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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.
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Rev1 has two important functions in the translesion synthesis pathway, including dCMP transferase activity, and acts as a scaffolding protein for other polymerases involved in translesion synthesis. However, the role of Rev1 in mutagenesis and tumorigenesis in vivo remains unclear. We previously generated Rev1-overexpressing (Rev1-Tg) mice and reported that they exhibited a significantly increased incidence of intestinal adenoma and thymic lymphoma (TL) after N-methyl-N-nitrosourea (MNU) treatment. In this study, we investigated mutagenesis of MNU-induced TL tumorigenesis in wild-type (WT) and Rev1-Tg mice using diverse approaches, including whole-exome sequencing (WES). In Rev1-Tg TLs, the mutation frequency was higher than that in WT TL in most cases. However, no difference in the number of nonsynonymous mutations in the Catalogue of Somatic Mutations in Cancer (COSMIC) genes was observed, and mutations involved in Notch1 and MAPK signaling were similarly detected in both TLs. Mutational signature analysis of WT and Rev1-Tg TLs revealed cosine similarity with COSMIC mutational SBS5 (aging-related) and SBS11 (alkylation-related). Interestingly, the total number of mutations, but not the genotypes of WT and Rev1-Tg, was positively correlated with the relative contribution of SBS5 in individual TLs, suggesting that genetic instability could be accelerated in Rev1-Tg TLs. Finally, we demonstrated that preleukemic cells could be detected earlier in Rev1-Tg mice than in WT mice, following MNU treatment. In conclusion, Rev1 overexpression accelerates mutagenesis and increases the incidence of MNU-induced TL by shortening the latency period, which may be associated with more frequent DNA damage-induced genetic instability.
Asunto(s)
ADN Polimerasa Dirigida por ADN , Metilnitrosourea , Mutagénesis , Nucleotidiltransferasas , Neoplasias del Timo , Animales , Ratones , ADN Polimerasa Dirigida por ADN/genética , ADN Polimerasa Dirigida por ADN/metabolismo , Secuenciación del Exoma , Linfoma/genética , Linfoma/inducido químicamente , Linfoma/patología , Metilnitrosourea/toxicidad , Ratones Transgénicos , Mutación , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Neoplasias del Timo/genética , Neoplasias del Timo/inducido químicamente , Neoplasias del Timo/patologíaRESUMEN
Mouse models are vital for assessing risk from environmental carcinogens, including ionizing radiation, yet the interspecies difference in the dose response precludes direct application of experimental evidence to humans. Herein, we take a mathematical approach to delineate the mechanism underlying the human-mouse difference in radiation-related cancer risk. We used a multistage carcinogenesis model assuming a mutational action of radiation to analyze previous data on cancer mortality in the Japanese atomic bomb survivors and in lifespan mouse experiments. Theoretically, the model predicted that exposure will chronologically shift the age-related increase in cancer risk forward by a period corresponding to the time in which the spontaneous mutational process generates the same mutational burden as that the exposure generates. This model appropriately fitted both human and mouse data and suggested a linear dose response for the time shift. The effect per dose decreased with increasing age at exposure similarly between humans and mice on a per-lifespan basis (0.72- and 0.71-fold, respectively, for every tenth lifetime). The time shift per dose was larger by two orders of magnitude in humans (7.8 and 0.046 years per Gy for humans and mice, respectively, when exposed at ~35% of their lifetime). The difference was mostly explained by the two orders of magnitude difference in spontaneous somatic mutation rates between the species plus the species-independent radiation-induced mutation rate. Thus, the findings delineate the mechanism underlying the interspecies difference in radiation-associated cancer mortality and may lead to the use of experimental evidence for risk prediction in humans.
