Cancer In Atomic Bomb Survivors Research Articles

Radiation Risk of Ovarian Cancer in Atomic Bomb Survivors: 1958-2009.

There is limited evidence concerning the association between radiation exposure and ovarian cancer. We evaluated radiation risk of ovarian cancer between 1958 and 2009 among 62,534 female atomic bomb survivors in the Life Span Study cohort, adding 11 years of follow-up from the previously reported study. Poisson regression methods were used to estimate excess relative risk per Gy (ERR/Gy) for total ovarian cancer and according to tumor type. We assessed the modifying effect of follow-up period and other factors on the radiation risk. We ascertained 288 first primary ovarian cancers including 77 type 1 epithelial cancers, 75 type 2 epithelial cancers, 66 epithelial cancers of undetermined type and 70 other cancers. Radiation dose was positively, although not significantly, associated with risk of total ovarian cancer [ERR/Gy = 0.30, 95% confidence interval (CI): -0.22 to 1.11]. There was a suggestion of heterogeneity in radiation effects (P = 0.08) for type 1 (ERR/Gy = -0.32, 95% CI: <-0.32 to 0.88) and type 2 cancers (ERR/Gy = 1.24, 95% CI: -0.08 to 4.16). There were no significant trends in the ERR with time since exposure or age at exposure. Further follow-up will help characterize more accurately the patterns of radiation risk for total ovarian cancer and its types.

Radiation Risks of Uterine Cancer in Atomic Bomb Survivors: 1958-2009.

BackgroundIonizing radiation is known to be capable of causing cancer of many organs, but its relationship with uterine cancer has not been well characterized.MethodsWe studied incidence of uterine cancer during 1958–2009 among 62 534 female atomic bomb survivors. Using Poisson regression analysis, we fitted excess relative risk (ERR) models to uterine cancer rates adjusted for several lifestyle and reproductive factors. Person-years at risk were also adjusted for the probability of prior hysterectomy, because it could affect the subsequent risk of uterine cancer. We assessed the modifying effect of age and other factors on the radiation risk. For analysis of the modifying effect of age at radiation exposure around menarche, we compared the radiation risk for several exposure-age categories as well as using parametric models.ResultsThere were 224 uterine corpus cancers and 982 cervical cancers. We found a significant association between radiation dose and risk of corpus cancer (ERR per Gray [ERR/Gy] = 0.73, 95% confidence interval [CI] = 0.03 to 1.87) but not for cervical cancer (ERR/Gy = 0.00, 95% CI = −0.22 to 0.31). For corpus cancer, we found statistically significant heterogeneity in ERR/Gy by age (Pheterogeneity = .001) with elevated risk for women exposed to radiation between ages 11 and 15 years (ERR/Gy = 4.10, 95% CI = 1.47 to 8.42) and no indication of a radiation effect for exposures before or after this exposure-age range.ConclusionsThe current data suggest that uterine corpus is especially sensitive to the carcinogenic effect of radiation exposure occurring during the mid-pubertal period preceding menarche. There is little evidence for a radiation effect on cervical cancer risk.

Epidemiological research on radiation-induced cancer in atomic bomb survivors.

The late effects of exposure to atomic bomb radiation on cancer occurrence have been evaluated by epidemiological studies on three cohorts: a cohort of atomic bomb survivors (Life Span Study; LSS), survivors exposed in utero, and children of atomic bomb survivors (F1). The risk of leukemia among the survivors increased remarkably in the early period after the bombings, especially among children. Increased risks of solid cancers have been evident since around 10 years after the bombings and are still present today. The LSS has clarified the dose–response relationships of radiation exposure and risk of various cancers, taking into account important risk modifiers such as sex, age at exposure, and attained age. Confounding by conventional risk factors including lifestyle differences is not considered substantial because people were non-selectively exposed to the atomic bomb radiation. Uncertainty in risk estimates at low-dose levels is thought to be derived from various sources, including different estimates of risk at background levels, uncertainty in dose estimates, residual confounding and interaction, strong risk factors, and exposure to residual radiation and/or medical radiation. The risk of cancer in subjects exposed in utero is similar to that in LSS subjects who were exposed in childhood. Regarding hereditary effects of radiation exposure, no increased risk of cancers associated with parental exposure to radiation have been observed in the F1 cohort to date. In addition to biological and pathogenetic interpretations of the present results, epidemiological investigations using advanced technology should be used to further analyze these cohorts.

