Bioassay Approach to Prescribe Safe-limits of Exposure to Non Ionizing Radiation in Ecosystems

A biological assay that quantifies hazardous response in living matter to an electromagnetic stimulus, is evolved. Considering the various susceptible aspects of physio-anatomical systems constituting a living subject, a dominance criterion to determine an optimum all-or-none response limit of exposure to electromagnetic pollutions is established. Based on the statistics of proneness and susceptibility of discrete physio-anatomical parts of living systems (biotic components) to polluting radiations (abiotic environment), the stochastic nature of damage involved is considered to formulate a quantal index which specifies a “safe” intensity-level of electromagnetic radiation to which living systems can be exposed without encountering any deleterious effects. The locations of vulnerable parts which are affected by radiation are identified through random mosaic modeling of a test subject. Using this model, a susceptance priority sequence of biotic components is constructed. This sequence is then terminated at a point of weightage proportional to the diversity of victim population. The biotic species falling within this limit of truncation are subsequently studied to assay the tolerance (optimum lethal dose) of the test subject to the radiation in question. The possibility of simulating the entire ecological system under consideration by means of a microprocessor is suggested.     

Diagnosis of Partial Body Radiation Exposure in Mice Using Peripheral Blood Gene Expression Profiles

In the event of a terrorist-mediated attack in the United States using radiological or improvised nuclear weapons, it is expected that hundreds of thousands of people could be exposed to life-threatening levels of ionizing radiation. We have recently shown that genome-wide expression analysis of the peripheral blood (PB) can generate gene expression profiles that can predict radiation exposure and distinguish the dose level of exposure following total body irradiation (TBI). However, in the event a radiation-mass casualty scenario, many victims will have heterogeneous exposure due to partial shielding and it is unknown whether PB gene expression profiles would be useful in predicting the status of partially irradiated individuals. Here, we identified gene expression profiles in the PB that were characteristic of anterior hemibody-, posterior hemibody- and single limb-irradiation at 0.5 Gy, 2 Gy and 10 Gy in C57Bl6 mice. These PB signatures predicted the radiation status of partially irradiated mice with a high level of accuracy (range 79–100%) compared to non-irradiated mice. Interestingly, PB signatures of partial body irradiation were poorly predictive of radiation status by site of injury (range 16–43%), suggesting that the PB molecular response to partial body irradiation was anatomic site specific. Importantly, PB gene signatures generated from TBI-treated mice failed completely to predict the radiation status of partially irradiated animals or non-irradiated controls. These data demonstrate that partial body irradiation, even to a single limb, generates a characteristic PB signature of radiation injury and thus may necessitate the use of multiple signatures, both partial body and total body, to accurately assess the status of an individual exposed to radiation.     

Probabilistic Analysis of Human Health Risks Associated with Background Concentrations of Inorganic Arsenic: Use of a Margin of Exposure Approach

Substantial evidence exists from epidemiological and mechanistic studies supporting a sublinear or threshold dose–response relationship for the carcinogenicity of ingested arsenic; nonetheless, current regulatory agency evaluations have quantified arsenic risks using default, generic risk assessment procedures that assume a linear, no-threshold dose–response relationship. The resulting slope factors predict risks from U.S. background arsenic exposures that exceed certain regulatory levels of concern, an outcome that presents challenges for risk communication and risk management decisions. To better reflect the available scientific evidence, this article presents the results of a Margin of Exposure (MOE) analysis to characterize risks associated with typical and high-end background exposures of the U.S. population to arsenic from food, water, and soil. MOE values were calculated by comparing a no-observable-adverse-effect-level (NOAEL) derived from the epidemiological literature with exposure estimates generated using a probabilistic (Monte Carlo) model. The plausibility and conservative nature of the exposure and risk estimates evaluated in this analysis are supported by sensitivity and uncertainty analyses and by comparing predicted urinary arsenic concentrations with empirical data. Using the more scientifically supported MOE approach, the analysis presented in this article indicates that typical and high-end background exposures to inorganic arsenic in U.S. populations do not present elevated risks of carcinogenicity.     

