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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 [ABSTRACT FROM AUTHOR]

Atherosclerosis is the main cause of coronary heart disease and stroke, the two major causes of death in developed society. There is emerging evidence of excess risk of cardiovascular disease at low radiation doses in various occupationally exposed groups receiving small daily radiation doses. Assuming that they are causal, the mechanisms for effects of chronic fractionated radiation exposures on cardiovascular disease are unclear. We outline a spatial reaction-diffusion model for atherosclerosis and perform stability analysis, based wherever possible on human data. We show that a predicted consequence of multiple small radiation doses is to cause mean chemo-attractant (MCP-1) concentration to increase linearly with cumulative dose. The main driver for the increase in MCP-1 is monocyte death, and consequent reduction in MCP-1 degradation. The radiation-induced risks predicted by the model are quantitatively consistent with those observed in a number of occupationally-exposed groups. The changes in equilibrium MCP-1 concentrations with low density lipoprotein cholesterol concentration are also consistent with experimental and epidemiologic data. This proposed mechanism would be experimentally testable. If true, it also has substantive implications for radiological protection, which at present does not take cardiovascular disease into account. The Japanese A-bomb survivor data implies that cardiovascular disease and cancer mortality contribute similarly to radiogenic risk. The major uncertainty in assessing the low-dose risk of cardiovascular disease is the shape of the dose response relationship, which is unclear in the Japanese data. The analysis of the present paper suggests that linear extrapolation would be appropriate for this endpoint. [ABSTRACT FROM AUTHOR]

The atomic bomb, dropped on August 6, 1945, destroyed Hiroshima, Japan. Survivors of the explosion were exposed to two types of radiation: g-rays and neutrons. There have been several estimates of how much radiation they received, based on interviews with survivors and responses to questionnaires about their location at the time of bombings. The most recent set of estimates, the so-called DS86 dosimetry system, was introduced in 1986. Although low-energy neutron radiation represented only a tiny fraction of the total neutron radiation that survivors received, the discrepancy between DS86 and the low-energy neutron measurements had troubling implications for the dosimetry system as a whole. Previous measurements of high-energy neutrons had been unable to verify the accuracy of DS86 at these distances. Taken together with previous validations of the estimated g-ray doses, and of the Nagasaki neutron doses, it is now clear that the DS86 dose estimates correctly reflect all components of radiation dose in the two cities.

Dosimetric measurement error is known to potentially bias the magnitude of the dose response, and can also affect the shape of dose response. In this report, generalized relative and absolute rate models are fitted to the latest Japanese atomic bomb survivor solid cancer, leukemia and circulatory disease mortality data (followed from 1950 through 2003), with the latest (DS02R1) dosimetry, using Bayesian techniques to adjust for errors in dose estimates and assessing other model uncertainties. Linear-quadratic models are fitted and used to assess lifetime mortality risks for contemporary UK, USA, French, Russian, Japanese and Chinese populations. For a test dose of 0.1 Gy absorbed dose weighted by neutron relative biological effectiveness, solid cancer, leukemia and circulatory disease mortality risks for a UK population using a generalized linear-quadratic relative rate model were estimated to be 3.88% Gy-1 [95% Bayesian credible interval (BCI): 1.17, 6.97], 0.35% Gy-1 (95% BCI: -0.03, 0.78) and 2.24% Gy-1 (95% BCI: -0.17, 13.76), respectively. Using a generalized absolute rate linear-quadratic model at 0.1 Gy, the lifetime risks for these three end points were estimated to be 3.56% Gy-1 (95% BCI: 0.54, 6.78), 0.41% Gy-1 (95% BCI: 0.01, 0.86) and 1.56% Gy-1 (95% BCI: -1.10, 7.21), respectively. There was substantial evidence of curvature for solid cancer (in particular, the group of solid cancers excluding lung, breast and stomach cancers) and leukemia, so that for solid cancer and leukemia, estimates of excess risk per unit dose were nearly doubled by increasing the dose from 0.01 to 1.0 Gy, with most of the increase occurring in the interval from 0.1 to 1.0 Gy. For circulatory disease, the dose-response curvature was inverse, so that risk per unit dose was nearly halved by going from 0.01 t o 1.0 Gy weighted absorbed dose, although there were substantial uncertainties. In general, there were higher radiation risks for females compared to males. This was true for solid cancer and circulatory disease overall, as well as for lung, breast, stomach and the group of other solid cancers, and was the case whether relative or absolute rate projection models were employed; however, for leukemia this pattern was reversed. Risk estimates varied somewhat between populations, with lower cancer risks in aggregate for China and Russia, but higher circulatory disease risks for Russia, particularly using the relative rate model. There was more pronounced variation for certain cancer sites and certain types of projection models, so that breast cancer risk was markedly lower in China and Japan using a relative rate model, but the opposite was the case for stomach cancer. There was less variation between countries using the absolute rate models for stomach cancer and breast cancer, but this was not the case for lung cancer and the group of other solid cancers, or for circulatory disease., (©2020 by Radiation Research Society. All rights of reproduction in any form reserved.)

