1 Radiation Protection Bureau, Health Canada, Ottawa, Ontario, Canada.
2 Health Protection Branch, Health Canada, Ottawa, Ontario, Canada.
3 Institute of Radiation Medicine, Chinese Academy of Medical Sciences, Tianjin, People's Republic of China.
4 Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
5 Health Statistics Division, Statistics Canada, Tunney's Pasture, Ottawa, Ontario, Canada.
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ABSTRACT |
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incidence; neoplasms; occupational exposure; radiation
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INTRODUCTION |
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There remains considerable uncertainty on how to extrapolate radiation cancer risks to low doses and low dose rates. Studies on occupational exposures, especially large-scale cohort studies, can provide useful information in this regard. The main challenge is to find a sufficiently large cohort for which accurate dose information is available, with a sufficient period of follow-up to evaluate cancer risk. The National Dose Registry is well suited for this purpose.
A number of studies on occupational radiation exposure have been carried out in the past (221
), which were most frequently cohort studies of cancer mortality. More recently, considerable effort has been made to increase the cohort size by combining data from studies conducted in different countries (2
). In this paper, we present a first analysis of cancer incidence in a large diverse cohort based on the National Dose Registry of Canada (22
, 23
), which contains the Canadian occupational radiation exposure records. This cohort includes workers involved in nuclear power production, as well as a large number of industrial, medical, and dental workers.
Incident cases of cancer among cohort members were identified by computerized record linkage to the Canadian Cancer Data Base. The cohort has been derived from a similar cohort used in an earlier mortality study (3). Cohort members who had no exposure data after 1969, the first year for which cancer incidence data were available, were excluded. Thus, the cohort is somewhat smaller, and the follow-up time shorter, than in the National Dose Registry mortality study (3
). However, the number of incident cases should, proportionally, exceed the number of cancer deaths, especially for cancers with low fatality rates. For such cancers it may be possible to assume associations with ionizing radiation that could not be identified using mortality data alone.
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MATERIALS AND METHODS |
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Cohort definition
The cohort was constructed from the set of all persons whose sex and year of birth are recorded in the National Dose Registry and who have one or more dose records dated between January 1, 1969 (the earliest date for which incidence records are available), and December 31, 1983. Miners were excluded because data on exposure to gamma radiation are available only from 1981 onward. Also excluded were people whose links were based on minimal identifying information, as determined by a preliminary computerized record linkage, because of the inherent uncertainty in the resolution of such links. The remaining 191,333 persons formed the cohort that was used in the analysis. For the cohort members, dose information from 1951 to 1988 was included.
Job classifications
The National Dose Registry contains work histories described in terms of an 80-category job classification code and a 14-category code describing the type of organization, such as industry or hospital (22, 23
). This information was used to define four broad occupational categories (dental, medical, industrial, and nuclear power workers). The same procedure was used for assigning occupational categories as in the mortality study (3
), except that workers at Atomic Energy of Canada Limited were assigned to the nuclear power category rather than to the industrial category. This was done because of the greater similarity of both the type of work and the socioeconomic status between nuclear power workers and Atomic Energy of Canada Limited workers.
Dosimetry
Exposure information for this study is obtained from the National Dosimetry Services of the Radiation Protection Bureau of Health Canada and from a few large organizations, such as nuclear power stations, that do their own monitoring. About 80 percent of the dose records in this cohort come from the National Dosimetry Service. Detailed descriptions of the dosimetry have been reported previously (3, 24
).
To avoid the use of complex radiation protection terminology, we shall use the term "dose" as a quantitative indicator of exposure to any type of ionizing radiation. For external radiation, the dose, expressed in millisieverts (mSv), is calculated as the amount of energy absorbed per gram of tissue, weighted by a modifying factor designed to take into account the relative biologic damage caused by different types of ionizing radiation (25). Internal doses can be converted to millisieverts and added to the external dose.
Monitoring of external gamma, beta, and x-ray exposures occurred throughout the period from 1951 to 1988. Monitoring of external neutron exposures occurred during this period for nuclear power station workers, well loggers, and workers on accelerators. Tritium exposures were determined from urinalyses and converted to millisieverts. Workers for whom these exposures were reported include Atomic Energy of Canada Limited workers, workers at nuclear power stations, and tritium luminizers. There is no regulatory requirement to report exposures to other radio-nuclides. These exposures have not been included in this study. However, there exists a potential for substantial doses from some of these radionuclides, such as radioactive iodine as 131I, used in medical procedures.
