From the Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.
Received for publication June 7, 2002; accepted for publication August 28, 2002.
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ABSTRACT |
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cerebrovascular disorders; cohort studies; medical staff; mortality; myocardial ischemia; radiation
Abbreviations: Abbreviation: CI, confidence interval.
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INTRODUCTION |
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We present results from a nationwide ongoing follow-up investigation of US radiologic technologists certified between 1926 and 1982 (7). For this cohort, we have data available on mortality, individual work histories (to characterize occupational radiation exposure), and known risk factors for diseases of the circulatory system. These data enabled us to carry out detailed analyses of mortality from circulatory system diseases in relation to radiation exposure, accounting for potential confounding by known risk factors.
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MATERIALS AND METHODS |
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The present analysis was based on the subset of 90,284 questionnaire respondents (68 percent response rate), including 69,511 women. We evaluated the year each subject first worked as a radiologic technologist, the duration of employment, and known risk factors for diseases of the circulatory system (education, cigarette smoking, alcohol consumption, body mass index, history of myocardial infarction, marital status, parity, age at menarche, menopausal status including surgical menopause, age at menopause, hormone replacement therapy, and use of oral contraceptives). The risk factors examined were considered potential confounders in the evaluation of the effect of radiation exposure.
Radiation exposure
Because individual radiation dose estimates were not available, we used self-reported work history data, that is, year first worked as a radiologic technologist and number of years worked in specific time periods, to construct proxy measures for characterizing the level of radiation exposure. This strategy takes into account the historical changes in radiation exposure. Radiation safety standards have improved markedly over the decades during which the cohort subjects worked, resulting in a reduction of occupational radiation exposure. The first formal standard proposed in 1934 was 0.1 roentgen per day (about 0.3 Sv per year, 1 year = 300 work days)about half of what had previously been considered "tolerant" (9). A limit of 0.15 Sv per year was adopted by the International Commission of Radiological Protection in early 1950 (9), and in 1957, the Commission recommended an occupational dose limit of 0.05 Sv per year, which largely remained unchanged until 1993 (9). Therefore, levels of exposure before 1950 may have been 612 times higher compared with more recent time periods, that is, 1980 or later.
Working specifically with fluoroscopy, multifilm, routine x-ray examinations, and radioisotope treatment may have increased radiation exposure (10), but most cohort members worked with several or all of these procedures including fluoroscopy (90.4 percent), multifilm (87.3 percent), routine x-ray examinations (88.3 percent), and radioisotope treatment (90.3 percent). This precluded separate evaluation of worker subgroups, where each performed a specific procedure.
Statistical analysis
Person-years were compiled according to sex, race (White, non-White), age (024, 2529, ..., 7579, 80 years), and calendar year (19801984, 19851989, 19901994, 19951998) from the date of questionnaire completion (19831990) through the end of 1997, the date of death, or the date of loss to follow-up, whichever came first. For subjects lost to follow-up, person-year accumulation ceased at the last date known alive. When there was an unknown date of death or when personal information to search the National Death Index was missing, subjects were considered lost to follow-up at their last date known alive. For subjects with an unknown cause of death, the person-year accumulation ceased at the date of death, but subjects did not contribute cases to any specific cause of death category except all causes of death.
Relative risks for mortality from diseases of the circulatory system and the subgroups of ischemic heart disease and cerebrovascular disease were estimated using log-linear Poisson regression models (11). The background risk was estimated using internal comparisons (the background risk estimated nonparametrically within the cohort using models stratified by calendar year, age, sex, and race) and external comparisons (the background risk assumed to be proportional to year-, age-, sex-, and race-specific US mortality rates). External comparisons were performed to evaluate the influence of secular trends on the internal comparisons. The year first worked and the number of years worked were found to be correlated with attained age and calendar year; mortality rates for diseases of the circulatory system are known to vary with age and calendar year (12). This can induce intrinsic confounding leading to collinearity in extreme situations. External comparisons can be useful in such situations because the background risk is taken from population data rather than being estimated from the cohort, although the assumption is that the background mortality in the cohort is proportional to that in the general population. (For a general description of the use of external rates, see reference 11, p. 151.)
The year first worked and the number of years worked were analyzed together in a multivariate model. Analyses of the number of years worked in different time periods were restricted to subjects between 15 and 65 years of age (and therefore eligible for employment) in the respective time period and were adjusted for the years worked in other time periods. We evaluated separately and combined the potential confounding effects of education, cigarette smoking, alcohol consumption, body mass index, history of myocardial infarction, marital status, parity, age at menarche, menopausal status, age at menopause, hormone replacement therapy, and use of oral contraceptives. Missing data were coded as a separate category (estimates not shown).
We used 95 percent Wald-based confidence intervals. Tests of trend for categorical variables were tests of the slope of the corresponding continuous variable. Effect modification was evaluated on the basis of improvement of model fit quantified by the likelihood ratio test statistic. All tests were two sided at the 5 percent significance level. EPICURE software was used for all analyses (13).