Effects of radiation on the incidence of prostate cancer among Nagasaki atomic bomb survivors

Atomic bomb survivors have been reported to have an increased risk of some cancers, especially leukemia. However, the risk of prostate cancer in atomic bomb survivors is not known to have been examined previously. This study examined the association between atomic bomb radiation and the incidence of prostate cancer among male Nagasaki atomic bomb survivors. The subjects were classified by distance from the hypocenter into a proximal group (<2 km), a distal group (≥2 km), and an early entrance group (those who entered the region <2 km from the hypocenter within 2 weeks after the explosion). Between 1996 and 2009, 631 new cases of prostate cancer were identified among approximately 18 400 male Nagasaki atomic bomb survivors who were alive in 1996. The Cox proportional hazard model was used to estimate the risk of prostate cancer development, with adjustment for age at atomic bomb explosion, attained age, smoking status, and alcohol consumption. Compared with the distal group, the proximal group had significant increased risks of total, localized, and high-grade prostate cancer (relative risk and 95% confidence interval: 1.51 [1.21-1.89]; 1.80 [1.26-2.57]; and 1.88 [1.20-2.94], respectively). This report is the first known to reveal a significant relationship between atomic bomb radiation and prostate cancer.

Linear No-Threshold Model vs. Radiation Hormesis

The atomic bomb survivor cancer mortality data have been used in the past to justify the use of the linear no-threshold (LNT) model for estimating the carcinogenic effects of low dose radiation. An analysis of the recently updated atomic bomb survivor cancer mortality dose-response data shows that the data no longer support the LNT model but are consistent with a radiation hormesis model when a correction is applied for a likely bias in the baseline cancer mortality rate. If the validity of the phenomenon of radiation hormesis is confirmed in prospective human pilot studies, and is applied to the wider population, it could result in a considerable reduction in cancers. The idea of using radiation hormesis to prevent cancers was proposed more than three decades ago, but was never investigated in humans to determine its validity because of the dominance of the LNT model and the consequent carcinogenic concerns regarding low dose radiation. Since cancer continues to be a major health problem and the age-adjusted cancer mortality rates have declined by only ∼10% in the past 45 years, it may be prudent to investigate radiation hormesis as an alternative approach to reduce cancers. Prompt action is urged.

Outcome and Status of Microsatellite Stability in Japanese Atomic Bomb Survivors with Early Gastric Carcinoma

In the decade after the 1945 atomic bombing of Hiroshima, a high incidence of leukemia was observed among atomic bomb survivors. However, the incidence of other cancers gradually increased, while that of leukemia decreased after this period. We evaluated the clinical outcome of early gastric cancer and microsatellite stability over a long-term period in atomic bomb survivors. The results of surgical treatment for early gastric cancer were reviewed for 117 atomic bomb survivors and 394 control patients between 1995 and 2006. In addition, immunohistochemical staining for hMSH2 and hMLH1 expression was performed to evaluate the status of microsatellite stability in 57 atomic bomb survivors and 82 control patients. The long-term survival rate for early gastric cancer in atomic bomb survivors was significantly lower than that in control patients (p<0.01). Multivariable analysis revealed that age and sex were significant and independent prognostic factors for early gastric cancer. Defective hMSH2 and/or hMLH1 expression was also significantly higher in survivors than in control patients (p<0.001). Logistic regression analysis revealed that atomic bomb survivorship was related to defective hMSH2 and/or hMLH1 expression. The prognosis of early gastric cancer in atomic bomb survivors was poor and was related to age and sex, rather than to being an atomic bomb survivor. Furthermore, a higher rate of defective hMSH2 and/or hMLH1 expression was observed in the survivors.

