Elizabeth Dupree Ellis

Background: The Rocky Flats (RF) Plant operated from 1951-1989 as part of the U.S. Department of Energy (DOE) nuclear complex. Its primary mission was weapons component fabrication, whereby workers were potentially exposed to radioactive and non-radioactive hazards. RF worker mortality was compared to the general population, and dose-response relationships between mortality and radiation organ doses were examined. Methods: RF workers first employed between 1951 through 1979 for ≥30 days were identified (n=9,397). Vital status was determined using national and state death records through 2017. Organ doses from external photons and neutrons irridation and internalized plutonium, americium, and uranium were modeled as cumulative lagged total dose per year. Beryllium exposure was evaluated as an effect modifier using data from the DOE Nationwide Beryllium Medical Program. Statistical analyses included standardized mortality ratios (SMRs), Cox proportional hazard models, and excess relative risk (ERR) models. Results: Approximately 53.2% were deceased by the end of study. Nearly 90% were monitored for radiation exposure, with mean weighted absorbed dose of 59.0 mGy for lung. Nearly 45% of workers had intakes of alpha-particle emitting radionuclides, and 46.7% were monitored for neutrons. Leading causes of death included ischemic heart disease (n=999) and lung cancer (n=361). The highest SMRs were observed for berylliosis (SMR: 176.9; 95% CI: 76.2, 348.7; n<10) and asbestosis (SMR: 4.65; 95% CI: 2.23, 8.55;n=10). Dose-response analyses showed no statistical increase in risk from low-dose radiation including lung cancer (ERR per 100 mGy: -0.02; 95% CI: -0.11, 0.08; n=361) and Parkinson’s disease (ERR per 100 mGy: 0.13; 95% CI: -0.26, 0.31; n=57). Approximately 45% of workers were monitored for beryllium, with a weak non-significant indication of effect modification for lung cancer risk. Conclusion: The RF cohort showed no evidence of statistically significant increase in mortality from occupational radiation exposure. However, this study was limited by low statistical power, which inhibits the ability to detect effects. Future pooling of MPS cohorts will provide further insights, particularly regarding plutonium as a carcinogen.

Purpose: The study of low dose and low-dose rate exposure is of immeasurable value in understanding the possible range of health effects from prolonged exposures to radiation. The Million Person Study (MPS) of low-dose health effects was designed to evaluate radiation risks among healthy American workers and veterans who are more representative of today’s populations than are the Japanese atomic bomb survivors exposed briefly to high-dose radiation in 1945. A million persons were needed for statistical reasons to evaluate low-dose and dose-rate effects, rare cancers, intakes of radioactive elements, and differences in risks between women and men. Methods and materials: The MPS consists of five categories of workers and veterans exposed to radiation from 1939 to the present. The U.S. Department of Energy (DOE) Health and Mortality study began over 40 years ago and is the source of ∼360,000 workers. Over 25 years ago, the National Cancer Institute (NCI) collaborated with the U.S. Nuclear Regulatory Commission (NRC) to effectively create a cohort of nuclear power plant workers (∼150,000) and industrial radiographers (∼130,000). For over 30 years, the Department of Defense (DoD) collected data on aboveground nuclear weapons test participants (∼115,000). At the request of NCI in 1978, Landauer, Inc., (Glenwood, IL) saved their dosimetry databases which became the source of a cohort of ∼250,000 medical and other workers. Results: Overall, 29 individual cohorts comprise the MPS of which 21 have been or are under active study (∼810,000 persons). The remaining eight cohorts (∼190,000 persons) will be studied as resources become available. The MPS is a national effort with critical support from the NRC, DOE, National Aeronautics and Space Administration (NASA), DoD, NCI, the Centers for Disease Control and Prevention (CDC), the Environmental Protection Agency (EPA), Landauer, Inc., and national laboratories. Conclusions: The MPS is designed to address the major unanswered question in radiation risk understanding: What is the level of health effects when exposure is gradual over time and not delivered briefly. The MPS will provide scientific understandings of prolonged exposure which will improve guidelines to protect workers and the public; improve compensation schemes for workers, veterans and the public; provide guidance for policy and decision makers; and provide evidence for or against the continued use of the linear nonthreshold dose-response model in radiation protection.

