A Historical Survey of Key Epidemiological Studies of Ionizing Radiation Exposure.

In this article we review the history of key epidemiological studies of populations exposed to ionizing radiation. We highlight historical and recent findings regarding radiation-associated risks for incidence and mortality of cancer and non-cancer outcomes with emphasis on study design and methods of exposure assessment and dose estimation along with brief consideration of sources of bias for a few of the more important studies. We examine the findings from the epidemiological studies of the Japanese atomic bomb survivors, persons exposed to radiation for diagnostic or therapeutic purposes, those exposed to environmental sources including Chornobyl and other reactor accidents, and occupationally exposed cohorts. We also summarize results of pooled studies. These summaries are necessarily brief, but we provide references to more detailed information. We discuss possible future directions of study, to include assessment of susceptible populations, and possible new populations, data sources, study designs and methods of analysis.

Solar ultraviolet radiation exposure, and incidence of childhood acute lymphocytic leukaemia and non-Hodgkin lymphoma in a US population-based dataset.

BACKGROUND: Acute lymphocytic leukaemia (ALL) and non-Hodgkin lymphoma (NHL) are among the commonest types of childhood cancer. Some previous studies suggested that elevated ultraviolet radiation (UVR) exposures increase ALL risk; many more indicate NHL risk is reduced. METHODS: We assessed age<20 ALL/NHL incidence in Surveillance, Epidemiology and End Results data using AVGLO-derived UVR irradiance/cumulative radiant exposure measures, using quasi-likelihood models accounting for underdispersion, adjusted for age, sex, racial/ethnic group and other county-level socioeconomic variables. RESULTS: There were 30,349 cases of ALL and 8062 of NHL, with significant increasing trends of ALL with UVR irradiance (relative risk (RR) = 1.200/mW/cm2 (95% CI 1.060, 1.359, p = 0.0040)), but significant decreasing trends for NHL (RR = 0.646/mW/cm2 (95% CI 0.512, 0.816, p = 0.0002)). There was a borderline-significant increasing trend of ALL with UVR cumulative radiant exposure (RR = 1.444/MJ/cm2 (95% CI 0.949, 2.197, p = 0.0865)), and significant decreasing trends for NHL (RR = 0.284/MJ/cm2 (95% CI 0.166, 0.485, p < 0.0001)). ALL and NHL trend RR is substantially increased among those aged 0-3. All-age trend RRs are most extreme (increasing for ALL, decreasing for NHL) for Hispanics for both UVR measures. CONCLUSIONS: Our more novel finding, of excess UVR-related ALL risk, is consistent with some previous studies, but is not clear-cut, and in need of replication.

Cancer risks among studies of medical diagnostic radiation exposure in early life without quantitative estimates of dose.

BACKGROUND: There is accumulating evidence of excess risk of cancer in various populations exposed at acute doses below several tens of mSv or doses received over a protracted period. There is also evidence that relative risks are generally higher after radiation exposures in utero or in childhood. METHODS AND FINDINGS: We reviewed and summarised evidence from 89 studies of cancer following medical diagnostic exposure in utero or in childhood, in which no direct estimates of radiation dose are available. In all of the populations studied exposure was to sparsely ionizing radiation (X-rays). Several of the early studies of in utero exposure exhibit modest but statistically significant excess risks of several types of childhood cancer. There is a highly significant (p < 0.0005) negative trend of odds ratio with calendar period of study, so that more recent studies tend to exhibit reduced excess risk. There is no significant inter-study heterogeneity (p > 0.3). In relation to postnatal exposure there are significant excess risks of leukaemia, brain and solid cancers, with indications of variations in risk by cancer type (p = 0.07) and type of exposure (p = 0.02), with fluoroscopy and computed tomography scans associated with the highest excess risk. However, there is highly significant inter-study heterogeneity (p < 0.01) for all cancer endpoints and all but one type of exposure, although no significant risk trend with calendar period of study. CONCLUSIONS: Overall, this large body of data relating to medical diagnostic radiation exposure in utero provides support for an associated excess risk of childhood cancer. However, the pronounced heterogeneity in studies of postnatal diagnostic exposure, the implied uncertainty as to the meaning of summary measures, and the distinct possibilities of bias, substantially reduce the strength of the evidence from the associations we observe between radiation imaging in childhood and the subsequent risk of cancer being causally related to radiation exposure.

