Atomic Bomb Radiation Exposure Research Articles

Effect of radiation exposure on survival after first solid cancer diagnosis in A-bomb survivors

BackgroundComparison of the estimated effect of atomic bomb radiation exposure on solid cancer incidence and solid cancer mortality in the RERF Life Span Study (LSS) reveals a difference in the magnitude and shape of the excess relative risk dose response. A possible contributing factor to this difference is pre-diagnosis radiation effect on post-diagnosis survival. Pre-diagnosis radiation exposure theoretically could influence post-diagnosis survival by affecting the genetic makeup and possibly aggressiveness of cancer, or by compromising tolerance for aggressive treatment for cancer. MethodsWe analyze the radiation effect on post-diagnosis survival in 20,463 LSS subjects diagnosed with first-primary solid cancer between 1958 and 2009 with particular attention to whether death was caused by the first-primary cancer, other cancer, or non-cancer diseases. ResultsFrom multivariable Cox regression analysis of cause-specific survival, the excess hazard at 1 Gy (EH1Gy) for death from the first primary cancer was not significantly different from zero – p = 0.23, EH1Gy = 0.038 (95 % CI: −0.023, 0.104). Death from other cancer and death from non-cancer diseases both were significantly associated with radiation dose: other cancer EH1Gy = 0.38 (95 % CI: 0.24, 0.53); non-cancer EH1Gy = 0.24 (95 % CI: 0.13, 0.36), both p < 0.001. ConclusionThere is no detectable large effect of pre-diagnosis radiation exposure on post-diagnosis death from the first primary cancer in A-bomb survivors. ImpactA direct effect of pre-diagnosis radiation exposure on cancer prognosis is ruled out as an explanation for the difference in incidence and mortality dose response in A-bomb survivors.

The Association of Radiation Exposure with Stable Chromosome Aberrations in Atomic Bomb Survivors Based on DS02R1 Dosimetry and FISH Methods.

The frequency of stable chromosome aberrations (sCA) in lymphocytes is a recognized radiation biological dosimeter. Its analysis can provide insights into factors that affect individual susceptibility as well as into the adequacy of radiation dose estimates used in studies of atomic bomb survivors. We analyzed the relationship between atomic bomb radiation exposure using the most recent DS02R1 dose estimates and the frequency of sCA as determined by FISH in 1,868 atomic bomb survivors. We investigated factors that may affect the background sCA rate and the shape and magnitude of the dose response. As in previous analyses of sCA in atomic bomb survivors that were based on Giemsa staining methods and used older DS86 dose estimates, the relationship between radiation dose and sCA rate was significant (P < 0.0001) with a linear-quadratic relationship at lower doses that did not persist at higher doses. As before, age at the time of the bombing and type of radiation shielding were significant dose-effect modifiers (P < 0.0001), but in contrast the difference in dose response by city was not so pronounced (P = 0.026) with a city effect not evident at doses below 1.25Gy. Background sCA rate increased with age at the time of examination (P < 0.0001), but neither sex, city, nor smoking was significantly associated with background rate. Based on FISH methods and recent dosimetry, the relationship between radiation dose and sCA frequency is largely consistent with previous findings, although the lesser importance of city as an effect modifier may reflect better dosimetry as well as more reproducible scoring of sCA. The persisting difference in sCA dose response by shielding category points to remaining problems with the accuracy or precision of radiation dose estimates in some A-bomb survivors.

Radiation Effects on Late-life Neurocognitive Function in Childhood Atomic Bomb Survivors: A Radiation Effects Research Foundation Adult Health Study.

High-dose radiation in childhood such as is used in radiation therapy causes cognitive decline, but there is insufficient research on the cognitive effects of low- to medium-dose radiation. We aimed to reveal the association between atomic bomb radiation exposure in childhood and late-life neurocognitive function. In 2011 and 2013, we mailed the Neurocognitive Questionnaire (NCQ) to subjects who were 12 years old or younger at the time of the atomic bombing. We converted the four NCQ subscales (metacognition, emotional regulation, motivation/organization, and processing speed) to T scores and defined the highest 10% of the controls (exposure dose < 5 mGy) as impaired. We used a generalized linear mixed model to evaluate the effect of radiation exposure on T scores and percentage impaired. We enrolled 859 participants. At the time of the bombing, the mean (SD) age was 6.7 (3.8) years for the control (N = 390) and 6.1 (3.8) years for the exposed (N = 469). At the time of replying to the questionnaire, the mean age of all the participants was 73.7 (3.8) years of age. After adjusting for cofactors, older age was related to the decline of all neurocognitive subscales. Sex and education level had relevance to some of the subscales. For neurocognitive function, exposure dose was not related except to percentage impaired, motivation/organization. Late-life neurocognitive function in atomic bomb survivors exposed as children was associated with age, but not clearly with radiation dose. More studies are needed to evaluate the effect of low-dose radiation during childhood on long-term neurocognitive function.

