Theory Of Dual Radiation Action Research Articles

Microdosimetry-based investigation of biological effectiveness of 252Cf brachytherapy source: TOPAS Monte Carlo study

Objective. To investigate biological effectiveness of 252Cf brachytherapy source using Monte Carlo-calculated microdosimetric distributions. Approach. 252Cf source capsule was placed at the center of the spherical water phantom and phase-space data were scored as a function of radial distance in water (R = 1–5 cm) using TOPAS Monte Carlo code. The phase-space data were used to calculate microdosimetric distributions at 1 μm site size. Using these distributions, Relative Biological Effectiveness (RBE), mean quality factor () and Oxygen Enhancement Ratio (OER) were calculated as a function of R. Main results. The overall shapes of the microdosimetric distributions are comparable at all the radial distances in water. However, slight variation in the bin-wise yield is observed with R. RBE, and OER are insensitive to R over the range 1–5 cm. Microdosimetric kinetic model based RBE values are about 2.3 and 2.8 for HSG tumour cells and V79 cells, respectively, whereas biological weighting function-based RBE is about 2.8. ICRP 60 and ICRU 40 recommendation-based values are about 14.5 and 16, respectively. Theory of dual radiation action based RBE is 11.4. The calculated value of OER is 1.6. Significance. This study demonstrates the relative insensitivity of RBE, and OER radially away from the 252Cf source along the distances of 1–5 cm in water.

Space radiation quality factor for Galactic Cosmic Rays and typical space mission scenarios using a microdosimetric approach

Space radiation exposure from omnipresent Galactic Cosmic Rays (GCRs) in interplanetary space poses a serious carcinogenic risk to astronauts due to the—limited or absent—protective effect of the Earth’s magnetosphere and, in particular, the terrestrial atmosphere. The radiation risk is directly influenced by the quality of the radiation, i.e., its pattern of energy deposition at the micron/DNA scale. For stochastic biological effects, radiation quality is described by the quality factor, Q, which can be defined as a function of Linear Energy Transfer (LET) or the microdosimetric lineal energy (y). In the present work, the average Q of GCR for different mission scenarios was calculated using a modified version of the microdosimetric Theory of Dual Radiation Action (TDRA). NASA’s OLTARIS platform was utilized to generate the radiation environment behind different aluminum shielding (0–30 g/cm2) for a typical mission scenario in low-earth orbit (LEO) and in deep space. The microdosimetric lineal energy spectra of ions (Zge 1) in 1 μm liquid water spheres were calculated by a generalized analytical model which considers energy-loss fluctuations and δ-ray transport inside the irradiated medium. The present TDRA-based Q-values for the LEO and deep space missions were found to differ by up to 10% and 14% from the corresponding ICRP-based Q-values and up to 3% and 6% from NASA’s Q-model. In addition, they were found to be in good agreement with the Q-values measured in the International Space Station (ISS) and by the Mars Science Laboratory (MSL) Radiation Assessment Detector (RAD) which represent, respectively, a LEO and deep space orbit.

Microdosimetry-based quality factors for ISO reference photon and beta sources: TOPAS Monte Carlo study

In radiological protection, personnel dosimeters are calibrated in terms of operational quantities such as H p (10) and H p (0.07) against ISO reference photon and beta sources, respectively. H p (10) and H p (0.07) are defined at 1 cm and 0.07 μm depths in the ICRU-4 element tissue phantom. In present study, mean quality factor Q̅ is calculated at these depths using the TOPAS-based microdosimetric distributions at 1 μm site size and FLUKA-based Linear Energy Transfer (LET) dependent Q̅. The sources simulated are ISO reference narrow series X-rays, 137Cs and 147Pm, 85Kr, 90Sr/90Y and 106Ru/106Rh beta sources. Using the calculated microdosimetric distributions, Q̅ is calculated based on ICRP60 and ICRU40 recommendations, Keller-Hahn (KH) approximation, Microdosimetric Kinetic Model (MKM), Clonogenic Survival and Theory of Dual Radiation Action (TDRA). The study includes FLUKA-based Q̅ values calculated using Q(L) vs L relationship as per ICRP Report 60. The MKM, Clonogenic Survival-based RBE, ICRU40, TDRA and KH-based Q values of all the investigated sources are about unity. Depending on the source, microdosimetry-based Q̅ values using ICRP60 recommendations show significant difference from that calculated using other models. Q̅ values of 137Cs are unity, independent of the models.