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Carcinogénesis , Neoplasias Inducidas por Radiación , Animales , Ratones , Neoplasias Inducidas por Radiación/mortalidad , Neoplasias Inducidas por Radiación/genética , Neoplasias Inducidas por Radiación/etiología , Humanos , Carcinogénesis/efectos de la radiación , Mutación , Relación Dosis-Respuesta en la Radiación , Modelos Teóricos , Supervivientes a la Bomba Atómica , Especificidad de la Especie , Radiación Ionizante , Femenino , MasculinoRESUMEN
While epidemiological data are available for the dose and dose-rate effectiveness factor (DDREF) for human populations, animal models have contributed significantly to providing quantitative data with mechanistic insights. The aim of the current review is to compile both the in vitro experiments with reference to the dose-rate effects of DNA damage and repair, and the animal studies, specific to rodents, with reference to the dose-rate effects of cancer development. In particular, the review focuses especially on the results pertaining to underlying biological mechanisms and discusses their possible involvement in the process of radiation-induced carcinogenesis. Because the concept of adverse outcome pathway (AOP) together with the key events has been considered as a clue to estimate radiation risks at low doses and low dose-rates, the review scrutinized the dose-rate dependency of the key events related to carcinogenesis, which enables us to unify the underlying critical mechanisms to establish a connection between animal experimental studies with human epidemiological studies.
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Glándulas Mamarias Humanas , Neoplasias Inducidas por Radiación , Exposición a la Radiación , Animales , Humanos , Relación Dosis-Respuesta en la Radiación , Neoplasias Inducidas por Radiación/etiología , Medición de Riesgo/métodos , Exposición a la Radiación/efectos adversos , Carcinogénesis , Modelos Animales , Tracto GastrointestinalRESUMEN
While epidemiological data have greatly contributed to the estimation of the dose and dose-rate effectiveness factor (DDREF) for human populations, studies using animal models have made significant contributions to provide quantitative data with mechanistic insights. The current article aims at compiling the animal studies, specific to rodents, with reference to the dose-rate effects of cancer development. This review focuses specifically on the results that explain the biological mechanisms underlying dose-rate effects and their potential involvement in radiation-induced carcinogenic processes. Since the adverse outcome pathway (AOP) concept together with the key events holds promise for improving the estimation of radiation risk at low doses and low dose-rates, the review intends to scrutinize dose-rate dependency of the key events in animal models and to consider novel key events involved in the dose-rate effects, which enables identification of important underlying mechanisms for linking animal experimental and human epidemiological studies in a unified manner.
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Sistema Hematopoyético , Neoplasias Inducidas por Radiación , Exposición a la Radiación , Animales , Humanos , Dosis de Radiación , Medición de Riesgo/métodos , Exposición a la Radiación/efectos adversos , Modelos Animales , Hígado , Pulmón , Relación Dosis-Respuesta en la RadiaciónRESUMEN
Age at exposure is a major modifier of radiation-induced carcinogenesis. We used mouse models to elucidate the mechanism underlying age-related susceptibility to radiation-induced tumorigenesis. Radiation exposure in infants was effective at inducing tumors in B6/B6-Chr18MSM-F1 ApcMin/+ mice. Loss of heterozygosity analysis revealed that interstitial deletion may be considered a radiation signature in this model and tumor number containing a deletion correlated with the susceptibility to radiation-induced tumorigenesis as a function of age. Furthermore, in Lgr5-eGFP-ires-CreERT2; Apcflox/flox mice, deletions of both floxed Apc alleles in Lgr5-positive stem cells in infants resulted in the formation of more tumors than in adults. These results suggest that tumorigenicity of Apc-deficient stem cells varies with age and is higher in infant mice. Three-dimensional immunostaining analyses indicated that the crypt architecture in the intestine of infants was immature and different from that in adults concerning crypt size and the number of stem cells and Paneth cells per crypt. Interestingly, the frequency of crypt fission correlated with the susceptibility to radiation-induced tumorigenesis as a function of age. During crypt fission, the percentage of crypts with lysozyme-positive mature Paneth cells was lower in infants than that in adults, whereas no difference in the behavior of stem cells or Paneth cells was observed regardless of age. These data suggest that morphological dynamics in intestinal crypts affect age-dependent susceptibility to radiation-induced tumorigenesis; oncogenic mutations in infant stem cells resulting from radiation exposure may acquire an increased proliferative potential for tumor induction compared with that in adults.
