Japanese Atomic Bomb Research Articles

Assessing the impact of neutron relative biological effectiveness on all solid cancer mortality risks in the Japanese atomic bomb survivors

Purpose Risk analyses, based on relative biological effectiveness (RBE) estimates for neutrons relative to gammas, were performed; and the change in the curvature of the risk to dose response with increasing neutron RBE was analyzed using all solid cancer mortality data from the Radiation Effect Research Foundation (RERF). Results were compared to those based on incidence data. Materials and methods This analysis is based on RERF mortality data with separate neutron and gamma doses for colon doses, from which organ averaged doses could be calculated. A model for risk ratio variation with RBE was developed. Results The best estimate of the neutron RBE considering mortality data was 200 (95% confidence interval (CI): 50–1010) for colon dose using the weighted-dose approach and for organ averaged dose 110 (95% CI: 30–350). The ERR risk ratios for all solid cancers combined, for the best fitting neutron RBE estimate and the neutron RBE of 10 result in a ratio of 0.54 (95% CI: 0.17–0.85) for colon dose and 0.55 (95% CI: 0.18–0.87) for organ averaged dose. The risk to dose response curvature became significantly negative (concave down) with increasing RBE, at a neutron RBE of 170 using colon dose and at an RBE of 90 using organ averaged dose for males when fitting a linear-quadratic dose response. For females, the curvature decreased toward linearity with increasing neutron RBE and remained significantly positive until RBE of 80 and 40 using colon and organ averaged dose, respectively. For higher neutron RBEs, no significant conclusion could be drawn about the shape of the dose–response curve. Conclusions Application of neutron RBE values higher than 10 results in substantially reduced cancer mortality risk estimates and a significant reduction in curvature of the risk to dose responses for males. Using mortality data, the best fitting neutron RBE is much higher than when incidence data is used. The neutron RBE ranges covered by the overlap in the CIs from both the mortality and incidence analyses are 50–190 using colon dose and in all cases, the best fitting neutron RBE and lower 95% CI are higher than the value of 10 traditionally applied by the RERF. Therefore, it is recommended to consider uncertainties in neutron RBE values when calculating radiation risks and discussing the shape of dose responses using Japanese A-bomb survivors data.

Discussion of uncertainties and the impact of different neutron RBEs on all solid cancer radiation incidence risks obtained from the Japanese A-bomb survivor data.

The most recent publicly available data on all solid cancer incidence from the Life Span Study (LSS) of Japanese A-bomb survivors provides colon dose contributions weighted with a relative biological effectiveness (RBE) of 10 for neutrons, relative to gammas. However, there is evidence from several investigations that the neutron RBE for A-bomb survivors may be higher than 10. The change in the shape of the corresponding dose-response curves was evaluated by Hafner and co-workers in a previous study by applying sex-specific linear-quadratic dose models to previous LSS data for all solid cancer incidence that include separate neutron and gamma absorbed doses for several organs, in contrast to the most recent data. The resulting curvature change became significantly negative for males at an RBE of 140 for colon, 100 for liver, and 80 for organ averaged dose. For females, the corresponding RBE values were 110, 80, and 60 for colon, liver, and organ averaged doses. The present study compares three different methods to calculate the 95% confidence intervals in an analysis of the curvature with increasing RBE. Further, the impact of a higher neutron RBE on the work of the International Commission on Radiological Protection, and the importance of including uncertainties and performing sensitivity analysis of different parameters in radiation risk assessment are discussed.

Assessing the impact of different neutron RBEs on the all solid cancer radiation risks obtained from the Japanese A-bomb survivors data

Purpose Development of a model characterizing risk variation with RBE to investigate how the incidence risk for all solid cancers combined varies with higher neutron RBEs and different organ dose types. Material and methods The model is based on RERF data with separate neutron and gamma dose information. Results For both additive and multiplicative linear excess risks per unit organ averaged dose, a reduction of 50% in the risk coefficient per weighted dose arises when a neutron RBE of 110 is used instead of 10. Considering risk per unit liver dose, this reduction occurs for an RBE of 130 and for risks per unit colon dose for an RBE of 190. The change in the shape of the dose response curve when using higher neutron RBEs is evaluated. The curvature changed and became significantly negative for males at an RBE of 140 for colon dose, 100 for liver dose and 80 for organ averaged dose. For females this is the case at an RBE of 110, 80 and 60, respectively. Conclusions Uncertainties in neutron RBE values should be considered when radiation risks and the shape of dose responses are deduced from cancer risk data from the atomic bomb survivors.

