High Relative Biological Effectiveness of 2 MeV Fast Neutrons for Induction of Medulloblastoma in Ptch1+/- Mice with Radiation-specific Deletion on Chromosome 13.

Neutron radiation, a high-linear energy transfer radiation, has a high relative biological effectiveness (RBE) for various end points. The age at exposure is an important modifier of the effects of radiation, including carcinogenesis, with infants being generally more radiosensitive. Ptch1+/- mice offer a unique experimental system for assessing radiation carcinogenesis. Spontaneous development of medulloblastoma tumors occurs in nonirradiated animals that lose their Ptch1+ allele, most frequently by a loss of heterozygosity (LOH) of chromosome 13 via recombination or non-disjunction (referred to as S-type tumors). In contrast, tumors occur in irradiated Ptch1+/- mice as a result of chromosome 13 LOH with an interstitial deletion (R-type), making spontaneous and radiation-induced tumors discernible. To elucidate the influence of age on the effect of fast neutrons, we irradiated Ptch1+/- mice with neutrons (mean energy, ∼2 MeV) or γ rays on embryonic day (E)14 and E17 and on postnatal day (P)1, 4 or 10 and classified the resulting medulloblastomas based on chromosome 13 aberrations. Instead of LOH, some tumors harbored mutations in their Ptch1+ gene via a nonirradiation-associated mechanism such as duplication, insertion, base substitution or deletion with microhomology-mediated end joining; thus, these tumors were classified as S-type. The RBE regarding the induction of R-type tumors was 12.9 (8.6, 17.2), 9.6 (6.9, 12.3), 21.5 (17.2, 25.8), and 7.1 (4.7, 9.5) (mean and 95% confidence interval) for mice irradiated on E14, E17, P1 and P4, respectively, with the highest value seen during the most active development of the tissue and P10 being completely resistant. These results indicate that the developmental stage at exposure of the tissue influences the RBE of neutrons.

Relative Biological Effectiveness and Non-Poissonian Distribution of Dicentric Chromosome Aberrations following Californium-252 Neutron Exposures of Human Peripheral Blood Lymphocytes.

Cells exposed to fast neutrons often exhibit a non-Poisson distribution of chromosome aberrations due to the high ionization density of the secondary reaction products. However, it is unknown whether lymphocytes exposed to californium-252 (252Cf) spectrum neutrons, of mean energy 2.1 MeV, demonstrate this same dispersion effect at low doses. Furthermore, there is no consensus regarding the relative biological effectiveness (RBE) of 252Cf neutrons. Dicentric and ring chromosome formations were assessed in human peripheral blood lymphocytes irradiated at doses of 12-135 mGy. The number of aberrations observed were tested for adherence to a Poisson distribution and the maximum low-dose relative biological effectiveness (RBEM) was also assessed. When 252Cf-irradiated lymphocytes were examined along with previously published cesium-137 (137Cs) data, RBEM values of 15.0 ± 2.2 and 25.7 ± 3.8 were found for the neutron-plus-photon and neutron-only dose components, respectively. Four of the five dose points were found to exhibit the expected, or close to the expected non-Poisson over-dispersion of aberrations. Thus, even at low doses of 252Cf fast neutrons, when sufficient lymphocyte nuclei are scored, chromosome aberration clustering can be observed.

Risk estimation of the low-dose fast neutrons on the molecular structure of the lipids of peripheral blood mononuclear cells.

Our immune system can be exposed to neutral ionizing radiation. This work proposed to investigate the impacts of low-dose fast neutrons on the molecular structure of the lipids of peripheral blood mononuclear cells (PBMCs) as the primary immune cells. The effects have been followed at the time of 0, 2, 4, and 8 days after neutron exposure. Sixty-four female Wistar rats were used in this work. Thirty-two of them were irradiated using a low-dose fast neutron (241Am-Be, 0.2 mGy/h). The other thirty-two were utilized as a control group. The changes in their lipids molecular structure were investigated using Fourier transform infrared (FTIR) spectroscopy. Besides, lipids were extracted, and the total phospholipids contents were estimated. At the time of 2 and 4 days after irradiation, the results showed significant changes in the molecular structure of lipids in those irradiated samples compare with their control samples, and multivariate analysis succeeded in differentiating between control and irradiated rats. In contrast, no alterations between control and irradiated were detected at the time of 0 and 8 days after. The low-dose fast neutron could induce free radicals, which indirectly affect the molecular structure of the lipids and could damage the phospholipids molecules, and the damage could be repaired.

