Establishment and activity of the planning and acting network for low dose radiation research in Japan (PLANET): 2016-2023.

The Planning and Acting Network for Low Dose Radiation Research in Japan (PLANET) was established in 2017 in response to the need for an all-Japan network of experts. It serves as an academic platform to propose strategies and facilitate collaboration to improve quantitative estimation of health risks from ionizing radiation at low-doses and low-dose-rates. PLANET established Working Group 1 (Dose-Rate Effects in Animal Experiments) to consolidate findings from animal experiments on dose-rate effects in carcinogenesis. Considering international trends in this field as well as the situation in Japan, PLANET updated its priority research areas for Japanese low-dose radiation research in 2023 to include (i) characterization of low-dose and low-dose-rate radiation risk, (ii) factors to be considered for individualization of radiation risk, (iii) biological mechanisms of low-dose and low-dose-rate radiation effects and (iv) integration of epidemiology and biology. In this context, PLANET established Working Group 2 (Dose and Dose-Rate Mapping for Radiation Risk Studies) to identify the range of doses and dose rates at which observable effects on different endpoints have been reported; Working Group 3 (Species- and Organ-Specific Dose-Rate Effects) to consider the relevance of stem cell dynamics in radiation carcinogenesis of different species and organs; and Working Group 4 (Research Mapping for Radiation-Related Carcinogenesis) to sort out relevant studies, including those on non-mutagenic effects, and to identify priority research areas. These PLANET activities will be used to improve the risk assessment and to contribute to the revision of the next main recommendations of the International Commission on Radiological Protection.

Sparing and enhancing dose protraction effects for radiation damage to the aorta of wild-type mice.

PURPOSE: Our previous work indicated the greater magnitude of damage to the thoracic aorta at 6 months after starting 5 Gy irradiation in descending order of exposure to X-rays in 25 fractions > acute X-rays > acute γ-rays > X-rays in 100 fractions ≫ chronic γ-rays, in which the limitations of the study included a lack of data for fractionated γ-ray exposure. To better understand effects of dose protraction and radiation quality, the present study examined changes after exposure to γ-rays in 25 fractions, and compared its biological effectiveness with five other irradiation regimens. MATERIALS AND METHODS: Male C57BL/6J mice received 5 Gy of 137Cs γ-rays delivered in 25 fractions spread over six weeks. At 6 months after starting irradiation, mice were subjected to echocardiography, followed by tissue sampling. The descending thoracic aorta underwent scanning electron microscopy, immunofluorescence staining and histochemical staining. The integrative analysis of multiple aortic endpoints was conducted for inter-regimen comparisons. RESULTS: Exposure to γ-rays in 25 fractions induced vascular damage (evidenced by increases in endothelial detachment and vascular endothelial cell death, decreases in endothelial waviness, CD31, endothelial nitric oxide synthase and vascular endothelial cadherin), inflammation (evidenced by increases in tumor necrosis factor α, CD68 and F4/80) and fibrosis (evidenced by increases in transforming growth factor ß1, alanine blue stain and intima-media thickness). The integrative analysis revealed biological effectiveness in descending order of exposure to X-rays in 25 fractions > acute X-rays > γ-rays in 25 fractions > acute γ-rays > X-rays in 100 fractions ≫ chronic γ-rays. CONCLUSIONS: The results suggest that dose protraction effects on aortic damage depend on radiation quality, and are not a simple function of dose rate and the number of fractions.

Thyroid cancer risk after radiation exposure in adults-systematic review and meta-analysis.

