Research and analysis

INWORKS: collaborative study using NRRW data

Updated 18 December 2023

The International Nuclear Workers Study (INWORKS) is an international epidemiological study on workers in the nuclear sector launched in 2011 and coordinated by the International Agency for Research on Cancer (IARC) which combines data from nuclear workers in the UK, US and France for pooled analysis. It seeks to gain greater knowledge relating to the risks of cancer and non-cancerous diseases linked to chronic exposure to low doses of ionising radiation at low dose rates. The UK component of the pooled data set is drawn from the NRRW-3 cohort.

Background

The effects of exposure to ionising radiation have been studied for many years and the health effects of moderate to high exposure are well understood. However, the effects of low-level, chronic exposure remain a subject of debate. Since the 1980s, studies of nuclear industry workers have been conducted to provide direct information about these effects. These cohorts are well suited for this purpose: they include a large number of workers, with individual (person-specific) monitoring of external doses and many years of follow-up. While early, cohort-specific studies generally found risks estimates that were compatible with those upon current radiation protection, recommendations are based on the fact that there was considerable uncertainty around these estimates.

To further improve the precision of estimates of radiation-induced cancer risk following protracted low doses of ionising radiation and to strengthen the scientific basis of radiation protection standards, an International Collaborative Study of Cancer Risk among Radiation Workers in the Nuclear Industry, the ‘15-Country Study’, was carried out using information from nearly 600,000 workers. Within the 15-country study, the cohorts of nuclear workers from France, the UK and the US provided the vast majority of the information available on early nuclear workers. They provided 62% of the person-years of follow-up and 67% of cancer and leukaemia deaths.

In recent years, the cohorts from France, the UK and the US have been updated. INWORKS was established to provide a basis for deriving more precise quantitative estimates of the risk of chronic, low-level exposure to ionising radiation, through an improved understanding of the association between protracted low-dose exposure to ionising radiation and mortality due to solid and haematological cancers, and non-cancer diseases. INWORKS is organised by, and data is housed at, the IARC.

Study population

In total the pooled cohort includes 308,297 nuclear workers from France, the UK and the US, with detailed individual monitoring data for external exposure to ionising radiation. Data for French workers was obtained from 3 major employers:

• Commissariat à l’Energie Atomique (CEA)
• AREVA Nuclear Cycle (AREVA)
• Electricité de France (EDF)

Data for UK workers was obtained from:

• the National Registry for Radiation Workers (NRRW), which contains information provided by the Atomic Weapons Establishment (AWE)
• British Nuclear Fuels Ltd. (BNFL)
• the United Kingdom Atomic Energy Authority (UKAEA)
• British Energy Generation
• Magnox Electric (BEGME)
• UK Ministry of Defence (MoD)

Data for US workers was obtained from:

• the Department of Energy’s Hanford Site
• Savannah River Site (SRS)
• Oak Ridge National Laboratory (ORNL)
• Idaho National Laboratory (INL)
• Portsmouth Naval Shipyard (PNS)

The pooled cohort had a mean duration of follow-up of 27 years, the number of observed deaths was 66,632, including 17,957 deaths due to solid cancers, 1,791 deaths due to haematological cancers and 27,848 deaths due to cardiovascular diseases. Mean individual cumulative external dose over the period of 1,945 to 2,005 was 25 mSv.

Methods

Using standard methods of statistical modelling, the dose-response relationship between external radiation exposure and mortality rate was studied for a range of causes of death including the solid cancer, haematological cancers and non-cancer outcomes.

Solid cancer results

Analyses demonstrated a significant association between colon dose and the risk of solid cancers. Results suggested a linear increase in the rate of cancer with increasing radiation exposure. The estimated rate of mortality from all cancers excluding leukaemia increased with cumulative dose by 48% per Sv (90% confidence interval 20% to 79%), lagged by 10 years. Similar associations were seen for mortality from all solid cancers (47% (18% to 79%)), and within each country. The estimated association over the dose range of 0 to 100 mSv was similar in magnitude to that obtained over the entire dose range but less precise. Smoking and occupational asbestos exposure are potential confounders. However, exclusion of deaths from lung cancer and pleural cancer did not affect the estimated association.