Review of the risk of cancer following low and moderate doses of sparsely ionising radiation received in early life in groups with individually estimated doses.

BACKGROUND: The detrimental health effects associated with the receipt of moderate (0.1-1 Gy) and high (>1 Gy) acute doses of sparsely ionising radiation are well established from human epidemiological studies. There is accumulating direct evidence of excess risk of cancer in a number of populations exposed at lower acute doses or doses received over a protracted period. There is evidence that relative risks are generally higher after radiation exposures in utero or in childhood. METHODS AND FINDINGS: We reviewed and summarised evidence from 60 studies of cancer or benign neoplasms following low- or moderate-level exposure in utero or in childhood from medical and environmental sources. In most of the populations studied the exposure was predominantly to sparsely ionising radiation, such as X-rays and gamma-rays. There were significant (p < 0.001) excess risks for all cancers, and particularly large excess relative risks were observed for brain/CNS tumours, thyroid cancer (including nodules) and leukaemia. CONCLUSIONS: Overall, the totality of this large body of data relating to in utero and childhood exposure provides support for the existence of excess cancer and benign neoplasm risk associated with radiation doses < 0.1 Gy, and for certain groups exposed to natural background radiation, to fallout and medical X-rays in utero, at about 0.02 Gy.

A review of studies of childhood cancer and natural background radiation.

PURPOSE: The projected existence and magnitude of carcinogenic effects of ionizing radiation at low doses and low-dose rates is perhaps the most important issue in radiation protection today. Studies of childhood cancer and natural background radiation have the potential to throw direct light on this question, into a dose range below a few tens of mSv. This paper describes the studies that have been undertaken and their context, discusses some problems that arise and summarizes the present position. CONCLUSIONS: Many such studies have been undertaken, but most were too small to have a realistic chance of detecting the small effects expected from such low doses, based on risk projections from higher exposures. Case-control or cohort studies are to be preferred methodologically to ecological studies but can be prone to problems of registration/participation bias. Interview-based studies of the requisite size would be prohibitively expensive and would undoubtedly also run into problems of participation bias. Register-based studies can be very large and are free of participation bias. However, they need to estimate the radiation exposure of study subjects using models rather than individual measurements in the homes of those concerned. At present, no firm conclusions can be drawn from the studies that have been published to date. Further data and perhaps pooled studies offer a way forward.

Strengths and Weaknesses of Dosimetry Used in Studies of Low-Dose Radiation Exposure and Cancer.

BACKGROUND: A monograph systematically evaluating recent evidence on the dose-response relationship between low-dose ionizing radiation exposure and cancer risk required a critical appraisal of dosimetry methods in 26 potentially informative studies. METHODS: The relevant literature included studies published in 2006-2017. Studies comprised case-control and cohort designs examining populations predominantly exposed to sparsely ionizing radiation, mostly from external sources, resulting in average doses of no more than 100 mGy. At least two dosimetrists reviewed each study and appraised the strengths and weaknesses of the dosimetry systems used, including assessment of sources and effects of dose estimation error. An overarching concern was whether dose error might cause the spurious appearance of a dose-response where none was present. RESULTS: The review included 8 environmental, 4 medical, and 14 occupational studies that varied in properties relative to evaluation criteria. Treatment of dose estimation error also varied among studies, although few conducted a comprehensive evaluation. Six studies appeared to have known or suspected biases in dose estimates. The potential for these biases to cause a spurious dose-response association was constrained to three case-control studies that relied extensively on information gathered in interviews conducted after case ascertainment. CONCLUSIONS: The potential for spurious dose-response associations from dose information appeared limited to case-control studies vulnerable to recall errors that may be differential by case status. Otherwise, risk estimates appeared reasonably free of a substantial bias from dose estimation error. Future studies would benefit from a comprehensive evaluation of dose estimation errors, including methods accounting for their potential effects on dose-response associations.