Microdosimetry Study of Proton Quality Factor Using Analytic Model Calculations

The quality factor (Q) is formally linked to the stochastic (e.g., carcinogenic) risk of diverse ionizing radiations at low doses and/or low dose rates. Q can be a function of the non-stochastic physical quantity Linear Energy Transfer (LET) or the microdosimetric parameter lineal energy (y). These two physical quantities can be calculated either by Monte Carlo (MC) track-structure simulations or by analytic models. In this work, various generalized analytical models were utilized and combined to determine the proton lineal energy spectra in liquid water spheres of various sizes (i.e., 10–3000 nm diameter) over the proton energy range of 1–250 MeV. The calculated spectra were subsequently used within the Theory of Dual Radiation Action (TDRA) and the ICRU Report 40 microdosimetric methodologies to determine the variation of Q¯ with proton energy. The results revealed that the LET-based Q values underestimated the microdosimetric-based Q¯ values for protons with energy below ~100 MeV. At energies relevant to the Bragg peak region (<20–30 MeV), the differences were larger than 20–50%, while reaching 200–500% at ~5 MeV. It was further shown that the microdosimetric-based Q¯ values for protons below ~100 MeV were sensitive to the sphere size. Finally, condensed-phase effects had a very small (<5%) influence on the calculated microdosimetric-based Q¯ over the proton energy range considered here.

Microdosimetric Investigation and a Novel Model of Radiosensitization in the Presence of Metallic Nanoparticles.

Auger cascades generated in high atomic number nanoparticles (NPs) following ionization were considered a potential mechanism for NP radiosensitization. In this work, we investigated the microdosimetric consequences of the Auger cascades using the theory of dual radiation action (TDRA), and we propose the novel Bomb model as a general framework for describing NP-related radiosensitization. When triggered by an ionization event, the Bomb model considers the NPs that are close to a radiation sensitive cellular target, generates dense secondary electrons and kills the cells according to a probability distribution, acting like a “bomb.” TDRA plus a distance model were used as the theoretical basis for calculating the change in α of the linear-quadratic survival model and the relative biological effectiveness (RBE). We calculated these quantities for SQ20B and Hela human cancer cells under 250 kVp X-ray irradiation with the presence of gadolinium-based NPs (AGuIXTM), and 220 kVp X-ray irradiation with the presence of 50 nm gold NPs (AuNPs), respectively, and compared with existing experimental data. Geant4-based Monte Carlo (MC) simulations were used to (1) generate the electron spectrum and the phase space data of photons entering the NPs and (2) calculate the proximity functions and other related parameters for the TDRA and the Bomb model. The Auger cascade electrons had a greater proximity function than photoelectric and Compton electrons in water by up to 30%, but the resulting increases in α were smaller than those derived from experimental data. The calculated RBEs cannot explain the experimental findings. The relative increase in α predicted by TDRA was lower than the experimental result by a factor of at least 45 for SQ20B cells with AGuIX under 250 kVp X-ray irradiation, and at least four for Hela cells with AuNPs under 220 kVp X-ray irradiation. The application of the Bomb model to Hela cells with AuNPs under 220 kVp X-ray irradiation indicated that a single ionization event for NPs caused by higher energy photons has a higher probability of killing a cell. NPs that are closer to the cell nucleus are more effective for radiosensitization. Microdosimetric calculations of the RBE for cell death of the Auger electron cascade cannot explain the experimentally observed radiosensitization by AGuIX or AuNP, while the proposed Bomb model is a potential candidate for describing NP-related radiosensitization at low NP concentrations.

