Risk of cancer and non-cancer diseases in the atomic bomb survivors

Late health effects of exposure to atomic bomb radiation have been evaluated in survivors. A cohort of 120 321 people has been followed since 1950 for mortality, including the cause of death using the Japanese population registry system (Life Span Study), and for cancer incidence using population-based cancer registries. Findings have included a markedly increased risk of leukaemia several years after the exposure, increased risk of various malignant tumours several decades after the exposure and, more recently, findings of increased rates of non-cancer diseases such as cardiovascular diseases.     

Meta-analysis of second cancer risk after radiotherapy among childhood cancer survivors

Cancer risks among childhood cancer survivors following radiotherapy have not yet been well characterised in terms of radiation dose. A meta-analysis of studies on the excess relative risk per gray (ERR) of second cancer was conducted previously; unfortunately, the small number of eligible studies restricted quantitative evaluations. To solve this problem, a statistical method to calculate ERR estimates from other estimates was developed, and a meta-analysis was conducted again. The PubMed database was searched and 26 relevant studies were identified. ERR estimates were available in 15 studies, and for the other 11 studies, the regression-based model was used to calculate ERR estimates from other estimates. The overall ERR estimate was 0.40, which was much lower than that of atomic bomb survivors exposed as young children. Heterogeneity of the risk among studies was suggested, and a further study is needed to explore the heterogeneity among studies.     

Preconception exposures to potential germ-cell mutagens

Radiation and other agents can cause germ-cell mutations in animal systems. No human germ-cell mutagen has been identified, but this does not mean that human germ-cells are not vulnerable to mutagenesis. There has been particular concern about the possible health effects on offspring following parental preconception exposure to ionizing radiation-both occupational and therapeutic. A strong association with preconception radiation exposure in the fathers of the cases was found in a case-control study of young people with leukaemia living near the Sellafield nuclear plant in the UK. Subsequent studies of workers occupationally exposed to ionizing radiation have failed to confirm these findings. No statistically significant effects have been reported from studies of possible indicators of germ-cell mutagenesis in the A-bomb survivors. Studies of offspring of cancer survivors who receive radiotherapy and mutagenic chemotherapy have found no evidence of germ-cell mutagenesis. Failure to detect human germ-cell mutagenic agents may be a consequence of inadequate study sizes or insufficiently sensitive laboratory techniques.     

Childhood leukaemia following medical diagnostic exposure to ionizing radiation in utero or after birth

A statistical association between childhood leukaemia and an abdominal X-ray examination of the pregnant mother was first reported in 1956 from a case-control study of childhood cancer mortality conducted in Great Britain. This study, later called the Oxford Survey of Childhood Cancers (OSCC), was continued and eventually showed a highly statistically significant approximately 50% proportional increase in the risk of childhood leukaemia associated with antenatal diagnostic radiography. The association has been confirmed by many case-control studies carried out around the world, the appropriately combined results of which show a highly statistically significant increase in risk that is compatible with the OSCC finding. There is no doubt about the reality of the statistical association, but a causal interpretation has been questioned. On balance, however, the evidence points to low-level irradiation of the fetus increasing the risk of leukaemia in childhood, with an excess relative risk coefficient of around 50 Gy(-1) (equivalent to an excess absolute risk coefficient of about 3% Gy(-1)), although the uncertainty associated with these coefficients is considerable and they are likely to be overestimates. In contrast to exposure in utero, the evidence from case-control studies for an association between childhood leukaemia and postnatal exposure to medical diagnostic irradiation is equivocal and sometimes conflicting. Since standard radiation risk models predict that low-level exposure in the early years of life should produce an increased risk of childhood leukaemia that is roughly similar to that arising from fetal exposure, this absence of persuasive evidence is likely to be due to various problems with the studies. This is unfortunate given the rise in relatively high dose diagnostic procedures (e.g. paediatric CT scans) that would be predicted to materially increase the relative risk of childhood leukaemia.     

