Comparative Analysis of Behavioral Reactions and Morphological Changes in the Rat Brain After Exposure to Ionizing Radiation with Different Physical Characteristics.

The aim of this research was to study behavioral reactions and morphological changes in the brain of adult female Sprague Dawley rats after exposure to 170 MeV and 70 MeV protons and gamma radiation (60Co) at a dose of 1 Gy. The analysis of the behavioral reactions in the T-maze showed that exposure to ionizing radiation with different LETs led to an increase in number of repeated entries into the arms of the maze in the spontaneous alternation test. In the Open Field test a decrease in overall motor activity in the group of irradiated animals (70 MeV protons at the Bragg peak) was observed. A decrease in the number of standing positions was seen in all groups of irradiated animals. Morphological analysis showed the development of early amyloidosis, autolysis of the ependymal layer, an increase in the number of neurodegenerative changes in various structures of the brain, and the development of neuronal hypertrophy on the 30th day after irradiation in the cerebellum and hippocampal hilus. Exposure to protons at a dose of 1 Gy leads to the development of structural and functional disorders of the central nervous system of animals on the 30th day after irradiation. These data indicate a damage of short-term memory, a decrease in motor activity and exploratory behavior of animals. With an increase in LET, there is an increase in the number of amyloid plaques in the forebrain of rats, autolysis of the ependymal layer of the ventricles, and the development of dystrophic changes. Investigations of behavioral reactions and morphological changes in various parts of the brain of adult rats on the 30th day after influence of ionizing radiation with different physical characteristics at a dose of 1 Gy. Various negative patho-morphological and cognitive-behavioral changes observed.

DNA Damage in Splenocytes of Mice Exposed to Secondary Radiation Created by 650 MeV Protons Bombarding a Concrete Shielding Barrier.

The proportion of splenocytes with a high level of DNA double-strand breaks was determined in mice exposed to primary and secondary radiation created by bombarding of a concrete barrier (thickness 20, 40, and 80 cm) by 650 MeV protons. The proportion of splenocytes with a high level of DNA double-strand breaks was assessed by flow cytometric analysis of γH2AX+ and TUNEL+ cells. It is shown that concrete barrier can significantly reduce primary proton radiation; the severity of negative biological effects in mice irradiated in the center of the proton beam decreased with increasing the thickness of this barrier. However, the spectrum of secondary radiation changes significantly with increasing the barrier thickness from 20 to 80 cm and the distance from central axis of the beam from 0 to 20 cm, and the proportion of the neutron component increases, which also causes negative biological effects manifesting in a significant (p<0.05) increase in the percentage of splenocytes with a high level of DNA damage in mice irradiated at a distance of 20 cm from the center of the proton beam and receiving relatively low doses (0.10-0.17 Gy).

[DEMONSTRATION OF LIKELIHOOD OF THE NEGATIVE EFFECT OF PHYSICAL PROTECTION DURING TOTAL PROTON IRRADIATION OF MICE].

The experiments were performed with outbred CD-1 male mice (SPF category). Total irradiation at 1.0; 2.5 and 5.0 Gy by protons with the average energy of 170 MeV was conducted in a level medical beam of the phasotron at the Joint Institute of Nuclear Investigations. Targets were 2 points of in-depth dose distribution, i.e. beam entrance of the object, and modified Bragg peak. As a physical protector, the comb filter increases linear energy transfer (LET) of 170 MeV entrance protons from 0.49 keV/µm to 1.6 keV/µm and, according to the bone marrow test, doubles the biological effectiveness of protons when comparing radiation doses that cause 37% inhibition of blood cell formation in the bone marrow. Physical protection increases dose rate from 0.37 Gy/min for entrance protons to 0.8 Gy/min for moderated protons which more than in thrice reduces time of irradiation needed to reach an equal radiobiological effect.

[IMMEDIATE RADIOBIOLOGICAL EFFECTS IN MICE FOLLOWING γ-IRRADIATION BY LOW DOSES].