Epidemiological Studies of Low-Dose Ionizing Radiation and Cancer: Summary Bias Assessment and Meta-Analysis.

BACKGROUND: Ionizing radiation is an established carcinogen, but risks from low-dose exposures are controversial. Since the Biological Effects of Ionizing Radiation VII review of the epidemiological data in 2006, many subsequent publications have reported excess cancer risks from low-dose exposures. Our aim was to systematically review these studies to assess the magnitude of the risk and whether the positive findings could be explained by biases. METHODS: Eligible studies had mean cumulative doses of less than 100 mGy, individualized dose estimates, risk estimates, and confidence intervals (CI) for the dose-response and were published in 2006-2017. We summarized the evidence for bias (dose error, confounding, outcome ascertainment) and its likely direction for each study. We tested whether the median excess relative risk (ERR) per unit dose equals zero and assessed the impact of excluding positive studies with potential bias away from the null. We performed a meta-analysis to quantify the ERR and assess consistency across studies for all solid cancers and leukemia. RESULTS: Of the 26 eligible studies, 8 concerned environmental, 4 medical, and 14 occupational exposure. For solid cancers, 16 of 22 studies reported positive ERRs per unit dose, and we rejected the hypothesis that the median ERR equals zero (P = .03). After exclusion of 4 positive studies with potential positive bias, 12 of 18 studies reported positive ERRs per unit dose (P = .12). For leukemia, 17 of 20 studies were positive, and we rejected the hypothesis that the median ERR per unit dose equals zero (P = .001), also after exclusion of 5 positive studies with potential positive bias (P = .02). For adulthood exposure, the meta-ERR at 100 mGy was 0.029 (95% CI = 0.011 to 0.047) for solid cancers and 0.16 (95% CI = 0.07 to 0.25) for leukemia. For childhood exposure, the meta-ERR at 100 mGy for leukemia was 2.84 (95% CI = 0.37 to 5.32); there were only two eligible studies of all solid cancers. CONCLUSIONS: Our systematic assessments in this monograph showed that these new epidemiological studies are characterized by several limitations, but only a few positive studies were potentially biased away from the null. After exclusion of these studies, the majority of studies still reported positive risk estimates. We therefore conclude that these new epidemiological studies directly support excess cancer risks from low-dose ionizing radiation. Furthermore, the magnitude of the cancer risks from these low-dose radiation exposures was statistically compatible with the radiation dose-related cancer risks of the atomic bomb survivors.

Epidemiological Studies of Low-Dose Ionizing Radiation and Cancer: Rationale and Framework for the Monograph and Overview of Eligible Studies.

Whether low-dose ionizing radiation can cause cancer is a critical and long-debated question in radiation protection. Since the Biological Effects of Ionizing Radiation report by the National Academies in 2006, new publications from large, well-powered epidemiological studies of low doses have reported positive dose-response relationships. It has been suggested, however, that biases could explain these findings. We conducted a systematic review of epidemiological studies with mean doses less than 100 mGy published 2006-2017. We required individualized doses and dose-response estimates with confidence intervals. We identified 26 eligible studies (eight environmental, four medical, and 14 occupational), including 91 000 solid cancers and 13 000 leukemias. Mean doses ranged from 0.1 to 82 mGy. The excess relative risk at 100 mGy was positive for 16 of 22 solid cancer studies and 17 of 20 leukemia studies. The aim of this monograph was to systematically review the potential biases in these studies (including dose uncertainty, confounding, and outcome misclassification) and to assess whether the subset of minimally biased studies provides evidence for cancer risks from low-dose radiation. Here, we describe the framework for the systematic bias review and provide an overview of the eligible studies.

Case-control study of paternal occupational exposures and childhood bone tumours and soft-tissue sarcomas in Great Britain, 1962-2010.

