Methylmercury exposure during the vulnerable window of the cerebrum in postnatal developing rats.

The developing brain is known to be sensitive to the toxic effects of methylmercury (MeHg). The effects of toxic levels of MeHg exposure during the most seemingly vulnerable window of the cerebrum are not well studied. In this study, we aimed to examine the specific effects of toxic levels of MeHg on neurobehavior, neurodegeneration, and selenoenzyme activity in the cerebrum of infant rats. Male Wistar rats (n = 8/group) were orally treated with MeHg at an acute toxic dose (8 mg Hg/kg/day) for 10 consecutive days starting on postnatal day 14 (P14). The MeHg-exposed rats showed a significant reduction in body weight after day 8 and severe neurological symptoms similar to dystonia on day 12 (P25). Motor coordination deficits determined using the rotarod performance test and short-term memory impairment determined using the Y-maze task were observed in the MeHg-exposed rats on day 11 (P24). The MeHg-exposed rats sacrificed on day 12 showed severe cerebral neuronal degeneration, reactive astrocytosis, and TUNEL-positive apoptotic nuclei, with the cerebral Hg concentration of 15.0 ± 1.6 µg/g. Furthermore, the activities of glutathione peroxidase and thioredoxin reductase in the cerebrum in MeHg-exposed rats were lower than those in control. These results indicate that MeHg exposure to infant rats will be useful to predict the effects of MeHg at the cerebral growth spurt in humans.

Factors influencing confabulation in Japanese patients with Alzheimer's disease.

BACKGROUND: Confabulations are often observed in patients with Alzheimer's disease (AD) and can increase family caregivers' burdens. Previous studies have focused on the relationship between confabulation and cognitive ability. However, few studies have investigated the association between confabulation and familial factors. Here, we aimed to examine whether confabulation relates to familial factors, such as the level of family caregivers' expressed emotion or the level of functioning of the family. METHODS: Twenty-seven outpatients with AD and their family caregivers participated in this study. We examined confabulations about episodic memory, semantic memory, and future planning using the Modified Confabulation Battery (MCB). We investigated correlations between scores on the MCB and scores on the Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS), Family Attitude Scale (FAS), and the Family Adaptability and Cohesion Evaluation Scale. Multiple regression analyses were performed using the total scores on the MCB and domain-specific scores on the MCB as dependent variables, and the scores on the MMSE, GDS, and FAS as independent variables. RESULTS: MCB scores were positively related to FAS scores (P < 0.01) and negatively to GDS scores (P < 0.05), but not to MMSE scores. Regarding the three domains the MCB measured, confabulation about episodic memory and future planning showed a positive relationship with FAS scores. CONCLUSIONS: Family attitude was the factor most related to confabulation in our study. Patients with AD may attempt to avoid confronting family caregivers' high emotional expression through confabulation, or confabulation itself might result in high emotional expression among family caregivers. Psychoeducational or therapeutic approaches for family caregivers might reduce confabulation in patients with AD.

Determination of HEL (Hexanoyl-lysine adduct): a novel biomarker for omega-6 PUFA oxidation.

Published evidences indicate that reactive oxygen species (ROS) can induce lipid peroxidation, which plays important role in the pathophysiology of numerous diseases including atherosclerosis, diabetes, cancer and aging process. Monitoring of oxidative modification or oxidative damages of biomolecules may therefore be essential for the understanding of aging, and age-related diseases. N-epsilon-Hexanoyl-lysine (HEL) is a novel lipid peroxidation biomarker which is derived from the oxidation of omega-6 unsaturated fatty acid. In this chapter, development of HEL ELISA and its applications are reported. Assay range of HEL ELISA was 2-700 nmol/L, and showed good linearity and reproducibility. Accuracy of this assay was validated by recovery test and absorption test. HEL concentration in human urine was 22.9 ± 15.4 nmol/L and it was suggested that HEL exists as low molecular substances, in a free or in the peptide-attached form. In contrast with the urine sample, serum HEL was suggested to exist in the protein-attached form, and hydrolysis by protease might be essential for the accurate measurement of HEL in protein containing samples such as serum and cultured cells. By sample pretreatment with proteases, HEL was successfully detected in oxidized LDL, oxidized serum, and rat serum. In conclusion, HEL ELISA can be applied to measure urine, serum, and other biological samples independent of the animal species, and may be useful for the assessment of omega-6 PUFA oxidation in the living bodies.

