Michael T. Mumma

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.

The American radium dial worker (RDW) cohort of over 3200 persons is being revisited as part of the Million Person Study (MPS) to include a modern approach to RDW dosimetry. An exceptional source of data and contextualization in this project is an extensive collection of electronic records (digitized from existing microfilm and microfiche) housed at the United States Transuranium and Uranium Registries (USTUR). Although the type, extent, and quality (e.g. legibility) of record(s) varies between individuals, the remarkable occupational, medical and demographic data include in vivo radiation measurements (e.g. radon breath, whole body counts), autopsy results, medical records (including copies of radiographs), interviews over the years, and correspondence. Of particular dosimetric interest are the details of radiation measurements. For example, there are some instances where hand-written and transcribed values are both available, along with notes providing context for why a particular measurement in a series of measurements was chosen to assign an intake, or if there were concerns about a particular measurement. Born prior to 1935, RDW have nearly all passed away. Thus, the updated dosimetry, especially for the skeletal tissues, will allow the correlation of lifetime cumulative dose with radiation risk. Here we review typical information available in this collection of historical records and highlight some interesting finds. Additionally, we discuss the relevance to current and ongoing work related to updating the dosimetry of the RDW in the MPS, including providing an example of the usefulness of information contained in these records. The RDW cohort provides a unique historical perspective on occupational exposure to radium, making it a valuable dataset for understanding long-term health effects and improving current radiation protection standards.

While there is a well-established link between ionizing radiation and cancer, there are uncertainties with effects following low doses delivered at low dose rates. To address these gaps, the ongoing Million Person Study of Radiation Workers and Veterans (MPS) is investigating the likelihood of a variety of cancer and non-cancer effects following chronic exposure to low dose-rate ionizing radiation. One challenge is and will be combining and harmonizing diverse cohorts with widely different measures of socio-economic status, birth cohorts, dose distributions and sex ratios. Herein, we have evaluated non-cancer mortality in three cohorts for which dose reconstructions have been completed: Rocketdyne (Atomics International, California, 1948–2008), Mound (Dayton, Ohio, 1944–2009) and nuclear weapons test participants (Atomic Veterans, 1945–2012). These three cohorts represent a small fraction of the overall MPS but provide valuable insight into methods of combining and harmonizing data from multiple diverse cohorts that can later be considered for all MPS cohorts. Heart disease mortality, including both underlying and contributing causes of death, was chosen for illustrating the statistical approaches. In all three cohorts, radiation dose estimates were distributed very differently by different measures of socio-economic status. Further, the effect of birth cohort was significantly different for heart disease mortality in all three cohorts, with all studies showing that later birth cohorts have lower rates of heart disease mortality than the earlier. The goal of this paper is not to quantify radiation effects based on these combined cohorts and it would be inappropriate to do so. Rather these cohorts are used to illustrate approaches for combining multiple data sets that incorporate the full set of individual confounder and cofactor information available from each cohort, though widely different. We identified five different methods to combine the results of these three datasets: the simple pooled analysis (PA), PA including study interactions, traditional stratified analysis, and both fixed and random effects meta-analysis. We describe the similarities and differences between the combined results using these approaches.

The radium dial painters (RDPs) are a well-described group of predominantly young women who incidentally ingested ²²⁶Ra and ²²⁸Ra as they painted luminescent watch dials in the first part of the twentieth century. In 1974 pathologist Dr William D. Sharpe published complete clinical and autopsy results for 42 former RDPs evaluated in the New Jersey Radium Research Project. This was an important paper due to the completeness of the observations. Surprisingly, in this study, clinicians noted a 35.5% incidence of hearing loss, both conductive and mixed etiologies. Since the 1974 publication, there has developed a considerable literature on radiation-induced hearing loss in patients undergoing radiotherapy for head and neck cancers. It is expected that hearing loss would also be associated with systemic inflammation. Recently, the neutrophil to lymphocyte ratio (NLR) has been shown in many cancer and non-cancer studies to be a nonspecific marker of inflammation. In prior collaborative efforts with the United States Transuranium and Uranium Registries and with the NCRP Million Person Study, it has been possible to evaluate NLR from medical records of a cohort of 166 former RDPs previously evaluated at Argonne National Laboratory. In addition, NLR was available in historic medical records of the sarcoma and nasopharyngeal cancer patients described in Rowland’s summary of the Argonne studies. Using elevation of the NLR as a non-specific marker of inflammation, chronic inflammation has been observed in all cohorts with significant dose. The RDP cohort has had a unique exposure to radium, but the incidence of radiation-induced hearing loss here is uncertain. Due to cosmic radiation dose to astronauts in space flight, there is a significant interest in high LET radiation dose to the brain, including the auditory system. This paper should be considered as hypothesis generating—that high LET radiation dose to the brain and auditory system may induce hearing loss.

