Changes in RBE of 14-MeV (d + T) neutrons for V79 cells irradiated in air and in a phantom: is RBE enhanced near the surface?

PURPOSE: The relative biological effectiveness (RBE) for inactivation of V79 cells was determined as function of dose at the Heidelberg 14-MeV (d + T) neutron therapy facility after irradiation with single doses in air and at different depths in a therapy phantom. Furthermore, to assess the reproducibility of RBE determinations in different experiments we examined the relationship between the interexperimental variation in radiosensitivity towards neutrons with that towards low LET 60Co photons. METHODS: Clonogenic survival of V79 cells was determined using the colony formation assay. The cells were irradiated in suspension in small volumes (1.2 ml) free in air or at defined positions in the perspex phantom. Neutron doses were in the range, Dt = 0.5-4 Gy. 60Co photons were used as reference radiation. RESULTS: The radiosensitivity towards neutrons varied considerably less between individual experiments than that towards photons and also less than RBE. However, the mean sensitivity of different series was relatively constant. RBE increased with decreasing dose per fraction from RBE = 2.3 at 4 Gy to RBE = 3.1 at 0.5 Gy. No significant difference in RBE could be detected between irradiation at 1.6 cm and 9.4 cm depth in the phantom. However, an approximately 20% higher RBE was found for irradiation free in air compared with inside the phantom. Combining the two effects, irradiation with 0.5 Gy free in air yielded an approximately 40% higher RBE than a dose of 2 Gy inside the phantom. CONCLUSION: The measured values of RBE as function of dose per fraction within the phantom is consistent with the energy of the neutron beam. The increased RBE free in air, however, is greater than expected from microdosimetric parameters of the beam and may be due to slow recoil protons produced by interaction of multiply scattered neutrons or to an increased contribution of alpha particles from C(n, alpha) reactions near the surface. An enhanced RBE in subcutaneous layers of skin combined with an increase in RBE at low doses per fraction outside the target volume could potentially have significant consequences for normal tissue reactions in radiotherapy patients treated with fast neutrons.     

Monte Carlo calculation of dose enhancement by neutron capture of 10B in fast neutron therapy

Since 1978 the Essen Medical Cyclotron Facility has been used for fast neutron therapy. The treatment of deep-seated tumours by d(14) + Be neutron beam therapy (mean energy = 5.8 MeV) is still limited because of the steep decrease in depth-dose distribution. The interactions of fast neutrons in tissue leads to a thermal neutron distribution. These partially thermalized neutrons can be used to produce neutron capture reactions with 10B. Thus incorporation of 10B in tumours treated with fast neutrons will increase the relative local tumour dose due to the reaction 10B (n, alpha) 7Li. The magnitude of dose enhancement by 10B depends on the distribution of the thermal neutron fluence, 10B concentration, field size of the neutron beam, beam energy and the specific phantom geometry. The slowing down of the fast neutrons, resulting in a thermal neutron distribution in a phantom, has been computed using a Monte Carlo model. This model, which includes a deep-seated tumour, was experimentally verified by measurements of the thermal neutron fluence rate in a phantom using neutron activation of gold foil. When non-boronated water phantoms were irradiated with a total dose of 1 Gy at a depth of 6 cm, the thermal fluencies at this depth were found to be 2 x 10(10) cm-2. The absorbed dose in a tumour with 100 ppm 10B, at the same depth, was enhanced by 15%.     

Characteristics of neutron beam generated by 500 MeV proton beam

A neutron irradiation facility was constructed at PARMS, University of Tsukuba to produce an ultrahigh energy neutron beam with a depth dose distribution superior to an x-ray beam generated by a modern linac. This neutron beam was produced from the reaction on a thick uranium target struck by a 500 MeV proton beam from the booster synchrotron of the High Energy Physics Laboratory. The percentage depth dose of this neutron beam was nearly equivalent to that of x-rays around 20 MV and the dose rate was 15 cGy per minute. The relative biological effectiveness (RBE) of this neutron beam has been estimated using the cell inactivation effect and the HMV-I cell line. The survival curve of cells after neutron irradiation has a shoulder with n and Dq of 8 and 2.3 Gy, respectively. The RBE value at the 10(-2) survival level for the present neutron beam as compared with 137Cs gamma rays was 1.24. The results suggest that the biological effects of ultrahigh energy neutrons are not large enough to be useful, although the depth dose distribution of neutrons can be superior to that of high energy linac x-rays.     