Notably, the growing use of radionuclear technology, especially in diagnostic and therapeutic procedures involving radiation exposure, raises concerns about the health effects of radiation. Although epidemiological studies have provided strong evidence for elevated thyroid cancer risk after radiation exposure in childhood, the risk of thyroid cancer associated with adult exposure remains to be investigated. We conducted a systematic review and meta-analysis of relevant studies on the risk of developing thyroid cancer after radiation exposure in adulthood. The PubMed and Web of Science databases were used to select eligible articles. After screening, a total of 15 studies were identified in which estimates of the standardized incidence ratio (SIR) and the relative risk (RR) of thyroid cancer were available in 8 and 11 studies, respectively. The overall SIR estimated by the random effects model was 2.19 [95% confidence interval (CI), 1.54, 3.10]. Cochran's Q test showed significant heterogeneity in the SIRs (Q = 178, P < 0.0001). The overall RR at 10 mGy was 1.0038 (95% CI, 0.9991, 1.0085), with no significant heterogeneity (Q = 9.30, P = 0.5041). The total SIR, as well as that from each study, indicated a statistically significant excess, which could be related to screening bias. Radiation-related thyroid cancer risk was elevated in a few studies; however, the overall estimate of the RR at 10 mGy was not significant. This study demonstrates no strong epidemiological evidence for the risk of thyroid cancer in radiation exposure during adulthood; however, further research is needed.

Car-borne survey and dose assessment from external radiation exposure in Bangka Island.

With a history of more than 200 years of tin mining, Bangka Island has brought along a byproduct of heavy minerals containing radionuclide elements. There are some concerns about this byproduct material contributing to natural radiation in the environment. In this study, a car-borne survey was conducted to accurately assess natural background radiation in Bangka Island. Indoor and outdoor ambient dose rates in 146 houses were also measured to assess the radiation dose from external exposure received by the public. Soil samples were collected and measured using a gamma spectroscopy system to evaluate the contributions of specific radionuclides to external terrestrial exposure. From 3790 measurement points during the car-borne survey, the highest ambient dose equivalent rate was 596 nSv h-1 measured in Muntok area, with a mean value of 101 nSv h-1 and a median value of 95 nSv h-1. The ambient dose equivalent rate distribution map showed a relatively higher value in the northern coastal area of the island, where the Pemali tin deposit is located. The annual effective dose received from external radiation in the 146 houses in Bangka Island ranged from 0.44 to 1.30 mSv year-1, with a median value of 0.66 mSv year-1. The soil contained a relatively high amount of thorium (232Th), which contributed 69% to external radiation exposure in Bangka Island.

Effect of exposure to radiation caused by an atomic bomb on endothelial function in atomic bomb survivors.

Background: The purpose of this study was to evaluate the effects of exposure to radiation caused by an atomic bomb in atomic bomb survivors on vascular function and vascular structure and to evaluate the relationships of radiation dose from the atomic bomb with vascular function and vascular structure in atomic bomb survivors. Methods: Flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID) as indices of vascular function, brachial-ankle pulse wave velocity (baPWV) as an index of vascular function and vascular structure, and brachial artery intima-media thickness (IMT) as an index of vascular structure were measured in 131 atomic bomb survivors and 1,153 control subjects who were not exposed to the atomic bomb. Ten of the 131 atomic bomb survivors with estimated radiation dose in a cohort study of Atomic Bomb Survivors in Hiroshima were enrolled in the study to evaluate the relationships of radiation dose from the atomic bomb with vascular function and vascular structure. Results: There was no significant difference in FMD, NID, baPWV, or brachial artery IMT between control subjects and atomic bomb survivors. After adjustment of confounding factors, there was still no significant difference in FMD, NID, baPWV, or brachial artery IMT between control subjects and atomic bomb survivors. Radiation dose from the atomic bomb was negatively correlated with FMD (ρ = -0.73, P = 0.02), whereas radiation dose was not correlated with NID, baPWV or brachial artery IMT. Conclusion: There were no significant differences in vascular function and vascular structure between control subjects and atomic bomb survivors. Radiation dose from the atomic bomb might be negatively correlated with endothelial function.

[Relationship between radiation knowledge and radiation effect anxiety on the next generation: An analysis of a questionnaire survey disseminated to residents in Fukushima Prefecture].