Outbred CD-1 mice females aged 4 to 4.5-months were investigated in 21-22 hours following total γ-irradiation at 10, 25, 50, 75, 100 and 200 mGy. Loss in bone marrow karyocytes, as well as spleen and thymus mass reductions were significant in the group of animals irradiated at 50 and 200 mGy and less dramatic in mice irradiated at 75 mGy. The orientative-trying behavior reaction (OTBR) in the open field tested in 19-20 hours after exposure to 10 and 25 mGy was reliably stronger than in the group of biological control; however, emotional status (ES) in the animals that received 10 mGy dropped significantly. Mice irradiated at 50 mGy were found to weaken the grip of their front limbs. Dose levels differing in opposite radiobiological effects on the parameters under study were established. Doses in the range from 10 to 25 mGy maximized OTBR and ES, while doses of 50, 100 and 200 mGy produced high reactions of the immune and hemopoietic organs.

[CYSTEAMINE-INDUCED MODIFICATION OF CYTOGENETIC DAMAGES TO THE CORNEAL EPITHELIUM OF MICE EXPOSED TO CORPUSCULAR RADIATION WITH VARYING LINEAR TRANSFER ENERGIES].

Cytogenetic damages to cells of the corneal epithelium were studied in mice exposed to protons (10, 25, 50 and 645 MeV), ions of boron, carbon and neon, and X-rays (180 keV) within the dose range from 25 to 750 cGy and injected with a radioprotector. Animals were subjected to a single exposure. The protective effect of ß-mercaptoethylamine was tested in the experiment. The radioprotector (0.2 ml) was introduced intraperitoneally 30 minutes before exposure in 350 mI/kg dose. Control animals received the same amount of sodium chloride solution. The animals were sacrificed by cervical dislocation in 24 and 72 hrs. after exposure. It was shown that cysteamine effectively protects in vivo corneal epithelium cells of mice exposed to electromagnetic radiation or protons in a broad energy spectrum (10 to 645 MeV), and to a broad range of radiation doses (25 to 750 cGy), as judged from levels of aberrant mitosis and mitotic activity. The radioprotector exhibited the highest effectiveness in animals exposed to the doses of 50 to 300 cGy. These findings prove that cysteamine may potentially be used for pharmacological protection from protons. The radioprotector failed to prevent chromosomal aberrations after exposure to heavy charged particles of boron, carbon and neon, which implies the need to design radioprotectors against this type of corpuscular radiation specifically.

[Cytogenetic damage to the corneal epithelium of mice due to the in vivo exposure to ionizing radiation with different levels of linear energy transfer].

Damages to corneal epithelium cells were studied in mice irradiated by protons with the energies of 10, 25, 50 and 645 MeV, 60Co γ-quanta and accelerated ions of boron, carbon and neon with the energies of 7.5; 2.5 and 6.0 MeV/nucleon, respectively. X-rays (180 keV) were used as a standard radiation. Animals were exposed to a single dose in the range from 25 to 760 cGy. The mitotic index and aberrant mitoses were counted in corneal preparations in 24 hrs after irradiation. No matter the type of radiation, the mitotic index had an inverse dose dependence, i.e. the higher the dose, the lower the mitotic index. Exposure to all types of radiation resulted in a sharp increase in the number of chromosomal aberrations in the corneal epithelium; frequency of aberrations was a function of dose and type of radiation. The number of chromosomal aberrations displayed a peculiar direct dose dependence irrespective of type of radiation; however, heavy ions of carbon and boron are the most damaging to the cytogenetic apparatus of epithelial cells. Protons at the Bragg peak and ensuing fall, and of 50 MeV also contribute to the production of chromosomal aberrations as compared with sparsely ionizing gamma- and X-rays and high-energy protons with low linear energy transfer. Coefficients of relative biological effectiveness were calculated based on the mitotic index and evidence of aberrant mitosis.

[MODIFICATION OF THE PROTON BEAM PHYSICAL PARAMETERS AND RADIOBIOLOGICAL CHARACTERISTICS BY ELEMENTS OF SPACECRAFT RADIATION PROTECTION].