Ethical standards
This study is approved annually by the National Cancer Institute Special Studies Institutional Review Board of Research Involving Human Subjects (protocol no. OH97-C-N053). Participants were informed of the objectives, procedures, and voluntary nature of the study in the cover letter to the questionnaire. Informed consent to participate in the study was obtained through completion and return of the questionnaire. Consent to access medical records was obtained with a separate signed consent form.
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RESULTS |
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The reasons for loss to follow-up were insufficient personal information to search the National Death Index (4,160 subjects), unknown date of death (69 subjects), or other (one subject). The median follow-up from questionnaire completion to study end was 13 years, with 1,107,100 person-years accrued. Table 1 shows the causes of death among the deceased cohort members. Almost as many men (n = 510) as women (n = 560) died of circulatory system diseases, although men constituted only 23 percent of the questionnaire respondents.
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Because of higher doses of ionizing radiation in the earlier calendar time periods, the cumulative years worked, excluding consideration of the decades worked, may not be a good surrogate for cumulative exposure. Table 5 shows the estimated relative risks according to the number of years worked in different time intervals. For diseases of the circulatory system, the relative risks based on internal comparisons increased with the number of years worked prior to 1950 (based on 853 cases, trend p = 0.007), when exposure to ionizing radiation was substantially higher, but not in more recent time intervals. For cerebrovascular disease, but not for ischemic heart disease, the risk rose significantly with the number of years worked before 1950: Relative risks based on internal comparisons were 1.48 (32 cases) and 2.01 (74 cases) for working up to 5 years and more than 5 years before 1950, respectively, compared with not working before 1950 (31 cases), adjusted for the number of years worked in other time intervals (trend p < 0.001).
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We evaluated whether the associations found differed by gender, age, race, or history of myocardial infarction. The risk estimates did not differ statistically or substantively by gender, age, and race. However, the increase in risk for all circulatory system diseases with earlier year first worked was restricted to subjects with no prior myocardial infarction (808 cases, data not shown).
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DISCUSSION |
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Our findings with respect to potential confounders were consistent with the literature. The data showed an increased mortality risk from circulatory system diseases associated with smoking (14, 15), a protective effect from moderate but not high alcohol consumption (16), and an increased risk in postmenopausal women (17). The reduced mortality risk from circulatory system diseases in parous women was unexpected and may be due to chance.
Studies of radiologists and radiologic technologists in the United States (7, 18), the United Kingdom (6), Canada (19), Japan (20), Denmark (21), and China (22), like ours, lacked individual dose estimates. Of these studies, data on the US radiologists showed excess mortality from circulatory system diseases (18), while data on radiologists from the United Kingdom did not (6). Other studies have not provided detailed analyses of diseases of the circulatory system. The radiologist cohort from the United Kingdom included subjects who started working as early as 1897 and therefore likely had higher exposures to ionizing radiation than did the US radiologic technologists. Berrington et al. (6) suggested that the lack of excess mortality from diseases of the circulatory system among radiologists from the United Kingdom may have reflected the healthy worker effect, dose fractionation reducing the risk, or possibly overestimation of doses. Our study, although sharing some of these limitations, differs from the United Kingdom study in individual adjustment for potential confounding factors and evaluating internal comparisons.
Excess heart disease mortality has been linked with high-dose radiation exposure used for treatment of Hodgkins disease or breast cancer (1, 2). During typical radiotherapy treatments, Hodgkins disease patients generally received cardiac doses up to 3035 Sv, and breast cancer patients received tumor doses of 4050 Sv. Therefore, radiation doses to the heart in these cancer patients were much higher than those likely received by medical radiation workers. The only quantitative risk estimates for lower ionizing radiation exposures in relation to circulatory system diseases are from the atomic bomb survivors (4). These can be used to assess whether the doses necessary to achieve the observed risks are compatible with the likely doses received by radiologic technologists, under the simplified assumption that risk does not depend on the instantaneous (atomic bomb survivors) or chronic (radiologic technologists) nature of exposure. Based on the risk estimates per sievert colon dose (a conventionally used measure for the representative dose to internal organs) derived from the data on atomic bomb survivors, the average yearly estimated dose linked with the relative risks for years prior to 1950 found in our study is 0.07 Sv for ischemic heart disease and 0.7 Sv for stroke. The regulatory limit before 1950 was between 0.3 and 0.5 Sv per year. Thus, the estimated dose linked with the relative risk seen in our study for ischemic heart disease, but not for stroke, is well within the regulatory limits. However, the regulatory limits are consistent with an estimated dose (0.3 Sv) linked with a relative risk for stroke at the lower 95 percent confidence limit. For an explanation of the calculations, see the Appendix.