Prejudice and Health Anxiety about Radiation Exposure from Second-Generation Atomic Bomb Survivors: Results from a Qualitative Interview Study.

The effect of atomic bomb radiation exposure on the survivors and their children has been a worrisome problem since soon after the 1945 Hiroshima and Nagasaki bombings. Researchers have examined physical and genetic effects; however, no research has focused on second-generation survivors’ (SGS) psychological effects. Consequently, this study shed light on the SGS’ experience of discrimination and prejudice and their anxiety concerning the genetic effects of radiation exposure. This study utilized semi-structured interviews with 14 SGS (10 women, mean age = 56 ± 6.25 years, range = 46–68 years). Data were analyzed using a modified version of the grounded theory approach. Three categories were extracted: low awareness as an SGS, no health anxiety regarding the effect of radiation, and health anxiety regarding the effect of radiation. The results did not reveal that SGS who grew up in the bombed areas experienced discrimination or prejudice. They had little health anxiety from childhood to adolescence. In this study, some of the SGS developed health anxiety about their third-generation children, but only among female participants. Perhaps the transgenerational transmission of anxiety concerning the genetic effects of radiation exposure causes stress, particularly among women with children. However, a change was seen in adulthood health anxiety regarding the effects of radiation, suggesting the possibility that changes in the psychological experiences of SGS can be observed throughout their lifetimes and that their own health status, and that of their children, the third-generation survivors, affects their health anxiety regarding radiation.

Mortality Analysis of the Life Span Study (LSS) Cohort Taking into Account Multiple Causes of Death Indicated in Death Certificates.

Mortality analyses have been performed using underlying causes of death as reported on death certificates; these are uniquely determined for a deceased person according to the World Health Organization coding system. Comorbidities, the disease conditions other than the underlying cause of death from death certificates recording multiple causes of death, have rarely been explored in Life Span Study subjects. The purpose of this study was to clarify associations between atomic bomb radiation exposure and mortality from combinations of the underlying cause of death and comorbidities. The focused follow-up period was 1977-2003, prior to which death certificate accuracy was unreliable. The study cohort was comprised of 10,017 people for whom the category "all circulatory disease" was listed as the underlying cause of death, of which heart disease (rheumatic, hypertensive and ischemic heart disease) and stroke were major subtypes. Comorbidities considered were pneumonia, renal disease, diabetes mellitus, cancer and the major circulatory disease subtypes listed above. Poisson regression models were used for analyses. Excess relative risks (ERRs) for mortality at 1 Gy were significantly increased when cancer was comorbid with all circulatory disease, heart disease, ischemic heart disease or stroke, ranging from 0.61 [95% confidence interval (CI): 0.13, 1.41; N = 177] for all circulatory diseases to 1.60 (CI: 0.07, 4.86; N = 42) for ischemic heart disease. Among the other comorbidities, only diabetes comorbid with heart disease had a significant radiation dose response (ERR at 1 Gy of 0.62, CI: 0.10, 1.46; N = 128). It remains uncertain if the high ERRs with comorbid cancers were anomalous due to the small number of cases or some dissimilarity in statistical methodologies, or if this might suggest some pathogenetic basis for increased fatality. For this reason, further investigation is required.

Poorly Differentiated Squamous Cell Carcinoma in an Atomic Bomb Survivor.

