Articles Radiation and Mortality of Workers at Oak Ridge National Laboratory: Positive Associations for Doses Received at Older Ages David B. Richardson and Steve Wing Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA We examined associations between low-level exposure to ionizing radiation and mortality among 14,095 workers hired at the Oak Ridge Nationl Laboratory between 1943 and 1972. Workers at the facility were individually monitored for external exosure to ionizing radiation and have been followed through 1990 to ascertain cause of death information. Positive associations were observed between low-level exposure to external ionizing radiation and mortality. These associa- tions were larger for doses received after 45 years of age, larger under longer lag assumptions, and primarily due to cancer causes of death. All cancer mortality was estimated to increase 4.98% [standard error (SE) = 1.5] per 10-mSv cumulative dose received after age 45 under a 10-year lag, and 7.31% (SE = 2.2) per 10-mSv cumulative dose received after age 45 under a 20-year lag. Associations between radiation dose and lung cancer were of similar magntude to associations between radiation dose and all cancers except lung cancer. Nonmalignant respiratory disease exhibited a positive association with cumulative radiation dose received after age 45, whereas ischemic heart disease exhibited no association with radiation dose. These findings suggest increases in cancer mortality associated with low-level external exposure to ionizing radiation and potentially greater sensitivity to the carcinogenic efcs of ionizing radiation with older ages at exposure. Key wordk: epidemiology, ionizing radiation, Oak Ridge National Laboratory. Environ Healt Perpect 107:649-656 (1999). [Online 29 June 1999] http://ehpnetl.niehs.nih.gov/docs/19991107p649-65 6richardson/abstraa. html People are exposed to ionizing radiation from a wide range of occupational and envi- ronmental sources. The effects of these exposures remain a topic of substantial con- cern and interest. Studies of atomic bomb survivors and patients receiving medical irradiation have provided widely cited epi- demiologic evidence about the effects of external exposure to ionizing radiation (1-4). Epidemiologic studies of workers in the nuclear industry, however, offer poten- tially valuable information about the effects of long-term, low-level ionizing radiation exposures; such studies may be particularly relevant to evaluations of the effects of the low dose rate exposures typically received in environmental and occupational settings. In this paper we describe associations between external exposure to ionizing radia- tion and mortality among workers employed at the Oak Ridge National Laboratory (ORNL; Oak Ridge, TN), a United States Department of Energy (DOE) facility. Workers at the ORNL have been involved in research and production of nuclear materials since the facility's construction in 1943 as part of the U.S. government's World War II program to develop atomic weapons. These workers have relatively complete external radiation dosimetry data and vital status fol- low-up (5,6). Previous studies of this work- force have reported excess leukemia mortality as compared to the general population (7,8) and positive associations between cumulative external ionizing radiation dose and cancer mortality among white males at the ORNL who had not been employed at other DOE facilities (8,9). Subsequent analyses found that these dose-response associations were primarily due to the association between can- cer mortality and radiation doses received at older ages (10,11). In contrast to previous studies, which focused on radiation-mortali- ty associations among white males at the ORNL who had not been employed at other DOE facilities (7-9), we describe analyses that include all ORNL workers for whom data were adequately complete. We exam- ined associations between external radiation dose and several specific causes of death and evaluated the sensitivity of these associations to assumptions about the latency between exposure and mortality. Materials and Methods This study included all employees hired at the ORNL between 1943 and 1972 who worked 30 or more days; for whom there was complete information on sex, race, dates of birth and hire; and who had no more than 2 years of missing annual whole-body dosimetry data from employment at other DOE facilities (n = 14,095). In contrast to previous studies of radiation-cancer associa- tions among workers at the ORNL, the cohort included women, nonwhite workers, and workers who were also employed at other DOE facilities (primarily other DOE facilities located in Oak Ridge, TN). Vital status was ascertained through 1990 by the use of records from the Social Security Administration, the National Death Index, and employers. Information on underlying cause of death, as well as contrib- utory causes of death related to cancer, was abstracted from death certificates and coded to the International Classification of Diseases, 8th Revision (ICD-8) adapted for the United States. Comparisons of mortality of workers to the general population are usually based only on underlying causes of death information; however, characterization of deaths by a single underlying cause leads to loss of information for decedents with multi- ple morbid conditions. Therefore, in this study, similar to previous analyses that have compared mortality of ORNL workers with different dose levels, we used both underly- ing and contributory cause of death informa- tion to define