Japanese pediatric and adult atomic bomb survivor dosimetry: potential improvements using the J45 phantom series and modern Monte Carlo transport

The radiation exposure estimates for the atomic bomb survivors at Hiroshima and Nagasaki have evolved over the past several decades, reflecting a constant strive by the Radiation Effects Research Foundation (RERF) to provide thorough dosimetry to their cohort. Recently, a working group has introduced a new series of anatomical models, called the J45 phantom series, which improves upon those currently used at RERF through greater age resolution, sex distinction, anatomical realism, and organ dose availability. To evaluate the potential dosimetry improvements that would arise from their use in an RERF Dosimetry System, organ doses in the J45 series are evaluated here using environmental fluence data for 20 generalized survivor scenarios pulled directly from the current dosimetry system. The energy- and angle-dependent gamma and neutron fluences were converted to a source term for use in MCNP6, a modern Monte Carlo radiation transport code. Overall, the updated phantom series would be expected to provide dose improvements to several important organs, including the active marrow, colon, and stomach wall (up to 20, 20, and 15% impact on total dose, respectively). The impacts were especially significant for neutron dose estimates (up to a two-fold difference) and within organs which were unavailable in the previous phantom series. These impacts were consistent across the 20 scenarios and are potentially even greater when biological effectiveness of the neutron dose component is considered. The entirety of the dosimetry results for all organs are available as supplementary data, providing confident justification for potential future DS workflows utilizing the J45 phantom series.

Cancer incidence risks above and below 1 Gy for radiation protection in space

The risk assessment quantities called lifetime attributable risk (LAR) and risk of exposure-induced cancer (REIC) are used to calculate the cumulative cancer incidence risks for astronauts, attributable to radiation exposure accumulated during long term lunar and Mars missions. These risk quantities are based on the most recently published epidemiological data on the Life Span Study (LSS) of Japanese A-bomb survivors, who were exposed to γ-rays and neutrons. In order to analyze the impact of a different neutron RBE on the risk quantities, a model for the neutron relative biological effectiveness (RBE) relative to gammas in the LSS is developed based on an older dataset with less follow-up time. Since both risk quantities are based on uncertain quantities, such as survival curves, and REIC includes deterministic radiation induced non-cancer mortality risks, modelled with data based on the general population, the risks for astronauts may not be optimally estimated. The suitability of these risk assessment measures for the use of cancer risk calculation for astronauts is discussed. The work presented here shows that the use of a higher neutron RBE than the value of 10, traditionally used in the LSS risk models, can reduce the risks up to almost 50%. Additionally, including an excess absolute risk (EAR) baseline scaling also increases the risks by between 0.4% and 8.1% for the space missions considered in this study. Using just an EAR model instead of an equally weighted EAR and excess relative risk (ERR) model can decrease the cumulative risks for the considered missions by between 0.4% and 4.1% if no EAR baseline scaling is applied. If EAR baseline scaling is included, the calculated risks with the EAR- and the mixed model, as well as the risks calculated with just the ERR model are almost identical and only small differences in the uncertainties are visible.

Biologically-based modeling of radiation risk and biomarker prevalence for papillary thyroid cancer in Japanese a-bomb survivors 1958–2005