Measurement of fast neutron contamination caused by the presence of wedge and block using CR-39 detector.

OBJECTIVE: Undesired neutron contamination imposed to patients during treatment is among the main factors increasing the risk of secondary cancer in radiotherapy. This additional undesirable dose is due to neutron contamination production in high-energy accelerators. In this study, neutron contamination is investigated in the presence of wedge and block in 15 MV photon fields of Siemens Primus linear accelerator. MATERIALS AND METHODS: Neutron production by 30°, 45°, and 60° wedges and cerrobend block was investigated. Measurements were conducted in a 10 cm × 10 cm field at the source to -surface distance of 100 cm at 0.5, 2, 3, and 4 cm depths of a 30 cm × 30 cm × 30 cm Perspex phantom using the CR-39 passive film detectors. Chemical etching was performed using sodium hydroxide solution with 6.25 M concentration as the etchant at 85°C for 3 h. RESULTS: The neutron dosimetry results reveal that the presence of wedge and block increases the neutron contamination. However, the 45° wedge is most effective in producing neutron contamination. The results also show that the fast neutron contamination is lower in the steeper depths. CONCLUSION: The presence of a wedge in a therapeutic high-energy photon field is a source of neutron contamination and may be of concern regarding clinical aspects. The results of this study show that superficial tissues such as skin will incur higher fast neutron contamination than the deep tissues.

Investigation of the neutron spectrum measurement method for dose evaluation in boron neutron capture therapy.

In boron neutron capture therapy, it is important to evaluate the dose administered to a patient's body outside the tumour area. The exposure dose is evaluated by calculation; however, the calculated value must be validated using a measured value. The dose evaluations based on the measured neutron spectrum are investigated. Multi-foil activation, combined with a LiCaAlF6 scintillation detector and an imaging plate, is proposed as a measurement method. The proposed method can measure the neutron spectrum at various points quickly.

Age Modifies the Effect of 2-MeV Fast Neutrons on Rat Mammary Carcinogenesis.

The relative biological effectiveness (RBE) of neutrons depends on their physical nature (e.g., energy) and the biological context (e.g., end points, materials). From the perspective of radiological protection, age is an important biological context that influences radiation-related cancer risk, but very few studies have addressed its potential impact on neutron effects. We therefore investigated the influence of age on the effect of accelerator-generated fast neutrons (mean energy, ∼2 MeV) in an animal model of breast carcinogenesis. Female Sprague-Dawley rats at 1, 3 and 7 weeks of age were irradiated with fast neutrons at absorbed doses of 0.0485-0.97 Gy. All animals were kept under specific pathogen-free conditions and screened weekly for mammary tumors by palpation until they were 90 weeks old. Tumors were diagnosed based on histology. Mathematical modeling was used to analyze mammary cancer incidence, collectively using data from this study and a previously reported experiment on 137Cs gamma rays. The results indicate that neutron irradiation elevated the risk of palpable mammary carcinoma with a linear dose response, the slope of which depended on age at time of irradiation. The RBE of neutron radiation was 7.5 ± 3.4, 9.3 ± 3.5 and 26.1 ± 8.9 (mean ± SE) for animals exposed at 1, 3 and 7 weeks of age, respectively. Our results indicate that age of the animal is an important factor influencing the effect of fast neutrons on breast cancer risk.

Neutron measurements in radiotherapy: A method to correct neutron sensitive devices for parasitic photon response.