Sodium bicarbonate protects uranium-induced acute nephrotoxicity through uranium-decorporation by urinary alkalinization in rats.

To evaluate the effectiveness of sodium bicarbonate (SB) in removing uranium and protecting animals from uranium toxicity, we intramuscularly administered 1 mg/kg of uranyl nitrate to 8-wk-old male SD rats, and 20 min after administration of uranyl nitrate, the animals were given a single oral administration of SB at 0.1, 0.3 or 1 g/kg. The SB treatment at a dose of 0.3 g/kg or more raised the pH of the rats' urine until 4 h after treatment, and it significantly reduced the uranium amounts in the kidneys at 1 day after treatment. In another experiment, rats were intramuscularly administered 1 mg/kg of uranyl nitrate, and 20 min later, the animals were treated with sodium bicarbonate (0.1 or 1 g/kg). The rats were autopsied at 1, 3 and 7 days after uranium treatment. High-dose SB resulted in a significant increase in urinary uranium excretion in the first 24 h and a reduction of uranium deposition in the kidneys and femurs, and it also significantly suppressed uranium-induced renal toxicity, as shown by both histopathology and clinical chemistry at 3 days after uranium treatment. Low-dose SB did not show such marked effects. Our findings demonstrated that the uranium decorporation effect of sodium bicarbonate was observed at the dosage showing urine alkalinization in rats and that decorporation effect of sodium bicarbonate might be beneficial if it is administered immediately after incorporation of soluble uranium.

Radiological protection issues arising during and after the Fukushima nuclear reactor accident.

Following the Fukushima accident, the International Commission on Radiological Protection (ICRP) convened a task group to compile lessons learned from the nuclear reactor accident at the Fukushima Daiichi nuclear power plant in Japan, with respect to the ICRP system of radiological protection. In this memorandum the members of the task group express their personal views on issues arising during and after the accident, without explicit endorsement of or approval by the ICRP. While the affected people were largely protected against radiation exposure and no one incurred a lethal dose of radiation (or a dose sufficiently large to cause radiation sickness), many radiological protection questions were raised. The following issues were identified: inferring radiation risks (and the misunderstanding of nominal risk coefficients); attributing radiation effects from low dose exposures; quantifying radiation exposure; assessing the importance of internal exposures; managing emergency crises; protecting rescuers and volunteers; responding with medical aid; justifying necessary but disruptive protective actions; transiting from an emergency to an existing situation; rehabilitating evacuated areas; restricting individual doses of members of the public; caring for infants and children; categorising public exposures due to an accident; considering pregnant women and their foetuses and embryos; monitoring public protection; dealing with 'contamination' of territories, rubble and residues and consumer products; recognising the importance of psychological consequences; and fostering the sharing of information. Relevant ICRP Recommendations were scrutinised, lessons were collected and suggestions were compiled. It was concluded that the radiological protection community has an ethical duty to learn from the lessons of Fukushima and resolve any identified challenges. Before another large accident occurs, it should be ensured that inter alia: radiation risk coefficients of potential health effects are properly interpreted; the limitations of epidemiological studies for attributing radiation effects following low exposures are understood; any confusion on protection quantities and units is resolved; the potential hazard from the intake of radionuclides into the body is elucidated; rescuers and volunteers are protected with an ad hoc system; clear recommendations on crisis management and medical care and on recovery and rehabilitation are available; recommendations on public protection levels (including infant, children and pregnant women and their expected offspring) and associated issues are consistent and understandable; updated recommendations on public monitoring policy are available; acceptable (or tolerable) 'contamination' levels are clearly stated and defined; strategies for mitigating the serious psychological consequences arising from radiological accidents are sought; and, last but not least, failures in fostering information sharing on radiological protection policy after an accident need to be addressed with recommendations to minimise such lapses in communication.