Purpose Thyroid cancer of papillary histology (PTC) is the dominant type in radio-epidemiological cohorts established after nuclear accidents or warfare. Studies on post-Chernobyl PTC and on thyroid cancer in the life span study (LSS) of Japanese a-bomb survivors consistently revealed high radiation risk after exposure during childhood and adolescence. For post-Chernobyl risk assessment overexpression of the CLIP2 gene was proposed as molecular biomarker to separate radiogenic from sporadic PTC. Based on such binary marker a biologically-based risk model of PTC carcinogenesis has been developed for observational Chernobyl data. The model featured two independent molecular pathways of disease development, of which one was associated with radiation exposure. To gain credibility the concept for a mechanistic risk model must be based on general biological features which transcend findings in a single cohort. The purpose of the present study is therefore to demonstrate portability of the model concept by application to PTC incidence data in the LSS. By exploiting the molecular two-path concept we improve the determination of the probability of radiation causing cancer (POC). Materials and methods The current analysis uses thyroid cancer incidence data of the LSS with thyroid cancer diagnoses and papillary histology (n = 292) from the follow-up period between 1958 and 2005. Risk analysis was performed with both descriptive and biologically-based models. Results Judged by goodness-of-fit all applied models described the data almost equally well. They yielded similar risk estimates in cohorts post-Chernobyl and LSS. The preferred mechanistic model was selected by biological plausibility. It reflected important features of an imperfect radiation marker which are not easily addressed by descriptive models. Precise model predictions of marker prevalence in strata of epidemiological covariables can be tested by molecular measurements. Application of the radiation-related molecular pathway from our preferred model in retrospective risk assessment decreases the threshold dose for 50% POC from 0.33 (95% confidence interval (CI) 0.18; 0.64) Gy to 0.04 (95% CI 0.01; 0.19) Gy for females and from 0.43 (95% CI 0.17; 1.84) Gy to 0.19 (95% CI 0.05; 1.00) Gy for males. These improvements are still not sufficient to separate radiation-induced from sporadic PTC cases at very low doses <0.015 Gy typical for the Fukushima accident. Conclusions Successful application of our preferred mechanistic model to LSS incidence data confirms and improves the biological two-path concept of radiation-induced PTC. Model predictions suggest further molecular validation studies to consolidate the basis of biologically-based risk estimation.

US Prisoners of War in Hiroshima: A 40-Year Investigative Journey of a Japanese Atomic-Bomb Survivor

ABSTRACTShigeaki Mori was an eight-year-old child living in Hiroshima when the United States attacked the city with an atomic bomb on 6 August 1945. In this interview, Mori recalls his experience of the bombing. One of the most memorable scenes for him is the cremation of victims in the playground of an elementary school. Thirty years after the bombing, he decided to begin research on the number of cremated corpses in the school. Later, he also conducted an investigation of US prisoners of war who happened to be detained in Hiroshima and experienced the atomic bombing. So far, he has identified 12 US soldiers who were killed by the bomb. In this interview, Mori looks back on how difficult his investigation was. But his efforts bore fruit. President Barack Obama invited him to the speech that the US leader delivered in the Hiroshima Peace Park in May 2016. In the final part of the interview, Mori shares with readers his encounter with the president, his visit to the United States in 2018, and his views on recent developments in nuclear issues.

Association Between Prevalence of Peripheral Artery Disease and Radiation Exposure in the Atomic Bomb Survivors.

BackgroundPast reports suggested that total‐body irradiation at 0.5 to 1.0 Gy could be responsible for atherosclerosis. Peripheral artery disease (PAD) is a manifestation of systematic atherosclerosis. Whether the consequences of a low‐to‐moderate dose of radiation include increased risk of PAD remains to be determined. The purpose of this study was to examine the association between radiation exposure and prevalence of PAD among Japanese atomic bomb survivors.Methods and ResultsRadiation exposure from the atomic bombing was assessed in 3476 participants (41.1% men, mean age 74.8 years with SD 6.4 years) with a cross‐sectional survey in 2010 to 2014. Left‐ and right‐side ankle‐brachial indexes and upstroke time (UT) were obtained using oscillometric VP‐2000. PAD was defined as an ankle‐brachial index of 1.0 or less or a prior history related to revascularization. UT was considered a sensitive marker of early‐stage PAD. Association between radiation exposure and PAD or UT was assessed using multivariable regression analyses with adjustment for potential confounding factors. Of 3476 participants, 79 (2.3%) were identified as having prevalent PAD. Multivariate logistic regression analysis indicated that radiation dose was unrelated to PAD prevalence (odds ratio, 0.83; 95% confidence interval [0.57‐1.21]). UT appeared to increase with radiation dose, but the increase was not statistically significant (1.09 ms/Gy; 95% confidence interval [−0.17 to 2.36]).ConclusionsWe found no clear association of radiation dose with PAD, but it remains to be determined whether UT is associated with radiation dose.

Radiation- and Age-Associated Changes in Peripheral Blood Dendritic Cell Populations among Aging Atomic Bomb Survivors in Japan.

