Reassessment of the cancer mortality risk among Hiroshima atomic-bomb survivors using a new dosimetry system,ABS2000D,compared with ABS93D

The aim of the present study was to examine the excess relative risk for leukemia mortality and all cancers, except leukemia, among Hiroshima atomic-bomb survivors by applying ABS93D and ABS2000D. Particular attention was given to any difference in the neutron-dose estimates between the two dosimetry systems. The study subjects were 51,532 atomic-bomb survivors registered in a database of the Research Institute for Radiation Biology and Medicine of Hiroshima University (RIRBM). The results obtained by both dosimetry systems are similar: the excess relative risk per Sv for leukemia mortality and all cancers except leukemia is significantly higher compared to the control group. In addition, the difference in the excess relative risks between the two systems is not significant. Therefore, it is indicated that a modification of the neutron-dose estimates would not markedly change the conclusions about the cancer mortality risk.     

Understanding estimation of time and age effect-modification of radiation-induced cancer risks among atomic-bomb survivors

In radiation risk assessment based on follow-up data, estimation of the excess relative cancer rate involves evaluation of effect-modification by time-related factors such as age at exposure, time since exposure, and attained age. Because these variables are collinear, the regression coefficients purportedly measuring effect-modification of the radiation-related excess relative rate by time and age factors generally differ from the individual effects of these factors. For example, depending on whether it is an age-at-exposure/attained-age effect-modification model or an age-at-exposure/time-since-exposure model which is used, the regression coefficient for the effect of changes in age at exposure on the excess relative rate per Gray measures the combined effects of changes in both age at exposure and time since exposure, or of age at exposure and attained age, respectively, rather than the individual effect of changes in age at exposure, which is of interest for scientific purposes. Such insights should be integrated when reporting and interpreting estimates for time-related risk modification in cohort studies of radiation-exposed populations. Cancer incidence data for the Life Span Study of atomic-bomb survivors are used for illustration in parallel to theory. In summary, model coefficients for time-since-exposure, age-at-exposure, and attained-age effects on radiation-induced cancer risks among atomic-bomb survivors and in other cohort studies estimate combined effects (estimable combined effects are explicated). An appropriate unequivocal display of results for effect-modification is suggested. Goodness of fit appears unreliable for sorting out the most significant effect-modifiers. For example, a model including only one of the effect-modifiers may provide a fit similar to a model including the other two effect-modifiers, even when only the latter are actually related to effect-modification. Also, due to collinearity between these effect-modifier variables, all three models with two of the effect-modifiers necessarily show equivalent fits.     

Radiation risk estimates in the beginning of the 21st century

In the early years of the 21st century, results from a number of epidemiologic studies of populations with specific ionizing radiation exposures will become available. These include populations with accidental exposures in the former Soviet Union and elsewhere and populations with occupational exposures from routine operations of nuclear power plants. The strengths and limitations of these studies are reviewed together with the radiation protection questions they may answer. Many of these studies will provide specific information to complement the atomic-bomb survivor studies, particularly the effects of dose-rate and exposure protraction, modifiers of radiation risks (both environmental and host factors), and different types of radiation. These studies will therefore be important as a test of the adequacy of the current scientific bases for the radiation protection of workers and the general public. An example is thyroid cancer risk in young children following the Chernobyl accident, which has brought attention to a very high sensitivity of very young children that was difficult to assess on the basis of atomic-bomb data alone. Radiation protection will also benefit from formal comparisons and combined analyses of data from populations with different exposure patterns and exposures. Finally, future epidemiological studies will be most valuable if they are well focused, designed specifically to answer outstanding radiation protection questions. An integrated approach based on epidemiology and mechanistic studies, in which epidemiologic studies are designed to test specific mechanistic hypotheses and realistic mechanistic models are used for the analysis of epidemiological data, will probably be the most fruitful for radiation protection.     

