Assessing the uniformity of plutonium alpha radiation dose in human lung: the Mayak experience

Radiation-induced lung cancer risk is currently estimated based on epidemiological data from populations exposed either to relatively uniform, low-LET radiation, or from uranium miners who inhaled radon and its progeny. Inhaled alpha-emitting radionuclides (e.g. Pu and Am) produce distinctive dose patterns that may not be adequately modelled at present. Thus the distribution of Pu is being measured in formalin-fixed autopsy lung tissue from former workers at the Mayak Production Association, and which is maintained in a tissue archive at SUBI. Lungs are sampled using contemporary stereological techniques and Pu particle activities and locations are determined using quantitative autoradiography and morphological identification of lung structures. To date, > 80% of Pu particles have been observed in parenchymal lung tissues with higher concentrations being found in scar tissue. Concentrations of Pu particles in conducting airways are uniformly low, thus indicating that long-term-retained Pu particles are non-uniformly distributed in human lung, mostly in the parenchyma.     

The distribution of the number of alpha hits per target cell: a new parameter to improve risk assessment for cancer induction using ICRP models

Doses are calculated from the total energy deposited within the different target regions of the organism. After inhalation exposure, only a few particles can be deposited within the respiratory tract that induces a heterogeneous dose distribution. A decrease in risk for lung tumours induction associated to the presence of hot spots has been reported. This was partly explained by a decrease in the transformation rate per gray when cells received more than one alpha hit. This study provides an estimate of the distribution of alpha hits per target cell of the extra thoracic region (ET2), after inhalation exposure to 238UO2, 239PuO2 or 238PuO2, obtained by a stochastic application of the biokinetic and dosimetric ICRP models. After exposure to one annual limit of intake, homogeneous irradiation of the target cells is observed for 238UO2, whereas, for PuO2, most of the dose is due to cells receiving daily tens or even hundreds of alpha hits. This underlines the uncertainties in risk assessment associated with a dose rate effect.     

Probability of bystander effect induced by alpha-particles emitted by radon progeny using the analytical model of tracheobronchial tree

Radiation-induced biological bystander effects have become a phenomenon associated with the interaction of radiation with cells. There is a need to include the influence of biological effects in the dosimetry of the human lung. With this aim, the purpose of this work is to calculate the probability of bystander effect induced by alpha-particle radiation on sensitive cells of the human lung. Probability was calculated by applying the analytical model cylinder bifurcation, which was created to simulate the geometry of the human lung with the geometric distribution of cell nuclei in the airway wall of the tracheobronchial tree. This analytical model of the human tracheobronchial tree represents the extension of the ICRP 66 model, and follows it as much as possible. Reported probabilities are calculated for various targets and alpha-particle energies. Probability of bystander effect has been calculated for alpha particles with 6 and 7.69 MeV energies, which are emitted in the (222)Rn chain. The application of these results may enhance current dose risk estimation approaches in the sense of the inclusion of the influence of the biological effects.     

Target cells in internal dosimetry

Data related to radium induced bone sarcomas in humans are used as a method of defining target cells on bone surfaces and in the bone marrow. The differential distribution of radiation induced bone sarcoma types, with a high ratio of non-bone producing, mainly fibroblastic tumours, challenges the ICRP concept that the bone lining cells are target cells. Multipotential mesenchymal stem cells are located within the range of alpha particles and are the most likely target cells for the fibroblastic type of bone sarcoma. The histogenesis of bone sarcomas after irradiation with alpha emitters shows that their final histopathology is not dependent on a single target cell. Each target cell has a microenvironment, which has to be regarded as a synergistic morpho-functional tissue unit. For this the concept of 'histion', a term used in general pathology, is proposed. Interactions between target cells that have been hit by alpha particles, leading to lethal, mutational or transformation events with all components of a 'histion', will prove critical to understanding the pathogenesis of both deterministic and stochastic late effects.     

