The risk of childhood leukaemia following exposure to ionising radiation--a review.

Since the early years of follow-up of the Japanese atomic-bomb survivors, it has been apparent that childhood leukaemia has a particular sensitivity to induction by ionising radiation, the excess relative risk (ERR) being expressed as a temporal wave with time since exposure. This pattern has been generally confirmed by studies of children treated with radiotherapy. Case-control studies of childhood leukaemia and antenatal exposure to diagnostic x-rays, a recent large cohort study of leukaemia following CT examinations of young people, and a recent large case-control study of natural background γ-radiation and childhood leukaemia have found evidence of raised risks following low-level exposure. These findings indicate that an ERR/Sv for childhood leukaemia of ~50, which may be derived from risk models based upon the Japanese atomic-bomb survivors, is broadly applicable to low dose or low dose-rate exposure circumstances.

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

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

Radiation and cancer risk in atomic-bomb survivors.

With the aim of accurately assessing the effects of radiation exposure in the Japanese atomic-bomb survivors, the Radiation Effects Research Foundation has, over several decades, conducted studies of the Life Span Study (LSS) cohort, comprising 93 000 atomic-bomb survivors and 27 000 controls. Solid cancer: the recent report on solid cancer incidence found that at age 70 years following exposure at age 30 years, solid cancer rates increase by about 35%  Gy(-1) for men and 58% Gy(-1) for women. Age-at-exposure is an important risk modifier. In the case of lung cancer, cigarette smoking has been found to be an important risk modifier. Radiation has similar effects on first-primary and second-primary cancer risks. Finally, radiation-associated increases in cancer rates appear to persist throughout life. Leukaemia: the recent report on leukaemia mortality suggests that radiation effects on leukaemia mortality persisted for more than 50 years. Moreover, significant dose-response for myelodysplastic syndrome was observed in Nagasaki LSS members even 40-60 years after radiation exposure. Future perspective: given the continuing solid cancer increase in the survivor population, the LSS will likely continue to provide important new information on radiation exposure and solid cancer risks for another 15-20 years, especially for those exposed at a young age.

Positive associations between ionizing radiation and lymphoma mortality among men.

The authors investigated the relation between ionizing radiation and lymphoma mortality in 2 cohorts: 1) 20,940 men in the Life Span Study, a study of Japanese atomic bomb survivors who were aged 15-64 years at the time of the bombings of Hiroshima and Nagasaki, and 2) 15,264 male nuclear weapons workers who were hired at the Savannah River Site in South Carolina between 1950 and 1986. Radiation dose-mortality trends were evaluated for all malignant lymphomas and for non-Hodgkin's lymphoma. Positive associations between lymphoma mortality and radiation dose under a 5-year lag assumption were observed in both cohorts (excess relative rates per sievert were 0.79 (90% confidence interval: 0.10, 1.88) and 6.99 (90% confidence interval: 0.96, 18.39), respectively). Exclusion of deaths due to Hodgkin's disease led to small changes in the estimates of association. In each cohort, evidence of a dose-response association was primarily observed more than 35 years after irradiation. These findings suggest a protracted induction and latency period for radiation-induced lymphoma mortality.

Ionizing radiation and leukemia mortality among Japanese Atomic Bomb Survivors, 1950-2000.

This paper provides the first comprehensive report on mortality by type of leukemia among the Japanese atomic bomb survivors in the Life Span Study (LSS). Analyses include 310 deaths due to leukemia during the period 1950-2000 among 86,611 people in the LSS. Poisson regression methods were used to evaluate associations between estimated bone marrow dose and leukemia mortality. Attention was given to variation in the radiation dose-leukemia mortality association by time since exposure, age at exposure, city and sex. The excess relative rate per gray of acute myeloid leukemia was best described by a quadratic dose-response function that peaked approximately 10 years after exposure. Acute lymphatic leukemia and chronic myeloid leukemia mortality were best described by a linear dose-response function that did not vary with time since exposure. Adult T-cell leukemia was not associated with estimated bone marrow dose. Overall, 103 of the 310 observed leukemia deaths were estimated to be excess deaths due to radiation exposure. In the most recent decade of observation (1991-2000), the estimated attributable fraction of leukemia deaths among those survivors exposed to >0.005 Gy was 0.34, suggesting that the effect of the atomic bombings on leukemia mortality has persisted in this cohort for more than five decades.

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

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

Leukaemia following childhood radiation exposure in the Japanese atomic bomb survivors and in medically exposed groups.