[Depression in dementia with Lewy bodies].

Depression is a risk factor for dementia in general, including Alzheimer's disease (AD), its premorbid signs are commonly observed, and the morbidity of depression is higher in dementia patients. Dementia with Lewy bodies (DLB) is considered to have an even higher depression prevalence and premorbid depression rate than other dementias such as AD. This led to depression being listed as a supportive feature in the 2005 criteria for the clinical diagnosis of DLB. However, studies investigating the difference in depression between AD and DLB failed to show consistent results. We examined the Geriatric Depression Scale score, which is designed specifically to rate depression in the elderly, for DLB and AD patients. The scores for DLB patients were twice as high as those for AD patients. There was no correlation between the GDS score and age, sex, or Mini-Mental Sate Examination scores. Depression-specific symptoms were more frequent in the DLB group than non-specific symptoms, while less than one third of DLB patients with very high GDS scores were diagnosed with depression or prescribed antidepressants for depressive symptoms. Other researchers reported that depression of DLB was associated with a higher prevalence of psychiatric symptoms other than major depression, and suggested that depression of DLB might be a part of psychiatric syndrome. There has been no systematic study on the validity or risk of pharmacological therapy, as well as the necessity of intervention, for depression or a high GDS score in DLB. Therefore, intervention must rely on the clinical decision of each doctor. In spite of the paucity of current findings, studies on depression of DLB may play a key role in the elucidation of its neuropathology and psychopathology and offer a new view point on understanding depression itself.

[Radiological protection: its concept and principles].

Main concepts and principles of radiation protection system are reviewed. Especially, the concept of LNT model and its background are discussed. Also, the major principles, i.e., (i) justification, (ii) optimization, and (iii) the application of dose limits, are reviewed with emphasis on the existing situation, which is mostly related to the current situation in Fukushima.

Dementia with Lewy bodies is associated with higher scores on the Geriatric Depression Scale than is Alzheimer's disease.

BACKGROUND: Several reports suggest a higher morbidity of depression in patients with dementia with Lewy bodies (DLB) than in patients with Alzheimer's disease (AD). However, these results have not been duplicated consistently. The psychiatric symptoms of dementia, including depression, are important for its diagnosis and management. Thus, the aim of the present study was to clarify the characteristics of the depressive symptoms in DLB compared with AD using the Geriatric Depression Scale (GDS). METHODS: We examined the GDS score for 86 patients with probable DLB (based on the Consensus Criteria for the clinical diagnosis of DLB) and 86 patients with probable AD (based on criteria of the National Institute for Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association), who were matched according to age, sex, education, and Mini-Mental State Examination (MMSE) scores. We also examined correlations between GDS scores and age, sex, or MMSE scores in both groups. Correlations between GDS scores and metaiodobenzylguanidine (MIBG) scintigraphy were examined in patients with DLB. To characterize the GDS in DLB, its profile was examined using factor structures. RESULTS: Scores for DLB patients were twice as high on the GDS as those for AD patients. There was no correlation between GDS score and age, sex, or MMSE scores in either group. Furthermore, there was no correlation between the results of MIBG scintigraphy and GDS scores in the DLB group. Using factor structures, the depression symptom profile of these diseases suggested that depression-specific symptoms, such as mood, worry, or future outlook, were more frequent in the DLB group than non-specific symptoms, such as lack of energy, decreased concentration, or apathy. CONCLUSIONS: The data suggest that depressive symptoms are highly specific symptoms of DLB, independent of other features of this disorder. The GDS could be used as a subsidiary tool in differentiating DLB from AD and is more useful than clinical observations of depression.