Objectives　Since the Fukushima Daiichi Nuclear Power Plant accident caused by the Great East Japan Earthquake, many people in Fukushima Prefecture have been concerned about the effects of radiation on their offspring. Although this fear should be relieved since no epidemiological study has shown evidential cases, situations wherein some people misunderstood the existence of evidence have been independently reported. Therefore, in this study, we examined the relationship between radiation knowledge and anxiety about radiation-based genetic effects using a survey mailed to residents in Fukushima Prefecture.Methods　In August 2016, we attempted to contact 2,000 people aged 20 to 79 years in Fukushima Prefecture through a survey distributed by mail inquiring about residents' health. We received 861 responses. Respondents selected their level of concern about radiation effects on the next generation on a four-point scale and answered five knowledge questions about radiation effects and protection. Responses were "correct," "incorrect," or "not sure." After adjusting according to residential area, family configuration, age, sex, academic background, media used, and trusted information source, we conducted multiple regression analyses to investigate the relationship between the level of concern and answers to the knowledge questions.Results　People who answered the knowledge questions more correctly had lower levels of anxiety. The number of "not sure" responses was unrelated to anxiety level. The results indicated that correct answers to questions related to radiation residuals in the body and genetic effects were negatively associated with anxiety. Incorrect answers to the question about genetic effects and another related to cell repair systems were positively associated with anxiety. Moreover, while a correct answer to another question related to the linear threshold model had a positive association, the association was insignificant. Further, any response related to radiation reference values in foods showed no association.Conclusion　Based on these results, we observed an association between the number of respondents with a correct knowledge of radiation and the degree of anxiety about radiation effects on the next generation. However, this relationship and its strength varied depending on the specific knowledge content. As a limitation of this study, the study could not establish any causality. Further studies, such as prospective interventional studies, should be conducted.

Oxidative Modification Status of Human Serum Albumin Caused by Chronic Low-Dose Radiation Exposure in Mamuju, Sulawesi, Indonesia.

The recently discovered high-level natural background radiation area (HBRA) of Mamuju in Indonesia provides a unique opportunity to study the biological effects of chronic low-dose radiation exposure on a human population. The mean total effective dose in the HBRA was approximately 69.6 mSv y-1 (range: 47.1 to 115.2 mSv y-1), based on a re-evaluation of the individual radiation exposure dose; therefore, proteomic analyses of serum components and oxidative modification profiling of residents living in the HBRA were reconducted using liquid chromatography-tandem mass spectrometry. The analysis of the oxidative modification sequences of human serum albumin revealed significant moderate correlations between the radiation dose and the modification of 12 sequences, especially the 111th methionine, 162nd tyrosine, 356th tyrosine, and 470th methionine residues. In addition, a dose-dependent variation in 15 proteins of the serum components was detected in the serum of residents exposed to chronic low-dose radiation. These findings suggest that the alterations in the expression of specific proteins and the oxidative modification responses of serum albumin found in exposed humans may be important indicators for considering the effects of chronic low-dose radiation exposure on living organisms, implying their potential utility as biomarkers of radiation dose estimation.

Detection of biological responses to low-dose radiation in humans.

It has been considered difficult to detect the biological effects of low-dose radiation exposure below approximately 100 mSv in humans. Serum proteomic analysis and oxidative modification profiling were conducted with blood samples collected from residents of a newly discovered high-level natural background radiation area (annual effective dose approximately 50 mSv y-1) and normal-level area (1.22 mSv y-1) in Mamuju, Indonesia, where many people have been living for generations. Dose-dependent oxidative modifications in amino acid sequences of human serum albumin, especially the 162nd and 356th tyrosine residues and 111th and 470th methionine residues, were found. None of these findings have been reported in humans exposed to chronic low-dose radiation. It can be used as a biomarker not only for the assessment of the presence or absence of radiation exposure but also for dose prediction in living organisms for chronic radiation. These results suggest that traces of radiation exposure are recorded in serum albumin and that there is a possibility of a new methodology that can evaluate biological responses below 100 mSv.

The First Attempt to Reevaluate Radon and Thoron Exposure in Gansu Province Study Using Radon-Thoron Discriminating Measurement Technique.

Although the epidemiological studies provide evidence for an increased risk of lung cancer risk associated with residential radon, an issue of radon-thoron discrimination remains to be solved. In this study, an updated evaluation of lung cancer risk among the residents in Gansu, China was performed where one of the major epidemiological studies on indoor radon demonstrated an increased risk of lung cancer. We analyzed data from a hospital-based case-control study that included 30 lung cancer cases and 39 controls with special attention to internal exposure assessment based on the discriminative measurement technique of radon isotopes. Results from the analyses showed non-significant increased lung cancer risks; odds ratios (ORs) adjusted for age, smoking, and total income were 0.35 (95% CI: 0.07-1.74) and 0.27 (95% CI: 0.04-1.74) for groups living in residences with indoor radon concentrations of 50-100 Bq m-3 and over 100 Bq m-3, respectively, compared with those with < 50 Bq m-3 indoor radon concentrations. Although the small sample size hampers the usefulness of present analyses, our study suggests that reevaluation of lung cancer risk associated with residential radon in the epidemiological studies will be required on the basis of precise exposure assessment.