Limited Internal Radiation Exposure Associated with Resettlements to a Radiation-Contaminated Homeland after the Fukushima Daiichi Nuclear Disaster

Resettlement to their radiation-contaminated hometown could be an option for people displaced at the time of a nuclear disaster; however, little information is available on the safety implications of these resettlement programs. Kawauchi village, located 12–30 km southwest of the Fukushima Daiichi nuclear power plant, was one of the 11 municipalities where mandatory evacuation was ordered by the central government. This village was also the first municipality to organize the return of the villagers. To assess the validity of the Kawauchi villagers’ resettlement program, the levels of internal Cesium (Cs) exposures were comparatively measured in returnees, commuters, and non-returnees among the Kawauchi villagers using a whole body counter. Of 149 individuals, 5 villagers had traceable levels of Cs exposure; the median detected level was 333 Bq/body (range, 309–1050 Bq/kg), and 5.3 Bq/kg (range, 5.1–18.2 Bq/kg). Median annual effective doses of villagers with traceable Cs were 1.1 x 10^-2 mSv/y (range, 1.0 x 10^-2-4.1 x 10^-2 mSv/y). Although returnees had higher chances of consuming locally produced vegetables, Cochran-Mantel-Haenszel test showed that their level of internal radiation exposure was not significantly higher than that in the other 2 groups (p=0.643). The present findings in Kawauchi village imply that it is possible to maintain internal radiation exposure at very low levels even in a highly radiation-contaminated region at the time of a nuclear disaster. Moreover, the risks for internal radiation exposure could be limited with a strict food control intervention after resettlement to the radiation-contaminated village. It is crucial to establish an adequate number of radio-contaminated testing sites within the village, to provide immediate test result feedback to the villagers, and to provide education regarding the importance of re-testing in reducing the risk of high internal radiation exposure.     

Minimal Internal Radiation Exposure in Residents Living South of the Fukushima Daiichi Nuclear Power Plant Disaster

Following the Fukushima nuclear power plant disaster, assessment of internal radiation exposure was indispensable to predict radiation-related health threats to residents of neighboring areas. Although many evaluations of internal radiation in residents living north and west of the crippled Fukushima nuclear power plant are available, there is little information on residents living in areas south of the plant, which were similarly affected by radio-contamination from the disaster. To assess the internal radio-contamination in residents living in affected areas to the south of the plant or who were evacuated into Iwaki city, a whole body counter (WBC) screening program of internal radio-contamination was performed on visitors to the Jyoban hospital in Iwaki city, which experienced less contamination than southern areas adjacent to the nuclear plant. The study included 9,206 volunteer subjects, of whom 6,446 were schoolchildren aged 4–15 years. Measurements began one year after the incident and were carried out over the course of two years. Early in the screening period only two schoolchildren showed Cs-137 levels that were over the detection limit (250 Bq/body), although their Cs-134 levels were below the detection limit (220 Bq/body). Among the 2,760 adults tested, 35 (1.3%) had detectable internal radio-contamination, but only for Cs-137 (range: 250 Bq/body to 859 Bq/body), and not Cs-134. Of these 35 subjects, nearly all (34/35) showed elevated Cs-137 levels only during the first year of the screening. With the exception of potassium 40, no other radionuclides were detected during the screening period. The maximum annual effective dose calculated from the detected Cs-137 levels was 0.029 and 0.028 mSv/year for the schoolchildren and adults, respectively, which is far below the 1 mSv/year limit set by the government of Japan. Although the data for radiation exposure during the most critical first year after the incident are unavailable due to a lack of systemic measurements, the present results suggest that internal radio-contamination levels more than one year after the incident were minimal for residents living south of the crippled Fukushima nuclear plant, and that the annual additional effective doses derived from internal Cs contamination were negligible. Thus, internal radio-contamination of residents living in southern radio-contaminated areas appears to be generally well controlled.     