Funding for radiation research: past, present and future.

For more than a century, ionizing radiation has been indispensable mainly in medicine and industry. Radiation research is a multidisciplinary field that investigates radiation effects. Radiation research was very active in the mid- to late 20th century, but has then faced challenges, during which time funding has fluctuated widely. Here we review historical changes in funding situations in the field of radiation research, particularly in Canada, European Union countries, Japan, South Korea, and the US. We also provide a brief overview of the current situations in education and training in this field. A better understanding of the biological consequences of radiation exposure is becoming more important with increasing public concerns on radiation risks and other radiation literacy. Continued funding for radiation research is needed, and education and training in this field are also important.

Role of DNA double-strand break repair genes in cell proliferation under low dose-rate irradiation conditions.

Radiation-induced DNA double-stand breaks (DSBs) lead to numerous biological effects. To elucidate the molecular mechanisms involved in cellular responses to low dose and low dose-rate radiation, it is informative to clarify the roles of DSB repair related genes. In higher vertebrate cells, there are at least two major DSB repair pathways, namely non-homologous end-joining (NHEJ) and homologous recombination (HR). Here, it is shown that in chicken DT40 cells irradiated with gamma-rays at a low dose-rate (2.4 cGy/day), the growth delay in NHEJ-related KU70- and PRKDC (encoding DNA-PKcs)-defective cells were remarkably higher than in cells defective for the HR-related RAD51B and RAD54 genes. DNA-PKcs- defective human M059J cells also showed an obvious growth delay when compared to control M059K cells. RAD54(-/-)KU70(-/-) cells demonstrated their highest degree of growth delay after an X-irradiation with a high dose-rate of 0.9 Gy/min. However they showed a lower degree of growth delay than that seen in KU70(-/-) and PRKDC(-/-/-) cells exposed to low dose-rate irradiation. These findings indicate that cellular responses to low dose-rate radiation are remarkably different from those to high dose-rate radiation. The fact that both DT40 and mammalian NHEJ-defective cells were highly sensitive to low dose-rate radiation, provide a foundation for the concept that NHEJ-related factors may be useful as molecular markers to predict the sensitivity of humans to low dose-rate radiation.

Low-dose radiation and its clinical implications: diabetes.

Induction of hormesis and adaptive response by low-dose radiation (LDR) has been extensively indicated. Adaptive response induced by LDR was not only resistant to damage caused by a subsequently high-dose radiation, but also cross-resistant to other non-radiation challenges, such as chemicals. Mechanisms by which LDR induces the preventive effect on radiation- or chemical-induced tissue damage include induced or up-regulated expression of protective proteins, such as heat shock proteins and antioxidants. Since oxidative damage to tissues is a major pathogenesis of many human diseases including diabetes, this review will summarize the available data with an emphasis of the preventive effect of LDR on the development of diabetes and the therapeutic effect of LDR on diabetic cardiovascular complications. The available data indicated that pre-exposure of mice to LDR reduced the incidence of alloxan-induced diabetes, and also delayed the onset of hyperglycaemia in diabetes-prone non-obese diabetic mice. Experiments with animals indicated the effectively therapeutic effect of low-intensity or power laser (LIL or LPL) radiation on skin wound healing, which has stimulated clinical use of LIL to cure skin ulcer in diabetic patients. Mechanisms by which LDR prevents diabetes, though are unclear now, may include the induction of pancreatic antioxidants to prevent beta cell from oxidative damage and immunomodulation to preserve pancreatic function. For LIL therapeutic effect on diabetic wound healing, mechanisms may include its antioxidant action, immunomodulation, cell proliferation stimulation as well as improvement of systemic and wound-regional microcirculation. Therefore, although only a few studies indicating LDR prevention of the development of diabetes, many studies have demonstrated LDR, specifically LIL, therapeutic effectiveness of diabetic wound healing. These preliminary results are really encouraging for us to further pursue the clinical implication of LDT to diabetes-related areas.