Synergistic Effects of Incubation in Rotating Bioreactors and Cumulative Low Dose 60Co γ-ray Irradiation on Human Immortal Lymphoblastoid Cells

The complex space environments can influence cell structure and function. The research results on space biology have shown that the major mutagenic factors in space are microgravity and ionizing radiation. In addition, possible synergistic effects of radiation and microgravity on human cells are not well understood. In this study, human immortal lymphoblastoid cells were established from human peripheral blood lymphocytes and the cells were treated with low dose (0.1, 0.15 and 0.2?Gy) cumulative ⁶⁰Co ??-irradiation and simulated weightlessness [obtained by culturing cells in the Rotating Cell Culture System (RCCS)]. The commonly used indexes of cell damage such as micronucleus rate, cell cycle and mitotic index were studied. Previous work has proved that Gadd45 (growth arrest and DNA-damage-inducible protein 45) gene increases with a dose-effect relationship, and will possibly be a new biological dosimeter to show irradiation damage. So Gadd45 expression is also detected in this study. The micronucleus rate and the expression of Gadd45?? gene increased with irradiation dose and were much higher after incubation in the rotating bioreactor than that in the static irradiation group, while the cell proliferation after incubation in the rotating bioreactor decreased at the same time. These results indicate synergetic effects of simulated weightlessness and low dose irradiation in human cells. The cell damage inflicted by ??-irradiation increased under simulated weightlessness. Our results suggest that during medium- and long-term flight, the human body can be damaged by cumulative low dose radiation, and the damage will even be increased by microgravity in space.     

纳米石墨片-羧基丁腈橡胶复合材料结构形态与电性能

利用电子束辐照法制备纳米石墨片(GnPs)-羧基丁腈橡胶(XNBR)复合材料,研究辐射剂量对胶乳共混体系稳定性的影响,并对GnPs-XNBR复合材料的交联度、热稳定性、电性能及其形貌予以表征。结果表明:辐照后GnPs-XNBR复合材料的交联度、热稳定性和体积电阻率提高,而共混乳液的稳定性显著降低。辐照强化了乳胶粒子与石墨片之间的界面结合,形成胶乳粒子包覆石墨片的核-壳结构,进而提高石墨片在基体中分散均匀性,并使GnPs-XNBR复合材料的热稳定性和介电常数提高,导电性和介电损耗降低。     

A novel photothermally controlled multifunctional scaffold for clinical treatment of osteosarcoma and tissue regeneration

After an osteosarcoma excision, recurrence, large bone defects, and soft tissue injury are significant challenges for clinicians. Conventional treatment by implanting bone replacement materials can induce bone regeneration after surgery, but this does not prevent bleeding, promote soft tissue repair, or help destroy the residual tumor cells. We attempted to develop a new multifunctional scaffold, with the clinical goals of facilitating tumor cell death through thermal ablation and promoting osteogenesis. Accordingly, we first investigated the effect of nano-hydroxyapatite/graphene oxide (nHA/GO) composite particles with different proportions on human osteosarcoma cells (HOS), pre-osteoblastic MC3T3-E1 cells, and human bone marrow mesenchymal stem cells (hBMSC) with or without 808-nm near-infrared (NIR) light irradiation. Next, we fabricated a novel temperature-controlled multifunctional nano-hydroxyapatite/graphene oxide/chitosan (nHA/GO/CS) scaffold, which can effectively kill human osteosarcoma cells under 808-nm NIR irradiation by reaching a temperature of 48 °C and further promote osteogenesis of hBMSC at 42 ± 0.5 °C in coordination with nHA. This scaffold demonstrates the best post-operative bone volume/tissue volume (BV/TV) ratio performance (20.36%) 8 weeks after scaffold implantation in the cranial defects of rats. Further exploration has revealed that NIR irradiation may promote the osteogenesis of hBMSC with the addition of nHA by enhancing the BMP2/Smad signaling pathway. Further, this scaffold has a good hemostatic effect and facilitates soft tissue repair under irradiation. This novel photothermally controlled multifunctional scaffold, which not only kills human osteosarcoma cells but also facilitates tissue regeneration, is a promising clinical tool for treating tissue injuries from an osteosarcoma resection.     