Investigating time patterns of variation in radiation cancer associations

Aims: In occupational settings, carcinogenic exposures are often repeated or protracted over time. The time pattern of exposure accrual may influence subsequent temporal patterns of cancer risk. The authors present several simple models that may be used to evaluate the influence of time since exposure or age at exposure on cancer incidence or mortality in an occupational cohort. Methods: A cohort of 40 415 nuclear industry workers was identified via the Canadian National Dose Registry. Vital status and cause of death were ascertained through 1994. Associations between ionising radiation and mortality due to lung cancer, leukaemia, and cancers other than lung and leukaemia were quantified using conditional logistic regression models with risk sets constructed by incidence density sampling. A step function, a bilinear function, and a sigmoid function were used to evaluate temporal variation in exposure effects. Results: Step and sigmoid functions were used to explore latency and morbidity periods. For analyses of lung cancer, leukaemia, and other cancers the best fitting models were obtained when exposure assignment was lagged by 13, 0, and 5 years, respectively. A bilinear function was used to evaluate whether exposure effects diminished with time since exposure. In analyses of lung cancer and leukaemia, there was evidence that radiation effects attenuated with protracted time since exposure. In analyses of age at exposure, there was evidence of variation in radiation mortality associations for analyses of lung cancer and leukaemia; discounting radiation doses accrued at younger ages (for example, 15–35 years) led to significant improvements in model fit. Conclusions: This paper illustrates empirical approaches to evaluating temporal variation in the effect of a protracted exposure on disease risk.     

日本原子弹爆炸幸存者辐射致癌效应及其干扰因素的研究进展

日本辐射效应研究基金会(RERF)在对1958—1998年原子弹爆炸幸存者（原爆幸存者）实体癌发生率研究的基础上,增加了11年（1999—2009年）的随访结果,对原爆幸存者50年（1958—2009年）实体癌发生率进行深入研究,考虑性别、吸烟、饮酒、BMI以及医疗暴露等因素的影响,对实体癌的放射风险估计值进行更新,并在研究过程中发现了性别特异性的剂量反应、暴露年龄与癌症发生率的关系等新问题,为下一步的研究提供了指导方向。     

A case-control study in Hiroshima and Nagasaki examining non-radiation risk factors for thyroid cancer

BACKGROUND: Because little is known about the etiology of thyroid cancer in Japan, we conducted a case-control study of thyroid cancer and lifestyle and other risk factors. The present report focuses on medical history, family history, smoking and alcohol drinking, and their interactions with radiation exposure. METHODS: Thyroid cancer cases reported to the Hiroshima and Nagasaki tumor registries during 1970-1986 were histologically reviewed by pathologists. For each of 362 cases with papillary or follicular adenocarcinoma diagnosed at <75 years of age, one control without cancer matched on city, sex, year of birth, and atomic-bomb radiation exposure was selected from the Life Span Study cohort or the offspring cohort. The cohort subjects were residents of Hiroshima and Nagasaki with or without atomic-bomb radiation exposure. Information on risk factors was obtained through a pre-structured interview carried out in 1986-1988. RESULTS: Analysis using conditional logistic regression showed history of goiter or thyroid nodule and family history of cancer to be significantly associated with an increased odds ratio for thyroid cancer. Smoking and alcohol drinking were significantly and independently associated with a reduced odds ratio. Interaction between smoking and alcohol drinking was not evident based on either an additive model or a multiplicative model. Radiation exposure did not significantly modify the associations between these factors and thyroid cancer risk. CONCLUSION: History of goiter/nodule and family history of cancer were risk factors for thyroid cancer. Smoking and alcohol drinking were independently associated with reduced risk. Self-reported retrospective information presents some limitations in interpretation of the data.     

Intrauterine radiation exposures and mental retardation

Small head size and mental retardation have been known as effects of intrauterine exposure to ionizing radiation since the 1920s. In the 1950s, studies of Japanese atomic-bomb survivors revealed that at 4-17 wk of gestation, the greater the dose, the smaller the brain (and head size), and that beginning at 0.5 Gy (50 rad) in Hiroshima, mental retardation increased in frequency with increasing dose. No other excess of birth defects was observed. Otake and Schull (1984) pointed out that the period of susceptibility to mental retardation coincided with that for proliferation and migration of neuronal elements from near the cerebral ventricles to the cortex. Mental retardation could be the result of interference with this process. Their analysis indicated that exposures at 8-15 wk to 0.01-0.02 Gy (1-2 rad) doubled the frequency of severe mental retardation. This estimate was based on small numbers of mentally retarded atomic-bomb survivors. Although nuclear accidents have occurred recently, new cases will hopefully be too rare to provide further information about the risk of mental retardation. It may be possible, however, to learn about lesser impairment. New psychometric tests may be helpful in detecting subtle deficits in intelligence or neurodevelopmental function. One such test is PEERAMID, which is being used in schools to identify learning disabilities due, for example, to deficits in attention, short- or long-term memory, or in sequencing information. This and other tests could be applied in evaluating survivors of intrauterine exposure to various doses of ionizing radiation. The results could change our understanding of the safety of low-dose exposures.     