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Intestinos , Células Madre , Ratones , Animales , Intestinos/patología , Células Madre/patología , Carcinogénesis/genética , Carcinogénesis/patología , Mucosa IntestinalRESUMEN
The uncertain cancer risk of protracted radiation exposure at low dose rates is an important issue in radiological protection. Tissue stem/progenitor cells are a supposed origin of cancer and may contribute to the dose-rate effect on carcinogenesis. The authors have shown that female rats subjected to continuous whole body γ irradiation as juveniles or young adults have a notably reduced incidence of mammary cancer as compared with those irradiated acutely. Experiments using the mammosphere formation assay suggested the presence of radioresistant progenitor cells. Cell sorting indicated that basal progenitor cells in rat mammary gland were more resistant than luminal progenitors to killing by acute radiation, especially at high doses. Thus, the evidence indicates a cell-type-dependent inactivation of mammary cells that manifests only at high acute doses, implying a link to the observed dose-rate effect on carcinogenesis.
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Exposición a la Radiación , Protección Radiológica , Animales , Carcinogénesis , Transformación Celular Neoplásica , Femenino , Glándulas Mamarias Animales/efectos de la radiación , Células Madre/efectos de la radiaciónRESUMEN
Since the Fukushima Dai-ichi Nuclear Power Plant (F1-NPP) accident in 2011, radiation effects on wildlife in the contaminated areas have been a major concern. The outskirts of the F1-NPP are mainly rural areas, where many rice fields, streams and reservoirs are located. We searched for wild medaka (small aquarium fish) around the F1-NPP and found two wild medaka habitats (S1 and S2). S1 is a stream located 4 km from the F1-NPP, where the ambient dose equivalent rate was 0.4-0.9 µSv/h (2013-14), and S2 is a reservoir located 7.5 km from the F1-NPP, where the ambient dose equivalent rate was 9.8-22 µSv/h (2013-14 and 2017-18). Dosimeters were placed for one day at the locations where the medaka were captured, and the absorbed dose rates were estimated. Radiation effects on wild medaka were examined using micronucleus assay between 2013 and 2018. No significant difference in frequency of micronucleated gill cells was observed among the wild medaka from S1, S2 and our cultivated medaka that were used as a control.
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Accidente Nuclear de Fukushima , Pruebas de Micronúcleos , Plantas de Energía Nuclear , Oryzias/fisiología , Animales , Relación Dosis-Respuesta en la Radiación , AguaRESUMEN
Uncertainties due to confounding factors in epidemiological studies have limited our knowledge of the effects of low-dose-rate chronic exposure on human health. Animal experiments, wherein each subject is considered to be nearly identical, can complement the limitations of epidemiological studies. Therefore, we conducted a joint analysis of previously published cancer mortality data in B6C3F1 female mice chronically and acutely irradiated with 137Cs γ rays to estimate the dose-rate effectiveness factor. In the chronically irradiated animal experiment conducted by the Institute for Environmental Sciences, mice received irradiation at dose rates of 0.05, 1.1 or 21 mGy per day for 400 days from 8 weeks of age. For the acutely irradiated animal experiment conducted by the National Institute of Radiological Sciences, mice received irradiation at 35, 105, 240 or 365 days of age with 1.9, 3.8 or 5.9 Gy at a dose rate of 0.98 Gy per min. Because the preliminary analyses suggested that the risk was dependent on the age at exposure, a model was applied that considered risk differences depending on this factor. The model analysis revealed a three-fold, significantly decreased risk per Gy in mice exposed to 21 mGy per day compared to that in acutely irradiated mice. This resulted in a dose-rate effectiveness factor larger than that reported previously.