Purpose: To present the methodology used to determine vital status and obtain cause of death (COD) within the Million Person Study of Low-Dose Health Effects (MPS). Data sources and vital status tracing techniques used to obtain vital status and COD for six (n = 424,238 subjects) of the ∼20+ cohorts under study are described. Methods and materials: A multistage approach using multiple sources of vital status information was used to determine vital status (or ‘trace’) study participants from as early as 1940 to the present. Mortality records from state departments of vital statistics and the Social Security Administration Death Master File (SSA-DMF) were matched to study participants by Social Security Number (SSN), full name, date of birth (DOB), and/or sex using deterministic and probabilistic algorithms. The National Death Index (NDI) and SSA Service for Epidemiological Researchers (SSA-SER) were used to obtain COD (after 1978) and verification of alive status, respectively. Online public records and ancestry services, death certificates, and specialized mortality sources were also utilized. Results: For the MPS cohorts traced to date (nuclear power plant workers, industrial radiographers, atomic veterans, and workers at Rocketdyne/Atomics International, Mound nuclear facility, and Mallinckrodt Chemical Works), vital status was confirmed for over 90% of all study subjects in all but one cohort (88%). The ascertainment of COD was over 96% for all cohorts. Conclusions: A hallmark of a high-quality epidemiologic cohort mortality study is a low percentage of subjects with unknown vital status and a low percentage of deaths without a COD. The sources and methods used for vital status tracing and COD determination for the MPS have been successful and should be useful for other investigators tracing large, historic study populations. Some of the approaches would be applicable for use in all cohort studies using regional-specific mortality data or modifications to the approach.

Background: The study of Japanese atomic bomb survivors, exposed briefly to radiation, finds the risk of radiation-induced lung cancer to be nearly three times greater for women than for men. Because protection standards for astronauts are based on individual lifetime risk projections, this sex-specific difference limits the time women can spend in space. Populations exposed to chronic or fractionated radiation were evaluated to learn whether similar differences exist when exposures occur gradually over years. Methods and materials: Five occupational cohorts within the Million Person Study of Low-Dose Health Effects (MPS) and a Canadian Fluoroscopy Cohort Study (CFCS) of tuberculosis patients who underwent frequent chest fluoroscopic examinations are evaluated. Included are male and female workers at the Mound nuclear facility, nuclear power plants (NPP), and industrial radiographers (IR). Workers at the Mallinckrodt Chemical Works and military participants at aboveground nuclear weapons tests provide information on the risk among males. Cox proportional hazards and Poisson regression models were used to estimate sex-specific radiation risks for lung cancer and to compare any differences. Results: Overall, 15,065 lung cancers occurred among the 443,684 subjects studied: 50,111 women and 395,573 men. The mean cumulative dose to the lung was 166.3 mGy (range 6 to 1,055 mGy) with the highest among the TB-fluoroscopy patients (mean 1,055 mGy). Mean lung dose for women in the worker cohorts was generally 4 times lower than for men. Of the 12 estimates of radiation-related risk, only one, for male IRs, showed a significant elevation (ERR 0.09; 95% CI 0.02–0.16, at 100 mGy). In contrast, the dose response for male NPP workers was negative (ERR −0.05; 95% CI −0.10, 0.01, at 100 mGy). Combined, these two cohorts provided little evidence for a radiation effect among males (ERR 0.01; 95% CI −0.04, 0.06, at 100 mGy). There was no significant dose-response among females within any cohort. There was no difference in the sex-specific estimates of lung cancer risk. Conclusions: There was little evidence that chronic or fractionated exposures increased the risk of lung cancer. There were no differences in the risks of lung cancer between men and women. However, the sex-specific analyses are limited because of small numbers of women and relatively low doses. A more definitive study is ongoing of medical radiation workers which include 85,000 women and 85,000 men (overall mean dose 82 mGy, max 1,140 mGy). Additional understanding will come from the ongoing follow-up of the CFCS.