Evidence Supporting Radiation Hormesis in Atomic Bomb Survivor Cancer Mortality Data

A recent update on the atomic bomb survivor cancer mortality data has concluded that excess relative risk (ERR) for solid cancers increases linearly with dose and that zero dose is the best estimate for the threshold, apparently validating the present use of the linear no threshold (LNT) model for estimating the cancer risk from low dose radiation. A major flaw in the standard ERR formalism for estimating cancer risk from radiation (and other carcinogens) is that it ignores the potential for a large systematic bias in the measured baseline cancer mortality rate, which can have a major effect on the ERR values. Cancer rates are highly variable from year to year and between adjacent regions and so the likelihood of such a bias is high. Calculations show that a correction for such a bias can lower the ERRs in the atomic bomb survivor data to negative values for intermediate doses. This is consistent with the phenomenon of radiation hormesis, providing a rational explanation for the decreased risk of cancer observed at intermediate doses for which there is no explanation based on the LNT model. The recent atomic bomb survivor data provides additional evidence for radiation hormesis in humans.

Significance of genomic instability in breast cancer in atomic bomb survivors: analysis of microarray-comparative genomic hybridization

BackgroundIt has been postulated that ionizing radiation induces breast cancers among atomic bomb (A-bomb) survivors. We have reported a higher incidence of HER2 and C-MYC oncogene amplification in breast cancers from A-bomb survivors. The purpose of this study was to clarify the effect of A-bomb radiation exposure on genomic instability (GIN), which is an important hallmark of carcinogenesis, in archival formalin-fixed paraffin-embedded (FFPE) tissues of breast cancer by using microarray-comparative genomic hybridization (aCGH).MethodsTumor DNA was extracted from FFPE tissues of invasive ductal cancers from 15 survivors who were exposed at 1.5 km or less from the hypocenter and 13 calendar year-matched non-exposed patients followed by aCGH analysis using a high-density oligonucleotide microarray. The total length of copy number aberrations (CNA) was used as an indicator of GIN, and correlation with clinicopathological factors were statistically tested.ResultsThe mean of the derivative log ratio spread (DLRSpread), which estimates the noise by calculating the spread of log ratio differences between consecutive probes for all chromosomes, was 0.54 (range, 0.26 to 1.05). The concordance of results between aCGH and fluorescence in situ hybridization (FISH) for HER2 gene amplification was 88%. The incidence of HER2 amplification and histological grade was significantly higher in the A-bomb survivors than control group (P = 0.04, respectively). The total length of CNA tended to be larger in the A-bomb survivors (P = 0.15). Correlation analysis of CNA and clinicopathological factors revealed that DLRSpread was negatively correlated with that significantly (P = 0.034, r = -0.40). Multivariate analysis with covariance revealed that the exposure to A-bomb was a significant (P = 0.005) independent factor which was associated with larger total length of CNA of breast cancers.ConclusionsThus, archival FFPE tissues from A-bomb survivors are useful for genome-wide aCGH analysis. Our results suggested that A-bomb radiation may affect the increased amount of CNA as a hallmark of GIN and, subsequently, be associated with a higher histologic grade in breast cancer found in A-bomb survivors.

Timing of Menarche and First Birth in Relation to Risk of Breast Cancer in A-Bomb Survivors

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. 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. 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. The radiation-associated risk of breast cancer does not vary significantly by reproductive status ATB. 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.

The long‐term outcome of atomic bomb survivors with gastric carcinoma

During the decade following the 1945 atomic bombing of Hiroshima, a high incidence of leukemia was observed among atomic bomb survivors. Subsequently, the incidence of other cancers gradually increased while that of leukemia decreased. We examined the long-term clinical outcome of gastric cancer and second primary cancer in atomic bomb survivors. Results of surgical treatment of gastric cancer were reviewed in 231 atomic bomb survivors and 759 control patients between 1995 and 2006. Long-term prognosis of gastric cancer in atomic bomb survivors was significantly poorer than that in control patients (P < 0.05). In a multivariate analysis, age, depth of tumor invasion, lymph node metastases, and curability were found to be significant and independent prognostic factors for gastric cancer. The incidence of second primary cancer after gastric cancer was significantly higher in survivors than in control patients (P < 0.01), because the number of elderly patients in the survivors was higher. Gastric cancer in survivors had a significantly poorer prognosis. Although the frequency of second primary cancer after gastric cancer in survivors was higher than that in control patients, it did not influence the prognosis.