Reduction of background mutations by low-dose X irradiation of Drosophila spermatocytes at a low dose rate.

A sex-linked recessive lethal mutation assay was performed in Drosophila melanogaster using immature spermatocytes and spermatogonia irradiated with X rays at a high or low dose rate. The mutation frequency in the sperm irradiated with a low dose at a low dose rate was significantly lower than that in the sham-irradiated group, whereas irradiation with a high dose resulted in a significant increase in the mutation frequency. It was obvious that the dose-response relationship was not linear, but rather was U-shaped. When mutant germ cells defective in DNA excision repair were used instead of wild-type cells, low-dose irradiation at a low dose rate did not reduce the mutation frequency. These observations suggest that error-free DNA repair functions were activated by low dose of low-dose-rate radiation and that this repaired spontaneous DNA damage rather than the X-ray-induced damage, thus producing a practical threshold.

Activation of antioxidative enzymes induced by low-dose-rate whole-body gamma irradiation: adaptive response in terms of initial DNA damage.

An adaptive response induced by long-term low-dose-rate irradiation in mice was evaluated in terms of the amount of DNA damage in the spleen analyzed by a comet assay. C57BL/ 6N female mice were irradiated with 0.5 Gy of (137)Cs gamma rays at 1.2 mGy/h; thereafter, a challenge dose (0.4, 0.8 or 1.6 Gy) at a high dose rate was given. Less DNA damage was observed in the spleen cells of preirradiated mice than in those of mice that received the challenge dose only; an adaptive response in terms of DNA damage was induced by long-term low-dose-rate irradiation in mice. The gene expression of catalase and Mn-SOD was significantly increased in the spleen after 23 days of the low-dose-rate radiation (0.5 Gy). In addition, the enzymatic activity of catalase corresponded to the gene expression level; the increase in the activity was observed at day 23 (0.5 Gy). These results suggested that an enhancement of the antioxidative capacities played an important role in the reduction of initial DNA damage by low-dose-rate radiation.

[Biological responses to low dose radiation--hormesis and adaptive responses].

"Hormesis" is defined, originally in the field of toxicology, as a phenomenon in which a harmful substance gives stimulating effects to living organisms when the quantity is small. The concept was extended and applied to ionizing radiation, high doses of which are harmful. Although radiation has been thought to be, based on findings in high dose ranges, harmful no matter low the dose is, recent investigation revealed that living organisms possess the ability to respond to low-dose radiation in very sophisticated ways. A good example of such responses is the so-called radiation adaptive response, a process in which acquired radioresistance is induced by low-dose radiation given in advance. The stimulation of certain bioprotective functions, including antioxidative capacity, DNA repair functions, apoptosis, and immune functions are thought to underly the adaptive response. The adaptive response is effective for chromosome induction, acute death, and tumorigenesis induced by high doses of radiation. Radiation hormesis and adaptive response provide a new scope in the risk assessment and medical application of ionizing radiation.

ESTIMATION OF EARLY INTERNAL DOSES TO FUKUSHIMA RESIDENTS AFTER THE NUCLEAR DISASTER BASED ON THE ATMOSPHERIC DISPERSION SIMULATION.

Estimating the early internal doses to residents in the Fukushima Daiichi Nuclear Power Station accident is a difficult task because limited human/environmental measurement data are available. Hence, the feasibility of using atmospheric dispersion simulations created by the Worldwide version of System for Prediction of Environmental Emergency Dose Information 2nd Version (WSPEEDI-II) in the estimation was examined in the present study. This examination was done by comparing the internal doses evaluated based on the human measurements with those calculated using time series air concentration maps (131I and 137Cs) generated by WSPEEDI-II. The results showed that the latter doses were several times higher than the former doses. However, this discrepancy could be minimised by taking into account personal behaviour data that will be available soon. This article also presents the development of a prototype system for estimating the internal dose based on the simulations.