Previous immunological studies in atomic bomb survivors have suggested that radiation exposure leads to long-lasting changes, similar to immunological aging observed in T-cell-adaptive immunity. However, to our knowledge, late effects of radiation on dendritic cells (DCs), the key coordinators for activation and differentiation of T cells, have not yet been investigated in humans. In the current study, we hypothesized that numerical and functional decreases would be observed in relationship to radiation dose in circulating conventional DCs (cDCs) and plasmacytoid DCs (pDCs) among 229 Japanese A-bomb survivors. Overall, the evidence did not support this hypothesis, with no overall changes in DCs or functional changes observed with radiation dose. Multivariable regression analysis for radiation dose, age and gender effects revealed that total DC counts as well as subpopulation counts decreased in relationship to increasing age. Further analyses revealed that in women, absolute numbers of pDCs showed significant decreases with radiation dose. A hierarchical clustering analysis of gene expression profiles in DCs after Toll-like receptor stimulation in vitro identified two clusters of participants that differed in age-associated expression levels of genes involved in antigen presentation and cytokine/chemokine production in cDCs. These results suggest that DC counts decrease and expression levels of gene clusters change with age. More than 60 years after radiation exposure, we also observed changes in pDC counts associated with radiation, but only among women.

Radiation- and Age-Associated Changes in Peripheral Blood Dendritic Cell Populations among Aging Atomic Bomb Survivors in Japan.

Previous immunological studies in atomic bomb survivors have suggested that radiation exposure leads to long-lasting changes, similar to immunological aging observed in T-cell-adaptive immunity. However, to our knowledge, late effects of radiation on dendritic cells (DCs), the key coordinators for activation and differentiation of T cells, have not yet been investigated in humans. In the current study, we hypothesized that numerical and functional decreases would be observed in relationship to radiation dose in circulating conventional DCs (cDCs) and plasmacytoid DCs (pDCs) among 229 Japanese A-bomb survivors. Overall, the evidence did not support this hypothesis, with no overall changes in DCs or functional changes observed with radiation dose. Multivariable regression analysis for radiation dose, age and gender effects revealed that total DC counts as well as subpopulation counts decreased in relationship to increasing age. Further analyses revealed that in women, absolute numbers of pDCs showed significant decreases with radiation dose. A hierarchical clustering analysis of gene expression profiles in DCs after Toll-like receptor stimulation in vitro identified two clusters of participants that differed in age-associated expression levels of genes involved in antigen presentation and cytokine/chemokine production in cDCs. These results suggest that DC counts decrease and expression levels of gene clusters change with age. More than 60 years after radiation exposure, we also observed changes in pDC counts associated with radiation, but only among women.

Red Bone Marrow and Male Breast Doses for a Cohort of Atomic Veterans.

Both red bone marrow and male breast doses with associated uncertainty have been reconstructed for a 1,982-person subset of a cohort of 114, 270 military personnel (referred to as "atomic veterans") who participated in U.S. atmospheric nuclear weapons testing from 1945 to 1962. The methods used to calculate these doses and corresponding uncertainty have been reported in detail by Till et al. in an earlier publication. In this current article we report the final results of those calculations. These doses are being used in a case-cohort design epidemiological investigation of leukemia and male breast cancer. This cohort of atomic veterans is one component in a broader-scope study of approximately one million U.S. persons designed to investigate risk from chronic low-dose radiation exposure. Doses to the atomic veterans in this sub-cohort were relatively low, with approximately two-thirds receiving red bone marrow doses <5 mGy and only four individuals receiving a red bone marrow dose >50 mGy. The average red bone marrow dose for members of the sub-cohort was 5.9 mGy. Doses to male breast were approximately 20% higher than red bone marrow doses. The uncertainty in the estimated doses was relatively low, considering relevant personnel dosimetry was available for only about 25% of the subjects, and most of the doses were reconstructed from film badges worn by co-workers or from the individual's military record and military unit activities. The average coefficient of variation for the individual dose estimates was approximately 0.5, comparable to the uncertainty in doses estimated for the Japanese A-bomb survivors. Although the reconstructed red bone marrow doses were about 36% lower on average than the conservative doses previously estimated by the military for compensation, the overall correlation was quite good, suggesting that the estimates of doses from external exposure by the military for all ∼115,000 cohort members could be adjusted appropriately and used in further epidemiological analyses.