One of the major causes of secondary malignancies after radiotherapy treatments are peripheral doses, known to increase for some newer techniques (such as IMRT or VMAT). For accelerators operating above 10MV, neutrons can represent important contribution to peripheral doses. This neutron contamination can be measured using different passive or active techniques, available in the literature. As far as active (or direct-reading) procedures are concerned, a major issue is represented by their parasitic photon sensitivity, which can significantly affect the measurement when the point of test is located near to the field-edge. This work proposes a simple method to estimate the unwanted photon contribution to these neutrons. As a relevant case study, the use of a recently neutron sensor for "in-phantom" measurements in high-energy machines was considered. The method, called "Dual Energy Photon Subtraction" (DEPS), requires pairs of measurements performed for the same treatment, in low-energy (6MV) and high energy (e.g. 15MV) fields. It assumes that the peripheral photon dose (PPD) at a fixed point in a phantom, normalized to the unit photon dose at the isocenter, does not depend on the treatment energy. Measurements with ionization chamber and Monte Carlo simulations were used to evaluate the validity of this hypothesis. DEPS method was compared to already published correction methods, such as the use of neutron absorber materials. In addition to its simplicity, an advantage of DEPs procedure is that it can be applied to any radiotherapy machine.

[CYTOGENETIC EFFECTS IN MICE BONE MARROW AFTER IRRADIATION BY FAST NEUTRONS].

Mechanisms of damaging mice bone marrow cells by 1.5 MeV neutrons at the dose of 25-250 cGy, dose rate of 23.9 cGy/s and γ-quants 6°Co as a standard radiation were studied. The mitotic index and aberrant mitoses in marrow preparations were counted in 24 and 72 hours after irradiation. Coefficients of relative biological effectiveness (RBE) of fast neutrons 24 and 72 hours post irradiation calculated from mitotic index reduction and aberrant mitoses formation were within the range from 4.1 ± 0.1 to 7.3 ± 0.1. Mean time of the existence of chromosomal aberrations in marrow cells was determined. For the specified doses from γ-rays, the period of aberrations existence was 1.4-1.1 cycles and for neutrons, 1.0-0.6 cycles. Morphologic analysis of neutron-induced damages and ratio of the most common breaks demonstrated a high production of bridges, which outnumbered cells with fragments in 3 to 4 times suggesting a more destructive effect on the genetic structures of cells. RBE of fast neutrons is a variable that grows with a radiation dose. Moreover, RBE estimated after 72 hours exceeded values it had 24 hours after irradiation.

Radioisotopes produced by neutron irradiation of food.

The use of neutrons for cargo interrogation has the potential to drastically improve threat detection. Previous research has focussed on the production of (24)Na, based on the isotopes produced in pharmaceuticals and medical devices. For both the total activity and the ingestion dose we show that a variety of isotopes contribute and that (24)Na is only dominant under certain conditions. The composition of the foods has a strong influence on the resulting activity and ingestion dose suggesting that the pharmaceuticals and medical devices considered initially are not a viable analogue for foodstuffs. There is an energy dependence to the isotopes produced due to the cross-sections of different reactions varying with neutron energy. We show that this results in different isotopes dominating the ingestion dose at different energies, which has not been considered in the previous literature.

[Ozone therapy for radiation reactions and skin lesions after neutron therapy in patients with malignant tumors].

The article discusses the problem of radiation complications from normal tissues in patients after therapy with fast neutrons of 6.3 MeV. The methods of treatment using ozone technologies in patients with radiation reactions and skin lesions on the areas of irradiation after neutron and neutron-photon therapy have been worked out. Ozone therapy showed its harmlessness and increased efficiency of complex treatment of these patients.

A study on the optimum fast neutron flux for boron neutron capture therapy of deep-seated tumors.