Background: Hepatocellular carcinoma (HCC) is becoming a leading cause of cancer-related mortality in the United States, with notable disparities observed among racial and ethnic minorities. The objective of this study is to examine the association between social determinants of health (SDoH) and HCC incidence by race (White and Black individuals) using data from the Southern Community Cohort Study. Methods: The Southern Community Cohort Study is a prospective cohort study with participants recruited from 2002 to 2009. Incident HCC cases were identified during follow-up. Exposure measures, including residential segregation, social vulnerability, population density, rurality, and poverty, were assessed at baseline. Cox proportional hazards regression models were used to estimate HRs associated with SDoH by race with the adjustment of known HCC risk factors. Results: Among the 79,367 eligible participants, there were 491 incident HCC cases diagnosed, 378 of whom were in Black individuals. In Black individuals, increased population density and urban residency were associated with an increased risk of HCC, even after adjusting for potential confounders [HR = 1.49; 95% confidence interval (CI), 1.04–2.13; HR = 1.70; 95% CI, 1.20–2.41, respectively]. White individuals living in the least segregated areas (HR = 2.83; 95% CI, 1.39–5.78) and in urban settings (HR = 2.34; 95% CI, 1.17–4.65) had an increased HCC risk, whereas population density was not associated with risk. Conclusions: We found that individuals residing in urban populations had an increased risk of HCC. These findings underscore the complex interplay of SDoH factors and geographic influences on HCC disparities. Impact: Our findings highlight the need for targeted interventions and further research to address HCC health inequities.

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: The risk of mesothelioma, including cancers of the pleura and peritoneum, was examined within two large cohorts of workers monitored for exposure to ionizing radiation. Methods and materials: Mortality was assessed among 253,632 workers routinely monitored for external radiation, including 30,724 industrial radiographers (IR) at shipyards, 142,583 workers at nuclear power plants (NPP), and 83,441 IR who had not worked at an NPP or shipyard. Follow-up was from 1969 through 2011. Standardized mortality ratios (SMRs) and 95% confidence intervals (CIs) were computed; observed numbers of deaths from mesothelioma (including cancers of the pleura and peritoneum) and asbestosis were compared with numbers expected based on age-, sex-, and calendar year-specific national mortality rates. Job history and quantitative asbestos exposure data were unavailable, but work at a shipyard was taken as a surrogate for the likelihood of exposure. Cox proportional hazards models were used to estimate hazard ratios (HRs) for mesothelioma in relation to estimated cumulative radiation exposure to the lung. Results: The mean duration of follow-up was 25.3 years (max 42 years). The mean cumulative lung dose was 28.6 mGy (7.3% > 250 mGy). Nearly 20% of the workers had died by 2011. A total of 421 mesothelioma deaths were found (75% occurring after 1999) with increased SMRs among workers monitored in shipyards (SMR 9.97; 95% CI 8.50–11.63) and for NPP workers (SMR 5.55; 95% CI 4.88–6.29), but not for IR who had not worked in shipyards (SMR 1.15; 95% CI 0.53–2.19). Likewise, deaths from asbestosis (n = 189) were also increased for shipyard and NPP workers (SMR = 18.1 and 9.2, respectively), but not among workers who never worked at a shipyard or NPP (SMR = 0.70; n = 1). Radiation dose to the lung was not associated with a statistically meaningful dose-response trend for mesothelioma in the combined cohorts (HR at 100 mGy = 1.10; 95% CI 0.96–1.27; p = .18), nor was mesothelioma risk associated with radiation exposure among IR who had not worked in a shipyard and assumed minimally exposed to asbestos. Conclusions: An elevated rate of death from mesothelioma was observed in two radiation-exposed occupational groups with potential for asbestos exposure. The increased risk of death from asbestosis, combined with little evidence of a rising trend in mesothelioma mortality with increasing radiation exposure, suggests that the mesothelioma (and asbestosis) excess in these workers was due to asbestos exposure in shipyards and power plants and not to occupational low-dose radiation.