'Lifestyle' and cancer rates in former East and West Germany: the possible contribution of diagnostic radiation exposures

Breast and prostatic cancer as well as leukaemia in childhood have remarkably increased over some decades in the Federal Republic of Germany as well as in several other highly developed industrial nations. Such increase was much less or not observable in East Germany between 1960 and 1989 where diagnostic exposures were applied to a lesser extent. Low-level radiation can cause these diseases and the difference of cancer rates gives rise to renewed evaluation of current risk estimates. Risk factors for radiation-induced childhood leukaemia and breast cancer are derived from the literature, considering a higher relative biological effectiveness of diagnostic X rays in comparison to the A-bomb gamma rays in Hiroshima and Nagasaki. The prostate is not considered as radiation sensitive by the ICRP. But following a variety of low-level findings in the last two decades it was shown by Myles et al. in the UK that prostatic cancer is inducible by diagnostic X-ray procedures. From their study in men below the age of 60, a doubling dose of about 20 mSv can be estimated. Medical exposures of the considered tissues are taken from published data for East and West Germany. The difference in breast cancer mortality can be explained by diagnostic exposures. The contribution of these to prostatic cancer and childhood leukaemia must be regarded as relevant in current incidences. Reduction of diagnostic exposures would be an important measure for preventing several prominent cancer diseases.     

Experimental simulation of A-bomb gamma ray spectra: revisited

It has been reported recently that the A-bomb gamma ray spectra received by the colon of the average Japanese survivor of Hiroshima and Nagasaki may be experimentally simulated using a hospital-based Philips SL15 linear accelerator. The simulated A-bomb gamma radiation may be used in radiobiology experiments to determine, amongst other things, the biological effectiveness of the A-bomb gamma radiation. However, in that study, the electron beams from the linear accelerator were poorly defined and photon contamination was ignored. In the study reported here, a Varian Clinac 2100C linear accelerator has been used for the same purpose but with photon contamination included in better defined output electron beams. It is found that the A-bomb gamma radiation can still be matched to an acceptable degree (<10%). The cause of the slightly poorer fit was due mainly to the different ranges of energies available from the linear accelerators used. The absorbed dose received by model breasts was also estimated in this study for the same situations as in the previous study. The ratio of the breast to colon doses was found to be only (3.9 +/- 4.0)% low compared with the expected values of 1.17 and 1.16 for Hiroshima and Nagasaki, respectively. These results provide further confirmation of the acceptability of the simple cylindrically symmetrical body models employed in these studies to represent the average Japanese survivor.     

Experimental simulation of A-bomb gamma ray spectra for radiobiology studies

Improved radiation protection of humans requires a better understanding of the mechanisms of radiation action and accurate estimates of radiation risk for both internal and external radiations. The Japanese atomic bomb survivors represent one of the most important sources of human data on the late carcinogenic effects of ionising radiations. The present study was undertaken to investigate whether it would be possible to use hospital radiotherapy/radiobiology equipment to mimic the spectra encountered in Hiroshima and Nagasaki. The estimated total gamma ray fluence spectra (including both prompt and delayed photons) at both Hiroshima and Nagasaki, for distances of 500, 1000, 1500 and 2000 m have been evaluated using DS86 data and previously unpublished information for delayed gamma radiations which constitute the major contribution to survivor doses. Monte Carlo (EGS4) simulations were performed to transport these photons through the body in order to investigate the variation in electron spectra for various body organs. The electron spectra obtained for these fluences at, for example, the colon, have been matched with combinations of electron spectra produced by linear accelerators to within 5% SD. These will, for the first time, enable a direct link to be made between radiobiological studies (for example, on mammography spectra) and the epidemiological data from Japan, which currently underpin radiation risk estimates.     

Exposure assessment: implications for epidemiological studies of ionizing radiation

Quantitative estimates of ionizing radiation exposure are often available for use in epidemiological studies. However, depending on the context, the quality of the exposure estimates can vary. For example, the estimates may be specific to individuals in the study or generic values averaged over populations; unavailable for some of the potential study subjects or vary in their form between individuals; based on contemporary measurements or assessed retrospectively; based on measurements alone, on surrogate measures of exposure, or on an exposure assessment model; or, as is often the case, cover one source of radiation exposure rather than all of them. Various ways in which ionizing radiation exposures have been assessed are illustrated through reference to some studies of childhood leukaemia, concerning environmental, medical, natural and parental occupational exposures. Based on this, implications for the interpretation of radiation epidemiological studies are discussed.     