Promoting Action of Radiation in the Atomic Bomb Survivor Cancer Incidence Data

Promoting Action of Radiation in the Atomic Bomb Survivor Cancer Incidence Data

Significance of HER2 and C‐MYC oncogene amplifications in breast cancer in atomic bomb survivors

It has been postulated that radiation induces breast cancers in atomic bomb (A-bomb) survivors. Oncogene amplification is an important mechanism during breast carcinogenesis and also serves as an indicator of genomic instability (GIN). The objective of this study was to clarify the association of oncogene amplification in breast cancer in A-bomb survivors with radiation exposure. In total, 593 breast cancers were identified in A-bomb survivors from 1968 to 1999, and the association between breast cancer incidence and A-bomb radiation exposure was evaluated. Invasive ductal cancers from 67 survivors and 30 nonsurvivors were analyzed for amplification of the HER2 and C-MYC genes by fluorescence in situ hybridization, and expression levels of hormone receptors were analyzed by immunostaining. The incidence rate increased significantly as exposure distance decreased from the hypocenter (hazard ratio per 1-km decrement, 1.47; 95% confidence interval [95% CI], 1.30-1.66). The incidence of HER2 and C-MYC amplification was increased significantly in the order of the control group, the distal group (P = .0238), and the proximal group (P = .0128). Multivariate analyses revealed that distance was a risk factor for the coamplification of C-MYC and HER2 in breast cancer in survivors (odds ratio per 1-km increment, 0.17; 95% CI, 0.01-0.63). The histologic grade of breast cancers became significantly higher in the order of the control group, the distal group, and the proximal group and was associated with oncogene amplifications. The current results suggested that A-bomb radiation may affect the development of oncogene amplification by inducing GIN and may be associated with a higher histologic grade in breast cancer among A-bomb survivors.

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.

Flexible dose-response models for Japanese atomic bomb survivor data: Bayesian estimation and prediction of cancer risk

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

Does radiation cause liver cancer? Comparison of radiation effects in atomic bomb survivors and other populations

Recent studies of atomic bomb survivors have shown that risks of liver cancer are significantly increased by radiation exposure. This contrasts with mortality studies of other radiation-exposed populations, which generally have not shown a significant radiation effect for this cancer. Because the liver is a frequent site to which other tumors metastasize, liver cancer is one of the most difficult cancers to correctly diagnose. Studies of liver cancer in A-bomb survivors and other populations have documented high percentages of tumors metastasized to the liver being incorrectly diagnosed as liver tumors. In addition, many deaths due to liver cancer have been incorrectly attributed to cirrhosis or chronic hepatitis. Studies of incident or pathology-confirmed liver cancer cases in A-bomb survivors have found higher radiation risk estimates for liver cancer than mortality studies in this cohort. Most studies of radiation and liver cancer in other radiation-exposed cohorts have been mortality studies, and thus, would include many misclassified liver cancers. Liver cancer was consistently associated with radiation exposure in studies of four cohorts exposed to Thorotrast, a previously used radiology contrast agent. However, the histologic subtypes of liver cancer and type of radiation exposure (external rather than internal) differ from those experienced by the A-bomb survivors. Liver cancer in atomic bomb survivors is primarily hepatocellular carcinoma (HCC), rather than the cholangiocarcinoma and hemangiosarcoma subtypes more associated with Thorotrast exposure. A recent case control study of the joint effects of radiation and viral hepatitis in the etiology of HCC, showed that A-bomb radiation had a significantly stronger effect among subjects who were infected with the hepatitis C virus (HCV). No significant interaction between hepatitis B viral infections and radiation in the etiology of this disease was found. We compared incidence and mortality studies of liver cancer conducted in a wide variety of radiation-exposed populations, in terms of their radiation risk estimates for liver cancer, the background level of liver cancer in the cohort, HCV prevalence in the population from which the cohort was drawn, and other factors. The differences between the radiation risk estimates for atomic bomb survivors and other cohorts may reflect liver cancer diagnosis errors. Varying risk estimates may also reflect differences in the prevalence of HCV in radiation-exposed cohorts.

Liver cancer in atomic-bomb survivors: histological characteristics and relationships to radiation and hepatitis B and C viruses.

