Dual Radiation Action Research Articles

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.

On target cell numbers in radiation-induced H4-RET mediated papillary thyroid cancer.

Radiation-induced human papillary thyroid cancer (PTC) is associated with chromosomal inversions that involve the genetic loci H4 and RET on chromosome 10. Recently, experimental data has shown that these loci lie in very close spatial proximity in a high proportion of adult human thyroid cells. Applying the generalized formulation of dual radiation action to this H4-to-RET geometric distance data, we predict here the radiation dose-response of H4-RET induction. The predicted H4-RET dose-response has a linear-to-quadratic transition dose of approximately 7 Gy, suggesting the validity of linear risk extrapolations to very low doses for H4-RET mediated radiation-induced PTC. In conjunction with A-bomb survivor data, the predicted H4-RET dose-response yields estimates of the number of PTC target cells that are of the order of approximately 10(6) to approximately 10(7) cells, i.e. considerably less than the total number of follicular cells in the thyroid gland.

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.

Low Level Dose Induced Chromosome Aberrations in Human Blood Lymphocytes

Unstable structural aberrations in chromosomes of human blood lymphocytes cannot be used as biological dosemeters in the low dose range, when extrapolating from high doses using a linear dose response, as required by the original formula of the dual radiation action theory. A survey is given of experimental dose-response curves of chromosome aberrations, obtained in investigations not only by this institute, in cooperation with many other laboratories, but also by various authors in different areas of the world. The results are not compatible with the predicted linear dose relationships at in vivo dose ranges up to 30 mGy.y-1. The aberration frequencies rise sharply with dose within the normal environmental exposure up to about twice that level. At higher doses, aberration frequencies increase less rapidly and reach a plateau. Some in vitro experiments of various authors with higher doses of low LET radiations, up to about 400 mGy have found dose responses with steps.

Low Level Dose Induced Chromosome Aberrations in Human Blood Lymphocytes

Unstable structural aberrations in chromosomes of human blood lymphocytes cannot be used as biological dosemeters in the low dose range, when extrapolating from high doses using a linear dose response, as required by the original formula of the dual radiation action theory. A survey is given of experimental dose-response curves of chromosome aberrations, obtained in investigations not only by this institute, in cooperation with many other laboratories, but also by various authors in different areas of the world. The results are not compatible with the predicted linear dose relationships at in vivo dose ranges up to 30 mGy.y-1. The aberration frequencies rise sharply with dose within the normal environmental exposure up to about twice that level. At higher doses, aberration frequencies increase less rapidly and reach a plateau. Some in vitro experiments of various authors with higher doses of low LET radiations, up to about 400 mGy have found dose responses with steps.

Compound Dual Radiation Action: I. General Aspects

The theory of dual radiation action (A. M. Kellerer and H. H. Rossi, Curr. Top. Radiat. Res. Q. 8, 85-158, 1972) has attributed the effects of ionizing radiation on eukaryotes to the production of molecular changes (sublesions) that combine pairwise to produce injury (lesions) responsible for radiation effects. If the yield of sublesions is independent of radiation quality (as is currently assumed), dual radiation action results in the well-known proportionality between the average yield of lesions and alpha D+beta D2, where beta is a radiation-independent quantity. It has, however, been observed that beta changes with radiation type. In this paper we propose an explanation of this discrepancy. Specifically, we suggest that dual radiation action-type processes where beta is variable are the result of a mechanism--termed compound dual radiation action--which consists of a sequence of simple dual radiation action processes, each process being the causative agent for the next one. The sequence, single-strand DNA breaks, double-strand DNA breaks (chromosome breaks), and exchange-type chromosomal aberrations, is one such example examined in the paper.

Microdosimetric single event spectra of Ytterbium-169 compared with commonly used brachytherapy sources and teletherapy beams

Ytterbium-169 has been developed as a possible replacement for Iridium-192 and Iodine-125. The Theory of Dual Radiation Action predicts that the initial slope of the cell survival curve and therefore the relative biological effect at low dose rate is proportional to dose average lineal energy, y d, which is the microscopic analog of the dose average linear energy transfered. The quality factor used in radiation protection has been shown to be a function of the frequency average lineal energy, y f. Single event microdosimetric spectra for 60Co 137Cs, 192Ir, 125I and 169Yb were measured in air and at several depths in phantom with a Rossi proportional counter. These spectra show marked differences between sources. The microscopic analogs of the track average and dose average LET, (y d and y f, respectively) differ between isotopes by factors of two or even higher in comparison to megavoltage electron beams. These y d's and y f's for 169Yb are consistently higher when compared to 60Co or 137Cs but are approximately equal to those for 125I. Values of y f, and y d for 192Ir are intermediate between 60Co and 169Yb The Theory of Dual Radiation Action predicts a low dose rate RBE (assuming a 1 micron effective site diameter) compared to 60Co (in air) of. 1.00 for 137Cs, 1.29 for 192Ir, 1.60 for 169Yb and 1.77 for 125I.