Comprehensive exposure assessments from the viewpoint of health in a unique high natural background radiation area, Mamuju, Indonesia.

Mamuju is one of the regions in Indonesia which retains natural conditions but has relatively high exposure to natural radiation. The goals of the present study were to characterize exposure of the entire Mamuju region as a high natural background radiation area (HNBRA) and to assess the existing exposure as a means for radiation protection of the public and the environment. A cross-sectional study method was used with cluster sampling areas by measuring all parameters that contribute to external and internal radiation exposures. It was determined that Mamuju was a unique HNBRA with the annual effective dose between 17 and 115 mSv, with an average of 32 mSv. The lifetime cumulative dose calculation suggested that Mamuju residents could receive as much as 2.2 Sv on average which is much higher than the average dose of atomic bomb survivors for which risks of cancer and non-cancer diseases are demonstrated. The study results are new scientific data allowing better understanding of health effects related to chronic low-dose-rate radiation exposure and they can be used as the main input in a future epidemiology study.

Prospects and status of the dosimetry system for atomic bomb survivor cohort study conducted at Research Institute for Radiation Biology and Medicine of Hiroshima University.

The Research Institute for Radiation Biology and Medicine (RIRBM) of Hiroshima University has been conducting a cohort study of atomic bomb survivors (ABS). Cohort members include those who were issued an Atomic Bomb Health Handbook from the Hiroshima local government. A series of dosimetry systems for the ABS were developed at RIRBM to evaluate the health effects associated with radiation exposure. The framework used to estimate individual doses in our dosimetry systems for ABS is mainly based on the Dosimetry System 86, and its revisions developed by the Radiation Effect Research Foundation. This article describes the design and computational principles for the dosimetry systems in RIRBM and the history of the revisions, from the first version of the system, ABS93D, to the most recent version, ABS16D. We then provide a perspective for further improvement and application of the dosimetry system.

The Effect and Effectiveness of Decontaminating a Pond in a Residential Area of Fukushima.

ABSTRACT: Special reconstruction and revitalization bases were designated in Fukushima's difficult-to-return zone by the Japanese government as targets of intensive decontamination to drastically lower air dose rates and enable residents to return. A pond amid residences of one of these bases was targeted for decontamination, and this study aimed at evaluating the effect and effectiveness of the decontamination using decontamination factor, air dose rate reduction factor, and the additional annual effective dose to residents. Air dose rates were measured in situ with the second-generation Kyoto University Radiation Mapping system, while soil core samples were collected and measured for radioactivity in the laboratory by gamma spectrometry. Lower decontamination factors were observed for more deeply distributed radiocesium soil profiles, whereas areas covered with gravel demonstrated the largest reduction in air dose rates. Decontamination effectively lowered the radiocesium inventory and air dose rates by 51-93% and 37-91%, respectively. Moreover, the additional annual effective dose to the public changed from 1.7 ± 0.79 mSv to 1.2 ± 0.57 mSv because of decontamination representing a dose aversion of 29%. These findings demonstrate how decontaminating ponds in residential areas can help to further lower the external exposure.

Lens opacity prevalence among the residents in high natural background radiation area in Yangjiang, China.