Purpose: To assess the shape of the dose-response for various circulatory disease endpoints, and modifiers by age and time since exposure., Methods and Materials: This was an analysis of the US peptic ulcer data testing for heterogeneity of radiogenic risk by circulatory disease endpoint (ischemic heart, cerebrovascular, other circulatory disease)., Results: There were significant excess risks for all circulatory disease, with an excess relative risk Gy(-1) of 0.082 (95% CI 0.031-0.140), and ischemic heart disease, with an excess relative risk Gy(-1) of 0.102 (95% CI 0.039-0.174) (both p = 0.01), and indications of excess risk for stroke. There were no statistically significant (p > 0.2) differences between risks by endpoint, and few indications of curvature in the dose-response. There were significant (p < 0.001) modifications of relative risk by time since exposure, the magnitude of which did not vary between endpoints (p > 0.2). Risk modifications were similar if analysis was restricted to patients receiving radiation, although the relative risks were slightly larger and the risk of stroke failed to be significant. The slopes of the dose-response were generally consistent with those observed in the Japanese atomic bomb survivors and in occupationally and medically exposed groups., Conclusions: There were excess risks for a variety of circulatory diseases in this dataset, with significant modification of risk by time since exposure. The consistency of the dose-response slopes with those observed in radiotherapeutically treated groups at much higher dose, as well as in lower dose-exposed cohorts such as the Japanese atomic bomb survivors and nuclear workers, implies that there may be little sparing effect of fractionation of dose or low-dose-rate exposure., (Published by Elsevier Inc.)

General reductions in cancer relative risk with increasing age at exposure are observed in the Japanese atomic bomb survivors and in other groups. However, there has been little evidence of heterogeneity in such trends by cancer type within the Japanese cohort, nor for cancer-type variations in other factors (sex, attained age) that modify relative risk. A recent report on the Japanese atomic bomb survivors published by Preston et al. in 2007 suggests that solid cancer relative risk exhibits a U-shaped relationship with age at exposure, and is initially decreasing and then increasing at older exposure ages. In this report, we reanalyse the latest Japanese atomic bomb survivor solid cancer mortality and incidence data analysed by Preston and co-workers, stratifying by cancer subtype where possible, the stratification being both in relation to the baseline and the radiation-associated excess. We find highly statistically significant (P < 0.001) variations of relative risk by cancer type, and statistically significant variations by cancer type in the adjustments for sex (P = 0.010) and age at exposure (P = 0.013) to the relative risk. There is no statistically significant (P > 0.2) variation by cancer type in the adjustment of relative risk for attained age. Although, for all incident solid cancers, there is marginally statistically significant (P = 0.033) variation of relative risk with a quadratic log-linear function of age at exposure, there is much weaker variation in the relative risk of solid cancer mortality (P > 0.1). However, the manner in which relative risk varies with age at exposure is qualitatively similar for incidence and mortality, so one should not make too much of these differences between the two datasets. Stratification by solid cancer type slightly weakens the evidence for quadratic variation in relative risk by age at exposure (P = 0.060).