Low dose radiation risks for women surviving the a-bombs in Japan: generalized additive model.

BackgroundAnalyses of cancer mortality and incidence in Japanese A-bomb survivors have been used to estimate radiation risks, which are generally higher for women. Relative Risk (RR) is usually modelled as a linear function of dose. Extrapolation from data including high doses predicts small risks at low doses. Generalized Additive Models (GAMs) are flexible methods for modelling non-linear behaviour.MethodsGAMs are applied to cancer incidence in female low dose subcohorts, using anonymous public data for the 1958 – 1998 Life Span Study, to test for linearity, explore interactions, adjust for the skewed dose distribution, examine significance below 100 mGy, and estimate risks at 10 mGy.ResultsFor all solid cancer incidence, RR estimated from 0 – 100 mGy and 0 – 20 mGy subcohorts is significantly raised. The response tapers above 150 mGy. At low doses, RR increases with age-at-exposure and decreases with time-since-exposure, the preferred covariate. Using the empirical cumulative distribution of dose improves model fit, and capacity to detect non-linear responses. RR is elevated over wide ranges of covariate values. Results are stable under simulation, or when removing exceptional data cells, or adjusting neutron RBE. Estimates of Excess RR at 10 mGy using the cumulative dose distribution are 10 – 45 times higher than extrapolations from a linear model fitted to the full cohort. Below 100 mGy, quasipoisson models find significant effects for all solid, squamous, uterus, corpus, and thyroid cancers, and for respiratory cancers when age-at-exposure > 35 yrs. Results for the thyroid are compatible with studies of children treated for tinea capitis, and Chernobyl survivors. Results for the uterus are compatible with studies of UK nuclear workers and the Techa River cohort.ConclusionNon-linear models find large, significant cancer risks for Japanese women exposed to low dose radiation from the atomic bombings. The risks should be reflected in protection standards.Electronic supplementary materialThe online version of this article (doi:10.1186/s12940-016-0191-3) contains supplementary material, which is available to authorized users.

The influence of follow-up on DS02 low-dose ranges with a significant excess relative risk of all solid cancer in the Japanese A-bomb survivors.

Determinations of the lowest colon dose, D min, below which there is a statistically significant excess relative risk of all solid cancer, when analyses are restricted to the range [0, D min], are of current interest in research related to radiation protection and risk assessment. In reviewing recent cancer mortality reports on the Life Span Study (LSS) of Japanese A-bomb survivors, reported D min values were found to vary between different reports. The report 12 (follow-up: 1950-1990) found a D min of 50mGy, but the most recent report 14 (follow-up: 1950-2003) found a D min of 200mGy. There were small dosimetry changes between report 12, which used DS86, and report 14, which used DS02, but these changes are unlikely to account for a difference in D min of a factor of 4. This short communication examines the reasons for this difference in D min by presenting further investigations into D min using different trial values for D min and various follow-up time spans, all with the same DS02 dosimetry. Magnitudes of the low-dose risks in different dose ranges are also presented. It is shown here that the main influence on D min comes from the length of follow-up and a D min of 50mGy may also be obtained with the most recent LSS mortality data and DS02, if a restricted follow-up is analyzed. A systematic trend was evident of lower D min values for earlier mortality follow-up periods, consistent with information from earlier LSS reports. Although it may seem surprising that the D min increases with longer follow-up and better statistics, this systematic trend appears to be a consequence of decreasing mortality risks with longer follow-up, even though the error bars on the risks are getting smaller with increasing follow-up. These systematic trends also persisted after accounting for differences between baseline cancer rates for two groups of survivors who were either proximal or distal to the A-bomb hypocenter. Similar systematic trends, although much less pronounced, were also found in the LSS cancer incidence data. Some evidence is provided here that results on low-dose radiation risks from earlier follow-up periods should not be ignored by radiation protection authorities, once the results from the new extended follow-ups are published. This is because of the possibility that the new data for extended follow-up beyond a certain calendar time, which pertain to very long times since exposure, may be contributing to an overall reduction in radiation related risks per unit dose compared to analogous risks determined from earlier follow-up periods, because of the risk effect modification of time since exposure.

Male Breast Cancer Incidence and Mortality Risk in the Japanese Atomic Bomb Survivors - Differences in Excess Relative and Absolute Risk from Female Breast Cancer.

