Neutron RBE for primate spinal cord treated with clinical regimens.

The RBEs of high-energy neutrons given in 9 or 12 fractions for cervical spinal cord injury in rhesus monkeys was determined using photons at 2.2 Gy per fraction as the reference radiation. Because the dose-response functions were not parallel, the RBE was not constant but rather increased with dose or, equivalently, with the probability of myelopathy. This required the development of a novel method of determining the RBE versus level of response. The RBE is presented as a function of probability of myelopathy from 0.1 to 99%. At a 50% incidence of myelopathy, the RBE (+/- 1 SE) was 5.22 +/- 0.15. A difference in the histopathology of lesions induced by photon and neutron treatments was observed.     

Dose-response curves for late functional changes in the normal rat brain after single carbon-on doses evaluated by magnetic resonance imaging: influence of follow-up time and calculation of relative biological effectiveness

This study investigated late effects in the brain after irradiation with carbon ions using a rat model. Thirty-six animals were irradiated stereotactically at the right frontal lobe using an extended Bragg peak with maximum doses between 15.2 and 29.2 Gy. Dose-response curves for late changes in the normal brain were measured using T1- and T2-weighted magnetic resonance imaging (MRI). Tolerance doses were calculated at several effect probability levels and times after irradiation. The MRI changes were progressive in time up to 17 months and remained stationary after that time. At 20 months the tolerance doses at the 50% effect probability level were 20.3 +/- 2.0 Gy and 22.6 +/- 2.0 Gy for changes in T1- and T2-weighted MRI, respectively. The relative biological effectiveness (RBE) was calculated on the basis of a previous animal study with photons. Using tolerance doses at the 50% effect probability level, RBE values of 1.95 +/- 0.20 and 1.88 +/- 0.18 were obtained for T1- and T2-weighted MRI. A comparison with data in the literature for the spinal cord yielded good agreement, indicating that the RBE values for single-dose irradiations of the brain and the spinal cord are the same within the experimental uncertainty.     

Accelerated heavy particles and the lens. VI. RBE studies at low doses

We report on the prevalence, hazard, and relative biological effectiveness (RBE) for various stages of lens opacification in rats induced by very low doses of fast argon ions of LET 88 keV/microns, compared to those for X rays. Doses of argon ions from 0.01 to 0.25 Gy were used and RBEs of these ions relative to X rays estimated using a nonparametric technique. At the end of the follow-up period, which encompasses a significant fraction of the animals' lifetime, 90% confidence intervals for the RBE of the argon ions relative to X rays were 4-8 at 0.25 Gy, 10-40 at 0.05 Gy, and 50-100 at 0.01 Gy. Our results are consistent with the point-estimate neutron RBEs in Japanese A-bomb survivors, though broad confidence bounds are present in the Japanese results. If a reasonable extrapolation to higher doses is used, our results are also consistent with data reported earlier at higher doses for argon-ion cataractogenesis in rats, mice, and rabbits. We conclude from these results that at very low doses the RBE for cataractogenesis from HZE particles in space is considerably more than 20, and use of a quality factor of at least 50 would be prudent.     

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.     

Response of colony-forming units-spleen to heavy charged particles

Survival of colony-forming units-spleen (CFU-S) was measured after single doses of photons or heavy charged particles from the BEVALAC. The purposes were to define the radiosensitivity to heavy ions used medically and to evaluate relationships between relative biological effectiveness (RBE) and dose-averaged linear energy transfer (LET infinity). In in vitro irradiation experiments. CFU-S suspensions were exposed to 220 kVp X rays or to 20Ne (372 MeV/micron) or 40Ar (447 MeV/micron) particles in the plateau portion of the Bragg curve. In in vivo irradiation experiments, donor mice from which CFU-S were harvested were exposed to 12C (400 MeV/micron). 20Ne (400 or 670 MeV/micron), or 40Ar (570 MeV/micron) particles in Bragg peaks spread to 4 or 10 cm by spiral ridge filters. Based on RBE at 10 survival, the maximum RBE of 2.1 was observed for 40Ar particles characterized by an LET infinity of approximately 100 keV/micron. Lower RBEs were determined at lower or higher estimated values of LET infinity and ranged from 1.1 for low energy 40Ar particles to 1.5-1.6 for low energy 12C and 20Ne. The responses of CFU-S are compared with responses of other model systems to heavy charged particles and with the reported sensitivity of CFU-S to neutrons of various energies. The maximum RBE reported here, 2.1 for high energy 40Ar particles, is somewhat lower than values reported for fission-spectrum neutrons, and is appreciably lower than values for monoenergetic 0.43-1.8 MeV neutrons. Low energy 12C and 20Ne particles have RBEs in the range of values reported for 14.7 MeV neutrons.     