The aim of the study was to evaluate the risk and threshold doses of lens opacity among residents exposed to low-dose radiation. Residents aged ≥45 years were recruited from a high natural background radiation (HNBR) area in Yangjiang City and a control area selected from nearby Enping City. Lens opacities (LOPs) were classified according to the Lens Opacities Classification System (LOCS) III system. Face-to-face interviews were conducted to collect information on lifestyles, migration and medical history. Life-time cumulative doses were estimated using gender, age, occupancy factors and environmental radiation doses received indoors and outdoors. Logistic regression analyses were conducted to estimate the dose response and determine thresholds. In the HNBR area, among 479 study participants, 101 (21.1%), 245(51.1%) and 23 cases (4.8%), respectively, of cortical, nuclear and posterior subcapsular (PSC) LOPs were found. In the control area, those types of LOPs were identified among 58 cases (12.6%), 206 cases (51.2%) and 6 cases (1.3%) of 462 examinees, respectively. Cumulative eye lens dose was estimated to be 189.5 ± 36.5 mGy in the HNBR area. Logistic analyses gave odds ratios at 100 mGy of 1.26 [95% confidence interval (CI) 1.00-1.60], 0.81 (95% CI 0.64-1.01) and 1.73 (95% CI 1.05-2.85) for cortical, nuclear and PSC LOPs, respectively. For cortical LOPs, a logistic analysis with a threshold dose gave a threshold estimate of 140 mGy (90% CI 110-160 mGy). The results indicated that population exposed to life-time, low-dose-rate environmental radiation was at an elevated risk of cortical and PSC LOPs. A statistically significant threshold dose was obtained for cortical LOPs and no threshold dose for PSC LOPs.

A unique high natural background radiation area - Dose assessment and perspectives.

The biological effects of low dose-rate radiation exposures on humans remains unknown. In fact, the Japanese nation still struggles with this issue after the Fukushima Dai-ichi Nuclear Power Plant accident. Recently, we have found a unique area in Indonesia where naturally high radiation levels are present, resulting in chronic low dose-rate radiation exposures. We aimed to estimate the comprehensive dose due to internal and external exposures at the particularly high natural radiation area, and to discuss the enhancement mechanism of radon. A car-borne survey was conducted to estimate the external doses from terrestrial radiation. Indoor radon measurements were made in 47 dwellings over three to five months, covering the two typical seasons, to estimate the internal doses. Atmospheric radon gases were simultaneously collected at several heights to evaluate the vertical distribution. The absorbed dose rates in air in the study area vary widely between 50 nGy h-1 and 1109 nGy h-1. Indoor radon concentrations ranged from 124 Bq m-3 to 1015 Bq m-3. That is, the indoor radon concentrations measured exceed the reference levels of 100 Bq m-3 recommended by the World Health Organization. Furthermore, the outdoor radon concentrations measured were comparable to the high indoor radon concentrations. The annual effective dose due to external and internal exposures in the study area was estimated to be 27 mSv using the median values. It was found that many residents are receiving radiation exposure from natural radionuclides over the dose limit for occupational exposure to radiation workers. This enhanced outdoor radon concentration might be as a result of the stable atmospheric conditions generated at an exceptionally low altitude. Our findings suggest that this area provides a unique opportunity to conduct an epidemiological study related to health effects due to chronic low dose-rate radiation exposure.

Secondary bone/soft tissue sarcoma in childhood cancer survivors: a nationwide hospital-based case-series study in Japan.

BACKGROUND: Secondary cancer is the most life-threatening late effect of childhood cancer. We investigated the clinical features of secondary bone/soft tissue sarcoma among childhood cancer survivors (CCSs). METHODS: We conducted a retrospective case-series study of 10 069 CCSs newly diagnosed with cancer between 1980 and 2009 across 15 Japanese hospitals. Twenty-one cases of pathologically diagnosed secondary bone/soft tissue sarcoma were selected, and the respective clinical courses were determined using additional questionnaires. RESULTS: The primary cancers included retinoblastoma (n = 7), acute lymphoblastic leukemia (n = 5), lymphoma (n = 5), osteosarcoma (n = 1), rhabdomyosarcoma (n = 1), brain tumor (n = 1) and Langerhans cell histiocytosis (n = 1). The median age at the primary cancer diagnosis was 2.9 years, and the male-to-female ratio was 16:5. The histological classifications of the secondary sarcoma included osteosarcoma (n = 10), malignant peripheral nerve sheath tumor (n = 4), rhabdomyosarcoma (n = 3), Ewing's sarcoma (n = 3) and primitive neuroectodermal tumor (n = 1). The median latency period to the secondary sarcoma was 10.2 years. Significant risk factors for secondary sarcoma in the multivariate Cox regression model included a history of retinoblastoma as the primary cancer (hazard ratio [HR], 20.9; 95% confidence interval [CI], 5.70-76.5) and autologous stem cell transplantation (SCT) (HR, 2.56; 95% CI, 1.08-6.03). Seventeen CCSs with secondary sarcoma underwent radiation, and nine, hematopoietic SCT. Twelve CCSs with secondary sarcoma achieved disease-free survival, while CCSs with hematological cancer or relapsed primary cancer who developed secondary sarcoma had the worst prognoses. CONCLUSION: The prognoses of CCSs with secondary sarcoma may depend on the primary cancer or prior relapse of primary cancer.