BACKGROUND: This nationwide study investigated associations between paternal occupational exposure and childhood bone tumours and soft- tissue sarcomas. METHODS: The UK National Registry of Childhood Tumours provided cases of childhood sarcomas born and diagnosed in Great Britain, 1962-2010. Control births, unaffected by childhood cancer, were matched on sex, birth period and birth registration sub-district. Fathers' occupations were assigned to one or more of 33 exposure groups and coded for occupational social class. RESULTS: We analysed 5,369 childhood sarcoma cases and 5380 controls. Total bone tumours, total soft-tissue sarcomas and the subgroups osteosarcoma, rhabdomyosarcoma and Ewing Sarcoma Family of Tumours (ESFT) were considered separately. Significant positive associations were seen between rhabdomyosarcoma and paternal exposure to EMFs (odds ratio = 1.67, CI = 1.22-2.28) and also for ESFT and textile dust (1.93, 1.01-3.63). There were putative protective effects on total bone tumours of paternal dermal exposure to hydrocarbons, metal, metal working or oil mists. CONCLUSIONS: Despite the large size and freedom from bias of this study, our results should be interpreted with caution. Many significance tests were undertaken, and chance findings are to be expected. Nevertheless, our finding of associations between ESFT and paternal exposure to textile dust may support related suggestions in the literature.

Case-control study of paternal occupational exposures and childhood lymphoma in Great Britain, 1962-2010.

BACKGROUND: This nationwide study investigates associations between paternal occupational exposure and childhood lymphoma. METHODS: The UK National Registry of Childhood Tumours provided cases of childhood lymphoma born and diagnosed in Great Britain 1962-2010. Control births, unaffected by childhood cancer, were matched on sex, birth period and birth registration sub-district. Fathers' occupations were assigned to one or more of 33 exposure groups and also coded for occupational social class. RESULTS: We analysed 5033 childhood lymphoma cases and 4990 controls. Total lymphoma and the subgroups Hodgkin, Burkitt and non-Hodgkin lymphoma were considered separately. No one exposure was significantly associated with increased risk within all subgroups and for total lymphoma. However, exposure to "ceramics and glass" was significantly associated with increased risk of total lymphoma, Hodgkin and non-Hodgkin lymphoma. Paternal lead exposure was associated with Burkitt lymphoma and exposure to metal fumes was associated with Hodgkin lymphoma. CONCLUSIONS: This study provides no support for previous suggestions of an association between childhood lymphoma and paternal occupational exposure to pesticides, solvents/hydrocarbons or infections potentially transmitted by father's social contacts. An association with exposure to "ceramics and glass" was noted for the two major lymphoma subtypes together comprising 80% of total lymphoma.

Childhood cancer research in oxford III: The work of CCRG on ionising radiation.

BACKGROUND: High doses of ionising radiation are a known cause of childhood cancer and great public and professional interest attaches to possible links between childhood cancer and lower doses, particularly of man-made radiation. This paper describes work done by the Childhood Cancer Research Group (CCRG) on this topic METHODS: Most UK investigations have made use of the National Registry of Childhood Tumours and associated controls. Epidemiological investigations have included national incidence and mortality analyses, geographical investigations, record linkage and case-control studies. Dosimetric studies use biokinetic and dosimetric modelling. RESULTS: This paper reviews the work of the CCRG on the association between exposure to ionising radiation and childhood cancer, 1975-2014. CONCLUSION: The work of CCRG has been influential in developing understanding of the causes of 'clusters' of childhood cancer and the risks arising from exposure to ionising radiation both natural and man-made. Some clusters around nuclear installations have certainly been observed, but ionising radiation does not seem to be a plausible cause. The group's work has also been instrumental in discounting the hypothesis that paternal preconception irradiation was a cause of childhood cancers and has demonstrated an increased leukaemia risk for children exposed to higher levels of natural gamma-ray radiation.

Childhood cancer research in Oxford II: The Childhood Cancer Research Group.