cancer death (8,1Z). We examined deaths due to all causes (any worker identified as deceased) because this outcome is of broad public health signif- icance and is not dependent on the accuracy of information about ctgses of death. All cancer mortality (any worker who had an underlying or contributory cause of death assigned ICD-8 codes 140-209) was exam- ined because radiation-induced cancers may occur at most, if not all, sites following whole-body exposure to ionizing radiation and because death certificate data may be more accurate for identifying all cancers as a group than for identifying specific types of cancer (2,13). The category of all causes except cancer (any worker who did not have an underlying or contributory cause of death assigned ICD-8 codes 140-209) was exam- ined to assess whether radiation-mortality associations were specific to malignant dis- eases. Lung cancer (any worker who had an underlying or contributory cause of death Address correspondence to D.B. Richardson, Department of Epidemiology, School of Public Health, CB # 8050, Nationsbank Plaza, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-8050 USA. Telephone: (919) 966-6305. Fax: (919) 966-6650. E-mail:drichard@sph.unc.edu The authors are grateful to J. Wood and S. Wolf at the University of North Carolina at Chapel Hill. This research was supported by grant R03 0H03343 from the National Institute for Occupational Safety and Health of the Centers for Disease Control and Prevention. Vital status fol- low-up, death certificate retrieval, and cause of death coding were conducted at the Center for Epidemiologic Research, Oak Ridge Associated Universities. Received 10 November 1998; accepted 29 March 1999. Environmental Health Perspectives * Volume 107, Number 8, August 1999 649 Articles . Richardson and Win assigned ICD-8 code 162) was examined because this was the most common cancer cause of death in the cohort and this cancer site is most strongly related to cigarette smok- ing, which potentially may confound studies of radiation-cancer associations (14). All can- cer mortality except lung cancer (any worker who had an underlying or contributory cause of death assigned ICD-8 codes of 140-209 except 162) was examined to assess the speci- ficity of radiation-cancer association to lung cancer. Ischemic heart disease (any worker who had an underlying cause of death assigned ICD-8 codes 410-414) was exam- ined because it was a leading noncancer cause of death, it was expected to be associated with cigarette smoking, and it was potentially indicative of bias due to selection of healthier workers into exposed jobs. Nonmalignant respiratory disease (any worker who had an underlying cause of death assigned ICD-8 codes 460-519) was examined as a non- cancer outcome expected to be associated with cigarette smoking. Personal monitoring data for whole-body exposure to external penetrating ionizing radiation (primarily gamma rays) were avail- able for the period 1943-1985 from records at the ORNL. External ionizing radiation exposure monitoring began at the ORNL in February 1943; by 1948 over 98% of the employed workers were monitored, and by November 1951 all ORNL workers were required to have a radiation dosimeter, which was later incorporated into a security badge required to be worn at all times (5,6). Annual external radiation doses were estimated for work-years at the ORNL with missing dose data by using dose estimates in adjacent time periods and average values for similar workers (15). Radiation dosimetry data from other facilities, including Y-12 (Oak Ridge, TN), K-25 (Oak Ridge, TN), Hanford (Richland, WA), and the Savannah River Site (Aiken, SC), were merged with the ORNL records; workers who had more than 2 years of miss- ing external radiation dose data during employment at other DOE facilities were excluded from analyses. Statistical methods. Statistical analyses of radiation-mortality associations were con- ducted using the Poisson regression method (16,11). Person-time and events were allo- cated in tables stratified by all covariates and cumulative radiation dose (18). Age at risk was classified in 5-year intervals from < 25 years to > 90 years. Birth cohort was classi- fied as births before 1905, between 1905 and 1915, between 1915 and 1925, or after 1925. Sex was included with two levels; race indicated whether or not a worker was classi- fied as white. Paycode, which was used to control for socioeconomic differences in can- cer mortality, was based on the worker's pay schedule when hired and indicated whether a worker was paid monthly, weekly, or hourly. Employment status, which indicated whether or not a worker had been employed within the last 2 years, was used to control for mortality differences between actively employed and terminated workers (19-21). Internal exposure to radionuclides has been monitored since 1951. Internal monitoring status was lagged the same number of years as external dose and indicated whether a worker was employed during those years when monitoring for internal radionuclide contamination was conducted, and if so, whether the worker had ever been moni- tored. Facility of employment was examined as a covariate that indicated whether or not the ORNL was the only DOE facility at which the worker was employed. After evaluation of the data, we deter- mined that a single term could be used to adjust for age at risk centered at 52.5 years in a log-log relationship for cancer causes of death and in a log-linear relationship for noncancer causes (22). This is similar to pre- vious analyses