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Radioisótopos de Cesio , Rayos gamma/efectos adversos , Neoplasias Inducidas por Radiación/mortalidad , Exposición a la Radiación/efectos adversos , Factores de Edad , Animales , Cruzamientos Genéticos , Relación Dosis-Respuesta en la Radiación , Femenino , Estimación de Kaplan-Meier , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Modelos Biológicos , Riesgo , Organismos Libres de Patógenos EspecíficosRESUMEN
Purpose: The aim of this study was to establish a new method of real-time, in vivo detection of radiation damage and recovery. Methods: The thymus was observed under fluorescent light in a green fluorescent protein transgenic medaka. After irradiation, medaka thymus images were analyzed to quantify the effects of radiation by measuring changes in thymus size. A single acute irradiation of X-rays (0-30 Gy) or heavy Fe ions (0-10 Gy) was delivered to the medaka. Images were captured 0, 1, 2, 3, 5, 7, 11, and 21 d after irradiation. Dose-response assessment was conducted to provide a direct measurement of the effects of the radiation. Conclusion: A biomonitoring system to detect the effects of radiation in real time was established. Using this system, the threshold doses for the induction of thymic atrophy by acute X-rays and Fe ions were 2-5 Gy and 0.5-1 Gy, respectively. The Relative Biological Effectiveness (RBE) of Fe-ion to X-rays was estimated to be around 3. This system may be used to evaluate the risk from concurrent exposure to hazards, such as chemicals and radiation, and for aging research.
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Timo/efectos de la radiación , Animales , Animales Modificados Genéticamente , Relación Dosis-Respuesta en la Radiación , Proteínas Fluorescentes Verdes , Dosificación Letal Mediana , OryziasRESUMEN
Although the risk of breast cancer after high-dose-rate irradiation has been firmly established, however, the risk incurred for low-dose-rate irradiation is not well understood. Here we provide experimental evidence for dose rate and age dependencies induced by continuous γ-ray irradiation on mammary carcinogenesis. Female rats received continuous whole-body irradiation at one of the following time points: at 7 weeks of age (denoted adults) at a dose rate of 3-60 mGy/h (4 Gy total); or at either 3 weeks (denoted juveniles) or 7 weeks of age at a dose rate of 6 mGy/h (1-8 Gy total). Additional rats were acutely irradiated at 13 weeks of age at a dose rate of 30 Gy/h (0.5-4 Gy total). We observed the incidence of mammary tumors by weekly palpation until they were 90 weeks old and after pathological inspection upon autopsy. The tumor incidence rate for each group was characterized by Cox regression analysis. When adult rats were irradiated at 60 mGy/h for a total of 4 Gy, their hazard ratio for mammary carcinoma significantly increased relative to nonirradiated controls; however, for adult rats irradiated at 3-24 mGy/h, even though they also received a total of 4 Gy, their hazard ratio for carcinoma incidence did not significantly increase. A larger increase in the incidence rate of carcinoma per dose was found for the juveniles than for the adults irradiated at 6 mGy/h, whereas age did not influence the effect of acute irradiation at 30 Gy/h; a threshold-like dose response was observed for irradiation at 6 mGy/h (threshold, â¼2.5 and â¼4 Gy for juveniles and adults, respectively). Regarding benign tumors of the mammary gland, a significant increase in their incidence was observed for irradiation down to 6 mGy/h, but not at 3 mGy/h and there was no evidence of age-dependent induction. Thus, induction of female rat mammary carcinogenesis by continuous γ-ray exposure was age dependent and drastically increased for adult rats that received between 24 and 60 mGy/h irradiation.