In-phantom dosimetry and spectrometry of photoneutrons from an 18 MV linear accelerator

A combination of three superheated drop detectors with different neutron energy responses was developed to evaluate dose-equivalent and energy distributions of photoneutrons in a phantom irradiated by radiotherapy high-energy x-ray beams. One of the three detectors measures the total neutron dose equivalent and the other two measure the contributions from fast neutrons above 1 and 5.5 MeV, respectively. In order to test the new method, the neutron field produced by the 10 cm X 10 cm x-ray beam of an 18 MV radiotherapy accelerator was studied. Measurements were performed inside a tissue-equivalent liquid phantom, at depths of 1, 5, 10 and 15 cm and at lateral distances of 0, 10, and 20 cm from the central axis. These data were used to calculate the average integral dose to the radiotherapy patient from direct neutrons as well as from neutrons transmitted through the accelerator head. The characteristics of the dosimeters were confirmed by results in excellent agreement with those of prior studies. Track etch detectors were also used and provided an independent verification of the validity of this new technique. Within the primary beam, we measured a neutron entrance dose equivalent of 4.5 mSv per Gy of photons. It was observed that fast neutrons above 1 MeV deliver most of the total neutron dose along the beam axis. Their relative contribution increases with depth, from about 60% at the entrance to over 90% at a depth of 10 cm. Thus, the average energy increases with depth in the phantom as neutron spectra harden.     

Neutron measurements in the stray field produced by 158 GeV c(-1) per nucleon lead ion beams

This paper discusses measurements carried out at CERN in the stray radiation field produced by 158 GeV c(-1) per nucleon 208Pb82+ ions. The purpose was to test and intercompare the response of several detectors, mainly neutron measuring devices, and to determine the neutron spectral fluence as well as the microdosimetric (absorbed dose and dose equivalent) distributions in different locations around the shielding. Both active instruments and passive dosimeters were employed, including different types of Andersson-Braun rem counters, a tissue equivalent proportional counter, a set of superheated drop detectors, a Bonner sphere system, and different types of ion chambers. Activation measurements with 12C plastic scintillators and with 32S pellets were also performed to assess the neutron yield of high energy lead ions interacting with a thin gold target. The results are compared with previous measurements and with measurements made during proton runs.     

Relative biological effectiveness of negative pi mesons for the immune response in mice

Immunologically competent mouse spleen cells were exposed to negative pi mesons in the entrance plateau or at the peak of the dose distribution at a maximum dosage of 5 rads/min. or to 60Co gamma rays at 4.96 rads/min. Survival curves from cells irradiated in vitro but incubated in vivo yielded RBE values of 2.15 for the peak and 1.84 for the entrance plateau at a surviving fraction of 0.1. The dose-rate dependence of antibody-forming spleen cells for both 60Co gamma rays and the lot-LET components of the pion beam is discussed. The authors suggest that these RBE values constitute an upper limit for normal mammalian cells exposed to pions and tha the RBE with clinically useful dose rates may be significantly lower than those reported here.     

