Cancer Risks and Low-Level Radiation in U. S. Shipyard Workers

Transcription

1 J. Radiat. Res., 49, (2008) Lecture Note Cancer Risks and Low-Level Radiation in U. S. Shipyard Genevieve M. MATANOSKI*, James A. TONASCIA, Adolfo CORREA-VILLASEÑOR, Katherine C. YATES, Nancy FINK, Elizabeth ELLIOTT, Bruce SANDERS and Deborah LANTRY US nuclear workers/cancer mortality/low dose radiation/epidemiology. The risks for four cancers, leukemia, lymphopoietic cancers (LHC), lung cancer and mesothelioma, were studied in workers from shipyards involved in nuclear powered ship overhauls. The population represented a sample of all workers based on radiation dose at study termination. The final sample included 28,000 workers with, 10,462 workers with and 33,353 non-nuclear workers. Nuclear workers had lower mortality rates for leukemia and LHC than US white males but higher rates of lung cancer and a significant five-fold excess of mesothelioma. Dose-dependent analyses of risks in the high exposure group indicated that for each cancer the risk increased at exposures above 10.0 msv. An internal comparison of workers with 50.0 msv exposures to workers with exposures of msv indicated relative risks for leukemia of 2.41 (95% CI: 0.5, 23.8), for LHC, 2.94 (95% CI: 1.0,12.0), for lung cancer, 1.26 (95% CI: 0.9, 1.9) and for mesothelioma, 1.61 (95% CI: 0.4, 9.7) for the higher exposure group. Except for LHC, these risks are not significant. However, the increasing risk with increasing exposure for these cancers, some of which are known to be related to radiation, suggests that low-level protracted exposures to gamma rays may be associated with these cancers. Other agents such as asbestos, which are common to shipyard work, may play a role especially in the risk of mesothelioma. Future follow up of the population would identify bounds on radiation risks for this population for comparison with similar risks estimated from other populations. INTRODUCTION The Japanese Atomic Bomb survivors have provided most of the current knowledge concerning the risks from exposure to external radiation. 1 3) Risks from fractionated long-term radiation exposures have been studied in underground uranium miners, but these exposures are limited to alpha particle radiation with lung cancer as the primary health outcome. 4 7) For the Japanese population risks are determined *Corresponding author: Phone: , Fax: , gmatanos@jhsph.edu Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 111 Market Place, Suite 850, Baltimore, MD , U.S.A.. This paper was presented on October 15, 2003, at the International Symposium Health Effects of Low Dose Radiation on Cancer Risk organized by Low Dose Radiation Research Center, Central Research Institute of Electric Power Industry, Tokyo. Lecture notes were assembled by K. Ishida, K. Sakai, and H. Tanooka and the paper rewritten by the author. The study described in this document has been reviewed and approved by the Committee on the Review of Use of Data from Human Subjects of the Johns Hopkins School of Public Heath. doi: /jrr from estimated exposures at a single point in time based on location of individuals in relation to the radiation source. For the uranium miners, risks are derived only from estimated exposures based on time spent in the mines. Scientists have questioned whether cumulative doses of gamma radiation based on one or a few high exposures versus multiple low exposures over extended time periods as occur in occupations are equivalent in terms of cancer risks. Recent research has suggested that perhaps low doses of radiation may act on cells in a different way than high dose exposure. 8 12) In addition, if doses based on low versus high dose rate exposure are not equivalent, then examining the risks associated with different external radiation exposure scenarios in populations other than the Japanese would be important. Approximately 30 years ago, the Department of Energy with the cooperation of the Navy undertook a study of shipyard workers in eight Navy and private shipyards that were involved in overhaul of nuclear vessels. The National Institute of Occupational Safety and Health (NIOSH) also undertook a study of one of these yards. The initial NIOSH report showed no risk of leukemia associated with radiation exposures 13) but a longer follow up has indicated that radiation exposures are associated with an increased risk of leukemia mortality. 14)

