Comparison of the risks of cancer incidence and mortality following radiation therapy for benign and malignant disease with the cancer risks observed in the Japanese A-bomb survivors

PURPOSES: To compare the radiation-associated relative risks of cancer incidence and mortality in groups exposed to ionizing radiation in the course of treatment for a variety of malignant and non-malignant conditions with those in the Japanese A-bomb survivor cancer incidence and mortality data. MATERIALS AND METHODS: Comparison of the excess relative risk coefficients derived from published information for each study with the excess relative risk coefficient in comparable (age at exposure, time since exposure, sex) matched subsets of the Japanese A-bomb survivor cancer incidence and mortality data. RESULTS: Sixty-five studies of persons who have received appreciable doses of ionizing radiation in the course of treatment and for whom there is adequate ascertainment of cancer incidence or mortality are identified, from which 116 cancer-site-specific estimates of excess relative risk are derived. Relative risks tend to be lower in the medical series than in the Japanese A-bomb survivors. The most marked discrepancies between the relative risks in the medical series and in the A-bomb survivors are for leukaemia, where 12 of the 17 medical studies have significantly lower relative risks than those observed in the Japanese data. However, the ratio between the relative risks in the medical studies and in the Japanese data tends to diminish with increasing average or maximal therapy dose. This is observed for all cancer sites and is particularly marked for leukaemia. After taking account of cell sterilization and dose fractionation the apparent differences between the relative risks for leukaemia in the Japanese A-bomb survivors and in the medical series largely disappear. This suggests that cell sterilization largely accounts for the discrepancy between the relative risks in the Japanese data and the medical studies. Other factors, such as the differences in underlying cancer risks between the Japanese A-bomb survivors and the medical series, and dose-fractionation effects, may also contribute. CONCLUSIONS: The relative risks of cancer in studies of persons exposed to appreciable doses of ionizing radiation in the course of treatment for a variety of malignant and non-malignant conditions are generally less than those in comparable subsets of the Japanese A-bomb survivor cancer incidence and mortality data. Cell sterilization effects can largely explain the discrepancy between the Japanese and the medical series.     

Radiation dose-dependent increases in inflammatory response markers in A-bomb survivors

PURPOSE: The well-documented increases in malignant tumours in the A-bomb survivors have recently been supplemented by reports that non-cancer diseases, including cardiovascular disease, may also have increased in incidence with increasing radiation dose. Given that low-level inflammatory responses are widely accepted as a significant risk factor for such diseases, we undertook a detailed investigation of the long-term effects of ionizing radiation on the levels of the inflammatory markers C-reactive protein (CRP) and interleukin 6 (IL-6) in A-bomb survivors. MATERIALS AND METHODS: Blood samples were taken from 453 participants in a long-term epidemiological cohort of A-bomb survivors. Plasma levels of CRP and IL-6 were measured using standard antibody-mediated procedures. Relationships between CRP or IL-6 levels and radiation dose were then investigated by multivariate regression analysis. Blood lymphocytes from each individual were used for immunophenotyping by flow cytometry with murine monoclonal antibodies to CD3, CD4 and CD8. RESULTS: CRP levels were significantly increased by about 31% Gy(-1) of estimated A-bomb radiation (p=0.0001). Higher CRP levels also correlated with age, male gender, body mass index and a history of myocardial infarction. After adjustments for these factors, CRP levels still appeared to have increased significantly with increasing radiation dose (about 28% increase at 1Gy, p=0.0002). IL-6 levels also appeared to have increased with radiation dose by 9.3% at 1Gy (p=0.0003) and after multiple adjustments by 9.8% at 1Gy (p=0.0007). The elevated CRP and IL-6 levels were associated with decreases in the percentages of CD4(+) helper T-cells in peripheral blood lymphocyte populations. CONCLUSIONS: Our results appear to indicate that exposure to A-bomb radiation has caused significant increases in inflammatory activity that are still demonstrable in the blood of A-bomb survivors and which may lead to increased risks of cardiovascular disease and other non-cancer diseases.     