Mortality among individuals exposed to atomic bomb radiation in utero: 1950–2012

We examined the mortality risks among 2463 individuals who were exposed in utero to atomic bomb radiation in Hiroshima or Nagasaki in August 1945 and were followed from October 1950 through 2012. Individual estimates of mother’s weighted absorbed uterine dose (DS02R1) were used. Poisson regression method was used to estimate the radiation-associated excess relative risk per Gy (ERR/Gy) and 95% confidence intervals (CI) for cause-specific mortality. Head size, birth weight, and parents’ survival status were evaluated as potential mediators of radiation effect. There were 339 deaths (216 males and 123 females) including deaths from solid cancer (n?=?137), lymphohematopoietic cancer (n?=?8), noncancer disease (n?=?134), external cause (n?=?56), and unknown cause (n?=?4). Among males, the unadjusted ERR/Gy (95% CI) was increased for noncancer disease mortality (1.22, 0.10–3.14), but not for solid cancer mortality (??0.18,?<???0.77–0.95); the unadjusted ERR/Gy for external cause mortality was not statistically significant (0.28,?<???0.60–2.36). Among females, the unadjusted ERRs/Gy were increased for solid cancer (2.24, 0.44–5.58), noncancer (2.86, 0.56–7.64), and external cause mortality (2.57, 0.20–9.19). The ERRs/Gy adjusted for potential mediators did not change appreciably for solid cancer mortality, but decreased notably for noncancer mortality (0.39,?<???0.43–1.91 for males; 1.48, ??0.046–4.55 for females) and external cause mortality (0.10,?<???0.57–1.96 for males; 1.38,?<???0.46–5.95 for females). In conclusion, antenatal radiation exposure is a consistent risk factor for increased solid cancer mortality among females, but not among males. The effect of exposure to atomic bomb radiation on noncancer disease and external cause mortality among individuals exposed in utero was mediated through small head size, low birth weight, and parental loss.

     

Age at exposure modifies the effects of low-level ionizing radiation on cancer mortality in an occupational cohort

In a cohort of 4,563 nuclear workers followed retrospectively from 1950 to 1994, we found that age at exposure modified the effects of external radiation dose on cancer mortality. Analyses involved application of conditional logistic regression to risk sets of age- and calendar time-matched cancer deaths, with covariates treated as time dependent and with cumulative radiation doses divided according to the age intervals in which exposure occurred. After adjustment for confounding factors, we found that workers exposed to external radiation after the age of 50 years experienced exposure-related elevations in mortality from cancer at any site [rate ratio (RR) = 1.98; 95% confidence interval (CI) = 0.63-6.26], radiosensitive solid cancer (RR = 3.29; 95% CI = 1.10-9.89), and lung cancer (RR = 3.89; 95% CI = 1.23-12.3) substantially greater (1.6- to 3.5-fold greater) than were seen in coworkers exposed at all earlier ages. In contrast, all of the radiation doses contributing to mortality from cancers of the blood and lymph system were received before age 50 (for age <50, RR = 2.73 and 95% CI = 1.46-5.10; for age > or =50, RR = 0.24 and 95% CI = 0.00-687). Our results for cancer of any site are consistent with the results of previous studies examining the effects of exposure age in nuclear workers. Thus, effects of low-level radiation doses may depend on exposure age, and furthermore, patterns of effect modification by age may differ by type of cancer.     

