Affiliations of authors: D. L. Preston, Department of Statistics, Radiation Effects Research Foundation, Hiroshima, Japan; E. Ron, K. Mabuchi, Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD; S. Yonehara, Second Department of Pathology, Hiroshima University School of Medicine, Hiroshima; T. Kobuke, Division of Clinical Research Laboratories, Koseiren Onomichi Hospital, Onomichi, Japan; H. Fujii, Division of Clinical Laboratories, Nagasaki Chuo National Hospital, Nagasaki, Japan; M. Kishikawa, Scientific Data Center for the Atomic Bomb Disaster, Nagasaki University School of Medicine, Nagasaki; M. Tokunaga, S. Tokuoka, Department of Epidemiology, Radiation Effects Research Foundation, Hiroshima.
Correspondence to: Dale L. Preston, Ph.D., Department of Statistics, Radiation Effects Research Foundation, 52 Hijiyama Park, Minami-ku, Hiroshima 732-0815 Japan (e-mail: preston{at}rerf.or.jp).
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ABSTRACT |
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INTRODUCTION |
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Although the etiology of nervous system tumors is not well described, several epidemiologic studies (512) have reported increased risks of meningiomas, nerve-sheath tumors, and gliomas after high-dose medical treatment, especially for those exposed during infancy or childhood. Less epidemiologic data are available regarding the risk of nervous system tumors for those exposed as adults. After reviewing five epidemiologic studies, Preston-Martin and White (13) concluded that increased risks of meningioma and schwannoma were associated with a history of diagnostic x-ray exposures (both dental and medical) performed many years ago when the level of radiation exposure may have been substantial. However, radiation associated with dental x-rays has not been related to an excess risk of nervous system tumors in other studies (14,15). Previous radiotherapy to the head has been related to excess risks of meningiomas and schwannomas (16). Information on glioma risks after low-dose radiation exposure or exposure as an adult is limited. Mortality studies (1719) of workers exposed to low radiation doses did not find statistically significant effects, but mortality data are a poor measure of risk for nervous system tumors with relatively good survival, such as meningiomas and schwannomas.
Using data for the period from 1961 through 1975, Seyama et al. (20) reported a fivefold increase in brain tumor incidence among male atomic bomb survivors exposed to radiation levels of 1 Gy or more. In the most recent general analysis of Life Span Study (LSS) cancer incidence data (21), an increased risk of extracranial neural tissue tumors was suggested, but there was little evidence of a radiation-associated increase in brain tumor risk. More recently, increased risks of meningioma associated with atomic bomb radiation exposure or distance from the bombs were reported in Hiroshima (22) and in Nagasaki (23).
To further understand the role of radiation in the etiology of brain and other neural tumors, we conducted a detailed incidence study, including a pathology review, in the LSS cohort of atomic bomb survivors. Specifically, we examined the doseresponse relationship, quantified radiation risks for specific histologic types of malignant and benign tumors, and evaluated the role of modifying factors on the dose response.
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MATERIALS AND METHODS |
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Gy (gray units) are used to refer to doses of radiation in which no allowance is made for the biologic effectiveness of different types of radiation. If allowance is made for the different effectiveness of various types of radiation, then the resulting dose equivalent is expressed using sieverts (Sv). An absorbed dose of 1 Gy is equal to 100 rad, and 1 Sv is equal to 100 rem. A given dose of neutrons is believed to have greater biologic effectiveness than the same dose of -rays or x-rays.