Risk of breast cancer following low-dose radiation exposure.

Risk of breast cancer following radiation exposure was studied, based on surveys of tuberculosis patients who had multiple fluoroscopic examinations of the chest, mastitis patients given radiotherapy, and atomic bomb survivors. Analysis suggests that the risk is greatest for persons exposed as adolescents, although exposure at all ages carries some risk. The dose-response relationship was consistent with linearity in all studies. Direct evidence of radiation risk at doses under 0.5 Gy (50 rad) is apparent among A-bomb survivors. Fractionation does not appear to diminish risk, nor does time since exposure (even after 45 years of observation). The interval between exposure and the clinical appearance of radiogenic breast cancer may be mediated by hormonal or other age-related factors but is unrelated to dose. Age-specific absolute risk estimates for all studies are remarkably similar. The best estimate of risk among American women exposed after age 20 is 6.6 excess cancers/10(4) WY-G-Y (10(6) WY-rad).     

Meta-analysis of non-tumour doses for radiation-induced cancer on the basis of dose-rate

Purpose: Quantitative analysis of cancer risk of ionising radiation as a function of dose-rate. Materials and methods: Non-tumour dose, D(nt), defined as the highest dose of radiation at which no statistically significant tumour increase was observed above the control level, was analysed as a function of dose-rate of radiation. Results: An inverse correlation was found between D(nt) and dose-rate of the radiation. D(nt) increased 20-fold with decreasing dose-rate from 1-10(-8) Gy/min for whole body irradiation with low linear energy transfer (LET) radiation. Partial body radiation also showed a dose-rate dependence with a 5- to 10-fold larger D(nt) as dose rate decreased. The dose-rate effect was also found for high LET radiation but at 10-fold lower D(nt) levels. Conclusions: The cancer risk of ionising radiation varies 1000-fold depending on the dose-rate of radiation and exposure conditions. This analysis explains the discrepancy of cancer risk between A-bomb survivors and radium dial painters.     

Radiation risks potentially associated with low-dose CT screening of adult smokers for lung cancer

PURPOSE: To estimate the radiation-related lung cancer risks associated with annual low-dose computed tomographic (CT) lung screening in adult smokers and former smokers, and to establish a baseline risk that the potential benefits of such screening should exceed. MATERIALS AND METHODS: The estimated lung radiation dose from low-dose CT lung examinations corresponds to a dose range for which there is direct evidence of increased cancer risk in atomic bomb survivors. Estimated dose-, sex-, and smoking status-dependent excess relative risks of lung cancer were derived from cancer incidence data for atomic bomb survivors and used to calculate the excess lung cancer risks associated with a single CT lung examination at a given age in a U.S. population. From these, the overall radiation risks associated with annual CT lung screening were estimated. RESULTS: A 50-year-old female smoker who undergoes annual CT lung screening until age 75 would incur an estimated radiation-related lung cancer risk of 0.85%, in addition to her otherwise expected lung cancer risk of approximately 17%. The radiation-associated cancer risk to other organs would be far lower. If 50% of all current and former smokers in the U.S. population aged 50-75 years received annual CT screening, the estimated number of lung cancers associated with radiation from screening would be approximately 36,000, a 1.8% (95% credibility interval: 0.5%, 5.5%) increase over the otherwise expected number. CONCLUSION: Given the estimated upper limit of a 5.5% increase in lung cancer risk attributable to annual CT-related radiation exposure, a mortality benefit of considerably more than 5% may be necessary to outweigh the potential radiation risks.     

Memory CD4 T-cell subsets discriminated by CD43 expression level in A-bomb survivors

Purpose:?Our previous study showed that radiation exposure reduced the diversity of repertoires of memory thymus-derived cells (T cells) with cluster of differentiation (CD)- 4 among atomic-bomb (A-bomb) survivors. To evaluate the maintenance of T-cell memory within A-bomb survivors 60 years after radiation exposure, we examined functionally distinct memory CD4 T-cell subsets in the peripheral blood lymphocytes of the survivors.

