Dual Radiation Action Research Articles

Maximum Likelihood Estimation for Cytogenetic Dose-Response Curves

In vitro dose-response curves are used to describe the relation between chromosome aberrations and radiation dose for human lymphocytes. The lymphocytes are exposed to low-LET radiation, and the resulting dicentric chromosome aberrations follow the Poisson distribution. The expected yield depends on both the magnitude and the temporal distribution of the dose. A general dose-response model that describes this relation has been presented by Kellerer and Rossi (1972, Current Topics on Radiation Research Quarterly 8, 85-158; 1978, Radiation Research 75, 471-488) using the theory of dual radiation action. Two special cases of practical interest are split-dose and continuous exposure experiments, and the resulting dose-time-response models are intrinsically nonlinear in the parameters. A general-purpose maximum likelihood estimation procedure is described, and estimation for the nonlinear models is illustrated with numerical examples from both experimental designs. Poisson regression analysis is used for estimation, hypothesis testing, and regression diagnostics. Results are discussed in the context of exposure assessment procedures for both acute and chronic human radiation exposure.

Track structure in biological models

High-energy heavy ions in the galactic cosmic radiation (HZE particles) may pose a special risk during long term manned space flights outside the sheltering confines of the earth's geomagnetic field. These particles are highly ionizing, and they and their nuclear secondaries can penetrate many centimeters of body tissue. The three dimensional patterns of ionizations they create as they lose energy are referred to as their track structure . Several models of biological action on mammalian cells attempt to treat track structure or related quantities in their formulation. The methods by which they do this are reviewed. The proximity function is introduced in connection with the theory of Dual Radiation Action (DRA). The ion-gamma kill (IGK) model introduces the radial energy-density distribution, which is a smooth function characterizing both the magnitude and extension of a charged particle track. The lethal, potentially lethal (LPL) model introduces λ, the mean distance between relevant ion clusters or biochemical species along the track. Since very localized energy depositions (within ∼ 10 nm) are emphasized, the proximity function as defined in the DRA model is not of utility in characterizing track structure in the LPL formulation.

Microdosimetry and Radiobiology

The role of microdosimetry in radiobiology is considered, with emphasis on recent developments in the theory of dual radiation action. These pertain to characteristic differences between intra-track and inter-track lesions, various types of saturation and possible effects on DNA by inter-track action.

Dual Radiation Action and the Initial Slope of Survival Curves

Dual Radiation Action and the Initial Slope of Survival Curves

Dual Radiation Action and the Initial Slope of Survival Curves

The concepts and tools of the Theory of Dual Radiation Action (e.g., proximity functions and gamma distributions) are outlined, and their connection to single-event cell inactivation is exemplified by an analysis and interpretation of the cross-section data obtained by Todd. It is shown that the biological effect of individual charged particles is dominated by the combined action of a few delta rays.

Microdosimetry and Thermoluminescence

The mechanism for production of light from a thermoluminescent phosphor requires the combination of a trapped electron and hole at a luminescent center. The kinetics is that of a second-order process. Accordingly one may expect a similarity in the formalism for describing thermoluminescent emission (TL) and the theory of dual radiation action in radiobiology (TDRA). The TDRA was developed to provide a framework for describing the effects of ionizing radiation on biological systems. It requires the interaction of two primary units of radiation damage called "sublesions" to form a "lesion" which may then be expressed as a biological effect. The physical parameters used in the TDRA come from microdosimetry, which deals with the deposition of energy by ionizing radiation in domains whose dimensions are of the order of micrometers. This paper explores the relationships between microdosimetric concepts and a description of TL properties, such as TL dose-response curves and TL LET dependence. This is then compared with similar quantities in biology to determine the possible relevance of TL as a biological model.

Modification of the Theory of Dual Radiation Action for Attenuated Fields: II. Application to the Analysis of Soft X-Ray Results

A formalism developed in the first paper in this series, based on the generalized Theory of Dual Radiation Action, is applied to survival data for cells exposed to soft X rays. It is shown that, in contrast to previous published analyses, this formalism--modified to account for the attenuation of dose across the sensitive matrix of the cell--is fully consistent with the experimental results. The reasons for previous disagreements are discussed.

Modification of the Theory of Dual Radiation Action for Attenuated Fields: I. Basic Formalism

A modification of the Theory of Dual Radiation Action is described to take into account the effects of an attenuated beam of radiation across the sensitive site of the cell. It is shown that, unlike the case of uniform radiation, the coefficient of the dose-squared (intertrack) term is not constant, but varies in a manner dependent on the attenuation coefficient of the radiation and the geometry of the site.

Microdosimetry of 10-15 MeV bremsstrahlung x rays.

