Chromosome aberrations among atomic-bomb survivors exposed in utero: updated analysis accounting for revised radiation doses and smoking.

A previous study of peripheral blood lymphocyte translocations around age 40 among atomic-bomb survivors exposed in utero revealed no overall association with radiation dose-despite a clear association between translocations and dose among their mothers-but the data suggested an increase at doses below 100 mGy with a definite peak. That analysis of the in utero-exposed survivors did not adjust for their subsequent smoking behavior, an established cause of chromosomal aberrations, or their subsequent exposures to medical irradiation, a potential mediator. In addition, atomic-bomb survivor radiation dose estimates have subsequently been updated and refined. We therefore re-estimated the dose response using the latest DS02R1 dose estimates and adjusting for smoking as well as for city and proximal-distal location at the time of exposure to the atomic bomb. Sex of the survivor, mother's age around the time of conception, and approximate trimester of gestation at the time of exposure were also considered as explanatory variables and modifiers. Precision of the estimated dose response was slightly lower due to greater variability near zero in the updated dose estimates, but there was little change in evidence of a low-dose increase and still no suggestion of an overall increase across the entire dose range. Adjustment for smoking behavior led to a decline in background number of translocations (the dose-response intercept), but smoking did not interact with dose overall (across the entire dose range). Adjustment for medical irradiation did not alter the association between dose and translocation frequency. Sex, mother's age, and trimester were not associated with number of translocations, nor did they interact with dose overall. Interactions with dose in the low-dose range could not be evaluated because of numerical instability.

Incidence of Diabetes in the Atomic Bomb Survivors: 1969-2015.

CONTEXT: Recent epidemiological studies have shown increased risk of diabetes among childhood cancer survivors who received high therapeutic doses of radiation, particularly to the total body or to the abdomen. However, the effect of low-to-moderate dose radiation (<4 Gy) on the risk of diabetes is still unknown. OBJECTIVES: To investigate the radiation effect on diabetes incidence among atomic bomb (A-bomb) survivors, and whether the dose response is modified by other factors including city, sex, and age at time of bombing (ATB). METHODS: 9131 participants without diabetes at baseline were observed through biennial clinical exams from 1969 to 2015. A Cox proportional hazards model was used to estimate hazard ratios (HR) to evaluate the dose response for diabetes incidence. RESULTS: During the study period, 1417 incident diabetes cases were identified. The overall crude incidence rate was 7.01/103 person-years. Radiation dose was significantly associated with diabetes incidence, with effect modification by city and age ATB. In Hiroshima, at ages 10 and 30 ATB, the HRs at 1 Gy of pancreatic radiation dose were 1.47 (95% CI, 1.31-1.66) and 1.13 (95% CI, 0.97-1.31), respectively. However, no significant radiation dose response was observed at these ages in Nagasaki. The HR for radiation dose was higher among those who were younger ATB and decreased 1% for each additional year of age. CONCLUSIONS: Among A-bomb survivors, a radiation association was suggested for incidence of diabetes. Results were inconsistent by city and age ATB, which could indicate potential confounding of the radiation association with diabetes.

Congenital Malformations and Perinatal Deaths Among the Children of Atomic Bomb Survivors: A Reappraisal.

From 1948 to 1954, the Atomic Bomb Casualty Commission conducted a study of pregnancy outcomes among births to atomic bomb survivors (Hiroshima and Nagasaki, Japan) who had received radiation doses ranging from 0 Gy to near-lethal levels. Past reports (1956, 1981, and 1990) on the cohort did not identify significant associations of radiation exposure with untoward pregnancy outcomes, such as major congenital malformations, stillbirths, or neonatal deaths, individually or in aggregate. We reexamined the risk of major congenital malformations and perinatal deaths in the children of atomic bomb survivors (n = 71,603) using fully reconstructed data to minimize the potential for bias, using refined estimates of the gonadal dose from Dosimetry System 2002 and refined analytical methods for characterizing dose-response relationships. The analyses showed that parental exposure to radiation was associated with increased risk of major congenital malformations and perinatal death, but the estimates were imprecise for direct radiation effects, and most were not statistically significant. Nonetheless, the uniformly positive estimates for untoward pregnancy outcomes among children of both maternal and paternal survivors are useful for risk assessment purposes, although extending them to populations other than the atomic bomb survivors comes with uncertainty as to generalizability.