NUMERICAL SIMULATION OF DIRECT MEASUREMENT TO DETERMINE THYROID 131I CONTENT OF TWO TEPCO WORKERS CONSIDERING INDIVIDUAL TISSUE THICKNESS.

After the Fukushima Daiichi Nuclear Power Station accident, the National Institute of Radiological Sciences examined seven heavily exposed emergency workers and performed internal dose estimations. The largest dose contributor was found to be (131)I, which was detected by thyroid monitor with an HPGe detector. Different energy peaks from (131)I were simultaneously identified in the pulse-height spectra of the two subjects with the highest doses regardless of late measurements. A closer look at the spectra indicated that the count ratio of the two peak areas at 80.2 and 365 keV differed somewhat between the individual workers, suggesting a difference in attenuation in the overlaying soft tissue and in the thyroid itself. In this study, the relationship between the count ratio (80.2/365 keV) and the thickness of soft tissue overlying the thyroid was investigated by means of numerical simulations performed using the Japanese Male (JM) phantom varying the thickness of the overlaying tissue. From the measured count ratios, it was possible to estimate that the overlaying tissue was thinner for Worker 1 (difference from the JM phantom: -0.34±1.29 cm) and thicker for Worker 2 (diff.: 2.5±1.2 cm). The thyroid (131)I contents evaluated taking into account the individual thicknesses were 4.3 kBq for Worker 1 and 8.4 kBq for Worker 2, resulting in a significant increase for Worker 2 compared with the content based on the default counting efficiency at 365 keV of the original JM phantom. However, the results have large uncertainty factors of 1.4 for Worker 1 and 1.3 for Worker 2 and should be carefully considered together with other factors influencing the attenuation.

Intake ratio of 131I to 137Cs derived from thyroid and whole-body doses to Fukushima residents.

This study deals with the intake ratio of (131)I to (137)Cs that allows for the utilisation of late whole-body measurements to reconstruct the internal thyroid doses to Fukushima residents. The ratio was derived from the thyroid dose distribution of children and the effective dose distribution of adults based on the assumption that various age groups of persons inhaled the two nuclides at the same activity ratio and at around the same time, while taking into account age-dependent ventilation rates. The two dose distributions were obtained from residents of Iitate village and Kawamata town, located northwest of Fukushima Daiichi nuclear power plant (FDNPP). As a result, the intake ratios for the residents were 2-3, which was much smaller than the activity ratio observed in air sampling. A main reason for this discrepancy presumably lies in the relatively smaller thyroid uptake for iodine in the Japanese subjects than that in the reference persons on whom the biokinetic model promulgated by International Commission on Radiological Protection is based. The actual intake ratio of the two nuclides is believed to have been higher south of the FDNPP; however, this would depend on which of three significant plume events dominantly contributed to the intake for individuals. Further studies are needed to clarify this issue as a part of the reconstruction of early internal doses related to the FDNPP accident.

Urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine analysis by an improved ELISA: An inter-laboratory comparison study.