Life Span Study Population
Case ascertainment was carried out for the full LSS cohort, which includes 93 000 atomic bomb survivors from Hiroshima and Nagasaki and 27 000 people who were not in the cities at the time of exposure. The population used in these analyses includes 80 160 members of the LSS cohort for whom organ dose estimates can be computed, who were in Hiroshima or Nagasaki at the time of the atomic bombings, and who were alive and not known to have had cancer at the time of the establishment of the Hiroshima and Nagasaki Tumor Registries (January 1958). The population differs from that described in (21) because of the inclusion of 234 people with dose estimates of 4 Gy or more and the exclusion of 46 people on the basis of new follow-up data. At the end of follow-up, in December 1995, slightly more than 50% of the cohort members were still alive. There are more women (60%) than men in the cohort (Table 1), particularly in the group of people who were 2039 years old at the time of the atomic bombings. Almost 68% of the study group was exposed to radiation from the bomb in Hiroshima. Individual weighted brain doses were calculated as the sum of the
-ray dose plus 10 times the neutron dose by using the DS86 system (24,25). Weighted dose was used to allow for the greater biologic effectiveness of neutron radiation doses. The dose estimates incorporate a correction for bias arising as a result of random errors in individual dose estimates (26). Approximately 40% of the cohort had a weighted brain dose of less than 0.005 Sv. Only 2811 survivors (3.5%) had dose estimates greater than 1 Sv. Mabuchi et al. (27) and Thompson et al. (21) have described the characteristics of the LSS cohort in detail.
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Tumors of the brain, cranial and spinal nerves, pituitary gland, and pineal gland were ascertained through the population-based Hiroshima and Nagasaki Tumor Registries, which were established in 1958 (27). To improve ascertainment for benign tumors, the tumor registry data were augmented with information obtained from the Hiroshima and Nagasaki Tissue Registries (established in 1973); autopsy, surgical pathology, and clinical records from the Radiation Effects Research Foundation (RERF); and from major medical institutions in Hiroshima and Nagasaki.
A broad range of reported tumor diagnoses were considered in the initial stages of the ascertainment process. The 9th revision of the International Classification of Diseases (ICD-9) topography codes (28) considered in the initial screening were codes 191 (brain), 192 (other and unspecified parts of the nervous system), 194.3 (pituitary gland), 194.4 (pineal gland), 171.9 (connective tissue including peripheral and sympathetic nerves), 225 (benign neoplasms of brain and other parts of nervous system), 227.3 (benign pituitary gland neoplasms), 227.4 (benign pineal gland tumors), 237 (neoplasms of uncertain behavior of endocrine glands and nervous system), 239.6 (brain neoplasms of unspecified nature), and 239.7 (neoplasms of unspecified nature of endocrine glands and other parts of nervous system). The study pathologists also reviewed the records of tumors occurring in neighboring anatomic locations that might include misclassified neural tumors.
The four study pathologists (S. Yonehara, T. Kobuke, H. Fujii, and M. Kishikawa) independently reviewed pathology slides, pathology reports, and clinical records and classified tumors by anatomic site (topography), histologic type (morphology), and tumor behavior, according to World Health Organization (WHO) criteria (29). When diagnoses differed, the pathology panel met to develop a consensus diagnosis.
Data Organization and Statistical Methods
Incidence for the various tumor types was cross-classified into 5-year age-at-exposure groups; 5-year attained-age groups; calendar time periods with an initial 3-year interval (from January 1, 1958, through December 31, 1960); and 5-year intervals for the period from January 1, 1961, through December 31, 1995; weighted brain dose estimates with cut points at 0, 0.005, 0.05, 0.1, 0.2, 0.5, 1, 2, 3, and 4 Sv; sex; city (Hiroshima or Nagasaki); and membership in the Adult Health Study (AHS) cohort (30). Rates were computed with and without inclusion of tumors detected only at autopsy. Members of the AHS receive biennial clinical examinations at RERF and, therefore, the likelihood of early tumor detection is increased, particularly for tumors with only minor clinical symptoms. Autopsies were performed on large numbers of deceased members of the LSS in the course of a major autopsy program carried out between 1960 and the mid-1970s. Because benign and malignant tumors were a major focus of this program, the number of autopsies conducted could have influenced tumor incidence rates.
For each stratum, person-years, tumor counts, person-year-weighted average values for radiation exposure dose, attained age, age at radiation exposure, and time since exposure were computed. Person-years of observation were calculated from January 1, 1958, until the earliest of a) the date of diagnosis of the first primary tumor, b) the date of death or last known vital status, or c) the end of follow-up (December 31, 1995). Because of the completeness of the Japanese family registration system, less than 1% of the LSS cohort members have been lost to follow-up; about half the cohort members who were lost to follow-up could not be traced at the time the cohort was defined; the remaining half consisted of people who emigrated from Japan (emigration date is known). As with most previous studies of tumor incidence in the LSS [including (21,31)], we excluded tumors diagnosed outside the Hiroshima and Nagasaki tumor registry catchment area and adjusted the person-years on the basis of immigration and emigration information obtained from AHS cohort records (21,32). This adjustment, which depends on city, sex, age, and time period, reduces the effective number of person-years by about 14%.