Exposure to electromagnetic fields and the risk of childhood leukaemia: a review

Extremely low-frequency magnetic fields have been classified as possibly carcinogenic to humans, mainly based on epidemiological studies consistently showing an association between long-term average exposures to magnetic fields above 0.3/0.4 microT and the risk of childhood leukaemia. No mechanism to explain this finding has been established and no support for a causal link emerged from experimental studies. Chance or bias cannot be ruled out with reasonable confidence as an explanation for the observed association. If the association is causal, it explains only a small fraction of childhood leukaemia cases. There were some reports of childhood leukaemia clusters in the vicinity of high-power radio and television broadcast transmitters in studies in Australia and Italy. However, recent large-scale systematic studies in Korea and Germany show no association between exposure to radio frequency electromagnetic fields emitted from broadcast towers and childhood leukaemia risk. Studies on mobile phone use and leukaemia risk in adolescents and young adults may be indicated.     

Studies on the Hiroshima and Nagasaki survivors, and their use in estimating radiation risks

Epidemiological studies of the survivors of the atomic bombings of Hiroshima and Nagasaki have been conducted over many years. These studies have examined, inter alia, mortality and cancer incidence among the survivors. This paper summarises the form of the studies undertaken, outlines the main findings and describes how these results can be used in deriving estimates of radiation risks. In doing so, some areas of uncertainty and open issues are highlighted, such as the magnitude of lifetime cancer risks and the evidence for raised risks of non-cancer diseases at low doses. Continued follow-up of the survivors will be important in shedding further light on these issues.     

Current risk estimates based on the A-bomb survivors data - a discussion in terms of the ICRP recommendations on the neutron weighting factor

Currently, most analyses of the A-bomb survivors' solid tumour and leukaemia data are based on a constant neutron relative biological effectiveness (RBE) value of 10 that is applied to all survivors, independent of their distance to the hypocentre at the time of bombing. The results of these analyses are then used as a major basis for current risk estimates suggested by the International Commission on Radiological Protection (ICRP) for use in international safety guidelines. It is shown here that (i) a constant value of 10 is not consistent with weighting factors recommended by the ICRP for neutrons and (ii) it does not account for the hardening of the neutron spectra in Hiroshima and Nagasaki, which takes place with increasing distance from the hypocentres. The purpose of this paper is to present new RBE values for the neutrons, calculated as a function of distance from the hypocentres for both cities that are consistent with the ICRP60 neutron weighting factor. If based on neutron spectra from the DS86 dosimetry system, these calculations suggest values of about 31 at 1000 m and 23 at 2000 m ground range in Hiroshima, while the corresponding values for Nagasaki are 24 and 22. If the neutron weighting factor that is consistent with ICRP92 is used, the corresponding values are about 23 and 21 for Hiroshima and 21 and 20 for Nagasaki, respectively. It is concluded that the current risk estimates will be subject to some changes in view of the changed RBE values. This conclusion does not change significantly if the new doses from the Dosimetry System DS02 are used.     

Epidemiological studies of leukaemia in children and young adults around nuclear facilities: a critical review

The existence of an increased risk of childhood leukaemia near nuclear installations is a recurrent issue. A review of the related epidemiological literature is presented here. Results for 198 nuclear sites throughout 10 countries were included in the review. In addition to local studies, 25 multi-site studies have been published for eight countries. A large variability was noticed in the quality of the data as well as in the definition of the study population and in the methods of analysis. Many studies present important limits that make the results difficult to interpret. The review confirms that some clusters of childhood leukaemia cases exist locally. However, results based on multi-site studies around nuclear installations do not indicate an increased risk globally. Many studies were launched to investigate possible origins of the observed clusters around specific sites, but up to now, none of the proposed hypotheses have explained them.     