Dear Editor: Many epidemiological studies of atomic bomb survivors in Japan demonstrate that exposure to radiation increases the risk of cancers, especially leukemia, in most organs1. The risk of non-melanoma skin carcinoma in atomic bomb survivors is elevated2, and the most common primary skin tumors among 152 skin tumors among patients exposed to atomic bomb radiation were basal cell carcinoma (42%), followed by squamous cell carcinoma (SCC) (26%), Bowen's disease (13%), and malignant melanoma (6%)3. Here, we report a case of poorly differentiated SCC in an atomic bomb survivor. An 86-year-old Japanese woman visited our hospital with a one-month history of subcutaneous tumor in the inguinal region. She noticed a tumor on her the left side of waist when she was 46 years old. She was exposed to atomic bomb radiation in Hiroshima at the age of 19 years. Physical examination revealed a 32×40-mm reddish dome-shaped tumor on her the left side of the waist (Fig. 1A) and a 65×72-mm painful subcutaneous tumor on her left inguinal region (Fig. 1B). Blood examination revealed no abnormal changes. Whole-body computed tomography revealed no remarkable changes. Fluorodeoxyglucose-positron emission tomography revealed abnormal uptake in the tumor of on the waist and left inguinal lymph nodes. Histopathological examination of the waist tumor demonstrated numerous tumor cells throughout the dermis and subcutis (Fig. 1C). Atypical large tumor cells had irregular nuclear contours and prominent nucleoli (Fig. 1D). Immunohistochemistry showed the tumor cells were positive for keratin, CK7, p63, p40, and NSE but negative for CK20, chromogranin A, synaptophysin, thyroid transcription factor-1 (TTF-1), CD56, Melan-A, S-100, and EBER (Fig. 2A~E). The results of the histological and immunohistochemical examinations of the inguinal tumor were same. On the basis of these findings, she was diagnosed with poorly differentiated SCC in the waist and metastasis in the inguinal lymph nodes. Tumors in the waist and inguinal regions were resected, and she was subsequently treated with electron beam radiation (total dose: 59 Gy). Eight months later, a metastatic lesion in the left lung was observed, but she refused additional treatment. Fig. 1 (A) Reddish dome-shaped tumor on the left side of the waist. (B) Painful subcutaneous tumor on the left inguinal region. (C, D) Histopathological examination of the waist tumor (HE C: ×40, D: ×1,000). (C) Numerous tumor cells ... Fig. 2 Immunohistochemical examination of the waist tumor. Tumor cells stained positive for (A) keratin and (B) CK7, and negative for (C) chromogranin A, (D) CK20, and (E) thyroid transcription factor-1 (A~E: ×400). Tumor cells were positive for keratin as well as squamous cell markers p63 and p40. The common markers of neuroendocrine carcinomas, including Merkel cell carcinoma, CK20, chromogranin A and synaptophysin, were negative. TTF-1, a marker of primary thyroid and lung carcinoma, was negative. These immunohistochemical results and the low differentiation pattern of tumors on hematoxylin & eosin staining lead to a final diagnosis of poorly differentiated SCC. Regarding the relationship between the extent of tumor differentiation and atomic bomb radiation exposure, the frequency of poorly differentiated adenocarcinoma of stomach in atomic bomb survivors is significantly higher than that in non-exposed individuals4. Nevertheless, the association between atomic bomb radiation exposure and poorly differentiated SCC in our patient is speculative. A recent study reports multiple basal cell carcinomas were developed in atomic bomb survivors more than 40 years after radiation exposure5. Thus, exposure to atomic bomb radiation might influence the risk of cancers; therefore, dermatologists should perform long-term surveillance for skin carcinomas in atomic bomb survivors.