of mortality of workers at the ORNL and has been demonstrated to be an efficient method for adjusting for age at risk (23,24). Other covariates were included using indicator terms. Terms were included to describe interactions between birth cohort and paycode, changes with age at risk in the association between cancer mortality and employment status, and differences by sex in the effects of race and birth cohort. Due to the limited number of lung cancer deaths among female workers, analyses of lung can- cer mortality could not support interactions between race or cohort and sex. Similarly, analyses of nonmalignant respiratory disease do not include a race-sex interaction term. Cumulative external ionizing radiation doses were classified in seven 20-mSv cate- gories from 0 mSv to > 100 mSv. To consid- er a lag between exposure and mortality, deaths and person-time were classified according to the cumulative external radia- tion dose received 5, 10, and 20 years earlier. In regression analyses, cumulative dose was evaluated as a continuous variable, providing an estimate of the percent change in mortali- ty per 10-mSv cumulative dose (see Appendix). We previously demonstrated that white male ORNL workers show sub- stantial heterogeneity in radiation-cancer associations with age at exposure (10,11) and that the best fitting model was produced when cumulative dose was partitioned at 45 years of age. In the analyses reported here, a regression model with separate terms for doses received before and after age 45 was compared to a nested regression model with a single term for all ages of exposure com- bined (see Appendix). Results include an indication of the change in deviance on inclusion of a dose term in the regression model. This value is referred to as likelihood ratio test (LRT) statistic and can be inter- preted using a chi-square distribution with one degree of freedom (df); larger values indicate a better fit of the regression model to the observed data (16). Results Vital status was ascertained for 94% of the cohort in follow-up through 1990 (Table 1). Of the 14,095 workers in the cohort, 3,269 (23%) were deceased at the end of follow- up. Death certificates were retrieved for 97% of the decedents, from which 879 deaths due to cancer were identified. The follow-up period includes 425,486 person-years. The distribution of person-time and deaths by study factors is described in Table 2. Lifetime cumulative dose was positively associated with all cancer mortality under 5-, 10-, and 20-year lag assumptions (Table 3). However, radiation-cancer associations were of larger magnitude and better fit when radiation doses received after age 45 were examined than when associations with lifetime cumulative dose were examined (Table 3). Cumulative dose received after 45 years of age was positively associated with all cancer mortality under a 5-year lag assumption (4.39%/10 mSv), 10-year lag assumption (4.98%/10 mSv), and 20-year lag assumptions (7.31%o/10 mSv). The LRT statistic for the association between doses received after age 45 and all cancer mortality was marginally larger under a 10-year lag assumption (LRT = 9.4; 1 df) than under a 5-year lag assumption (LRT = 8.7; 1 df) or 20-year lag assumption (LRT = 8.4; 1 df). We used a nested regression model to com- pare the fit of the dose-response model for lifetime cumulative dose to the fit of the model that allowed the association to differ for exposures received before and after age 45 (Table 3). The change in deviance between nested regression models provided an LRT of the heterogeneity in dose-response associa- tions for exposures received before and after 45 years of age; the results indicate substan- tial improvement under the assumption that the dose-response association differed for Table 1. Vital status of the study cohort of Oak Ridge National Laboratory workers as of 31 December 1990. Alive Dead Unknown No. men l%l 7,399 (691) 2,890 (27.0) 417 (3.9) No. women (%) 2,568 (75.8) 379 (11 2) 442 (13.0) Total no. l%l 9,967 (70.7) 3,269 (23.2) 859 (6.1) Volume 1 07, Number 8, August 1999 * Environmental Health Perspectives 650 Articles * Radiation and mortality of workers at ORNL exposures received at older and younger ages for associations between all cancer mortality (Table 3). Adjustment of dose-response and radiation doses received before age 45 associations for doses received before age 45 in the model, we estimated a 4.54% (SE = had little effect on the estimated associations 1.33) increase in all cancer mortality per 10 between doses received after age 45 and all mSv dose received after age 45 under a 10- cancer mortality. When we did not adjust year lag assumption. Table 2. Distribution of person-years and deaths by study factors among Oak Ridge National Laboratory (ORNL) workers. All All Lung Ischemic Nonmalignant Person- cause cancer cancer heart disease respiratory years of deaths deaths deaths deaths deaths follow-up Age <30 59 6 1 0 0 52,693 30-50 475 98 23 100 9 214,198 50-70 1,684 519 156 543 63 140,007 70+ 1,051 256 65 333 95 18,589 Sex Male 2,890 750 219 913 150 326,767 Female 379 129 26 63 17 98,718 Race White 2,961 819 235 906 156 398,674 Other 308 60 10 70 11 26,812 Facility of employment ORNL only 2,576 693 189 781 135 334,318 Other 693 186 56 195 32 91,168 Pay code Hourly 690 181 67 209 40 65,706 Weekly 1,706 442 134 493 91 214,684 Monthly 873 256 44 274 36 145,096 Birth cohort <1905 778 162 38 306 49 22,902 1905-1915 985 252 68 318 77 55,968 1915-1925 1,017 321 105 263 35 139,233 1925+ 489 144 34 89 6 207,383 Employment