Point defects and the blue emission in fired quartz at high doses: a comparative luminescence and EPR study

The fundamental assumption implicit in the use of the atomic bomb survivor data to derive risk estimates for occupational and medical exposures is that the gamma rays of Hiroshima and Nagasaki are considered as equal efficiencies to other low LET radiations up to an LET of 10 keV.micron-1. For breast cancer induction, neoplastic cell transformation, mutation, reciprocal translocations and dicentrics in human lymphocytes, a strong and very similar dependence of the RBE values on photon energy or on LET is observed. Experimental data on mutation induction and neoplastic cell transformation in human cells show that 29 kVp X rays are by a factor of 4 and 3.4, respectively, more effective compared with 200 kVp X rays. These data are in excellent agreement with the data in the literature.     

Exposure to infections through day-care attendance and risk of childhood leukaemia

There is growing evidence supporting a role for infections in the aetiology of childhood leukaemia. Hypotheses proposed by both Greaves and Kinlen describe childhood leukaemia to be a rare response to one or more common infections acquired through personal contacts. Previous epidemiological studies have used day-care attendance as an indicator of the increased likelihood of early and frequent exposure to infections. It is well-documented that in developed countries, exposures to common infections occur more frequently in this type of setting. Within the Northern California Childhood Leukaemia Study, the role of social contact has been assessed and a unique 'child-hours' summary measure incorporating information on the number of months attending a day-care, mean hours per week at this day-care and the number of children in the day-care setting was constructed. In this review, the previously reported day-care results have been described, showing that in non-Hispanic White children, children in the highest category of total child-hours of exposure had a reduced risk of acute lymphoblastic leukaemia (ALL), particularly common B-cell precursor ALL (c-ALL), compared with children without such exposures, with evidence of a dose-response effect. In addition, a literature review of relevant studies has been conducted, examining the relationship between day-care attendance and risk of childhood ALL. Overall, the 14 studies identified provided consistent support for this hypothesis, with the majority of studies reporting some evidence of a reduced risk. A meta-analysis is currently underway, which will provide a quantitative evaluation of the overall consistency and strength of the association between day-care attendance or social contact and risk of childhood ALL.     

Residential exposures to pesticides and childhood leukaemia

Like many chemicals, carcinogenicity of pesticides is poorly characterised in humans, especially in children, so that the present knowledge about childhood leukaemia risk derives primarily from epidemiological studies. Overall, case-control studies published in the last decade have reported positive associations with home use of insecticides, mostly before the child's birth, while findings for herbicides are mixed. Previous studies relied solely on self-reports, therefore lacking information on active ingredients and effects of potential recall bias. Few series to date have examined the influence of children's genetic susceptibility related to transport and metabolism of pesticides. To overcome these limitations, investigators of the Northern California Childhood Leukaemia Study (NCCLS) have undertaken, in collaboration with a multidisciplinary team, a comprehensive assessment of residential pesticide exposure, including: (1) quality control of self-reports; (2) home pesticide inventory and linkage to the Environmental Protection Agency to obtain data on active ingredients; (3) collection and laboratory analyses of approximately 600 home dust samples for over 60 pesticides and (4) geographic information studies using California environmental databases to assess exposure to agricultural pesticides. The NCCLS is also conducting large-scale genotyping to evaluate the role of genes in xenobiotic pathways relevant to the transport and metabolism of pesticides. A better quantification of children's exposures to pesticides at home is critical to the evaluation of childhood leukaemia risk, especially for future gene-environment interaction studies.     

Recommended improvements to the DS02 dosimetry system's calculation of organ doses and their potential advantages for the Radiation Effects Research Foundation

The Radiation Effects Research Foundation (RERF) uses a dosimetry system to calculate radiation doses received by the Japanese atomic bomb survivors based on their reported location and shielding at the time of exposure. The current system, DS02, completed in 2003, calculates detailed doses to 15 particular organs of the body from neutrons and gamma rays, using new source terms and transport calculations as well as some other improvements in the calculation of terrain and structural shielding, but continues to use methods from an older system, DS86, to account for body self-shielding. Although recent developments in models of the human body from medical imaging, along with contemporary computer speed and software, allow for improvement of the calculated organ doses, before undertaking changes to the organ dose calculations, it is important to evaluate the improvements that can be made and their potential contribution to RERF's research. The analysis provided here suggests that the most important improvements can be made by providing calculations for more organs or tissues and by providing a larger series of age- and sex-specific models of the human body from birth to adulthood, as well as fetal models.     