Evaluation of the relative biological effectiveness of a clinical epithermal neutron beam using dog brain

This investigation was designed to determine the relative biological effectiveness (RBE) of an epithermal neutron beam (FiR 1 beam) using the brains of dogs. The FiR 1 beam was developed for the treatment of patients with glioma using boron neutron capture therapy. Comparisons were made between the effects of whole-brain irradiation with epithermal neutrons and 6 MV photons. For irradiations with epithermal neutrons, three dose groups were used, 9.4 +/- 0.1, 10.2 +/- 0.1 and 11.5 +/- 0.2 Gy. These physical doses were given as a single exposure and are quoted at the 90% isodose. Four groups of five dogs were irradiated with single doses of 10, 12, 14 or 16 Gy of 6 MV photons to the 100% isodose. Different reference isodoses were used to obtain the most comparable dose distribution in the brain for the two different irradiation modalities. Sequential magnetic resonance images (MRI) were taken for 77-115 weeks after irradiation to detect changes in the brain. Dose-effect relationships were established for changes in the brain as detected either by MRI or by subsequent gross morphology and histology. The doses that caused a specified response in 50% of the animals (ED(50)) were calculated from these dose-effect curves for each end point, and these values were used to calculate the RBE values for the different end points. The RBE values for the FiR 1 beam, based on changes observed on MRI, were in the range 1.2-1.3. For microscopic and gross pathological lesions, the values were in the range 1.2-1.4. The corresponding RBE values for the MRI and pathological end points for the high-LET components (protons from nitrogen capture and recoil protons from fast neutrons) were in the ranges 3.5-4.0 and 3.4-4.4, respectively. This assumed a dose-rate reduction factor of 0.6 for the low-dose-rate gamma-ray component of this beam. Finally, a comparison was made between experimentally derived photon doses, for a specified end point, with calculated photon equivalent doses, which were obtained using the weighting factors for clinical studies on the epithermal neutron beam on the Brookhaven Medical Research Reactor (BNL) in New York. This indicated that the radiation-induced lesions seen in the present study were, on average, detected at a 12% lower photon dose than predicted by the use of the BNL clinical weighting factors. This indicates the need for caution in the extrapolation of results from one reactor-based epithermal neutron beam to another.     

Relative biological effectiveness of high-energy photons (up to 50 MV) and electrons (50 MeV)

In vitro studies of the relative biological effectiveness (RBE) of 50-MV X rays have shown an RBE of 1.1 relative to 4-MV X rays. This will be important in clinical radiotherapy. The aim of this study was to verify these results and to investigate whether photonuclear processes might cause the difference in RBE. To do so, 50- and 20-MV X rays and 50-MeV electrons were investigated with respect to RBE. Chinese hamster V79 cells were irradiated in a specially designed system which allows for a high reproducibility of geometry and dosimetry. Fractionation experiments were also carried out to establish the RBE at the clinically relevant dose level, 2 Gy. Fricke dosimetry was used, and the results were confirmed with ionization chamber measurements. The RBE for 50-MV X rays was estimated to be 1.14 at a surviving fraction of 0.1 and 1.12 at a surviving fraction of 0.01. The RBEs for the other qualities were equal to one. The RBE calculated for the 2 Gy/fraction experiments was 1.17.     

Functional and histological changes in rat lung after boron neutron capture therapy

The motivation for this work was an unexpected occurrence of lung side effects in two human subjects undergoing cranial boron neutron capture therapy (BNCT). The objectives were to determine experimentally the biological weighting factors in rat lung for the high-LET dose components for a retrospective assessment of the dose to human lung during cranial BNCT. Lung damage after whole-thorax irradiation was assessed by serial measurement of breathing rate and evaluation of terminal lung histology. A positive response was defined as a breathing rate 20% above the control group mean and categorized as occurring either early (<110 days) or late (>110 days). The ED(50) values derived from probit analyses of the early breathing rate dose-response data for X rays and neutrons were 11.4+/-0.4 and 9.2+/-0.6 Gy, respectively, and were similar for the other end points. The ED(50) values for irradiation with neutrons plus p-boronophenylalanine were 8.7+/-1.0 and 6.7+/-0.4 for the early and late breathing rate responses, respectively, and 7.0+/-0.5 Gy for the histological response. The RBEs for thermal neutrons ranged between 2.9+/-0.7 and 3.1+/-1.2 for all end points. The weighting factors for the boron component of the dose differed significantly between the early (1.4+/-0.3) and late (2.3+/-0.3) breathing rate end points. A reassessment of doses in patients during cranial BNCT confirmed that the maximum weighted doses were well below the threshold for the onset of pneumonitis in healthy human lung.     