Mathematical Model of Biological Order State or Syndrome in Traditional Chinese Medicine: Based on Electromagnetic Radiation within the Human Body

In this study, based on the resonator model and exciplex model of electromagnetic radiation within the human body, mathematical model of biological order state, also referred to as syndrome in traditional Chinese medicine, was established and expressed as: “ \textSy = n/ln(6I + 1) {\text{Sy}} = \nu /\ln (6I + 1) ”. This model provides the theoretical foundation for experimental research addressing the order state of living system, especially the quantitative research syndrome in traditional Chinese medicine.     

Cladribine Exposure Results in a Sustained Modulation of the Cytokine Response in Human Peripheral Blood Mononuclear Cells

Background and Objectives

Cladribine is a cytotoxic drug which ameliorates the clinical course of relapsing-remitting multiple sclerosis. In addition to cytotoxicity, the mode of action may include immunomodulatory mechanisms. This in vitro study was designed to investigate cladribine’s effects on cell function after the removal of cladribine to distinguish cytotoxic versus immunomodulatory effects.

Methods

Cells were incubated in the absence or presence of cladribine (1×10^-8 M to 1×10^-5 M) for 72 h. Cladribine was removed from the cell culture and surviving peripheral blood mononuclear cells were cultured up to 58 days to determine the immunomodulatory effects of cladribine on cell function (e.g., proliferation and cytokine release).

Results

In the long-term, brief cladribine exposure did not impair the proliferation of surviving peripheral blood mononuclear cells. However, it induced an anti-inflammatory shift in the cytokine milieu with significantly enhanced release of IL-4 (Days 9 and 44, p<0.01; Day 58, p<0.05) and IL-5 (Day 9, p<0.01), resulting in an increased IL-4/INF-gamma ratio (Days 9 and 44, p<0.01; Day 58, p<0.05). Additionally, a trend towards an increased IL-10 production was observed. No changes were found in the production of IFN-gamma, TNF-alpha, IL-6, IL-8, IL-17A, IL-23 or NGF-beta.

Conclusions

In vitro cladribine exposure induces a sustained anti-inflammatory shift in the cytokine profile of surviving peripheral blood mononuclear cells. This immunomodulatory action might contribute to cladribine’s beneficial effects in the treatment of multiple sclerosis.     

Internal Radiation Exposure Dose in Iwaki City,Fukushima Prefecture after the Accident at Fukushima Dai-ichi Nuclear Power Plant

As a result of the accident at the Fukushima Daiichi Nuclear Power Plant (FNPP) on 11 March 2011, a huge amount of radionuclides, including radiocesium, was released and spread over a wide area of eastern Japan. Although three years have passed since the accident, residents around the FNPP are anxious about internal radiation exposure due to radiocesium. In this study, we screened internal radiation exposure doses in Iwaki city of Fukushima prefecture, using a whole-body counter. The first screening was conducted from October 2012 to February 2013, and the second screening was conducted from May to November 2013. Study participants were employees of ALPINE and their families who underwent examination. A total of 2,839 participants (1,366 men and 1,473 women, 1–86 years old) underwent the first screening, and 2,092 (1,022 men and 1,070 women, 1–86 years old) underwent the second screening. The results showed that 99% of subjects registered below 300 Bq per body in the first screening, and all subjects registered below 300 Bq per body in the second screening. The committed effective dose ranged from 0.01–0.06 mSv in the first screening and 0.01–0.02 mSv in the second screening. Long-term follow-up studies are needed to avoid unnecessary chronic internal exposure and to reduce anxiety among the residents by communicating radiation health risks.     