2 84 G. M. Matanoski et al. BACKGROUND The nuclear workers in shipyards differ from many radiation-exposed workers in that their jobs are not directly related to working with a radiation source as do radiological technicians for example. They are exposed incidentally to radioactive materials when carrying out tasks related to their trades because the materials they handle have become radioactive. For example, plumbers working on pipes and other materials that receive coolant water from the reactor are exposed. Other workers performing the same job in other parts of the ship remote from the reactor have little or no exposure. The source of exposure for shipyard workers is from neutron-activated corrosion products in the coolant system. The major effective radiation exposure is to cobalt-60 (half-life 5.3 years), which decays with 1 low energy beta emission and 2 high energy gamma rays. The dosimetry database of the Navy also includes as part of the monitoring program, a small number of radiographers and medical personnel who may have had different radiation exposures. A second important characteristic of the shipyard population is that individual exposures have been measured from the first overhaul. Members of the radiation safety program continuously monitor workers for compliance with both wearing and positioning of badges or dosimeters. Therefore, this shipyard population has measured exposures for each individual for the entire period of overhauls. In summary, radiation exposure among shipyard workers is associated with specific trades and areas worked within the ship during overhaul. This exposure occurs at varying low dose levels over time and a comprehensive monitoring program provides dosimetry data for all individuals. Thus, this population provides a unique opportunity to study low dose exposure to gamma radiation over a prolonged period of time. The current article includes the early analysis of the mortality of workers through January 1, These preliminary reported results completed in the late 1980s include data from only seven shipyards and for only four selected cancers that were examined in detail. These cancers were selected because of their suspected association with radiation and asbestos exposure. The results summarize the data reported to the U.S. Department of Energy in the early 1990s. METHODS AND POPULATION Study population The initial population represented all employees in eight shipyards and consisted of about 800,000 workers, 700,000 of whom were non-nuclear workers, as seen in Table 1. The roster of workers was established from all records of employees in each shipyard. Most workers in the nonnuclear group were excluded because they had completed employment before the start of nuclear overhauls, which represented the beginning of potential radiation exposure for most jobs. Radiation exposed workers were defined as all workers certified to work in areas having potential exposure to radioactivity at some time from the start of the nuclear ship overhauls and who had an employment record and a dosimetry record on the radiation database. Since women and African-Americans represented a very small number of the population of nuclear workers, their data were excluded from analysis. Follow up of all workers in one shipyard was not complete at the time of analysis and so all data for that yard were omitted from the preliminary analysis. workers considered comparable to the nuclear workers were defined as all persons employed at any time during overhauls of nuclear vessels in each shipyard who were not considered certified to work in areas with potential radiation. Since this population of 77,000 nuclear and 117,000 non-nuclear workers represented a large group, follow up was limited to a stratified random sample of the group. The final sample included all nuclear workers with lifetime exposures in the shipyard of 5.0 msv or more at the time of death or end of Table 1. Population for Study Initial Population 35,079 71, ,612 Study Population 28,060 49, ,718 Stratified Random Sample 28,000 10,462 33,353 Person-years of follow-up* 356, , ,070 Median age at entry to follow-up Median year at entry to follow-up * Unconfirmed deaths omitted from analysis. Includes data from seven shipyards only.

3 Cancer Mortality in Shipyard 85 follow up on January 1982 (28,000), about 20% of nuclear workers with lifetime exposures below that dose (10,462), and about 30% of non-nuclear workers (33,353). Additional exclusions included military personnel and workers with employment for less than 1 year. 13) Exposure assessment Nuclear ship overhauls began at different times in each of the eight shipyards from 1957 through 1967 but similar radiation monitoring programs were started in each shipyard with initial overhaul. The monitoring techniques to determine exposures of individuals differed during the period of follow up. Exposures were measured initially using film badges with open and closed windows to record both beta and gamma radiation. However, the population rarely received recordable beta radiation. The badges were read monthly. The minimum detectable effective dose was estimated to be 0.1 msv. In 1973 to 1974, all shipyards converted to thermal luminescent dosimeters (TLDs) that were read daily. The new procedure led to a reduction in all annual doses due to the limitation of measuring low doses in the minimum detection range when cumulated doses