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Envejecimiento , Carcinogénesis/efectos de la radiación , Rayos gamma/efectos adversos , Neoplasias Mamarias Experimentales/patología , Neoplasias Mamarias Experimentales/fisiopatología , Animales , Relación Dosis-Respuesta en la Radiación , Femenino , Modelos Lineales , Ratas , Ratas Sprague-DawleyRESUMEN
The relative biological effectiveness (RBE) of neutrons depends on their physical nature (e.g., energy) and the biological context (e.g., end points, materials). From the perspective of radiological protection, age is an important biological context that influences radiation-related cancer risk, but very few studies have addressed its potential impact on neutron effects. We therefore investigated the influence of age on the effect of accelerator-generated fast neutrons (mean energy, â¼2 MeV) in an animal model of breast carcinogenesis. Female Sprague-Dawley rats at 1, 3 and 7 weeks of age were irradiated with fast neutrons at absorbed doses of 0.0485-0.97 Gy. All animals were kept under specific pathogen-free conditions and screened weekly for mammary tumors by palpation until they were 90 weeks old. Tumors were diagnosed based on histology. Mathematical modeling was used to analyze mammary cancer incidence, collectively using data from this study and a previously reported experiment on 137Cs gamma rays. The results indicate that neutron irradiation elevated the risk of palpable mammary carcinoma with a linear dose response, the slope of which depended on age at time of irradiation. The RBE of neutron radiation was 7.5 ± 3.4, 9.3 ± 3.5 and 26.1 ± 8.9 (mean ± SE) for animals exposed at 1, 3 and 7 weeks of age, respectively. Our results indicate that age of the animal is an important factor influencing the effect of fast neutrons on breast cancer risk.
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Envejecimiento , Neutrones Rápidos/efectos adversos , Neoplasias Mamarias Experimentales/etiología , Neoplasias Mamarias Experimentales/fisiopatología , Envejecimiento/efectos de la radiación , Animales , Ciclo Estral/efectos de la radiación , Femenino , Neoplasias Inducidas por Radiación/etiología , Neoplasias Inducidas por Radiación/fisiopatología , Ratas , Ratas Sprague-Dawley , Efectividad Biológica RelativaRESUMEN
Since the Fukushima Dai-ichi Nuclear Power Plant accident, radiation effects on nonhuman biota in the contaminated areas have been a major concern. Here, we analyzed the frequencies of chromosomal aberrations (translocations and dicentrics) in the splenic lymphocytes of large Japanese field mice (Apodemus speciosus) inhabiting Fukushima Prefecture. A. speciosus chromosomes 1, 2, and 5 were flow-sorted in order to develop A. speciosus chromosome-specific painting probes, and FISH (fluorescence in situ hybridization) was performed using these painting probes to detect the translocations and dicentrics. The average frequency of the translocations and dicentrics per cell in the heavily contaminated area was significantly higher than the frequencies in the case of the noncontaminated control area and the slightly and moderately contaminated areas, and this aberration frequency in individual mice tended to roughly increase with the estimated dose rates and accumulated doses. In all four sampling areas, the proportion of aberrations occurring in chromosome 2 was approximately >3 times higher than that in chromosomes 1 and 5, which suggests that A. speciosus chromosome 2 harbors a fragile site that is highly sensitive to chromosome breaks induced by cellular stress such as DNA replication. The elevated frequency of chromosomal aberrations in A. speciosus potentially resulting from the presence of a fragile site in chromosome 2 might make it challenging to observe the mild effect of chronic low-dose-rate irradiation on the induction of chromosomal aberrations in A. speciosus inhabiting the contaminated areas of Fukushima.
