Dudley T. Goodhead

Cancer risks attributable to low doses of ionizing radiation: Assessing what we really know

High doses of ionizing radiation clearly produce deleterious consequences in humans, including, but not exclusively, cancer induction. At very low radiation doses the situation is much less clear, but the risks of low-dose radiation are of societal importance in relation to issues as varied as screening tests for cancer, the future of nuclear power, occupational radiation exposure, frequent-flyer risks, manned space exploration, and radiological terrorism. We review the difficulties involved in quantifying the risks of low-dose radiation and address two specific questions. First, what is the lowest dose of x- or γ-radiation for which good evidence exists of increased cancer risks in humans? The epidemiological data suggest that it is ≈10–50 mSv for an acute exposure and ≈50–100 mSv for a protracted exposure. Second, what is the most appropriate way to extrapolate such cancer risk estimates to still lower doses? Given that it is supported by experimentally grounded, quantifiable, biophysical arguments, a linear extrapolation of cancer risks from intermediate to very low doses currently appears to be the most appropriate methodology. This linearity assumption is not necessarily the most conservative approach, and it is likely that it will result in an underestimate of some radiation-induced cancer risks and an overestimate of others.

Initial Events in the Cellular Effects of Ionizing Radiations: Clustered Damage in DNA

General correlations are found between the detailed spatial and temporal nature of the initial physical features of radiation insult and the likelihood of final biological consequences. These persist despite the chain of physical, chemical and biological processes that eliminate the vast majority of the early damage. Details of the initial conditions should provide guidance to critical features of the most relevant early biological damage and subsequent repair. Ionizing radiations produce many hundreds of different simple chemical products in DNA and also multitudes of possible clustered combinations. The simple products, including single-strand breaks, tend to correlate poorly with biological effectiveness. Even for initial double-strand breaks, as a broad class, there is apparently little or no increase in yield with increasing ionization density, in contrast with the large rise in relative biological effectiveness for cellular effects. Track structure analysis has revealed that clustered DNA damage of severity greater than simple double-strand breaks is likely to occur at biologically relevant frequencies with all ionizing radiations. Studies are in progress to describe in more detail the chemical nature of these clustered lesions and to consider the implications for cellular repair. It has been hypothesized that there is reduced repair of the more severe examples and that the spectrum of lesions that dominate the final cellular consequences is heavily skewed towards the more severe, clustered components.

Computational modelling of low-energy electron-induced DNA damage by early physical and chemical events

Modelling and calculations are presented as a first step towards mechanistic interpretation and prediction of radiation effects based on the spectrum of initial DNA damage produced by low energy electrons (100 eV-4.5 keV) that can be compared with experimental information. Relative yields of single and clustered strand breaks are presented in terms of complexity and source of damage, either by direct energy deposition or by reaction of OH radicals, and dependence on the activation probability of OH radicals and the amount of energy required to give a single strand break (ssb). Data show that the majority of interactions in DNA do not lead to damage in the form of strand breaks and when they do occur, they are most frequently simple ssb. However, for double-strand breaks (dsb), a high proportion (approximately 30%) are of more complex forms, even without considering additional complexity from base damage. The greater contribution is from direct interactions in the DNA but reactions of OH radicals add substantially to this, both in terms of the total number of breaks and in increasing the complexity within a cluster. It has been shown that the lengths of damaged segments of DNA from individual electron tracks tend to be short, indicating that consequent deletion length (simply by loss of a fragment between nearby dsb) would be short, very seldom exceeding a few tens of base pairs.

Effects of Radiations of Different Qualities on Cells: Molecular Mechanisms of Damage and Repair

Studies of ionizing radiations of different quality are discussed with particular emphasis on damage to DNA of mammalian cells. Three related themes are followed. Firstly, inactivation and mutation experiments with ultrasoft X-rays and slow heavy ions, coupled with theoretical analyses of the structures of the radiation tracks, have emphasized the biological importance of localized track features over nanometre dimensions. This led to the suggestion that the critical physical features of the tracks are the stochastic clusterings of ionizations, directly in or very near to DNA, resulting in clustered initial molecular damage including various combinations of breaks, base damages, cross-links, etc. in the DNA. The quantitative hypotheses imply that final cellular effects from high-LET radiations are dominated by their more severe, and therefore less repairable, clustered damage, and that these are qualitatively different from the dominant low-LET damage. Second, relative effectiveness of different types of ...