Incidence and mortality risks of radiation-associated leukaemia are surveyed in the Japanese atomic bomb (A-bomb) survivors exposed in early childhood and in utero. Leukaemia incidence and mortality risks are also surveyed in 16 other studies of persons who received appreciable doses of ionizing radiation in the course of treatment in childhood and for whom there is adequate dosimetry and cancer incidence or mortality follow-up. Relative risks tend to be lower in the medical series than in the Japanese A-bomb survivors. The relative risks in the medical studies tend to diminish with increasing average therapy dose. After taking account of cell sterilisation 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 sterilisation largely accounts for the discrepancy between the relative risks in the Japanese data and the medical studies. Excess absolute risk has also been assessed in four studies, and there is found to be more variability in this measure than in excess relative risk. In particular, there is a substantial difference between the absolute risk in the Japanese atomic bomb survivor data and those in three other (European) populations. In summary, the relative risks of leukaemia 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 in childhood are generally less than those in the Japanese A-bomb survivor data. The effects of cell sterilisation can largely explain the discrepancy between the Japanese and the medical series.

Sex ratio in the offspring of parents with chronic radiation exposure from nuclear testing in Kazakhstan.

The former Soviet Union conducted a nuclear test program in the Semipalatinsk region of northeastern Kazakhstan in 1949-1989. The population in the vicinity of the test site was chronically exposed to radiation fallout, especially from above-ground tests during 1949-1956. Male:female sex ratio has been proposed as a measure of reproductive health, with some reports suggesting an alteration in the sex ratio of offspring of parents exposed to radiation. We investigated the impact of radiation exposure and other factors on the sex ratio in the population inhabiting the exposed region. A total of 11,464 singleton births of 3,992 mothers exposed to radiation during 1949-1956 were analyzed. The overall sex ratio was 1.07, similar to the current sex ratio in Kazakhstan (1.06). The sex ratio increased from 1.04 where mothers received <20.0 cSv to 1.12 where mothers received > or =60.0 cSv. However, the linear trend across exposures was not significant (P = 0.42). No consistent association was found between the sex ratio and the time since parental radiation exposure, parental age at exposure, or year of birth. Sex ratio was significantly associated with maternal age, birth order and possibly ethnicity but not with paternal age, parental educational level or season. In conclusion, no significant association was found between radiation exposure level and sex ratio, but some previously suggested demographic factors were positively associated with sex ratio.

Systolic blood pressure and systolic hypertension in adolescence of atomic bomb survivors exposed in utero.

Annual medical examinations were conducted during adolescence for the in utero clinical study sample subjects exposed prenatally to the atomic bombs in Hiroshima and Nagasaki. Systolic blood pressure and several anthropometric measurements were recorded during these examinations. For 1014 persons exposed in utero, two types of longitudinal analyses were performed, for a total of 7029 observations (6.93 observations per subject) of systolic blood pressure (continuous data) and systolic hypertension (binary data) for persons aged 9 to 19 years. Body mass index (BMI) and/or body weight were considered in the analyses as potential confounders. For the measurements of systolic blood pressure, the common dose effect was 2.09 mmHg per Gy and was significant (P = 0.017). The dose by trimester interaction was suggestive (P = 0.060). A significant radiation dose effect was found in the second trimester (P = 0.001), with an estimated 4.17 mmHg per Gy, but in the first and third trimesters, radiation dose effects were not significant (P > 0.50). For prevalence of systolic hypertension, the radiation dose effect was significant (P = 0.009); the odds ratio at 1 Gy was 2.23 [95% confidence interval (CI): 1.23, 4.04], and the dose by trimester interaction was not significant (P = 0.778). The dose response of systolic hypertension had no dose threshold, with a threshold point estimate of 0 Gy (95% CI: <0.0, 1.1 Gy). The dose response for systolic blood pressure was most pronounced in the second trimester, the most active organogenesis period for the organs relevant to blood pressure.

Selection bias in cancer risk estimation from A-bomb survivors.

We consider the possible bias in cancer risk estimation from A-bomb survivors due to selection of the cohort by survival. The paper considers both relevant information from the data and basic theoretical issues involved. The most direct information from the data comes from making various restrictions on the dose-distance range, partly to reduce differential selection and partly just to reduce the magnitude of the selection. These analyses suggest that there are no serious biases, but they are not conclusive. Theoretical considerations include laying out more explicitly than usual just how biases could result from the selection. This involves heterogeneities in the ability to survive acute effects, in baseline and radiogenic cancer rates, and most importantly the correlation between survival-related and cancer-related heterogeneities. Following on this, idealized modeling is used to quantify the extent of possible bias in terms of the assumed values of the magnitude of these heterogeneities and their correlation. It is indicated that these values would need to be very large to introduce substantial bias. Based on all these considerations, it seems unlikely that the bias in cancer risk estimation could be large in relation to other uncertainties in generalizing from what is seen among A-bomb survivors; in particular, indications are that the bias in relative risks is unlikely to be as large as 0.05 to 0.07. For solid cancer this would correspond to bias in the excess relative risk at 1 Sv of at most about 15-20%.