Imprecision in LSS survivor dose estimates results in an underestimation of radiation risk and some distortion in the shape of the radiation doseresponse curve. To adjust for the impact of radiation dose errors, extremely large shielded body surface dose estimates were truncated to 4 Gy, and DS86 estimates were replaced with expected survivor dose estimates computed using the method developed by Pierce et al. (26) to produce bias-corrected risk estimates. These adjustments increase estimates of the slope of the dose response curve by about 10% in linear models.
Poisson regression methods (33) were used to compute maximum likelihood estimates for both excess relative risk (ERR) and excess absolute rate (EAR) models (34). Parameter estimates, likelihood-ratio tests, and likelihood-based confidence intervals (CIs) (33) were computed with the AMFIT computer program (34). We analyzed the data using general ERR models (the background rate times 1 plus the ERR) written as
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and general EAR models (the background rate plus the EAR) written as
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In these models, () describes background nervous system tumor rates as a function of city (c), sex (g), time period (p), attained age (a), and membership in the AHS (m). These fitted background rates are estimates of the rates for an unexposed population. The function
() describes the doseresponse shape. The functions
() and
*() describe effect modification in the ERR and EAR models, respectively. Potential effect modifiers included the covariates c, g, a, and m, as well as age at exposure (e) and time since exposure (t). We generally present excess risk (ERR or EAR) estimates corresponding to specified values of any effect-modifying factors in the model. For example, if a model includes age at exposure or attained-age effects, we present the excess risk estimates at attained age 60 for a person exposed at age 30. The ERR, a dimensionless ratio, is positive if radiation increases risk, zero if there is no radiation effect, and negative when radiation exposure reduces risk. EARs have units of excess cases per 10 000 person-years per Sv and are positive when radiation increases tumor risk.
The log of the background rates was modeled as a sex-specific linear function of log-attained age with additional effects for time period and birth cohort. Categorical time period effects (19581971, 19721981, 19821995) were included to allow for the impact of the autopsy program. Neither city nor AHS membership had appreciable effects on the background rates. In some analyses, we excluded cases diagnosed only at autopsy. All P values are based on two-sided statistical tests.
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RESULTS |
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Analyses were limited to tumors diagnosed in the tumor registry catchment area between January 1, 1958, and December 31, 1995, among persons in Hiroshima or Nagasaki at the time of the atomic bombings for whom DS86 dose estimates can be computed. With the use of these criteria, 146 tumors were excluded because 27 cases occurred in cohort members outside the study period, 73 tumors occurred in cohort members not in Hiroshima or Nagasaki at the time of the bombings, 11 tumors occurred in cohort members who lived outside the tumor registry catchment area at the time of diagnosis, and 35 tumors occurred in cohort members who do not have DS86 dose estimates. Because treatment for the first primary tumor could cause a subsequent tumor and because close medical surveillance might increase the chance of diagnosing a subsequent tumor, we excluded 58 nervous system tumors diagnosed after one or more earlier primary tumors. Seven of the exclusions involved simultaneous nervous system tumors, including three people with two primary meningiomas, one person with two schwannomas, two people with a meningioma (taken as the first primary) and a schwannoma, and one person with both an astrocytoma (taken as the first primary) and a cavernous hemangioma.
After these restrictions and exclusions, 228 first primary tumors of the brain or other parts of the nervous system, 35 tumors of the pituitary gland and adjacent areas (sellar region), and no tumors of the pineal gland were identified among the LSS members (Tables 1 and 2). Of the 263 tumors, 169 occurred among women and 94 occurred among men. The most frequent tumor types were meningioma (88 tumors) and schwannoma (55 tumors). There were also 43 gliomas (including astrocytomas), 15 other nervous system tumors of known type, 27 other nervous system tumors for which the available information was not adequate to histologically classify the tumor, and 35 pituitary gland tumors. The meningiomas were largely calvarial (69 cases, 78%). There were only three malignant meningiomas, all of which were calvarial. More than half the schwannomas were cranial (33 cases, 60%), generally occurring in the acoustic nerve (27 cases). The majority of gliomas were glioblastomatous (24 cases, 56%) or astrocytic tumors (14 cases, 33%). Tumors of the sellar region included 34 pituitary adenomas and one craniopharyngioma.