Background:There are well-known associations of ionizing radiation with female breast cancer, and emerging evidence also for male breast cancer. In the United Kingdom, female breast cancer following occupational radiation exposure is among that set of cancers eligible for state compensation and consideration is currently being given to an extension to include male breast cancer.Objectives:We compare radiation-associated excess relative and absolute risks of male and female breast cancers.Methods:Breast cancer incidence and mortality data in the Japanese atomic-bomb survivors were analyzed using relative and absolute risk models via Poisson regression.Results:We observed significant (p ≤ 0.01) dose-related excess risk for male breast cancer incidence and mortality. For incidence and mortality data, there are elevations by factors of approximately 15 and 5, respectively, of relative risk for male compared with female breast cancer incidence, the former borderline significant (p = 0.050). In contrast, for incidence and mortality data, there are elevations by factors of approximately 20 and 10, respectively, of female absolute risk compared with male, both statistically significant (p < 0.001). There are no indications of differences between the sexes in age/time-since-exposure/age-at-exposure modifications to the relative or absolute excess risk. The probability of causation of male breast cancer following radiation exposure exceeds by at least a factor of 5 that of many other malignancies.Conclusions:There is evidence of much higher radiation-associated relative risk for male than for female breast cancer, although absolute excess risks for males are much less than for females. However, the small number of male cases and deaths suggests a degree of caution in interpretation of this finding.Citation:Little MP, McElvenny DM. 2017. Male breast cancer incidence and mortality risk in the Japanese atomic bomb survivors – differences in excess relative and absolute risk from female breast cancer. Environ Health Perspect 125:223–229; http://dx.doi.org/10.1289/EHP151

Genetic radiation risks: a neglected topic in the low dose debate.

ObjectivesTo investigate the accuracy and scientific validity of the current very low risk factor for hereditary diseases in humans following exposures to ionizing radiation adopted by the United Nations Scientific Committee on the Effects of Atomic Radiation and the International Commission on Radiological Protection. The value is based on experiments on mice due to reportedly absent effects in the Japanese atomic bomb (Abomb) survivors.MethodsTo review the published evidence for heritable effects after ionising radiation exposures particularly, but not restricted to, populations exposed to contamination from the Chernobyl accident and from atmospheric nuclear test fallout. To make a compilation of findings about early deaths, congenital malformations, Down’s syndrome, cancer and other genetic effects observed in humans after the exposure of the parents. To also examine more closely the evidence from the Japanese A-bomb epidemiology and discuss its scientific validity.ResultsNearly all types of hereditary defects were found at doses as low as one to 10 mSv. We discuss the clash between the current risk model and these observations on the basis of biological mechanism and assumptions about linear relationships between dose and effect in neonatal and foetal epidemiology. The evidence supports a dose response relationship which is non-linear and is either biphasic or supralinear (hogs-back) and largely either saturates or falls above 10 mSv.ConclusionsWe conclude that the current risk model for heritable effects of radiation is unsafe. The dose response relationship is non-linear with the greatest effects at the lowest doses. Using Chernobyl data we derive an excess relative risk for all malformations of 1.0 per 10 mSv cumulative dose. The safety of the Japanese A-bomb epidemiology is argued to be both scientifically and philosophically questionable owing to errors in the choice of control groups, omission of internal exposure effects and assumptions about linear dose response.

Radiation risk models for all solid cancers other than those types of cancer requiring individual assessments after a nuclear accident.