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Aberraciones Cromosómicas , Accidente Nuclear de Fukushima , Murinae/genética , Plantas de Energía Nuclear , Animales , Hibridación Fluorescente in Situ , RatonesRESUMEN
Epidemiology studies have shown that children are at greater overall risk of radiation-induced cancer, but the modifying effect of age at exposure in different tissues is heterogeneous. Early epidemiology findings of increased lung cancer risk with increasing age at the time of exposure have been dismissed, with suggestions that the trend is an artefact from a failure to adequately correct for the effects of tobacco smoking. Yet, differing models used in subsequent analyses have shown that the increased susceptibility with age, counter to the overall solid tumor trend, can either be confirmed or discounted depending on the model parameters used. In this study, we analyzed the induction of tumors in female Wistar rats exposed to increasing thoracic doses of X-ray as neonates, juveniles or young adults, to allow the effect of age at exposure in this early period to be observed in the absence of any interactions with smoking. Histology was used to compare tumor subtypes among groups, and genomic DNA copy number alterations in a number of tumors arising after irradiation at different ages were examined. Induction of lung cancers increased with radiation dose, with the frequency of early occurring lung adenomas greater in rats irradiated at older ages. At the highest dose, the rats irradiated at 5 or 15 weeks of age showed increased age-specific rates of lung adenocarcinomas in later life compared to those irradiated at 1 week of age. However, thoracic mammary gland tumors induced by the highest dose at the later ages significantly decreased the lifespan in these groups, reducing the number of rats at risk of radiation-induced lung adenocarcinoma. There was no induction of mammary tumors outside of the irradiated field. Lung adenocarcinomas showed widespread DNA copy number aberrations at the chromosome level, but the only recurrent lesions were intragenic Fhit deletions and losses on chromosome 4. The results presented here suggest that the risk of radiation-induced lung cancer after irradiation may not monotonically decrease with age, and demonstrate that increasing lung cancer risk with exposure age can be observed independent of corrections for smoking, and that mammary tumors may show a similar relationship with age.
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Envejecimiento/efectos de la radiación , Neoplasias Pulmonares/etiología , Neoplasias Mamarias Experimentales/etiología , Neoplasias Inducidas por Radiación/etiología , Tórax/efectos de la radiación , Animales , Variaciones en el Número de Copia de ADN/efectos de la radiación , Femenino , Incidencia , Neoplasias Pulmonares/genética , Neoplasias Mamarias Experimentales/genética , Neoplasias Inducidas por Radiación/genética , Ratas , Ratas Wistar , Rayos X/efectos adversosRESUMEN
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.
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Neoplasias Inducidas por Radiación/mortalidad , Neoplasias Inducidas por Radiación/prevención & control , Órganos en Riesgo/efectos de la radiación , Protección Radiológica/métodos , Radioterapia/mortalidad , Radioterapia/métodos , Animales , Investigación Biomédica/tendencias , Relación Dosis-Respuesta en la Radiación , Medicina Basada en la Evidencia , Humanos , Incidencia , Dosificación Radioterapéutica , Factores de Riesgo , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Following the Fukushima Dai-ichi Nuclear Power Plant accident, radiation effects on nonhuman biota in the contaminated areas have been a great concern. The induction of chromosomal aberrations in splenic lymphocytes of small Japanese field mice (Apodemus argenteus) and house mice (Mus musculus) inhabiting Fukushima Prefecture was investigated. In mice inhabiting the slightly contaminated area, the average frequency of dicentric chromosomes was similar to that seen in mice inhabiting a noncontaminated control area. In contrast, mice inhabiting the moderately and heavily contaminated areas showed a significant increase in the average frequencies of dicentric chromosomes. Total absorbed dose rate was estimated to be approximately 1 mGy d(-1) and 3 mGy d(-1) in the moderately and heavily contaminated areas, respectively. Chromosomal aberrations tended to roughly increase with dose rate. Although theoretically, the frequency of chromosomal aberrations was considered proportional to the absorbed dose, chromosomal aberrations in old mice (estimated median age 300 days) did not increase with radiation dose at the same rate as that observed in young mice (estimated median age 105 days).
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Aberraciones Cromosómicas , Accidente Nuclear de Fukushima , Plantas de Energía Nuclear , Contaminantes Radiactivos/análisis , Animales , Arvicolinae , Ciclo Celular/efectos de la radiación , Cromosomas de los Mamíferos/genética , Relación Dosis-Respuesta en la Radiación , Linfocitos/citología , Linfocitos/efectos de la radiación , Metafase/efectos de la radiación , Ratones , Monitoreo de RadiaciónRESUMEN
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.