Impact of a spatially dependent dose delivery time structure on the biological effectiveness of scanning proton therapy.

In the scanning beam delivery of protons, different portions of the target are irradiated with different linear energy transfer protons with various time intervals and irradiation times. This research aimed to evaluate the spatially dependent biological effectiveness of protracted irradiation in scanning proton therapy. One and two parallel opposed fields plans were created in water phantom with the prescribed dose of 2 Gy. Three scenarios (instantaneous, continuous, and layered scans) were used with the corresponding beam delivery models. The biological dose (physical dose × relative biological effectiveness) was calculated using the linear quadratic model and the theory of dual radiation action to quantitatively evaluate the dose delivery time effect. In addition, simulations using clinical plans (postoperative seminoma and prostate tumor cases) were conducted to assess the impact of the effects on the dose volume histogram parameters and homogeneity coefficient (HC) in targets. In a single-field plan of water phantom, when the treatment time was 19 min, the layered-scan scenario showed a decrease of<0.2% (almost 3.3%) in the biological dose from the plan on the distal (proximal) side because of the high (low) dose rate. This is in contrast to the continuous scenario, where the biological dose was almost uniformly decreased over the target by approximately 3.3%. The simulation with clinical geometry showed that the decrease rates in D99% were 0.9% and 1.5% for every 10 min of treatment time prolongation for postoperative seminoma and prostate tumor cases, respectively, whereas the increase rates in HC were 0.7% and 0.2%. In protracted irradiation in scanning proton therapy, the spatially dependent dose delivery time structure in scanning beam delivery can be an important factor for accurate evaluation of biological effectiveness.

Microdosimetry-based relative biological effectiveness calculations for radiotherapeutic electron beams: a FLUKA-based study.

Based on FLUKA, the present study is aimed at calculating the microdosimetric distributions of electron beams (6, 12 and 18MeV) for radiotherapy as a function of depth in water at a site-size of 1μm using a tissue-equivalent proportional counter (TEPC). Using the calculated microdosimetric distributions, the depth-specific relative biological effectiveness (RBE) of electron beams used in radiotherapy is calculated based on the theory of dual radiation action (TDRA) and the microdosimetric kinetic model (MKM). The TDRA-based calculation shows the variation of RBE of an electron beamwith the absorbed dose and depth in water. In this study, we compared the RBE values calculated based on the TDRA and MKM. The FLUKA-based microdosimetric distributions in water obtained using the pre-calculated electron fluence spectra resulted in an improvement in the computational efficiency by a factor of 110 when compared with a full simulation. Depending on the beam energy and depth of water, RBETDRA was in the range 0.67-0.78. RBEMKM at 10% survival of HSG tumor cells was 0.84, which was nearly independent of the depth and beam energy.

Microdosimetric investigation of the radiation quality of low-medium energy electrons using Geant4-DNA