Causal mediation analysis in nested case-control studies using conditional logistic regression.

The paper proposes an approach to causal mediation analysis in nested case-control study designs, often incorporated with countermatching schemes using conditional likelihood, and we compare the method's performance to that of mediation analysis using the Cox model for the full cohort with a continuous or dichotomous mediator. Simulation studies are conducted to assess our proposed method and investigate the efficiency relative to the cohort. We illustrate the method using actual data from two studies of potential mediation of radiation risk conducted within the Adult Health Study cohort of atomic-bomb survivors. The performance becomes comparable to that based on the full cohort, illustrating the potential for valid mediation analysis based on the reduced data obtained through the nested case-control design.

Type 2 diabetes, obesity, and breast cancer risk among Japanese women of the atomic bomb survivor cohort.

BACKGROUND: Much less is known about diabetes than obesity as a predictor of breast cancer incidence and most previous studies have been conducted in white populations. Therefore, this project within the Radiation Effects Research Foundation's cohort of Japanese atomic bomb survivors aimed to determine the independent contributions of obesity and diabetes to develop breast cancer. METHODS: After excluding women with unknown A-bomb radiation dose, a radiation dose of ≥100 mGy, a pre-existing history of breast cancer, and missing body mass index (BMI), the analysis included 29,818 women. Breast cancer status and deaths until 2009 were identified from cancer registries and vital records. Cox regression with age as the time metric was applied to estimate hazard ratios (HR) and 95% confidence intervals (CI) for BMI and diabetes status as time-varying exposures alone and in combination while adjusting for known confounders. RESULTS: Diabetes prevalence increased from 2.6% to 5.3% and 7.5% from the first to the second and third data collection. During 27.6 ± 12.2 years of follow-up, 703 women had developed breast cancer (mean age of 66.0 ± 12.9 years) and 31 (4.4%) had been diagnosed with diabetes. A diagnosis of diabetes was not significantly associated with breast cancer incidence without (HR 1.12, 95% CI 0.77-1.64) and with BMI (HR 1.01, 95% CI 0.69-1.49) as a covariate. The respective HRs for overweight and obesity were 1.61 (95% CI 1.34-1.93) and 2.04 (95% CI 1.40-2.97). CONCLUSIONS: Among a long-time Japanese cohort, excess body weight but not a diabetes diagnosis was significantly associated with breast cancer risk.

Body composition and development of diabetes: a 15-year follow-up study in a Japanese population.

BACKGROUND/OBJECTIVES: Few longitudinal studies have examined the association between diabetes risk and body composition in Asians. The aim of this prospective cohort study was to determine the role of body composition, estimated by whole-body dual-energy X-ray absorptiometry, in the development of diabetes and to examine the impact of body composition on diabetes risk in normal weight (body mass index (BMI) <23 kg/m2) and overweight/obese groups (≥23 kg/m2). SUBJECTS/METHODS: We measured the body composition for 1532 diabetes-free subjects (463 men and 1069 women), aged 48-79 years, at the baseline examination period from 1994-96 and followed-up to detect new cases of diabetes over the next 15 years (median 13.4 years). RESULTS: After being adjusted for BMI and other potential confounding factors, body fat distribution was associated with diabetes risk. Percentage of trunk fat was positively associated with the development of diabetes (hazards ratio (HR) per 1 SD (95% confidential interval (CI)), 1.58 (1.10-2.28) in men, and 1.34 (0.99-1.83) in women), and percentage of leg fat was negatively associated with the development of diabetes (HR per 1 SD (95% CI), 0.68 (0.50-0.91) in men and 0.68 (0.55-0.85) in women). The estimated HRs of % trunk and leg fat on the development of diabetes differed little between normal weight and overweight/obese subjects. Appendicular lean mass was also negatively associated with diabetes risk only in normal weight men. CONCLUSIONS: Opposite associations of trunk fat and leg fat with diabetes risk were observed. Assessment of body composition might help in the evaluation of diabetes risk.