Chromosome aberrations in human fibroblasts induced by monoenergetic neutrons. I. Relative biological effectiveness

The relative biological effectiveness (RBE) of neutrons for many biological end points varies with neutron energy. To test the hypothesis that the RBE of neutrons varies with respect to their energy for chromosome aberrations in a cell system that does not face interphase death, we studied the yield of chromosome aberrations induced by monoenergetic neutrons in normal human fibroblasts at the first mitosis postirradiation. Monoenergetic neutrons at 0.22, 0.34, 0.43, 1, 5.9 and 13.6 MeV were generated at the Accelerator Facility of the Center for Radiological Research, Columbia University, and were used to irradiate plateau-phase fibroblasts at low absorbed doses from 0.3 to 1.2 Gy at a low dose rate. The reference low-LET, low-dose-rate radiation was 137Cs-gamma rays (0.66 MeV). A linear dose response (Y = alphaD) for chromosome aberrations was obtained for all monoenergetic neutrons and for the gamma rays. The yield of chromosome aberrations per unit dose was high at low neutron energies (0.22, 0.34 and 0.43 MeV) with a gradual decline with the increase in neutron energy. Maximum RBE (RBEm) values varied for the different types of chromosome aberrations. The highest RBE (24.3) for 0.22 and 0.43 MeV neutrons was observed for intrachromosomal deletions, a category of chromosomal change common in solid tumors. Even for the 13.6 MeV neutrons the RBEm (11.1) exceeded 10. These results show that the RBE of neutrons varies with neutron energy and that RBEs are dissimilar between different types of asymmetric chromosome aberrations and suggest that the radiation weighting factors applicable to low-energy neutrons need firmer delineation. This latter may best be attained with neutrons of well-defined energies. This would enable integrations of appropriate quality factors with measured radiation fields, such as those in high-altitude Earth atmosphere. The introduction of commercial flights at high altitude could result in many more individuals being exposed to neutrons than occurs in terrestrial workers, emphasizing the necessity for better-defined estimates of risk.     

Direct determination of kerma for a d(48.5) + Be therapy beam

An experimental determination of the neutron kerma ratio between muscle tissue and A-150 plastic was performed at the newly commissioned d(48.5)+ Be therapy facility in Detroit. Low-pressure proportional counters with separate walls made from A-150 plastic, graphite, zirconium oxide and zirconium served to measure ionization yield spectra. The absorbed dose in the wall of each counter was determined and rendered the A-150 and carbon kerma directly, whilst that for oxygen was deduced from differences between the matched metal oxide and metal pair. This enabled the evaluation of an effective kerma ratio as a function of radiation field size and hydrogenous filtration. Although filtration was observed to harden the beam, the application of a single kerma ratio for the various irradiation conditions investigated was found to be appropriate. A neutron kerma ratio of 0.90+/-0.03 was assessed for the Detroit facility, which is lower at the 1sigma level than the 0.95 currently recommended in the dosimetry protocol for high-energy neutron beams.     

The clinical RBE and microdosimetric characterization of radiation quality in fast neutron therapy

High-LET radiation therapy using fast neutrons is being applied regularly at several centres worldwide and in the future, other types of radiation qualities, such as protons and heavier ions and boron neutron capture therapy (BNCT) are likely to be used. The neutron beams used are of considerably varying energy and thus considerable variations in the relative biological effectiveness (RBE) have been found. At present, no generally accepted method exists for the quantitative specification of these differences in radiation quality for clinical purposes. This is in clear discrepancy with the accuracy requirements in clinical dosimetry. An approach is presented which is based on a single parameter radiation quality characterization determined in combined microdosimetric and radiobiological experiments. It is shown that the method can meet the accuracy requirements of clinical dosimetry and that it is applicable within a concept of formalized procedure of clinical practice and experience ('clinical RBE').     

Neutron induced recoil protons of restricted energy and range and biological effectiveness