The In Vivo Radiosensitizing Effect of Gold Nanoparticles Based MRI Contrast Agents

Owing to the high atomic number (Z) of gold element, the gold nanoparticles appear as very promising radiosensitizing agents. This character can be exploited for improving the selectivity of radiotherapy. However, such an improvement is possible only if irradiation is performed when the gold content is high in the tumor and low in the surrounding healthy tissue. As a result, the beneficial action of irradiation (the eradication of the tumor) should occur while the deleterious side effects of radiotherapy should be limited by sparing the healthy tissue. The location of the radiosensitizers is therefore required to initiate the radiotherapy. Designing gold nanoparticles for monitoring their distribution by magnetic resonance imaging (MRI) is an asset due to the high resolution of MRI which permits the accurate location of particles and therefore the determination of the optimal time for the irradiation. We recently demonstrated that ultrasmall gold nanoparticles coated by gadolinium chelates (Au@DTDTPA‐Gd) can be followed up by MRI after intravenous injection. Herein, Au@DTDTPA and Au@DTDTPA‐Gd were prepared in order to evaluate their potential for radiosensitization. Comet assays and in vivo experiments suggest that these particles appear well suited for improving the selectivity of the radiotherapy. The dose which is used for inducing similar levels of DNA alteration is divided by two when cells are incubated with the gold nanoparticles prior to the irradiation. Moreover, the increase in the lifespan of tumor bearing rats is more important when the irradiation is performed after the injection of the gold nanoparticles. In the case of treatment of rats with a brain tumor (9L gliosarcoma, a radio‐resistant tumor in a radiosensitive organ), the delay between the intravenous injection and the irradiation was determined by MRI.     

Chromosome aberration induction is dependent on the spatial distribution of energy deposition through a cell nucleus

The importance of the spatial distribution of energy deposition through the nucleus in determining the resultant chromosome rearrangements was investigated using fluorescent in situ hybridisation technique following either uniform or partial irradiation of HF19 human fibroblast cells with low-LET 1.5 keV ultrasoft X-rays. Irradiations were performed with and without a copper irradiation mask with a Poisson distribution of micron-sized holes immediately below the irradiation dish and the results are compared with previous results obtained following exposure to a Poisson distribution of alpha particles. For the same radiation quality, the spatial distribution of energy deposition within the nucleus was found to be important in determining the ultimate biological response, with an increased ratio of complex-to-simple aberrations observed for partial compared to uniform irradiation. Comparisons between low-LET ultrasoft X-rays and high-LET alpha particles indicate that the sub-micron clustering of damage along the alpha particle track is more important than just the total number of double-strand breaks produced.     

The microdosimetry of boron neutron capture therapy in a randomised ellipsoidal cell geometry

Two reactions deliver the majority of local dose in boron neutron capture therapy. The ionised particles (protons, alpha particles and lithium nuclei) produced in the two reactions, 10B(n,alpha,gamma)7Li and 14N(n,p)14O, have short ranges that are less than -14 microm (which is on the order of the diameter of a typical human cell). The ionised particles are heavy and are in the 2+ charge state in the case of the boron reactions. These heavy 2+ ions will do significant damage to molecules near their tracks. Thus, the distribution of nitrogen and, in particular, of boron determines the spatial characteristics of the radiation field. Since the distribution of nitrogen is nearly homogeneous in the brain and is not easily altered for the purpose of radiotherapy, the spatial variation in the radiation dose is due mainly to the spatial distribution of boron. This implies that the spatial distribution of boron determines the microscopic energy deposition and therefore the spatial characteristics of the microscopic dose. The microscopic dose from the (n,alpha) and (n,p) reactions has been examined in detail and, as averred, the proton dose is relatively homogeneous except for statistical variability. The statistical variability in essence adds a false spatial variability that would not be seen if a large number of histories were performed. Since the majority of spatial variability occurs in the boron distribution, the (n,p) reaction can be suppressed to better understand the spatial distribution effects on the microscopic dose. Programs have been written in FORTRAN using Monte Carlo techniques to model ellipsoidal cells that are either randomly sized and located in the region of interest or are arranged in a face centred cubic array and are identical except for the location of the nuclei, which may be random. It is shown that closely packed prolate ellipsoidal cells with a large eccentricity in one dimension will receive a larger nuclear dose than cells that are more sparsely packed. This demonstrates that the boron content of a cell and its nucleus can have a significant impact upon the dose to neighbouring cells. The local boron distribution in a region of interest can be shown to affect the macrodosimetric dose, with possible implications for clinical outcomes.     