are fractionated into daily rather than monthly readings. The actual recorded radiation exposure for each worker was used to represent the effective dose of cobalt 60 without adjustment for differences in potential detection level with different devices, differing procedures over time or other potential sources of exposure to radiation such as medical x-rays. The radiation records were obtained from a database available from the Navy. The information was validated on a random sample of individual records using the workers medical records where dose was recorded independently. The effective dose was used to define the samples and, thus, was used in the analysis for consistency in reviewing all cancers. Organ doses will be considered for any future analysis. The yards require constant monitoring of each worker for compliance in wearing dosimeters. They also conduct continuous air monitoring programs to detect air releases of radiation. Routine surveillance procedures include external and internal reviews to validate the accuracy of dosimeter measurements using standard exposures. 15) The annual and cumulative measurements of radiation exposures from monitoring were available for each nuclear worker from the start of overhaul to end of follow up on January 1, Study sample The study sample was selected to be similar in distribution to the characteristics of the group in regard to birth year, hire year, total duration worked, duration of pre-nuclear work and job hazard index. Simultaneous adjustment for these time factors during the sample selection resulted in a carefully balanced population in regard to time of exposures. The job hazard index was not intended to control for specific shipyard exposures but was used as a stratification variable to control for general industrial exposures among the three exposure groups. The hazard index score was developed for each job through a unique procedure that ranked all jobs based on the overall exposure to hazardous substances for that job. A team of industrial hygienists with experience in the shipyard environment were polled until they reached a consensus agreement on the hazard score for each job. For example, the jobs that represented three or more percent of the workers and were included in the high rank level were welder, painter and pipefitter. In this scheme a job hazard index is not determined from a single agent but from many possible hazardous agents. This stratification variable was required for the entire population of nuclear and non-nuclear workers for purposes of sampling. The only job records that could be abstracted efficiently in order to assign a hazard score from such a large number of records (about 200,000) was the last job held. Thus, each individual was ranked based on his last job. Since most shipyard jobs represent skilled trades, this classification procedure was deemed appropriate since most workers remain in one trade throughout their shipyard employment. Pre-nuclear work periods represented the time employed prior to the start of dosimetry records for individual nuclear workers. In order to balance the groups for the duration worked before starting nuclear work, a pseudo pre-nuclear period was developed for each non-nuclear worker by creating a subgroup of these workers that were similar to the subgroup for the other four variables. Then the non-nuclear workers were assigned a pseudo pre-nuclear work variable, which represented a duration of pre-nuclear work that was the same or greater than the distribution of that variable in the comparable nuclear reference group. Since 40 percent of nuclear workers were recruited into the radiation program after five or more years of employment, inclusion of the pseudo prenuclear work time variable assured that the non-nuclear worker group had the same long employment prior to radiation start as did the nuclear workers. This avoided any survival bias that might occur in nuclear workers related to the fact that they were actively working at recruitment into radiation work. As seen in Table 2, the three exposure categories were not similar based on the five strata characteristics before selection of the sample. workers had increased proportions in the older and younger age groups, more recent years of hire, jobs with lower hazard indices and shorter durations worked. After random selection of the samples from the nuclear worker group at and the nonnuclear workers, all three groups were similar in all characteristics (Table 3). Although jobs were not directly compared in the three groups, all nuclear compared to non-nuclear workers initially did have some differences in the distribution of jobs based on last job title. Jobs were divided into 49 occupational title codes as well as 21 prefix codes, the latter representing a