Low energy neutrons (<2 MeV), those of principal concern in radiation protection, principally initiate recoil protons in biological tissues. The recoil protons from monoenergetic neutrons form rectangular distributions with energy. Monoenergetic neutrons of different energies (<2 MeV) will then produce overlapping recoil proton spectra. By overlapping the effects of individual deposition events, determined microdosimetrically for cell nuclear dimensions, from such neutron beams the biological effectiveness of recoil protons within defined energy and range bounds can be determined. Here chromosomal aberrations per cell have been quantified following irradiation of Vicia faba cells with monoenergetic neutrons of 230, 320, 430, and 1,910 keV. Aberration frequencies from cells from part of the cell cycle, thereby limiting nuclear dimensions, were linearly related to dose and to the frequency of proton recoils per nucleus. The 320 keV neutrons were the most biologically effective per unit absorbed dose and 430 keV neutrons most effective per recoil proton, with 21% of recoils inducing aberrations. After extraction of effectiveness per proton recoil within each energy and range bounds (0-230, 230-320, 320-430, and 430-1,910 keV), it was concluded that recoil protons with energies of about 200-300 keV, traveling 2.5-4 microm and depositing energy at about 80 keV micrometer(-1), are more efficient at aberration induction than those recoil protons of lesser range though near equivalent LET and those of greater range through lesser LET. This approach allows for assessment of the biological effectiveness of individual energy deposition events from low energy neutrons, the lowest dose a cell can receive, and provides an alternative to considerations of relative biological effectiveness.     

Neutron RBEs for cytopenia and repopulation of stroma and hematopoietic stem cells: mathematical models of marrow cell kinetics

The objectives of this study were to (a) extend previous bone-marrow cell kinetics models that have been published for ionizing photons to include neutron radiations, and (b) provide Relative Biological Effectiveness (RBE) values for time-specific cell killing (cytopenia) and compensatory cellular proliferation (repopulation in response to toxic injury) for neutron doses ranging from 0.01 to 4.5 Gy delivered uniformly over one minute, hour, day, week, and month. RBEs for cytopenia of a cell lineage were based on ratios of protocol-specific doses that determined the same cell population nadir, whereas the RBEs for repopulation of a lineage were based on the ratios of protocol-specific doses that corresponded to the same total number of cells killed over the radiation treatments, and which should be replaced for long-term survival of the animal. Time-dependent RBEs were computed for neutron exposures relative to the effect of 60Co gamma rays given as a prompt dose. By the use of these RBE factors, low or variable dose rates, dose fractionations given over long periods of time, and different protocols involving several radiation qualities can be converted realistically, and by standard convention, into an equivalent dose of a reference radiation comprised of x or gamma rays given either as a pulse or at any other reference dose rate for which risk information based on epidemiological or animal dose-response data are available. For stromal tissues irradiated by fission neutrons, time-dependent RBEs for cytopenia were computed to range from 4.24 to 0.70 and RBEs for repopulation varied from a high of 6.88 to a low of 2.24. For hematopoietic stem cells irradiated by fission neutrons, time-dependent RBEs for cytopenia were computed to range from 5.02 to 0.22 and RBEs for repopulation varied from a high of 5.02 to a low of 1.98. RBEs based on tissue-kerma-free-in-air would be about twofold lower for isotropic cloud or rotational exposure geometries because marrow dose from isotropic neutron fields suffer factor-of-two greater attenuation than the gamma doses from gamma photons. For certain doses and dose rates, the RBE values computed for compensatory cellular proliferation clearly demonstrate the behavior that is commonly referred to as an inverse dose-rate effect, i.e., protraction of exposure may-under certain conditions-increase the magnitude of the dose response. Furthermore, because of non-linear rates for repair and repopulation, the highest RBEs are not necessarily found for the lowest doses nor the lowest RBEs always found at the highest doses.     

The risk of non-melanoma skin cancer incidence in the Japanese atomic bomb survivors

