Ethical thinking in occupational and environmental medicine: Commentaries from the Selikoff Fund for Occupational and Environmental Cancer Research.

A tribute to Dr. Irving J. Selikoff MD, the founder of this journal, is indeed welcome now more than two decades after his passing. He was known during his lifetime as the US Father of Environmental Medicine which at the time encompassed occupational medicine and much more as industry also polluted the general environment. The 1970s were a busy time as OSHA and the EPA were newly formed and high exposures to workers were no exception. Dr. Selikoff was a brave pioneer examining workers throughout the country and Canada, publicizing their exposures, and writing and presenting the scientific results. Industry was not always receptive and controlled an astounding amount of narrative, with the creation of the American Journal of Industrial Medicine filling a void of scientific need. We four authors write about the ethics of occupational health, the plight of nuclear energy workers, the climate crisis and opportunity for unions to engage workers, and the global march toward educating medical students on workers' health and safety. All four of us interacted with Dr. Selikoff during his tenure at Mount Sinai, and over the years joined each other in promoting his legacy. Toward that end we have written articles honoring his memory.

Incidence risks for cerebrovascular diseases and types of stroke in a cohort of Mayak PA workers.

Incidence risks for cerebrovascular diseases (CeVD) and some types of stroke in a cohort of 22,377 Russian Mayak nuclear workers chronically exposed to ionising radiation and followed up until the end of 2018 are reported. Among total 9469 cases of CeVD, 2078 cases were strokes that included 262 hemorrhagic strokes (HS) and 1611 ischemic strokes (IS). Data evaluation was performed with categorical and dose-response analyses estimating the relative risk (RR) and excess relative risk (ERR) per unit cumulative liver absorbed dose of external gamma-ray or internal alpha-particle exposure based on a linear model utilizing the AMFIT module of the EPICURE software. CeVD incidence was found to be significantly associated with cumulative radiation dose: ERR/Gy was 0.37 (95% confidence interval (CI) 0.27, 0.47) in males and 0.47 (95% CI 0.31, 0.66) in females for external exposure, and 0.31 (95% CI 0.11, 0.59) in males and 0.32 (95% CI 0.11, 0.61) in females for internal exposure. When the model for the analysis of external radiation effect did not include an adjustment for alpha radiation dose (and vice versa), the radiogenic risk estimate increased notably both for males and for females. In contrast, exclusion from or inclusion in the model of additional adjustments for non-radiation factors did not notably change the risk estimates. ERR/Gy of external gamma dose for CeVD incidence significantly decreased with increasing attained age (males and females) and duration of employment (females). No significant associations of either stroke or its types with cumulative gamma-ray dose of external exposure or alpha-particle dose of internal exposure were found.

Risk of cancer associated with low-dose radiation exposure: comparison of results between the INWORKS nuclear workers study and the A-bomb survivors study.

The Life Span Study (LSS) of Japanese atomic bomb survivors has served as the primary basis for estimates of radiation-related disease risks that inform radiation protection standards. The long-term follow-up of radiation-monitored nuclear workers provides estimates of radiation-cancer associations that complement findings from the LSS. Here, a comparison of radiation-cancer mortality risk estimates derived from the LSS and INWORKS, a large international nuclear worker study, is presented. Restrictions were made, so that the two study populations were similar with respect to ages and periods of exposure, leading to selection of 45,625 A-bomb survivors and 259,350 nuclear workers. For solid cancer, excess relative rates (ERR) per gray (Gy) were 0.28 (90% CI 0.18; 0.38) in the LSS, and 0.29 (90% CI 0.07; 0.53) in INWORKS. A joint analysis of the data allowed for a formal assessment of heterogeneity of the ERR per Gy across the two studies (P = 0.909), with minimal evidence of curvature or of a modifying effect of attained age, age at exposure, or sex in either study. There was evidence in both cohorts of modification of the excess absolute risk (EAR) of solid cancer by attained age, with a trend of increasing EAR per Gy with attained age. For leukemia, under a simple linear model, the ERR per Gy was 2.75 (90% CI 1.73; 4.21) in the LSS and 3.15 (90% CI 1.12; 5.72) in INWORKS, with evidence of curvature in the association across the range of dose observed in the LSS but not in INWORKS; the EAR per Gy was 3.54 (90% CI 2.30; 5.05) in the LSS and 2.03 (90% CI 0.36; 4.07) in INWORKS. These findings from different study populations may help understanding of radiation risks, with INWORKS contributing information derived from cohorts of workers with protracted low dose-rate exposures.

Overview of epidemiological studies of nuclear workers: opportunities, expectations, and limitations.