Thyroid Dysfunction and Autoimmune Thyroid Diseases Among Atomic Bomb Survivors Exposed in Childhood.

Context: The risk of thyroid cancer increases and persists for decades among individuals exposed to ionizing radiation in childhood, although the long-term effects of childhood exposure to medium to low doses of radiation on thyroid dysfunction and autoimmune thyroid diseases have remained unclear. Objective: To evaluate radiation dose responses for the prevalence of thyroid dysfunction and autoimmune thyroid disease among atomic bomb survivors exposed in childhood. Design, Setting, and Participants: Hiroshima and Nagasaki atomic bomb survivors who were younger than 10 years old at exposure underwent thyroid examinations at the Radiation Effects Research Foundation between 2007 and 2011, which was 62 to 66 years after the bombing. Data from 2668 participants (mean age, 68.2 years; 1455 women) with known atomic bomb thyroid radiation doses (mean dose, 0.182 Gy; dose range, 0 to 4.040 Gy) were analyzed. Main Outcome and Measures: Dose-response relationships between atomic bomb radiation dose and the prevalence of hypothyroidism, hyperthyroidism (Graves' disease), and positive for antithyroid antibodies. Results: Prevalences were determined for hypothyroidism (129 cases, 7.8%), hyperthyroidism (32 cases of Graves' disease, 1.2%), and positive for antithyroid antibodies (573 cases, 21.5%). None of these was associated with thyroid radiation dose. Neither thyroid antibody-positive nor -negative hypothyroidism was associated with thyroid radiation dose. Additional analyses using alternative definitions of hypothyroidism and hyperthyroidism found that radiation dose responses were not significant. Conclusions: Radiation effects on thyroid dysfunction and autoimmune thyroid diseases were not observed among atomic bomb survivors exposed in childhood, at 62 to 66 years earlier. The cross-sectional design and survival bias were limitations of this study.

Association of radiation dose with prevalence of thyroid nodules among atomic bomb survivors exposed in childhood (2007-2011).

IMPORTANCE: Few studies have evaluated the association of radiation dose with thyroid nodules among adults exposed to radiation in childhood. OBJECTIVE: To evaluate radiation dose responses on the prevalence of thyroid nodules in atomic bomb survivors exposed in childhood. DESIGN, SETTING, AND PARTICIPANTS: This survey study investigated 3087 Hiroshima and Nagasaki atomic bomb survivors who were younger than 10 years at exposure and participated in the thyroid study of the Adult Health Study at the Radiation Effects Research Foundation. Thyroid examinations including thyroid ultrasonography were conducted between October 2007 and October 2011, and solid nodules underwent fine-needle aspiration biopsy. Data from 2668 participants (86.4% of the total participants; mean age, 68.2 years; 1213 men; and 1455 women) with known atomic bomb thyroid radiation doses (mean dose, 0.182 Gy; median dose, 0.018 Gy; dose range, 0-4.040 Gy) were analyzed. MAIN OUTCOMES AND MEASURES: The prevalence of all thyroid nodules having a diameter of 10 mm or more (consisting of solid nodules [malignant and benign] and cysts), prevalence of small thyroid nodules that were less than 10 mm in diameter detected by ultrasonography, and atomic bomb radiation dose-responses. RESULTS: Thyroid nodules with a diameter of 10 mm or more were identified in 470 participants (17.6%): solid nodules (427 cases [16.0%]), malignant tumors (47 cases [1.8%]), benign nodules (186 cases [7.0%]), and cysts (49 cases [1.8%]), and all were significantly associated with thyroid radiation dose. Excess odds ratios per gray unit were 1.65 (95% CI, 0.89-2.64) for all nodules, 1.72 (95% CI, 0.93-2.75) for solid nodules, 4.40 (95% CI, 1.75-9.97) for malignant tumors, 2.07 (95% CI, 1.16-3.39) for benign nodules, and 1.11 (95% CI, 0.15-3.12) for cysts. The interaction between age at exposure and the dose was significant for the prevalence of all nodules (P = .003) and solid nodules (P < .001), indicating that dose effects were significantly higher with earlier childhood exposure. No interactions were seen for sex, family history of thyroid disease, antithyroid antibodies, or seaweed intake. No dose-response relationships were observed for small (<10-mm diameter) thyroid nodules. CONCLUSIONS AND RELEVANCE: Radiation effects on thyroid nodules exist in atomic bomb survivors 62 to 66 years after their exposure in childhood. However, radiation exposure is not associated with small thyroid nodules.