The study provides a direct estimate of the association between protracted low dose exposure to ionising radiation and solid cancer mortality. Although high dose rate exposures are thought to be more dangerous than low dose rate exposures, the risk per unit of radiation dose for cancer among radiation workers was similar to estimates derived from studies of Japanese atomic bomb survivors. Quantifying the cancer risks associated with protracted radiation exposures can help to strengthen the foundation for radiation protection standards.

Lymphoma and leukaemia results

Analyses demonstrated a significant association between red bone marrow dose and the risk of leukaemia. The excess relative risk of leukaemia mortality (excluding chronic lymphocytic leukaemia) was 2·96 per Sv (90% CI 1·17–5·21, lagged 2 years), most notably because of an association between radiation dose and mortality from chronic myeloid leukaemia (excess relative risk per Sv 10·45, 90% CI 4·48–19·65).

The results of the study reinforce the evidence of the existence of a relationship between leukaemia risk and exposure to ionising radiation. They show that this relationship is observed for chronic exposure to low doses of radiations, thus reinforcing one of the foundations of the current system of radiological protection.

Non-cancer results

A statistically significant association between radiation dose and all non-cancer causes of death was observed [excess relative risk per sievert (ERR/Sv) = 0.19; 90% CI: 0.07, 0.30]. This was largely driven by the association between radiation dose and mortality due to circulatory diseases (ERR/Sv = 0.22; 90% CI: 0.08, 0.37), with slightly smaller positive, but nonsignificant, point estimates for mortality due to non-malignant respiratory disease (ERR/Sv = 0.13; 90% CI: −0.17, 0.47) and digestive disease (ERR/Sv = 0.11; 90% CI: −0.36, 0.69). The point estimate for the association between radiation dose and deaths due to external causes of death was non-significantly negative (ERR = −0.12; 90% CI: <−0.60, 0.45). Within circulatory disease subtypes, associations with dose were observed for mortality due to cerebrovascular disease (ERR/Sv = 0.50; 90% CI: 0.12, 0.94) and mortality due to ischemic heart disease (ERR/Sv = 0.18; 90% CI: 0.004, 0.36). The estimates of associations between radiation dose and non-cancer mortality are generally consistent with those observed in atomic bomb survivor studies.

The findings of this study provide further evidence that non-cancer disease risks may be increased by external radiation exposure, particularly for ischemic heart disease and cerebrovascular disease. However, heterogeneity in the estimated ERR/Sv was observed, which warrants further investigation. Further work on elucidating the biological mechanisms that might cause these non-cancer effects at low doses is also needed.

Conclusions

INWORKS has assembled some of the strongest evidence to strengthen the scientific basis for the protection of adults from low dose, low-dose rate, exposures to ionising radiation. The study provides a direct estimate of the association between protracted low dose exposure to ionising radiation and solid cancer mortality. Although high dose rate exposures are thought to be more dangerous than low dose rate exposures, the risk per unit of radiation dose for cancer among radiation workers was similar to estimates derived from studies of Japanese atomic bomb survivors. Quantifying the cancer risks associated with protracted radiation exposures can help strengthen the foundation for radiation protection standards.

List of publications on the INWORKS cohort

Details of the INWORKS study findings were presented in a series of publications and further details on the above findings along with associated additional information can be found in the following publications:

• Hamra GB, Richardson DB, Cardis E, Daniels RD, Gillies M, O’Hagan JA, and others. Cohort Profile: The International Nuclear Workers Study (INWORKS). Int J Epidemiol. 2016;45(3):693-9.
• Richardson DB, Cardis E, Daniels RD, Gillies M, O’Hagan JA, Hamra GB, and others. Risk of cancer from occupational exposure to ionising radiation: retrospective cohort study of workers in France, the United Kingdom, and the United States (INWORKS). BMJ. 2015;351:h5359.
• Leuraud K, Richardson DB, Cardis E, Daniels RD, Gillies M, O’Hagan JA, and others. Ionising radiation and risk of death from leukaemia and lymphoma in radiation-monitored workers (INWORKS): an international cohort study. Lancet Haematol. 2015;2(7):e276-81.
• Schubauer-Berigan MK, Leuraud K, Richardson DB, Cardis E, Daniels RD, Gillies M, and others. INWORKS study: risk of leukaemia from protracted radiation exposure - Authors’ reply. Lancet Haematol. 2015;2(10):e405-6.
• Thierry-Chef I, Richardson DB, Daniels RD, Gillies M, Hamra GB, Haylock R, and others. Dose Estimation for a Study of Nuclear Workers in France, the United Kingdom and the United States of America: Methods for the International Nuclear Workers Study (INWORKS). Radiat Res. 2015;183(6):632-42.
• Laurier D, Richardson DB, Cardis E, Daniels RD, Gillies M, O’Hagan J, and others. The International Nuclear Workers Study (Inworks): A Collaborative Epidemiological Study to Improve Knowledge About Health Effects of Protracted Low-Dose Exposure. Radiat Prot Dosimetry. 2017;173(1-3):21-5.
• Gillies M, Richardson DB, Cardis E, Daniels RD, O’Hagan JA, Haylock R, and others. Mortality from Circulatory Diseases and other Non-Cancer Outcomes among Nuclear Workers in France, the United Kingdom and the United States (INWORKS). Radiat Res. 2017;188(3):276-90.
• Daniels RD, Bertke SJ, Richardson DB, Cardis E, Gillies M, O’Hagan JA, and others. Examining temporal effects on cancer risk in the international nuclear workers’ study. Int J Cancer. 2017;140(6):1260-9.
• Richardson DB, Cardis E, Daniels RD, Gillies M, Haylock R, Leuraud K, and others. Site-specific Solid Cancer Mortality After Exposure to Ionizing Radiation: A Cohort Study of Workers (INWORKS). Epidemiology. 2018;29(1):31-40.
• Leuraud K, Richardson DB, Cardis E, Daniels RD, Gillies M, Haylock R, and others. Risk of cancer associated with low-dose radiation exposure: comparison of results between the INWORKS nuclear workers study and the A-bomb survivors study. Radiat Environ Biophys. 2021.

Legacy publications using NRRW data

The INWORKS study grew out of an earlier pooled international study also coordinated by IARC. The first of these studies was the 3-nations study with examined associations between radiation exposure and mortality in a pooled cohort of nuclear workers from the UK, US and Canada. This study used data from the first NRRW analysis. A follow-on to this study was the 15-country study, which combined data from 15 countries, including data from the second NRRW analysis. Further details of these legacy studies can be found in the following publications:

• Cardis E, Gilbert ES, Carpenter L, Howe G, Kato I, Armstrong BK, and others. Effects of low doses and low dose rates of external ionizing radiation: cancer mortality among nuclear industry workers in three countries. Radiat Res. 1995;142(2):117-32.
• Cardis E, Vrijheid M, Blettner M, Gilbert E, Hakama M, Hill C, and others. Risk of cancer after low doses of ionising radiation: retrospective cohort study in 15 countries. BMJ. 2005;331(7508):77.
• Vrijheid M, Cardis E, Ashmore P, Auvinen A, Bae JM, Engels H, and others. Mortality from diseases other than cancer following low doses of ionizing radiation: results from the 15-Country Study of nuclear industry workers. Int J Epidemiol. 2007;36(5):1126-35.
• Vrijheid M, Cardis E, Blettner M, Gilbert E, Hakama M, Hill C, and others. The 15-Country Collaborative Study of Cancer Risk Among Radiation Workers in the Nuclear Industry: design, epidemiological methods and descriptive results. Radiat Res. 2007;167(4):361-79.
• Cardis E, Vrijheid M, Blettner M, Gilbert E, Hakama M, Hill C, and others. The 15-Country Collaborative Study of Cancer Risk among Radiation Workers in the Nuclear Industry: estimates of radiation-related cancer risks. Radiat Res. 2007;167(4):396-416.