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

Height loss starting in middle age predicts increased mortality in the elderly

The purpose of this study was to determine the mortality risk among Japanese men and women with height loss starting in middle age, taking into account lifestyle and physical factors. A total of 2498 subjects (755 men and 1743 women) aged 47 to 91 years old underwent physical examinations during the period 1994 to 1995. Those individuals were followed for mortality status through 2003. Mortality risk was estimated using an age-stratified Cox proportional hazards model. In addition to sex, adjustment factors such as radiation dose, lifestyle, and physical factors measured at the baseline--including smoking status, alcohol intake, total cholesterol, blood pressure, and diagnosed diseases--were used for analysis of total mortality and mortality from each cause of death. There were a total of 302 all-cause deaths, 46 coronary heart disease and stroke deaths, 58 respiratory deaths including 45 pneumonia deaths, and 132 cancer deaths during the follow-up period. Participants were followed for 20,787 person-years after baseline. Prior history of vertebral deformity and hip fracture were not associated with mortality risk. However, more than 2 cm of height loss starting in middle age showed a significant association with all-cause mortality among the study participants (HR = 1.76, 95% CI 1.31 to 2.38, p = 0.0002), after adjustment was made for sex, attained age, atomic-bomb radiation exposure, and lifestyle and physical factors. Such height loss also was significantly associated with death due to coronary heart disease or stroke (HR = 3.35, 95% CI 1.63 to 6.86, p = 0.0010), as well as respiratory-disease death (HR = 2.52, 95% CI 1.25 to 5.22, p = 0.0130), but not cancer death. Continuous HL also was associated with all-cause mortality and CHD- or stroke-caused mortality. Association between height loss and mortality was still significant, even after excluding persons with vertebral deformity. Height loss of more than 2 cm starting in middle age was an independent risk factor for cardiovascular and respiratory-disease mortality among the elderly, even after adjusting for potential risk factors.

Cancer and non-cancer effects in Japanese atomic bomb survivors**Presented as an invited paper at the 21st LH Gray Conference ‘The Radiobiology—RadiationProtection Interface’, Royal College of Physicians, Edinburgh 4–6 June 2008.

The survivors of the atomic bombings in Hiroshima and Nagasaki are a general populationof all ages and sexes and, because of the wide and well characterised range of dosesreceived, have been used by many scientific committees (International Commission onRadiological Protection (ICRP), United Nations Scientific Committee on the Effects ofAtomic Radiation (UNSCEAR), Biological Effects of Ionizing Radiations (BEIR)) as thebasis of population cancer risk estimates following radiation exposure. Leukaemia was thefirst cancer to be associated with atomic bomb radiation exposure, with preliminaryindications of an excess among the survivors within the first five years after the bombings.An excess of solid cancers became apparent approximately ten years after radiationexposure. With increasing follow-up, excess risks of most cancer types have beenobserved, the major exceptions being chronic lymphocytic leukaemia, and pancreatic,prostate and uterine cancer. For most solid cancer sites a linear dose response isobserved, although in the latest follow-up of the mortality data there is evidence (p = 0.10) for an upward curvature in the dose response for all solid cancers. The only cancer siteswhich exhibit (upward) curvature in the dose response are leukaemia, and non-melanomaskin and bone cancer. For leukaemia the dose response is very markedly upwardcurving, indeed largely describable as a pure quadratic dose response, particularlyin the low dose (0–2 Sv) range. Even 55 years after the bombings over 40% ofthe Life Span Study cohort remain alive, so continued follow-up of this group isvital for completing our understanding of long-term radiation effects in people.In general, the relative risks per unit dose among the Japanese atomic bomb survivors aregreater than those among comparable subsets in studies of medically exposed individuals.Cell sterilisation largely accounts for the discrepancy in relative risks between these twopopulations, although other factors may contribute, such as the generally higher underlyingcancer risks in the medical series than in the Japanese atomic bomb survivors. Risks amongoccupationally exposed groups such as nuclear workforces and underground miners aregenerally consistent with those observed in the Japanese atomic bomb survivors. Ingeneral, consistent patterns of variation of risk with age at exposure are also seen inall studies—risks for all cancer types diminish with increasing age at exposure.There are also excess risks of various types of non-malignant disease in the Japanese atomicbomb survivors, in particular cardiovascular, respiratory and digestive diseases. Indeed,risks are elevated to much the same degree for a number of non-malignant diseaseendpoints, suggestive of bias. However, in contrast with the cancer data, there is much lessconsistency in the pattern of risk between the atomic bomb survivors and other exposedgroups; for example, radiation-associated respiratory and digestive diseases have not beenseen in these other groups. Although cardiovascular risks have been seen elsewhere,particularly in medically exposed groups, in contrast with the cancer data there is muchless consistency in risk between studies: risks per unit dose in epidemiological studiesvary over at least two orders of magnitude, possibly as a result of confoundingfactors. In the absence of a convincing mechanistic explanation of epidemiologicalevidence, at present a cause-and-effect interpretation of the reported statisticalassociations for cardiovascular disease is unreliable but cannot be excluded. Furtherepidemiological and biological evidence will allow a firmer conclusion to be drawn.