The latest Japanese atomic bomb survivor non-melanoma skin cancer incidence dataset is analysed and indicates substantial curvilinearity in the dose-response curve, consistent with a possible dose threshold of about 1 Sv, or with a dose-response in which the excess relative risk is proportional to the fourth power of dose, with a turning-over in the dose-response at high doses (> 3 Sv). The time distribution of the radiation-induced excess risk is best described by a model in which the relative excess risk is proportional to a product of powers of time since exposure and attained age. The fits of generalized relative risk models with exponential functions of time and age at exposure (and in particular of attained age) to adjust the relative risk are less satisfactory, as also are the fits of other models in which products of powers of time since exposure, age at exposure and attained age adjust the excess absolute risk. Sensitivity analyses indicate the importance of likely adjustments to the Hiroshima neutron doses for the optimal model parameters, particularly if values of the neutron relative biological effectiveness (RBE) of more than 5 are assumed. If adjustments recently proposed are made to the Hiroshima neutron doses, then using the optimal model (in which excess risk is proportional to the fourth power of dose) the best estimate of the neutron RBE is 1.3 (95% CI < 07.1). However, uncertainties in skin dose estimates for the atomic bomb survivors means that the findings with respect to the neutron RBE and the non-linearity in the dose-response curve should be treated with caution.     

Application of fission track detectors to californium-252 neutron dosimetry in tissue near the radiation source

Fission track detectors were applied to a unique problem in neutron dosimetry. Measurements of neutron doses were required at locations within a tumor of 1 cm diameter implanted on the back of a mouse and surrounded by a square array of four 252Cf medical sources. Measurements made in a tissue-equivalent mouse phantom showed that the neutron dose rate to the center of the tumor was 2.18 rads micrograms-1 h-1 +/- 8.4%. The spatial variation of neutron dose to the tumor ranged from 1.88 to 2.55 rads micrograms-1 h-1. These measurements agree with calculated values of neutron dose to those locations in the phantom. Fission track detectors have been found to be a reliable tool for neutron dosimetry for geometries in which one wishes to know neutron dose values which may vary considerably over distances of 1 cm or less.     

Phantoms with 10BF3 detectors for boron neutron capture therapy applications

Two acrylic cube phantoms have been constructed for BNCT applications that allow the depth distribution of neutrons to be measured with miniature 10BF3 detectors in 0.5-cm steps beginning at 1-cm depth. Sizes and weights of the cubes are 14 cm, 3.230 kg, and 11 cm, 1.567 kg. Tests were made with the epithermal neutron beam from the patient treatment port of the Brookhaven Medical Research Reactor. Thermal neutron depth profiles were measured with a bare 10BF3 detector at a reactor power of 50 W, and Cd-covered detector profiles were measured at a reactor power of 1 kW. The resulting plots of counting rate versus depth illustrate the dependence of neutron moderation on the size of the phantom. But more importantly the data can serve as benchmarks for testing the thermal and epithermal neutron profiles obtained with accelerator-based BNCT facilities. Such tests could be made with these phantoms at power levels about five orders of magnitude lower than that required for the treatment of patients with brain tumors.     

Perturbation corrections for flat and thimble-type cylindrical standard ionization chambers for 60Co gamma rays: Monte Carlo calculations

The use of an ionization chamber for absorbed dose determinations in a medium requires one to take into account perturbation corrections due to the presence of the chamber cavity in the medium. Evaluation of these corrections for perturbation and their variation with depth in the medium has been performed for a flat cylindrical and a cylindrical (thimble-type) ionization chamber placed in a graphite phantom irradiated by a 60Co gamma beam using Monte Carlo calculations (EGS4 system with correlated sampling variance reduction technique). The results of these calculations agree with published experimental and theoretical data to better than 0.18%, with a statistical uncertainty of less than 0.17%.     

Theoretical and experimental determination of phantom scatter factors for photon fields with different radial energy variation

The output factor used for monitor unit determination in radiotherapy can be divided into two factors: the head scatter factor and the phantom scatter factor. Theoretical and experimental phantom scatter factors have been compared for different beam qualities between 4 MV and 50 MV and field sizes from 5 cm x 5 cm to 30 cm x 30 cm. The theoretical data were obtained through a convolution method based on Monte Carlo calculated energy spectra and dose kernels. The calculations have been performed both for accelerators with a rather large energy variation within the field and for accelerators with a constant energy distribution in the field. Deviations between theoretical and experimental data were found to be less than 1%.     