Experimental techniques have been developed for obtaining microdosimetric spectra on a hospital-based linear accelerator. Teletherapy beams of 10 and 15 MeV bremsstrahlung x rays from a Varian Clinac-18 and Clinac-20, respectively, have been produced at ultralow dose rates (50-200 microGy/h) which enables direct measurements of lineal energy distributions with a conventional Rossi-type gas proportional counter. Extensive measurements have been made to insure that the dosimetric properties of these low dose rate beams are nearly identical to those produced under high dose rate clinical conditions. Analytical procedures have been developed to correct measured lineal energy spectra for pileup caused by the low duty factor of the linear accelerator. The lineal energy spectra of these megavoltage beams differ significantly from Co-60, with dose averaged lineal energies (yD) being 20%-30% lower than for Co-60. Although such differences may not be important at clinical doses, the theory of dual radiation action does predict a lower biological effectiveness for these beams at very low dose levels.

A study of cell survival in mammalian cells exposed to spatially correlated triads of protons.

Cellular survival results for late-S Chinese hamster V79 cells exposed to triads of protons of variable mean separations are reported. The data are analyzed within the framework of the Theory of Dual Radiation Action [8]. This analysis provides a new estimation of the function gamma (chi) representing the probability of two energy transfers separated by the distance chi to produce a lesion. In agreement with an earlier study [6] involving pairs of deuterons, it is concluded that: a) the process of lesion formation depends strongly on the relative separation of energy deposition events, and b) intratrack and intertrack lesions correspond to substantially different separations of pairwise energy transfers.

An Assessment of the Role of Microdosimetry in Radiobiology

A brief outline is given of the concepts of microdosimetry and the development of the theory of dual radiation action, which was proposed as the link between the physical properties of radiation (microdosimetry) and their biological effects. A good deal of experimental evidence was consistent with the theory in its original site model form, but there were also areas of significant disagreement. More recent experiments with ultrasoft x rays and beams of correlated ions have provided critical tests which have shown that the site model does not give an adequate description of the mechanism of radiation action. A large proportion, at least, of the radiation-induced lesions are produced by highly localized energy concentrations without the need for long-range interaction of sublesions. Attempts have been made to allow for such lesions within the original postulates of the theory of dual radiation action by development of the distance model or generalized formalism using a distance-dependent interaction probability. Some of the present limitations of this approach are discussed. An alternative hypothesis, involving dose-dependent repair acting directly upon the lesions, is described. A comparison is made between consequences of these two alternative approaches. The validity of the application of microdosimetric measurements to a varietymore » of problems is considered.« less

Microdosimetric measurements of radiation quality variations in homogeneous phantoms irradiated by fast neutron beams.

The Dual Radiation Action Theory of Kellerer and Rossi (DRA), along with presently available microdosimetric techniques, is applied to the determination of radiation quality variation within tissue equivalent phantoms irradiated by collimated fast neutron beams. The neutron beams investigated were produced by the bombardment of 22.5 and 16 MeV d + on beryllium and by the T(d,n)4He reaction (15-MeV neutrons). Microdosimetric spectra were obtained at points of varying depth and lateral distance from the central axis within a tissue equivalent phantom, including points within the penumbra. From the microdosimetric spectra the parameter RQ, a first approximation to RBE derived from DRA theory, is calculated for each point. All RQ values are calculated for the same level of effect. For these three different beams the results show that the RQ values for the total radiation spectrum of neutron and gamma radiation remain fairly constant with depth and with lateral distance from the beam axis at 2 and 10 cm depths. The largest central axis variation in RQ is 8% for the d(16) + Be beam. The largest variation between a penumbra and an on-axis RQ value is 4% at 2 cm depth in the d(22.5) + Be beam. The results for the d (22.5) + Be beam disagree with previously reported radiological results while the 15 McV beam results are in good agreement.

Biophysical Studies with Spatially Correlated Ions: 4. Analysis of Cell Survival Data for Diatomic Deuterium

An analysis is given of previously reported results of experiments in which cells have been irradiated with pairs of ions of variable mean separation. These studies were motivated by the theory of dual radiation action and specifically by the postulate that the lesions responsible for cell impairment by ionizing radiation are formed by the combination of pairs of sublesions that are molecular alterations produced by individual energy transfers in the cell nucleus. It is concluded that the observations are consistent with dual radiation action, and the most striking finding is that there appears to be a bimodal distribution of interaction distances with maxima at less than 0.1 ..mu..m and more than 1 ..mu..m. Single tracks cause primarily the lesions produced in short-range interactions but they also contribute, at least in late S phase, a relatively small proportion of the long-range interactions which are principally due to a two-track mechanism. The experiments suggest that the radiation-sensitive components of the cell are arranged in a highly nonuniform pattern which may take the form of floccules having diameters of less than 100 nm.

The Synergistic Effects of Different Radiations

Theoretical expressions, based on the Theory of Dual Radiation Action, are derived to calculate the effects of mixed radiation exposures on survival distributions. Temporal effects (such as recovery from sublethal injury) are explicitly included in the calculations. The results indicate the synergistic effect of sequential exposures due to the interaction between sublesions produced by the different types of radiation.