Prevalence and Cause of Death in Patients with Monoclonal Gammopathy in Atomic Bomb Survivors in Hiroshima

Purpose: To examine the effect of Atomic bomb (A-bomb) radiation exposure condition on the development M-proteinemia in A-bomb survivors in Hiroshima.Back ground: The influence of radiation exposure on the development of M-proteinemia remained unclear. The screening test for monoclonal gammopathy in A- bomb survivors in Hiroshima was started from Sep. 1988 at the Hiroshima Atomic Bomb Casualty Council Health management center to challenge this problem with the free access policy.Materials: The peak year of the examined population was 1989, which was examined 42915 survivors. This population was designed as study population. This population consisted of five groups of irradiated conditions as follows, 60% was exposed directly in all over the Hiroshima city at A- bombing, 27% entered to center of Hiroshima city within 14 days after A-bombing, 9% helped the victims of A- bombing at the suburbs and 1% was exposed in prenatal state.Examination study: Each participant was examined one test yearly. Routine laboratory tests, such as complete blood cell counts, serum biochemical examination and serum protein electrophoresis on cellulose acetate were performed for the first step screening. M-protein or low level of gammaglobulin was subsequently assessed in a detailed analysis by immunoelectrophoresis of serum and urine, and measurement of serum concentration of immunoglobulin andβ2-Microglobulin.Results: One thousand and hundred eighty two cases of M-proteinemia were detected for 18 years. The over all prevalence rate was 2.75%, and 4.1% in males and 2.1% in females. Nine hundred twenty nigh cases of MGUS(78.6%), 147 cases of MM(12.4%), 80 cases of IgM Macroglobulinemia(6.8%) and 26 cases of two clone M-proteinemia(2.2%) were detected. Of these M-proteinemia, 669cases(2.6%) were developed in directly exposed population, 368cases(3.1%) were in entered population and 133 cases(3.4%) were in helper population. The prevalence rate of these M-proteinemia was increased depend on aging. Forty three cases (4.6%) of MGUS moved to overt MM for 18 years. The mean duration time from MGUS to overt MM was 8.9 years (2~18 years). Four hundred sixteen cases (35.2%) were died with MM or lymphoproliferative diseases (99cases,23.8%), cancer (93cases,22.3%), infection (50cases,12%), cardio or cerebral vascular diseases (89 cases,21.4%) and others (85cases,21%). The 101 cases (13.2%) of 766 living cases combined some cancer throughout the follow up. No significant differences in the prevalence rate of M-proteinemia and death from MM or combination with cancer were observed among any A-bomb irradiated conditions.Conclusions: There were no clear correlations between the development or disease state of M-proteinemia and the irradiated conditions. We are now starting to analyze the individual radiation dose effects longitudinally on the development of M-proteinemia.

RET/PTC Rearrangements Preferentially Occurred in Papillary Thyroid Cancer among Atomic Bomb Survivors Exposed to High Radiation Dose

A major early event in papillary thyroid carcinogenesis is constitutive activation of the mitogen-activated protein kinase signaling pathway caused by alterations of a single gene, typically rearrangements of the RET and NTRK1 genes or point mutations in the BRAF and RAS genes. In childhood papillary thyroid cancer, regardless of history of radiation exposure, RET/PTC rearrangements are a major event. Conversely, in adult-onset papillary thyroid cancer among the general population, the most common molecular event is BRAF(V600E) point mutation, not RET/PTC rearrangements. To clarify which gene alteration, chromosome aberration, or point mutation preferentially occurs in radiation-associated adult-onset papillary thyroid cancer, we have performed molecular analyses on RET/PTC rearrangements and BRAF(V600E) mutation in 71 papillary thyroid cancer cases among atomic bomb survivors (including 21 cases not exposed to atomic bomb radiation), in relation to radiation dose as well as time elapsed since atomic bomb radiation exposure. RET/PTC rearrangements showed significantly increased frequency with increased radiation dose (P(trend) = 0.002). In contrast, BRAF(V600E) mutation was less frequent in cases exposed to higher radiation dose (P(trend) < 0.001). Papillary thyroid cancer subjects harboring RET/PTC rearrangements developed this cancer earlier than did cases with BRAF(V600E) mutation (P = 0.03). These findings were confirmed by multivariate logistic regression analysis. These results suggest that RET/PTC rearrangements play an important role in radiation-associated thyroid carcinogenesis.