Doses from the individual workers' various types of exposures have been combined into "annual doses," which are the basis of calculations in this study.
The National Dose Registry has recorded a value of zero for all doses below the reporting limit of their respective dosimetry processors, which was 0.20 mSv in most cases. This procedure could underestimate the cumulative lifetime doses and thus overestimate the risk. Although unlikely, considerable underestimation of a cumulative dose could occur if all doses recorded as zero were actually just below the reporting limit. We had insufficient information to determine the degree of underestimation that could result from this practice.
No dose records exist for exposures incurred before 1951. Consequently, the lifetime dose of some workers could be underestimated, although the impact on risk estimates is not expected to be great.
In cases where a dosimeter was lost, an estimated dose was entered into the files of the National Dose Registry, based on previous doses received by the worker or doses received by coworkers.
Record linkage
The National Dose Registry cohort had previously been linked internally to construct a unique dose history for each member of the cohort (24,
, 27
). Incidence data were obtained from the Canadian Cancer Data Base, derived from the National Cancer Incidence Reporting System, and were then linked internally to facilitate subsequent linkage to the National Dose Registry file. This created a person-based file, hereafter referred to as the incidence file. This file was then linked to the National Dose Registry.
In the linkage process, pairs of records were assigned probabilistic link weights as follows. Surnames were assigned phonetic surname codes (28). Record pairs with the same phonetic and sex codes were assigned a weight that reflected the likelihood of a match between a person in the National Dose Registry and a person in the incidence file. Weights of potential links were computed on the basis of agreements, partial agreements, and discrepancies between both records of the pair, following the same procedures as in the mortality study (3
). As a result, 7,871 of the original 191,333 workers were identified as potential incident cases. Where two or more National Dose Registry workers linked to the same incidence record, only the most likely link was retained in the analysis. It should be noted, however, that one National Dose Registry worker could link to more than one incidence record.
The disease status of the workers was determined by resolution of the links in the incidence file. Workers with multiple incidence links had their links resolved by manual inspection on a case-by-case basis (835 persons, 321 males and 514 females). In the case of multiple incidences, only the first incidence was included in the analysis. The links of workers with one incidence link were resolved by probabilistic record linkage (7,036 persons, 3,154 males and 3,882 females).
Links were assigned to one of three linkage groups, defined by the type of information available for comparison between both records of the record pair. This decision was based on the observation that the linkage groups have different distributions of link weights, which is a consequence of the comparison rules used in calculating the weights. A fourth linkage group, in which there was only minimal information available for comparison, had already been excluded, at the stage of cohort definition. For each linkage group, threshold weights were set for males and females separately. Links with weights above the threshold were classified as matches, and those with weights below the threshold as nonmatches. Thresholds were set at values that were estimated to balance the linkage errors and thus minimize the bias introduced in this procedure. This was done by manually resolving small samples of links and setting the thresholds at such values that the number of false positives in the sample (nonmatches above the threshold) was equal to the number of false negatives in the sample (matches at or below the threshold).
Disease classification
The disease codes in the incidence database are all in the International Classification of Diseases, Ninth Revision, format; codes in the Eighth Revision format had been converted prior to inclusion in the database. Because the reporting procedures for nonmelanoma skin cancer vary widely among provinces, this was excluded from the analysis.
Statistical methods
Dose information from 1951 to 1988 was used in calculating excess relative risk for this cohort. The data were grouped into categories, defined in terms of the following covariates: age (5-year intervals; table 2), calendar year (5-year intervals), occupational group (table 3), time since first exposure (5-year intervals), and cumulative whole body dose (table 1). Person-years at risk and cases were allocated on the basis of these categories and were computed according to the same methods as in the mortality study (3).
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Relative risk regression models were fitted to the data with the AMFIT program (30), which calculates excess relative risk from internal comparisons of cumulative dose and disease status. Specifically, the expected number of incident cases was described by a linear excess relative risk model Nj
j(1 + ßdj), where Nj is the number of person-years at risk in the j-th stratum,
j is the baseline incidence rate in the absence of radiation exposure, dj is the cumulative dose weighted by the number of person-years at risk, and ß is the excess relative risk per unit of dose. Two-sided 90 percent confidence limits on ß were also calculated. The strata were constructed from the same age, sex, and calendar year groupings as in the standardized incidence ratio calculations. The weighting in the calculation of dj addresses the fact that a person's cumulative dose generally increases over the years that contribute to a given stratum. Confidence intervals were based on the profile likelihood, calculated with the AMFIT PROFILE command (30
).