Secondary cancer after a childhood cancer diagnosis: viewpoints considering primary cancer.

BACKGROUNDS: Multidisciplinary therapy has increased the risk of subsequent late effects, but detailed analyses on secondary cancers in childhood cancer survivors (CCSs) are limited in Asian countries. METHODS: This was a retrospective cohort study comprising 10,069 CCSs who were diagnosed between 1980 and 2009 across 15 Japanese hospitals. We conducted secondary analyses to estimate the incidence of secondary cancer according to each primary malignancy and to elucidate the association between primary and secondary cancers. We also explored the risk factors for the development of secondary cancer in each independent primary malignancy. RESULTS: The cumulative incidence of secondary cancer at 20 years varied among primary cancers: hematological malignancy, 3.1% (95% CI 2.2-4.3); retinoblastoma, 6.6% (95% CI 1.5-16.8); pediatric solid tumor, 2.5% (95% CI 1.3-4.2); brain tumors, 5.2% (95% CI 1.7-11.8) bone/soft tissue sarcoma, 5.2% (95% CI 2.3-10.1); and others, 3.3% (95% CI 1.6-6.0) (p = 0.015). The cumulative incidence of secondary cancers is highest in those with osteosarcoma (13.1%) followed by those with hepatoblastoma (8.4%) and retinoblastoma (6.6%). Close association between the primary and secondary cancer diagnoses was found. The risk factors for secondary cancer development depended on the primary cancer, but autologous/allogeneic stem cell transplantation was a relatively common risk factor. CONCLUSION: The cumulative incidence of secondary cancer varied among primary cancers. The primary cancer was closely associated with the secondary cancer but stem cell transplantation was a common risk factor for secondary cancers among CCSs.

Biological measures to minimize the risk of radiotherapy-associated second cancer: A research perspective.

Purpose Second cancers are among the most serious sequelae for cancer survivors who receive radiotherapy. This article aims to review current knowledge regarding how the risk of radiotherapy-associated second cancer can be minimized by biological measures and to discuss relevant research needs. Results The risk of second cancer can be reduced not only by physical measures to decrease the radiation dose to normal tissues but also by biological means that interfere with the critical determinants of radiation-induced carcinogenesis. Requirements for such biological means include the targeting of tumor types relevant to radiotherapy-associated risk, concrete safety and efficacy evidence and feasibility and minimal invasiveness. Mechanistic insights into the process of radiation carcinogenesis provide rational approaches to minimize the risk. Five mechanism-based strategies are proposed herein based on the current state of knowledge. Epidemiological studies on the joint effects of radiation and lifestyle or other factors can provide evidence for factors that modify radiation-associated risks if deliberately controlled. Conclusions Mechanistic and epidemiological evidence indicates that it is possible to develop interventional measures to minimize the second cancer risk associated with radiotherapy. Research is needed regarding the critical determinants of radiation-induced carcinogenesis available for intervention and joint effects of radiation and controllable factors.

Secondary cancers after a childhood cancer diagnosis: a nationwide hospital-based retrospective cohort study in Japan.