Epidemiological studies of those exposed occupationally to ionising radiation offer an important opportunity to directly check the assumptions underlying the international system of radiological protection against low-level radiation exposures. Recent nuclear worker studies, notably the International Nuclear Workers Study (INWORKS) and studies of the Mayak workforce in Russia, provide powerful investigations of a wide range of cumulative photon doses received at a low dose-rate over protracted periods, and broadly confirm radiation-related excess risks of leukaemia and solid cancers at around the levels predicted by standard risk models derived mainly from the experience of the Japanese atomic-bomb survivors acutely exposed principally to gamma radiation. However, the slope of the dose-response for solid cancers expressed in terms of the excess relative risk per unit dose, ERR/Gy, differs between INWORKS and Mayak, such that when compared with the slope derived from the atomic-bomb survivors, INWORKS does not provide obvious support for the use in radiological protection of a dose and dose-rate effectiveness factor greater than one whereas the Mayak workforce apparently does. This difference could be a chance effect, but it could also point to potential problems with these worker studies. Of particular concern is the adequacy of recorded doses received in the early years of operations at older nuclear installations, such as the potential for 'missed' photon doses. A further issue is how baseline cancer rates may influence radiation-related excess risks. There is scope for a considerable increase in the statistical power of worker studies, with longer follow-up capturing more deaths and incident cases of cancer, and further workforces being included in collaborative studies, but the difficulties posed by dosimetry questions should not be ignored and need to be the subject of detailed scrutiny.

High Cancer Risk in US Naval Personnel Serving in Nuclear Powered Ships.

The USA Defense Threat Reduction Agency provided data in 2014 on the health status, including cancer, of the 4,843 sailors on the nuclear-powered United States Ship (USS) Ronald Reagan over the 2.55-year period from May 12, 2011 to Dec 31, 2013. Also provided were data on a matched control group of 65,269 US Navy personnel. Examination of the control population relative to the US national data gives a relative risk for all malignancies of RR = 9.2 (95% CI 8.48 < 9.2 < 9.96). The result suggests a significant cancer risk associated with serving on a nuclear-powered ship, one which is not predicted by the science underlying current radiation protection legislation.

Chronic bronchitis incidence in the extended cohort of Mayak workers first employed during 1948-1982.

OBJECTIVES: This paper describes findings from the study of chronic bronchitis (CB) incidence after occupational exposure to ionising radiation among workers employed at Russian Mayak Production Association (PA) during 1948 and 1982 and followed up until 2008 based on 'Mayak Worker Dosimetry System 2008'. METHODS: Analyses were based on 2135 verified cases among 21 417 workers. Rate ratios (RR) were estimated by categorical analysis for non-radiation and radiation factors. Excess rate ratios per Gy (ERR/Gy) of external or internal exposures with adjustments via stratification on other factors were calculated. RESULTS: The interesting finding in relation to non-radiation factors was a sharp increase in the RR for CB incidence before 1960, which could be caused by a number of factors. Analyses restricted to the follow-up after 1960 revealed statistically significant associations of the CB incidence and external γ-ray radiation, ERR/Gy=0.14 (95% CI 0.02 to 0.28) having adjusted for sex, attained age, calendar period, plant, smoking status and lung α-particle dose, and internal α-particle radiation, ERR/Gy=1.14 (95% CI 0.41 to 2.18) having adjusted for sex, attained age, calendar period, plant, smoking status and lung γ-ray dose and ERR/Gy=1.19 (95% CI 0.32 to 2.53) having additionally adjusted for pre-employment occupational hazards and smoking index instead of smoking status. CONCLUSIONS: Analyses of CB incidence in the study cohort identified positive significant association with occupational exposure to radiation: however, there are no similar studies of CB incidence in relation to radiation in other cohorts to date with which a meaningful comparison of the results could be made.

External radiation dose and cancer mortality among French nuclear workers: considering potential confounding by internal radiation exposure.

OBJECTIVES: French nuclear workers have detailed records of their occupational exposure to external radiation that have been used to examine associations with subsequent cancer mortality. However, some workers were also exposed to internal contamination by radionuclides. This study aims to assess the potential for bias due to confounding by internal contamination of estimates of associations between external radiation exposure and cancer mortality. METHODS: A cohort of 59,004 workers employed for at least 1 year between 1950 and 1994 by CEA (Commissariat à l'Energie Atomique), AREVA NC, or EDF (Electricité de France) and badge-monitored for external radiation exposure were followed through 2004 to assess vital status and cause of death. A flag based on a workstation-exposure matrix defined four levels of potential for internal contamination. Standardized mortality ratios were assessed for each level of the internal contamination indicator. Poisson regression was used to quantify associations between external radiation exposure and cancer mortality, adjusting for potential internal contamination. RESULTS: For solid cancer, the mortality deficit tended to decrease as the levels of potential for internal contamination increased. For solid cancer and leukemia excluding chronic lymphocytic leukemia, adjusting the dose-response analysis on the internal contamination indicator did not markedly change the excess relative risk per Sievert of external radiation dose. CONCLUSIONS: This study suggests that in this cohort, neglecting information on internal dosimetry while studying the association between external dose and cancer mortality does not generate a substantial bias. To investigate more specifically the health effects of internal contamination, an effort is underway to estimate organ doses due to internal contamination.