4 86 G. M. Matanoski et al. Table 2. Characteristics of Study Population by Sampling Strata, Birthyear, Year of Hire, Job Hazard Index, Duration of Pre-nuclear Work and Total Duration Worked* NW 5.0 NW < 5.0 NNW (N = 28,542) (N = 49,635) (N = 119,179) Variable No. % No. % No. % Birthyear < Year of Hire < Job Hazard Index Missing Low Medium High Duration of Pre-Nuclear Work 0- years N/A N/A 2- years N/A N/A 5- years N/A N/A 10- years N/A N/A 20+ years N/A N/A Total Duration Worked 0- years years years years years *Includes data from eight shipyards Table 3. Characteristics of Random Sample by Strata, Birthyear, Year of Hire, Job Hazard Index, Duration of Pre-Nuclear Work and Total Duration Worked NW 5.0 NW < 5.0 NNW (N = 28,542) (N = 10,462) (N = 33,353) Variable No. % No. % No. % Birthyear < % % % % % % % % % % % % % 794 8% % Year of Hire < % % % % % % % % % % % % Job Hazard Index Missing % 547 5% % Low % % % Medium % % % High % % % Duration of Pre-Nuclear Work 0- years % % % 2- years % % % 5- years % % % 10- years % % % 20+ years % % % Total Duration Worked 0- years 870 3% 537 4% % 2- years % % % 5- years % % % 10- years % % % 20+ years % % % skill or responsibility level (e.g. foreman). The differences in the distribution of jobs between nuclear and non-nuclear workers were small and would have been partially controlled by the stratification on the hazard index (Table 4). A review of prefix codes indicates that, in general, the nuclear workers have a higher percentage of foremen, inspectors and planners among these titles compared to non-nuclear workers whereas the latter group have more worker and help-

5 Cancer Mortality in Shipyard 87 Table 4. Distribution of Selected Last Occupational Title Codes* for in Four Shipyards Based on Radiation Status (N = 24130) (N = ) Significant Job Title* N % N % at p < = Electrician NS 8 Engineer S 23 Laborer S 25 Machinist NS 30 Nuclear Engineer S 35 Pipefitter S 37 Rigger NS 42 Shipfitter S 47 Welder S 88 Administrative S *Specific job titles are included if they represented four percent or more of jobs for either nuclear or non-nuclear worker. er classifications. (Data are not shown.) As shown in Table 4, among the specific job titles that represent at least four percent or more of the distribution of job titles of either nuclear or non-nuclear workers, three were significantly higher in nuclear and four in non-nuclear workers with the remaining three jobs equally distributed in the two groups. The most important differences may be the higher proportion of pipefitters among nuclear workers and the higher proportion of shipfitters and welders among non-nuclear workers. Thus, even after balancing the populations by job hazard index, the nuclear workers could differ from nonnuclear workers in regard to exposure to other agents common in shipyards. Follow up of population Multiple data sources were searched to determine the vital status of each worker including Social Security Administration files, Civil Service Administration files, Health Care Financing Administration (HCFA) files, Virginia mortality files and the National Death Index. All of these files could determine whether a worker was deceased. In addition, Social Security, HCFA, and Civil Service Administration had separate files that could determine whether the enrollee was alive. All shipyard workers who were current employees at any time during the final year of the study were classified as alive if there was no confirmation of a death from a death certificate. Vital status, either living or deceased, was determined on all but four percent of the workers. Follow up was not complete for one shipyard at study termination and all data on those workers are excluded from the analysis. The outcomes were determined from underlying causes of death listed on death certificates with confirmation of the diagnoses of selected cancers through review of hospital records and cancer registry databases. The cancers in the current analysis do not reflect the results of these hospital records searches. Since the U.S. data used for comparison consisted of death certificate information only, the same data had to be used for causes of death for the shipyard workers in order to be comparable. Hospital records were used only to verify the accuracy of the death certificates. For these cancers this verification process confirmed that virtually all death certificate results were accurate. The study team obtained death certificates on over 99 percent of the suspected deaths from the four specific cancers. Analysis Two independent analyses were performed on the data. First, a categorical analysis was performed using three lifetime cumulative dose groups defined as cumulative dose at death or study termination corrected by age and calendar time to US white male rates. A second dose sensitive analysis using the Life Table method 16) was performed on workers with lifetime exposures of 5.0 msv or more. For this analysis, the risk of cancer deaths for each individual at each dose they experienced at a specified age