Medical effects and risks of exposure to ionising radiation

Effects and risk from exposure to ionising radiation depend upon the absorbed dose, dose rate, quality of radiation, specifics of the tissue irradiated and other factors such as the age of the individual. Effects may be apparent almost immediately or may take decades to be manifest. Cancer is the most important stochastic effect at absorbed doses of less than 1 Gy. The risk of cancer induction varies widely across different tissues; however, the risk of fatal radiation-induced cancer for a general population following chronic exposure is about 5% Sv(-1). Quantification of cancer risk at doses of less than 0.1 Gy remains problematic. Hereditary risks from irradiation that might result in effects to offspring of humans appear to be much lower and any such potential risks can only be estimated from animal models. At high doses (over 1 Gy) cell killing and modification causes deterministic effects such as skin burns, and bone marrow depression, in which case immunosuppression becomes a critical issue. Acute whole body penetrating gamma irradiation at doses in excess of 2 Gy results in varying degrees of acute radiation sickness and doses over 10 Gy are usually lethal as a result of combined organ injury.     

Age-at-exposure effects on risk estimates for non-cancer mortality in the Japanese atomic bomb survivors.

Statistically significant increases in non-cancer disease mortality with radiation dose have been observed among survivors of the atomic bombings of Hiroshima and Nagasaki. The increasing trends arise particularly for diseases of the circulatory, digestive, and respiratory systems. Rates for survivors exposed to a dose of 1 Sv are elevated by about 10%, a smaller relative increase than that for cancer. The aetiology of this increased risk is not yet understood. Neither animal nor human studies have found clear evidence for excess non-cancer mortality at the lower range of doses received by A-bomb survivors. In this paper, we examine the age and time patterns of excess risks in the A-bomb survivors. The results suggest that the excess relative risk of non-cancer disease mortality might be highest for exposure at ages 30-49 years, and that those exposed at ages 0-29 years might have a very low excess relative risk compared with those exposed at older ages. The differences in excess relative risk for different age-at-exposure groups imply that the dose response relationships for non-cancer disease mortality need to be modelled with adjustment for age-at-exposure.     

Radiation effects on atherosclerosis in atomic bomb survivors: a cross‐sectional study using structural equation modeling

Past reports indicated that total-body irradiation at low to moderate doses could be responsible for cardiovascular disease risks, but the mechanism remains unclear. The purpose of this study was to investigate the association between radiation exposure and atherosclerosis, an underlying pathology of cardiovascular diseases, in the Japanese atomic bomb survivors. We performed a cross-sectional study measuring 14 clinical-physiological atherosclerosis indicators during clinical exams from 2010 to 2014 in 3274 participants of the Adult Health Study cohort. Multivariable analyses were performed by using a structural equation model with latent factors representing underlying atherosclerotic pathologies: (1) arterial stiffness, (2) calcification, and (3) plaque　as measured with indicators chosen a priori on the basis of clinical-physiological knowledge. Radiation was linearly associated with calcification (standardized coefficient per Gy 0.15, 95?% confidence interval: CI [0.070, 0.23]) and plaque (0.11, 95?% CI [0.029, 0.20]), small associations that were comparable to about 2 years of aging per Gy of radiation exposure, but not with arterial stiffness (0.036, 95?% CI [??0.025, 0.095]). The model fitted better and had narrower confidence intervals than separate ordinary regression models explaining individual indicators independently. The associations were less evident when the dose range was restricted to a maximum of 2 or 1 Gy. By combining individual clinical-physiological indicators that are correlated because of common, underlying atherosclerotic pathologies, we found a small, but significant association of radiation with atherosclerosis.

     

Effects of prenatal exposure to ionizing radiation

Prenatal exposure to ionizing radiation induces some effects that are seen at birth and others that cannot be detected until later in life. Data from A-bomb survivors in Hiroshima and Nagasaki show a diminished number of births after exposure under 4 wk of gestational age. Although a wide array of congenital malformations has been found in animal experimentation after such exposure to x rays, in humans only small head size (exposure at 4-17 wk) and mental retardation (exposure primarily at 8-15 wk) have been observed. In Hiroshima, small head size occurred after doses of 0.10-0.19 Gy or more, and an excess of mental retardation at 0.2-0.4 Gy or more. Intelligence test scores were reduced among A-bomb survivors exposed at 8-15 wk of gestational age by 21-29 IQ points per Gy. Other effects of in-utero exposure to atomic radiation include long-lasting complex chromosome abnormalities.     