Radiation risk of individual multifactorial diseases in offspring of the atomic-bomb survivors: a clinical health study.

There is no convincing evidence regarding radiation-induced heritable risks of adult-onset multifactorial diseases in humans, although it is important from the standpoint of protection and management of populations exposed to radiation. The objective of the present study was to examine whether parental exposure to atomic-bomb (A-bomb) radiation led to an increased risk of common polygenic, multifactorial diseases-hypertension, hypercholesterolaemia, diabetes mellitus, angina pectoris, myocardial infarction or stroke-in the first-generation (F1) offspring of A-bomb survivors. A total of 11,951 F1 offspring of survivors in Hiroshima or Nagasaki, conceived after the bombing, underwent health examinations to assess disease prevalence. We found no evidence that paternal or maternal A-bomb radiation dose, or the sum of their doses, was associated with an increased risk of any multifactorial diseases in either male or female offspring. None of the 18 radiation dose-response slopes, adjusted for other risk factors for the diseases, was statistically significantly elevated. However, the study population is still in mid-life (mean age 48.6 years), and will express much of its multifactorial disease incidence in the future, so ongoing longitudinal follow-up will provide increasingly informative risk estimates regarding hereditary genetic effects for incidence of adult-onset multifactorial disease.

Biomarkers of radiosensitivity in a-bomb survivors pregnant at the time of bombings in hiroshima and nagasaki.

Purpose. There is evidence in the literature of increased maternal radiosensitivity during pregnancy. Materials and Methods. We tested this hypothesis using information from the atomic-bomb survivor cohort, that is, the Adult Health Study database at the Radiation Effects Research Foundation, which contains data from a cohort of women who were pregnant at the time of the bombings of Hiroshima and Nagasaki. Previous evaluation has demonstrated long-term radiation dose-response effects. Results/Conclusions. Data on approximately 250 women were available to assess dose-response rates for serum cholesterol, white blood cell count, erythrocyte sedimentation rate, and serum hemoglobin, and on approximately 85 women for stable chromosome aberrations, glycophorin A locus mutations, and naïve CD4 T-cell counts. Although there is no statistically significant evidence of increased radiosensitivity in pregnant women, the increased slope of the linear trend line in the third trimester with respect to stable chromosome aberrations is suggestive of an increased radiosensitivity.

A nation-wide survey on indoor radon from 2007 to 2010 in Japan.

In two previous nation-wide surveys in the late 1980s and early 1990s, Japanese indoor radon concentrations increased in homes built after the mid 1970s. In order to ascertain whether this trend continued, a nation-wide survey was conducted from 2007 to 2010. In total 3,900 houses were allocated to 47 prefectures by the Neyman allocation method and 3,461 radon measurements were performed (88.7% success). The fraction of reinforced concrete / concrete block buildings was 32.4%, similar to the value from national statistics. Arithmetic mean (standard deviation, SD) and geometric mean (geometric SD) of radon concentration after adjusting for seasonal fluctuation were 14.3 (14.7) and 10.8 (2.1) Bq/m(3). The corresponding population-weighted values were 13.7 (12.3) and 10.4 (2.0) Bq/m(3), respectively. It was estimated that only 0.1% of dwellings exceed 100 Bq/m(3), a new WHO reference level for indoor radon. Radon concentrations were highest in houses constructed in the mid 1980s and decreased thereafter. In conclusion, arithmetic mean indoor radon in the present survey was slightly lower than in previous surveys and significant reductions in indoor radon concentrations in both wooden and concrete houses can be attributed to alterations in Japanese housing styles in recent decades.