After ingestion or inhalation of radionuclides, internal organs of the human body will be exposed to ionising radiation. Current risk estimates of radiation-associated cancer from internal emitters are largely based on extrapolation of risk from high-dose externally exposed groups. Concerns have been expressed that extrapolated risk estimates from internal emitters are greatly underestimated, by factors of ten or more, thus implying a severe underestimation of the true risks. Therefore, data on cancer mortality and incidence in a number of groups who received exposure predominantly from internal emitters are examined and excess relative risks per Sv are compared with comparable (age at exposure, time since exposure, gender) matched subsets of the Japanese atomic bomb survivor cohort. Risks are examined separately for low LET and high LET internal emitters. There are eight studies informative for the effects of internal low LET radiation exposure and 12 studies informative for the effects of internal high LET radiation. For 11 of the 20 cancer endpoints (subgroups of particular study cohorts) examined in the low LET internal emitter studies, the best estimate of the excess relative risk is greater than the corresponding estimate in the Japanese atomic bomb survivors and for the other nine it is less. For four of these 20 studies, the relative risk is significantly (2-sided P < 0.05) different from that in the Japanese atomic bomb survivors, in three cases greater than the atomic bomb survivor relative risk and in one case less. Considering only those six low LET studies/endpoints with 100 or more deaths or cases, for four out of six studies/endpoints the internal emitter risk is greater than that in the Japanese atomic bomb survivors. For seven of the 24 cancer endpoints examined in the high LET internal emitter studies the best estimate of the ERR in the internal emitter study is greater than the corresponding estimate in the Japanese atomic bomb survivors and for the other 17 it is less. For six studies, the relative risk is significantly (2-sided P < 0.05) different from that in the Japanese atomic bomb survivors, in one case greater than the atomic bomb survivor relative risk and in five cases less. Considering only those eight high LET studies/endpoints with 100 or more deaths or cases, for five out of eight studies/endpoints the internal emitter risk is greater than that in the Japanese atomic bomb survivors. These results suggest that excess relative risks in the internal emitter studies do not appreciably differ from those in the Japanese atomic bomb survivors. However, there are substantial uncertainties in estimates of risks in the internal emitter studies, particularly in relation to lung cancer associated with radon daughter (alpha particle) exposure, so a measure of caution should be exercised in these conclusions.

There is much uncertainty about cancer risks at the high radiation doses used in radiotherapy (RT). It has generally been assumed that cancer induction decreases rapidly at high doses due to cell killing. However, this is not seen in all RT groups, and a model recently developed by Sachs and Brenner [2005. Solid tumor risks after high doses of ionizing radiation. Proc. Natl Acad. Sci. USA 102, 13040-13045] proposed a mechanism for repopulation of cells after radiation exposure that explained why this might happen, at least for solid tumours. In this paper, this model is generalized to allow for heterogeneity in the dose received, and various alternate patterns of repopulation are also considered. The model is fitted to the Japanese atomic bomb survivor leukaemia incidence data, and data for various therapeutically irradiated groups. Two sets of parameters from these model fits are used to assess the sensitivity of model predictions. It is shown that in general allowing for heterogeneity in dose distribution and haematopoietic stem cell migration results in lower risks than the same average dose administered uniformly and without such migration, although this does not hold in the limiting case of complete stem cell repopulation between radiation dose fractions. We also investigate the difference made by assuming a compartmental repopulation signal, and a global repopulation signal. In general we show that in the absence of stochastic extinction, compartmental repopulation always predicts a larger number of mutated cells than global repopulation. However, in certain dose regimes stochastic extinction cannot be ignored, and in these cases the numbers of mutated cells predicted with global repopulation can exceed that for compartmental repopulation. In general, mutant cell numbers are highly overdispersed, with variance much greater than the mean.