High-energy neutrons, named fast neutrons which have a number of undesirable biological effects on tissue, are a challenging problem in beam designing for Boron Neutron Capture Therapy, BNCT. In spite of this fact, there is not a widely accepted criterion to guide the beam designer to determine the appropriate contribution of fast neutrons in the spectrum. Although a number of researchers have proposed a target value for the ratio of fast neutron flux to epithermal neutron flux, it can be shown that this criterion may not provide the optimum treatment condition. This simulation study deals with the determination of the optimum contribution of fast neutron flux in the beam for BNCT of deep-seated tumors. Since the dose due to these high-energy neutrons damages shallow tissues, delivered dose to skin is considered as a measure for determining the acceptability of the designed beam. To serve this purpose, various beam shaping assemblies that result in different contribution of fast neutron flux are designed. The performances of the neutron beams corresponding to such configurations are assessed in a simulated head phantom. It is shown that the previously used criterion, which suggests a limit value for the contribution of fast neutrons in beam, does not necessarily provide the optimum condition. Accordingly, it is important to specify other complementary limits considering the energy of fast neutrons. By analyzing various neutron spectra, two limits on fast neutron flux are proposed and their validity is investigated. The results show that considering these limits together with the widely accepted IAEA criteria makes it possible to have a more realistic assessment of sufficiency of the designed beam. Satisfying these criteria not only leads to reduction of delivered dose to skin, but also increases the advantage depth in tissue and delivered dose to tumor during the treatment time. The Monte Carlo Code, MCNP-X, is used to perform these simulations.

Fast neutron radiotherapy for primary mucosal melanomas of the head and neck.

BACKGROUND: Primary head and neck mucosal melanomas (HNMMs) are rare tumors managed with surgery and/or radiotherapy and associated with poor outcomes. Given their radioresistance, high linear energy transfer radiotherapy with neutrons may improve local control. METHODS: We conducted a retrospective review of 14 patients with HNMM treated with neutrons at the University of Washington from 1990 to 2012. Five patients had T3 disease, 9 had T4 disease, 3 had regional nodal disease, and 4 had distant metastases at diagnosis. Primary sites were sinonasal (n=10), lip (n=2), and palate (n=2). Ten patients had initial surgical resection/debulking. RESULTS: Nine patients had gross residual disease, 6 had complete response, and 3 had partial response. Local control was achieved in 79% until death or last follow-up, and 50% developed distant metastases. Kaplan-Meier 5-year local control was 66% and overall survival was 21%. CONCLUSION: High rates of locoregional control were achieved with neutrons, despite the presence of gross disease. Survival was limited by early distant metastases.

Malignant salivary gland tumours: can fast neutron therapy results point the way to carbon ion therapy?

BACKGROUND AND PURPOSE: To evaluate the outcome of malignant salivary gland tumours treated with neutron therapy to assess the potential for other high linear energy transfer (LET) beams. MATERIALS AND METHODS: Neutrons at iThemba LABS are produced by the reaction of 66MeV protons on a beryllium target. A median dose 20.4Gy, in 12 fractions in 4weeks or 15 fractions in 5weeks, was given to 335 patients with 176 irresectable, 104 macroscopically residual and 55 unresected tumours. RESULTS: Locoregional control was 60.6% at 5years and 39.1% at 10years and DSS was 66.8% and 53.7% at 5 and 10years respectively. In the univariate analysis T4, >4cm, high grade, squamous carcinoma, unresected and irresectable tumours, and positive nodes were significantly worse for LRC. In the multivariate analysis tumours >6cm, squamous carcinoma, irresectable tumours and nodes were significantly worse for LRC. Tumours >6cm, high grade, squamous carcinoma and nodes were significantly worse for DSS. Neither LRC nor DSS was influenced by age, sex, site, dose, fractionation or for initial or recurrent disease. CONCLUSIONS: Neutron therapy appears to be the treatment of choice for macroscopically incompletely excised and irresectable salivary gland tumours with improved survival rates. Further improvement may be achieved with other high LET modalities with a superior dose profile, such as carbon ions.

Distribution of thermal neutron flux around a PET cyclotron.

