Characterization of neutron beams for boron neutron capture therapy: in-air radiobiological dosimetry

The survival curves and the RBE for the dose components generated in boron neutron capture therapy (BNCT) were determined separately in neutron beams at Japan Research Reactor No. 4. The surviving fractions of V79 Chinese hamster cells with or without 10B were obtained using an epithermal neutron beam (ENB), a mixed thermal-epithermal neutron beam (TNB-1), and a thermal (TNB-2) neutron beam; these beams were used or are planned for use in BNCT clinical trials. The cell killing effect of the neutron beam in the presence or absence of 10B was highly dependent on the neutron beam used and depended on the epithermal and fast-neutron content of the beam. The RBEs of the boron capture reaction for ENB, TNB-1 and TNB-2 were 4.07 +/- 0.22, 2.98 +/- 0.16 and 1.42 +/- 0.07, respectively. The RBEs of the high-LET dose components based on the hydrogen recoils and the nitrogen capture reaction were 2.50 +/- 0.32, 2.34 +/- 0.30 and 2.17 +/- 0.28 for ENB, TNB-1 and TNB-2, respectively. The RBEs of the neutron and photon components were 1.22 +/- 0.16, 1.23 +/- 0.16, and 1.21 +/- 0.16 for ENB, TNB-1 and TNB-2, respectively. The approach to the experimental determination of RBEs outlined in this paper allows the RBE-weighted dose calculation for each dose component of the neutron beams and contributes to an accurate inter-beam comparison of the neutron beams at the different facilities employed in ongoing and planned BNCT clinical trials.     

Assessment of ideal neutron beams for neutron capture therapy.

The discrete-ordinates transport computer code DORT has been used to develop a two-dimensional cylindrical phantom model for use as a tool to assess beam design and dose distributions for boron neutron capture therapy. The model uses an S8 approximation for angular fluxes and a P3 Legendre approximation for scattering cross sections. A one-dimensional discrete-ordinates model utilizing the computer code ANISN was used to validate the energy-group structure used in the two-dimensional calculations. In the two-dimensional model the effects of varying basic parameters such as aperture width, neutron source energy, and tissue composition have been studied. Identical results were obtained when comparing narrow beam calculations to fine-mesh higher-order Sn treatments (up to S32), and with P5 cross sections. It is shown that, when the correct assessment volume is used, narrow beams will give little or no advantage for therapy even with an optimum-energy ideal neutron beam.     

Epithermal neutron beams for clinical studies of boron neutron capture therapy: a dosimetric comparison of seven beams

A comparison of seven epithermal neutron beams used in clinical studies of boron neutron capture therapy (BNCT) in Sweden (Studsvik), Finland (Espoo), Czech Republic (ReZ), The Netherlands (Petten) and the U.S. (Brookhaven and Cambridge) was performed to facilitate sharing of preclinical and clinical results. The physical performance of each beam was measured using a common dosimetry method under conditions pertinent to brain irradiations. Neutron fluence and absorbed dose measurements were performed with activation foils and paired ionization chambers on the central axis both in air and in an ellipsoidal water phantom. The overall quality of each beam was assessed by figures of merit determined from the total weighted dose profiles that assumed the presence of boron in tissue. The in-air specific beam contamination from both fast neutrons and gamma rays ranged between 8 and 65 x 10(-11) cGy(w) cm2 for the different beams and the epithermal neutron flux intensities available at the patient position differed by more than a factor of 20 from 0.2-4.3 x 10(9) n cm(-2) s(-1). Percentage depth dose profiles measured in-phantom for the individual photon, thermal and fast-neutron dose components differed only subtly in shape between facilities. Assuming uptake characteristics consistent with the currently used boronated phenylalanine, all the epithermal beams exhibit a useful penetration of 8 cm or greater that is sufficient to irradiate a lesion seated at the brain midline. The performance of the existing facilities will benefit from the introduction of advanced compounds through improved beam penetrability. This could increase by as much as 2 cm for the purest of beams, although the beam intensities generally need to be increased to between 2-5 x 10(9) n cm(-2) s(-1) to maintain manageable irradiation times. These data provide the first consistent measurement of beam performance at the different centers and will enable a preliminary normalization of the calculated patient dosimetry.     