status Employed within last 536 162 41 146 8 169,816 2 years Not employed 2,733 717 204 830 159 255,670 Internal radiation monitoring Not monitored 2,202 565 150 669 116 91,619 Monitored 1,002 304 92 297 50 273,513 Not eligible to be 65 10 3 10 1 60,354 monitored Total 3,269 879 245 976 167 425,486 The fit of these regression models to the observed data was examined graphically, eval- uating associations between radiation dose and all cancer mortality under a 10-year lag assumption (Figure 1). Figure 1 shows the relationship between all cancer mortality and lifetime cumulative dose (Figure 1A), cumu- lative dose received before age 45 (Figure 1B), and cumulative dose received after age 45 (Figure 1C). There do not appear to be any systematic departures from linearity. These radiation-cancer dose-response associations were based on a multiplicative relative risk model in which mortality is described as increasing on a natural log scale with increasing cumulative radiation dose. However, within the range of observed cumulative doses, the magnitude of associa- tion between all cancer mortality and radia- tion doses received after 45 years of age was similar when estimated using an additive rel- ative risk model. Under an additive relative -a uAJ ca -I U 5U 1W0 15U 2 2U 3W 3au Lifetime cumulative dose (mSv) 0 50 100 150 200 250 3 350 Cumulative dose received before age 45 (mSv) Table 3. Estimated percent increase in all cancer mortality among Oak Ridge National Laboratory (ORNL) workers per 10-mSv cumulative external ionizing radiation dose under 5-, 10-, and 20-year lag assumptions. Model 1: Partitioned Model 2: Lifetime Model 1 versus cumulative dose cumulative dose Model 2 Cumulative dose Cumulative dose Cumulative dose received before received after received after age 45 age 45 age 16 LRTa 5-year lag Percent increase -0.86 4.39 1.06 SE 1.05 1.36 0.61 LRT,1 df 0.7 8.7 2.7 6.22 10-year lag Percent increase -0.69 4.98 1.21 SE 1.05 1.48 0.65 LRT,1 df 0.5 9.4 3.0 6.62 20-year lag Percent increase 0.24 7.31 1.73 SE 1.12 2.24 0.86 LRT,1 df 0.05 8.4 3.5 5.79 Abbreviations: df, degree of freedom; LRT, likelihood ratio test; SE, standard error. Adjusted for age, race, sex, birth cohort, employment status, paycode, internal radionuclide monitoring, and the interaction between race and sex, sex and birth cohort, paycode and birth cohort, and employment status and age. LRT comparing Model 1 to Model 2, which has a chi-square distribution with 1 df. 2.0 : 1.5 C K 1. * % 0.5 l -1.5 0 50 1W 150 200 250 3 350 Cumulatve dose received after age 45 (mSv) Figure 1. Ratio of observed (Obs) to expected (Exp) number of all cancer deaths by cumulative dose under a 10-year lag. (A) Association with lifetime cumulative dose. (B) Association with cumulative dose received before the age of 45 years. (C) Association with cumulative dose received after the age of 45 years. Points repre- sent the ratio of observed cancer deaths to the number expected in each cumulative dose cate- gory based on the covariate-specific distribution of person-time. Solid lines represent the estimat- ed percent increase in cancer mortality with increasing cumulative dose. Environmental Health Perspectives E Volume 107, Number 8, August 1999 2.0 1.5 A 1 1.0 0.5 0.0 -0.5 -1.0 -1.5 2.0 i.s 1 ,a i.o X LU ,a 0.5 .0 g 0.0 -9 -0.5 -1.0 -1.5 - 651 Articles * Richardson and Wing risk model, cumulative dose received after age 45 was associated with a 6.85% (SE = 3.10; LRT = 8.6; 1 df) increase in all cancer mortality per 10 mSv under a 10-year lag assumption. All cause mortality was also positively associated with cumulative radiation dose received after 45 years of age; associations increased in magnitude tinder longer lag asstimptions, from 1.100/10 mSv under a 5-year lag assumption to 3.54%/l 0 mSv under a 20-year lag assumption (Table 4). However, associations between cumulative dose received after age 45 and cancer mortal- ity were of substantially larger magnittide and better fit than associations with all cause mortality (Table 4). Associations between radiation dose received after age 45 and all causes of death except cancer were negative under 5- or 10-year lag assumptions and positive under a 20-year lag asstimptionl. Likelihood ratio tests indicate relatively little contribution of the dose term to fit of the models for noncancer mortality (Table 4). We divided the category of all cancer mortality into two groups: lung cancer and all cancers other than lung cancer (Table 4). Estimated associations between cumulative radiation dose received after 45 years of age and lung cancer were positive tinder a 5-vear lag assumption (5.19%/10 mSv), a 10year lag assumption (5.48%/10 mSv), and a 20- year lag asstimption (6.63%/10 mSv). Similarly, estimated associations between cumulative radiation dose received after 45 years of age and cancer other than lung can- cer were positive under a 5-year lag assump- tion (3.88o/l0 mSv), a 10-year lag asstimp- tion (4.67%/10 mSv), and a 20-year lag assumption (7.69%/10 mSv). The best fit- ting models were a 5-year lag assumption for- lung cancer mortality (LRT = 4.5; 1 dXf) and a 20-year lag assumption for other cancers (LRT= 6.6; 1 df). Associations between ischemic heart dis- ease and cumulative dose received after age 45 were negative under all lag assumptions, w ith small likelihood ratio test statistics (Tlable 4). Nonmalignant respiratory disease was posi- tively associated with cumtilative dose received after 45 years of age, with small LRT statistics under 5- and 20-year lag assump- tions. The magnitude (5.6600/10 msv) and goodness of fit (I.RT = 3.2; 1 df) of the asso- ciation between nonmalignant respiratory dis- ease and radiation dose was largest tinder a 1 0-year lag assumption. There were few deaths at higher doses when the association between nonmalignant respiratory disease and doses received after 45 years of age were examined tinder a 20-year lag assumptionl. To ftirther describe the fit of these mod- els for radiation-cancer dose-responise associ- arions to the observed data, ratios of observed Table 4. Estimated percent increase in cause-specific mortality among Oak Ridge National Laboratory workers per 10-mSv cumulative external radiation dose received after age 45, under 5-, 10-, and 20-year lag assumptions. 