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In the analyses of incidence, we first examined crude nervous system tumor incidence rates stratified by sex and radiation dose category (Table 2). The most striking suggestion of a dose response was seen for schwannoma, but the crude rates also suggest an increasing doseresponse relationship for other tumor types. The doseresponse relationships were more evident for tumors among men than among women. After modeling the baseline rates using the full dataset with allowance for radiation effects, the age-adjusted baseline rates for meningioma were almost three times higher for women than for men (female-to-male ratio = 2.6, 95% CI = 1.5 to 4.9), but for all other tumors combined, age-adjusted baseline rates for women were only about 65% of those for men (95% CI = 46% to 90%).
When the radiation effect was assumed to be linear in dose, the estimated ERR per Sv (ERRSv) was statistically significantly greater than zero for all nervous system tumors combined (ERRSv = 1.2, 95% CI = 0.6 to 2.1) (Table 3). Although the largest ERRSv estimate was observed for schwannomas (ERRSv = 4.5, 95% CI = 1.9 to 9.2), the ERRSv for all nervous system tumors other than schwannomas was also increased (ERRSv = 0.6, 95% CI = 0.1 to 1.4). Glioma (ERRSv = 0.6, 95% CI = 0.2 to 2.0), meningioma (ERRSv = 0.6, 95% CI = 0.01 to 1.8), and other or unspecified neural tumors (ERRSv = 0.5, 95% CI = <0.2 to 2.2) all had similar ERRSv estimates, but the excess risk was not statistically significant for any of these diagnostic groups. These risk estimates indicate that, of the 228 nervous system tumors, about 32 (95% CI = 18 to 46), or 14%, were related to the radiation exposure. Schwannoma accounted for about two thirds of the excess (20 excess cases, 95% CI = 12 to 28). The estimated risk for pituitary gland tumors (ERRSv = 1.0, 95% CI = 0.1 to 3.1), although not statistically significant, was somewhat larger than that for non-schwannoma nervous system tumors. About four (95% CI = 0.8 to 10) of the 34 pituitary tumors were estimated to be related to radiation exposure.
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We investigated the adequacy of the linear doseresponse model by considering various alternative descriptions of the dose response. Fig. 1 presents linear (solid line), nonparametric (points), and smoothed nonparametric (thick dashed line) (35) doseresponse functions for schwannoma and for nervous system tumors other than schwannoma. The thin dashed lines indicate the uncertainty (± one standard error) in the nonparametric smoothed dose response. There is very good agreement between the linear fit and the smoothed data for nervous system tumors other than schwannoma, suggesting that the linear dose response model describes these data quite well. For schwannoma, the relatively low but poorly estimated risk at very high doses tended to reduce the apparent linear low-dose slope and had an even stronger influence on the smoothed doseresponse function. More formally, consideration of linear quadratic doseresponse models provided little evidence of a statistically significant lack of fit of the linear doseresponse model for schwannoma (P = .09) and no indication of a significant lack of fit for other nervous system (P>.5) tumors. For both groups, the linear model appears to provide a good description of the low-dose (e.g., <1 Sv) risks. For nervous system tumors as a group (P = .01) and for schwannoma (P<.001), the dose response was statistically significant when the analyses were carried out using only cohort members with doses of less than 1 Sv. In neither of these groups, nor for nervous system tumors other than schwannoma, was there any evidence of statistically significant differences in the slope over this low-dose range and that over the full-dose range. Taken together, these findings suggest that the LSS data are consistent with a linear dose response for doses ranging from zero to two or more Sv.
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Because inclusion of the autopsy-only cases could bias estimates of effect modification, particularly in terms of age and time, we also assessed effect modification excluding these cases. There were no marked changes in the parameter estimates or conclusions about the statistical significance of these effects.