Locomotor responses of human CD45 lymphocyte subsets: preferential locomotion of CD45RO+ lymphocytes in response to attractants and mitogens

Conversion factors between the energy imparted to the patient in pediatric radiography and air collision kerma integrated over beam area are presented. The values have been derived from Monte Carlo calculations in soft tissue phantoms and extend results published earlier to cover children from early infancy to the age of 15 years. Variations related to phantom size as well as to focus-phantom distance, radiation field size, orientation of view (a.p., lateral), tube potential, and beam filtration are given. We show that the conversion factor increases with increasing half-value layer of the X-ray beam and the anterioposterior width of the simulated child. Increasing the focus-phantom distance increases the conversion factor, while increasing the field size decreases the factors due to more scattered radiation escaping laterally from the phantom.     

Dose-related cardiovascular effects of amrinone and epinephrine in reversing bupivacaine-induced cardiovascular depression

Effective dose, an indicator of the stochastic effect of radiation, has been widely used in dose evaluation in the environment. Though conversion factors have been used to obtain E from the air kerma or air absorbed dose, the variation of the conversion factors due to the change of exposure conditions has not been sufficiently investigated. This report documents an investigation of the variation of the effective dose per air kerma for environmental gamma rays depending on the exposure conditions using anthropomorphic phantoms and Monte Carlo calculations, taking into account the precise angular and energy distributions of the environmental gamma rays incident on the human body. As causes of the variation, posture of human bodies, biases of environmental source distributions, and body size were considered. The variation of effective dose in a prone position compared with that in a standing position was found to be within 30%. The bias of environmental sources causes the effective dose per air kerma to vary by 20% at maximum, but in some cases for low-energy gamma rays the variation was found to be up to 40% due to the change in the energy spectrum. The effective dose for a new born infant was estimated to be higher than that for an adult by a maximum of 80-90% for low-energy gamma rays from anthropogenic sources because of a lower shielding effect of the smaller body. The variation of the effective dose equivalent shows a similar tendency to the effective dose. Consequently, this study made it possible to estimate the uncertainties of effective dose and effective dose equivalent evaluated from air kerma or absorbed dose in air using the standard available conversion factors.     

Combined use of FLUKA and MCNP-4A for the Monte Carlo simulation of the dosimetry of 10B neutron capture enhancement of fast neutron irradiations

Boron neutron capture enhancement (BNCE) of the fast neutron irradiations use thermal neutrons produced in depth of the tissues to generate neutron capture reactions on 10B within tumor cells. The dose enhancement is correlated to the 10B concentration and to thermal neutron flux measured in the depth of the tissues, and in this paper we demonstrate the feasibility of Monte Carlo simulation to study the dosimetry of BNCE. The charged particle FLUKA code has been used to calculate the primary neutron yield from the beryllium target, while MCNP-4A has been used for the transport of these neutrons in the geometry of the Biomedical Cyclotron of Nice. The fast neutron spectrum and dose deposition, the thermal flux and thermal neutron spectrum in depth of a Plexiglas phantom has been calculated. The thermal neutron flux has been compared with experimental results determined with calibrated thermoluminescent dosimeters (TLD-600 and TLD-700, respectively, doped with 6Li or 7Li). The theoretical results were in good agreement with the experimental results: the thermal neutron flux was calculated at 10.3 X 10(6) n/cm2 s1 and measured at 9.42 X 10(6) n/cm2 s1 at 4 cm depth of the phantom and with a 10 cm X 10 cm irradiation field. For fast neutron dose deposition the calculated and experimental curves have the same slope but different shape: only the experimental curve shows a maximum at 2.27 cm depth corresponding to the build-up. The difference is due to the Monte Carlo simulation which does not follow the secondary particles. Finally, a dose enhancement of, respectively, 4.6% and 10.4% are found for 10 cm X 10 cm or 20 cm X 20 cm fields, provided that 100 micrograms/g of 10B is loaded in the tissues. It is anticipated that this calculation method may be used to improve BNCE of fast neutron irradiations through collimation modifications.