Generalised absolute risk models were fitted to the latest Japanese atomic bomb survivor cancer incidence data using Bayesian Markov Chain Monte Carlo methods, taking account of random errors in the DS86 dose estimates. The resulting uncertainty distributions in the relative risk model parameters were used to derive uncertainties in population cancer risks for a current UK population. Because of evidence for irregularities in the low-dose dose response, flexible dose-response models were used, consisting of a linear-quadratic-exponential model, used to model the high-dose part of the dose response, together with piecewise-linear adjustments for the two lowest dose groups. Following an assumed administered dose of 0.001 Sv, lifetime leukaemia radiation-induced incidence risks were estimated to be 1.11 x 10(-2) Sv(-1) (95% Bayesian CI -0.61, 2.38) using this model. Following an assumed administered dose of 0.001 Sv, lifetime solid cancer radiation-induced incidence risks were calculated to be 7.28 x 10(-2) Sv(-1) (95% Bayesian CI -10.63, 22.10) using this model. Overall, cancer incidence risks predicted by Bayesian Markov Chain Monte Carlo methods are similar to those derived by classical likelihood-based methods and which form the basis of established estimates of radiation-induced cancer risk.

Recently released data on non-cancer mortality in Japanese atomic bomb survivors are analysed using a variety of generalised relative risk models that take account of errors in estimates of dose to assess the dose-response at low doses. If linear-threshold, quadratic-threshold or linear-quadratic-threshold relative risk models (the dose-response is assumed to be linear, quadratic or linear-quadratic above the threshold, respectively) are fitted to the non-cancer data there are no statistically significant ( p>0.10) indications of threshold departures from linearity, quadratic curvature or linear-quadratic curvature. These findings are true irrespective of the assumed magnitude of dosimetric error, between 25%-45% geometric standard deviations. In general, increasing the assumed magnitude of dosimetric error had little effect on the central estimates of the threshold, but somewhat widened the associated confidence intervals. If a power of dose model is fitted, there is little evidence ( p>0.10) that the power of dose in the dose-response is statistically significantly different from 1, again irrespective of the assumed magnitude of dosimetric errors in the range 25%-45%. Again, increasing the size of the errors resulted in wider confidence intervals on the power of dose, without marked effect on the central estimates. In general these findings remain true for various non-cancer disease subtypes.

Purposes: To ascertain possible evidence for radiosensitive subgroups in the Japanese atomic-bomb survivors., Materials and Methods: Time- and age-adjusted relative risk models were fitted to the Japanese atomic-bomb survivor mortality data, taking account of the modifying effects of acute injury status and adjusting for random dosimetric errors., Results: For leukaemia, there were statistically significantly higher relative risks among those persons reporting either epilation (two-sided p=0.03) or burns (two-sided p=0.02), but after adjustment is made for the effects of dosimetric error these results become statistically non-significant (two-sided p>0.05) For all other endpoints (cancers other than leukaemia, benign neoplasms, cardiovascular disease, non-cancer and non-cardiovascular disease) there were no statistically significant modifying effects on relative risk of acute injury status, whether or not adjustment is made for the effects of dosimetric error., Conclusions: Apart from leukaemia, there are generally no indications for cancer or other disease endpoints of variations in dose-response by acute injury status. The increased risks observed for leukaemia among those reporting epilation or burns are much diminished after adjustment for dosimetric error, and so there is no strong evidence of a sensitive subgroup within the Life Span Study cohort.

Case-control studies of childhood cancer and foetal exposure to diagnostic x-rays suggest that doses as small as 10 mSv increase the risk of cancer to a detectable extent. A comparison of the risk coefficient derived from the largest such study with that obtained from the Japanese atomic bomb survivors irradiated in utero (average dose, approximately 300 mGy) shows that, once all sources of uncertainty are taken into account, these risk estimates are not incompatible. The absence of a discernible variation in the risk per unit dose over this dose range is consistent with a linear dose-response. However, uncertainties are such that definitive conclusions on the shape of the dose-response at low doses cannot be drawn from this epidemiological evidence alone. Nonetheless, the evidence does suggest that the risk is not zero at doses of the order of 10 mSv.