The experiment was performed with outbred ICR (CD-1). female mice (SPF). The animals were irradiated by 171 MeV protons at a dose of 20 cGy. The spacecraft radiation protection elements used in the experiment were a construction of wet hygiene wipes called a "protective blind", and a glass plate imitating an ISS window. Physical obstacles on the path of 171 MeV protons increase their linear energy transfer leading to the absorbed dose elevation and strengthening of the radiobiological effect. In the experiment, two types of obstacles together raised the absorbed dose from 20 to 23.2 cGy. Chemically different materials (glass and water in the wipes) were found to exert unequal modifying effects on physical and biological parameters of the proton-irradiated mice. There was a distinct dose-dependent reduction of bone marrow cellularity within the dose range from 20 cGy to 23.2 cGy in 24 hours after exposure. No modifying effect of the radiation protection elements on spontaneous motor activity was discovered when compared with entrance protons. The group of animals protected by the glass plate exhibited normal orientative-trying reactions and weakened grip with the forelimbs. Rationalization of physical methods of spacecrew protection should be based as on knowledge in physical dosimetry (ionizing chambers, thermoluminescent, track detectors etc.), so the radiobiological criteria established in experiments with animals.

Dose distribution outside the target volume for 170-MeV proton beam.

Dose delivered outside the proton field during radiotherapy can potentially lead to secondary cancer development. Measurements with a 170-MeV proton beam were performed with passive detectors (track etched detectors and thermoluminescence dosemeters) in three different depths along the Bragg curve. The measurement showed an uneven decrease of the dose outside of the beam field with local enhancements. The major contribution to the delivered dose is due to high-energy protons with linear energy transfer (LET) up to 10 keV µm(-1). However, both measurement and preliminary Monte Carlo calculation also confirmed the presence of particles with higher LET.

[Mitigation of mice radiation damage after acute and prolonged γ-irradiation by a laser device].

Effects of 7 Gy 60Co γ-radiation (acute and prolonged exposure), and combined exposure to 650 nm laser and γ-radiation on survival, peripheral blood, karyocyte count and mitotic index of bone marrow cells were studied in young C57BL/6 mice. All mice died following acute γ-irradiation at the dose rate of 1.14 Gy/min for 5 days or combined exposure for 11 days. Thirty percent survival from prolonged exposure to the dose rate of 0.027 Gy/min was observed after 19-day γ- and 38-day combined irradiation. Peripheral blood parameters did not differ significantly after acute and prolonged exposure; however, hyperchromemia was observed in mice after 24 hours of acute γ-irradiation. The count of mitoses per 1000 nucleus-containing BM cells evidenced that BM was virtually collapsed after 72 hours since the acute γ-exposure. It was demonstrated that laser can manage protection from a broad range of ionizing radiation doses and mitigate the adverse effects of equally acute and prolonged radiation exposure.

[Proton three-demensional conformal radiosurgery of arteriovenous malformation of the brain].

The proton beam radiosurgery was performed to 65 patients with brain AVM since December, 2001 till February, 2012, in Joint Institute for Nuclear Research, Dubna, Russia. We have analyzed data for 56 patients. The follow up time varied from 24 to 109 months. The volumes of brain AVMs varied from 0.92 to 82 cc. The mean isocenter dose was 24.61 +/- 0.12 Gy E. The edge of the target was included in 70-90% isodose. The proton beam surgery was splitted in two similar doses and delivered in two consecutive days in vast majority of patients. Ten patients were missed for follow up due to some reasons. The radiosurgery was resulted in full obliteration of AVM in 23 from remaining 46 (50%) patients. There was full obliteration in 46.6% of patients with volume of AVM 10-24.9 cc; and this rate is significantly more than for photon radiosurgery of same size brain AVM. The partial obliteration was obtained in 21 patients. Only one patients suffered hemorrhage from partially obliterated AVM. We could not see any effect in 2 patients. There were delayed radiation toxicity in 5 patients in 12 months after treatment: in 4 patients, these reactions were assessed as 2 according to RTOG scale and were dissipated in 1 month after commencement of corticosteroid treatment. There was radiation necrosis in one patient, and it was relieved in 12 months after several courses of dehydration and corticosteroid therapy. So, proton beam therapy is effective and safe modality for treatment of inoperable brain AVM, especially of middle- and large size.