Histological features of primary liver cancer among atomic-bomb survivors and their relationship to hepatitis B (HBV) and C viral (HCV) infections are of special interest because of the increased risk of liver cancer in persons exposed to ionizing radiation and the high and increasing liver cancer rates in Japan and elsewhere. We conducted a pathology review of liver cancers occurring from 1958 to 1987 among subjects in the 120,321 member cohort of 1945 Hiroshima and Nagasaki residents. A panel of pathologists classified tumor histological types and defined accompanying cirrhotic changes of the liver. Archival tissue samples were assessed for HBV using pathology stains and PCR. Reverse transcriptase (RT) PCR was used to determine HCV status. We used unconditional logistic regression to compare 302 hepatocellular carcinoma (HCC) cases to 53 cholangiocarcinoma (CC) cases, adjusting for age, year of diagnosis, sex and viral status. Cirrhotic changes occurred significantly more often among HCC than CC cases (76% in HCC and 6% in CC). Compared to CC cases, HCC cases were 10.9 times more likely to be HBV-positive (95% confidence interval: 2.1-83.2) and 4.3 times more likely to be HCV-positive (95% confidence interval: 1.1-20.5). No significant differences were found between HCC and CC cases in radiation exposures. The predominance of HCC in the atomic-bomb survivors follows the background liver cancer pattern in Japan. Our findings suggest that HBV and HCV are involved in the pathogenesis of HCC with or without cirrhosis and are significantly less important in that of CC.

Projection of cancer risks from the Japanese atomic bomb survivors to the England and Wales population taking into account uncertainty in risk parameters.

Generalized relative risk models, with adjustments to the relative risk for time after exposure and age at exposure and incorporating a linear-quadratic dose response, were fitted to the latest (Life Span Study Report 12) Japanese atomic bomb survivor cancer mortality data using Bayesian Markov Chain Monte Carlo methods, taking account of random errors in the DS86 dose estimates. The resulting uncertainty distributions in the relative risk model parameters were used to derive uncertainties in population cancer risks for a current UK population. Following an assumed administered dose of 1 Sv, leukaemia mortality risks were estimated to be 1.93x10(-2) Sv(-1) (95% CI 1.14, 3.38), or 0.44 years of life lost Sv(-1) (95% CI 0.22, 0.94). Following an assumed administered dose of 1 Sv, solid cancer mortality risks were calculated to be 10.36x10(-2) Sv(-1) (95% CI 8.41, 12.42), or 1.38 years of life lost Sv(-1) (95% CI 1.11, 1.68). In general, solid cancer risks were very similar to those predicted by classical likelihood-based methods; however, leukaemia risks were somewhat higher, by 10-35%, than those predicted by classical likelihood-based methods. This is so in both cases, irrespective of whether or not adjustments are made in these likelihood-based fits for the effects of measurement errors, and the discrepancy for leukaemia tends to be greater at higher doses. Overall, cancer risks predicted by Bayesian Markov Chain Monte Carlo methods are similar to those derived by classical likelihood-based methods and which form the basis of established estimates of radiation-induced cancer risk.

Radiation dose dependences in the atomic bomb survivor cancer mortality data: a model-free visualization.

Chomentowski, M., Kellerer, A. M. and Pierce, D. A. Radiation Dose Dependences in the Atomic Bomb Survivor Cancer Mortality Data: A Model-Free Visualization. The standard approach to obtaining nominal risk coefficients for radiation-related cancer involves fitting linear or linear-quadratic dose-response functions. This is usually complemented by a more direct visualization where the data are subdivided into distinct dose categories and the effect level is quantified for each of these categories. Such model-free computations, however, can be quite dependent on the arbitrary choice of the cutpoints in dose. The method proposed here largely avoids this arbitrariness by choosing a dose category width-constant on a log scale-to obtain the desired degree of smoothing, and then superimposing results for all placements of the resulting log-dose grids. The method is applied to leukemia and solid cancer mortality of the A-bomb survivors.