ELISA is commonly used for the detection of urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a marker of whole body oxidative stress. However, the method has been criticized for high inter-laboratory variability and poor agreement with chromatographic techniques. We performed an inter-laboratory comparison of 8-oxodG assessed in 30 urine samples and a urine spiked with four different concentrations of 8-oxodG by ELISA using standardized experimental conditions, including: sample pre-treatment with solid-phase extraction (SPE), performing analysis using a commercial kit from a single manufacturer and strict temperature control during the assay. We further compared the ELISA results with high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and performed tentative identification of compounds that may contribute to the discrepancy between both methods. For all but one participating laboratory (Data 1) we observed consistent ELISA results lying mostly within 1SD of the mean 8-oxodG concentration. Mean 8-oxodG levels assessed by ELISA correlated with the data obtained by HPLC-MS/MS (R=0.679, p<0.001). The correlation improved when Data 1 were excluded from the analysis (R=0.749, p<0.001). We identified three outlying urine samples; one with an ELISA 8-oxodG concentration lower, and two with 8-oxodG levels higher, than those measured by HPLC-MS/MS. Omitting these samples further improved inter-methodology agreement (R=0.869, p<0.001). In the outliers with high 8-oxodG estimates various aromatic and heterocyclic compounds were tentatively identified using gas chromatography-mass spectrometry (GC-MS). Application of authentic standards revealed the presence of saccharides, including d-glucose and d-galactose as putative interfering substances. In summary, assay standardization improved ELISA inter-laboratory agreement, although some variability is still observed. There are still compounds contributing to overestimation of 8-oxodG by ELISA, but only in some urine samples. Thus, despite significant improvement, ELISA still should not be considered a robust alternative to chromatographic techniques.

Further study of prolongation of life span associated with immunological modification by chronic low-dose-rate irradiation in MRL-lpr/lpr mice: effects of whole-life irradiation.

MRL-lpr/lpr mice carry a deletion in the apoptosis-regulating Fas gene that markedly shortens life due to multiple severe diseases. In our previous study (Radiat. Res. 161, 168- 173, 2004), chronic low-dose-rate gamma irradiation of mice at 0.35 or 1.2 mGy/h for 5 weeks markedly prolonged the life span, accompanied by immunological activation. This report shows that extension of the irradiation period to the entire life of the mice at the same dose rates improved survival further. The 50% survival time for untreated mice, 134 days, was prolonged to 502 days by 1.2 mGy/h life-long irradiation. Also obtained were a time course and a radiation dose-rate response for the activation of the immune system as indicated by a significant increase in CD4+ CD8+ T cells in the thymus and CD8+ T cells in the spleen and also by a significant decrease in CD3+ CD45R/B220+ cells and CD45R/B220+ CD40+ cells in the spleen. Drastic ameliorations of multiple severe diseases, i.e. total-body lymphadenopathy, splenomegaly and serious autoimmune diseases including proteinuria, and kidney and brain-central nervous system syndromes, were found in parallel with these immunological activations, with lifelong low-dose-rate irradiation being more effective than 5-week irradiation at low dose rates.

Suppression of thymic lymphoma induction by life-long low-dose-rate irradiation accompanied by immune activation in C57BL/6 mice.

The induction of thymic lymphomas by whole-body X irradiation with four doses of 1.8 Gy (total dose: 7.2 Gy) in C57BL/6 mice was suppressed from a high frequency (90%) to 63% by preirradiation with 0.075 Gy X rays given 6 h before each 1.8-Gy irradiation. This level was further suppressed to 43% by continuous whole-body irradiation with 137Cs gamma rays at a low dose rate of 1.2 mGy/h for 450 days, starting 35 days before the challenging irradiation. Continuous irradiation at 1.2 mGy/h resulting in a total dose of 7.2 Gy over 258 days yielded no thymic lymphomas, indicating that this low-dose-rate radiation does not induce these tumors. Further continuous irradiation up to 450 days (total dose: 12.6 Gy) produced no tumors. Continuously irradiated mice showed no loss of hair and a greater body weight than unirradiated controls. Immune activities of the mice, as measured by the numbers of CD4+ T cells, CD40+ B cells, and antibody-producing cells in the spleen after immunization with sheep red blood cells, were significantly increased by continuous 1.2-mGy/h irradiation alone. These results indicate the presence of an adaptive response in tumor induction, the involvement of radiation-induced immune activation in tumor suppression, and a large dose and dose-rate effectiveness factor (DDREF) for tumor induction with extremely low-dose-rate radiation.