Methods:?Three functionally different subsets of memory CD4 T cells were identified by differential CD43 expression levels and measured using flow cytometry. These subsets consist of functionally mature memory cells, cells weakly responsive to antigenic stimulation, and those cells functionally anergic and prone to spontaneous apoptosis.

Results:?The percentages of these subsets within the peripheral blood CD4 T-cell pool all significantly increased with age. Percentages of functionally weak and anergic subsets were also found to increase with radiation dose, fitting to a log linear model. Within the memory CD4 T-cell pool, however, there was an inverse association between radiation dose and the percentage of functionally mature memory cells.

Conclusion:?These results suggest that the steady state of T cell memory, which is regulated by cell activation and/or cell survival processes in subsets, may have been perturbed by prior radiation exposure among A-bomb survivors.     

Cataract in atomic bomb survivors

PURPOSE: Ophthalmologic examinations were conducted on atomic bomb (A-bomb) survivors 55 years after exposure. MATERIALS AND METHODS: A-bomb survivors who had been exposed before 13 years of age at the time of the bombings in 1945 or who had been examined in a previous study between 1978 and 1980. The examinations, conducted between June 2000 and September 2002, included slit-lamp examination, digital photography and a cataract grading system for three parts of the lens (nucleus, cortex and posterior subcapsule) as an outcome variable. Proportional odds logistic regression analysis was conducted using the lowest grading class as a reference and included explanatory variables such as age, sex, city, dose and various cataract-related risk factors. When the grades in an individual differed, the worst grade was used. RESULTS: Results indicate that odds ratios (ORs) at 1 Sv were 1.07 (95% confidence intervals [CI] 0.90, 1.27) in nuclear colour, 1.12 (95% CI 0.94, 1.30) in nuclear cataract, 1.29 (95% CI 1.12, 1.49) in cortical cataract and 1.41 (95% CI 1.21, 1.64) in posterior subcapsular cataract. The same was true after excluding 13 people whose posterior subcapsular cataracts had been previously detected. CONCLUSION: Significant radiation effects were observed in two types of cataracts in A-bomb survivors.     

Problems Inherent in the Assessment of Long-TermLow-Dose Radiation Carcinogenesis

Risk estimates derived from studies based on actual exposure to low dose radiation(LDR),I. E populations exposed to fallout,those living in the vicinity of nuclear reactors,scattered x- radiation. Nuclear industry and in utero exposure(1-8),vary from extrapolations coming from highdose studies. i. e A-bomb survivors and indi viduals exposed to therapeutic irradiation(9-12).     

Persistent subclinical inflammation among A-bomb survivors

PURPOSE: To investigate the associations between inflammation tests and radiation dose in A-bomb survivors. SUBJECTS AND METHODS: Subjects were A-bomb survivors who underwent inflammation tests of leukocyte counts, neutrophil counts, erythrocyte sedimentation rate, corrected erythrocyte sedimentation rate, alpha-1 globulin, alpha-2 globulin and sialic acid between 1988 and 1992. Associations with radiation dose (DS86) were analyzed by regression analysis and heterogeneity among inflammatory diseases, anaemia at examination, or history of cancer was also tested. RESULTS: The associations with radiation dose were statistically significant for leukocyte counts (71.0mm(-3) Gy(-1), p=0.015), erythrocyte sedimentation rate (1.58 mm h(-1) Gy(-1) , p = 0.0001), corrected erythrocyte sedimentation rate (1.14mm h(-1) Gy(-1), p=0.0001), alpha-1 globulin (0.0057 g dl(-1) Gy(-1), p=0.0001), alpha-2 globulin (0.0128 g dl(-1) Gy(-1), p=0.0001), and sialic acid (1.2711 mg dl(-1) Gy(-1), p=0.0001) but not for neutrophil counts (29.9 mm(-3) Gy(-1), p=0.17). Heterogeneity was not statistically significant. Among inflammatory diseases, associations were the strongest for chronic thyroiditis and chronic liver diseases. CONCLUSIONS: This study suggests statistically significant association between inflammation in A-bomb survivors and radiation dose of during 1988-1992. The association might contribute, as an epigenetic and/or bystander effect, to development of several radiation-induced disorders.     