The increasing clinical use of low-energy photon and electron sources (below few tens of keV) has raised concerns on the adequacy of the existing approximation of an energy-independent radiobiological effectiveness. In this work, the variation of the quality factor (Q) and relative biological effectiveness (RBE) of electrons over the low-medium energy range (0.1 keV–1 MeV) is examined using several microdosimetry-based Monte Carlo methodologies with input data obtained from Geant4-DNA track-structure simulations. The sensitivity of the results to the different methodologies, Geant4-DNA physics models, and target sizes is examined. Calculations of Q and RBE are based on the ICRU Report 40 recommendations, the Kellerer-Hahn approximation, the site version of the theory of dual radiation action (TDRA), the microdosimetric kinetic model (MKM) of cell survival, and the calculated yield of DNA double strand breaks (DSB). The stochastic energy deposition spectra needed as input in the above approaches have been calculated for nanometer spherical volumes using the different electron physics models of Geant4-DNA. Results are normalized at 100 keV electrons which is here considered the reference radiation. It is shown that in the energy range ~50 keV-1 MeV, the calculated Q and RBE are approximately unity (to within 1–2%) irrespective of the methodology, Geant4-DNA physics model, and target size. At lower energies, Q and RBE become energy-dependent reaching a maximum value of ~1.5–2.5 between ~200 and 700 eV. The detailed variation of Q and RBE at low energies depends mostly upon the adopted methodology and target size, and less so upon the Geant4-DNA physics model. Overall, the DSB yield predicts the highest RBE values (with RBEmax≈2.5) whereas the MKM the lowest RBE values (with RBEmax≈1.5). The ICRU Report 40, Kellerer-Hahn, and TDRA methods are in excellent agreement (to within 1–2%) over the whole energy range predicting a Qmax≈2. In conclusion, the approximation Q=RBE=1 was found to be valid only above ~50 keV whereas at lower energies both Q and RBE become strongly energy-dependent. It is envisioned that the present work will contribute towards establishing robust methodologies to determine theoretically the energy-dependence of radiation quality of individual electrons which may then be used in subsequent calculations involving practical electron and photon radiation sources.

The impact of dose delivery time on biological effectiveness in proton irradiation with various biological parameters

The purpose of this study is to evaluate the sublethal damage (SLD) repair effect in prolonged proton irradiation using the biophysical model with various cell-specific parameters of (α/β)x and T1/2 (repair half time). At present, most of the model-based studies on protons have focused on acute radiation, neglecting the reduction in biological effectiveness due to SLD repair during the delivery of radiation. Nevertheless, the dose-rate dependency of biological effectiveness may become more important as advanced treatment techniques, such as hypofractionation and respiratory gating, come into clinical practice, as these techniques sometimes require long treatment times. Also, while previous research using the biophysical model revealed a large repair effect with a high physical dose, the dependence of the repair effect on cell-specific parameters has not been evaluated systematically. Biological dose [relative biological effectiveness (RBE)×physical dose] calculation with repair included was carried out using the linear energy transfer (LET)-dependent linear-quadratic (LQ) model combined with the theory of dual radiation action (TDRA). First, we extended the dose protraction factor in the LQ model for the arbitrary number of different LET proton irradiations delivered sequentially with arbitrary time lags, referring to the TDRA. Using the LQ model, the decrease in biological dose due to SLD repair was systematically evaluated for spread-out Bragg peak (SOBP) irradiation in a water phantom with the possible ranges of both (α/β)x and repair parameters ((α/β)x =1-15Gy, T1/2 =0-90min). Then, to consider more realistic irradiation conditions, clinical cases of prostate, liver, and lung tumors were examined with the cell-specific parameters for each tumor obtained from the literature. Biological D99% and biological dose homogeneity coefficient (HC) were calculated for the clinical target volumes (CTVs), assuming dose-rate structures with a total irradiation time of 0-60min. The differences in the cell-specific parameters resulted in considerable variation in the repair effect. The biological dose reduction found at the center of the SOBP with 30min of continuous irradiation varied from 1.13% to 14.4% with a T1/2 range of 1-90min when (α/β)x is fixed as 10Gy. It varied from 2.3% to 6.8% with an (α/β)x range of 1-15Gy for a fixed value of T1/2 =30min. The decrease in biological D99% per 10min was 2.6, 1.2, and 3.0% for the prostate, liver, and lung tumor cases, respectively. The value of the biological D99% reduction was neither in the order of (α/β)x nor prescribed dose, but both comparably contributed to the repair effect. The variation of HC was within the range of 0.5% for all cases; therefore, the dose distribution was not distorted. The reduction in biological dose caused by the SLD repair largely depends on the cell-specific parameters in addition to the physical dose. The parameters should be considered carefully in the evaluation of the repair effect in prolonged proton irradiation.