and calendar time period was compared to the risk in the 5 9 msv reference population using the same adjustment methods. This time dependent analysis results in all individuals with high cumulative doses adding person-years to all lower dose groups included in the time dependent analysis although they would not have an event at the lower doses. The group with < 5 msv could not be used as a reference because that group was excluded from the time dependent analysis. Since the category of was a sample of all workers with a final dose of that level and since the multistrata sampling was complicated making it impossible to reconstruct the original population from the sample, this group could not be included as part of the dose, age and calendar time dependent analysis. Adding person-years from the 5 msv or more population to a sample of the < 5 msv group would have inflated the person-years in the < 5 msv exposure group and artificially lowered the risk in this group. The risks were analyzed with lagging for different exposure periods. This adjustment excludes any radiation exposure during a specified lag period from the worker s exposure for the person years or events accrued in that period. Thus, the cumulative person-years and any events occurring at any point in the follow up are attributed to the cumulative radiation dose to that time minus any dose accrued during the lag period. The lag periods included no lag and 2, 5, 10, and 15 years. The short lag period represented the time when first cases of leukemia reportedly have appeared after exposures to a known leukemogen. The longer lag periods were included to represent possible latency periods of solid tumors. However, the

6 88 G. M. Matanoski et al. number of workers with 10 or more years of follow up was limited since the median follow up period for all workers was 13 years. Therefore, the analysis reported includes only a lag of two years for leukemia and five years for all other cancers as well as the analysis with no lag. RESULTS Four cancer sites were selected for initial analyses because of their potential association with either radiation or asbestos exposure: leukemia, lymphoma and hematopoetic cancers, lung cancer and mesothelioma. For each cancer, the upper portion of the Tables 5 9 represents the overall categorical results by lifetime radiation exposure status and the lower portion represents the calendar time, age and dose dependent Life Table analysis of the complete 5.0 msv or more population. The all cause mortality ratios, as shown in Table 5, indicate that the risk of death in shipyard workers is equal to or lower than that of US white males. However, only in the two nuclear categories are the risks significantly lower than the general population. The relative risks for all outcomes are higher in both nuclear workers at and non-nuclear workers than in the reference category of nuclear workers with doses of 5.0 to 10.0 msv. In the dose dependent analysis with a lag of five years, the risk increases with increasing dose. This increase, even at the highest dose, is not Table 5. Age-adjusted All Cause Mortality by Radiation Group Table 6. Age-adjusted Leukemia Mortality by Radiation Group Deaths SMR % CI (0.56,1.39) (0.11,1.07) (0.65,1.39) No Lag Lag 2 years Nuclear Risk 95% CI Risk 95% CI 10.0-* 2.63 (0.6,24.2) 3.05 (0.7,27.8) 50.0-* 2.41 (0.5,23.8) 2.29 (0.4,23.2) Nuclear 1.02 (0.2,11.3) 1.07 (0.2,11.9) 2.37 (0.6,20.5) 2.54 (0.6,21.9) *Dose dependent analysis (Reference msv) Table 7. Age-adjusted Lymphatic and Hematopoietic Cancer Mortality by Radiation Group Deaths SMR % CI (0.73, 0.79) (0.76, 0.86) (0.97, 1.03) No Lag Lag 5 years Nuclear Risk 95% CI Risk 95% CI 10.0-* 1.10 (0.89,1.23) 1.08 (0.96,1.22) 50.0-* 1.03 (0.91,1.16) 1.13 (0.99,1.30) Nuclear 1.13 (1.01,1.26) 1.15 (1.02,1.30) 1.39 (1.26,1.53) 1.39 (1.24,1.55) *Dose dependent analysis (Reference msv) Deaths SMR % CI (0.61, 1.08) (0.28, 0.91) (0.88, 1.37) No Lag Lag 5 years Nuclear Risk 95% CI Risk 95% CI 10.0-* 3.23 (1.1, 12.6) 5.84 (1.5, 50.8) 50.0-* 2.94 (1.0, 12.0) 5.37 (1.2, 48.7) Nuclear 1.71 (0.57, 7.2) 2.95 (0.6, 27.4) 3.58 (1.3, 13.5) 5.63 (1.5, 47.5) *Dose dependent analysis (Reference msv)