Effects of IL-10 and IL-6 Gene Polymorphisms and Atomic-bomb Radiation Exposure on Gastric Cancer Risk

Cells repair DNA double-strand breaks (DSBs) through a complex set of pathways critical for maintaining genomic integrity. To systematically map these pathways, we developed a high-throughput screening approach called Repair-seq that measures the effects of thousands of genetic perturbations on mutations introduced at targeted DNA lesions. Using Repair-seq, we profiled DSB repair products induced by two programmable nucleases (Cas9 and Cas12a) in the presence or absence of oligonucleotides for homology-directed repair (HDR) after knockdown of 476 genes involved in DSB repair or associated processes. The resulting data enabled principled, data-driven inference of DSB end joining and HDR pathways. Systematic interrogation of this data uncovered unexpected relationships among DSB repair genes and demonstrated that repair outcomes with superficially similar sequence architectures can have markedly different genetic dependencies. This work provides a foundation for mapping DNA repair pathways and for optimizing genome editing across diverse modalities.

Solid Cancer Incidence in Atomic Bomb Survivors: 1958–1998

This is the second general report on radiation effects on the incidence of solid cancers (cancers other than malignancies of the blood or blood-forming organs) among members of the Life Span Study (LSS) cohort of Hiroshima and Nagasaki atomic bomb survivors. The analyses were based on 17,448 first primary cancers (including non-melanoma skin cancer) diagnosed from 1958 through 1998 among 105,427 cohort members with individual dose estimates who were alive and not known to have had cancer prior to 1958. Radiation-associated relative risks and excess rates were considered for all solid cancers as a group, for 19 specific cancer sites or groups of sites, and for five histology groups. Poisson regression methods were used to investigate the magnitude of the radiation-associated risks, the shape of the dose response, how these risks vary with gender, age at exposure, and attained age, and the evidence for inter-site variation in the levels and patterns of the excess risk. For all solid cancers as a group, it was estimated that about 850 (about 11%) of the cases among cohort members with colon doses in excess of 0.005 Gy were associated with atomic bomb radiation exposure. The data were consistent with a linear dose response over the 0- to 2-Gy range, while there was some flattening of the dose response at higher doses. Furthermore, there is a statistically significant dose response when analyses were limited to cohort members with doses of 0.15 Gy or less. The excess risks for all solid cancers as a group and many individual sites exhibit significant variation with gender, attained age, and age at exposure. It was estimated that, at age 70 after exposure at age 30, solid cancer rates increase by about 35% per Gy (90% CI 28%; 43%) for men and 58% per Gy (43%; 69%) for women. For all solid cancers as a group, the excess relative risk (ERR per Gy) decreases by about 17% per decade increase in age at exposure (90% CI 7%; 25%) after allowing for attained-age effects, while the ERR decreased in proportion to attained age to the power 1.65 (90% CI 2.1; 1.2) after allowing for age at exposure. Despite the decline in the ERR with attained age, excess absolute rates appeared to increase throughout the study period, providing further evidence that radiation-associated increases in cancer rates persist throughout life regardless of age at exposure. For all solid cancers as a group, women had somewhat higher excess absolute rates than men (F:M ratio 1.4; 90% CI 1.1; 1.8), but this difference disappears when the analysis was restricted to non-gender-specific cancers. Significant radiation-associated increases in risk were seen for most sites, including oral cavity, esophagus, stomach, colon, liver, lung, non-melanoma skin, breast, ovary, bladder, nervous system and thyroid. Although there was no indication of a statistically significant dose response for cancers of the pancreas, prostate and kidney, the excess relative risks for these sites were also consistent with that for all solid cancers as a group. Dose-response estimates for cancers of the rectum, gallbladder and uterus were not statistically significant, and there were suggestions that the risks for these sites may be lower than those for all solid cancers combined. However, there was emerging evidence from the present data that exposure as a child may increase risks of cancer of the body of the uterus. Elevated risks were seen for all of the five broadly classified histological groups considered, including squamous cell carcinoma, adenocarcinoma, other epithelial cancers, sarcomas and other non-epithelial cancers. Although the data were limited, there was a significant radiation-associated increase in the risk of cancer occurring in adolescence and young adulthood. In view of the persisting increase in solid cancer risks, the LSS should continue to provide important new information on radiation exposure and solid cancer risks for at least another 15 to 20 years.