We also examined EARs for schwannoma, nervous system tumors other than schwannoma, and meningioma (Table 5). Although there was no evidence of statistically significant variation in the excess rates with attained age, the point estimates of the change in the EAR per decade are relatively large for nervous system tumors other than schwannoma and meningioma separately. Similar to the ERR estimates, there was a suggestion that the EAR is greater for men than for women. This difference approaches statistical significance for schwannoma (P = .08) and for nervous system tumors other than schwannoma (P = .06), but not for meningioma considered separately (P>.5).
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DISCUSSION |
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Although our data show a statistically significant increased risk of all nervous system tumors combined, the risk was substantially higher for schwannoma than for any other nervous system tumor type. When considered individually, risks for glioma, meningioma, or other non-schwannoma nervous system tumors were not found to exhibit statistically significant radiation-related increases in risk. However, because the ERR estimates were elevated for each histologic type, analyses of all non-schwannoma nervous system tumors combined demonstrated a statistically significant radiation effect.
An enhanced risk of glioma has been seen following moderate-dose radiotherapy for tinea capitis (5,6), and large risks of gliomas have been reported following very high radiation doses, e.g., after prophylactic radiation therapy in childhood for acute lymphoblastic leukemia (11,12) or after radiation therapy for pituitary tumors (36). In some studies, excess relative risks were greater for schwannoma than for other nervous system tumors (5,6,12). Our results are generally consistent with these observations.
To date, most reports of radiation-associated nervous system tumors have been based on childhood exposures. The LSS is unique in that it permits direct assessment of how radiation effects on nervous system tumor incidence vary over a large range of ages at exposure. This study has several additional strengths. LSS cohort members have individually estimated organ doses. Tumor incidence could be ascertained on the basis of data from population-based tumor and tissue registries, with final pathology review carried out on the basis of consistently applied, modern diagnostic criteria. The fact that 20% of the benign tumors in this study were identified at autopsy is also a potential strength of the study because inclusion of these cases increases the ability of the study to characterize radiation effects. Although the use of these cases raises concerns about potential biases in the radiation risk estimates resulting from dose-related ascertainment rate differences, our analyses suggested that after allowing for temporal variation in autopsy rates, there are no indications of bias in the radiation risk estimates.
Our results for nervous system tumors other than schwannoma and for meningioma considered separately are consistent with a marked decrease in the ERRSv with increasing age at exposure, but the effect is not statistically significant, possibly because of the relatively small number of radiation-associated cases in this population. The lack of a statistically significant attained-age effect on the radiation risks for nervous system tumor incidence may also reflect these limitations of the data. However, the age-group-specific point estimates of the ERRSv do not suggest a consistent pattern of change with increasing age, and statistically significant attained-age effects have not been reported in other studies.
Although the evidence for sex differences in excess relative risks was not strong, men generally had higher excess relative risks than women, even for meningioma, for which background rates are considerably greater for women than for men. In one population-based incidence study, meningioma rates increase with age, are about two times higher among women than among men, and typically account for about 20% of intracranial tumors (37). In the LSS data, background meningioma incidence rates increased with age, women had about three times the incidence of men, and meningioma comprised almost 50% of the nervous system tumors, mostly because of the large number of meningiomas detected at autopsy. The background sex difference was reduced, but not eliminated, when analyses were restricted to meningiomas not discovered at autopsy. Although the sex difference in the ERRSv for meningioma in this cohort was not statistically significant (P = .4), the point estimate of the sex ratio (female-to-male ratio = 0.3) of the excess relative risks is consistent with observations from another study (38), in which it was noted that men have somewhat greater age-specific rates of meningioma than women.
The mechanisms of tumorigenesis in the human brain are believed to be different than those in other tissues and organs because the brain is well protected, not exposed to many exogenous agents, and only glial cells (probably astrocytes) proliferate after puberty (39). Inskip et al. (3) have suggested that traumatic injury to the brain increases cell proliferation or breakdown of the bloodbrain barrier, thus increasing the risk of brain tumor development.