Track structure simulations of proximity functions in liquid water using the Geant4-DNA toolkit

The mechanistic Monte Carlo modeling of biological effects of ionising radiation at sub-cellular and DNA scale requires the accurate simulation of track structures in the biological medium, commonly approximated as liquid water. The formalism of microdosimetry allows one to describe quantitatively the spatial distribution of energy deposition in the irradiated medium, which is known to relate to the deleterious effects in the irradiated cellular targets. The Geant4-DNA extension of the Geant4 open-source and general-purpose Monte Carlo simulation toolkit has been recently evaluated for the simulation of microdosimetry spectra, allowing, in particular, the calculation of lineal energy distributions. In this work, we extend the microdosimetric functionalities of Geant4-DNA by the development of a new Geant4-DNA example dedicated to the simulation of differential proximity functions. Simulation results are presented for the proximity function of electrons, protons, and alpha particles over a wide energy range using the different physical models of electron interactions available in Geant4-DNA. The influence of sub-excitation processes and electron tracking cut is discussed. Results are compared to literature data when available. As an example, a simple calculation of the relative biological effectiveness (RBE) in the context of the Theory of Dual Radiation Action using the present proximity functions yields up to a factor of 2 variation of the electron RBE in the energy range from 100 eV to 100 keV.

Upper limit of magnetic effect on α/β ratio

Magnetic resonance imaging (MRI) is being integrated into radiotherapy delivery for MRI-guided radiotherapy. The purpose of this work is to investigate theoretically the upper limit of any potential magnetic effect on the α/β ratio, an important radiobiological parameter in radiation therapy. Based on the theory of dual radiation action, the α/β ratio can be expressed by an integral of the product of two microdosimetry quantities and , where is the probability that two energy transfers, a distance x apart, results in a lesion, and is the proximity function, which is the energy-weighted point-pair distribution of distances between energy transfer points in a track. The quantity depends on the applied magnetic field. An analytical approach has been used to derive a formula that can be used to calculate the α/β ratio in an extremely strong magnetic field, which gives the upper limit of the potential changes of the α/β ratio due to the presence of a magnetic field. For V79 Chinese hamster cells the upper limit of the increase of the α/β ratio with a magnetic field has been found to be 2.90 times for Pd-103, 2.97 times for I-125 and 2.3 times for Co-60 sources.

SU‐E‐T‐227: Could the Alpha/Beta Ratio Change in a Strong Magnetic Field?

Purpose:Magnetic resonance imaging (MRI) is being integrated into radiotherapy delivery for MRI‐guided radiotherapy. The presence of a strong magnetic field from a MRI machine during radiotherapy delivery presents a new challenge since the trajectories of electrons liberated by ionizing radiation in patients are strongly dependent on the applied magnetic field. The purpose of this work is to explore the potential effect of a strong magnetic field on the α/β ratio, an important radiobiological parameter in radiotherapy.Methods:Based on the theory of dual radiation action, the α/β ratio can be expressed by an integral of the product of two microdosimetry quantities γ(x) and t(x), where γ(x) is the probability that two energy transfers, a distance × apart, results in a lesion, and t(x) is the proximity function, which is the energy‐weighted point‐pair distribution of distances between energy transfer points in a track. The quantity t(x) depends on the applied magnetic field. An analytical approach has been used to derive a formula that can be used to calculate the α/β ratio in an extremely strong magnetic field.Results:The α/β ratio has been evaluated in the special case when the applied magnetic field approaches infinity, which gives the upper limit of the potential change of the α/β ratio due to the presence of a strong magnetic field. For V79 Chinese hamster cells it has been shown that the α/β ratio could be increased by 2.90 times for Pd‐103, 2.97 times for I‐125 and about 2.3 times for Co‐60 sources when the applied magnetic field approaches infinity.Conclusion:It has been shown theoretically that the α/β ratio can change in a strong magnetic field, and there could be up to a nearly three‐fold increase in the α/β ratio, depending on the strength of the applied magnetic field, the cell type and the radiation used.