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Neoplasias Inducidas por Radiación/epidemiología , Neoplasias Inducidas por Radiación/radioterapia , Neoplasias Primarias Secundarias/epidemiología , Guerra Nuclear/estadística & datos numéricos , Radioterapia/estadística & datos numéricos , Medición de Riesgo/métodos , Sobrevivientes/estadística & datos numéricos , Niño , Preescolar , Interpretación Estadística de Datos , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Metaanálisis como Asunto , Armas Nucleares , Prevalencia , Modelos de Riesgos Proporcionales , Dosis de RadiaciónRESUMEN
The Tohoku hynobiid salamanders, Hynobius lichenatus, were chronically irradiated with γ-rays from embryonic to juvenile stages for 450 days. At 490 µGy h(-1) or lower dose rates, growth and survival were not significantly affected by irradiation, and any morphological aberrations and histological damages were not observed. At 4600 µGy h(-1), growth was severely inhibited, and all the individuals died mostly at the juvenile stage. Chronic LD50 was 42 Gy as a total dose. In the liver, the number of hematopoietic cells was significantly reduced in the living juveniles, and these cells disappeared in the dead juveniles. In the spleen, mature lymphocytes were depleted in the living larvae, and almost all the heamtopoietic cells disappeared in the dead juveniles. These results suggest that this salamander died due to acute radiation syndrome, i.e., hematopoietic damage and subsequent sepsis caused by immune depression. The death would be also attributed to skin damage inducing infection. At 18,000 µGy h(-1), morphological aberrations and severe growth inhibition were observed. All the individuals died at the larval stage due to a multiple organ failure. Chronic LD50 was 28 Gy as a total dose. Assuming that chronic LD50 was 42 Gy at lower dose rates than 4600 µGy h(-1), a chronic median lethal dose rate could be estimated to be <340 µGy h(-1) for the whole life (>14 years). These results suggest that, among guidance dose rates, i.e., 4-400 µGy h(-1), proposed by various organisations and research programmes for protection of amphibians and taxonomic groups or ecosystems including amphibians, most of them would protect this salamander but the highest value may not on the whole life scale.
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Rayos gamma/efectos adversos , Urodelos , Animales , Relación Dosis-Respuesta en la RadiaciónRESUMEN
Although various mechanisms have been inferred for combinatorial actions of multiple carcinogens, these mechanisms have not been well demonstrated in experimental carcinogenesis models. We evaluated mammary carcinogenesis initiated by combined exposure to various doses of radiation and chemical carcinogens. Female rats at 7 weeks of age were γ-irradiated (0.2-2 Gy) and/or exposed to 1-methyl-1-nitrosourea (MNU) (20 or 40 mg/kg, single intraperitoneal injection) or 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) (40 mg/kg/day by gavage for 10 days) and were observed until 50 weeks of age. The incidence of mammary carcinoma increased steadily as a function of radiation dose in the absence of chemicals; mathematical analysis supported an additive increase when radiation was combined with a chemical carcinogen, irrespective of the chemical species and its dose. Hras mutations were characteristic of carcinomas that developed after chemical carcinogen treatments and were overrepresented in carcinomas induced by the combination of radiation and MNU (but not PhIP), indicating an interaction of radiation and MNU at the level of initiation. The expression profiles of seven classifier genes, previously shown to distinguish two classes of rat mammary carcinomas, categorized almost all examined carcinomas that developed after individual or combined treatments with radiation (1 Gy) and chemicals as belonging to a single class; more comprehensive screening using microarrays and a separate test sample set failed to identify differences in gene expression profiles among these carcinomas. These results suggest that a complex, multilevel interaction underlies the combinatorial action of radiation and chemical carcinogens in the experimental model.