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Introduction: Mallinckrodt Chemical Works was a uranium processing facility during the Manhattan Project from 1942 to 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 Methods: Individual, 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., Results: Vital 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/m 3 -year were associated with nonmalignant 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/m 3 -year., Conclusions: This 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/m 3 -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.

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 ( 235 U) 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 <300 mGy. NMRD and non-Hodgkin lymphoma were not associated with estimated absorbed dose to the lung or TLN., Conclusions: There was little evidence that radiation increased the risk of lung cancer, suggesting that inhalation of uranium dust and the associated high-LET alpha particle exposure to lung tissue experienced over a few years is less effective in causing lung cancer than other types of exposures. There was no statistically significant difference in the lung cancer risk estimates between men and women. The elevation of certain causes of death such as CeVD is unexplained and will require additional scrutiny of workplace or lifestyle factors given that radiation is an unlikely contributor since only the lung and lymph nodes received appreciable dose.

This article summarizes a Symposium on 'Radiation risks of the central nervous system' held virtually at the 67th Annual Meeting of the Radiation Research Society, 3-6 October 2021. Repeated low-dose radiation exposure over a certain period could lead to reduced neuronal proliferation, altered neurogenesis, neuroinflammation and various neurological complications, including psychological consequences, necessitating further research in these areas. Four speakers from radiation biology, genetics and epidemiology presented the latest data from their studies seeking insights into this important topic. This symposium highlighted new and important directions for further research on mental health disorders, neurodegenerative conditions and cognitive impairment. Future studies will examine risks of mental and behavioral disorders and neurodegenerative diseases following protracted radiation exposures to better understand risks of occupational exposures as well as provide insights into risks from exposures to galactic cosmic rays.

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: 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 -3 year -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.

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: 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.

Background: Approximately 235,000 military personnel participated at one of 230 U.S. atmospheric nuclear weapons tests from 1945 through 1962. At the Nevada Test Site (NTS), the atomic veterans participated in military maneuvers, observed nuclear weapons tests, or provided technical support. At the Pacific Proving Ground (PPG), they served aboard ships or were stationed on islands during or after nuclear weapons tests., Material and Methods: Participants at seven test series, previously studied with high-quality dosimetry and personnel records, and the first test at TRINITY formed the cohort of 114,270 male military participants traced for vital status from 1945 through 2010. Dose reconstructions were based on Nuclear Test Personnel Review records, Department of Defense. Standardized mortality ratios (SMR) and Cox and Poisson regression models were used in the analysis., Results: Most atomic veterans were enlisted men, served in the Navy at the PPG, and were born before 1930. Vital status was determined for 96.8% of the veterans; 60% had died. Enlisted men had significantly high all-causes mortality SMR (1.06); officers had significantly low all-causes mortality SMR (0.71). The pattern of risk over time showed a diminution of the 'healthy soldier effect': the all-causes mortality SMR after 50 years of follow-up was 1.00. The healthy soldier effect for all cancers also diminished over time. The all-cancer SMR was significantly high after 50 years (SMR 1.10) primarily from smoking-related cancers, attributed in part to the availability of cigarettes in military rations. The highest SMR was for mesothelioma (SMR 1.56) which was correlated with asbestos exposure in naval ships. Prostate cancer was significantly high (SMR 1.13). Ischemic heart disease was significantly low (SMR 0.84). Estimated mean doses varied by organ were low; e.g., the mean red bone marrow dose was 6 mGy (maximum 108 mGy). Internal cohort dose-response analyses provided no evidence for increasing trends with radiation dose for leukemia (excluding chronic lymphocytic leukemia (CLL)) [ERR (95% CI) per 100 mGy -0.37 (-1.08, 0.33); n  = 710], CLL, myelodysplastic syndrome, multiple myeloma, ischemic heart disease, or cancers of the lung, prostate, breast, and brain., Conclusion: No statistically significant radiation associations were observed among 114,270 nuclear weapons test participants followed for up to 65 years. The 95% confidence limits were narrow and excluded mortality risks per unit dose that are two to four times higher than those reported in other investigations. Significantly elevated SMRs were seen for mesothelioma and asbestosis, attributed to asbestos exposure aboard ships.

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.

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: 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.