Chromosomal aberrations in the bone marrow cells of mice induced by accelerated 12C 6+ ions

The whole bodies of 6-week-old male Kun-Ming mice were exposed to different doses of 12C 6+ ions or X-rays. Chromosomal aberrations of the bone marrow (gaps, terminal deletions and breaks, fragments, inter-chromosomal fusions and sister-chromatid union) were scored in metaphase 9 h after exposure, corresponding to cells exposed in the G 2-phase of the first mitosis cycle. Dose–response relationships for the frequency of chromosomal aberrations were plotted both by linear and linear-quadratic equations. The data showed that there was a dose-related increase in the frequency of chromosomal aberrations in all treated groups compared to controls. Linear-quadratic equations were a good fit for both radiation types. The compound theory of dual radiation action was applied to decipher the bigger curvature ( D 2) of the dose–response curves of X-rays compared to those of 12C 6+ ions. Different distributions of the five types of aberrations and different degrees of homogeneity were found between 12C 6+ ion and X-ray irradiation and the possible underlying mechanism for these phenomena were analyzed according to the differences in the spatial energy deposition of both types of radiation.

From DNA radiation damage to cell death: theoretical approaches.

Some representative models of radiation-induced cell death, which is a crucial endpoint in radiobiology, were reviewed. The basic assumptions were identified, their consequences on predicted cell survival were analyzed, and the advantages and drawbacks of each approach were outlined. In addition to “historical” approaches such as the Target Theory, the Linear-Quadratic model, the Theory of Dual Radiation Action and Katz' model, the more recent Local Effect Model was discussed, focusing on its application in Carbon-ion hadrontherapy. Furthermore, a mechanistic model developed at the University of Pavia and based on the relationship between cell inactivation and chromosome aberrations was presented, together with recent results; the good agreement between model predictions and literature experimental data on different radiation types (photons, protons, alpha particles, and Carbon ions) supported the idea that asymmetric chromosome aberrations like dicentrics and rings play a fundamental role for cell death. Basing on these results, a reinterpretation of the TDRA was also proposed, identifying the TDRA “sublesions” and “lesions” as clustered DNA double-strand breaks and (lethal) chromosome aberrations, respectively.

Mammalian Cell Killing by Ultrasoft X Rays and High-Energy Radiation: An Extension of the MK Model

An alternate formulation of the microdosimetric-kinetic (MK) model is presented that applies to irradiation of mammalian cells with ultrasoft X rays as well as high-energy radiations of variable linear energy transfer (LET). Survival and DNA double-strand break measurements for V79 cells from the literature are examined to illustrate application of the model. It is demonstrated that the linear component of the linear-quadratic survival relationship (alpha) is enhanced because repairable potentially lethal lesions formed from a single ultrasoft X-ray energy deposition event, when closer on average than for a single high-energy radiation event, are more likely to combine to form a lethal lesion. The quadratic component (beta) of the linear-quadratic survival relationship is increased because the potentially lethal lesions formed by ultrasoft X rays are created with greater efficiency than those of high-energy radiation. In addition, potentially lethal lesions from very low-energy carbon K-shell X rays may be enriched in structural forms that favor combination to form lethal lesions instead of repair. These features account for the increased effectiveness of killing of V79 cells by ultrasoft X rays compared to cobalt-60 gamma radiation. The importance of pairwise combination of potentially lethal lesions to form exchange chromosome aberrations that become lethal lesions is discussed. The extended MK model explains and reconciles differences between the MK model and the theory of dual radiation action on the one hand, and on the other, the view that variation in the RBE with radiation quality is explained by differences in energy deposition in nanometer- rather than micrometer-size volumes.

Models for mixed irradiation with a 'reciprocal-time' pattern of the repair function.