In the assessment of health risks after nuclear accidents, some health consequences require special attention. For example, in their 2013 report on health risk assessment after the Fukushima nuclear accident, the World Health Organisation (WHO) panel of experts considered risks of breast cancer, thyroid cancer and leukaemia. For these specific cancer types, use was made of already published excess relative risk (ERR) and excess absolute risk (EAR) models for radiation-related cancer incidence fitted to the epidemiological data from the Japanese A-bomb Life Span Study (LSS). However, it was also considered important to assess all other types of solid cancer together and the WHO, in their above-mentioned report, stated "No model to calculate the risk for all other solid cancer excluding breast and thyroid cancer risks is available from the LSS data". Applying the LSS models for all solid cancers along with the models for the specific sites means that some cancers have an overlap in the risk evaluations. Thus, calculating the total solid cancer risk plus the breast cancer risk plus the thyroid cancer risk can overestimate the total risk by several per cent. Therefore, the purpose of this paper was to publish the required models for all other solid cancers, i.e. all solid cancers other than those types of cancer requiring special attention after a nuclear accident. The new models presented here have been fitted to the same LSS data set from which the risks provided by the WHO were derived. Although it is known already that the EAR and ERR effect modifications by sex are statistically significant for the outcome "all solid cancer", it is shown here that sex modification is not statistically significant for the outcome "all solid cancer other than thyroid and breast cancer". It is also shown here that the sex-averaged solid cancer risks with and without the sex modification are very similar once breast and thyroid cancers are factored out. Some other notable model differences between those already published for all solid cancers and those presented here for all other solid cancers are also given here. The models presented here can be used to improve on the methodology adopted by WHO after Fukushima and could contribute to emergency preparedness for future nuclear accidents.

CD14 and IL18 gene polymorphisms associated with colorectal cancer subsite risks among atomic bomb survivors.

Colorectal cancer (CRC) is a common malignancy worldwide, and chronic inflammation is a risk factor for CRC. In this study, we carried out a cohort study among the Japanese atomic bomb (A-bomb) survivor population to investigate any association between immune- and inflammation-related gene polymorphisms and CRC. We examined the effects of six single-nucleotide polymorphisms of CD14 and IL18 on relative risks (RRs) of CRC. Results showed that RRs of CRC, overall and by anatomic subsite, significantly increased with increasing radiation dose. The CD14–911A/A genotype showed statistically significant higher risks for all CRC and distal CRC compared with the other two genotypes. In addition, the IL18–137 G/G genotype showed statistically significant higher risks for proximal colon cancer compared with the other two genotypes. In phenotype–genotype analyses, the CD14–911A/A genotype presented significantly higher levels of membrane and soluble CD14 compared with the other two genotypes, and the IL18–137 G/G genotype tended to be lower levels of plasma interleukin (IL)-18 compared with the other two genotypes. These results suggest the potential involvement of a CD14-mediated inflammatory response in the development of distal CRC and an IL18-mediated inflammatory response in the development of proximal colon cancer among A-bomb survivors.

Age at exposure and attained age variations of cancer risk in the Japanese A-bomb and radiotherapy cohorts.

Phenomenological risk models for radiation-induced cancer are frequently applied to estimate the risk of radiation-induced cancers at radiotherapy doses. Such models often include the effect modification, of the main risk to radiation dose response, by age at exposure and attained age. The aim of this paper is to compare the patterns in risk effect modification by age, between models obtained from the Japanese atomic-bomb (A-bomb) survivor data and models for cancer risks previously reported for radiotherapy patients. Patterns in risk effect modification by age from the epidemiological studies of radiotherapy patients were also used to refine and extend the risk effect modification by age obtained from the A-bomb survivor data, so that more universal models can be presented here. Simple log-linear and power functions of age for the risk effect modification applied in models of the A-bomb survivor data are compared to risks from epidemiological studies of second cancers after radiotherapy. These functions of age were also refined and fitted to radiotherapy risks. The resulting age models provide a refined and extended functional dependence of risk with age at exposure and attained age especially beyond 40 and 65 yr, respectively, and provide a better representation than the currently available simple age functions. It was found that the A-bomb models predict risk similarly to the outcomes of testicular cancer survivors. The survivors of Hodgkin's disease show steeper variations of risk with both age at exposure and attained age. The extended models predict solid cancer risk increase as a function of age at exposure beyond 40 yr and the risk decrease as a function of attained age beyond 65 yr better than the simple models. The standard functions for risk effect modification by age, based on the A-bomb survivor data, predict second cancer risk in radiotherapy patients for ages at exposure prior to 40 yr and attained ages before 55 yr reasonably well. However, for larger ages, the refined and extended models can be applied to predict the risk as a function of age.

Genomic instability and radiation risk in molecular pathways to colon cancer.