Leukocyte Activity Is Altered in a Ground Based Murine Model of Microgravity and Proton Radiation Exposure

Immune system adaptation during spaceflight is a concern in space medicine. Decreased circulating leukocytes observed during and after space flight infer suppressed immune responses and susceptibility to infection. The microgravity aspect of the space environment has been simulated on Earth to study adverse biological effects in astronauts. In this report, the hindlimb unloading (HU) model was employed to investigate the combined effects of solar particle event-like proton radiation and simulated microgravity on immune cell parameters including lymphocyte subtype populations and activity. Lymphocytes are a type of white blood cell critical for adaptive immune responses and T lymphocytes are regulators of cell-mediated immunity, controlling the entire immune response. Mice were suspended prior to and after proton radiation exposure (2 Gy dose) and total leukocyte numbers and splenic lymphocyte functionality were evaluated on days 4 or 21 after combined HU and radiation exposure. Total white blood cell (WBC), lymphocyte, neutrophil, and monocyte counts are reduced by approximately 65%, 70%, 55%, and 70%, respectively, compared to the non-treated control group at 4 days after combined exposure. Splenic lymphocyte subpopulations are altered at both time points investigated. At 21 days post-exposure to combined HU and proton radiation, T cell activation and proliferation were assessed in isolated lymphocytes. Cell surface expression of the Early Activation Marker, CD69, is decreased by 30% in the combined treatment group, compared to the non-treated control group and cell proliferation was suppressed by approximately 50%, compared to the non-treated control group. These findings reveal that the combined stressors (HU and proton radiation exposure) result in decreased leukocyte numbers and function, which could contribute to immune system dysfunction in crew members. This investigation is one of the first to report on combined proton radiation and simulated microgravity effects on hematopoietic, specifically immune cells.     

已烯雌酚在人体各器官转移模型的变结构控制

本文通过线性系统极点配置,李雅普诺夫方法研究了已烯雌酚在人体各器官转移模型的变结构控制问题,得到了使系统尽快达到稳定平衡点的变结构控制器．该问题为生物模型综合控制问题的研究奠定了基础．     

A Model of Cardiovascular Disease Giving a Plausible Mechanism for the Effect of Fractionated Low-Dose Ionizing Radiation Exposure

Atherosclerosis is the main cause of coronary heart disease and stroke, the two major causes of death in developed society. There is emerging evidence of excess risk of cardiovascular disease at low radiation doses in various occupationally exposed groups receiving small daily radiation doses. Assuming that they are causal, the mechanisms for effects of chronic fractionated radiation exposures on cardiovascular disease are unclear. We outline a spatial reaction-diffusion model for atherosclerosis and perform stability analysis, based wherever possible on human data. We show that a predicted consequence of multiple small radiation doses is to cause mean chemo-attractant (MCP-1) concentration to increase linearly with cumulative dose. The main driver for the increase in MCP-1 is monocyte death, and consequent reduction in MCP-1 degradation. The radiation-induced risks predicted by the model are quantitatively consistent with those observed in a number of occupationally-exposed groups. The changes in equilibrium MCP-1 concentrations with low density lipoprotein cholesterol concentration are also consistent with experimental and epidemiologic data. This proposed mechanism would be experimentally testable. If true, it also has substantive implications for radiological protection, which at present does not take cardiovascular disease into account. The Japanese A-bomb survivor data implies that cardiovascular disease and cancer mortality contribute similarly to radiogenic risk. The major uncertainty in assessing the low-dose risk of cardiovascular disease is the shape of the dose response relationship, which is unclear in the Japanese data. The analysis of the present paper suggests that linear extrapolation would be appropriate for this endpoint.     

Evaluation of an Oral Subchronic Exposure of Deoxynivalenol on the Composition of Human Gut Microbiota in a Model of Human Microbiota-Associated Rats

Background

Deoxynivalenol (DON), a mycotoxin produced by Fusarium species, is one of the most prevalent mycotoxins present in cereal crops worldwide. Due to its toxic properties, high stability and prevalence, the presence of DON in the food chain represents a health risk for both humans and animals. The gastrointestinal microbiota represents potentially the first target for these food contaminants. Thus, the effects of mycotoxins on the human gut microbiota is clearly an issue that needs to be addressed in further detail. Using a human microbiota-associated rat model, the aim of the present study was to evaluate the impact of a chronic exposure of DON on the composition of human gut microbiota.