[Radiobiological effects of total mice irradiation with Bragg's peak protons].

Outbred CD-1 female mice were irradiated in a proton beam (171 MeV, 5 Gy) on the phasotron at the Joint Institute of Nuclear Research (Dubna, Russia). Radiation was delivered in two points of the depth dose distribution: at the beam entry and on Bragg's peak. Technical requirements for studying the effects of Bragg's peak protons on organism of experimental animals were specified. It was recognized that protons with high linear energy transfer (mean LET = 1.6 keV/microm) cause a more severe damaging effect to the hemopoietic system and cytogenetic apparatus in bone marrow cells as compared with entry protons and 60Co gamma-quanta. It was shown that recovery of the main hemopoietic organs and immunity as well as elimination of chromosomal aberrations take more time following irradiation with Bragg's peak protons but not protons with the energy of 171 MeV.

Minimum detectable annual dose calculation for routine individual monitoring programme in case of plutonium and uranium contamination of the workplace.

An example of a numerical method application for minimum detectable annual dose calculation that can be guaranteed by the operating monitoring programmes for plutonium and uranium is presented. The method analyses the frequency distribution for a total number of counts obtained in n measurements performed during n monitoring intervals that are inside the calendar year. Urine sample radiometric measurement technique for plutonium and uranium operating monitoring programmes is investigated, showing dependences of the detection limits on the frequency of measurements, on number of calendar years under observation and on the activity median aerodynamic diameter (AMAD). Only a probability density function (PDF), for the background number of counts, stochastic variability of urine excretion and uncertainty of the intake pattern were taken into account as the main variables influencing the calculated detection limits. But there is no limitation for the proposed method to include the variability of other influencing model parameters in the calculation procedure.

A simple algorithm for solving the inverse problem of interpretation of uncertain individual measurements in internal dosimetry.

The individual monitoring of internal exposure of workers comprises two steps: measurement and measurement interpretation. The latter consists in reconstructing the intake of a radionuclide from the activity measurement and calculating the dose using a biokinetic model of the radionuclide behavior in the human body. Mathematically, reconstructing the intake is solving an inverse problem described by a measurement-model equation. The aim of this paper is to propose a solution to this inverse problem when the measurement-model parameters are considered as uncertain. For that, an analysis of the uncertainty on the intake calculation is performed taking into account the dispersion of the measured quantity and the uncertainties of the measurement-model parameters. It is shown that both frequentist and Bayesian approaches can be used to solve the problem according to the measurement-model formulation. A common calculation algorithm is proposed to support both approaches and applied to the examples of tritiated water intake and plutonium inhalation by a worker.

Internal dosimetry: towards harmonisation and coordination of research.

The CONRAD Project is a Coordinated Network for Radiation Dosimetry funded by the European Commission 6th Framework Programme. The activities developed within CONRAD Work Package 5 ('Coordination of Research on Internal Dosimetry') have contributed to improve the harmonisation and reliability in the assessment of internal doses. The tasks carried out included a study of uncertainties and the refinement of the IDEAS Guidelines associated with the evaluation of doses after intakes of radionuclides. The implementation and quality assurance of new biokinetic models for dose assessment and the first attempt to develop a generic dosimetric model for DTPA therapy are important WP5 achievements. Applications of voxel phantoms and Monte Carlo simulations for the assessment of intakes from in vivo measurements were also considered. A Nuclear Emergency Monitoring Network (EUREMON) has been established for the interpretation of monitoring data after accidental or deliberate releases of radionuclides. Finally, WP5 group has worked on the update of the existing IDEAS bibliographic, internal contamination and case evaluation databases. A summary of CONRAD WP5 objectives and results is presented here.

Internal dose assessments: uncertainty studies and update of ideas guidelines and databases within CONRAD project.