5-Year lag 10-Year lag 20-Year lag All cause mortality Percent increase per 10 mSv 1.10 1.19 3,54 SE 087 096 1.42 LRT,1 df 1.5 1,5 55 All cancer mortality Percent increase per 10 mSv 4 39 4 98 7.31 SE 136 148 2.24 LRT,1 df 87 94 84 All causes except cancer Percent increase per 10 mSv -0.30 -0.44 2.04 SE 1.12 125 181 LRT, l df 0.1 0.1 12 Lung cancera Percent increase per 10 mSv 5.19 5.48 6 63 SE 221 245 418 LRT,1 df 45 41 20 All cancers except lung Percent increase per 10 mSv 3.88 4.67 7.69 SE 1.74 1 87 264 LRT,1 df 42 52 66 Ischemic heart disease Percent increase per 10 mSv -2.39 -2.86 -0.16 SE 181 206 299 LRT,1 df 1.9 21 00 Nonmalignant respiratory disease, Percent increase per 10 mSv 4.55 5.66 3.57 SE 279 293 495 LRT, 1 df 2.3 3.2 0.5 Abbreviations: df, degree of freedom; LRT, likelihood ratio test; SF standard error. Adjusted for cumulative dose received before age 45, age, race, sex, birth cohort, employment status, paycode, internal radionuclide monitoring, and the inter- action between race and sex, sex and birth cohort, paycode and birth cohort, and employment status and age. aThere is no race-sex interaction in the model for nonmalignant respiratory disease, and no race-sex or sex-cohort interactions in the model for lung cancer. to expected cancer deaths were tabulated by categories of cumulative dose received after 45 years of age under 5-, 10-, and 20-year lag assumptions (Table 5). This table also pro- vides a description of the distribution of per- son-time and deaths by level of cumulative external radiation dose received after age 45. The ratio of observed to expected deaths tenided to increase with increasing dose received after age 45 for each of the three cat- egories of death examined (Table 5). As longer lag assumptions were evaltiated and deaths and personi-years shifted to lower ctitnulative dose groups, the ratio of observed to expected deaths tended to increase for the higllest cumulative dose categories. Discussion Epidemiologic studies of badge-monitored workers in the nuclear industry provide a potenitially important source of evidence ahbott the healtlh effects of low-level expo- sure to ionizing radiation. Studies of work- ers employed at the ORNL allow examina- tion of a cohort with a long duration of fol- loss-up, nearly complete external radiation dosimetry records, and a high level of vital status followt-up. Previotis analyses determined that, over- all, workers at the ORNI have low mortality rates in compaison to the general population (8,12). This observation is consistent with other studies of DOE workers and typical of mortality patterns for well-paid, highly edu- cated workers in the United States (25). An exception to the low overall mortality rates among ORNL workers as compared to the general population, however, is the observed excess mortality due to leukemia and ill- defined causes (7,8). Previous investigations of radiation-cancer associations among ORNL workers have focused on white male ORNL workers who were not employed at other DOE facilities. These workers have the most complete radiation dosimetry data and vital status follow-up. In that subcohort, pos- itive associations between cumulative whole- body ionizing radiation dose and mortality, primarily due to cancer, were reported with follow-up through 1984 (8). Subsequent analyses of that subcohort reported that asso- ciations between radiation dose and cancer mortality were primarily due to radiation doses accrued at older ages (10, 11,24). In this paper, we examine an expanded cohort of ORNI workers, with follow-up through 1990. Given this expanded cohort and additional period of follow-up, these analyses include twice as many deaths as pre- vious reports on radiation-cancer associations Volume 107, Number 8 August 1 999 * Environmental Health Perspectives 652 Articles * Radiation and mortality of workers at ORNL Table 5. Ratio of observed to expected deaths for cancer causes of death and observed deaths (shown in parentheses) by lag period and grouped dose received after the age of 45 years. Dose received after age 45 Cause of death 0 mSv 0-20 mSv 20-40 mSv 40-60 mSv 60-80 mSv 80-100 mSv 100+ mSv All cancer 5-year lag 0.99 0.96 1.12 1.24 0.83 1.26 1.88 (561) (237) (32) (17) (8) (5) (19) 10-year lag 0.99 0.97 0.99 1.09 1.18 0.92 2.22 (593) (217) (25) (13) (10) (3) (18) 20-year lag 1.00 0.91 1.35 0.78 1.03 3.27 2.68 (703) (135) (20) (5) (4) (5) (7) All cancer except lung 5-year lag 0.99 0.99 0.97 1.22 0.78 0.78 1.88 (411) (174) (19) (11) (5) (2) (12) 10-year lag 1.00 0.97 0.94 1.16 1.08 0.47 2.14 (436) (155) (16) (9) (6) (1) (1 1) 20-year lag 1.00 0.93 1.29 0.70 0.37 3.70 2.76 (508) (100) (13) (3) (1) (4) (5) Lung cancer 5-year lag 0.98 0.90 1.43 1.27 0.92 2.08 1.85 (150) (63) (13) (6) (3) (3) (7) 10-year lag 0.98 0.96 1.09 0.96 1.37 1.73 2.33 (157) (62) (9) (4) (4) (2) (7) 20-year