Background: Epidemiologic studies of radiation-exposed populations form the basis for human safety standards. They also help shape public health policy and evidence-based health practices by identifying and quantifying health risks of exposure in defined populations. For more than a century, epidemiologists have studied the consequences of radiation exposures, yet the health effects of low levels delivered at a low-dose rate remain equivocal., Materials and Methods: The Million Person Study (MPS) of U.S. Radiation Workers and Veterans was designed to examine health effects following chronic exposures in contrast with brief exposures as experienced by the Japanese atomic bomb survivors. Radiation associations for rare cancers, intakes of radionuclides, and differences between men and women are being evaluated, as well as noncancers such as cardiovascular disease and conditions such as dementia and cognitive function. The first international symposium, held November 6, 2020, provided a broad overview of the MPS. Representatives from four U.S. government agencies addressed the importance of this research for their respective missions: U.S. Department of Energy (DOE), the Centers for Disease Control and Prevention (CDC), the U.S. Department of Defense (DOD), and the National Aeronautics and Space Administration (NASA). The major components of the MPS were discussed and recent findings summarized. The importance of radiation dosimetry, an essential feature of each MPS investigation, was emphasized., Results: The seven components of the MPS are DOE workers, nuclear weapons test participants, nuclear power plant workers, industrial radiographers, medical radiation workers, nuclear submariners, other U.S. Navy personnel, and radium dial painters. The MPS cohorts include tens of thousands of workers with elevated intakes of alpha particle emitters for which organ-specific doses are determined. Findings to date for chronic radiation exposure suggest that leukemia risk is lower than after acute exposure; lung cancer risk is much lower and there is little difference in risks between men and women; an increase in ischemic heart disease is yet to be seen; esophageal cancer is frequently elevated but not myelodysplastic syndrome; and Parkinson's disease may be associated with radiation exposure., Conclusions: The MPS has provided provocative insights into the possible range of health effects following low-level chronic radiation exposure. When the 34 MPS cohorts are completed and combined, a powerful evaluation of radiation-effects will be possible. This final article in the MPS special issue summarizes the findings to date and the possibilities for the future. A National Center for Radiation Epidemiology and Biology is envisioned.

Background: During World War II (WWII), the Manhattan Engineering District established a secret laboratory in the mountains of northern New Mexico. The mission was to design, construct and test the first atomic weapon, nicknamed 'The Gadget' that was detonated at the TRINITY site in Alamogordo, NM. After WWII, nuclear weapons research continued, and the laboratory became the Los Alamos National Laboratory (LANL)., Materials and Methods: The mortality experience of 26,328 workers first employed between 1943 and 1980 at LANL was determined through 2017. Included were 6157 contract workers employed by the ZIA Company. Organ dose estimates for each worker considered all sources of exposure, notably photons, neutrons, tritium, 238 Pu and 239 Pu. Vital status determination included searches within the National Death Index, Social Security Administration and New Mexico State Mortality Files. Standardized Mortality Ratios (SMR) and Cox regression models were used in the analyses., Results: Most workers (55%) were hired before 1960, 38% had a college degree, 25% were female, 81% white, 13% Hispanic and 60% had died. Vital status was complete, with only 0.1% lost to follow-up. The mean dose to the lung for the 17,053 workers monitored for radiation was 28.6 weighted-mGy (maximum 16.8 weighted-Gy) assuming a Dose Weighting Factor of 20 for alpha particle dose to lung. The Excess Relative Risk (ERR) at 100 weighted-mGy was 0.01 (95%CI -0.02, 0.03; n  = 839) for lung cancer. The ERR at 100 mGy was -0.43 (95%CI -1.11, 0.24; n  = 160) for leukemia other than chronic lymphocytic leukemia (CLL), -0.06 (95%CI -0.16, 0.04; n  = 3043) for ischemic heart disease (IHD), and 0.29 (95%CI 0.02, 0.55; n  = 106) for esophageal cancer. Among the 6499 workers with measurable intakes of plutonium, an increase in bone cancer (SMR 2.44; 95%CI 0.98, 5.03; n  = 7) was related to dose. The SMR for berylliosis was significantly high, based on 4 deaths. SMRs for Hispanic workers were significantly high for cancers of the stomach and liver, cirrhosis of the liver, nonmalignant kidney disease and diabetes, but the excesses were not related to radiation dose., Conclusions: There was little evidence that radiation increased the risk of lung cancer or leukemia. Esophageal cancer was associated with radiation, and plutonium intakes were linked to an increase of bone cancer. IHD was not associated with radiation dose. More precise evaluations will await the pooled analysis of workers with similar exposures such as at Rocky Flats, Savannah River and Hanford.

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.