A comparison of the degree of curvature in the cancer incidence dose-response in Japanese atomic bomb survivors with that in chromosome aberrations measured in vitro

Purposes : To compare the degree of curvature in the dose-response for chromosome aberrations and for radiation-induced cancer. Materials and methods : Comparison of the ratio of the quadratic and linear coeffcients (in dose) in Japanese atomic bomb survivor cancer incidence data, based on follow-up to 1987 and taking account of random errors in DS86 dose estimates with the same ratio in four datasets of chromosome aberrations in peripheral blood lymphocytes measured in vitro and exposed to 60 Co gamma radiation. Results : There are no statistically significant differences between the four in vitro datasets in the ratio of the quadratic to the linear coeffcients for dicentrics or chromosome translocations, nor are there indications of differences between this ratio for dicentrics and that for complete chromosome translocations (p >0.1 in all cases). If the 0-4 Gy dose range is used in the Japanese atomic bomb survivor data, the ratio of the quadratic to the linear coeffcients for all solid cancers is 0.06 Sv 1 (95% CI 0.22, 0.67) and so is not significantly different from 0; this ratio is statistically highly inconsistent (p <0.0001) with the analogous ratio estimated for the in vitro chromosome aberration data (4.20Sv 1; 95% CI 3.06, 6.51). By contrast, there are no statistically significant differences (p =0.42) between the ratio of the quadratic to the linear coeffcients for leukaemia incidence in the Japanese cohort, 1.81 Sv 1 (95% CI 0.21, > 1000), with that for chromosome aberrations in vitro. These results are not markedly changed if the 0-2 Gy dose range is used in the Japanese atomic bomb survivor data. Conclusions : It is unlikely that in vitro chromosome aberrations could be a correlate for the initiating radiogenic lesions leading to radiation-induced solid cancers. However, taken together with certain other biological information, it may not be unreasonable on this basis to use in vitro chromosome aberrations in peripheral blood lymphocytes as a correlate of the radiogenic lesions leading to radiation-induced leukaemia.

Derivation of low-dose extrapolation factors from analysis of curvature in the cancer incidence dose response in Japanese atomic bomb survivors

Purposes : To assess the degree of overestimation in low-dose cancer risk when models linear in dose are fitted to cancer data. Materials and methods : Examination of the quadratic and the linear coefficients (in dose) in the Japanese atomic bomb survivor cancer incidence data, based on follow-up to 1987 and taking separate account of random errors in DS86 neutron and DS86 gamma dose estimates and systematic errors in Hiroshima DS86 neutron dose estimates. Results : When the 0-4 Gy dose range is used, the low-dose extrapolation factor for all solid tumours, assessing the degree to which low-dose cancer risks are overestimated by fitting a model linear in dose, is 1.06 (95% CI 0.78, 1.62) and so is not significantly different from 1; the associated ratio of the quadratic to the linear coefficients is 0.06 Sv -1 (95% CI - 0.22, 0.67). The best estimate of the low-dose extrapolation factor for leukaemia is 2.47 (95% CI 1.24, > 1000). The ratio of the quadratic to the linear coefficients is 1.81 Sv -1 (95% CI 0.21, > 1000). When various types and groupings of solid tumours are considered there is not generally any strong evidence for upward curvature; for only two out of the six solid tumour groupings are there indications of appreciable upward curvature in the dose response, and in no instance is this statistically significant. Consideration of a lower dose range (0-2 Gy rather than 0-4 Gy) results in the low-dose extrapolation factor for solid tumours increasing to 1.21 (95% CI 0.81, 2.45), with corresponding increases for solid tumour subtypes; the corresponding quantity for leukaemia decreases to 1.73 (95% CI 0.79, 147.67). Three out of the six solid tumour subtypes now show appreciable upward curvature. If there is additional adjustment of the Hiroshima neutron dose estimates over the 0-2 Gy dose range, the low-dose extrapolation factor for all solid tumours increases still further, to 1.43 (95% CI 0.97, 2.72), whereas for leukaemia this quantity is further reduced, to 1.58 (95% CI 0.90, 10.58). Conclusions : There is marked upward curvature in the dose response for leukaemia. For solid tumours there is little indication of upward curvature in the dose response over the 0-4 Gy dose range, although over the 0-2 Gy dose range and after adjustment of Hiroshima DS86 neutron dose estimates the upward curvature is more pronounced. Uncertainties in the likely adjustments to the Hiroshima DS86 neutron dose estimates imply that these findings should be treated with caution.