The number of positron emission tomography (PET) examinations has greatly increased world-wide. Since positron emission nuclides for the PET examinations have short half-lives, they are mainly produced using on-site cyclotrons. During the production of the nuclides, significant quantities of neutrons are generated from the cyclotrons. Neutrons have potential to activate the materials around the cyclotrons and cause exposure to the staff. To investigate quantities and distribution of the thermal neutrons, thermal neutron fluxes were measured around a PET cyclotron in a laboratory associating with a hospital. The cyclotron accelerates protons up to 18 MeV, and the mean particle current is 20 µA. The neutron fluxes were measured during both 18F production and C production. Gold foils and thermoluminescent dosimeter (TLD) badges were used to measure the neutron fluxes. The neutron fluxes in the target box averaged 9.3 × 10(6) cm(-2) s(-1) and 1.7 × 10(6) cm(-2) s(-1) during 18F and 11C production, respectively. Those in the cyclotron room averaged 4.1 × 10(5) cm(-2) s(-1) and 1.2 × 10(5) cm(-2) s(-1), respectively. Those outside the concrete wall shielding were estimated as being equal to or less than ∼3 cm s, which corresponded to 0.1 µSv h(-1) in effective dose. The neutron fluxes outside the concrete shielding were confirmed to be quite low compared to the legal limit.

Effect of wall thickness on measurement of dose for high energy neutrons.

Neutrons produced from the interaction between galactic cosmic rays and spacecraft materials are responsible for a very important portion of the dose received by astronauts. The neutron energy spectrum depends on the incident charged particle spectrum and the scattering environment but generally extends to beyond 100 MeV. Tissue-equivalent proportional counters (TEPC) are used to measure the dose during the space mission, but their weight and size are very important factors for their design and construction. To achieve ideal neutron dosimetry, the wall thickness should be at least the range of a proton having the maximum energy of the neutrons to be monitored. This proton range is 0.1 cm for 10 MeV neutrons and 7.6 cm for 100 MeV neutrons. A 7.6 cm wall thickness TEPC would provide charged particle equilibrium (CPE) for neutrons up to 100 MeV, but for space applications it would not be reasonable in terms of weight and size. In order to estimate the errors in measured dose due to absence of CPE, MCNPX simulations of energy deposited by 10 MeV and 100 MeV neutrons in sites with wall thickness between 0.1 cm and 8.5 cm were performed. The results for 100 MeV neutrons show that energy deposition per incident neutron approaches a plateau as the wall thickness approaches 7.6 cm. For the 10 MeV neutrons, energy deposition per incident neutron decreases as the wall thickness increases above 0.1 cm due to attenuation.

In vitro neutron irradiation of glioma and endothelial cultured cells.

To fully develop its potential boron neutron capture therapy (BNCT) requires the combination of a suitable thermal/epithermal neutron flux together with a selective intake of (10)B-boron nuclei in the target tissue. The latter condition is the most critical to be realized as none of the boron carriers used for experimental or clinical purposes proved at the moment an optimal selectivity for cancer cells compared to normal cells. In addition to complex physical factors, the assessment of the intracellular concentration of boron represent a crucial parameter to predict the dose delivered to the cancer cells during the treatment. Nowadays the dosimetry calculation and then the prediction of the treatment effectiveness are made using Monte Carlo simulations, but some of the model assumption are still uncertain: the radiobiological dose efficacy and the probability of tumour cell survival are crucial parameters that needs a more reliable experimental approach. The aim of this work was to evaluate the differential ability of two cell lines to selectively concentrate the boron-10 administered as di-hydroxyboryl-phenylalanine (BPA)-fructose adduct, and the effect of the differential boron intake on the damage produced by the irradiation with thermal neutrons; the two cell lines were selected to be representative one of normal tissues involved in the active/passive transport of boron carriers, and one of the tumour. Recent in vitro studies demonstrated how BPA is taken by proliferating cells, however the mechanism of BPA uptake and the parameters driving the kinetics of influx and the elimination of BPA are still not clarified. In these preliminary studies we analysed the survival of F98 and human umbilical vein endothelial cells (HUVEC) cells line after irradiation, using different thermal fluencies at the same level of density population and boron concentration in the growing medium prior the irradiation. This is first study performed on endothelium model obtained by a primary human cell line (HUVEC). The perspective application of this work is to develop a model able to foresee the effects produced by different combination of boron influx with a thermal neutron fluencies, applying a standardized radiobiological methodology, and in particular to continue the investigation of the radiobiological effects on the endothelium model as the main tissue involved in the transport of boronated molecules.

Neutron dose per fluence and weighting factors for use at high energy accelerators.