Persistent subclinical inflammation among A-bomb survivors

Purpose : To investigate the associations between inflammation tests and radiation dose in A-bomb survivors. Subjects and methods : Subjects were A-bomb survivors who underwent inflammation tests of leukocyte counts, neutrophil counts, erythrocyte sedimentation rate, corrected erythrocyte sedimentation rate, α -1 globulin, α -2 globulin and sialic acid between 1988 and 1992. Associations with radiation dose (DS86) were analyzed by regression analysis and heterogeneity among inflammatory diseases, anaemia at examination, or history of cancer was also tested. Results : The associations with radiation dose were statistically significant for leukocyte counts (71.0mm -3 Gy -1, p =0.015), erythrocyte sedimentation rate (1.58mm h -1 Gy -1, p =0.0001), corrected erythrocyte sedimentation rate (1.14 mm h -1 Gy -1, p =0.0001), α -1 globulin (0.0057 g dl -1 Gy -1, p =0.0001), α -2 globulin (0.0128 g dl -1 Gy -1, p =0.0001), and sialic acid (1.2711 mg dl -1 Gy -1, p =0.0001) but not for neutrophil counts (29.9mm -3 Gy -1, p =0.17). Heterogeneity was not statistically significant. Among inflammatory diseases, associations were the strongest for chronic thyroiditis and chronic liver diseases. Conclusions : This study suggests statistically significant association between inflammation in A-bomb survivors and radiation dose of during 1988-1992. The association might contribute, as an epigenetic and/or bystander effect, to development of several radiation-induced disorders.     

Meta-analysis of non-tumour doses for radiation-induced cancer on the basis of dose-rate

Purpose:?Quantitative analysis of cancer risk of ionising radiation as a function of dose-rate.

Materials and methods:?Non-tumour dose, D_nt, defined as the highest dose of radiation at which no statistically significant tumour increase was observed above the control level, was analysed as a function of dose-rate of radiation.

Results:?An inverse correlation was found between D_nt and dose-rate of the radiation. D_nt increased 20-fold with decreasing dose-rate from 1–10^?8 Gy/min for whole body irradiation with low linear energy transfer (LET) radiation. Partial body radiation also showed a dose-rate dependence with a 5- to 10-fold larger D_nt as dose rate decreased. The dose-rate effect was also found for high LET radiation but at 10-fold lower D_nt levels.

Conclusions:?The cancer risk of ionising radiation varies 1000-fold depending on the dose-rate of radiation and exposure conditions. This analysis explains the discrepancy of cancer risk between A-bomb survivors and radium dial painters.     

Long-lasting alterations of the immune system by ionizing radiation exposure: implications for disease development among atomic bomb survivors

PURPOSE: The immune systems of the atomic-bomb (A-bomb) survivors were damaged proportionately to irradiation levels at the time of the bombing over 60 years ago. Although the survivor's immune system repaired and regenerated as the hematopoietic system has recovered, significant residual injury persists, as manifested by abnormalities in lymphoid cell composition and function. This review summarizes the long-lasting alterations in immunological functions associated with atomic-bomb irradiation, and discusses the likelihood that damaging effects of radiation on the immune system may be involved partly in disease development so frequently observed in A-bomb survivors. CONCLUSIONS: Significant immunological alterations noted include: (i) attrition of T-cell functions, as reductions in mitogen-dependent proliferation and interleukin-2 (IL-2) production; (ii) decrease in helper T-cell populations; and (iii) increase in blood inflammatory cytokine levels. These findings suggest that A-bomb radiation exposure perturbed one or more of the primary processes responsible for T-cell homeostasis and the balance between cell renewal and survival and cell death among naive and memory T cells. Such perturbed T-cell homeostasis may result in acceleration of immunological aging. Persistent inflammation, linked in some way to the perturbation of T-cell homeostasis, is key in addressing whether such noted immunological changes observed in A-bomb survivors are in fact associated with disease development.     