RBE of the MIT epithermal neutron beam for crypt cell regeneration in mice

The RBE of the new MIT fission converter epithermal neutron capture therapy (NCT) beam has been determined using intestinal crypt regeneration in mice as the reference biological system. Female BALB/c mice were positioned separately at depths of 2.5 and 9.7 cm in a Lucite phantom where the measured total absorbed dose rates were 0.45 and 0.17 Gy/ min, respectively, and irradiated to the whole body with no boron present. The gamma-ray (low-LET) contributions to the total absorbed dose (low- + high-LET dose components) were 77% (2.5 cm) and 90% (9.7 cm), respectively. Control irradiations were performed with the same batch of animals using 6 MV photons at a dose rate of 0.83 Gy/min as the reference radiation. The data were consistent with there being a single RBE for each NCT beam relative to the reference 6 MV photon beam. Fitting the data according to the LQ model, the RBEs of the NCT beams were estimated as 1.50 +/- 0.04 and 1.03 +/- 0.03 at depths of 2.5 and 9.7 cm, respectively. An alternative parameterization of the LQ model considering the proportion of the high- and low-LET dose components yielded RBE values at a survival level corresponding to 20 crypts (16.7%) of 5.2 +/- 0.6 and 4.0 +/- 0.7 for the high-LET component (neutrons) at 2.5 and 9.7 cm, respectively. The two estimates are significantly different (P = 0.016). There was also some evidence to suggest that the shapes of the curves do differ somewhat for the different radiation sources. These discrepancies could be ascribed to differences in the mechanism of action, to dose-rate effects, or, more likely, to differential sampling of a more complex dose-response relationship.     

Biological dosimetry for astronauts: a real challenge

Manned space missions recently increased in number and duration, thus it became important to estimate the biological risks encountered by astronauts. They are exposed to cosmic and galactic rays, a complex mixture of different radiations. In addition to the measurements realized by physical dosimeters, it becomes essential to estimate real biologically effective doses and compare them to physical doses. Biological dosimetry of radiation exposures has been widely performed using cytogenetic analysis of chromosomes. This approach has been used for many years in order to estimate absorbed doses in accidental or chronic overexposures of humans. In addition to conventional techniques (Giemsa or FPG staining, R- or G-banding), faster and accurate means of analysis have been developed (fluorescence in situ hybridization [FISH] painting). As results accumulate, it appears that strong interindividual variability exists in the basal level of aberrations. Moreover, some aberrations such as translocations exhibit a high background level. Radiation exposures seem to induce variability between individual responses. Its extent strongly differs with the mode of exposure, the doses delivered, the kind of radiation, and the cytogenetic method used. This paper aims to review the factors that may influence the reliability of cytogenetic dosimetry. The emphasis is on the exposure to high linear energy transfer (LET) particles in space as recent studies demonstrated interindividual variations in doses estimated from aberration analysis after long-term space missions. In addition to the problem of dose estimates, the heterogeneity of cosmic radiation raises questions relating to the real numbers of damaged cells in an individual, and potential long-term risks. Actually, densely ionizing particles are extremely potent to induce late chromosomal instability, and again, interindividual variability exists in the expression of damage.     

Analytical applications of guided neutron beams

Biological Trace Element Research - Guided beams of thermal and cold neutrons have become available to analysts at several reactors during the past decade. The very pure beams from these guides...     

Proportional counter dosimetry and microdosimetry for radiotherapy with multiple pion beams

At the Swiss Institute for Nuclear Research (SIN) cancer patients are irradiated with negatively charged pi mesons using a 60-beam medical pion generator, the Piotron. A low-pressure tissue-equivalent proportional counter was used to measure absorbed dose and microdosimetric spectra. A method was developed to allow discrimination of events from different beam components, i.e., beam contamination (electrons and muons), pions in flight, and stopping pions. Measurements were performed along the axis and at lateral distances off one of these identical pion beams. The marked changes of total microdosimetric spectra with depth in phantom detected in earlier measurements are mainly due to large variations in the dose contributions of the beam components and much less to changes in the shapes of the individual microdosimetric spectra. The single beam measurements were used to calculate three-dimensional distributions of absorbed dose and of dose mean lineal energy, yD, for dynamic patient irradiations. Within the whole target volume yD remains nearly constant when irradiated with all 60 beams, whereas considerable changes were found for irradiations with 31 beams coming from a semicircle. Both size and shape of target volumes influence yD, the maximum values ranging from 30 to 45 keV/micron.     