LUNG CANCER IN RATS FROM PROLONGED EXPOSURE TO HIGH CONCENTRATIONS OF CARBONACEOUS PARTICLES: IMPLICATIONS FOR HUMAN RISK ASSESSMENT

High incidences of lung cancers have been observed in a number of studies in which rats were chronically exposed by inhalation to high concentrations of diesel engine exhaust and carbon black particles. These particles have previously been viewed as being relatively innocuous compared with other particles such as benzo[a]pyrene that are carcinogenic because of specific chemical properties. Studies with mice and Syrian hamsters exposed to similar concentrations of diesel exhaust did not produce an excess of lung cancer or yielded equivocal outcomes. Diesel exhaust soot and carbon black particles are readily inhaled and deposited in the pulmonary region, where they are retained with a long half-life because of their low solubility. Substantial evidence indicates that the increased incidence of rat lung cancers results from the accumulation of large burdens of particles in the lungs, altered clearance of particles from the lungs, persistent inflammation, increased cell turnover, and induction of mutations in lung epithelial cells. The mutations and subsequent tumors are hypothesized to occur as a result of persistent inflammation and increased cell turnover rather than as a result of direct interaction of chemical constituents of the particles with DNA of lung cells. The observed effects in rats appear to be threshold phenomena that occur only with prolonged exposure to high concentrations of particles. Thus the rat lung cancer findings at high concentrations should not be extrapolated to low concentrations using the linearized multistage model typically used as a default assumption for assessing (he cancer risk of chemicals. This article reviews past approaches to evaluating the carcinogenic risk of diesel exhaust and carbon black and suggests alternative approaches to characterizing their human cancer risk.     

Monte Carlo dosimetry for targeted irradiation of individual cells using a microbeam facility

Microbeam facilities provide a unique opportunity to investigatethe effects of ionising radiation on living biological cellswith a precise control of the delivered dose. This paper describesdosimetry calculations performed at the single-cell level inthe microbeam irradiation facility available at the Centre d'EtudesNucléaires de Bordeaux-Gradignan in France, using theobject-oriented Geant4 Monte Carlo simulation toolkit. The cellgeometry model is based on high-resolution three-dimensionalvoxelised phantoms of a human keratinocyte (HaCaT) cell line.Such phantoms are built from confocal microscopy imaging andfrom ion beam chemical elemental analysis. Results are presentedfor single-cell irradiation with 3 MeV incident alpha particles.     

Novel approaches with track segment alpha particles and cell co-cultures in studies of bystander effects

There is now a significant body of data that indicate that the effects of ionising radiation may extend to more than those cells that directly suffer damage to DNA in the cell nucleus. Cells neighbouring those cells that are irradiated, or even well separated from those that are irradiated demonstrate several responses that are recorded in hit cells as a function of absorbed dose. That is, the responding non-hit cells are bystanders of hit cells. A protocol has been devised which allows for examination of one means of eliciting bystander responses, specifically, effects on non-contacting cells. Cell culture chambers are set up such that a population of cells is physically separate from the energy depositions of track segment charged particles. Absorption of energy in sub-millimetre distances in the cell culture medium ensures that one population of cells can only respond to factors generated in the irradiated medium or in another population of irradiated co-cultured cells, which may be of similar or dissimilar origin. For irradiation of medium alone, enhanced levels of micronuclei, and of delays in cell cycle progression occur in normal human fibroblasts, but not epithelial cells. This procedure allows for a defining of the factors responsible for initiating bystander effects and for determining their quantitative relevance.     