Elements of microdosimetry

This is an introductory tutorial to the field of microdosimetry. Following a brief historical outline, we review the physics of experimental and theoretical microdosimetry and the application of microdosimetry to radiation biology within the so-called "site" approximation. Modern interpretations of microdosimetry that make use of methods developed in integral geometry are described under the heading "structural microdosimetry;" this also illustrates the conceptual basis of dual radiation action. A discussion concerning some future prospects of this field concludes the review.

Microdosimetric single‐event spectra for megavoltage electrons

Experimental techniques have been developed for obtaining single-event microdosimetric spectra from hospital based linear accelerators. Therapeutic electrons of 12, 15, 18, and 20 MeV from Clinic 18 and 20 accelerators have been produced at ultralow dose rates. Details of the experimental methods have been described previously by the authors. Single-event lineal energy spectra for these beams, as measured by a Rossi chamber differ significantly from cobalt-60 both in shape and dose average lineal energy (yd) which, depending on electron energy, can be 20-40% lower. The spectral peaks for electrons are greatly enhanced compared to cobalt. The yd for electrons also differs from previously reported values for 10-15 MV photon beams. These differences are less pronounced than for differences with cobalt. Spectral peaks and shapes correlate well with the actual electron stopping powers in tissue. The theory of dual radiation action predicts changes in relative biological effectiveness at low doses for megavoltage photon and electrons. Although at clinical doses the predicted differences are not statistically significant.

Microdosimetry of a 42 MeV therapy neutron beam

Radiation quality of fast neutron therapy beams can change with depth. For a neutron beam generated by p → Be, the primary effect is a “hardening” of the neutron beam produced by the scattering of slow neutron components. A 42 MeV neutron therapy beam was investigated using microdosimetric techniques. We report measurements of dose mean and saturation-corrected lineal energy in water phantom at build-up depth, 5, 15, and 30 cm, and show representative logarithmic dose distributions in lineal energy. RBE is also calculated using assumptions based on the Theory of Dual Radiation Action and presented as a function of dose and depth.

Interaction Function γ(x) for Chinese Hamster Cells Treated with Hypertonic Phosphate-Buffered Saline after Irradiation

The repair of potentially lethal damage (PLD) in stationary-phase V79 Chinese hamster cells, which was expressible by a postirradiation treatment with hypertonic (0.5 M NaCl) phosphate-buffered saline (PBS), was analyzed within the framework of the theory of dual radiation action. The interaction function gamma(x) was estimated for cells permitted to repair PLD for various intervals of time. The experimental data indicated that 50-60% of the lethal lesions produced at the time of irradiation were repaired in 120 min. The repair of PLD was implicitly involved in the probability of the interaction of sublesions. That is, g(x,trep) was defined as the probability that two sublesions separated by distance x interact to produce a lethal lesion which will not be repaired until the fixation by treatment with hypertonic PBS at time trep after irradiation. It is concluded that the time dependence of the repair of PLD is not independent of the interaction distance x. Three conclusions are drawn: (1) The repair of a lesion produced by a long distance interaction is not detectable by postirradiation treatment with hypertonic PBS. (2) A lesion produced by a short distance interaction is rapidly repaired in about 20 min. (3) A lesion produced by the interaction of sublesions separated by a distance of about 100 nm is repaired slowly.

On the probability of interaction between elementary radiation-induced chromosomal injuries.

Within the Theory of Dual Radiation Action, the heuristically useful function, gamma(chi), that two energy depositions, a distance chi apart, will result in observable damage can be written in terms of two more fundamental quantities: One, s(chi), describes the structure of the sensitive matrix of the cell. The other, g(chi), describes the probability that two elementary injuries, a distance chi apart, will combine to produce observable damage. A priori, the known enhancement exhibited by gamma(chi) at nanometer separations could be due to an enhancement of s(chi), g(chi) or both. For the endpoint of chromatid exchanges in Chinese hamster cells, gamma(chi) has been evaluated from experimental data and s(chi) from a model system. From these g(chi) has been estimated and is roughly constant below approximately 1 micron, decreasing rapidly at larger separations. Thus the enhanced short-range effect appears to be a function more of the spatial characteristics of the target rather than the probability of damage interaction.