Relative biological effectiveness of 12C and 28Si radiation in C57BL/6J mice

Study of heavy ion radiation-induced effects on mice could provide insight into the human health risks of space radiation exposure. The purpose of the present study is to assess the relative biological effectiveness (RBE) of (12)C and (28)Si ion radiation, which has not been reported previously in the literature. Female C57BL/6J mice (n = 15) were irradiated using 4-8 Gy of (28)Si (300 MeV/nucleon energy; LET 70 keV/μm) and 5-8 Gy of (12)C (290 MeV/nucleon energy; LET 13 keV/μm) ions. Post-exposure, mice were monitored regularly, and their survival observed for 30 days. The LD(50/30) dose (the dose at which 50 % lethality occurred by 30-day post-exposure) was calculated from the survival curve and was used to determine the RBE of (28)Si and (12)C in relation to γ radiation. The LD(50/30) for (28)Si and (12)C ion is 5.17 and 7.34 Gy, respectively, and the RBE in relation to γ radiation (LD(50/30)-7.25 Gy) is 1.4 for (28)Si and 0.99 for (12)C. Determination of RBE of (28)Si and (12)C for survival in mice is not only important for space radiation risk estimate studies, but it also has implications for HZE radiation in cancer therapy.     

The Relative Biological Effectiveness for Carbon and Oxygen Ion Beams Using the Raster-Scanning Technique in Hepatocellular Carcinoma Cell Lines

BackgroundAim of this study was to evaluate the relative biological effectiveness (RBE) of carbon (12C) and oxygen ion (16O)-irradiation applied in the raster-scanning technique at the Heidelberg Ion beam Therapy center (HIT) based on clonogenic survival in hepatocellular carcinoma cell lines compared to photon irradiation.MethodsFour human HCC lines Hep3B, PLC, HepG2 and HUH7 were irradiated with photons, 12C and 16O using a customized experimental setting at HIT for in-vitro trials. Cells were irradiated with increasing physical photon single doses of 0, 2, 4 and 6 Gy and heavy ionsingle doses of 0, 0.125, 0.5, 1, 2, 3 Gy (12C and 16O). SOBP-penetration depth and extension was 35 mm +/−4 mm and 36 mm +/−5 mm for carbon ions and oxygen ions respectively. Mean energy level and mean linear energy transfer (LET) were 130 MeV/u and 112 keV/um for 12C, and 154 MeV/u and 146 keV/um for 16O. Clonogenic survival was computated and realtive biological effectiveness (RBE) values were defined.ResultsFor all cell lines and both particle modalities α- and β-values were determined. As expected, α-values were significantly higher for 12C and 16O than for photons, reflecting a steeper decline of the initial slope of the survival curves for high-LET beams. RBE-values were in the range of 2.1–3.3 and 1.9–3.1 for 12C and 16O, respectively.ConclusionBoth irradiation with 12C and 16O using the rasterscanning technique leads to an enhanced RBE in HCC cell lines. No relevant differences between achieved RBE-values for 12C and 16O were found. Results of this work will further influence biological-adapted treatment planning for HCC patients that will undergo particle therapy with 12C or 16O.     

Neutron RBEs for mouse skin at low doses per fraction

The effect of low doses of 240 kVp X rays or of 3 MeV neutrons has been investigated using skin reactions on mouse feet as the biological system. Eight or nine repeated small doses of radiation were used, followed by graded "top-up" doses to bring the reactions into a detectable range. By comparing dose-response curves, the RBE has been determined for neutron doses per fraction ranging from 0.25-1.0 Gy. The data are consistent with a limiting RBE of between 7 and 10 at very low doses. A review of other published RBE values for low doses per fraction shows a wide range of RBEs . Very few studies show a plateau value for the RBE. These findings are more consistent with dose-response data that fit a linear-quadratic model than with a multitarget single-hit model.     