Purpose: To present how the Department of Energy’s (DOE) Comprehensive Epidemiologic Data Resource (CEDR) is integrated into the Million Person Study of Low Dose Health Effects (MPS). The history of DOE’s worker health surveillance and its epidemiology program are described. Methods and materials: A standard protocol is used to extract data from CEDR for use in the MPS. The data files are pulled from CEDR to form the basis for the cohort analyzed in the MPS. The previous study data are reviewed to formulate the protocol for the MPS study cohort. The activities needed to update the data to construct the new analytic files are carried out in parallel. The primary efforts relate to updating the vital status, retrieving cause of death information and calculating annual radiation doses for the specific organs of interest. Working data files containing the updated data are produced for construction of analytic data files used in the biostatistical analysis. At study completion the working and analytic data files are placed into CEDR for use by other researchers. Results: The use of CEDR to study the scientific and maintenance workers at the Los Alamos National Laboratory which is currently underway is used to demonstrate the process. Conclusions: There is a pressing need to answer the question of the health risk of exposure to chronic low-level exposure to ionizing radiation. Using CEDR as the starting point to identify new cohorts to include in the MPS is a cost-effective and a time efficient way to expedite answering this question.

Purpose: A substantial body of epidemiologic literature addresses risks associated with occupational radiation exposure but comparing results between studies is often difficult as different statistical models are commonly used. It is unclear whether different methods produce similar results for estimates of radiation risk when applied to the same data. The goal of this study was to compare the radiation risk estimates for leukemia other than chronic lymphocytic leukemia (non-CLL) and ischemic heart disease (IHD) produced by both Cox and Poisson regression models for time-dependent dose-response analyses of occupational exposure. Materials and methods: For brevity, this methods paper presents the results from one cohort, the Nuclear Power Plant workers (NPP), though the evaluation considered five cohorts of varying size and exposure as part of the Million Worker Study. Cox Proportional Hazards models, with age as the underlying timescale for hazard, were conducted using three computer software programs: SAS, R, and Epicure. Doses lagged 2 years for non-CLL and 10 years for ischemic heart disease were treated as time-dependent exposures at the annual level and were examined both in categories and as a continuous term. Hazard ratios (HR) and 95% confidence intervals (CI) were reported for each model in SAS and R, while the Peanuts program of Epicure was utilized to produce Excess Relative Risk (ERR) estimates and 95% CI. All models were adjusted for gender and year of birth. Four piece-wise exponential Poisson models (log-linear regression for rate) were developed with varying cutpoints for age strata from very fine to broad categories using both R and the Amfit program in Epicure for ERR estimates. Results: Comparable estimates of risk (both RR and ERR) were observed from Cox and Poisson models, regardless of software utilized, as long as appropriately narrow categories of age were utilized to control the confounding of age in Poisson models. The ERR estimates produced in Epicure tended to agree very closely with the HR or RR estimates, and the statistical software program used had no impact to risk estimates for the same model. Conclusions: As computational power is no longer the burden today as it has been in the past, the results of this evaluation support the use of the Cox proportional hazards or the ungrouped Poisson approach to analyzing time-dependent dose-response relationships to ensure that maximum control over the confounding of age is achieved in studies of mortality for cohorts occupationally exposed to radiation.