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

BACKGROUNDBecause 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.METHODSThyroid 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.RESULTSAnalysis 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.CONCLUSIONHistory 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.

Histologic characteristics of skin cancer in Hiroshima and Nagasaki: Background incidence and radiation effects

Skin cancers, though rare in Japan, have reportedly been on the rise, but little else is known about epidemiologic features of different histologic types of skin cancer. The Life Span Study cohort, which consists of 93,700 atomic-bomb survivors, many of whom were exposed to negligibly low radiation doses, and 26,600 people not exposed to radiation, enables a population-based study of spontaneous as well as radiation-related cancer risk. Skin tumor incident cases diagnosed between 1958 and 1987 were ascertained by linkage to the Hiroshima and Nagasaki tumor registries augmented by searches of other data sources. Study pathologists reviewed tumor specimens and pathology reports and classified tumors using the World Health Organization classification scheme. They identified 274 primary incident skin cancers, of which 106 were basal cell carcinoma (BCC), 81 were squamous cell carcinoma (SCC), and 14 were malignant melanomas. Background incidence rates and radiation effects were assessed by Poisson regression models allowing for the effects of demographic and other covariates. BCC and SCC background incidence rates were both about 3 per 100,000 per year. BCCs were mainly on the head/neck (81%), whereas SCCs occurred most frequently on the arms/legs (45%) and head/neck (29%), consistent with the presumed role played by solar UV exposure in skin cancer. The BCC rates increased significantly between 1958 and 1987, whereas the SCC rates remained unchanged. The excess absolute risk of BCC per unit skin surface area related to atomic-bomb radiation exposure did not differ between UV-exposed and shielded parts of the body, suggesting the additivity of the radiation-related and background BCC risks.

Lifestyle Factors, Radiation and Gastric Cancer in Atomic-Bomb Survivors (Japan)

To examine the association between the incidence of gastric cancer and lifestyle factors such as cigarette smoking, alcohol drinking, and diet as well as atomic bomb radiation exposure. Longitudinal study including 38,576 atomic-bomb survivors in Hiroshima and Nagasaki, Japan, followed-up between 1980 and 1999. Individual radiation dose was estimated according to the Dosimetry System 1986 (DS86). Lifestyle determinants were based on the responses to a mail survey sent at baseline. 1270 incident carcinomas of gastric cancer were identified during the 485,575 person-years of follow-up. Poisson regression was used to estimate incidence rate ratios. Ionizing radiation exposure, male gender, age, and smoking were significantly associated with an increased risk of stomach cancer. No association was suggested between the frequency of consumption of fruit, vegetables, green tea, and soy products and gastric cancer. In this Japanese population, although radiation and smoking were strong determinants of stomach cancer, no supportive evidence could be shown for the effect of dietary factors.

Prevalence of atherosclerosis in relation to atomic bomb radiation exposure: An RERF Adult Health Study

Purpose: To determine whether exposure to atomic bomb radiation altered the prevalence of asymptomatic atherosclerosis.Material and methods: In a cross-sectional analysis, we examined aortic arch calcification by plain chest radiography and common carotid artery intima-media thickness (IMT) by ultrasonography among 1804 survivors of the atomic bombing in Hiroshima. We evaluated the association between atherosclerotic changes and radiation exposure, while adjusting for potentially confounding factors.Results: Multivariate logistic regression analysis showed that aortic arch calcification was significantly associated with radiation exposure (p < 0.05). The odds ratio at 1 Gy was 1.30 (95% confidence interval [CI]: 1.05 – 1.53) for men and 1.31 (95% CI: 1.13 – 1.51) for women. Carotid artery IMT did not vary significantly with radiation dose (p = 0.18).Conclusion: Radiation dose contributed to the prevalence of aortic atherosclerosis but not carotid artery atherosclerosis in atomic bomb survivors.

Improving the efficiency of nested case-control studies of interaction by selecting controls using counter matching on exposure.