In June 2007, the United States Department of Energy incorporated revised values of neutron weighting factors into its occupational radiation protection regulation Title 10, Code of Federal Regulations Part 835, as part of updating its radiation dosimetry system. This has led to a reassessment of neutron radiation fields at high energy accelerators such as those at the Fermi National Accelerator Laboratory (Fermilab) in the context of the amended regulation and contemporary guidance of the International Commission on Radiological Protection (ICRP). Values of dose per fluence factors appropriate for accelerator radiation fields calculated elsewhere are collated and radiation weighting factors compared. The results of this revision to the dosimetric system are applied to americium-beryllium neutron energy spectra commonly used for instrument calibrations. Also, a set of typical accelerator neutron energy spectra previously measured at Fermilab are reassessed in light of the new dosimetry system. The implications of this revision and of recent ICRP publications are found to be of moderate significance.

Responses of selected neutron monitors to cosmic radiation at aviation altitudes.

Cosmic radiation exposure of aircraft crew, which is generally evaluated by numerical simulations, should be verified by measurements. From the perspective of radiological protection, the most contributing radiation component at aviation altitude is neutrons. Measurements of cosmic neutrons, however, are difficult in a civilian aircraft because of the limitations of space and electricity; a small, battery-operated dosimeter is required whereas larger-size instruments are generally used to detect neutrons with a broad range of energy. We thus examined the applicability of relatively new transportable neutron monitors for use in an aircraft. They are (1) a conventional rem meter with a polyethylene moderator (NCN1), (2) an extended energy-range rem meter with a tungsten-powder mixed moderator (WENDI-II), and (3) a recoil-proton scintillation rem meter (PRESCILA). These monitors were installed onto the racks of a business jet aircraft that flew two times near Japan. Observed data were compared to model calculations using a PHITS-based Analytical Radiation Model in the Atmosphere (PARMA). Excellent agreement between measured and calculated values was found for the WENDI-II. The NCN1 showed approximately half of predicted values, which were lower than those expected from its response function. The observations made with PRESCILA showed much higher than expected values; which is attributable to the presence of cosmic-ray protons and muons. These results indicate that careful attention must be paid to the dosimetric properties of a detector employed for verification of cosmic neutron dose.

Relative biological effectiveness of fast neutrons in a multiorgan assay for apoptosis in mouse.

This study compared the effects of high linear energy transfer (LET) fast neutrons on the induction of apoptosis in several tissue types (hair follicle, intestine crypt, testis) of ICR mouse exposed to low LET 60Co gamma-rays. The changes that occurred from 0 to 24 h after exposing the mice to either 2 Gy of gamma-rays (2 Gy/min) or 0.8 Gy of neutrons (94 mGy/min, 35 MeV) were examined. The maximum frequency of apoptosis was observed at 8 or 12 h after irradiation. The mice that had received 0-8 Gy of gamma-rays or 0-1.6 Gy of neutrons were examined 8 h after irradiation. The best-fitting dose-response curves were linear-quadratic, and there was a significant relationship between the number of apoptotic cells and the dose. The stained products in the TUNEL-positive cells or bodies correlated with the typical morphologic characteristics of apoptosis observed by optical microscopy. In the follicles showing an apoptosis frequency between 2 and 14 per hair follicle, the relative biological effectiveness (RBE) of the neutrons in the small and large follicles was 2.09 +/- 0.31 and 2.15 +/- 0.18, respectively. In the intestine crypts showing an apoptosis frequency between 1 and 3 per crypt, the RBE of the neutrons was 4.03 +/- 0.06 and 3.87 +/- 0.04 in the base and total crypts, respectively. The RBE of the neutrons in the seminiferous tubule showing an apoptosis frequency between 0.5 and 2 per tubule was 5.18 +/- 0.06. The results determined the time-response relations and the RBE for fast neutron-induced apoptosis in several organs at the same time. The differences in RBE observed between the high and low LET radiation and it is believed that the difference in the DSB repair capacity in hair follicle, intestine crypt, and seminiferous tubule cells plays a role in determining the RBE of the high-LET radiation for the induced apoptotic cell formation.