, in which all exposures were below age 15, no ERR is shown; the EAR is similar to that seen in the other studies. In one study (Inskip and others 1993), an effort was made to estimate separately the effects of external exposures, 226Ra, and the combination of the two. Estimates of risk from 226Ra alone or in combination with external radiation are TABLE 7-5 Risk Estimates for Cancer Incidence and Mortality from Studies of Radiation Exposure: Leukemia Excluding CLL Reference Study Radiation Type Average Dose (Gy) Dose Range Cases Controls/Population ERR per Gy 95% CI EAR/104 PY/Gy LB UB Comments Incidence Boice and others (1985) Cervix External 7 143 745 0.88 (SE: 0.69) X-rays + intracavitary 226Ra Ron and others (1988b) Tinea capitis External 0.3 14a 10,834 0.9 X-ray Inskip and others (1990b) Uterine bleeding 226Ra 0.53 34a 4,483 1.90 (0.8, 3.2) 2.6 Inskip and others (1993) Benign gynecological disease Overall 39 8,352 2.90 1.2 Rad + ext 2.03 9 1,437 2.10 (0.5, 8.3) 1.0 (0.3, 1.9) 226Ra 2.31 26 5,508 3.70 (−1, 15) 1.5 (0.3, 2.9) External 0.59 4 1,407 0.50 (−0.6, 3.3) 0.1 (−0.2, 0.6) Lundell and Holm (1996) Hemangioma Mostly Ra 0.13 <0.01–4.6 20 14,624 1.60 (−0.6, 5.5) Overall 0.13 <0.01–4.6 9 14,624 5.01 (0.1, 15) Childhood leukemia only 0.13 <0.01–4.6 11 14,624 −0.02 (−0.8, 1.9) Adult leukemia only Mortality Weiss and others (1995) Ankylosing spondylitis External 4.38 1.27–6.99b 35 1,745c 12.4 (2.25, 52.1) X-ray NOTE: The number of cases and controls (or population size in cohort studies) as well as the mean dose and range relate to exposed persons only. Empty cells indicate data not available from publication. LB = lower bound; UB = upper bound of CI. aAll forms of leukemia combined. b10–90% range. cSubcohort with reconstructed doses.
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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2 FIGURE 7-5 Distribution of study-specific estimates of ERR/Gy for leukemia according to level of average dose to the active bone marrow.
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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2 similar; the ERR/Gy for external exposures appears to be lower, but this result is based on only four cases exposed. Stomach Cancer Incidence rates for stomach cancer vary considerably throughout the world, with particularly high rates in Japan. Many countries have seen decreases in incidence and mortality over the past 50 years or so, believed in large part to be due to healthier diets with increased fruits and vegetables and less salt. Of all the studies reviewed on medical uses of radiation, five provide dose-specific estimates of ERR and/or EAR. Table 7-6 and Figure 7-6 summarize the results from these studies. In the figure, results are shown for all studies as well as restricted to studies in which the average dose to the active bone marrow was less than 1 Gy. Among the studies of populations with external radiation exposure and/or 226Ra, the estimates of ERR/Gy range from negative (in the hemangioma study) to 1.3 Gy−1 in the study of benign breast disease. The confidence intervals are wide, and they all overlap, indicating that these estimates are statistically compatible. An ERR of 1.32 Gy−1 (not significantly different from zero) was seen among patients treated for hyperthyroidism with 131I. Radiation and Circulatory Diseases Although radiation exposure is well established as a risk factor for cancer, a clear understanding of the relationship between radiation exposure and other diseases is lacking. It has been postulated that the cardiovascular system is resistant to radiation-induced injury (Stewart and others 1995). However, it appears that tissue damage may occur as a result of both therapeutic (Stewart and Fajardo 1984) and A-bomb radiation exposure (Villeneuve and Morrison 1997; Shimizu and others 1999). Capillaries represent the most radiosensitive component of the cardiovascular system, with characteristic changes including detachment of endothelial cells and thrombosis. Arterial changes resulting from radiation exposure depend on vessel size, with small and medium-sized arteries undergoing changes in all vessel layers, and large arteries appearing to be relatively radioresistant, although radiation exposure may predispose larger vessels to the development of atherosclerosis (Louis and others 1974). Radiation exposure has also been implicated in the development of cerebrovascular injury (O’Connor and Mayberg 2000). Specific conditions postulated to arise from irradiation include vasculopathy, intracranial aneurysm formation, cerebral radiation necrosis, intracranial atherosclerosis, and stroke (Trivedi and Hannan 2004). Both animal and human studies have identified intimal thickening, lipid deposition, and adventitial fibroses of the TABLE 7-6 Risk Estimates for Cancer Incidence and Mortality from Studies of Radiation Exposure: Stomach Cancer Reference Study Radiation Type Average Dose (Gy) Dose Range Cases Controls/Population ERR/Gy 95% CI EAR/104 PY/Gy LB UB Comments Incidence Boice and others (1989) Cervix External 2 0.5–3.5 348 658 0.54 (0.05, 1.5)a 3.2 (0.1, 10.4) X-rays + intracavitary 226Ra Holm and others (1991) Hyperthyroidism 131I 0.07 29 1.3 9.6 Lundell and Holm (1995) Hemangioma Mostly Ra 0.09 5 14,351 <0 <0 Mattsson and others (1997) Benign breast disease External 0.66 0–5.4 14 1,216 1.3 (0, 4.4) Weiss and others (1994) Ankylosing spondylitis External 3.2 0.52–5.8 127 1,745b −0.004 (−0.05, 0.05) X-ray Carr and others (2002) Peptic ulcer External 8.9 11 1,859 0.20 (0, 0.73) Among subjects with stomach dose 10 Gy NOTE: The number of cases and controls (or population size in cohort studies) as well as the mean dose and range relate to exposed persons only. Empty cells indicate data not available from publication. LB = lower bound; UB = upper bound of CI. a90% confidence interval. bSubcohort with reconstructed doses.