Preston-Martin et al. (40) also suggested that head trauma may be an important risk factor for meningioma. It is possible that increased cell proliferation or breakdown of the bloodbrain barrier resulting from head injury during the atomic bombings enhanced the tumorigenic effects of radiation exposure. Because benign tumors frequently occur outside the brain and the protection of the bloodbrain barrier, they may be more susceptible to radiation damage. Even though there is a positive association between non-radiation-related injury and radiation dose among the LSS survivors, the effects of head trauma are unlikely to fully explain the radiation dose response because the risk of physical trauma was also quite high for many survivors who received little or no radiation dose. If trauma was playing a major role in the dose response, we would expect the incidence of nervous system tumors among the 15 600 proximal survivors (i.e., within 3 km) with low radiation exposure (<5 mSv) to be greater than that for the 23 500 more distal survivors with similar low radiation exposure but much less trauma. In fact, such differences were not observed for all nervous system tumors as a group, for schwannomas, or for meningiomas when considered separately. Our results support those of Ron et al. (5), who noted large radiation-associated risks for schwannomas in the Israeli tinea capitis study in which trauma is not a risk factor. Thus, it is unlikely that the effects of physical trauma in the atomic bomb survivors are seriously confounding or biasing the radiation risk estimates.
This study indicates that relatively low-dose radiation exposure plays a role in the etiology of nervous system and pituitary tumors, with a weak indication of somewhat higher relative risks for those exposed during childhood. Although most of the tumors were benign, radiation-induced meningiomas reportedly have more atypical or anaplastic histology than spontaneous meningiomas and have a high rate of recurrence (4143). Among the LSS cases, there were three anaplastic and one atypical meningioma (two in cohort members with zero dose and two in cohort members with doses of about 1 Sv), making it difficult to draw any firm conclusion regarding radiation-induced meningioma.
New uses of medical irradiation involving exposure of the central nervous system have heightened interest in radiation effects on nervous system cancer risks. The use of radiation treatment for benign diseases of the nervous system, such as for intracranial arteriovenous malformation (44), can result in high doses to parts of the brain. In addition, the use of pediatric computed tomography (CT) scans (45), including brain scans, has increased dramatically over the last decade. It has been predicted (46) that the rapid rise in the use of CT scans will lead to increases in the lifetime risk of cancers of the brain and other tissue. Although additional follow-up of the LSS cohort and other exposed populations will be necessary to fully quantify the lifetime risks for nervous system tumors, our findings demonstrate that radiation exposure can increase the risk of nervous system tumors and suggest that these increased risks persist throughout lifetime, regardless of the age at exposure.
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NOTES |
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Present address: M. Kishikawa, Department of Morphology, Institute for Developmental Research, Aichi Human Service Center, Aichi, Japan.
Present address: M. Tokunaga, Kodama Hospital, Kagoshima, Japan.
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REFERENCES |
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1 Kleihues P, Cavenee W. Pathology and genetics of tumours of the nervous system. 2nd ed. Lyon (France): IARC Press; 2000.
2 Prados MD, Berger MS, Wilson CB. Primary central nervous system tumors: advances in knowledge and treatment. CA Cancer J Clin 1998;48:33160.
3 Inskip PD, Linet MS, Heineman EF. Etiology of brain tumors in adults. Epidemiol Rev 1995;17:382414.[Medline]
4 Davis FG, Preston-Martin S. Epidemiology: incidence and survival. In: Bigner DD, McLendon RE, Bruner JM, editors. Russell and Rubinsteins pathology of the nervous system. Vol 1. 6th ed. New York (NY): Oxford University Press; 1998. p. 545.