Comparative pulmonary toxicity assessments of C60 water suspensions in rats: few differences in fullerene toxicity in vivo in contrast to in vitro profiles

It has previously been reported that the in vitro cytotoxic effects of water-soluble fullerene species are a sensitive function of their surface derivatization status. In a recent study, it was reported that doses of an aggregated form of underivatized C60, termed nano-C60, were 3-4 orders of magnitude more toxic to human dermal fibroblasts, lung epithelial cells, and normal human astrocytes when compared to identical exposures of these cell types to a fully derivatized, highly water-soluble derivative, C60(OH)24. Accordingly, the aim of this study was to test and validate these in vitro findings by comparing the in vivo pulmonary toxicity effects in rats of intratracheally instilled nano-C60 and C60(OH)24. In two combined studies, groups of rats were instilled with doses of either 0.2, 0.4, 1.5, or 3.0 mg/kg of nano-C60, C60(OH)24, or alpha-quartz particle types using Milli-Q water as the vehicle. Subsequently, the lungs of vehicle and particle-exposed rats were assessed using bronchoalveolar lavage (BAL) fluid biomarkers, oxidant and glutathione endpoints, airway and lung parenchymal cell proliferation methods, and histopathological evaluation of lung tissue at 1 day, 1 week, 1 month, and 3 months postinstillation exposure. Exposures to both nano-C60 or water-soluble C60(OH)24 produced only transient inflammatory and cell injury effects at 1 day postexposure (pe) and were not different from water instilled controls at any other pe time periods. An increase in lipid peroxidation endpoints vs controls was measured in BAL fluids of rats exposed to 1.5 and 3 mg/kg of nano-C60 at 1 day and 3 month pe time points. In addition, no adverse lung tissue effects were measured at 3 months postinstillation exposures to the highest dose of the two types of fullerenes. In contrast, pulmonary exposures to quartz particles in rats produced dose-dependent lung inflammatory responses characterized by neutrophils and foamy lipid-containing alveolar macrophage accumulation as well as evidence of early lung tissue thickening consistent with the development of pulmonary fibrosis. The results demonstrated little or no difference in lung toxicity effects between the two fullerene samples when compared to controls, and these data are not consistent with the previously reported in vitro effects. The findings exemplify both the difficulty in interpreting and extrapolating in vitro toxicity measurements to in vivo effects and highlight the complexities associated with probing the relevant toxicological responses of fullerene nanoparticle systems.     

Dose dependent in vivo metabolic characteristics of titanium dioxide nanoparticles

Nanoparticle in vivo characteristics and interactions between nanoparticles and organisms are key components of nanotoxicology. 1H NMR was used to analyze rat urine metabolites exposed to TiO, nanopartcles by intratracheal instillation in low (0.8 mg/kg), medium (4 mg/kg) and high doses (20 mg/kg). Significant metabolite (Acetate, Valine, Dimethylamine, Taurine, Hippurate, and 2-Oxoglutarate) changes were only observed in the low dose group. These compensatory changes resolve within seven days, and the results of serum biochemical assays also implied no parenchymal damages in the liver or kidney. Rats exposed to medium and high dose nanoparticles had pulmonary inflammation because most of the instilled particles aggregated into larger sizes and accumulated in lung tissue. We conclude that low dose instillation of nano-TiO, can recoverably impact metabolic function because the scattered nanoparticles can migrate from the lung to liver or kidney, but particles in higher doses will aggregate and deposit in the lung without migration.     