The effectiveness of monoenergetic neutrons at 565 keV in producing dicentric chromosomes in human lymphocytes at low doses

The induction of dicentric chromosomes in human lymphocytes from one individual irradiated in vitro with monoenergetic neutrons at 565 keV was examined to provide additional data for an improved evaluation of neutrons with respect to radiation risk in radioprotection. The resulting linear dose-response relationship obtained (0.813 +/- 0.052 dicentrics per cell per gray) over the dose range of 0.0213-0.167 Gy is consistent with published results obtained for irradiation with neutrons from different sources and with different spectra at energies lower than 1000 keV. Comparing this value to previously published "average" dose-response curves obtained by different laboratories for (60)Co gamma rays and orthovoltage X rays resulted in maximum RBEs (RBE(m)) of about 37 +/- 8 and 16 +/- 4, respectively. However, when our neutron data were matched to low-LET dose responses that were constructed several years earlier for lymphocytes from the same individual, higher values of RBE(m) resulted: 76.0 +/- 29.5 for (60)Co gamma rays and 54.2 +/- 18.4 for (137)Cs gamma rays; differentially filtered 220 kV X rays produced values of RBE(m) between 20.3 +/- 2.0 or 37.0 +/- 7. 1. The results highlight the dependence of RBE(m) on the choice of low-LET reference radiation and raise the possibility that differential individual response to low-LET radiations may need to be examined more fully in this context.     

Response of Chinese hamster v79 multicellular spheroids exposed to high-energy carbon ions

Chinese hamster V79-379A spheroids 200 +/- 30 microm (+/- SD) in diameter were irradiated in agitated medium in different oxygen atmospheres with (1) 227 MeV/nucleon (12)C(+6) ions (plateau region) to model tissue in the entrance channel during therapy, (2) carbon ions in the extended Bragg peak modeling tissue in the target volume, or (3) X rays as a reference modality. Cell survival curves were similar for modes (1) and (3), indicating the absence of a contact effect and the presence of a pronounced oxygen effect with oxygen enhancement ratios (OERs) of 2.8 and 2.9, respectively. In contrast, the oxygen effect was substantially smaller in mode (2) with an OER of 1.4. Under normal or restricted oxygen supply conditions (external pO(2) = 145 or 0 mmHg), the relative biological effectiveness (RBE) was 2.1 or 4.3, respectively, for Bragg-peak irradiation. This modality induced apoptosis and a dose-dependent accumulation of cells in G(2)/M phase even at pO(2) = 0 mmHg. The volume ratios of treated to untreated spheroids exhibited cyclic variations after heavy-particle treatment that were not directly attributable to cell cycle synchronization. In summary, the results suggest that carbon ions in the extended Bragg peak are more effective than conventional X rays, particularly under hypoxic conditions.     

Radiation quality and rat motor performance

The effects of bremsstrahlung, electron, gamma, and neutron radiations were investigated on the motor performance of male Sprague-Dawley rats. Rats were irradiated at a midline tissue dose rate of 20 Gy/min +/- 1 with one of the following: 18.6-MeV electrons (N = 40) or 18.1-MVp bremsstrahlung (N = 57) from a linear accelerator, 60Co 1.25-MeV gamma-ray photons (N = 48), or reactor neutrons at 1.67 MeV tissue-kerma weighted-mean energy (N = 43). Radiation effects were determined by establishing median effective doses (ED50) for rats trained on an accelerod, a shock-avoidance motor performance test. ED50's were based on 10-min postexposure performance. The ED50's were 61 Gy for electrons, 81 Gy for bremsstrahlung, 89 Gy for gamma-ray photons, and 98 Gy for neutrons. In terms of relative biological effectiveness to produce early performance decrement (10 min from the start of irradiation), significant differences existed between the electrons and the other three fields and between the bremsstrahlung and neutron fields. These differences could not be explained by macroscopic dose distribution patterns in the irradiated animals. The data imply that different radiation qualities are not equally effective at disrupting performance, with high-energy electrons being the most effective and neutrons the least.     

Relative biological effectiveness of high-energy iron ions for micronucleus formation at low doses