5 Ron E, Modan B, Boice JD Jr, Alfandary E, Stovall M, Chetrit A, et al. Tumors of the brain and nervous system after radiotherapy in childhood. N Engl J Med 1988;319:10339.[Abstract]
6 Shore RE, Albert RE, Pasternack BS. Follow-up study of patients treated by X-ray epilation for Tinea capitis; resurvey of post-treatment illness and mortality experience. Arch Environ Health 1976;31:218.[Medline]
7 Karlsson P, Holmberg E, Lundell M, Mattsson A, Holm LE, Wallgren A. Intracranial tumors after exposure to ionizing radiation during infancy: a pooled analysis of two Swedish cohorts of 28,008 infants with skin hemangioma. Radiat Res 1998;150:35764.[Medline]
8 Little MP, de Vathaire F, Shamsaldin A, Oberlin O, Campbell S, Grimaud E, et al. Risks of brain tumour following treatment for cancer in childhood: modification by genetic factors, radiotherapy and chemotherapy. Int J Cancer 1998;78:26975.[Medline]
9 Sznajder L, Abrahams C, Parry DM, Gierlowski TC, Shore-Freedman E, Schneider AB. Multiple schwannomas and meningiomas associated with irradiation in childhood. Arch Intern Med 1996;156:18738.[Abstract]
10 Hawkins MM, Draper GJ, Kingston JE. Incidence of second primary tumours among childhood cancer survivors. Br J Cancer 1987;56:33947.[Medline]
11 Neglia JP, Meadows AT, Robison LL, Kim TH, Newton WA, Ruymann FB, et al. Second neoplasms after acute lymphoblastic leukemia in childhood. N Engl J Med 1991;325:13306.[Abstract]
12 Walter AW, Hancock ML, Pui CH, Hudson MM, Ochs JS, Rivera GK, et al. Secondary brain tumors in children treated for acute lymphoblastic leukemia at St Jude Childrens Research Hospital. J Clin Oncol 1998;16:37617.[Abstract]
13 Preston-Martin S, White SC. Brain and salivary gland tumors related to prior dental radiography: implications for current practice. J Am Dent Assoc 1990;120:1518.[Medline]
14 Ryan P, Lee MW, North B, McMichael AJ. Amalgam fillings, diagnostic dental x-rays and tumours of the brain and meninges. Eur J Cancer B Oral Oncol 1992;28B:915.
15 McCredie M, Maisonneuve P, Boyle P. Perinatal and early postnatal risk factors for malignant brain tumours in New South Wales children. Int J Cancer 1994;56:115.[Medline]
16 Preston-Martin S, Pogoda JM, Schlehofer B, Blettner M, Howe GR, Ryan P, et al. An international case-control study of adult glioma and meningioma: the role of head trauma. Int J Epidemiol 1998;27:57986.[Abstract]
17 Cardis E, Gilbert ES, Carpenter L, Howe G, Kato I, Armstrong BK, et al. Effects of low doses and low dose rates of external ionizing radiation: cancer mortality among nuclear industry workers in three countries. Radiat Res 1995;142:11732.[Medline]
18 Muirhead CR, Goodill AA, Haylock RG, Vokes J, Little MP, Jackson DA, et al. Occupational radiation exposure and mortality: second analysis of the National Registry for Radiation Workers. J Radiol Prot 1999;19:326.[Medline]
19 Doody MM, Mandel JS, Lubin JH, Boice JD Jr. Mortality among United States radiologic technologists, 192690. Cancer Causes Control 1998;9:6775.[Medline]
20 Seyama S, Ishimaru T, Iijima S, Mori K. Primary intracranial tumors among atomic bomb survivors and controls, Hiroshima and Nagasaki, 196175. J Hiroshima Med Assoc 1981;34:105665.
21 Thompson DE, Mabuchi K, Ron E, Soda M, Tokunaga M, Ochikubo S, et al. Cancer incidence in atomic bomb survivors. Part II: Solid tumors, 19581987. Radiat Res 1994;137(2 Suppl):S1767.[Medline]
22 Shintani T, Hayakawa N, Hoshi M, Sumida M, Kurisu K, Oki S, et al. High incidence of meningioma among Hiroshima atomic bomb survivors. J Radiat Res (Tokyo) 1999;40:4957.[Medline]
23 Sadamori N, Shibata S, Mine M, Miyazaki H, Miyake H, Kurihara M, et al. Incidence of intracranial meningiomas in Nagasaki atomic-bomb survivors. Int J Cancer 1996;67:31822.[Medline]
24 Radiation Effects Research Foundation (RERF). U.S.Japan joint reassessment of atomic bomb radiation dosimetry in Hiroshima and Nagasaki: final report. Hiroshima (Japan): RERF; 1987.