The cumulative dose was lagged 2 years for leukemia and 10 years for solid tumors to allow for a latent period of cancer induction. Consequently, exposures occurring within either 2 or 10 years of incidence due to leukemia or solid tumors, respectively, were excluded from the cumulative dose.
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RESULTS |
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The average dose of the entire cohort is 6.64 mSv, with the males receiving a much higher average dose than the females (11.50 mSv vs. 1.75 mSv). Table 1 shows the dose distribution of all workers and of cancer cases. With nearly equal numbers of males and females in the cohort, there are substantially more males than females in all but the lowest dose category. Table 2 shows the number of workers and number of incident cases for males and females by attained age (i.e., age at first incidence or end of study, 1988). The age groups with the most workers are 3640 (males) and 3135 (females) years. Information on person-years at risk, accumulated dose, and cancer incidence is summarized in table 3. The mean cumulative dose for nuclear power workers is much higher, and for dental workers much smaller, than for medical and for industrial workers. The average length of follow-up is 14 years, as calculated by dividing the number of person-years by the number of people.
The standardized incidence ratios for males, females, and both sexes combined are shown in tables 4, 5, and 6, respectively. The excess relative risks for males and for both sexes combined are shown in table 7. For many cancer types the excess relative risk estimate has unrealistically wide confidence intervals, or the excess relative risk could not be estimated because the likelihood function had no true maximum. This was caused by the lack of a clear dose trend, often because there were very few high doses. In table 7, the only cancer types listed are those for which more than five cases have a cumulative dose exceeding 4.9 mSv and for which an excess relative risk estimate was found. This excludes most cancer types with very wide confidence intervals. It also excludes all cancer types in females.
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Significant results for males included a deficit in the standardized incidence ratios for all cancers combined; an elevated standardized incidence ratio for melanoma; and positive excess relative risks for leukemia, colon (marginally significant), rectum, pancreas, lung, testis, all cancers combined, all except lung, and all except leukemia.
Significant results for females included a deficit in the standardized incidence ratios for all cancers combined and a high standardized incidence ratio for thyroid cancer.
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DISCUSSION |
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This study replicates a number of previously reported associations between occupational radiation exposure and various types of cancer. Significant positive excess relative risks have been reported for leukemia (57
), as well as for cancer of the rectum (8
), pancreas (7
), and lung (3
, 7
). The association between exposure to ionizing radiation and leukemia has been well established and is one of the main outcomes of the studies on atomic bomb survivors (31
). The estimated excess relative risk of 5.4 Sv-1 (significant) for both sexes combined is high compared with that from the three-country study by Cardis et al. (2
) (1.55 Sv-1, not significant) and the most recent National Registry for Radiation Workers study (4
) (1.20 Sv-1, not significant) and somewhat higher than the value given in the latest report on the atomic bomb survivors (31
) (4.62 Sv-1, significant). In our excess relative risk calculations, we include "leukemia excluding chronic lymphatic leukemia," believed to be more strongly correlated to exposure to ionizing radiation than leukemia itself. For leukemia excluding chronic lymphatic leukemia, this study found an excess relative risk of 2.7 Sv-1 (not significant) for males; the values for females and for both sexes combined could not be determined because the likelihood function did not show a clear maximum. The result is close to the excess relative risk from the three-country study (2
) (2.18 Sv-1, significant) and the National Registry for Radiation Workers study (4
) (2.55 Sv-1, significant). Our result could become significant in a follow-up study. (The latest atomic bomb report (31
) does not list leukemia excluding chronic lymphatic leukemia.) None of the corresponding standardized incidence ratios are significantly elevated, although it is possible that the association is masked by the healthy worker effect. For all cancers combined except leukemia, there is a significantly elevated excess relative risk of 2.3 Sv-1. Neither the National Dose Registry mortality study (3
), the three-country study (2
), nor the most recent National Registry for Radiation Workers study (4
) found a dose effect; however, the latest atomic bomb survivor report (31
) gives a significant excess relative risk of 0.40 Sv-1. For cancer of the pancreas, the excess relative risk was significant in males but not in both sexes combined; this is a consequence of the low doses for the females.
Other previously reported associations with cancer have not been reproduced in this study, namely, multiple myeloma (, 9
, 10
), Hodgkin's disease (8
), and cancer of the brain (8
). However, the cohort is still young (table 2), including only 6 percent of the number of cancers expected at extinction (32
), and the average follow-up time (14 years) is short. Updates on this study may be powerful enough to detect some of these associations. For example, the excess relative risk for Hodgkin's disease is large in males and females combined. The large confidence interval, extending below 0, is caused by the lack of sufficient cases with high doses.