Biophysical Studies with Spatially Correlated Ions: 1. Background and Theoretical Considerations

According to the Theory of Dual Radiation Action most of the effects of ionizing radiation on cells of higher organisms are due to lesions that are produced as a result of combinations of pairs of sublesions. One principal question relates to the initial intracellular separation of sublesions over which these combinations can take place. The experimental method that has been devised to determine this dependence employs pairs of charged particles that traverse cells at varying mean separation. These pairs are produced by accelerating diatomic ions of hydrogen isotopes and causing them to impinge on this foils where the electron is stripped off and the nuclei separate by multiple coulomb scattering. The emerging pairs of ions then traverse mammalian cells that are attached to the exit surface of the foils. This first paper of a series deals with the background and theoretical information and presents an overall view of the experimental approach.

The role of microdosimetry in radiobiology.

Microdosimetry is a branch of radiological physics that provides quantitative characterization of the non-uniformity of energy deposition in uniformly irradiated matter. Consideration based on microdosimetry indicate that the action of ionizing radiation on the cells of higher organisms depends on the square of the specific energy absorbed in subcellular volumes. This is the basis of the Theory of Dual Radiation Action. The basic postulate of this theory is reviewed and four factors are discussed that modify its elementary formulation.

Effectiveness of 0·3 keV Carbon Ultrasoft X-rays for the Inactivation and Mutation of Cultured Mammalian Cells

Carbon K characteristic ultrasoft X-rays of energy 0.278 keV were found to be effective in inducing inactivation and mutation to thioguanine resistance in cultured V79 Chinese hamster cells and human diploid fibroblasts. These X-rays act as a probe of the sensitive sites within the cells since they produce low-energy photoelectron tracks of range about 7 nm; this is an order of magnitude smaller than those produced by the 1.5 keV aluminium X-rays used in previous studies. A detailed interpretation of the results requires assumptions to be made about the positions of the sensitive sites within the cells but, for any reasonable set of assumptions, the carbon X-rays are found to be more effective than gamma-rays and are probably at least as effective as long tracks of helium ions of similar LET. These observations extend the conclusions previously drawn from the observed effectiveness of aluminium X-rays regarding the sizes of the subcellular sites involved in inactivation and mutation. They imply that the sensitive sites smaller than about 7 nm, and that highly localized energy depositions consisting of less than or approximately 14 ionizations are sufficient to produce biological effects. These results are also in contradiction to models of radiation action which require relatively large sites, such as the usual form of the 'theory of dual radiation action'.

A Generalized Formulation of Dual Radiation Action

THE nucleation of polymer crystallization by various heterogeneous additives has been studied empirically1–4 some authors have attempted to understand the mechanism of the nucleation process5. In an examination of isotactic polypropylene crystallization on carbon fibres, we showed the importance of substrate geometry on the nucleation of polymer crystallization from the melt6. Here we report further work which confirms that the effectiveness of a heterogeneous nucleant depends on its structure. The novelty of these studies lies in our use of a replication technique to transform “non-active” surfaces into surfaces which readily nucleate crystallization from polymer melts.

The Effects of Small Doses of Ionizing Radiation Fundamental Biophysical Characteristics

From an application of the concepts of microdosimetry to a wide range of radiobiological data on higher organisms, it has become apparent that the first step in the biological action of ionizing radiation is the induction of subcellular lesions. Two basic characteristics of this process are that it depends only on the first and (sometimes) the second power of the absorbed dose and that the yield of such lesions, as well as the magnitude of the domain where energy concentration determines the yield of lesions, is relatively constant even for cells and effects that differ greatly in radiosensitivity. These observations have led to the formulation of the theory of dual radiation action, which postulates that the yield of these lesions depends on the square of the specific energy in domains having an effective diameter which differs from 1 μm by much less than an order of magnitude. It has furthermore been deduced that lesions are produced by the interaction of pairs of sublesions which are presumed to be alt...

Inactivation and Mutation of Cultured Mammalian Cells by Aluminium Characteristic Ultrasoft X-rays

The induction of inactivation and mutation to thioguanine-resistance of two types of cultured mammalian cells, V79 Chinese hamster and HF19 human diploid, was studied after irradiation with aluminium K characteristic ultrasoft X-rays, helium ion track intersections of different LET, 42 MeV d-Be neutrons, and hard X- or gamma-rays. The form of the dose-response curves was different for the two cell-types, and there was an overall difference in radiosensitivity, the human cells being the more sensitive to all radiations. However, for both inactivation and mutation-induction, the relative responses of both cell-types to these radiations was similar. Aluminium X-rays were considerably more effective than hard X- or gamma-rays and were at least as effective as helium ions of 20-28 keV micron-1, although aluminium X-rays produce tracks of very limited range (less than about 0.07 micron). Single track effects by aluminium X-rays cannot, therefore, extend beyond about 0.07 micron, and the subcellular sites involved in inactivation and mutation cannot be greater than this dimension or else the effectiveness of aluminium X-rays would be similar to that of low-LET radiations. This observation is in contradiction to models of radiation action which require relatively large sensitive sites; for example the 'theory of dual radiation action' requires a site diameter of about 0.4 micron to explain the shape of the dose-response curves for V79 hamster cells.