lag 1.01 0.83 1.51 0.98 2.54 2.25 2.57 (195) (35) (7) (2) (3) (1) (2) Person-years 387,873 31,881 27,497 1,228 748 323 686 1 0-year lag Adjusted for age, race, sex, birth cohort, employment status, paycode, internal radionuclide monitoring, and the interac- tion between race and sex, sex and birth cohort, paycode and birth cohort, and employment status and age. among white male ORNL workers followed through 1984 (8). With these data we inves- tigated associations between age-specific cumulative radiation doses and cause-specific mortality. Cumulative doses received after age 45 were associated with all cancer mortal- ity under a range of lag assumptions and were associated with lung cancer mortality as well as mortality from cancers other than lung cancer (Table 4). We evaluated age at exposure using a single critical age value. However, this should not be interpreted as suggesting that sensitivity to radiation changes abruptly at a particular age. Previous analyses demonstrat- ed that the magnitude of association between cancer mortality and external radia- tion dose increased as critical ages between 40 and 55 years were considered (11,24), although age 45 yielded the best fitting model. In these analyses, there was little evi- dence of associations between cancer mortal- ity and doses accrued at younger ages (Table 3). This may be a consequence of smaller magnitude associations between radiation doses accrued at younger ages and cancer mortality; additionally, selection of young, healthy workers into jobs with higher radia- tion exposures due, for example, to occupa- tional health screening might have led to a downward bias in dose-response associations for exposures accrued at younger ages. Although this study included more work- ers than previous studies of radiation-cancer associations among ORNL workers, the study still had a limited ability to examine associations between radiation and many specific cancers, in part because of the cross- classification of events by younger and older age exposures. Consequently, these analyses focused on all cancer, lung cancer, and all cancers except lung cancer because there were adequate data to support investigations of dose-response associations for these causes of death. Leukemia mortality, while of potential interest, occurred too infrequently in this cohort to allow investigation of associations with radiation doses received after 45 years of age; only one leukemia death was observed among workers who received > 40 mSv cumulative dose after age 45 (24). Radiation-cancer associations may differ between men and women; however, there were insufficient data to evaluate differences in radiation-cancer associations between male and female workers in this cohort. These analyses included 3,389 women, among whom 129 deaths due to cancer were identified (Table 2). Deaths occurred primar- ily among weekly paid women who tended to have relatively low cumulative recorded external radiation doses. We considered sepa- rate analyses of radiation-cancer associations among women; however, only 16 cancer deaths occurred among women with cumula- tive external doses of ? 10 mSv, and there was only one cancer death among women who received > 50 mSv. We examined demographic and employ- ment variables in these analyses for two reasons: to investigate whether mortality pat- terns for workers in this occupational cohort conformed to expectations from the epi- demiologic literature, and to adjust for potential confounding of radiation-mortality associations. Given observations of changes in age-specific cancer mortality rates between historical periods, we adjusted for potential confounding by birth cohort. We examined paycode as a measure of socioeconomic sta- tus; workers who were paid monthly tended to be employed in higher socioeconomic jobs, whereas workers who were paid either hourly or weekly were typically employedf in lower socioeconomic status jobs. We adjusted for employment status in order to evaluate potential confounding due to health-related selection of people out of the workforce (described as a "healthy worker survivor effect") (19,21). Some previous analyses that examined data for ORNL workers did not adjust for employment status (23,26). Dropping the employment status terms from our model yielded an estimated 5.36% (SE = 1.46) increase in all cancer mortality per 10 mSv cumulative dose received after 45 years of age under a 10-year lag, as compared to the 4.98%/10 mSv estimate derived after adjustment for employment status (Table 4). We found that with the exception of age at risk, adjustment for these demographic and employment factors exerted little influence on our estimates of associations between external radiation dose and cancer mortality. For the ORNL workers included in this study, there was little quantitative informa- tion about individual exposure to agents other than external ionizing radiation. There is the potential for confounding, or modifi- cation, of radiation-mortality associations by chemical and internal radionuclide expo- sures. In previous analyses of white male ORNL workers, however, neither examina- tion of job titles, which were used as an indi- cator of occupational exposures other than external ionizing radiation, nor evaluation of potential exposure to beryllium, lead, and mercury substantially changed estimates of the association between radiation and cancer mortality (9). Although data from internal exposure monitoring provided only a poor indicator of exposure from internally deposited radionuclides, radionuclide