Proliferation of nuclear weapons: opportunities for control and abolition.

Nuclear weapons pose a particularly destructive threat. Prevention of the proliferation and use of nuclear weapons is urgently important to public health. "Horizontal" proliferation refers to nation-states or nonstate entities that do not have, but are acquiring, nuclear weapons or developing the capability and materials for producing them. "Vertical" proliferation refers to nation-states that do possess nuclear weapons and are increasing their stockpiles of these weapons, improving the technical sophistication or reliability of their weapons, or developing new weapons. Because nation-states or other entities that wish to use or threaten to use nuclear weapons need methods for delivering those weapons, proliferation of delivery mechanisms must also be prevented. Controlling proliferation--and ultimately abolishing nuclear weapons--involves national governments, intergovernmental organizations, nongovernmental and professional organizations, and society at large.

Dose estimation for atomic bomb survivor studies: its evolution and present status.

In the decade after the bombings of Hiroshima and Nagasaki, several large cohorts of survivors were organized for studies of radiation health effects. The U.S. Atomic Bomb Casualty Commission (ABCC) and its U.S./Japan successor, the Radiation Effects Research Foundation (RERF), have performed continuous studies since then, with extensive efforts to collect data on survivor locations and shielding and to create systems to estimate individual doses from the bombs' neutrons and gamma rays. Several successive systems have been developed by extramural working groups and collaboratively implemented by ABCC and RERF investigators. We describe the cohorts and the history and evolution of dose estimation from early efforts through the newest system, DS02, emphasizing the technical development and use of DS02. We describe procedures and data developed at RERF to implement successive systems, including revised rosters of survivors, development of methods to calculate doses for some classes of persons not fitting criteria of the basic systems, and methods to correct for bias arising from errors in calculated doses. We summarize calculated doses and illustrate their change and elaboration through the various systems for a hypothetical example case in each city. We conclude with a description of current efforts and plans for further improvements.

A dose-dependent decrease in the fraction of cases harboring M6P/IGF2R mutations in hepatocellular carcinomas from the atomic bomb survivors.

The risk for hepatocellular carcinoma (HCC) development is significantly heightened in the atomic bomb survivors, but the mechanism is unclear. We have previously reported finding a radiation dose-dependent increase in HCCs with TP53 mutations from the survivors. We now show that, in the same HCC samples, the frequency of 3'-untranslated region (3'UTR) mutations in M6P/IGF2R, a candidate HCC tumor suppressor gene, decreases with dose (P = 0.0091), implying a radiation dose-dependent negative selection of cells harboring such mutations. The fact that they were in the 3'UTR implicates changes in transcript stability rather than in protein function as the mechanism. Moreover, these M6P/IGF2R 3'UTR mutations and the TP53 mutations detected previously were mutually exclusive in most of the tumors, suggesting two independent pathways to HCC development, with the TP53 pathway being more favored with increasing radiation dose than the M6P/IGF2R pathway. These results suggest that tumors attributable to radiation may be genotypically different from tumors of other etiologies and hence may provide a way of distinguishing radiation-induced cancers from "background" cancers--a shift from the current paradigm.

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.

Around Semipalatinsk nuclear test site: progress of dose estimations relevant to the consequences of nuclear tests (a summary of 3rd Dosimetry Workshop on the Semipalatinsk nuclear test site area, RIRBM, Hiroshima University, Hiroshima, 9-11 of March, 2005).