Methodology/Principal Findings

Four groups of 5 germ free male rats each, housed in 4 sterile isolators, were inoculated with a different fresh human fecal flora. Rats were then fed daily by gavage with a solution of DON at 100 µg/kg bw for 4 weeks. Fecal samples were collected at day 0 before the beginning of the treatment; days 7, 16, 21, and 27 during the treatment; and 10 days after the end of the treatment at day 37. DON effect was assessed by real-time PCR quantification of dominant and subdominant bacterial groups in feces. Despite a different intestinal microbiota in each isolator, similar trends were generally observed. During oral DON exposure, a significant increase of 0.5 log10 was observed for the Bacteroides/Prevotella group during the first 3 weeks of administration. Concentration levels for Escherichia coli decreased at day 27. This significant decrease (0.9 log10 CFU/g) remained stable until the end of the experiment.

Conclusions/Significance

We have demonstrated an impact of oral DON exposure on the human gut microbiota composition. These findings can serve as a template for risk assessment studies of food contaminants on the human gut microbiota.     

Operational Changes in a Shared Resource Laboratory with the Use of a Product Lifecycle Management Approach: A Case Study

Shared Resource Laboratories (SRLs) provide investigators access to necessary scientific and resource expertise to leverage complex technologies fully for advancing high-quality biomedical research in a cost-effective manner. At the University of Nebraska Medical Center, the Flow Cytometry Research Facility (FCRF) offered access to exceptional technology, but the methods of operation were outdated and unsustainable. Whereas technology has advanced and the institute has expanded, the operations at the facility remained unchanged for 35 yr. To rectify this, at the end of 2013, we took a product lifecycle management approach to affect large operational changes and align the services offered with the SRL goal of education, as well as to provide service to researchers. These disruptive operational changes took over 10 mo to complete and allowed for independent end-user acquisition of flow cytometry data. The results have been monitored for the past 12 mo. The operational changes have had a positive impact on the quality of research, increased investigator-facility interaction, reduced stress of facility staff, and increased overall use of the resources. This product lifecycle management approach to facility operations allowed us to conceive of, design, implement, and monitor effectively the changes at the FCRF. This approach should be considered by SRL management when faced with the need for operationally disruptive measures.     

Triglycerides in the Human Kidney Cortex: Relationship with Body Size

Obesity is associated with increased risk for kidney disease and uric acid nephrolithiasis, but the pathophysiological mechanisms underpinning these associations are incompletely understood. Animal experiments have suggested that renal lipid accumulation and lipotoxicity may play a role, but whether lipid accumulation occurs in humans with increasing body mass index (BMI) is unknown. The association between obesity and abnormal triglyceride accumulation in non-adipose tissues (steatosis) has been described in the liver, heart, skeletal muscle and pancreas, but not in the human kidney. We used a quantitative biochemical assay to quantify triglyceride in normal kidney cortex samples from 54 patients undergoing nephrectomy for localized renal cell carcinoma. In subsets of the study population we evaluated the localization of lipid droplets by Oil Red O staining and measured 16 common ceramide species by mass spectrometry. There was a positive correlation between kidney cortex trigyceride content and BMI (Spearman R = 0.27, P = 0.04). Lipid droplets detectable by optical microscopy had a sporadic distribution but were generally more prevalent in individuals with higher BMI, with predominant localization in proximal tubule cells and to a lesser extent in glomeruli. Total ceramide content was inversely correlated with triglycerides. We postulate that obesity is associated with abnormal triglyceride accumulation (steatosis) in the human kidney. In turn, steatosis and lipotoxicity may contribute to the pathogenesis of obesity-associated kidney disease and nephrolithiasis.