Purpose: Adjusting for smoking status or a reliable surrogate [such as socioeconomic status (SES)] is critically important in occupational epidemiology studies when any smoking-related cancer or cardiovascular disease is an outcome of interest. Sometimes, however, data on smoking patterns or individual-level smoking surrogates such as job title, education, pay scale or other measures of SES are not readily available in occupational cohorts. Methods and materials: To obtain a surrogate measure for missing smoking or individual-level SES data, we demonstrate a method used to obtain and geocode residential address histories which were then linked to area-level SES measures from the United States Census in three test samples and then in a full cohort of workers from the Mound nuclear weapons facility in Dayton, Ohio, USA. The mean educational attainment of the Census Block Group was used to derive a categorical estimate of educational attainment which was compared to self-reported (SR) education available from Mound worker histories using Kappa statistics. Lung cancer mortality patterns between area-derived (AD) and SR education were investigated using Standardized Mortality Ratios (SMR) and Cox Proportional Hazards models with stratification or adjustment by either SR or AD education. Results: Home address histories were obtained from linkages of individual worker data to online resources. In the test cohorts, mean educational attainment was the Census Block Group measure found to have the largest magnitude association with individual-level SES measures. Among 7251 Mound workers, 5685 (78.4%) had at least one residential address match (mean 4.9 addresses) identified. The SR and AD educational attainment measures were highly correlated (weighted Kappa coefficient 0.10, p < .0001). SMR patterns by SR and AD educational attainment were similar, with steadily decreasing mortality with increased educational attainment by either measure. Cox models for lung cancer using AD education produced similar results as those using SR education as an adjustment factor. Conclusion: When individual-level SES indicators are not available for statistical adjustment, area-level SES measures can serve as a reliable surrogate when investigating outcomes that are affected by lifestyle factors such as smoking.

Purpose: Mallinckrodt Chemical Works (MCW) was the earliest uranium processing facility in the United States, and in 1942 produced the uranium oxide used for the first sustained and controlled nuclear fission chain-reaction at the University of Chicago. A second follow-up through 2012 was conducted of 2514 White male workers employed 1942–1966 at the MCW for dose-response analyses for selected causes of death. Materials and methods: Organ/tissue-specific dose reconstruction included both external (12,686 MCW film badge records, 210 other facility film badge records, and 31,297 occupational chest x-rays) and internal sources of uranium and radium (39,451 urine bioassays, 2341 breath radon measurements, and 6846 ambient radon measurements). Dust measurements from pitchblende facilitated quantitative risk estimates for non-radiogenic effects on the lung and kidney. Vital status was determined from multiple sources including the National Death Index and the Social Security Administration. Cox regression models were used for dose response analyses. Results: Vital status was determined for 99% of the workers, of whom 75% had died. The mean lung dose from all sources of external and internal radiation combined was 69.9 mGy (maximum 885 mGy; percent workers >100 mGy, 10%) and there was no evidence for a dose response for lung cancer (Hazard Ratio (HR) of 0.95 (95% CI = 0.81–1.12) at 100 mGy). A significant association with radiation was found for kidney cancer (HR of 1.73 (95% CI = 1.04–2.79) at 100 mGy) and suggested for nonmalignant kidney diseases (HR of 1.30 (95% CI = 0.96–1.76) at 100 mGy). A non-radiation etiology could not be discounted, however, because of the possible renal toxicities of uranium, a heavy metal, and silica, a component of pitchblende dust. Non-significant HRs at 100 mGy for other sites of a priori interest were 0.36 (0.06–2.03) for leukemia other than CLL, 0.68 (0.17–2.77) for liver cancer, and 1.23 (0.79–1.90) for non-Hodgkin lymphoma. The HR at 100 mGy was 1.09 (0.99–1.20) for ischemic heart disease. An association was seen between dust and combined malignant and non-malignant lung disease, HR at 10 mgm⁻³year⁻¹ of 1.01 (1.00–1.02). Conclusions: A positive radiation dose response was observed for malignant and non-malignant kidney disease, and a negative dose response for malignant and non-malignant lung disease. Cumulative measures of dust were significantly associated with malignant and non-malignant lung disease and suggested for malignant and non-malignant kidney disease. Small numbers preclude definitive interpretations which will await the combination with similar studies of early uranium processing workers.