Colon cancer is caused by multiple genomic alterations which lead to genomic instability (GI). GI appears in molecular pathways of microsatellite instability (MSI) and chromosomal instability (CIN) with clinically observed case shares of about 15–20% and 80–85%. Radiation enhances the colon cancer risk by inducing GI, but little is known about different outcomes for MSI and CIN. Computer-based modelling can facilitate the understanding of the phenomena named above. Comprehensive biological models, which combine the two main molecular pathways to colon cancer, are fitted to incidence data of Japanese a-bomb survivors. The preferred model is selected according to statistical criteria and biological plausibility. Imprints of cell-based processes in the succession from adenoma to carcinoma are identified by the model from age dependences and secular trends of the incidence data. Model parameters show remarkable compliance with mutation rates and growth rates for adenoma, which has been reported over the last fifteen years. Model results suggest that CIN begins during fission of intestinal crypts. Chromosomal aberrations are generated at a markedly elevated rate which favors the accelerated growth of premalignant adenoma. Possibly driven by a trend of Westernization in the Japanese diet, incidence rates for the CIN pathway increased notably in subsequent birth cohorts, whereas rates pertaining to MSI remained constant. An imbalance between number of CIN and MSI cases began to emerge in the 1980s, whereas in previous decades the number of cases was almost equal. The CIN pathway exhibits a strong radio-sensitivity, probably more intensive in men. Among young birth cohorts of both sexes the excess absolute radiation risk related to CIN is larger by an order of magnitude compared to the MSI-related risk. Observance of pathway-specific risks improves the determination of the probability of causation for radiation-induced colon cancer in individual patients, if their exposure histories are known.

Abstract 2209: Effects of IL10 haplotypes and atomic bomb radiation exposure on risks of gastric cancer subtypes

Abstract Background: Gastric cancer is one of the cancers whose risks of incidence and mortality clearly increased among Japanese atomic-bomb (A-bomb) survivors. Gastric cancer incidence in the Radiation Effects Research Foundation's (RERF) Life Span Study cohort population increased with radiation dose and remains high even today, more than 65 years since exposure. In this study, we specifically examined the association between risk of gastric cancer (intestinal and diffuse types) and radiation exposure by haplotypes of the immunosuppressive gene IL10 to investigate inter-individual differences in gastric cancer susceptibility associated with radiation exposure. Methods: We analyzed the follow-up data from the RERF Immunogenome Study Cohort of 4,690 A-bomb survivors at baseline covering 1981-2005: a total of 200 gastric cancer cases comprising 93 intestinal-type, 96 diffuse-type, and 11 other subtypes. Relative risk (RR) for IL10 and excess relative risk (ERR) for radiation of gastric cancer subtypes were estimated. Using a single haplotype block composed of four haplotype-tagging single nucleotide polymorphisms (comprising major haplotype allele IL10-ATTA and minor haplotype allele IL10-GGCG), multiplicative and additive models for joint effects of radiation and this IL10 haplotyping were examined. Results: The RR of intestinal-type gastric cancer among A-bomb survivors harboring the minor homozygote was significantly high, being 2.2 (95% confidence interval (CI): 1.1-4.3), compared to those harboring the major homozygote. In other words, the IL10 minor haplotype allele was considered to be a risk factor for intestinal-type gastric cancer. However, no significant association was observed between radiation exposure and intestinal-type gastric cancer, and no statistical interaction was observed between radiation exposure and IL10 haplotypes. The IL10 minor haplotype allele was not a risk factor for diffuse-type gastric cancer. The ERR per Gy of radiation exposure by haplotype showed statistical significance only for the major homozygote (0.46/Gy, 95% CI: 0.02-1.4). On the other hand, the ERR per Gy for the minor homozygote was close to 0, with no statistical significance. Therefore, the IL10 minor haplotype allele might act to suppress the radiation-associated risk elevation of diffuse-type gastric cancer. Conclusion: This study of A-bomb survivors suggests that IL10 haplotypes may be associated with the development of radiation-related diffuse-type gastric cancer. There is a possibility, therefore, that immune/inflammatory-related gene polymorphisms may be involved in inter-individual differences in radiation-related cancer risks. Further studies based on genome-wide association analysis are currently underway. Citation Format: Tomonori Hayashi, John B. Cologne, Yiqun Hu, Kengo Yoshida, Waka Ohishi, Ikue Hayashi, Junko Kajimura, Seishi Kyoizumi, Yoichiro Kusunoki, Kei Nakachi. Effects of IL10 haplotypes and atomic bomb radiation exposure on risks of gastric cancer subtypes. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2209. doi:10.1158/1538-7445.AM2014-2209