conta- mination was not considered to be a major hazard among workers at the ORNL. Cigarette smoking has also been consid- ered as a possible confounder of radiation- cancer dose-response relationships at the ORNL (8,27,28). Historical smoking data were not available for these workers; conse- quently, we evaluated the plausibility of con- founding by cigarette smoking indirectly. Radiation dose-response relationships were compared between causes of death with dif- ferent magnitudes of association with smok- ing (8,27-29). Lung cancer is the primary component of associations between smoking and cancer mortality; the excess relative risk Environmental Health Perspectives * Volume 107, Number 8, August 1999 653 Articles * Richardson and Wing for smoking and lung cancer is approximately one order of magnitude greater than for smoking and other cancers (14). If cigarette smoking were positively associated with radia- tion dose, observed associations between radi- ation and lung cancer would be much larger than associatjons between radiation and can- cers other than lung cancer. However, we found that radiation-cancer dose-response associations were not substantially stronger for lung cancer than for other cancers; in fact, the radiation-cancer dose-response relation- ship was of smaller magnitude for lung cancer than for other cancers under a 20-year lag assumption (Table 4). Among other smok- ing-related causes of death, associations with radiation doses received after the age of 45 years were positive for nonmalignant respira- tory disease and negative for ischemic heart disease, but imprecise in both cases (Table 4). These findings, which provide little sugges- tion of confounding by cigarette smoking, conform to expectations from the literature. General discussions about occupational epi- demiology studies that use internal rather than external referent groups (29,30), empiri- cal investigations in other worker studies (31-33), and simulations (34) suggest that confounding by cigarette smoking would be "relatively modest in most situations"(34). In addition, if smoking is the reason for the observed associations, smoking patterns would have to be positively associated with cumulative doses received at older ages, but not associated with cumulative doses received at younger ages. Furthermore, this age at exposure-related association must occur with- in strata of age at risk, sex, birth cohort, pay- code (a marker of socioeconomic status), and period of hire (9,24). This study used annual external ionizing radiation dosimetry records as a measure of the primary exposure of interest. A substantial amount of attention has been given to evalua- tions of ORNL dosimetry data. While the external dosimetry records for ORNL workers are relatively complete, attention has been given to the issue of missing annual external dosimetry records. As an alternative to the assumption that values for missing annual external dosimetry records were zero, we esti- mated doses for years of employment at ORNL with missing records (15). Attention has also been given to potential underestima- tion of doses due to the practice of recording zeros for dosimetry readings that were less than the minimum detectable level of the dosimeters used at the ORNI (6,35-37). However, in previous evaluations of an adjustment method for dose underestimation, little influence on dose-response estimates was found (12). Current understanding of the biologic processes involved in carcinogenesis supports the conclusion that age at exposure may play an important role in modifying radiation- cancer associations (38-41). Ionizing radia- tion is a well-established carcinogen known to cause aberrations and point mutations in human chromosomes (2). Fortunately, the body has mechanisms for identifying and destroying damaged cells, and mechanisms for repairing radiation-induced damage to clhromosomes (2). However, with increasing age, the accuracy and efficiency of these cel- 1lular-repair processes, and of immune responses, declines (42-45). This is one rea- son why associations between radiation doses and cancer might be larger for ionizing radia- tioni doses received at older ages. Theoretical models of a multistage process of carcinogen~ esis also suggest that the effect of a carcino- genic exposure may depend upon the age at which exposure was received (38,46). The conclusion that sensitivity to exter- nal ionizing radiation increases with age among adults, however, is at odds with con- clusions drawn from the Life Span Study (LSS) of atomic bomb survivors, which has played an influential role in radiation risk estimation (2,47). When considering atomic bomb survivors who were adults at the time of the attack, radiation-cancer associations show different trends with age at exposure for different causes of death. The excess rela- tive risk for cancers of the trachea, bronchus, and lung has been reported to increase with older age at exposure (4/), and the excess risk for leukemia was larger for atomic bomb survivors who were over 40 years of age at the time of bombing than for adults 20-40 years of age (48). In contrast, associations between radiation and breast cancer, for example, have been reported to decline sub- stantiallv with age at exposure in the LSS (47); similar findings have been reported in stuidies of medical irradiation (49). Such observations suggest the need to consider variation in patterns of radiation risk with age at exposure by cancer type. This study of ORNL workers provided insufficient data to examine radiation-cancer