Mitotic arrest caused by an X-ray microbeam in a single cell expressing EGFP-aurora kinase B

Although the highest radiosensitivity of cells in the M phase among the other cell phases, such as the G(1), S and G(2) phases, has been known, the exact mechanism of radiosensitivity in mitotic cells remains unclear. Recently, mitotic arrest caused by DNA-damaging reagents has been shown, and the molecular mechanism in the arrest has been discussed in detail. In this study, abnormal cell-cycle progression in the M phase was investigated when a single mitotic cell in each mitotic stage was irradiated with a 5.35 keV X-ray microbeam focused on the cell nucleus. An X-ray microbeam irradiation system installed at BL-27 in Photon Factory, High Energy Accelerator Research Organization (HEARO, Tsukuba) was used. HeLa cells, genetically modified and expressing enhanced green fluorescent protein-tagged aurora kinase B, were used as irradiated samples in order to recognise the stage of each cell in the M phase. Thus, 10 Gy irradiation concentrated at the nucleus of a single cell elongated the cell-cycle progression in the M phase by delaying the metaphase/anaphase transition. The dose dependence of the elongation of the M phase was also examined. An irregular distribution of DNA in anaphase cells was observed after irradiation.     

Preparation and Characterization of Fe3O4 Magnetic Nano-particles by 60Co γ-ray Irradiation

By using a new method, ^60Co γ-ray irradiation, Fe3O4 magnetic nano-particles were successfully synthesized at room temperature under ambient pressure. The structure, morphology and magnetic properties of these nanoparticles were characterized by X-ray diffraction （XRD）, transmission electron microscope （TEM） and vibrating sample magnetometer （VSM）, respectively. The radiation formation mechanism was also discussed. The results show that the absorbed dose can greatly influence the structure, morphology and magnetic properties of the products. XRD and TEM studies show that the product prepared by γ-ray irradiation （10 kGy） is pure FesO4 phase and the mean diameter of these nano-particles is about 21 nm. The Fe3O4 nano-particles synthesized by γ-ray irradiation （10 kGy） are mainly in small cubic shape and the size uniformity of these particles is good.     

Uncertainty analysis of the weighted equivalent lung dose per unit exposure to radon progeny in the home

A parameter uncertainty analysis has been performed to derive the probability distribution of the weighted equivalent dose to lung for an adult (w(lung) H(lung)) per unit exposure to radon progeny in the home. The analysis was performed using the ICRP Publication 66 human respiratory tract model (HRTM) with tissue weighting factor for the lung, w(lung) = 0.12 and the radiation weighting factor for alpha particles, wR = 20. It is assumed that the HRTM is a realistic representation of the physical and biological processes, and that the parameter values are uncertain. The parameter probability distributions used in the analysis were based on a combination of experimental results and expert judgement from several prominent European scientists. The assignment of the probability distributions describing the uncertainty in the values of the assigned fractions (ABB, Abb, AAI) of the tissue weighting factor proved difficult in practice due to lack of quantitative data. Because of this several distributions were considered. The results of the analysis give a mean value of w(lung) H(lung) per unit exposure to radon progeny in the home of 15 mSv per working level month (WLM) for a population. For a given radon gas concentration, the mean value of w(lung) H(lung) per unit exposure is 13 mSv per 200 Bq.m(-3).y of 222Rn. Parameters characterising the distributions of w(lung) H(lung) per unit exposure are given. If the ICRP weighting factors are fixed at their default values (ABB, Abb, AAI = 0.333, 0.333, 0.333; w(lung) = 0.12; and wr = 20) then on the basis of this uncertainty analysis it is extremely unlikely (P approximately 0.0007) that a value of Hw/Pp for exposure in the home is as low as 4 mSv per WLM, the value determined with the epidemiological approach. Even when the uncertainties in the ABB, Abb, AAI, values are included then this probability is predicted to be between 0.01 to 0.08 depending upon the distribution assumed for describing the uncertainties in the ABB, Abb, AAI, values. Thus, it is concluded that the uncertainties in the HRTM parameters considered in this study cannot totally account for the discrepancy between the dosimetric and epidemiological approaches.