25 Fujita S. Versions of DS86. RERF Update 1989;1:3.
26 Pierce DA, Stram DO, Vaeth M. Allowing for random errors in radiation dose estimates for the atomic bomb survivor data. Radiat Res 1990;123:27584.[Medline]
27 Mabuchi K, Soda M, Ron E, Tokunaga M, Ochikubo S, Sugimoto S, et al. Cancer incidence in atomic bomb survivors. Part I: Use of the tumor registries in Hiroshima and Nagasaki for incidence studies. Radiat Res 1994;137:S116.[Medline]
28 World Health Organization (WHO). International Classification of Diseases: Manual of Statistical Classification of Diseases, Injuries, and Causes of Death, 1975 Revision. Vol 1. Geneva (Switzerland): WHO; 1977.
29 Kleihues P, Burger PC, Scheithauer BW. Histolgical typing of tumours of the central nervous system. New York (NY): Springer-Verlag; 1993.
30 Wong FL, Yamada M, Sasaki H, Kodama K, Akiba S, Shimaoka K, et al. Noncancer disease incidence in the atomic-bomb survivors: 19581986. Radiat Res 1993;135:41830.[Medline]
31 Ron E, Preston DL, Kishikawa M, Kobuke T, Iseki M, Tokuoka S, et al. Skin tumor risk among atomic-bomb survivors in Japan. Cancer Causes Control 1998;9:393401.[Medline]
32 Sposto R, Preston DL. Correcting for catchment area nonresidency in studies based on tumor registry data. CR192. Hiroshima (Japan); RERF: 1992.
33 McCullagh P, Nelder JA. Generalized linear models. London (U.K.); Chapman & Hall Ltd; 1999. p. 2145.
34 Preston D, Lubin J, Pierce D, McConney M. Epicure users guide. Seattle (WA): Hirosoft International Corporation; 1993.
35 Pierce DA, Preston DL. Radiation-related cancer risks at low doses among atomic bomb survivors. Radiat Res 2000;154:17886.[Medline]
36 Brada M, Ford D, Ashley S, Bliss JM, Crowley S, Mason M, et al. Risk of second brain tumour after conservative surgery and radiotherapy for pituitary adenoma. BMJ 1992;304:13436.[Medline]
37 Longstreth WT, Dennis LK, McGuire VM, Drangsholt MT, Koepsell TD. Epidemiology of intracranial meningioma. Cancer 1993;72:63948.[Medline]
38 Rabin BM, Meyer JR, Berlin JW, Marymount MH, Palka PS, Russell EJ. Radiation-induced changes in the central nervous system and head and neck. Radiographics 1996;16:105572.[Abstract]
39 Bigner DD, McLendon RE, Bryner JM. Russell and Rubinsteins pathology of tumors of the nervous system. Vols 1 and 2. 6th ed. New York (NY): Oxford University Press; 1998.
40 Preston-Martin S, Pogoda JM, Mueller BA, Lubin F, Modan B, Holly EA, et al. Results from an international case-control study of childhood brain tumors: the role of prenatal vitamin supplementation. Environ Health Perspect 1998;106 Suppl 3:88792.[Medline]
41 Shoshan Y, Chernova O, Juen SS, Somerville RP, Israel Z, Barnett GH, et al. Radiation-induced meningioma: a distinct molecular genetic pattern? J Neuropathol Exp Neurol 2000;59:61420.[Medline]
42 Soffer D, Pittaluga S, Feiner M, Beller AJ. Intracranial meningiomas following low-dose irradiation to the head. J Neurosurg 1983;59:104853.[Medline]
43 Rubinstein AB, Shalit MN, Cohen ML, Zandbank U, Reichenthal E. Radiation-induced cerebral meningioma: a recognizable entity. J Neurosurg 1984;61:96671.[Medline]
44 Heros RC, Korosue K. Radiation treatment of cerebral arteriovenous malformations. N Engl J Med 1990;323:1279.[Medline]
45 Mettler FA Jr, Wiest PW, Locken JA, Kelsey CA. CT scanning: patterns of use and dose. J Radiol Prot 2000;20:3539.[Medline]
46 Brenner D, Elliston C, Hall E, Berdon W. Estimated risks of radiation-induced fatal cancer from pediatric CT. AJR Am J Roentgenol 2001;176:28996.
Manuscript received January 8, 2002; revised July 16, 2002; accepted August 8, 2002.
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