The third analysis of cancer mortality among Japanese nuclear workers, 1991-2002: estimation of excess relative risk per radiation dose

The present study estimated excess relative risk per sievert (ERR/Sv) of cancer mortality among the cohort of 200?583 male Japanese nuclear workers, with an average individual cumulative dose of 12.2 mSv (<10 mSv, 75.4%; 100 + mSv, 2.6%), conducting Poisson regression using dose category specific observed and expected numbers of deaths, and average doses obtained from the official report of the Radiation Effects Association (REA) on the analysis of mortality of Japanese nuclear industry workers for 1991-2002, which reported the estimates of ERR/Sv for leukaemia but not for all cancers or any other cancer site. The possible confounding biases from drinking alcohol and smoking tobacco were evaluated by examining the association of cumulative radiation dose with the mortality of cancers related to drinking or smoking. For leukaemia (80 deaths), the estimate of ERR/Sv was - 1.93 (95% confidence interval (CI) = - 6.12, 8.57). For all cancers excluding leukaemia (2636 deaths), while the ERR/Sv was estimated to be 1.26 (95%CI = - 0.27, 3.00), confounding by alcohol consumption was suspected since the ERR/Sv estimate of alcohol-related cancers was 4.64 (95%CI = 1.13, 8.91) and the ERR/Sv estimate of all cancers excluding leukaemia and alcohol-related cancers was 0.20 (95%CI = - 1.42, 2.09). In conclusion, confounding by important lifestyle factors related to cancer risk may have a substantial effect on risk estimates, especially when conducting studies of low cumulative dose and, accordingly, low statistical power. Pooled analysis or meta-analysis of nuclear workers for solid cancers needs to take this point into account.     

Risk analysis of leukaemia incidence among people living along the Techa River: a nested case-control study.

Large quantities of radioactive materials released over time from the Mayak nuclear weapons facility caused significant internal and external exposure for people living along the banks of the Techa River (Southern Urals, Russia). We conducted a nested case-control study in the Extended Techa River Cohort to determine whether the risk of leukaemia incidence increased with protracted exposure to ionising radiation or with other non-radiation risk factors. The study included 83 cases identified over 47 years of follow-up and 415 controls matched for sex, age at diagnosis, age (within a 5 year age group), and date of initial residence in the riverside area. External and internal doses have been calculated using the Techa River Dosimetry System 1996 (TRDS96). Conditional logistic regression was used to calculate odds ratios per Gray (OR/Gy) and 95% confidence intervals (95% CI). After excluding cases of chronic lymphoid leukaemia, the OR/Gy of total, external, and internal doses were 4.6 (95% CI: 1.7-12.3), 7.2 (95%CI: 1.7-30.0) and 5.4 (95%CI: 1.1-27.2), respectively. A history of solid tumour, either malignant or benign, before the leukaemia diagnosis was associated with a 2.5-fold increase in the leukaemia risk (95% CI: 1.1-5.9). Even though the analysis of confounders was less useful than expected because of missing data, multivariate analyses that took the exposure dose into account confirmed the association between leukaemia incidence and tumour history.     

Epidemiologic data on radiation-induced breast cancer

BackgroundFemale breast cancer is the most frequent cancer, both in incidence and mortality. It is well known that exposure to ionizing radiation increases the risk, but some questions remain concerning low dose and low-dose rate effects and cofactors. These potential effects have to be taken into account to carry out adequate risk assessment on medically exposed populations. A literature review is proposed on this issue.MethodsA Medline research was undertaken. Keywords used were ionizing radiation, breast cancer and epidemiology. More studies were added through references included in the first list of articles. The focus was placed on studies including quantitative dose–effect relationship analyses.ResultsA latency of five to 10 to 13 years is observed in the appearance of risk. The risk diminishes with age at exposure. A diminution with age at risk is also suspected. The excess relative risk per gray varies between 0.3 and 1.5 for an age at first exposure of 25 years. The study of Hiroshima and Nagasaki survivors shows that risk is increased even if doses are restricted to below 0.5 Gy. Above high doses (20 Gy), the risk no longer increases. This can be interpreted as a cell-killing effect. The excess subsists if doses are fractionated, but a diminution of the effect is suspected.ConclusionThe effects of exposure to levels of doses used for medical diagnostic are very difficult to study in the general population by epidemiological methods. Only studies conducted on very young children could achieve enough power, because of their high radiosensitivity. Available information on the effects of doses above 0.5 Gy allows extrapolation on maximal effects. Models deduced from existing cohorts can be used to assess risk, with their limits due to associated uncertainties. Preston et al. proposed an excess absolute-risk model, which makes estimates from the more comprehensive cohorts compatible. This model has been retained by the 2006 committee “Biological effects of ionizing radiation” (report VII).     