7 Cancer Mortality in Shipyard 89 Table 8. Age-adjusted Lung Cancer Mortality by Radiation Group Deaths SMR % CI (0.94, 1.21) (0.90, 1.35) (1.02, 1.29) No Lag Lag 5 years Nuclear Risk 95% CI Risk 95% CI 10.0-* 1.08 (0.8, 1.6) 1.05 (0.7, 1.6) 50.0-* 1.26 (0.9, 1.9) 1.36 (0.9, 2.1) Nuclear 1.16 (0.8, 1.7) 1.25 (0.9, 1.9) 1.21 (0.9, 1.7) 1.22 (0.9, 1.7) *Dose dependent analysis (Reference msv) Table 9. Age-adjusted Mesothelioma Mortality by Radiation Group Deaths SMR % CI (3.03, 8.08) (2.48, 11.33) (1.16, 4.43) No Lag Lag 5 years Nuclear Risk 95% CI Risk 95% CI 10.0-* 1.21 (0.3, 9.1) 1.24 (0.3, 7.2) 50.0-* 1.61 (0.4, 9.7) 1.50 (0.3, 9.2) Nuclear 1.45 (0.4, 8.5) 1.31 (0.3, 7.8) 0.61 (0.2, 3.4) 0.57 (0.1, 3.3) *Dose dependent analysis (Reference msv) significant. The leukemia risk by lifelong exposure category indicates that the highest mortality ratio compared to U.S. white males occurs in non-nuclear workers as seen in Table 6. Although all ratios indicate risks below that of the general population of US white males, comparison of the low and high radiation exposure in categorical groups indicates a leukemia mortality that is two times higher in the group with highest lifetime exposures compared to the low exposure group. In the dose dependent analysis shown in the lower portion of the table, there is a suggestion of an increase in risk with dose but the relative risks in each dose group are non-significant due to small numbers. The risk of leukemia for workers with doses of 50 msv or more is 2.41 (95% CI: 0.5, 23.8) times higher than the reference category of msv. The numbers by cell type are too small for analyses. Myeloid leukemias represent 60 percent of all cases with identified types. The overall mortality from lymphatic and hematopoetic cancers (LHC) including leukemia shown in Table 6 indicates a significantly low LHC death rate for those exposed at compared to US white males with the pattern of SMRs by category that is similar to that for leukemia. The ratio for those in the category is higher than the lowest radiation exposure group. In the dose dependent analysis, the relative risk at 50 msv or more is significantly higher (RR = 2.94; 95% CI: 1.0, 12.0) than risks at 5.0 to 10.0 msv. That difference is even more apparent when the exposures in the last 5 years of follow up before a specific calendar time or event (lag 5 years) are omitted (RR = 5.37; 95% CI: 1.2, 48.7). The lung cancer standardized mortality ratios using the comparison US population for the life long exposure categories indicate little difference in ratio between the three groups as shown in Table 8. All ratios are above 1.00 but only non-nuclear workers have a significantly higher mortality ratio from lung cancer compared to US white males. In the dose dependent analysis, the risk of lung cancer mortality is about 30 percent higher for those receiving 50 msv or more exposure compared to 5.0 to 10.0 msv (RR = 1.26; 95% CI: 0.9,1.9) and there is a suggested dose response for both lag-periods. For the 277 lung cancers with hospital record reviews, data on morphology indicated 36 percent had squamous cell carcinoma, 20 percent had adenocarcinoma, 15 percent had small cell carcinoma and 18 percent had an undifferentiated cell type with smaller percentages of other cell types. Mesothelioma was examined because radiation workers jobs may involve exposures both to asbestos and radiation. The mortality from mesothelioma based on life long categories of radiation exposure indicate that shipyard workers in all groups have 2.4 to 5.8 times higher mortality compared to US white males and that SMRs are 2.1 to 2.4 times higher in the radiation exposed groups compared to the nonexposed (Table 9). The dose dependent comparison of risks

8 90 G. M. Matanoski et al. suggests that the risk of mesothelioma increases with increasing radiation in the group. The dose category of 50.0 msv or more has a RR = 1.6 (95% CI: 0.4, 9.7) compared to the workers with 5.0 to 10.0 msv exposures. None of these observations are significantly different from 1.0 (or no excess risk) due to small numbers in each category. The increases could be related to differences in asbestos exposure that may be correlated with the radiation dose although there is no apparent reason to suggest that this should occur. DISCUSSION involved with overhaul of nuclear powered ships represent an occupational group exposed intermittently to low-level gamma-ray exposure from cobalt 60 while performing their usual jobs. The mortality analysis based on lifetime radiation exposure shows that these nuclear workers with cumulative exposures both below and above 5.0 msv have lower risks of leukemia, lung cancer and LHC than non-nuclear workers. The radiation exposed workers are selected into the program from the group of all shipyard workers primarily on the basis of work performance since one of the shipyard s aims is to complete an overhaul of the reactor area in the shortest time period possible to reduce the total radiation exposure per overhaul. The workers also must complete a physical exam, radiation training and certification prior to being allowed to work in the potentially exposed areas. Thus, selection bias may explain the overall lower SMR of these cancers in nuclear versus non-nuclear workers since healthier and more efficient workers may be selected for radiation training and certification. Mesothelioma risks that are known to be associated with asbestos exposure actually show higher SMRs in nuclear versus nonnuclear workers suggesting there may be differences in exposure to confounding agents, especially asbestos, in nuclear work. For example, Table 4 