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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2 FIGURE 7-6 Distribution of study-specific estimates of ERR/Gy for stomach cancer according to level of average dose to the stomach. vascular system following irradiation. These changes are associated with atherosclerosis and the normal aging process, although irradiation may accelerate the development of these conditions (Trivedi and Hannan 2004). Although the dose required to produce specific conditions or vascular effects is uncertain, it appears that over extended periods, the nature of the changes induced are similar for low doses (on the order of 5 Gy) and for high doses (in the region of 40 Gy). There is a broad spectrum and severity of cardiovascular diseases, with radiation being only one of many possible risk factors that may act directly or indirectly on the vasculature. To clarify the role of radiation in the etiology of cardiovascular diseases, further studies involving long-term, low-level exposures are needed, taking into account all of the known risk factors for cardiovascular outcomes. Excess heart disease mortality has been observed among women with breast cancer who were irradiated with cobalt-
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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2 60 (Host and Loeb 1986, not reviewed here) and among persons with HD who received mediastinal irradiation (Boivin and Hutchison 1982; Hancock and others 1993b, 1993c). Most affected patients had received at least 30 Gy to the mediastinum, although some had received less (Trivedi and Hannan 2004). DISCUSSION Since the publication of BEIR V (NRC 1990), new information concerning health effects of radiation exposures has become available from epidemiologic studies of populations exposed to medical uses of ionizing radiation. The longer follow-up periods in recent reports have increased the statistical power in examining dose-response relationships at the doses used for medical purposes. Available studies of the effects of radiotherapy for malignant or benign diseases confirm the presence of a heightened risk of development of a number of primary or second primary cancers on follow-up. Because the doses in most series far exceed 100 mGy to the site of interest, they provide limited direct quantitative information on the risk of low-level radiation, particularly when they involve large doses where cell killing may lead to underestimation of the risk per unit dose. These studies provided valuable information for the study of risk modifiers, including age at exposure, attained age, and possible differences in patterns of risk across countries. Analyses that are restricted to populations with low doses are complicated by the limitations of statistical variability as well as by limitations of sample size and study design, including dose reconstruction. Limitations also include chance, small undetected biases, and the consequences of doing multiple tests of statistical significance. Indeed, among diagnostic radiation studies, only studies of repeated chest fluoroscopy and scoliosis examinations are informative concerning the magnitude of ERR and EAR as a function of dose. It must be noted that although the dose rates in these studies are low, the cumulative doses received by tuberculosis patients are high, and even scoliosis patients followed radiologically for spine curvature received average cumulative doses of the order of 100 mGy or more. Most of the information on radiation risks therefore still comes from studies of populations with medium to high doses, with the notable exceptions of childhood cancer risk following in utero exposures and thyroid cancer risk following childhood exposures, for which significant increases have been shown consistently in the low- to medium-dose range. SUMMARY In this chapter on medical radiation, particular attention has been paid to estimating the risk of cancer at specific sites—namely, the lung, breast, thyroid, and stomach, as well as leukemia risk. Information that has become available since 1989 has contributed to the examination of risks for these malignancies. A large number of studies involving radiation exposure for medical reasons have been described and discussed. Although these studies of medically exposed cohorts have increased our general knowledge of radiation risks, not all of them contribute substantially to quantitative risk assessment. Many studies lack the sample size and high-quality dosimetry that are necessary for precise estimation of risk as a function of dose, a point that is illustrated by the large confidence intervals for many of the risk estimates shown in Tables 7-2 to 7-6 and by the limited number of studies for which risk estimates per gray are available. Nevertheless, studies of populations exposed to therapeutic and diagnostic radiation provide information on issues that cannot be addressed with atomic bomb survivor data alone. Some examples are the evaluation of risk in Caucasian populations where baseline cancer and other disease risks may be very different from those in a Japanese cohort. Also, studies of medically exposed cohorts allow