BACKGROUND: We summarise the work of the Childhood Cancer Research Group, particularly in relation to the UK National Registry of Childhood Tumours (NRCT). METHODS: The Group was responsible for setting up and maintaining the NRCT. This registry was based on notifications from regional cancer registries, specialist children's tumour registries, paediatric oncologists and clinical trials organisers. For a large sample of cases, data on controls matched by date and place of birth were also collected. RESULTS: Significant achievements of the Group include: studies of aetiology and of genetic epidemiology; proposals for, and participation in, international comparative studies of these diseases and on a classification system specifically for childhood cancer; the initial development of, and major contributions to, follow-up studies of the health of long-term survivors; the enhancement of cancer registration records by the addition of clinical data and of birth records. The Group made substantial contributions to the UK government's Committee on Medical Aspects of Radiation in the Environment. CONCLUSION: An important part of the ethos of the Group was to work in collaboration with many other organisations and individuals, both nationally and internationally: many of the Group's achievements described here were the result of such collaborations.

Effects of incomplete residential histories on studies of environmental exposure with application to childhood leukaemia and background radiation.

When evaluating environmental exposures, residential exposures are often most relevant. In most countries, it is impossible to establish full residential histories. In recent publications, childhood leukaemia and background radiation have been studied with and without full residential histories. This paper investigates the consequences of lacking such full data. Data from a nationwide Finnish Case-Control study of Childhood Leukaemia and gamma rays were analysed. This included 1093 children diagnosed with leukaemia in Finland in 1990-2011. Each case was matched by gender and year of birth to three controls. Full residential histories were available. The dose estimates were based on outdoor background radiation measurements. The indoor dose rates were obtained with a dwelling type specific conversion coefficient and the individual time-weighted mean red bone marrow dose rates were calculated using age-specific indoor occupancy and the age and gender of the child. Radiation from Chernobyl fallout was included and a 2-year latency period assumed. The median separation between successive dwellings was 3.4 km and median difference in red bone marrow dose 2.9 nSv/h. The Pearson correlation between the indoor red bone marrow dose rates of successive dwellings was 0.62 (95% CI 0.60, 0.64). The odds ratio for a 10 nSv/h increase in dose rate with full residential histories was 1.01 (95% CI 0.97, 1.05). Similar odds ratios were calculated with dose rates based on only the first dwelling (1.02, 95% CI 0.99, 1.05) and only the last dwelling (1.00, 95% CI 0.98, 1.03) and for subjects who had lived only in a single dwelling (1.05, 95% CI 0.98, 1.10). Knowledge of full residential histories would always be the option of choice. However, due to the strong correlation between exposure estimates in successive dwellings and the uncertainty about the most relevant exposure period, estimation of overall exposure level from a single address is also informative. Error in dose estimation is likely to cause some degree of classical measurement error resulting in bias towards the null.

Improving Assessment of Lifetime Solar Ultraviolet Radiation Exposure in Epidemiologic Studies: Comparison of Ultraviolet Exposure Assessment Methods in a Nationwide U.S. Occupational Cohort.

Solar ultraviolet radiation is the primary risk factor for skin cancers and sun-related eye disorders. Estimates of individual ambient ultraviolet irradiance derived from ground-based solar measurements and from satellite measurements have rarely been compared. Using self-reported residential history from 67 189 persons in a nationwide occupational US radiologic technologists' cohort, we estimated ambient solar irradiance using data from ground-based meters and noontime satellite measurements. The mean distance moved from city of longest residence in childhood increased from 137.6 km at ages 13-19 to 870.3 km at ages ≥65, with corresponding increases in absolute latitude difference moved. At ages 20/40/60/80, the Pearson/Spearman correlation coefficients of ground-based and satellite-derived potential solar ultraviolet exposure, using irradiance and cumulative radiant exposure metrics, were high (=0.87-0.92). There was also moderate correlation (Pearson/Spearman correlation coefficients = 0.51-0.60) between irradiance at birth and at last-known address, for ground-based and satellite data. Satellite-based lifetime estimates of ultraviolet radiation were generally 14-15% lower than ground-based estimates, albeit with substantial uncertainties, possibly because ground-based estimates incorporate fluctuations in cloud and ozone, which are incompletely incorporated in the single noontime satellite-overpass ultraviolet value. If confirmed elsewhere, the findings suggest that ground-based estimates may improve exposure assessment accuracy and potentially provide new insights into ultraviolet radiation-disease relationships in epidemiologic studies.