Impact of chemical exposure on cancer mortality in a French cohort of uranium processing workers.

BACKGROUND: Nuclear workers may be exposed to a variety of chemical hazards, in addition to radiation. We examined the effect of chemical exposures on cancer mortality among French uranium processing workers at the AREVA NC Pierrelatte facility. METHODS: A cohort of 2,897 uranium processing workers employed for at least 6 months was followed from 1968 through 2006. Exposure to uranium and potentially carcinogenic chemicals was assessed with a plant-specific job-exposure matrix. Mortality hazard ratios (HRs) for cancers of the lung, lymphohematopoietic system, kidney and bladder, brain and central nervous system (BCNS), and prostate were estimated for each specific chemical exposure, with Cox regression models stratified for sex and calendar period and adjusted for socioeconomic status. Additional adjustments enabled us to examine the effect of co-exposure to uranium and other chemicals. RESULTS: Exposure to aromatic solvents was associated with increased risk of BCNS malignancies after adjustment for other chemicals (HR=6.53, 95% CI=1.14-37.41; n=6) and for other chemicals and uranium (HR=7.26, 95% CI=0.90-58.19) in the annual exposure status model. Selected groups of lymphohematopoietic cancers were found associated with solvent exposure. Inconclusive results were found regarding chromium (VI) exposure, since only 2 workers died from lung cancer among 109 exposed. CONCLUSION: Based on our pilot study, it seemed important to take into account chemical exposures in the analyses of cancer mortality among French uranium processing workers.

Ionizing radiation and solid cancer mortality among US nuclear facility workers.

BACKGROUND: The risk of solid cancers from low-level protracted ionizing radiation is not well characterized. Nuclear workers provide valuable information on the effects of ionizing radiation in contemporary exposure scenarios relevant to workers and the public. METHODS: We evaluated the association between penetrating ionizing radiation exposure and solid cancer mortality among a pooled cohort of nuclear workers in the USA, with extended follow-up to examine cancers with long latencies. This analysis includes 101 363 workers from five nuclear facilities, with 12 069 solid cancer deaths between 1944 and 2016. The association between cumulative equivalent dose measured in sieverts (Sv) and solid cancer subtypes were modelled as the excess relative rate per Sv (ERR Sv-1) using Cox regression. RESULTS: For the association between ionizing radiation exposure and all solid cancer mortality we observed an elevated rate (ERR Sv-1=0.19; 95% CI: -0.10, 0.52), which was higher among a contemporary sub-cohort of workers first hired in 1960 or later (ERR Sv-1= 2.23; 95% CI: 1.13, 3.49). Similarly, we observed an elevated rate for lung cancer mortality (ERR Sv-1= 0.65; 95% CI: 0.09, 1.30) that was higher among contemporary hires (ERR Sv-1= 2.90; 95% CI: 1.00, 5.26). CONCLUSIONS: Although concerns remain about confounding, measurement error and precision, this analysis strengthens the evidence base indicating there are radiogenic risks for several solid cancer types.

The challenges of defining hormesis in epidemiological studies: The case of radiation hormesis.

In the current radiation protection system, preventive measures and occupational exposure limits for controlling occupational exposure to ionizing radiation are based on the linear no-threshold extrapolation model. However, currently an increasing body of evidence indicates that this paradigm predicts very poorly biological responses in the low-dose exposure region. In addition, several in vitro and in vivo studies demonstrated the presence of hormetic dose response curves correlated to ionizing radiation low exposure. In this regard, it is noteworthy that also the findings of different epidemiological studies, conducted in different categories of occupationally exposed workers (e.g., healthcare, nuclear industrial and aircrew workers), observed lower rates of mortality and/or morbidity from cancer and/or other diseases in exposed workers than in unexposed ones or in the general population, then suggesting the possible occurrence of hormesis. Nevertheless, these results should be considered with caution since the identification of hormetic response in epidemiological studies is rather challenging because of a number of major limitations. In this regard, some of the most remarkable shortcomings found in epidemiological studies performed in workers exposed to ionizing radiation are represented by lack or inadequate definition of exposure doses, use of surrogates of exposure, narrow dose ranges, lack of proper control groups and poor evaluation of confounding factors. Therefore, considering the valuable role and contribution that epidemiological studies might provide to the complex risk assessment and management process, there is a clear and urgent need to overcome the aforementioned limits in order to achieve an adequate, useful and more real-life risk assessment that should also include the key concept of hormesis. Thus, in the present conceptual article we also discuss and provide possible approaches to improve the capacity of epidemiological studies to identify/define the hormetic response and consequently improve the complex process of risk assessment of ionizing radiation at low exposure doses.

Environmental and industrial developments in radiation cataractogenesis.

PURPOSE: This review discusses recent developments in our understanding of biological and physiological mechanisms underlying radiation cataractogenesis. The areas discussed include effects of low-dose exposures to the lens including potential relevance of non-targeted effects, the development of new personal-protective equipment (PPE) and standards in clinical and nuclear settings motivated by the updated ICRP recommendations to mitigate exposures to the lens of the eye. The review also looks at evidence from the field linking cataracts in birds and mammals to low dose exposures. CONCLUSIONS: The review suggests that there is evidence that cataractogenesis is not a tissue reaction (deterministic effect) but rather is a low dose effect which shows a saturable dose response relationship similar to that seen for non-targeted effects in general. The review concludes that new research is needed to determine the dose response relationship in environmental studies where field data are contradictory and lab studies confined to rodent models for human exposure studies.

Updated Mortality Analysis of SELTINE, the French Cohort of Nuclear Workers, 1968-2014.

Cohorts of nuclear workers are particularly relevant to study the health effects of protracted exposures to low doses at low dose-rates of ionizing radiation (IR). In France, a cohort of nuclear workers badge-monitored for external IR exposure has been followed-up for several decades. Its size and follow-up period have recently been extended. The present paper focuses on mortality from both cancer and non-cancer diseases in this cohort. The SELTINE cohort of nuclear workers employed by CEA, Orano, and EDF companies was followed-up for mortality from 1968 to 2014. Mortality in the cohort was compared to that in the French general population. Poisson regression methods were used to estimate excess relative rates of mortality per unit of cumulative dose of IR, adjusted for calendar year, age, company, duration of employment, and socioeconomic status. The cohort included 80,348 workers. At the end of the follow-up, the mean attained age was 63 years, and 15,695 deaths were observed. A strong healthy worker effect was observed overall. A significant excess of pleural cancer mortality was observed but not associated with IR dose. Death from solid cancers was positively but non-significantly associated with radiation. Death from leukaemia (excluding chronic lymphocytic leukaemia), dementia, and Alzheimer's disease were positively and significantly associated with IR dose. Estimated dose-risk relationships were consistent with those from other nuclear worker studies for all solid cancers and leukaemia but remained associated with large uncertainty. The association between IR dose and dementia mortality risk should be interpreted with caution and requires further investigation by other studies.

Inflammatory profile dysregulation in nuclear workers occupationally exposed to low-dose gamma radiation.

Chronic inflammation is a common denominator linking a wide range of health conditions, including tissue response to radiation exposure. This pilot study investigates whether inflammatory cytokines-interleukins IL-6, -8, -10, monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor α (TNFα)-can be used as early biomarkers of radiation-induced adverse health effects in occupationally exposed individuals. The study included 33 workers externally exposed to gamma radiation from the nuclear industry with cumulated doses from 0.11 to 190 mSv and 42 non-exposed controls of comparable age and socio-economic status. IL-6, IL-8, MCP-1, TNFα and IL-10 were analyzed by enzyme-linked assay (ELISA) in blood plasma samples. Total antioxidant status (TAS) of blood plasma was determined by a colorimetric assay. The radiation-exposed and control groups measured significantly different levels of MCP-1, TNFα and IL-10. Seventy-five percent of radiation workers had either high MCP-1 levels or low IL-10 levels and 30% had all three cytokines dysregulated. Approximately 50% of workers showed upregulated antioxidant status, which appeared to compensate the pro-inflammatory cytokine shift in these individuals. In contrast, only 2% of the control subjects were found to have three dysregulated cytokines, and all of them measured within the normal TAS range. The present study may represent an important step towards the establishment of a reliable set of biomarkers for health-risk estimation in population cohorts exposed to low radiation doses.

Harriet Hardy and the workers of Los Alamos: a campus-community historical investigation.

Harriet Hardy, protégé of Alice Hamilton, spent 1948 in the Health Division of Los Alamos Scientific Laboratory. The contemporary campaign for federal legislation to compensate nuclear workers brought to the fore living retirees in whose cases of occupational illness Hardy had a role in diagnosis or case management. A third case is documented in archival records. Methods of participatory action research were used to better document the cases and strategize in light of the evidence, thereby assisting the workers with compensation claims. Medical and neuropsychological exams of the mercury case were conducted. Hardy's diary entries and memoirs were interpreted in light of medicolegal documentation and workers' recollections. Through these participatory research activities, Harriet Hardy's role and influence both inside and outside the atomic weapons complex have been elucidated. An important lesson learned is the ongoing need for a system of protective medical evaluations for nuclear workers with complex chemical exposures.