associations sepa- rately for many types of cancer. There are also other possible explanations for differ- ences in findings between the LSS and this study. This study of ORNL workers investi- gates the effects of long-term, low-level external radiation exposure among relatively healthy workers. In contrast, it has been sug- gested that patterns of selective survival fol- lowing acute high-level radiation exposure may have obscured evidence of age-related differences in radiation sensitivity among atomic bomb survivors. Mortality due to the acute effects of the atomic bombing (from radiation exposure, as well as physical injuries from the explosion and environmental depri- vation) among residents in Hiroshima and Nagasaki, Japan, may have led to selective survival and a lack of comparability in sensi- tivity to the carcinogenic effects of ionizing radiation between the higlher and lower exposed sirvivors (50-52). Some previous studies of workers exposed to low-level ionizing radiation haxvc shown no evidence of differences in radia- tion-mortality associations with age at expo- sure (23,26), whereas othei- stLudies have reported stronger dose-response associatiolns with older ages at exposure (10,11,45,-53). When contrasting findings from this stud) of ORNL workers with other studies, it is important to recognize the differences in the patterns of exposure, study populations, sources of data, and follow-up. Thlis study includes 14,095 workers; although this is a sizable epidemiologic cohort, the sstudy includes substantially fewer people than recent pooled analyses of nuclear workers (12,26,53). However, althoLIgh a larger sam- ple size increases the precision of risk esti- mates, it does not reduce bias. Inclusion of a large number of workers with incomplete or inaccurate exposure informationi, for exanm- plc, may produce biased findings rather than increase the abilitv of a studv to detect an associatioin. OneC recent pooled analysis of DOE workers suggested that pooling ORNI. cohort data with data for the Oak Ridge Y- 12 facility could obscure radiation-mortality associations because exposure informatioil was less complete for Y-12 workers (12). In occupational cohort studies of nuclear work- ers at several DOE facilities, Stewart and Kneale (4i5, 53) reported that the magniitde of radiation-cancer associations iincreased with older age at exposure. Stewart and Kneale (45,53), however, also reported that evidence of heterogeneitv in radiation-can- cer associations between cohorts suggests that pooling data may be inappropriate. In a study that pooled data from four uraniunm processing facilities, Dupree et al. ( 54) also reported that positive associations betweeni external radiation and ling cancei were observed only among workers first hired after 45 years of age. An estimated 600,000 workers have beena employed by the DOE (55), with millions more people worldwide exposed to low-level ionizing radiation through occupational and environmental releases from commercial nuclear facilities and medical and industrial sources. Recent initiatives to fund indepen- dent investigations into the health effects of low-level radiation, to provide more open communication aboLit research findings, to allow public access to epidemiologic data, and to offer information about environmen- tal sources of radiation exposLire are intend- ed to help open discussions and increase puiblic participation in decisions about the Volume 1 07, Number 8, August 1999 * Environmental Health Perspectives 654 Articles * Radiation and mortality of workers at ORNL uses of nuclear technologies (55-57). The data used in these analyses are publicly avail- able via the Comprehensive Epidemiological Data Resource (57). This is encouraging- because the involvement of labor organiza- tions and community groups in epidemio- logic research, in the scrutiny of findings, and in the use of studies for advocacy has been central to achieving the public health goals of occupational and environmental protection (58,59). While there are acknowledged limita- tions to the available data for studying work- ers in the nuclear industry, such studies offer one approach to addressing concerns about long-term, low-level exposures to ionizing radiation that are typical of occupational and environmental settings (60). The magni- tudes of the radiation-cancer associations observed in these analyses are substantially larger than estimates derived from the LSS; these differences are important to consider because the LSS has served as a quantitative basis for current radiation protection stan- dards (2,4). The observed effect of age at exposure in these analyses suggests that fur- ther attention should be given to factors that influence sensitivity to the carcinogenic effects of ionizing radiation. A more com- plete understanding of the effects of ionizing radiation exposures, however, also requires consideration of a wider range of health out- comes. Although exposures received at older adult ages may be important for cancer mor- tality, exposures received at younger ages may be important for other biologic effects of ionizing radiation (such as nonfatal dis- eases and reproductive effects). A better understanding of variation in radiation sensi- tivity among individuals, and investigations of other potential biologic effects of radia- tion exposure, should inform and support efforts to protect workers' health and to minimize unnecessary environmental expo- sures to ionizing radiation. REFERENCES AND NOTES 1. 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