Background: There are few occupational studies of women exposed to ionizing radiation. During World War II, the Tennessee Eastman Corporation (TEC) operated an electromagnetic field separation facility of 1152 calutrons to obtain enriched uranium (²³⁵U) used for the Hiroshima atomic bomb. Thousands of women were involved in these operations. Materials and methods: A new study was conducted of 13,951 women and 12,699 men employed at TEC between 1943 and 1947 for at least 90 days. Comprehensive dose reconstruction techniques were used to estimate lung doses from the inhalation of uranium dust based on airborne measurements. Vital status through 2018/2019 was obtained from the National Death Index, Social Security Death Index, Tennessee death records and online public record databases. Analyses included standardized mortality ratios (SMRs) and Cox proportional hazards models. Results: Most workers were hourly (77.7%), white (95.6%), born before 1920 (58.3%), worked in dusty environments (57.0%), and had died (94.9%). Vital status was confirmed for 97.4% of the workers. Women were younger than men when first employed: mean ages 25.0 years and 33.0 years, respectively. The estimated mean absorbed dose to the lung was 32.7 mGy (max 1048 mGy) for women and 18.9 mGy (max 501 mGy) for men. The mean dose to thoracic lymph nodes (TLNs) was 127 mGy. Statistically significant SMRs were observed for lung cancer (SMR 1.25; 95% CI 1.19, 1.31; n = 1654), nonmalignant respiratory diseases (NMRDs) (1.23; 95% CI 1.19, 1.28; n = 2585), and cerebrovascular disease (CeVD) (1.13; 95% CI 1.08, 1.18; n = 1945). For lung cancer, the excess relative rate (ERR) at 100 mGy (95% CI) was 0.01 (–0.10, 0.12; n = 652) among women, and −0.15 (–0.38, 0.07; n = 1002) among men based on a preferred model for men with lung doses

IntroductionMallinckrodt Chemical Works was a uranium processing facility during the Manhattan Project from 1942-1966. Thousands of workers were exposed to low-dose-rates of ionizing radiation from external and internal sources. This third follow-up of 2514 White male employees updates cancer and noncancer mortality potentially associated with radiation and silica dust.Materials and methodsIndividual, annualized organ doses were estimated from film badge records (n monitored = 2514), occupational chest x-rays (n = 2514), uranium urinalysis (n = 1868), radium intake through radon breath measurements (n = 487), and radon ambient measurements (n = 1356). Silica dust exposure from pitchblende processing was estimated (n = 1317). Vital status and cause of death determination through 2019 relied upon the National Death Index and Social Security Administration Epidemiological Vital Status Service. The analysis included standardized mortality ratios (SMRs), Cox proportional hazards, and Poisson regression models.ResultsVital status was confirmed for 99.4% of workers (84.0% deceased). For a dose weighting factor of 1 for intakes of uranium, radium, and radon decay products, the mean and median lung doses were 65.6 and 29.9 mGy, respectively. SMRs indicated a difference in health outcomes between salaried and hourly workers, and more brain cancer deaths than expected [SMR: 1.79; 95% confidence interval (CI): 1.14, 2.70]. No association was seen between radiation and lung cancer [hazard ratio (HR) at 100 mGy: 0.93; 95%CI: 0.78, 1.11]. The relationship between radiation and kidney cancer observed in the previous follow-up was maintained (HR at 100 mGy: 2.07; 95%CI: 1.12, 3.79). Cardiovascular disease (CVD) also increased significantly with heart dose (HR at 100 mGy: 1.11; 95%CI: 1.02, 1.21). Exposures to dust ≥23.6 mg/m³-year were associated with non-malignant kidney disease (NMKD) (HR: 3.02; 95%CI: 1.12, 8.16) and kidney cancer combined with NMKD (HR: 2.46; 95%CI: 1.04, 5.81), though without evidence of a dose-response per 100 mg/m³-year.ConclusionsThis third follow-up of Mallinckrodt uranium processors reinforced the results of the previous studies. There was an excess of brain cancers compared with the US population, although no radiation dose-response was detected. The association between radiation and kidney cancer remained, though potentially due to few cases at higher doses. The association between levels of silica dust ≥23.6 mg/m³-year and NMKD also remained. No association was observed between radiation and lung cancer. A positive dose-response was observed between radiation and CVD; however, this association may be confounded by smoking, which was unmeasured. Future work will pool these data with other uranium processing worker cohorts within the Million Person Study.