Dose-response curves for micronucleus (MN) formation were measured in Chinese hamster V79 and xrs6 (Ku80(-)) cells and in human mammary epithelial MCF10A cells in the dose range of 0.05-1 Gy. The Chinese hamster cells were exposed to 1 GeV/nucleon iron ions, 600 MeV/nucleon iron ions, and 300 MeV/nucleon iron ions (LETs of 151, 176 and 235 keV/microm, respectively) as well as with 320 kVp X rays as reference. Second-order polynomials were fitted to the induction curves, and the initial slopes (the alpha values) were used to calculate RBE. For the repair-proficient V79 cells, the RBE at these low doses increased with LET. The values obtained were 3.1 +/- 0.8 (LET = 151 keV/microm), 4.3 +/- 0.5 (LET = 176 keV/microm), and 5.7 +/- 0.6 (LET = 235 keV/microm), while the RBE was close to 1 for the repair-deficient xrs6 cells regardless of LET. For the MCF10A cells, the RBE was determined for 1 GeV/nucleon iron ions and was found to be 5.5 +/- 0.9, slightly higher than for V79 cells. To test the effect of shielding, the 1 GeV/nucleon iron-ion beam was intercepted by various thicknesses of high-density polyethylene plastic absorbers, which resulted in energy loss and fragmentation. It was found that the MN yield for V79 cells placed behind the absorbers decreased in proportion to the decrease in dose both before and after the iron-ion Bragg peak, indicating that RBE did not change significantly due to shielding except in the Bragg peak region. At the Bragg peak itself with an entrance dose of 0.5 Gy, where the LET is very high from stopping low-energy iron ions, the effectiveness for MN formation per unit dose was decreased compared to non-Bragg peak areas.     

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.     

Relative biological effectiveness measurements using murine lethality and survival of intestinal and hematopoietic stem cells after fermilab neutrons compared to JANUS reactor neutrons and 60Co gamma rays

The relative biological effectiveness (RBE) of the 25-MeV (average energy) neutron beam at the Fermi National Accelerator Laboratory was measured using murine bone marrow (LD50/30) and gut (LD50/6) lethality and killing of hematopoietic colony forming units (CFU-S) or intestinal clonogenic cells (ICC). The reference radiation was 60Co gamma rays. The LD50/30 and LD50/6 for mice exposed to the Fermilab neutron beam were 6.6 and 8.7 Gy, respectively, intermediate between those of JANUS neutrons and 60Co gamma rays. The D0 values for CFU-S and ICC were 47 cGy and 1.05 Gy, respectively, also intermediate between the lowest values found for JANUS neutrons and the highest values found after 60Co gamma rays. The split-dose survival ratios for CFU-S at intervals of 1-6 hr between doses were essentially 1.0 for both neutron sources, while the corresponding split-dose survival ratio for 60Co gamma rays was consistantly above 1, reaching a maximum of 1.7 with a 1-hr interval between doses. The 3-hr split-dose survival ratios for ICC were 1.0 for JANUS neutrons, 1.85 for Fermilab neutrons, and 6.5 for 60Co gamma rays. The RBE estimates for LD50/30 were 1.5 and 2.3 for Fermilab and JANUS neutrons, respectively. Based on LD50/6, the RBEs were 1.9 (Fermilab) and 3.0 (JANUS). The RBEs for CFU-S D0 were 1.4 (Fermilab) and 1.9 (JANUS) and for jejunal microcolony D0 1.4 (Fermilab) and 2.8 (JANUS).     

Therapeutic gain factors for fractionated radiation treatment of spontaneous murine tumors using fast neutrons, photons plus O2(1) or 3 ATA, or photons plus misonidazole

Therapeutic gain factors (TGFs) have been determined for three spontaneous tumors of the C3H mouse treated by photons + normobaric oxygen (O2(1) ATA), photons + hyperbaric oxygen (O2 3 ATA), photons + misonidazole, or fast neutrons. The tumors were early generation isotransplants of spontaneous tumors: MCaIV, a mammary carcinoma; FSaII, a fibrosarcoma; and SCCVII, a squamous cell carcinoma. The tumors, transplanted to the right leg, were 6 mm at start of treatment. Normal tissue responses studied were acute reaction of normal skin (all treatment modalities) and LD50 following irradiation of the upper abdomen (in test of photons + O2 at 1 or 3 ATA). Thus both the tumor and normal tissues would be classified as "acute responding." All subject tissues were at congruent to 34.5-35 degrees C at irradiation. Treatments were based on d(25)Be or p(43)Be fast neutron beams, 60Co and 137Cs photon beams. Treatments were given in 5 or 15 equal doses in 5 days. For photon treatments, TGFs (air/O2 3 ATA) were substantially and significantly larger than 1 for all three tumor systems treated at small or large doses per fraction when related to skin or abdominal tissue responses. The TGFs (air/O2 1 ATA) were greater than 1 at small doses per fraction for MCaIV and FSaII for skin as the normal tissue; the TGFs for all three tumors and at all doses per fraction would be greater than 1 when related to upper abdominal tissues. TGFs (O2 1 ATA/O2 3 ATA) for photon irradiation greater than 1 were found only for SCCVII and that obtained for both large and small doses per fraction. Misonidazole achieved impressive TGFs (air/air + miso or air/O2 1 ATA + miso); the drug was tested only at 10-12 Gy/fraction and relative to skin. RBEs(FN) for the three tumors were lower at 1.5-2 Gy(FN)/fraction than at 5-6 Gy(FN)/fraction, i.e. the opposite to that reported for normal tissue (RBE increases with decreasing dose per fraction). A TGF (relative to skin reaction) greater than 1 for fast neutron therapy was found only for SCCVII when treated at large doses/fraction; this was true for air or O2 1 ATA conditions.     