The paper is an analytical overview of the main results presented at the 3rd Dosimetry Workshop in Hiroshima(9-11 of March 2005), where different aspects of the dose reconstruction around the Semipalatinsk nuclear test site(SNTS) were discussed and summarized. The results of the international intercomparison of the retrospective luminescence dosimetry(RLD) method for Dolon' village(Kazakhstan) were presented at the Workshop and good concurrence between dose estimations by different laboratories from 6 countries (Japan, Russia, USA, Germany, Finland and UK) was pointed out. The accumulated dose values in brick for a common depth of 10mm depth obtained independently by all participating laboratories were in good agreement for all four brick samples from Dolon' village, Kazakhstan, with the average value of the local gamma dose due to fallout (near the sampling locations) being about 220 mGy(background dose has been subtracted).Furthermore, using a conversion factor of about 2 to obtain the free-in-air dose, a value of local dose approximately 440 mGy is obtained, which supports the results of external dose calculations for Dolon': recently published soil contamination data, archive information and new models were used for refining dose calculations and the external dose in air for Dolon village was estimated to be about 500 mGy. The results of electron spin resonance(ESR) dosimetry with tooth enamel have demonstrated the notable progress in application of ESR dosimetry to the problems of dose reconstruction around the Semipalatinsk nuclear test site. At the present moment, dose estimates by the ESR method have become more consistent with calculated values and with retrospective luminescence dosimetry data, but differences between ESR dose estimates and RLD/calculation data were noted. For example mean ESR dose for eligible tooth samples from Dolon' village was estimated to be about 140 mGy(above background dose), which is less than dose values obtained by RLD and calculations. A possible explanation of the differences between ESR and RLD/calculations doses is the following: for interpretation of ESR data the "shielding and behaviour" factors for investigated persons should be taken into account. The "upper level" of the combination of "shielding and behaviour" factors of dose reduction for inhabitants of Dolon' village of about 0.28 was obtained by comparing the individual ESR tooth enamel dose estimates with the calculated mean dose for this settlement. The biological dosimetry data related to the settlements near SNTS were presented at the Workshop. A higher incidence of unstable chromosome aberrations, micronucleus in lymphocytes, nuclear abnormalities of thyroid follicular cells, T-cell receptor mutations in peripheral blood were found for exposed areas (Dolon', Sarjal) in comparison with unexposed ones(Kokpekty). The significant greater frequency of stable translocations (results of analyses of chromosome aberrations in lymphocytes by the FISH technique) was demonstrated for Dolon' village in comparison with Chekoman(unexposed village). The elevated level of stable translocations in Dolon' corresponds to a dose of about 180 mSv, which is close to the results of ESR dosimetry for this village. The importance of investigating specific morphological types of thyroid nodules for thyroid dosimetry studies was pointed out. In general the 3rd Dosimetry Workshop has demonstrated remarkable progress in developing an international level of common approaches for retrospective dose estimations around the SNTS and in understanding the tasks for the future joint work in this direction. In the framework of a special session the problems of developing a database and registry in order to support epidemiological studies around SNTS were discussed. The results of investigation of psychological consequences of nuclear tests, which are expressed in the form of verbal behaviour, were presented at this session as well.

Radiological situation in the vicinity of Semipalatinsk nuclear test site: Dolon, Mostik, Cheremushka and Budene settlements.

The present situation of radioactive contamination at the village of Dolon and nearby villages such as Mostik, Cheremushka and Budene was investigated to serve as an aid to resolve dose discrepancy between model calculations and TL measurements made for external gamma-ray dose in air in Dolon. The paper was focused on the reevaluation of the accumulated levels and distribution of long-lived radionuclides 137Cs and Pu isotopes in soil using long core samples up to a depth of 30 and 100 cm. The inventories of 137Cs and 239,240Pu found were in the wide range of 140-10,310 and 140-14,320 Bq/m2, respectively. Most of the Pu in soil was tightly incorporated into various sizes of fused particles. Both 137Cs and 239,240Pu in soil were accumulated in the smaller soil size fraction of <125 microm, and the presence of hot particles, probably due to Pu, was clearly observed by star-like patterns from alpha-tracks. The obtained data will be helpful for evaluating the current and future radiation risks to the people living around there.

External radiation in Dolon village due to local fallout from the first USSR atomic bomb test in 1949.

Dolon village, located about 60 km from the border of the Semipalatinsk Nuclear Test Site, is known to be heavily contaminated by local fallout from the first USSR atomic bomb test in 1949. External radiation in Dolon was evaluated based on recent 137Cs data in soil and calculation of temporal change in the fission product composition. After fitting a log-normal distribution to the soil data, a 137Cs deposition of 32 kBq m-2, which corresponds to the 90th-percentile of the distribution, was tentatively chosen as a value to evaluate the radiation situation in 1949. Our calculation indicated that more than 95% of the cumulative dose for 50 y had been delivered within 1 y after the deposition. The resulting cumulative dose for 1 y after the deposition, normalized to the initial contamination containing 1 kBq m-2 of 137Cs, was 15.6 mGy, assuming a fallout arrival time of 3 h and a medium level of fractionation. Finally, 0.50 Gy of absorbed dose in air was derived as our tentative estimate for 1-year cumulative external dose in Dolon due to local fallout from the first USSR test in 1949.