Timing of menarche and first birth in relation to risk of breast cancer in A-bomb survivors.

BACKGROUND: The length of the interval between age at menarche and age at first birth is positively associated with breast cancer risk. We examined the risk of breast cancer in atomic bomb survivors to investigate whether women exposed to radiation between menarche and first birth had a higher risk of radiogenic breast cancer than women exposed at the same age but outside this interval. METHODS: Women (n = 30,113) were classified into three reproductive status at the time of the bombings (ATB) categories (premenarche, between menarche and first birth, or after first birth). Poisson regression was used to test the primary hypothesis. RESULTS: When the background rate of breast cancer was taken to depend on city, age ATB, and attained age only, the radiation-related excess relative risk (ERR) varied significantly among the three categories (P = 0.049). However, after controlling for significant heterogeneity in the baseline risk of breast cancer between reproductive status ATB groups (P < 0.001), no significant heterogeneity (P = 0.88) was observed in the ERR, with an ERR per Gy of 1.36 [95% confidence interval (CI), 0.54-2.75] for women exposed between menarche and first birth ATB, and 1.07 (95% CI, 0.22-3.62) and 1.53 (95% CI, 0.63-2.90) for those exposed premenarche or after first birth, respectively. CONCLUSIONS: The radiation-associated risk of breast cancer does not vary significantly by reproductive status ATB. IMPACT: It is possible that radiation exerts similar carcinogenic effects on the breast regardless of its stage of differentiation, or that the differences in radiosensitivity are too small to be detected in this cohort.

Longitudinal trends of total white blood cell and differential white blood cell counts of atomic bomb survivors.

In studying the late health effects of atomic-bomb (A-bomb) survivors, earlier findings were that white blood cell (WBC) count increased with radiation dose in cross-sectional studies. However, a persistent effect of radiation on WBC count and other risk factors has yet to be confirmed. The objectives of the present study were 1) to examine the longitudinal relationship between A-bomb radiation dose and WBC and differential WBC counts among A-bomb survivors and 2) to investigate the potential confounding risk factors (such as age at exposure and smoking status) as well as modification of the radiation dose-response. A total of 7,562 A-bomb survivors in Hiroshima and Nagasaki were included in this study from 1964-2004. A linear mixed model was applied using the repeated WBC measurements. During the study period, a secular downward trend of WBC count was observed. Radiation exposure was a significant risk factor for elevated WBC and differential WBC counts over time. A significant increase of WBC counts among survivors with high radiation dose (> 2 Gy) was detected in men exposed below the age of 20 and in women regardless of age at exposure. Effects on WBC of low dose radiation remain unclear, however. Cigarette smoking produced the most pronounced effect on WBC counts and its impact was much larger than that of radiation exposure.

White blood cell count, especially neutrophil count, as a predictor of hypertension in a Japanese population.

Although several studies have shown that high WBC count is a risk factor for hypertension, the relationship between WBC count and the incidence of hypertension in Japanese is poorly understood, as are the effects of WBC components on that relationship. Our objective was to verify in a Japanese population whether WBC or differential WBC count predicts hypertension incidence. A total of 9,383 initially hypertension-free subjects (3,356 men and 6,027 women), whose WBC counts were within the normal range (3,000 to < 10,000 cells/mm3), were followed from 1965 to 2004. During this 40-year follow-up, 4,606 subjects developed hypertension. After adjusting for conventional risk factors, including smoking status, we found that elevated WBC count was associated with hypertension incidence in a Cox regression model with both fixed and time-varying covariates for women. For men, elevated WBC count was a significant risk factor for hypertension only in the time-varying Cox-regression covariate. We also observed a significant association between increased neutrophil count and hypertension incidence among women. In a fully adjusted model, the relative risks of hypertension incidence, from the lowest to the highest quartiles of neutrophil count, were 1.00, 1.18, 1.28, and 1.22 in women (p for trend < 0.001). In conclusion, elevated WBC count predicted an increased incidence of hypertension in Japanese, especially among females. Moreover, neutrophils were the major WBC component contributing to the increased risk.