This study found significant results for cancer types for which no association with ionizing radiation was reported in previous occupational studies. The standardized incidence ratio for melanoma was significantly elevated in males. The excess relative risk was positive, but this result was not statistically significant; in fact, the only occupational category with significant standardized incidence ratios is the dental category, which has the lowest doses. There is little evidence from previous studies that links melanoma even to high doses; for instance, the 1994 report from the United Nations' Scientific Committee on the Effects of Atomic Radiation (1) makes no mention of it. The interpretation of our results for melanoma is therefore unclear. The result could be attributed to chance, in view of the many types of cancer considered in the analysis. It could also be related to lifestyle through exposure to ultraviolet radiation, but there are insufficient data to come to a conclusion in this matter. The excess relative risk for colon cancer is positive in males, but only marginally significant, and the standardized incidence ratio is less than unity. The excess relative risk for colon cancer is positive but not significant in both sexes combined; this is a consequence of the low doses for the females. In view of the absence of previously reported positive findings, it seems reasonable to attribute this result to chance. The excess relative risk for cancer of the testis is significant and very large, but the confidence intervals are wide. The standardized incidence ratio, although not significant, is slightly above 1. This evidence suggests that this type of cancer merits attention in future studies, but the result needs to be interpreted with caution.
This study found highly significant standardized incidence ratios for thyroid cancer, but the excess relative risk could not be estimated because there were few high doses. The high standardized incidence ratio is mainly due to the medical workers, as the standardized incidence ratios for the other categories are not significantly elevated, except marginally for the dental category, and then for both sexes combined only. Possible explanations for the high standardized incidence ratio for the medical workers are the effects of external whole body doses, internal doses from radioisotopes, and risk factors not related to radiation. Although adults are less susceptible to radiation-induced thyroid cancer than children (1), there are studies supporting the idea of external occupational radiation doses being a risk factor for thyroid cancer (11
, 33
). However, in this study the doses for medical workers are low compared with those for industrial and nuclear power workers, who do not show a significantly high standardized incidence ratio. Because no detailed information is available concerning geometry, time, field intensity, and shielding related to a worker's potential exposure, no further assessment can be made. Internal exposure to radioactive isotopes is another possible explanation for the high standardized incidence ratio for thyroid cancer, especially exposure to isotopes of thyroid-seeking iodine, used in medical procedures in hospitals. The exposure could occur through inhalation of volatile compounds of 131I exhaled by patients who have received therapeutic doses containing this isotope. The combined evidence from previous studies seems as yet inconclusive (1
, 4
, 12
, 34
, 35
). This study cannot make a significant contribution in this respect, since radioiodine exposures are not available. The possibility of risk factors other than radiation, for both medical and dental workers, cannot be ruled out.
In conclusion, in this first analysis of cancer incidence using data from the National Dose Registry of Canada, a number of associations with occupational exposure to ionizing radiation were noted. In the light of results from previous studies, our findings for the cancers of the thyroid and testis are of particular note. In the search for an explanation for the high standardized incidence ratio for thyroid cancer, solid occupational radioiodine exposure data could be helpful in assessing the possibility of this type of exposure's being a risk factor. A nested case-control study based on the cases of this study may also shed some light on the matter. In order to get a better interpretation of the high excess relative risk for testicular cancer, one may want to include the analysis of this type of cancer specifically in future studies rather than folding it into "miscellaneous cancers."
As the cohort matures, follow-up studies will have greater power, which may permit firmer conclusions on associations between cancer incidence and occupational exposure to ionizing radiation.
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ACKNOWLEDGMENTS |
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Incidence data were provided to Health Canada from the Canadian Cancer Data Base, derived from the National Cancer Incidence Reporting System at Statistics Canada. The cooperation of the provincial and territorial cancer registries that supply the data to Statistics Canada is gratefully acknowledged.
The authors thank R. Semenciw for providing a summary of Canadian reference data for cancer incidence. They also thank D. Zuccarini, C. Poliquin, C. Powell, M. Luscombe, D. Holder, B. F. Davies, R. Gao, and H. Thi for their assistance in the record linkage.
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NOTES |
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Editor's note: An invited commentary on this paper appears on page 319 and the author's response, on page 323.
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REFERENCES |
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