for the evaluation of risk from protracted exposures. In addition, studies of medical uses of radiation have been important in establishing the lack of radiation risk for CLL, since this cancer is very rare in Japan. Often there is interest in comparing results from different studies to gain information on the modifying effects of factors such as baseline risks and protraction of exposure that may differ among the studies. It should be kept in mind that such comparisons can be difficult to interpret since there are nearly always several differences among the cohorts being compared. As an illustration, the ERR/Gy for breast cancer in the Life Span Study cohort has been found to be higher than the ERR/Gy in tuberculosis fluoroscopy patients (Howe and McLaughlin 1996; Little and Boice 1999; Preston and others 2002a). However, it is not clear whether this difference occurs because of the higher baseline risks in the Caucasian fluoroscopy cohorts, the lower dose rate in these patients, the lower energy of the X-ray exposure used in fluoroscopy (Brenner 1999), or some combination of these factors. For lung cancer, the ERR/Gy from the studies of acute, high-dose-rate exposures are statistically compatible and in the range 0.1–0.4 Gy−1. It is difficult to evaluate the effects of age at exposure or of exposure protraction based on these studies because only one study (the hemangioma cohort) is available in which exposure occurred at very young ages and in which protracted low-dose-rate exposures were received. The study of tuberculosis patients appears to indicate that substantial fractionation of exposure leads to a reduction of risk. For breast cancer, EARs appears to be similar (of the order of 9.9 per 104 PY per gray at age 50) following acute and fractionated exposures to moderate- to high-dose-rate radiation. Effects of attained age and age at exposure are impor-
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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2 tant modifiers of risk. The excess risks appear to be higher in populations of women treated for benign breast conditions, suggesting that these women may be at an elevated risk of radiation-induced breast cancer. The hemangioma cohorts showed lower risks, suggesting a possible reduction of risks following protracted low-dose-rate exposures. For thyroid cancer, all of the studies providing quantitative information about risks are studies of children who received radiotherapy for benign conditions. A combined analysis of data from some of these cohorts with data from the atomic bomb survivors and from two case-control studies of thyroid cancer nested within the International Cervical Cancer Survivor Study and the International Childhood Cancer Survivor Study provides the most comprehensive information about thyroid cancer risks. For subjects exposed below the age of 15, a linear dose-response was seen, with a leveling or decrease in risk at the higher doses used for cancer therapy. The pooled ERR was 7.7 Gy−1 and the EAR 4.4 per 104 PY per gray. Both estimates were significantly affected by age at exposure, with a strong decrease in risk with increasing age at exposure and little apparent risk for exposures after age 20. The ERR appeared to decline over time about 30 years after exposure but was still elevated at 40 years. Little information on thyroid cancer risk in relation to 131I exposure in childhood was available. Studies of the effects of 131I exposure later in life provide little evidence of an increased risk of thyroid cancer following 131I exposure after childhood. For leukemia, ERR estimates from studies with average doses ranging from 0.1 to 2 Gy are relatively close, in the range 1.9 to 5 Gy−1, and are statistically compatible. Estimates of EAR are also similar across studies, ranging from 1 to 2.6 per 104 PY per gray. Little information is available on the effects of age at exposure or of exposure protraction. For stomach cancer, the estimates of ERR/Gy range from negative to 1.3 Gy−1. The confidence intervals are wide and they all overlap, indicating that these estimates are statistically compatible. Finally, results of two studies of patients having undergone radiotherapy for HD or breast cancer suggest that there may be some risk of cardiovascular morbidity and mortality for very high doses and dose-rate exposures. The magnitude of the radiation risk and the shape of the dose-response curve for these outcomes, if an effect exists, are uncertain. In conclusion, studies of medically irradiated populations provide information on the magnitude of risk estimates (mainly in the medium- to high-dose range) and on the effects of factors, such as exposure pattern and age at exposure, that may modify risk. Further studies of medically exposed populations are needed to study possible gene-radiation interactions that may render parts of the population more sensitive to radiation-induced health effects. Studies of populations (particularly children and infants) with lower-to medium-dose diagnostic exposures also are needed because of the increasing use of procedures such as CT and radiological monitoring of infants.
Representative terms from entire chapter: