Leukaemia, lymphoma, and multiple myeloma mortality after low-level exposure to ionising radiation in nuclear workers (INWORKS): updated findings from an international cohort study.

BACKGROUND: A major update to the International Nuclear Workers Study (INWORKS) was undertaken to strengthen understanding of associations between low-dose exposure to penetrating forms of ionising radiation and mortality. Here, we report on associations between radiation dose and mortality due to haematological malignancies. METHODS: We assembled a cohort of 309 932 radiation-monitored workers (269 487 [87%] males and 40 445 [13%] females) employed for at least 1 year by a nuclear facility in France (60 697 workers), the UK (147 872 workers), and the USA (101 363 workers). Workers were individually monitored for external radiation exposure and followed-up from Jan 1, 1944, to Dec 31, 2016, accruing 10·72 million person-years of follow-up. Radiation-mortality associations were quantified in terms of the excess relative rate (ERR) per Gy of radiation dose to red bone marrow for leukaemia excluding chronic lymphocytic leukaemia (CLL), as well as subtypes of leukaemia, myelodysplastic syndromes, non-Hodgkin and Hodgkin lymphomas, and multiple myeloma. Estimates of association were obtained using Poisson regression methods. FINDINGS: The association between cumulative dose to red bone marrow, lagged 2 years, and leukaemia (excluding CLL) mortality was well described by a linear model (ERR per Gy 2·68, 90% CI 1·13 to 4·55, n=771) and was not modified by neutron exposure, internal contamination monitoring status, or period of hire. Positive associations were also observed for chronic myeloid leukaemia (9·57, 4·00 to 17·91, n=122) and myelodysplastic syndromes alone (3·19, 0·35 to 7·33, n=163) or combined with acute myeloid leukaemia (1·55, 0·05 to 3·42, n=598). No significant association was observed for acute lymphoblastic leukaemia (4·25, -4·19 to 19·32, n=49) or CLL (0·20, -1·81 to 2·21, n=242). A positive association was observed between radiation dose and multiple myeloma (1·62, 0·06 to 3·64, n=527) whereas minimal evidence of association was observed between radiation dose and non-Hodgkin lymphoma (0·27, -0·61 to 1·39, n=1146) or Hodgkin lymphoma (0·60, -3·64 to 4·83, n=122) mortality. INTERPRETATION: This study reports a positive association between protracted low dose exposure to ionising radiation and mortality due to some haematological malignancies. Given the relatively low doses typically accrued by workers in this study (16 mGy average cumulative red bone marrow dose) the radiation attributable absolute risk of leukaemia mortality in this population is low (one excess death in 10 000 workers over a 35-year period). These results can inform radiation protection standards and will provide input for discussions on the radiation protection system. FUNDING: National Cancer Institute, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Institut de Radioprotection et de Sûreté Nucléaire, Orano, Electricité de France, UK Health Security Agency. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Site-specific cancer mortality after low level exposure to ionizing radiation: Findings from an update of the International Nuclear Workers Study (INWORKS).

A major update to the International Nuclear Workers Study was undertaken that allows us to report updated estimates of associations between radiation and site-specific solid cancer mortality. A cohort of 309,932 nuclear workers employed in France, the United Kingdom, and United States were monitored for external radiation exposure and associations with cancer mortality were quantified as the excess relative rate (ERR) per gray (Gy) using a maximum likelihood and a Markov chain Monte Carlo method (to stabilize estimates via a hierarchical regression). The analysis included 28,089 deaths due to solid cancer, the most common being lung, prostate, and colon cancer. Using maximum likelihood, positive estimates of ERR per Gy were obtained for stomach, colon, rectum, pancreas, peritoneum, larynx, lung, pleura/mesothelioma, bone and connective tissue, skin, prostate, testis, bladder, kidney, thyroid, and residual cancers; negative estimates of ERR per Gy were found cancers of oral cavity and pharynx, esophagus, and ovary. A hierarchical model stabilized site-specific estimates of association, including for lung (ERR per Gy=0.65; 95% credible interval [CrI]: 0.24, 1.07), prostate (ERR per Gy=0.44; 95% CrI: -0.06, 0.91), and colon cancer (ERR per Gy=0.53; 95% CrI: -0.07, 1.11). The results contribute evidence regarding associations between low dose radiation and cancer.

Central nervous system tumours and occupational ionising radiation exposure: a nested case-control study among the ORICAMs cohort of healthcare workers in France.

OBJECTIVE: This study aimed at investigating the relationship between occupational exposure to external ionising radiation and central nervous system (CNS) tumours mortality in healthcare workers working in France. DESIGN AND SETTING: The Occupational Radiation-Induced Cancer in Medical staff (ORICAMs) nested case-control study was conducted based on the dosimetric records of the national register of occupational dosimetry (Système d'information de la surveillance de l'exposition aux rayonnements ionisants). PARTICIPANTS AND METHODS: 33 CNS tumour deaths occurred between 2002 and 2012 among the ORICAMs cohort composed of 164 015 healthcare workers. Each case was matched to five controls alive at the time of the corresponding case's death, based on sex, year of birth, date of enrolment in the cohort and duration of follow-up. All participants were badge monitored for external radiation exposure, expressed in Hp(10). Conditional logistic regression was used to analyse the dose-response relationship between radiation dose and CNS mortality. RESULTS: Cases were exposed to a mean cumulative career radiation dose of 5.8±13.7 (max: 54.3) millisievert (mSv) compared with 4.1±15.2 (142.2) mSv for controls. No statistically significant association was found between CNS tumour mortality and cumulative whole-body career dose (OR=1.00, 95% CI 0.98 to 1.03), duration of exposure (OR=1.03; 95% CI 0.95 to 1.12) or age at first exposure (OR=0.98; 95% CI 0.91 to 1.06). CONCLUSION: We found no evidence of an association between external radiation exposure and CNS tumour risk in healthcare workers. Limitations of the study include low statistical power and short duration of follow-up.

A multidisciplinary and structured investigation of three suspected clusters of transverse upper limb reduction defects in France.

INTRODUCTION: Between 2019-2021, facing public concern, a scientific expert committee (SEC) reanalysed suspected clusters of transverse upper limb reduction defects (TULRD) in three administrative areas in France, where initial investigations had not identified any risk exposure. We share here the national approach we developed for managing suspicious clusters of the same group of congenital anomalies occurring in several areas. METHODS: The SEC analysed the medical records of TURLD suspected cases and performed spatiotemporal analyses on confirmed cases. If the cluster was statistically significant and included at least three cases, the SEC reviewed exposures obtained from questionnaires, environmental databases, and a survey among farmers living near to cases' homes concerning their plant product use. RESULTS: After case re-ascertainment, no statistically significant cluster was observed in the first administrative areas. In the second area, a cluster of four children born in two nearby towns over two years was confirmed, but as with the initial investigations, no exposure to a known risk factor explaining the number of cases in excess was identified. In the third area, a cluster including just two cases born the same year in the same town was confirmed. DISCUSSION: Our experience highlights that in the event of suspicious clusters occurring in different areas of a country, a coordinated and standardised approach should be preferred.

Radiotherapy for non-cancer diseases: benefits and long-term risks.

PURPOSE: The discovery of X-rays was followed by a variety of attempts to treat infectious diseases and various other non-cancer diseases with ionizing radiation, in addition to cancer. There has been a recent resurgence of interest in the use of such radiotherapy for non-cancer diseases. Non-cancer diseases for which use of radiotherapy has currently been proposed include refractory ventricular tachycardia, neurodegenerative diseases (e.g. Alzheimer's disease and dementia), and Coronavirus Disease 2019 (COVID-19) pneumonia, all with ongoing clinical studies that deliver radiation doses of 0.5-25 Gy in a single fraction or in multiple daily fractions. In addition to such non-cancer effects, historical indications predominantly used in some countries (e.g. Germany) include osteoarthritis and degenerative diseases of the bones and joints. This narrative review gives an overview of the biological rationale and ongoing preclinical and clinical studies for radiotherapy proposed for various non-cancer diseases, discusses the plausibility of the proposed biological rationale, and considers the long-term radiation risks of cancer and non-cancer diseases. CONCLUSIONS: A growing body of evidence has suggested that radiation represents a double-edged sword, not only for cancer, but also for non-cancer diseases. At present, clinical evidence has shown some beneficial effects of radiotherapy for ventricular tachycardia, but there is little or no such evidence of radiotherapy for other newly proposed non-cancer diseases (e.g. Alzheimer's disease, COVID-19 pneumonia). Patients with ventricular tachycardia and COVID-19 pneumonia have thus far been treated with radiotherapy when they are an urgent life threat with no efficient alternative treatment, but some survivors may encounter a paradoxical situation where patients were rescued by radiotherapy but then get harmed by radiotherapy. Further studies are needed to justify the clinical use of radiotherapy for non-cancer diseases, and optimize dose to diseased tissue while minimizing dose to healthy tissue.

Cancer mortality after low dose exposure to ionising radiation in workers in France, the United Kingdom, and the United States (INWORKS): cohort study.

OBJECTIVE: To evaluate the effect of protracted low dose, low dose rate exposure to ionising radiation on the risk of cancer. DESIGN: Multinational cohort study. SETTING: Cohorts of workers in the nuclear industry in France, the UK, and the US included in a major update to the International Nuclear Workers Study (INWORKS). PARTICIPANTS: 309 932 workers with individual monitoring data for external exposure to ionising radiation and a total follow-up of 10.7 million person years. MAIN OUTCOME MEASURES: Estimates of excess relative rate per gray (Gy) of radiation dose for mortality from cancer. RESULTS: The study included 103 553 deaths, of which 28 089 were due to solid cancers. The estimated rate of mortality due to solid cancer increased with cumulative dose by 52% (90% confidence interval 27% to 77%) per Gy, lagged by 10 years. Restricting the analysis to the low cumulative dose range (0-100 mGy) approximately doubled the estimate of association (and increased the width of its confidence interval), as did restricting the analysis to workers hired in the more recent years of operations when estimates of occupational external penetrating radiation dose were recorded more accurately. Exclusion of deaths from lung cancer and pleural cancer had a modest effect on the estimated magnitude of association, providing indirect evidence that the association was not substantially confounded by smoking or occupational exposure to asbestos. CONCLUSIONS: This major update to INWORKS provides a direct estimate of the association between protracted low dose exposure to ionising radiation and solid cancer mortality based on some of the world's most informative cohorts of radiation workers. The summary estimate of excess relative rate solid cancer mortality per Gy is larger than estimates currently informing radiation protection, and some evidence suggests a steeper slope for the dose-response association in the low dose range than over the full dose range. These results can help to strengthen radiation protection, especially for low dose exposures that are of primary interest in contemporary medical, occupational, and environmental settings.

Cohort profile: ORICAMs, a French cohort of medical workers exposed to low-dose ionizing radiation.

Medical personnel represent the largest group of workers occupationally exposed to ionizing radiation. Although the health risks associated with occupational exposure to low doses of ionizing radiation in the medical field have been investigated in several national cohorts, no study has been conducted in France to date. The ORICAMs (Occupational Radiation Induced Cancer in Medical staff) cohort is a nationwide French longitudinal cohort of medical workers exposed to ionizing radiation aiming to investigate the risk of radiation-associated cancer and non-cancer mortality. The ORICAMs cohort was set up in 2011 and includes all medical personnel monitored for ionizing radiation exposure with at least one dosimetric record in the SISERI database (the national registry for monitoring ionizing radiation exposure in workers) over the period 2002-2012. Causes of death were abstracted from death certificates and coded according to ICD-10. The follow-up ended on 31/12/2013. Standardized mortality ratios (SMRs) were calculated by cause of death to compare the mortality in the cohort to that in the French population, by gender, age group and calendar period. Among the 164,015 workers included in the cohort (60% women) a total of 1,358 deaths (892 in male and 466 in female) were reported. The observed number of all-cause deaths was significantly lower than expected based on national rates in both male (SMR = 0.35; 95% CI: 0.33, 0.38; ndeaths = 892) and female (SMR = 0.41; 95% CI: 0.38, 0.45; ndeaths = 466). This analysis leads to the conclusion that mortality in French workers exposed to medical radiation is significantly lower than the national reference rates. However, these results based on a comparative analysis with national rates may be impacted by the healthy worker effect towards low SMRs, and do not enable to establish a potential relationship between occupational exposure and mortality risk, even if we may suspect an impact of high SES of these professionals on the observed decreased mortality. Thus, further dose-response analyses based on individual ionizing radiation exposure and job's type will be conducted to characterize correlation between risk of cancer mortality and occupational exposure.

The scientific basis for the use of the linear no-threshold (LNT) model at low doses and dose rates in radiological protection.

The linear no-threshold (LNT) model was introduced into the radiological protection system about 60 years ago, but this model and its use in radiation protection are still debated today. This article presents an overview of results on effects of exposure to low linear-energy-transfer radiation in radiobiology and epidemiology accumulated over the last decade and discusses their impact on the use of the LNT model in the assessment of radiation-related cancer risks at low doses. The knowledge acquired over the past 10 years, both in radiobiology and epidemiology, has reinforced scientific knowledge about cancer risks at low doses. In radiobiology, although certain mechanisms do not support linearity, the early stages of carcinogenesis comprised of mutational events, which are assumed to play a key role in carcinogenesis, show linear responses to doses from as low as 10 mGy. The impact of non-mutational mechanisms on the risk of radiation-related cancer at low doses is currently difficult to assess. In epidemiology, the results show excess cancer risks at dose levels of 100 mGy or less. While some recent results indicate non-linear dose relationships for some cancers, overall, the LNT model does not substantially overestimate the risks at low doses. Recent results, in radiobiology or in epidemiology, suggest that a dose threshold, if any, could not be greater than a few tens of mGy. The scientific knowledge currently available does not contradict the use of the LNT model for the assessment of radiation-related cancer risks within the radiological protection system, and no other dose-risk relationship seems more appropriate for radiological protection purposes.

Radiation and CNS effects: summary of evidence from a recent symposium of the Radiation Research Society.

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.

Ionizing radiation exposure during adulthood and risk of developing central nervous system tumors: systematic review and meta-analysis.

Many studies on ionizing radiation (IR) exposure during childhood have shown deleterious effects on the central nervous system (CNS), however results regarding adult exposure are inconsistent, and no systematic reviews have been performed. The objectives are to synthesize the findings and draw evidence-based conclusions from epidemiological studies on the risk of benign and malignant brain and CNS tumors in humans exposed to low-to-moderate doses (< 0.5 Gy) of IR during adulthood/young adulthood. A systematic literature search of four electronic databases, supplemented by a hand search, was performed to retrieve relevant epidemiological studies published from 2000 to 2022. Pooled excess relative risk (ERRpooled) was estimated using a random effect model. Eighteen publications were included in the systematic review and twelve out of them were included in a meta-analysis. The following IR sources were considered: atomic bombs, occupational, and environmental exposures. No significant dose-risk association was found for brain/CNS tumors (ERRpooled at 100 mGy = - 0.01; 95% CI: - 0.05, 0.04). Our systematic review and meta-analysis did not show any association between exposure to low-to-moderate doses of IR and risk of CNS tumors. Further studies with histological information and precise dose assessment are needed.

Risk of Developing Non-Cancerous Central Nervous System Diseases Due to Ionizing Radiation Exposure during Adulthood: Systematic Review and Meta-Analyses.

Background: High-dose ionizing radiation (IR) (>0.5 Gy) is an established risk factor for cognitive impairments, but this cannot be concluded for low-to-moderate IR exposure (<0.5 Gy) in adulthood as study results are inconsistent. The objectives are to summarize relevant epidemiological studies of low-to-moderate IR exposure in adulthood and to assess the risk of non-cancerous CNS diseases. Methods: A systematic literature search of four electronic databases was performed to retrieve relevant epidemiological studies published from 2000 to 2022. Pooled standardized mortality ratios, relative risks, and excess relative risks (ERR) were estimated with a random effect model. Results: Forty-five publications were included in the systematic review, including thirty-three in the quantitative meta-analysis. The following sources of IR-exposure were considered: atomic bomb, occupational, environmental, and medical exposure. Increased dose-risk relationships were found for cerebrovascular diseases incidence and mortality (ERRpooled per 100 mGy = 0.04; 95% CI: 0.03−0.05; ERRpooled at 100 mGy = 0.01; 95% CI: −0.00−0.02, respectively) and for Parkinson's disease (ERRpooled at 100 mGy = 0.11; 95% CI: 0.06−0.16); Conclusions: Our findings suggest that adult low-to-moderate IR exposure may have effects on non-cancerous CNS diseases. Further research addressing inherent variation issues is encouraged.

Childhood cancer risks estimates following CT scans: an update of the French CT cohort study.

OBJECTIVES: Increased risks of central nervous system (CNS) tumors and leukemia associated with computed tomography (CT) exposure during childhood have been reported in recent epidemiological studies. However, no evidence of increased risks was suggested in a previous analysis of the French CT cohort. This study benefits from an updated cohort with a longer follow-up and a larger sample size of patients. METHODS: The patients were followed from the date of their first CT (between 2000 and 2011) until their date of cohort exit defined as the earliest among the following: 31 December 2016, date of death, date of first cancer diagnosis or date of their 18th birthday. Cancer incidence, vital status, cancer predisposing factors (PFs), and additional CT scans were collected via external national databases. Hazard ratios (HRs) associated to cumulative organ doses and sex were estimated from Cox models. RESULTS: At the end of follow-up, mean cumulative doses were 27.7 and 10.3 mGy for the brain and the red bone marrow (RBM), respectively. In patients without PFs, an HR per 10 mGy of 1.05 (95% CI: 1.01-1.09) for CNS tumors, 1.17 (95% CI: 1.09-1.26) for leukemia, and 0.96 (95% CI: 0.63-1.45) for lymphoma was estimated. These estimates were not modified by the inclusion of CT scans performed outside the participating hospitals or after the inclusion period. CONCLUSIONS: This study shows statistically significant dose-response relationships for CNS tumors and leukemia for patients without PFs. KEY POINTS: • Computed tomography is the most important contributor to the collective dose for diagnostic imaging to the French population. • Concerns have been raised about possible cancer risks, particularly after exposure to CT in childhood, due to the greater radiation sensitivity of children and to their longer life expectancy. • Analysis of the updated French CT cohort shows statistically significant dose-response relationships for CNS tumors and leukemia.

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.

Exposure to low-dose ionising radiation from cardiac catheterisation and risk of cancer: the COCCINELLE study cohort profile.

PURPOSE: The COCCINELLE study is a nationwide retrospective French cohort set up to evaluate the risk of cancer in patients who undergone cardiac catheterisation (CC) procedures for diagnosis or treatment of congenital heart disease during childhood. PARTICIPANTS: Children who undergone CC procedures from 1 January 2000 to 31 December 2013, before the age of 16 in one of the 15 paediatric cardiology departments which perform paediatric CC in mainland France were included. The follow-up started at the date of the first recorded CC procedure until the exit date, that is, the date of death, the date of first cancer diagnosis, the date of the 18th birthday or the 31 December 2015, whichever occurred first. The cohort was linked to the National Childhood Cancer Registry to identify patients diagnosed with cancer and with the French National Directory for the Identification of Natural Persons to retrieve the patients' vital status. FINDINGS TO DATE: A total of 17 104 children were included in the cohort and followed for 110 335 person-years, with 22 227 CC procedures collected. Among the patients, 81.6% received only one procedure. Fifty-nine cancer cases were observed in the cohort. Standardised incidence ratios (SIRs) were increased for all-cancer (SIR=3.8, 95% CI: 2.9 to 4.9), leukaemia (SIR=3.3, 95% CI: 2.0 to 5.4), lymphoma (SIR=14.9, 95% CI: 9.9 to 22.5) and solid cancers excluding central nervous system (CNS) tumours (SIR=3.3, 95% CI: 2.0 to 5.5) compared with the general population. FUTURE PLANS: Dose reconstruction is currently underway to estimate individual cumulative doses absorbed to relevant organs, including red bone marrow and brain for respectively haematologic disorders and CNS tumours risk estimation. A dose-response analysis will be conducted with consideration to confounding factors such as age at exposure, gender, predisposing factors to cancer and other sources of medical diagnostic low-dose ionising radiation.

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.

Early life ionizing radiation exposure and cancer risks: systematic review and meta-analysis.

BACKGROUND: Ionizing radiation use for medical diagnostic purposes has substantially increased over the last three decades. Moderate to high doses of radiation are well established causes of cancer, especially for exposure at young ages. However, cancer risk from low-dose medical imaging is debated. OBJECTIVE: To review the literature on cancer risks associated with prenatal and postnatal medical diagnostic ionizing radiation exposure among children and to assess this risk through a meta-analysis. MATERIALS AND METHODS: A literature search of five electronic databases supplemented by a hand search was performed to retrieve relevant epidemiological studies published from 2000 to 2019, including patients younger than 22 years of age exposed to medical imaging ionizing radiation. Pooled odds ratio (ORpooled) and pooled excess relative risk (ERRpooled) representing the excess of risk per unit of organ dose were estimated with a random effect model. RESULTS: Twenty-four studies were included. For prenatal exposure (radiographs or CT), no significant increased risk was reported for all cancers, leukemia and brain tumors. For postnatal exposure, increased risk was observed only for CT, mostly for leukemia (ERRpooled=26.9 Gy-1; 95% confidence interval [CI]: 2.7-57.1) and brain tumors (ERRpooled=9.1 Gy-1; 95% CI: 5.2-13.1). CONCLUSION: CT exposure in childhood appears to be associated with increased risk of cancer while no significant association was observed with diagnostic radiographs.

Meta-analysis of published excess relative risk estimates.

A meta-analytic summary effect estimate often is calculated as an inverse-variance-weighted average of study-specific estimates of association. The variances of published estimates of association often are derived from their associated confidence intervals under assumptions typical of Wald-type statistics, such as normality of the parameter. However, in some research areas, such as radiation epidemiology, epidemiological results typically are obtained by fitting linear relative risk models, and associated likelihood-based confidence intervals are often asymmetric; consequently, reasonable estimates of variances associated with study-specific estimates of association may be difficult to infer from the standard approach based on the assumption of a Wald-type interval. Here, a novel method is described for meta-analysis of published results from linear relative risk models that uses a parametric transformation of published results to improve on the normal approximation used to assess confidence intervals. Using simulations, it is illustrated that the meta-analytic summary obtained using the proposed approach yields less biased summary estimates, with better confidence interval coverage, than the summary obtained using the more classical approach to meta-analysis. The proposed approach is illustrated using a previously published example of meta-analysis of epidemiological findings regarding circulatory disease following exposure to low-level ionizing radiation.

Analysis of the association between ionizing radiation and mortality in uranium workers from five plants involved in the nuclear fuel production cycle in France.

PURPOSE: The aim is to investigate associations between mortality and exposure to ionizing radiation in a cohort of uranium workers with potential for internal and external radiation exposures. METHODS: Workers employed for at least 6 months between 1958 and 2006 in five plants involved in the French nuclear fuel cycle were included and followed up between 1968 and 2013. Cause-specific standardized mortality ratios were calculated. Analyses of associations between individual cumulative radiation dose (both internal and external, lagged by 5-15 years) and mortality were conducted using Poisson regression. RESULTS: The cohort includes 4541 workers. The mean cumulative external dose was 11.12 mGy. Mean cumulative internal doses ranged, depending on modelling hypotheses, from 0.05 to 0.09 mGy (liver) and from 4.22 to 10.90 mGy (lung). At the end of the follow-up, 838 workers were deceased and 28 lost to follow-up. A healthy worker effect was observed. The risk of prostate and lung cancers mortality was significantly higher for workers exposed to cumulative external dose above 50 mGy compared to non-exposed, but these associations were based only on three cases and became non-significant, although of similar magnitude, after adjustment for smoking. Associations with internal dose showed no consistent pattern. CONCLUSIONS: For the first time, a study was conducted in a French cohort of uranium workers with a complete reconstruction of internal dose. Results are preliminary and must be interpreted with caution because of the limited cohort size and significant sources of uncertainty. Future steps of this study will overcome these limitations.

Impact of considering non-occupational radiation exposure on the association between occupational dose and solid cancer among French nuclear workers.

OBJECTIVES: The French nuclear worker cohort allows for the assessment of cancer risk associated with occupational radiation exposure, but workers are also exposed to medical and environmental radiation which can be of the same order of magnitude. This study aims to examine the impact of non-occupational radiation exposures on the dose-risk analysis between occupational radiation exposure and cancer mortality. METHODS: The cohort included workers employed before 1995 for at least one year by CEA, AREVA NC or EDF and badge-monitored for external radiation exposure. Monitoring results were used to calculate occupational individual doses. Scenarios of work-related X-ray and environmental exposures were simulated. Poisson regression was used to quantify associations between occupational exposure and cancer mortality adjusting for non-occupational radiation exposure. RESULTS: The mean cumulative dose of external occupational radiation was 18.4 mSv among 59 004 workers. Depending on the hypotheses made, the mean cumulative work-related X-ray dose varied between 3.1 and 9.2 mSv and the mean cumulative environmental dose was around 130 mSv. The unadjusted excess relative rate of cancer per Sievert (ERR/Sv) was 0.34 (90% CI -0.44 to 1.24). Adjusting for environmental radiation exposure did not substantially modify this risk coefficient, but it was attenuated by medical exposure (ERR/Sv point estimate between 0.15 and 0.23). CONCLUSIONS: Occupational radiation risk estimates were lower when adjusted for work-related X-ray exposures. Environmental exposures had a very slight impact on the occupational exposure risk estimates. In any scenario of non-occupational exposure considered, a positive but insignificant excess cancer risk associated with occupational exposure was observed.