BACKGROUND: The epidemiology of secondary cancers in childhood cancer survivors has been unknown in Asian countries. Our aim is to assess the incidence and risk factors for secondary cancers through a nationwide survey in Japan. METHODS: A retrospective cohort study comprising 10,069 children who were diagnosed with cancer between 1980 and 2009 was conducted in 15 Japanese hospitals. The cumulative incidence rate was calculated using death as the competing risk and compared by the Gray method. The standardized incidence ratio (SIR) was defined as the ratio of the number of observed cancers divided by the number of expected cancers. The risk factors were analyzed using Cox regression analysis. RESULTS: One hundred and twenty-eight patients (1.3 %) developed secondary cancers within a median follow-up of 8.4 years. The cumulative incidence rate was 1.1 % (95 % confidence interval [CI] 0.9-1.4) at 10 years and 2.6 % (95 % CI 2.1-3.3) at 20 years after primary cancer diagnosis. Sensitivity analysis, limited to 5-year survivors (n = 5,387), confirmed these low incidence rates. The SIR of secondary cancers was 12.1 (95 % CI 10.1-14.4). In the Cox analysis, the hazard ratios for secondary cancers were 3.81 (95 % CI 1.53-9.47) for retinoblastoma, 2.78 (95 % CI 1.44-5.38) for bone/soft tissue sarcomas, and 1.81 (95 % CI 1.16-2.83) for allogeneic stem cell transplantation. CONCLUSIONS: The cumulative incidence of secondary cancers in children in Japan was not high; however, the SIR was relatively high. Retinoblastoma or sarcoma in addition to allogeneic stem cell transplantation were significant risk factors for secondary cancers.

Methodological extensions of meta-analysis with excess relative risk estimates: application to risk of second malignant neoplasms among childhood cancer survivors treated with radiotherapy.

Although radiotherapy is recognized as an established risk factor for second malignant neoplasms (SMNs), the dose response of SMNs following radiotherapy has not been well characterized. In our previous meta-analysis of the risks of SMNs occurring among children who have received radiotherapy, the small number of eligible studies precluded a detailed evaluation. Therefore, to increase the number of eligible studies, we developed a method of calculating excess relative risk (ERR) per Gy estimates from studies for which the relative risk estimates for several dose categories were available. Comparing the calculated ERR with that described in several original papers validated the proposed method. This enabled us to increase the number of studies, which we used to conduct a meta-analysis. The overall ERR per Gy estimate of radiotherapy over 26 relevant studies was 0.60 (95%CI: 0.30-1.20), which is smaller than the corresponding estimate for atomic bomb survivors exposed to radiation as young children (1.7; 95% CI: 1.1-2.5). A significant decrease in ERR per Gy with increase in age at exposure (0.85 times per annual increase) was observed in the meta-regression. Heterogeneity was suggested by Cochran's Q statistic (P < 0.001), which may be partly accounted for by age at exposure.

Combined exposure to X-irradiation followed by N-ethyl-N-nitrosourea treatment alters the frequency and spectrum of Ikaros point mutations in murine T-cell lymphoma.

Ionizing radiation is a well-known carcinogen, but its potency may be influenced by other environmental carcinogens, which is of practical importance in the assessment of risk. Data are scarce, however, on the combined effect of radiation with other environmental carcinogens and the underlying mechanisms involved. We studied the mode and mechanism of the carcinogenic effect of radiation in combination with N-ethyl-N-nitrosourea (ENU) using doses approximately equal to the corresponding thresholds. B6C3F1 mice exposed to fractionated X-irradiation (Kaplan's method) followed by ENU developed T-cell lymphomas in a dose-dependent manner. Radiation doses above an apparent threshold acted synergistically with ENU to promote lymphoma development, whereas radiation doses below that threshold antagonized lymphoma development. Ikaros, which regulates the commitment and differentiation of lymphoid lineage cells, is a critical tumor suppressor gene frequently altered in both human and mouse lymphomas and shows distinct mutation spectra between X-ray- and ENU-induced lymphomas. In the synergistically induced lymphomas, we observed a low frequency of LOH and an inordinate increase of Ikaros base substitutions characteristic of ENU-induced point mutations, G:C to A:T at non-CpG, A:T to G:C, G:C to T:A and A:T to T:A. This suggests that radiation doses above an apparent threshold activate the ENU mutagenic pathway. This is the first report on the carcinogenic mechanism elicited by combined exposure to carcinogens below and above threshold doses based on the mutation spectrum of the causative gene. These findings constitute a basis for assessing human cancer risk following exposure to multiple carcinogens.