Aspects in practical neutron dosimetry with ionization chambers

Summary The calibration procedure to determine the absorbed dose within a phantom irradiated with fast neutrons is described for ionization chambers. A comparison between values of the neutron dose determined with paired ionization chambers and values of the neutron fluence measured with a fission chamber (²³⁸U) is given. The comparison indicates the energy variation of the fast neutrons within a phantom irradiated with 14 MeV neutrons.Dedicated to Prof. Dr. Dr. h. c. mult. B. Rajewsky on the occasion of his 80th birthday.     

Determination of the thermal and epithermal neutron sensitivities of an LBO chamber

An LBO (Li₂B₄O₇) walled ionization chamber was designed to monitor the epithermal neutron fluence in boron neutron capture therapy clinical irradiation. The thermal and epithermal neutron sensitivities of the device were evaluated using accelerator neutrons from the ⁹Be(d, n) reaction at a deuteron energy of 4 MeV (4 MeV d-Be neutrons). The response of the chamber in terms of the electric charge induced in the LBO chamber was compared with the thermal and epithermal neutron fluences measured using the gold-foil activation method. The thermal and epithermal neutron sensitivities obtained were expressed in units of pC cm², i.e., from the chamber response divided by neutron fluence (cm^?2). The measured LBO chamber sensitivities were 2.23 × 10^?7 ± 0.34 × 10^?7 (pC cm²) for thermal neutrons and 2.00 × 10^?5 ± 0.12 × 10^?5 (pC cm²) for epithermal neutrons. This shows that the LBO chamber is sufficiently sensitive to epithermal neutrons to be useful for epithermal neutron monitoring in BNCT irradiation.     

A Monte Carlo investigation of the dosimetric properties of monoenergetic neutron beams for neutron capture therapy

A Monte Carlo simulation study has been carried out to investigate the suitability of neutron beams of various energies for therapeutic efficacy in boron neutron capture therapy. The dosimetric properties of unidirectional, monoenergetic neutron beams of varying diameters in two different phantoms (a right-circular cylinder and an ellipsoid) made of brain-equivalent material were examined. The source diameter was varied from 0.0 to 20.0 cm; neutron energies ranged from 0.025 eV up to 800 keV, the maximum neutron energy generated by a tandem cascade accelerator using 2.5-MeV protons in a 7Li(p,n)7Be reaction. Such a device is currently under investigation for use as a neutron source for boron neutron capture therapy. The simulation studies indicate that the maximum effective treatment depth (advantage depth) in the brain is 10.0 cm and is obtainable with a 10-keV neutron beam. A useful range of energies, defined as those neutron energies capable of effectively treating to a depth of 7 cm in brain tissue, is found to be 4.0 eV to 40.0 keV. Beam size is shown not to affect advantage depth as long as the entire phantom volume is used in determining this depth. Dose distribution in directions parallel to and perpendicular to the beam direction are shown to illustrate this phenomenon graphically as well as to illustrate the differences in advantage depth and advantage ratio and the contribution of individual dose components to tumor dose caused by the geometric differences in phantom shape.     

Biological UV dosimetry using the DLR-biofilm.

Changes of environmental UV radiation as part of global atmospheric changes will influence the biosphere substantially. The determination of the biological effects of these changes requires accurate and reliable UV monitoring systems that weight the spectral irradiance according to the biological responses under consideration. Biological UV dosimeters, which directly weight the incident UV components of sunlight in relation to the effectiveness of the different wavelengths and the potential interactions between them, can complement weighted physical UV measurements. Up to now several UV-dependent endpoints in biomolecules (e.g. uracil, DNA, provitamin D3), bacteriophages (e.g. T7), bacteria (e.g.E. coli, B. subtilis) and cultured eukaryotic cells have been suggested as sensing elements in biological UV dosimeters. One example is the DLR-biofilm consisting of immobilised spores of the bacterium B. subtilis as a UV sensor. It weights per se the incident UV radiation according to its DNA-damaging effectiveness. In several examples the applicability of the DLR-biofilm technique for personal UV dosimetry as well as for the measurement of the biologically weighted irradiance of the sun and of artificial UV sources is demonstrated.     

An evaluation of thermal and epithermal neutron activation analysis compton suppression methods for biological reference materials

For neutron activation analysis (NAA), the usual matrix problems of sodium, chlorine, and bromine are well known to give rise to high backgrounds that inhibit the determination of several trace elements for short-lived or medium-lived NAA. For long counting times in long-lived NAA, very low backgrounds are required to achieve good sensitivities. We have investigated the use of thermal and epithermal NAA in conjunction with Compton suppression to determine several elements such as arsenic, antimony, cadmium, and mercury, at the level of a few nanograms. The values of these techniques are discussed in contrast to the standard radiochemical methods.     