Suzuki presented models for mixed irradiation with two and multiple types of radiation by extending the Zaider and Rossi model, which is based on the theory of dual radiation action. In these models, the repair function was simply assumed to be semi-logarithmically linear (i.e., monoexponential), or a first-order process, which has been experimentally contradicted. Fowler, however, suggested that the repair of radiation damage might be largely a second-order process rather than a first-order one, and presented data in support of this hypothesis. In addition, a second-order repair function is preferred to an n-exponential repair function for the reason that only one parameter is used in the former instead of 2n-1 parameters for the latter, although both repair functions show a good fit to the experimental data. However, according to a second-order repair function, the repair rate depends on the dose, which is incompatible with the experimental data. We, therefore, revised the models for mixed irradiation by Zaider and Rossi and by Suzuki, by substituting a 'reciprocal-time' pattern of the repair function, which is derived from the assumption that the repair rate is independent of the dose in a second-order repair function, for a first-order one in reduction and interaction factors of the models, although the underlying mechanism for this assumption cannot be well-explained. The reduction factor, which reduces the contribution of the square of a dose to cell killing in the linear-quadratic model and its derivatives, and the interaction factor, which also reduces the contribution of the interaction of two or more doses of different types of radiation, were formulated by using a 'reciprocal-time' pattern of the repair function. Cell survivals calculated from the older and the newly modified models were compared in terms of the dose-rate by assuming various types of single and mixed irradiation. The result implies that the newly modified models for mixed irradiation can express or predict cell survival more accurately than the older ones, especially when irradiation is prolonged at low dose rates.

Biologically based risk estimation for radiation-induced CML. Inferences from BCR and ABL geometric distributions.

Chronic myeloid leukemia (CML) invites biologically based radiation risk modeling because CML is simultaneously well-understood, homogeneous and prevalent. CML is known to be caused by a translocation involving the ABL and BCR genes, almost all CML patients have the BCR-ABL translocation, and CML is prevalent enough that its induction is unequivocally detected among Hiroshima A-bomb survivors. In a previous paper, a linear-quadratic-exponential (LQE) dose-response model was used to estimate the lifetime excess risk of CML in the limit of low doses of gamma-rays, R gamma. This estimate assumed that BCR-ABL translocation dose-response curves in stem cells for both neutrons and gamma-rays, differ only by a common proportionality constant from dicentric aberration dose-response curves in lymphocytes. In the present paper we challenge this assumption by predicting the BCR-ABL dose response. The predictions are based on the biophysical theory of dual radiation action (TDRA) as it applies to recent BCR-to-ABL distance data in G0 human lymphocytes; this data shows BCR and ABL geometric distributions that are not uniform and not independent, with close association of the two genes in some cells. The analysis speaks against the previous proportionality assumption. We compute 11 plausible LQE estimates of R gamma, 2 based on the proportionality assumption and 9 based on TDRA predictions. For each estimate of R gamma we also compute an associated estimate of the number of CML target cells, N; the biological basis of the LQE model allows us to form such estimates. Consistency between N and hematological considerations provides a plausibility check of the risk estimates. Within the group of estimates investigated, the most plausible lifetime excess risk estimates tend to lie near R gamma = 0.01 Gy-1, substantially higher than risk estimates based on the proportionality assumption.

A microdosimetric-kinetic theory of the dependence of the RBE for cell death on LET.

Experiments with cultured mammalian cells exposed to ionizing radiation of varying LET are examined in the context of a microdosimetric-kinetic (MK) model of radiation induced mammalian. cell killing similar to the site model of the theory of dual radiation action. The experimentally measured RBE, in the limit of zero dose, increases linearly with LET for LET less than a value that lies in the range of about 40-90 keV per micron. It is shown that the tendency of the RBE to increase linearly with LET can be explained as a result of the random variation of specific energy among microscopic sized domains (sites), into which the nucleus may be partitioned, and the effect of this variation on the formation of lethal lesions by pairwise combination of repairable primary lesions in DNA. the microscopic subunits corresponding to a site have diameter in the range of 0.56-0.75 microns. The linearity of RBE with increasing LET implies that value of the quadratic parameter of the linear-quadratic survival relation (beta) is constant, at least for LET low enough to be in the linear range, and this in turn implies the production of primary DNA lesion, likely double strand breaks, does not increase with LET. the experiments, interpreted with MK model, also imply that the repairability and potential for lethality of the primary DNA lesion does not change with variation of LET within the linear range. The failure of RBE to maintain its linear increase for higher values of LET, and the resulting RBE maximum at about 100 keV per micron, are likely primarily due to the departure of the distribution of lethal lesions among cells from the Poisson distribution. Some implications concerning the use of radiation to treat cancer are noted.