Background: The aim of the Million Person Study of Low-Dose Health Effects (MPS) is to examine the level of radiation risk for chronic exposures received gradually over time and not acutely as was the case for the Japanese atomic bomb survivors. Nuclear power plant (NPP) workers comprise nearly 15 percent of the MPS. Leukemia, selected cancers, Parkinson’s disease, ischemic heart disease (IHD) and other causes of death are evaluated. Methods and material: The U.S. Nuclear Regulatory Commission’s Radiation Exposure Information and Reporting System (REIRS) and the Landauer, Inc. dosimetry databases identified 135,193 NPP workers first monitored 1957–1984. Annual personal dose equivalents [Hp(10)] were available for each worker. Radiation records from all places of employment were sought. Vital status was determined through 2011. Mean absorbed doses to red bone marrow (RBM), esophagus, lung, colon, brain and heart were estimated by adjusting the recorded Hp(10) for each worker by scaling factors, accounting for exposure geometry and energy of the incident gamma radiation. Standardized mortality ratios (SMR) were calculated. Radiation risks were estimated using Cox proportional hazards models. Results: Nearly 50% of workers were employed for more than 20 years. The mean duration of follow-up was 30.2 y. Overall, 29,124 total deaths occurred, 296 from leukemia other than chronic lymphocytic leukemia (CLL), 3382 from lung cancer, 140 from Parkinson’s disease and 5410 from IHD. The mean dose to RBM was 37.9 mGy (maximum 1.0 Gy; percent >100 mGy was 9.2%), 43.2 mGy to lung, 43.7 mGy to colon, 33.2 mGy to brain, and 43.9 mGy to heart. The SMRs (95% CI) were 1.06 (0.94; 1.19) for leukemia other than CLL, 1.10 (1.07; 1.14) for lung cancer, 0.90 (0.76; 1.06) for Parkinson’s disease, and 0.80 (0.78; 0.82) for IHD. The excess relative risk (ERR) per 100 mGy for leukemia other than CLL was 0.15 (90% CI −0.001; 0.31). For all solid cancers the ERR per 100 mGy (95% CI) was 0.01 (–0.03; 0.05), for lung cancer −0.04 (–0.11; 0.02), for Parkinson’s disease 0.24 (–0.02; 0.50), and for IHD −0.01 (–0.06; 0.04). Conclusion: Prolonged exposure to radiation increased the risk of leukemia other than CLL among NPP workers. There was little evidence for a radiation association for all solid cancers, lung cancer or ischemic heart disease. Increased precision will be forthcoming as the different cohorts within the MPS are combined, such as industrial radiographers and medical radiation workers who were assembled and evaluated in like manner.

Background: Estimates of radiation risks following prolonged exposures at low doses and low-dose rates are uncertain. Medical radiation workers are a major component of the Million Person Study (MPS) of low-dose health effects. Annual personal dose equivalents, H _P(10), for individual workers are available to facilitate dose-response analyses for lung cancer, leukemia, ischemic heart disease (IHD) and other causes of death. Materials and methods: The Landauer, Inc. dosimetry database identified 109,019 medical and associated radiation workers first monitored 1965–1994. Vital status and cause of death were determined through 2016. Mean absorbed doses to red bone marrow (RBM), lung, heart, and other organs were estimated by adjusting the recorded H _P(10) for each worker by scaling factors, accounting for exposure geometry, the energy of the incident photon radiation, sex of the worker and whether an apron was worn. There were 4 exposure scenarios: general radiology characterized by low-energy x-ray exposure with no lead apron use, interventional radiologists/cardiologists who wore aprons, nuclear medicine personnel and radiation oncologists exposed to high-energy photon radiation, and other workers. Standardized mortality ratio (SMR) analyses were performed. Cox proportional hazards models were used to estimate organ-specific radiation risks. Results: Overall, 11,433 deaths occurred (SMR 0.60; 95%CI 0.59,0.61), 126 from leukemia other than chronic lymphocytic leukemia (CLL), 850 from lung cancer, and 1654 from IHD. The mean duration of monitoring was 23.7 y. The excess relative rate (ERR) per 100 mGy was estimated as 0.10 (95% CI −0.34, 0.54) for leukemia other than CLL, 0.15 (0.02, 0.27) for lung cancer, and −0.10 (–0.27, 0.06) for IHD. The ERR for lung cancer was 0.16 (0.01, 0.32) among the 55,218 male workers and 0.09 (–0.19, 0.36) among the 53,801 female workers; a difference that was not statistically significant (p-value = 0.23). Conclusions: Medical radiation workers were at increased risk for lung cancer that was higher among men than women, although this difference was not statistically significant. In contrast, the study of Japanese atomic bomb survivors exposed briefly to radiation in 1945 found females to be nearly 3 times the radiation risk of lung cancer compared with males on a relative scale. For medical workers, there were no statistically significant radiation associations with leukemia excluding CLL, IHD or other specific causes of death. Combining these data with other cohorts within the MPS, such as nuclear power plant workers and nuclear submariners, will enable more precise estimates of radiation risks at relatively low cumulative doses.

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.