Because routine monitoring of radiation exposure in workplaces was not introduced until early 1950, estimating radiation doses is difficult for subjects who started working before 1950. However, levels of exposure may be inferred from historical changes in protection standards and other published information. In 1924, the American Roentgen Ray Society recommended a tolerance dose of one hundredth of an erythema dose per month for radiation workers, which is equivalent to about 0.7 Sv per year (9). Ten years later, the US Advisory Committee on X-ray and Radium Protection proposed the first formal standard of 0.1 roentgen per day (or 0.3 Sv per year, 1 year = 300 workdays) (9). One study estimated that radiologic workers using nonprotective equipment, that is, machines without shielding of the tube housing and walls, during the period of 19201930 could have been exposed to 1 Sv per year (23). A small number of the subjects in the present study worked during this period. The conditions must have improved toward the late 1930s. A 1940 survey of a large number of US hospitals showed that the average exposure ranged from about 0.01 to 0.25 Sv per year, depending upon how well the installations were shielded (24). These levels of exposure may have persisted until late 1950. Thus, in a 1953 survey of the radiologic technologists at the Cleveland Clinic, the usual weekly dose exceeded 0.1 roentgen (0.05 Sv per year, 1 year = 50 workweeks) but rarely exceeded 0.3 roentgen (0.15 Sv per year) (25). Subgroups of the cohort for which elevated relative risks were found in this study worked during this period. In 1957, the International Commission of Radiological Protection recommended a dose limit of 0.05 Sv per year (9)a large reduction compared with previous limits. Based on these figures, a cumulative dose of 2 Sv or more is conceivable for a radiologic technologist who started working in 1935 and continued to work during the 1940s and 1950s.
Findings from sensitivity analyses, performed to check the robustness, specificity, and generalizability of our results, included the following: similar results for external and internal comparisons (although we emphasize internal comparisons because standard US population rates may not be an appropriate comparison for worker rates because of a healthy worker bias that can vary with work characteristics (26)); no relation of year first worked or number of years worked with other causes of death presumably unrelated to radiation exposure (including infectious, parasitic, and respiratory diseases or injuries and poisoning); similar results in an extension of our analysis to the entire cohort including nonrespondents and subjects who died before questionnaire administration (although the extended analysis had to be restricted to the only occupational data available, i.e., the year first certified as a radiologic technologist and number of years certified); and similar findings, albeit with wider confidence intervals, in a restriction of the analyses to the subset of workers with complete observations.
Our cohort is one of the few that includes a large number of female workers exposed to chronic low-dose ionizing radiation. Strengths of the study include nationwide representation, nearly complete follow-up, and the availability of individual worker data on lifestyle and other known risk factors for circulatory system diseases. The consistency of the effects of known risk factors for mortality from circulatory system diseases in our study and those from the literature supports the validity of the cause of death information.
A limitation is the lack of information on other known risk factors for circulatory system diseases (including hypertension, diabetes, hypercholesterolemia, and family history of circulatory system diseases). Failure to account for these established important risk factors could introduce confounding bias. However, all analyses were adjusted for body mass index, linked with diabetes, hypercholesterolemia, and hypertension (15, 27). The major weakness is the absence of radiation dose estimates. However, earlier years of first employment were also associated in this cohort with increased risk for breast cancer, a known radiogenic cancer (7). This lends credibility to the use of year first worked as a surrogate measure for radiation exposure. Moreover, increased risk for diseases of the circulatory system was observed several decades after first occupational radiation exposure because the most significant radiation exposures are likely to have occurred in the early years, in agreement with the results for atomic bomb survivors (4).
A number of mechanistic hypotheses have been proposed (2830). Although based primarily on high radiation doses, they provide some useful insights. Radiation exposure can damage myocardial microvasculature directly (28) or indirectly by forming fibrosis via the effect on the microvasculature (29). Damage to the microvasculature may limit cardiac responsiveness to additional stressors, such as hypertension and subclinical ischemia, over the life span. Further, inflammation and chronic infection may play a significant role in atherogenesis (30), although an association between radiation and inflammation is not established. Epidemiologic insights are needed to help elucidate the possible mechanisms, but data on the association between chronic low-dose radiation and diseases of the circulatory system are currently limited.
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ACKNOWLEDGMENTS |
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The authors are grateful to the radiologic technologists who participated in this study; Jerry Reid of the American Registry of Radiologic Technologists for continued support of this project; Diane Kampa of the University of Minnesota for data collection and coordination; Kathy Chimes of Westat for data management; Roy Van Dusen of Information Management Services, Inc., for biomedical computing; and Drs. Tamara B. Harris and Jay H. Lubin for helpful advice. They also wish to acknowledge their appreciation to Drs. John Boice, Jr., and Jack Mandel who played a critical role in the initiation, design, and maintenance of this cohort study for many years.
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APPENDIX |
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NOTES |
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REFERENCES |
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