Lack of association between acute exposure to ionizing radiation and liver cirrhosis

PURPOSE: Although previous studies have shown significantly increased risks of liver cirrhosis and chronic liver disease for acute radiation exposure among survivors of the atomic bombings of Hiroshima and Nagasaki, Japan, these studies have not taken into account hepatitis B virus (HBV) infections. Because HBV is associated with both A-bomb radiation and liver cirrhosis, our goal was to investigate the relationship of acute ionizing radiation to liver cirrhosis adjusting for HBV, co-occurring primary liver cancer (PLC), and other potential confounders. MATERIALS AND METHODS: Using a cross-sectional design and pathology review of a cohort of Japanese atomic-bomb survivors, we found that 213 of 335 (63.6%) subjects with PLC and 55 of 776 (7.1%) subjects without PLC had cirrhosis. RESULTS: We found no association between acute exposure to A-bomb radiation and liver cirrhosis. The adjusted odds ratio of cirrhosis per Sv liver irradiation was 0.59 (95% confidence interval: 0.27 - 1.27). Cirrhosis risks for the highest tertile of radiation exposure (mean exposure 0.7 Sv) were also not elevated (0.8, 0.26 - 2.12 and 0.2, 0.03 - 0.98 among subjects with and without PLC. CONCLUSIONS: Acute exposure to liver irradiation does not increase risks of liver cirrhosis, regardless of PLC status.     

Rapid translocation frequency analysis in humans decades after exposure to ionizing radiation.

This paper presents an analysis of the utility of fluorescence in situ hybridization (FISH) with whole-chromosome probes for measurement of the genomic frequency of translocations found in the peripheral blood of individuals exposed to ionizing radiation. First, we derive the equation: Fp = 2.05fp(1-fp)FG, relating the translocation frequency, Fp, measured using FISH to the genomic translocation frequency, FG, where fp is the fraction of the genome covered by the composite probe. We demonstrate the validity of this equation by showing that: (a) translocation detection efficiency predicted by the equation is consistent with experimental data as fp is changed; (b) translocation frequency dose-response curves measured in vitro using FISH agree well with dicentric frequency dose-response curves measured in vitro using conventional cytogenetic procedures; and (c) the genomic translocation frequencies estimated from FISH measurements for 20 Hiroshima A-bomb survivors and four workers exposed to ionizing radiation during the Y-12 criticality accident are approximately the same as the translocation frequencies measured using G-banding. We also show that translocation frequency dose response curves estimated using FISH are similar for Hiroshima A-bomb survivors and for first division lymphocytes irradiated in vitro. We conclude with a discussion of the potential utility of translocation frequency analysis for assessment of the level of acute radiation exposure independent of the time between analysis and exposure.     

Routine screening mammography: how important is the radiation-risk side of the benefit-risk equation?

The potential radiation hazards associated with routine screening mammography, in terms of breast cancer induction, are discussed in the context of the potential benefits. The very low energy X-rays used in screening mammography (26-30 kVp) are expected to be more hazardous, per unit dose, than high-energy X- or γ-rays, such as those to which A-bomb survivors (from which radiation risk estimates are derived) were exposed. Based on in vitro studies using oncogenic transformation and chromosome aberration end-points, as well as theoretical estimates, it seems likely that low doses of low-energy X-rays produce an increased risk per unit dose (compared with high energy photons) of about a factor of 2. Because of the low doses involved in screening mammography, the benefit-risk ratio for older women would still be expected to be large, though for younger women the increase in the estimated radiation risk suggests a somewhat later age than currently recommended--by about 5-10 years--at which to commence routine breast screening.     

Routine screening mammography: how important is the radiation-risk side of the benefit-risk equation?