Relative biological effectiveness of 144 keV neutrons in producing dicentric chromosomes in human lymphocytes compared with 60Co gamma rays under head-to-head conditions

The RBE for neutrons was assessed in a head-to-head experiment in which cultures of lymphocytes from the same male donor were irradiated simultaneously with 144 keV neutrons and with 60Co gamma rays as the reference radiation and evaluated using matched time, culture conditions, and the end point of chromosomal aberrations to avoid potential confounding factors that would influence the outcome of the experiment. In addition, the irradiation time was held constant at 2 h for the high-dose groups for both radiation types, which resulted in rather low dose rates. For the induction of dicentric chromosomes, the exposure to the 144 keV neutrons was found to be almost equally as effective (yield coefficient alpha(dic) = 0.786 +/- 0.066 dicentrics per cell per gray) as that found previously for irradiation with monoenergetic neutrons at 565 keV (alpha(dic) = 0.813 +/- 0.052 dicentrics per cell per gray) under comparable exposure and culture conditions (Radiat. Res. 154, 307-312, 2000). However, the values of the maximum low-dose RBE (RBE(m)) relative to 60Co gamma rays that were determined in the present and previous studies show an insignificant but conspicuous difference: 57.0 +/- 18.8 and 76.0 +/- 29.5, respectively. This difference is mainly due to the difference in the alpha(dic) value of the 60Co gamma rays, the reference radiation, which was 0.0138 +/- 0.0044 Gy(-1) in the present study and 0.0107 +/- 0.0041 Gy(-1) in the previous study. In the present experiment, irradiations with 144 keV neutrons and 60Co gamma rays were both performed at 21 degrees C, while in the earlier experiment irradiations with 565 keV neutrons were performed at 21 degrees C and the corresponding reference irradiation with gamma rays was performed at 37 degrees C. However, the temperature difference between 21 degrees C and 37 degrees C has a minor influence on the yield of chromosomal alterations and hence RBE values. The large cubic PMMA phantom that was used for the gamma irradiations in the present study results in a larger dose contribution from Compton-scattered photons compared to the mini-phantom used in the earlier experiments. The contribution of these scattered photons may explain the large value of alpha(dic) for gamma irradiation in the present study. These results indicate that the yield coefficient alpha(dic) for 144 keV neutrons is similar to the one for 565 keV neutrons, and that modification of the alpha(dic) value of the low-LET reference radiation, due to changes in the experimental conditions, can influence the RBE(m). Consequently, alpha(dic) values cannot be shared between cytogenetic laboratories for the purpose of assessment of RBM(m) without verification of the comparability of the experimental conditions.     

Biological effectiveness of accelerated particles for the induction of chromosome damage measured in metaphase and interphase human lymphocytes

Chromosome aberrations were investigated in human lymphocytes after in vitro exposure to 1H-, 3He-, 12C-, 40Ar-, 28Si-, 56Fe-, or 197Au-ion beams, with LET ranging from approximately 0.4-1393 keV/microm in the dose range of 0.075-3 Gy. Dose-response curves for chromosome exchanges, measured at the first mitosis postirradiation using fluorescence in situ hybridization (FISH) with whole-chromosome probes, were fitted with linear or linear-quadratic functions. The relative biological effectiveness (RBE) was estimated from the initial slope of the dose-response curve for chromosomal damage with respect to low- or high-dose-rate gamma rays. Estimates of RBEmax values for mitotic spreads, which ranged from near 0.7 to 11.1 for total exchanges, increased with LET, reaching a maximum at about 150 keV/microm, and decreased with further increase in LET. RBEs for complex aberrations are undefined due to the lack of an initial slope for gamma rays. Additionally, the effect of mitotic delay on RBE values was investigated by measuring chromosome aberrations in interphase after chemically induced premature chromosome condensation (PCC), and values were up to threefold higher than for metaphase analysis.