The biophysical stage of radiation carcinogenesis.

The dependence of the induction of cancer on the absorbed dose of ionizing radiations has been specified in terms of increasing complexity. The first notion of simple proportionality (the "linear hypothesis") is now frequently replaced with a dependence of both the first and second powers of the dose (the "linear-quadratic model"), which implies proportionality at low doses only. Microdosimetric considerations, in particular the theory of dual radiation action, would be in accord with this relation if tumors were to arise from single cells as the result of a transformation that is autonomous (i.e., depends only on the radiation received by the cell). In this case, it must be expected that the linear portion of the dose-effect curve is dose rate independent, but that the quadratic component may decrease with decreasing dose rate because of repair during the interval between two events (energy depositions by individual particles). Various data appeared to be in agreement with this picture. However, it was shown some time ago that the dose-incidence relation of some neoplasms indicates a non-autonomous response because of departure from a linear dependence when the mean number of events in cells is much less than one in neutron irradiations. Another discrepancy is the repeated observation that reduction of dose rate, while resulting in the expected lessening of the effectiveness of low-LET radiation, increases the effectiveness of neutrons (especially in the case of oncogenic cell transformation). As will be shown, it is possible to account for this phenomenon, although at this point the limitations of the available data make the explanation semi-quantitative and therefore still somewhat hypothetical. However, it should be noted that it does not even require a nonautonomous response and thus is at least an example of the complexities that can arise in the earliest (biophysical) stage of radiation carcinogenesis.

Indirect effects in dual radiation action

In this paper we examine the consequences for models of radiation of allowing energy transfer events to diffuse before interacting with biological targets. In particular we describe a formulation of the theory of dual radiation action in which indirect action is explicitly included. The application of this formalism is illustrated by reanalyzing some of the data reported by Chapman et al. ( Radiat. Environ. Biophys. 1979, 16, 29) on the effects of the radioprotector dimethyl sulphoxide (DMSO) on mammalian cell survival.

A microdosimetric characterization of a cyclotron-produced therapeutic neutron beam.

The therapeutic neutron beam of the Cyclotron Corporation's CP-42 negative-ion cyclotron is generated by protons of 42 MeV bombarding a thin beryllium target. Microdosimetric measurements were made for this neutron beam in a full-scatter water phantom at nine positions inside and outside the useful beam. The lineal energy distribution and the variations of dose-mean, frequency-mean, and saturated lineal energy are compared for these positions. The dose fraction due to gamma rays is also calculated at each of these positions, based upon previously published techniques. A theoretical relative biologic effectiveness, based upon the dual radiation action model of Kellerer and Rossi [Curr. Top. Radiat. Res. 8, 85 (1972)] is also shown for the positions of measurement.

Estimation of Interaction Function γ(X) with Sparsely Ionizing Radiation

The interaction function gamma(chi), which was introduced in the theory of dual radiation action as the probability that two energy transfers separated by distance chi combine with each other to produce a lesion, was estimated with sparsely ionizing radiation (60Co gamma rays and 40 kV X rays). Gamma(chi) was deduced on the assumption that the sensitive matrix is made up of small spherical flocculi distributed over the cell nucleus. The diameter of a flocculus was estimated at (4.0-11.2) X 10(-8) m when the diameter of the cell nucleus d was assumed to be 5 microns, and (4.0-11.4) X 10(-8) m when d was assumed to be 10 microns. It seems reasonable to hypothesize that the flocculus corresponds to the linker DNA in the chromatin structure of DNA, because the size of the linker DNA as a target (about 40 nm) is consistent with the diameter of flocculi obtained in this study.

Inactivation of Synchronized Mammalian Cells with Low-Energy X Rays: Results and Significance

Results for inactivation of hydroxyurea-synchronized V-79 cells by ultrasoft aluminum characteristic X rays of energy 1.5 keV are presented. Limiting RBEs at low doses, relative to 137Cs gamma rays, of 1.8 and 6.4 are, respectively, found for cells at the G1/S and late S stages of the cell cycle. The late-S data are analyzed in the light of previous experiments carried out under similar conditions, also designed to probe the effects of energy deposition in nanometer-sized sites, in which cells were irradiated with correlated pairs of ions. Within the framework of the theory of dual radiation action, the results for ultrasoft X rays and gamma rays can be deduced solely from track simulations and the results of the high-LET molecular ion experiment.