suggests a higher proportion of pipefitters who have potential asbestos exposure among nuclear compared to non-nuclear workers. The dose dependent data analyses suggest that doses of radiation of 10.0 msv or more are associated with an increased risk of leukemia, LHC, lung cancer and mesothelioma compared to workers with doses of 5.0 to 10.0 msv. For each cancer the risks appear to increase with increased dose but few values except for LHC show significant differences. However, the case numbers are small and only three dose groups are analyzed which limits any use of trend analysis. The small number of deaths can be attributed to the fact that overhauls began between 1957 and 1967 and recruitment of workers ceased at the end of follow up in 1982 resulting in only about 13 years as the median period of observation. The population for study represented three groups that were carefully balanced for several confounding time factors such as age, year of hire and duration of pre-nuclear work as well as a work exposure factor termed the hazard index. However, that hazard factor was not meant to control for specific exposures. Therefore, the increased risk of mesothelioma and lung cancer could have been related to confounding exposures to asbestos and for lung cancer, differences in smoking by radiation exposure also could have played a role in the observed risks. Unfortunately, the smoking habits of all individuals in the study were not available. However, a survey of one shipyard suggested no difference in the ageadjusted rates of ever smokers in nuclear and non-nuclear workers and a lower rate of current smokers in the nuclear groups. Thus, if all shipyards were similar to the one surveyed, smoking could have explained the difference in the higher lung cancer risks in non-nuclear versus nuclear workers. However, smoking differences are unlikely explanations for the increased risks observed in the higher radiation exposed group versus the lower dose reference groups. The data on jobs of workers indicate a higher proportion of pipefitter jobs in nuclear versus non-nuclear workers. Since asbestos is one hazardous agent associated with pipefitting work, one might expect higher rates of mesothelioma in nuclear compared to non-nuclear workers and that is the case (Table 9). However, although jobs may have differed between nuclear and non-nuclear workers, it is less likely that the jobs differed between workers at the various dose levels. Therefore, the increases in risk by radiation dose, even though not significant, suggest that radiation may be playing a role. Further investigation of the joint effects of asbestos and radiation on the risk of mesothelioma has been completed on the total study population by one of the coinvestigators. 17) The results suggest that each agent may independently increase the risk of this cancer. Further adjustment for possible confounding occupational exposures should be included as part of future studies of this population. Stratification on the general hazard index in the study sample should not interfere with the ability to examine specific agents of interest. The only results that conflict with this apparent dose response effect from radiation are that for many of these cancers, leukemia, lung cancer and LHC, the non-nuclear workers have as high a risk as the highest radiation dose. As suggested, a probable explanation for these findings is that selection of workers for the radiation program may introduce a bias that is reflected in inherently low risks of cancer in nuclear versus non-nuclear workers at comparable ages. This phenomenon, which might be termed an enhanced healthy worker effect, results from a two step selection process for nuclear workers. They must be selected to work in shipyards at time of hire (the usual healthy worker effect ) and then they are selected again to become nuclear workers based on health and work performance while employed. Therefore, the analyses of nuclear workers by dose are the most reliable assessment of the potential risks from low dose radiation in this population. Unfortunately, the lowest dose

9 Cancer Mortality in Shipyard 91 of is only analyzed as a category because the sampling strategy was complicated and that group could not be expanded to utilize in dose dependent analysis. The consistency of the finding of an increased risk with increasing dose for each cancer in the dose-dependent analysis is highly suggestive that radiation is associated with the risk of these cancers. In addition, the LHC cancers, which include leukemias and multiple myelomas as well as non- Hodgkin lymphomas, are recognized or suspected to be associated with an increased risk from radiation exposure. These cancers show a significant and very high five to sixfold excess risk in 50 msv or more radiation-exposed workers compared to those in the low dose reference group. Therefore, these data on increasing risks from