The work of Task Group 5.1 (uncertainty studies and revision of IDEAS guidelines) and Task Group 5.5 (update of IDEAS databases) of the CONRAD project is described. Scattering factor (SF) values (i.e. measurement uncertainties) have been calculated for different radionuclides and types of monitoring data using real data contained in the IDEAS Internal Contamination Database. Based upon this work and other published values, default SF values are suggested. Uncertainty studies have been carried out using both a Bayesian approach as well as a frequentist (classical) approach. The IDEAS guidelines have been revised in areas relating to the evaluation of an effective AMAD, guidance is given on evaluating wound cases with the NCRP wound model and suggestions made on the number and type of measurements required for dose assessment.

Evaluation of scattering factor values for internal dose assessment following the IDEAS guidelines: preliminary results.

The IDEAS Guidelines for the assessment of internal doses from monitoring data suggest default measurement uncertainties (i.e. scattering factors, SFs) to be used for different types of monitoring data. However, these default values were mainly based upon expert judgement. In this paper, SF values have been calculated for different radionuclides and types of monitoring data using real data contained in the IDEAS Internal Contamination Database. Results are presented.

Analysis of the uncertainty in internal dose estimate resulting from biological stochastic variability of excretion.

A method for investigating the uncertainty in internal dose estimate resulting from biological stochastic variability of excretion is proposed in the paper. The method is based on analysing generated cases of individual monitoring data using Monte Carlo simulation technique. In case of a single intake and assumption of stochastic variability of excretion is a single source of uncertainty it was shown that the intake (dose) uncertainty depends exclusively on the uncertainty of the bioassay data and the number of daily urine (faeces) measurements. Assuming a log-normal distribution for describing the variability of excretion a simple expression for calculating the uncertainty was proposed. In case of routine monitoring data it was shown that the uncertainty of annual intake (dose) estimate would depend on biological stochastic variability of excretion, type of excretion function and the number of monitoring intervals in a year. By the example of Pu and U aerosols it was shown that the effects of decreasing uncertainty in the dose estimate resulting from increasing the number of monitoring intervals in a year and from decreasing the uncertainty of bioassay data (performing a number of successive daily measurements, once in a year) should be estimated to optimise the routine monitoring program.

Coordination of research on internal dosimetry in Europe: the CONRAD project.

The EUropean RAdiation DOSimetry Group (EURADOS) initiated in 2005 the CONRAD Project, a Coordinated Network for Radiation Dosimetry funded by the European Commission (EC), within the 6th Framework Programme (FP). The main purpose of CONRAD is to generate a European Network in the field of Radiation Dosimetry and to promote both research activities and dissemination of knowledge. The objective of CONRAD Work Package 5 (WP5) is the coordination of research on assessment and evaluation of internal exposures. Nineteen institutes from 14 countries participate in this action. Some of the activities to be developed are continuations of former European projects supported by the EC in the 5th FP (OMINEX and IDEAS). Other tasks are linked with ICRP activities, and there are new actions never considered before. A collaboration is established with CONRAD Work Package 4, dealing with Computational Dosimetry, to organise an intercomparison on Monte Carlo modelling for in vivo measurements of (241)Am deposited in a knee phantom. Preliminary results associated with CONRAD WP5 tasks are presented here.

Dependence of the dose estimate on the time pattern of intake by the example of tritiated water intakes.

The uncertainties related to activity measurement and time pattern of intake in routine monitoring of internal exposure are considered through the example of tritiated water intakes. For this purpose, a combination of intake-to-bioassay and bioassay-to-intake calculations with Monte Carlo integration technique is introduced as a method of investigation. The time pattern of intake and the measured activity are defined as random input quantities. The probability density functions (PDFs) of the input quantities are defined and a Monte Carlo integration is performed to obtain the PDF of the output quantity which is either the value of intake estimated from a measured value of activity or the estimated activity from a given value of intake. Different possible estimates of the intake are considered: some represent the parameters of the PDF of the output quantity, others are derived from the commonly used constant chronic, I(CC), and mid-point, I(1/2), methods. The combinations of activity and intake estimates that would provide a stable estimate of the initial intake in intake-to-bioassay and bioassay-to-intake calculations were studied. Several intake estimates satisfying this requirement can be chosen depending on the task to be solved by adjusting the proper activity estimate.