Studies of the effect of exposure to a risk factor measured in an entire cohort may be augmented by nested case-control subsets to investigate confounding or effect modification by additional factors not practically assessed on all cohort members. We compared three control-selection strategies-matching on exposure, counter matching on exposure, and random sampling-to determine which was most efficient in a situation where exposure is a known, continuous variable and high doses are rare. We estimated the power to detect interaction using four control-to-case ratios (1:1, 2:1, 4:1, and 8:1) in a planned case-control study of the joint effect of atomic bomb radiation exposure and serum oestradiol levels on breast cancer. Radiation dose is measured in the entire cohort, but because neither serum oestradiol level nor the true degree of interaction was known, we simulated values of oestradiol and hypothetical levels of oestradiol-radiation interaction. Compared with random sampling, power to detect interaction was similarly higher with either matching or counter matching with two or more controls. Because counter matching is generally at least as efficient as random sampling, whereas matching on exposure can result in loss of efficiency and precludes estimation of exposure risk, we recommend counter matching for selecting controls in nested case-control studies of the joint effects of multiple risk factors when one is previously measured in the full cohort.

Tumors of the nervous system and pituitary gland associated with atomic bomb radiation exposure.

The risk of developing nervous system tumors following exposure to ionizing radiation is not well quantified. We characterized the incidence of nervous system tumors among atomic bomb survivors as a function of radiation dose. Tumors of the nervous system and pituitary gland diagnosed between 1958 and 1995 among 80 160 atomic bomb survivors were ascertained using the Hiroshima and Nagasaki tumor registries, medical records, and death certificates. Pathologists reviewed slides and medical records to provide histologic diagnoses. Poisson regression analyses were used to characterize radiation effects on tumor incidence, which are expressed as excess relative risk per sievert (ERR(Sv)). All statistical tests were two-sided. A statistically significant dose-related excess of nervous system tumors was observed in the cohort (ERR(Sv) = 1.2, 95% confidence interval [CI] = 0.6 to 2.1). The highest ERR(Sv) was seen for schwannoma (4.5, 95% CI = 1.9 to 9.2). The risk for all other nervous system tumors as a group is also statistically significantly elevated (ERR(Sv) = 0.6, 95% CI = 0.1 to 1.3). Risk increases, although not statistically significant, were seen for meningiomas (ERR(Sv) = 0.6, 95% CI = -0.01 to 1.8), gliomas (ERR(Sv) = 0.6, 95% CI = -0.2 to 2.0), other nervous system tumors (ERR(Sv) = 0.5, 95% CI = <-0.2 to 2.2), and pituitary tumors (ERR(Sv) = 1.0, 95% CI = <-0.2 to 3.5). The dose-response relationships were linear. For nervous system tumors other than schwannoma, excess risks were higher for men than for women and for those exposed during childhood than for those exposed during adulthood. A statistically significant dose response was observed for all nervous system tumors combined and for schwannoma considered separately, indicating that exposure to even moderate doses (i.e., <1 Sv) of radiation is associated with an elevated incidence of nervous system tumors.

Current perspectives on radiation-induced breast cancer.

An approach to screening and detection of radiation-induced breast cancer is offered. Primary and secondary prevention strategies are suggested and the need for prospective clinical trials is emphasized. Data are reviewed from published evidence of radiation-induced breast cancer secondary to atomic bomb radiation, occupational, and therapeutic exposure, especially that incurred during successful treatment of Hodgkin's disease (HD). Preclinical studies are reviewed to explore potential risk factors. Risk factors evident in the link between radiation and breast cancer include the differentiation of breast tissue as mediated by age and hormonal influence. Evidence is presented exploring the link between genetics and breast cancer, including specific genes such as the BRCA1 and BRCA2 genes, the p53 gene, the ataxia telangiectasia (AT) gene, and other nonspecific alterations in DNA repair proficiency. In light of these findings, steps toward primary prevention are discussed, including avoiding radiation exposure, genetic screening, and manipulation of the hormonal milieu. Secondary prevention may also be possible with the use of tamoxifen, low-fat diets, and/or the consumption of flaxseed. Our current recommendations for patients irradiated before 30 years of age for Hodgkin's disease include breast self-examination (BSE) monthly, yearly mammography 8 years postirradiation, and regular physical examinations every 6 months. Given the clear link between radiation exposure and breast cancer, we strongly recommend a prospective trial randomize patients to different levels of intensity of surveillance to monitor the efficacy of such screening efforts.