Childhood leukaemia and socioeconomic status: what is the evidence?

The objectives of this systematic review are to summarise the current literature on socioeconomic status (SES) and the risk of childhood leukaemia, to highlight methodological problems and formulate recommendations for future research. Starting from the systematic review of Poole et al. (Socioeconomic status and childhood leukaemia: a review. Int. J. Epidemiol. 2006;35(2):370-384.), an electronic literature search was performed covering August 2002-April 2008. It showed that (1) the results are heterogeneous, with no clear evidence to support a relation between SES and childhood leukaemia; (2) a number of factors, most importantly selection bias, might explain inconsistencies between studies; (3) there is some support for an association between SES at birth (rather than later in childhood) and childhood leukaemia and (4) if there are any associations, these are weak, limited to the most extreme SES groups (the 10-20% most or least deprived). This makes it unlikely that they would act as strong confounders in research addressing associations between other exposures and childhood leukaemia. Future research should minimise case and control selection bias, distinguish between different SES measures and leukaemia subtypes and consider timing of exposures and cancer outcomes.     

The use of biologically based cancer risk models in radiation epidemiology

Biologically based risk projection models for radiation carcinogenesis seek to describe the fundamental biological processes involved in neoplastic transformation of somatic cells into malignant cancer cells. A validated biologically based model, whose parameters have a direct biological interpretation, can also be used to extrapolate cancer risks to different exposure conditions with some confidence. In this article biologically based models for radiation carcinogenesis, including the two-stage clonal expansion (TSCE) model and its extensions, are reviewed. The biological and mathematical bases for such models are described, and the implications of key model parameters for cancer risk assessment examined. Specific applications of versions of the TSCE model to important epidemiological datasets are discussed, including the Colorado uranium miners' cohort; a cohort of Chinese tin miners; the lifespan cohort of atomic bomb survivors in Hiroshima and Nagasaki; and a cohort of over 200,000 workers included in the National Dose Registry (NDR) of Canada.     

The 'Kinderkrebs in der Umgebung von Kernkraftwerken' study: results put into perspective

A German case-control study on leukaemia in children below 5 y of age near nuclear installations showed a trend of increasing risk with decreasing distance of place of residence from the sites. The radiation exposure from the sites is considered as being too low by a factor of at least 1000 to explain the observed effect, but little is known about radiation effects from pre- or postnatal exposures on the leukaemia risk for ages up to 4 y. Within the study, it was shown that the observed trend in risk decreases over time. That could be indicative of some agent being involved for which the prevalence is reduced over time. Previous ecological studies showed increased risks among the youngest age groups in the closest vicinity of the sites, but no elevated risks for children of all ages (0-14). This could implicate a shift towards an earlier onset of the disease.     

Radiations in space: risk estimates

The complexity of radiation environments in space makes estimation of risks more difficult than for the protection of terrestrial populations. In deep space the duration of the mission, position in the solar cycle, number and size of solar particle events (SPE) and the spacecraft shielding are the major determinants of risk. In low-earth orbit missions there are the added factors of altitude and orbital inclination. Different radiation qualities such as protons and heavy ions and secondary radiations inside the spacecraft such as neutrons of various energies, have to be considered. Radiation dose rates in space are low except for short periods during very large SPEs. Risk estimation for space activities is based on the human experience of exposure to gamma rays and to a lesser extent X rays. The doses of protons, heavy ions and neutrons are adjusted to take into account the relative biological effectiveness (RBE) of the different radiation types and thus derive equivalent doses. RBE values and factors to adjust for the effect of dose rate have to be obtained from experimental data. The influence of age and gender on the cancer risk is estimated from the data from atomic bomb survivors. Because of the large number of variables the uncertainities in the probability of the effects are large. Information needed to improve the risk estimates includes: (1) risk of cancer induction by protons, heavy ions and neutrons: (2) influence of dose rate and protraction, particularly on potential tissue effects such as reduced fertility and cataracts: and (3) possible effects of heavy ions on the central nervous system. Risk cannot be eliminated and thus there must be a consensus on what level of risk is acceptable.