Nondestructive determination of arsenic in urine by epithermal neutron activation analysis and Compton suppression

Biological Trace Element Research - Epithermal neutron activation analysis, in conjunction with Compton suppression, has been employed to determine arsenic levels in artificially doped urine...     

Radiobiological intercomparison of clinical neutron beams for growth inhibition in Vicia faba bean roots

Relative biological effectiveness (RBE) and oxygen enhancement ratio (OER) values of different neutron beams produced at the variable energy cyclotron Cyclone of Louvain-la-Neuve (Belgium) were determined. The neutrons were obtained by bombarding a beryllium target with 34-, 45-, 65-, or 75-MeV protons or with 50-MeV deuterons. The biological system was growth inhibition in Vicia faba bean roots. Taking the p(65) + Be neutron beam as a reference, RBE values were found equal to 1.36 +/- 0.2, 1.20 +/- 0.1, 1.00 (ref), 0.98 +/- 0.1, and 1.18 +/- 0.1, respectively; the doses corresponding to 50% growth inhibition were 0.39, 0.44, 0.53, 0.54, and 0.45 Gy. For the same beams, OER values were found equal to 1.55 +/- 0.1, 1.38 +/- 0.1, 1.29 +/- 0.1, 1.41 +/- 0.1, and 1.60 +/- 0.2, respectively.     

Chromium,nickel, and arsenic determinations in human samples by thermal and epithermal neutron activation analyses

Both thermal and epithermal neutron activation analyses have been employed to determine chromium and nickel in lung tissue and arsenic in urine. Based on accuracy, precision, and detection limits, these techniques have been successfully used to analyze lung tissue from a deceased welder, who died, from cancer, and to paratake in an interlaboratory toxicological urine program.     

Prompt gamma-ray analysis using cold and thermal guided neutron beams at JAERI

A highly sensitive neutron-induced prompt γ-ray analysis (PGA) system, usable at both cold and thermal neutron beam guides of JRR-3M, has been constructed. The system was designed to achieve the lowest γ-ray background by using lithium fluoride tiles as neutron shielding, by placing the samples in a He atmosphere and by using a Ge-bismuth germanate detector system for Compton suppression. The γ-ray spectrometer can acquire three modes of spectra simultaneously: single, Compton suppression, and pair modes. Because of the low-energy guided neutron beams and the low-background system, analytical sensitivities and detection limits better than those in usual PGA systems have been achieved. Boron and multielemental determination by a comparative standardization have been investigated, and accuracy, precision, and detection limits for the elements in various materials were evaluated. The system has been applied to the determination of B and multielements in samples of various fields such as medical, environmental, and geological sciences.     

Biological effects of ion beams in Nicotiana tabacum L.

The biological effects of ion beams on Nicotiana tabacum L., particularly the induction of chromosome aberrations, were investigated. Dry seeds were exposed to ¹²C⁵⁺, ⁴He²⁺ and ¹H⁺ beams with linear energy transfer (LET) ranging from 1 to 111 keV/μm and irradiated with gamma-rays. Ion beams were more effective in reducing germination and survival of the seeds than gamma-rays. The LD₅₀ for ¹²C⁵⁺ beams, ⁴He²⁺ beams and gamma-rays were 35, 60 and 500 Gy, respectively. The frequencies of mitotic cells with chromosome aberrations, such as chromosome bridges, acentric fragments and lagging chromosomes in the root tip cells of the exposed seeds, increased linearly with increasing doses. Relative biological effectiveness (RBE) values, based on the doses that induced a survival inhibition of 50% and a 10% frequency of aberrant cells, were 14.3–17.5 for the ¹²C⁵⁺ beams, 7.0–8.3 for the ⁴He²⁺ beams and 7.8 for the ¹H⁺ beams. Furthermore, the relative ratios of the chromosome aberration types were significantly different between the ion beam and the gamma-ray regimes: chromosome fragments were more frequent in the former, and chromosome bridges in the latter. Based on these results, we concluded that the repair process of initial lesions induced by ion beams may be different from that induced by low- LET radiation. Received: 29 October 1998 / Accepted in revised form: 25 March 1999