Cardiovascular disease risk among atomic bomb survivors exposed in utero, 1978-2003.

Given the well-documented association of in utero radiation exposure with childhood cancer and developmental impairments, the possibility of effects on adult onset diseases is an important issue. The objectives of the present study were to examine the effects of atomic bomb radiation dose on the incidence of hypertension, hypercholesterolemia and cardiovascular disease (myocardial infarction and stroke) among survivors exposed in utero and to compare their risk estimates with those of survivors exposed in childhood (<10 years old) at the time of the bombing. A total of 506 participants exposed in utero and 1,053 participants exposed in childhood were followed during 1978-2003 with biennial clinical examinations. There were no significant radiation dose effects for any diseases in the entire in utero-exposed cohort or in trimester-of-exposure subgroups, though there was a suggestion of an increased risk when fatal and nonfatal cardiovascular disease cases were combined. Positive radiation dose effects were found for hypertension and cardiovascular disease in the childhood-exposure cohort, but there were no statistically significant differences in the relative risks when we compared the two cohorts. Since the in utero cohort was under age 60 at the latest examination, continued follow-up is needed to document cardiovascular disease risk more fully.

Feasibility of freeze-dried sera for serological and molecular biological detection of hepatitis B and C viruses.

We compared hepatitis B virus (HBV) surface antigen, anti-hepatitis C virus (HCV) antibody, and HCV RNA quantification in frozen and freeze-dried serum samples to assess the usefulness of freeze-dried sera for detection of HBV and HCV. The results indicated that freeze-dried sera as well as frozen sera can be useful for serological and molecular biological analyses of HBV and HCV.

Smoking and alcohol habits as risk factors for benign digestive diseases in a Japanese population: the radiation effects research foundation adult health study.

BACKGROUND: Although an association between benign digestive diseases and smoking or drinking habits was reported, consistent results have not been obtained either in European, American or Japanese populations. METHODS: Smoking and alcohol habits as risk factors for the incidence of gastric ulcer, duodenal ulcer, chronic liver disease and cirrhosis as well as cholelithiasis were examined using the longitudinal data of the Adult Health Study collected biennially between 1958 and 1998. During 1958-1998, 1,093 gastric ulcers, 437 duodenal ulcers, 2,054 chronic liver diseases and cirrhoses, and 1,136 cholelithiasis cases were newly detected based on medical history, fluoroscopy or endoscopy and ultrasonography. Smoking and drinking histories were obtained from five and three questionnaires, respectively, administered during different periods. The relative risks (RRs) for ever smoked to never smoked and that for ever drank to never drank were estimated after adjustment for city, sex, age, birth cohort, calendar time and radiation dose. RESULTS: The analysis showed a positive association of smoking with gastric ulcer (RR: 2.03, 95% CI: 1.71-2.41), duodenal ulcer (RR: 1.31, 95% CI: 0.99-1.72), chronic liver disease and cirrhosis (RR: 1.23, 95% CI: 1.08-1.39) and cholelithiasis (RR: 1.19, 95% CI: 1.02-1.40), and a positive association of drinking with chronic liver disease and cirrhosis (RR: 1.10, 95% CI: 0.99-1.23). CONCLUSIONS: The peptic ulcer, chronic liver disease and cholelithiasis incidence increased significantly with smoking, and the chronic liver disease incidence increased significantly with drinking simultaneously in a prospective study of a Japanese population.