Microdosimetric evaluation of relative biological effectiveness for 103Pd, 125I, 241Am, and 192Ir brachytherapy sources

Purpose : To determine the microdosimetric-derived relative biological (RBE) of 103Pd, 125I, 241Am, and 192Ir brachytherapy sources at low doses and/or low dose rates. Methods and Materials : The Theory of Dual Radiation Action can be used to predict expected RBE values based on the spatial distribution of energy deposition at microscopic levels from these sources. Single-event lineal energy spectra for these isotopes have been obtained both experimentally and theoretically. A grid-defined wall-less proportional counter was used to measure the lineal energy distributions. Unlike conventional Rossi proportional counters, the counter used in these measurements has a conducting nylon fiber as the central collecting anode and has no metal parts. Thus, the Z-dependence of the photoelectric effect is eliminated as a source of measurement error. Single-event spectra for these brachytherapy sources have been also calculated by: (a) the Monte Carlo code MCNP to generate the electron slowing down spectrum, (b) transport of monoenergetic electron tracks, event by event, with our Monte Carlo code DELTA, (c) using the concept of associated volume to obtain the lineal energy distribution f(y) for each monoenergetic electron, and (d) obtaining the composite lineal energy spectrum for a given brachtherapy source based on the electron spectrum caculated at step (a). Results : Relative to 60Co, the RBE values obtained from this study are: 2.3 for 103Pd, 2.1 for 125I, 2.1 for 241Am, and 1.3 for 192Ir. Conclusions : These values are consistent with available data from invitro cell survival experiments. We suggest that, at least for these brachytherapy sources, microdosimetry may be used as a credible alternative to timeconsuming (and often uncertain) radiobiological experiments to obtain information on radiation quality and make reliable predictions of RBE in low dose rate brachytherapy.

Dose-Survival Curves, Alpha/Beta Ratios, RBE Values, and Equal Effect per Fraction for Neutron Irradiation of Jejunal Crypt Cells

Jejunal crypt cell survival after regimens of one, two, three and five fractions was used to reconstruct composite single-dose survival curves for neutrons of five different energies. There is no obvious shoulder, but there is a gradual divergence from linearity that is most evident at low levels of cell survival (high doses). The effect of dose fractionation is relatively small, especially at the low doses characteristic of each treatment session in neutron radiotherapy. The alpha/beta values for the linear-quadratic survival curves range from 27 to 40 Gy. The curves for neutrons are different from the curves for gamma rays mainly in their alpha coefficients, as predicted by Kellerer and Rossi's theory of dual radiation action, but both alpha and beta values are higher the lower the mean neutron energy, which is not consistent with the theory. The ratio of alpha coefficients reported here for various neutron beams to those for gamma rays reported elsewhere ranges between 3.2 and 4.6. This range of values represents the maximum limits for RBEn/gamma values (at very low doses), and is sometimes referred to as RBEm. These values increase with decreasing neutron energy. The ratios of beta coefficients for neutron and gamma-ray survival curves were lower than the alpha ratios, ranging between 0.9 and 1.9, although not reliably distinguished from 1.0. Each of a series of equal dose fractions given at 3-h intervals produced a constant (logarithmic) decrease in cell survival as evidenced by the consistency of the estimate of cell survival from a certain single dose fraction, regardless of the level of cell survival (number of dose fractions) from which the estimate was made. Even more significant than the overlap of individual data points is the excellent fit of all the data to survival curves reconstructed on the assumption of an equal effect per fraction. An implication of these results is that, with neutrons, too little unrepaired injury persists at 3 h to influence the response to a subsequent exposure measurably.