Variation with socioeconomic status of indoor radon levels in Great Britain: The less affluent have less radon.

We demonstrate a strong correlation between domestic radon levels and socio-economic status (SES) in Great Britain, so that radon levels in homes of people with lower SES are, on average, only about two thirds of those of the more affluent. This trend is apparent using small area measures of SES and also using individual social classes. The reasons for these differences are not known with certainty, but may be connected with greater underpressure in warmer and better-sealed dwellings. There is also a variation of indoor radon levels with the design of the house (detached, terraced, etc.). In part this is probably an effect of SES, but it appears to have other causes as well. Data from other countries are also reviewed, and broadly similar effects seen in the United States for SES, and in other European countries for detached vs other types of housing. Because of correlations with smoking, this tendency for the lower SES groups to experience lower radon levels may underlie the negative association between radon levels and lung cancer rates in a well-known ecological study based on US Counties. Those conducting epidemiological studies of radon should be alert for this effect and control adequately for SES.

Childhood and adult cancers: contrasts and commonalities.

Tumours occurring in children differ considerably from those occurring at older ages but exhibit common features. Those occurring in the teenage/young adult (TYA) years represent a transitional mixture of child and adult tumours and pose a considerable challenge for optimal clinical management and service provision. Nevertheless the fundamental processes of malignant change, arising from genetic/epigenetic interaction with environmental exposures, seem to operate across all ages and the entire tumour spectrum. We focus here on the ways in which genotype (and epigenetic modification), growth processes (particularly in utero), and exposure to ionising radiation (in conjunction with genetic susceptibility) affect cancer risk from childhood to adulthood, whether as a primary occurrence, or a second primary tumour following earlier primary occurrence and treatment.

Numbers and proportions of leukemias in young people and adults induced by radiation of natural origin.

Natural sources contribute a large fraction of the radiation exposure of the general public. Under the linear no-threshold hypothesis risk decreases in proportion to decreasing dose without a threshold. We use recent estimates of doses to the red bone marrow to calculate the number and proportion of cases of leukemia in England induced by natural radiation. We calculate that about 5% of cases of leukemia, excluding chronic lymphocytic leukemia, up to the age of 80 years are induced by this background radiation. In young people up to the age of 25 years the attributable fraction is about 15%, substantially lower than a previous estimate.

Updated estimates of the proportion of childhood leukaemia incidence in Great Britain that may be caused by natural background ionising radiation.

The aetiology of childhood leukaemia remains generally unknown, although exposure to moderate and high levels of ionising radiation, such as was experienced during the atomic bombings of Japan or from radiotherapy, is an established cause. Risk models based primarily upon studies of the Japanese A-bomb survivors imply that low-level exposure to ionising radiation, including to ubiquitous natural background radiation, also raises the risk of childhood leukaemia. In a recent paper (Wakeford et al 2009 Leukaemia 23 770-6) we estimated the proportion of childhood leukaemia incidence in Great Britain attributable to natural background radiation to be about 20%. In this paper we employ the two sets of published leukaemia risk models used previously, but use recently published revised estimates of natural background radiation doses received by the red bone marrow of British children to update the previous results. Using the newer dosimetry we calculate that the best estimate of the proportion of cases of childhood leukaemia in Great Britain predicted to be attributable to this source of exposure is 15-20%, although the uncertainty associated with certain stages in the calculation (e.g. the nature of the transfer of risk between populations and the pertinent dose received from naturally occurring alpha-particle-emitting radionuclides) is significant. The slightly lower attributable proportions compared with those previously derived by Wakeford et al (Leukaemia 2009 23 770-6) are largely due to the lower doses (and in particular lower high LET doses) for the first year of life.