Tracking the errant cell after the atomic bombings: what went wrong?

Epidemiological data collected after the atomic-bomb blasts of Hiroshima and Nagasaki have established a link between radiation exposure and human cancer development and are the major source of information for current radiation-induced cancer risk assessment. To determine the mechanistic basis for radiation carcinogenesis, retrospective molecular analyses of archival hepatocellular carcinoma tissues from the atomic-bomb survivors were conducted. The tumor suppressor genes p53 and M6P/IGF2r were examined. HCC cases had either p53 mutations or M6P/IGF2r mutations, but rarely both. Moreover, the frequency of cases with M6P/ IGF2r mutations actually decreased with dose, while those for p53 increased. This implies two independent selection processes leading to liver cancer and that in radiation-induced HCC tumors the spectrum of molecular changes is different from that in "background" tumors.     

Factors affecting recognition of cancer risks of nuclear workers.

OBJECTIVES--To discover whether direct estimates of the risks of cancer for nuclear workers agree with indirect estimates based on survivors of the atomic bomb; whether relations between age at exposure and risk of cancer are the same for workers and survivors, and whether dosimetry standards are sufficiently uniform to allow pooling of data from different nuclear industrial sites. METHOD--Data from five nuclear sites in the United States were included in a cohort analysis that as well as controlling for all the usual factors also allowed for possible effects of three cancer modulating factors (exposure age, cancer latency, and year of exposure). This analysis was first applied to three distinct cohorts, and then to two sets of pooled data. RESULTS--From each study cohort there was evidence of a risk of cancer related to dose, and evidence that the extra radiogenic cancers had the same overall histological manifestations as naturally occurring cancers and were largely the result of exposures after 50 years of age causing deaths after 70 years. There were, however, significant differences between the five sets of risk estimates. CONCLUSIONS--Although the risks of cancer in nuclear workers were appreciably higher than estimates based on the cancer experiences of survivors of the atomic bomb, some uncertainties remained as there were non-uniform standards of dosimetry in the nuclear sites. The differences between nuclear workers and survivors of the atomic bomb were largely the result of relations between age at exposure and risk of cancer being totally different for workers and survivors and, in the occupational data, there were no signs of the special risks of leukaemia found in atomic bomb data and other studies of effects of high doses.     

Relations between age at occupational exposure to ionising radiation and cancer risk.

OBJECTIVES: To discover how the age when a given dose of ionising radiation is received (exposure age) affects the subsequent cancer risk, and whether the types of cancer caused by repeated exposure to small doses during adult life differ from naturally occurring cancers at that age. METHOD: A nested case-control design with all possible controls in a cohort of nuclear workers, and a Mantel-Haenszel test (requiring only one degree of freedom) to discover whether there was any level of exposure age where the null hypothesis of no effects of radiation was rejected. This analysis was followed by inspection of how different types of cancers were related to the cancer risk. RESULTS: For radiation received at least 15 years before a cancer death (to allow for cancer latency) evidence of a dose related risk was found which was largely the result of exposures during the last 10 years of working life (between 55 and 65 years of age). The relative frequency of site specific cancers showed no signs of being different for radiogenic and idiopathic cancers, and there was no evidence of the exceptionally strong association between radiation and leukaemia found in atomic bomb data and other high dose situations. CONCLUSIONS: Sensitivity to carcinogenic effects of radiation increases progressively with age during adult life and, provided the dose is too small to produce many cell deaths, the ratio of leukaemias to solid tumours is no different for radiogenic and idiopathic cancers.