The potential radiation hazards associated with routine screening mammography, in terms of breast cancer induction, are discussed in the context of the potential benefits. The very low energy X-rays used in screening mammography (26-30 kVp) are expected to be more hazardous, per unit dose, than high-energy X- or gamma-rays, such as those to which A-bomb survivors (from which radiation risk estimates are derived) were exposed. Based on in vitro studies using oncogenic transformation and chromosome aberration end-points, as well as theoretical estimates, it seems likely that low doses of low-energy X-rays produce an increased risk per unit dose (compared with high energy photons) of about a factor of 2. Because of the low doses involved in screening mammography, the benefit-risk ratio for older women would still be expected to be large, though for younger women the increase in the estimated radiation risk suggests a somewhat later age than currently recommended--by about 5-10 years--at which to commence routine breast screening.     

Organ doses received by atomic bomb survivors during radiological examinations at the Radiation Effects Research Foundation

When evaluating the risks of oncogenesis and cancer mortality following exposure to the radiations of the atomic bombs (A-bombs), the medical X-ray doses received by the A-bomb survivors must also be estimated and considered. Using a human phantom, dosimetry was performed to estimate the X-ray doses received by A-bomb survivors during medical examinations at the Radiation Effects Research Foundation (RERF) as part of the long-term follow-up on the Adult Health Study (AHS). These examinations have been estimated to represent nearly 45% of the survivors' cumulative medical irradiation dose. Doses to the salivary glands, thyroid gland, lung, breast, stomach and colon were measured using thermoluminescent dosimeters. The results, which are reported here, will aid in estimating organ doses received by individual AHS participants.     

Microsatellite instability in acute myelocytic leukaemia developed from A-bomb survivors

Purpose : Genetic alterations, including microsatellite instability (MSI), are ultimate steps toward malignant process. To investigate MSI in A-bomb survivors, leukaemic cells were analysed from 13 acute myelocytic leukaemia patients with a history of radiation exposure and also in 12 de novo patients. Materials and methods : To assess the microsatellite changes, a fluorescent system in 10 loci (BAT40, D3S643, D5S107, IRF1, MYC, D9S171, WT1, TP53, DM, D17S855) was used. Results : MSI analysis revealed a high frequency of multiple microsatellite changes in the exposed patients (84.6%) compared with non-exposed patients (8.3%). There was a significant difference (p <0.001) between the two groups. Conclusions : These analyses clearly demonstrate that leukaemic cells from heavily exposed patients contain a number of genetic instabilities that may strongly influence the development of leukaemia among people exposed to the Hiroshima A-bomb radiation.     

Early Mortality Rate of Atomic Bomb Survivors Based on House Reconstruction Survey

This paper studies the mortality rate experienced by over 23 000 A-bomb survivors in Nagasaki between September 1945 and 1950 when the RERF-ABCC initiated the follow-up of the large LSS cohort. The study is based on the data of the 10-year House Reconstruction Survey. As expected, these data show an increasing mortality rate with increasing proximity to the hypocenter of the bomb. What was not anticipated was a higher mortality rate in the 1400–1699 m band than in the closer distance interval of 1200–1399 m. This suggests a possible selective survival among A-bomb survivors. Whether this affects the cancer risk estimates has not as yet been determined.     

Microsatellite instability in acute myelocytic leukaemia developed from A-bomb survivors

PURPOSE: Genetic alterations, including microsatellite instability (MSI), are ultimate steps toward malignant process. To investigate MSI in A-bomb survivors, leukaemic cells were analysed from 13 acute myelocytic leukaemia patients with a history of radiation exposure and also in 12 de novo patients. MATERIALS AND METHODS: To assess the microsatellite changes, a fluorescent system in 10 loci (BAT40, D3S643, D5S107, IRF1, MYC, D9S171, WT1, TP53, DM, D17S855) was used. RESULTS: MSI analysis revealed a high frequency of multiple microsatellite changes in the exposed patients (84.6%) compared with non-exposed patients (8.3%). There was a significant difference (p < 0.001) between the two groups. CONCLUSIONS: These analyses clearly demonstrate that leukaemic cells from heavily exposed patients contain a number of genetic instabilities that may strongly influence the development of leukaemia among people exposed to the Hiroshima A-bomb radiation.