radiation exposure for LHC support the findings from similar studies in the literature. The consistency of the increase in risk with dose for each cancer and the significantly high risk of LHC associated with radiation doses of 10 msv or more indicate that the shipyard population, which was still very early in follow up at the time of termination of the study, needs to have additional follow up to determine the risks of leukemia, LHC and solid tumors. These early data suggest the workers may have a risk of some cancers from low dose radiation. A precise estimate of risks from nuclear work in this population could be obtained by examining the mortality for all 77,000 nuclear workers in the study population plus additional entrants into the program and extending the follow up to more recent years. The additional data provided could identify the boundaries of the estimates of risks from lowlevel repeated doses of gamma radiation and these results could be compared to risks derived from the Japanese Atomic Bomb survivors who essentially had a single radiation dose. Any future analyses also should adjust the radiation risks for other job exposures. REFERENCES 1. Shimizu, Y., Kato, H. and Schull, W. J. (1990) Studies of the mortality of A-bomb survivors. Mortality, : Part 2. Cancer mortality based on the recently revised doses (DS86) Radiat. Res. 121: Pierce, D. A., Shimizu, Y., Preston, D. L., Vaeth, M. and Mabuchi, K. (1996) Studies of the mortality of atomic bomb survivors. Report 12, Part I. Cancer: Radiat. Res. 146: Pierce, D. A. and Preston, D. I. (2000) Radiation-related cancer risks at low doses among atomic bomb survivors. Radiat. Res. 154: BEIR VI (1988) National Research Council, U. S. A. Health Risks of Radon and Other Internally Deposited Alpha- Emitters. National Academy Press, Washington, D. C. 5. Lubin, J. H., Boice, J. D., Edling, C.,Hornung, R. W., Howe, G. R., Kunz, E., Kusiak, R. A., Morrison, H. I., Radford, E. P., Samet, J. M., Turmarche, M., Woodward, A., Yao, S. X. and Pierce, D. A. (1995) Lung cancer in radon-exposed miners and estimation of risk from indoor exposure. J. Natl. Cancer Inst. 11: BEIR V (1990) National Research Council, U. S. A. Health Effects of Exposure in Low Levels of Ionizing Radiation, National Academy Press, Washington, D. C. 7. UNSCEAR (1993) United Nations Scientific Committee. Sources and Effects of Ionizing Radiation. Report to the General Assembly with Scientific Annex. United Nations, New York. 8. Azzam, E. I., de Toledo, S. M. and Little, J. B. (2001) Direct evidence for the participation of gap junction-mediated intercellular communication in the transmission of damage signals from α-particle irradiated to nonirradiated cells. Proceedings of National Acad. of Sci. 98: Bettega, D., Calzolari, P., Chiorda, G. N. and Tallone- Lombardi, L. (1992) Transformation of C3H 10T1/2 cells with 4.3 MeV α particles at low doses: effects of single and fractionated doses. Radiat. Res. 131: Hei, T. K., Wu, L. J., Lui, S. X., Vannais, D., Waldren, C. A. and Randers-Pehrson, G. (1997) Mutagenic effects of a single and exact number of alpha particles in mammalian cells. Proc. of the Nat. Acad. Sci. 94: Miller, R. C., Marino, S. A., Brenner, D. J., Martin, S. G., Richards, M., Randers-Pehrson, G. and Hall, E. J. (1995) The biological effectiveness of radon-progeny alpha particles. II. Oncogenic transformation as a function of linear energy transfer. Radiat. Res. 142: Miller, R. C., Randers-Pehrson, G., Geard, C. R., Hall, E. J. and Brenner, D. J. (1999) The oncogenic transforming potential of the passage of single α particles through mammalian cell nuclei. Proc. Natl. Acad. of Sci. USA. 96: Stern, F. B., Waxweiler, R. A., Beaumont, J. J., Lee, S. T., Rinsky, R. A., Zumwalde, R. D., Halperin, W. E., Bierbaum, P. J., Landrigan, P. J. and Murray, W. E. Jr. (1986) A casecontrol study of leukemia at a naval nuclear shipyard. Am. J. of Epidemiol. 123: Kubale, T. L., Daniels, R. D., Yiin, J. H., Couch, J., Schubauer- Berigan, M. K., Kinnes, G. M., Silver, S. R., Nowlin, S. J. and Chen, P. H. (2005) A nested case-control study of leukemia mortality and ionizing radiation at the Portsmouth Naval Shipyard. Radiat. Res. 164: Matanoski, G. M. (1991) Health Effects of Low-Level radiation in Shipyard, Final Report, DOE/EV/10095-T2, National Technical Information Service, Springfield, Virginia, U.S.A. 16. Steenland, K., Beaumont, J., Spaeth, S., Brown, D., Okun, A., Jurcenko, L., Ryan, B., Phillips, S., Roscoe, R. and Stayner, L., et al. (1990) New developments in the Life Table Analysis System of the National Institute for Occupational Safety and Health. J. Occup. Med. 32: Correa-Villaseñor, A. (1987). A case control study of mesothelioma in the shipyard industry. Thesis (Ph. D.) Johns Hopkins University. Lecture on October 15, 2003 Received on September 15, 2006 Accepted on July 24, 2007 J-STAGE Advance Publication Date: August 10, 2007