α-particle-induced chromosomal instability in human bone marrow cells

alpha-particles, which are ionising radiation of high linear-energy-transfer emitted, for example, from radon or plutonium, pass through tissue as highly structured tracks. Single target cells in the path of the tracks might be damaged by even low-dose alpha-irradiation. We found non-clonal cytogenetic aberrations, characterised by a high frequency of chromatid aberrations with chromosome aberrations, in clonal descendants of haemopoietic stem cells after exposure to alpha-particles of bone marrow cells from two of four haematologically normal individuals (up to 25% abnormal metaphases). The data are consistent with a transmissible genetic instability induced in a stem cell resulting in a diversity of aberrations in its clonal progeny many cell divisions later.

Track Structure Analysis of Ultrasoft X-rays Compared to High- and Low-LET Radiations

Monte-Carlo track structure simulations of ultrasoft X-rays, and of selected low- and high-LET radiations for comparison, have been used to obtain statistically valid frequency distributions of energy deposition in small subcellular targets which resemble the dimensions of short segments of DNA, nucleosomes and short segments of chromatin fibre. It is found that in all cases large numbers (approximately 10(3] of direct energy deposition events occur in these targets in a single mammalian cell irradiated with 1 Gy of any of these radiations. In almost all cases the numbers of energy depositions of substantial size (say, approximately greater than 100 eV in a DNA segment, approximately greater than 300 eV in a nucleosome or approximately greater than 800 eV in a segment of chromatin fibre) are also quite large, being approximately 10 to 100 per cell per Gy. It seems clear therefore that the direct effects of radiation on macromolecules must be considered in assessing the biological effects of any ionizing radiations on mammalian cells. The calculations also show that high-LET radiations can produce uniquely large energy depositions in the targets, such as are virtually unachievable by any of the other radiations; this allows the possibility of unique biochemical and cellular damage by high-LET radiations. At any realistic dose for mammalian cells, virtually all the energy depositions in these targets, from all the radiations, are due to single independent tracks; the multi-track component is negligibly small. The absolute numbers of energy depositions of approximately greater than 100 eV in DNA segments in a cell are similar to experimentally measured numbers of DNA double-strand breaks, but both these sets of numbers are one or two orders of magnitude larger than the numbers of lethal events produced in mammalian cells. The frequency of threshold energy of approximately 120 eV in a DNA segment correlates reasonably well with the relative biological effectiveness of ultrasoft X-rays and low-LET radiations for relatively radioresistant cells, but a lower threshold energy may be required for other, more sensitive, cells.

The effects of delta rays on the number of particle-track traversals per cell in laboratory and space exposures

It is a common practice to estimate the number of particle-track traversals per cell or cell nucleus as the product of the ions linear energy transfer (LET) and cell area. This practice ignores the effects of track width due to the lateral extension of delta rays. We make estimates of the number of particle-track traversals per cell, which includes the effects of delta rays using radial cutoffs in the ionization density about an ions track of 1 mGy and 1 cGy. Calculations for laboratory and space radiation exposures are discussed, and show that the LET approximation provides a large underestimate of the actual number of particle-track traversals per cell from high-charge and energy (HZE) ions. In light of the current interest in the mechanisms of radiation action, including signal transduction and cytoplasmic damage, these results should be of interest for radiobiology studies with HZE ions.

M-FISH analysis shows that complex chromosome aberrations induced by α-particle tracks are cumulative products of localized rearrangements

Complex chromosome aberrations are characteristically induced after exposure to low doses of densely ionizing radiation, but little is understood about their formation. To address this issue, we irradiated human peripheral blood lymphocytes in vitro with 0.5 Gy densely ionizing α-particles (mean of 1 α-particle/cell) and analyzed the chromosome aberrations produced by using 24-color multiplex fluorescence in situ hybridization (M-FISH). Our data suggest that complex formation is a consequence of direct nuclear α-particle traversal and show that the likely product of illegitimate repair of damage from a single α-particle is a single complex exchange. From an assessment of the “cycle structure” of each complex exchange we predict α-particle-induced damage to be repaired at specific localized sites, and complexes to be formed as cumulative products of this repair.

Inactivation and mutation of cultured mammalian cells by aluminium characteristic ultrasoft X-rays I. Properties of aluminium X-rays and preliminary experiments with Chinese hamster cells

Irradiation with ultrasoft X-rays produces electron tracks of short defined lengths in the irradiated material. This property is of particular interest in distinguishing between different models of radiation action on living organisms. The production, absorption and dosimetry of aluminium K characteristic X-rays of energy 1.5 keV are described. Quantitative experiments on mammalian cells with these X-rays are possible, and they were found to be considerably more effective than gamma-rays in inactivating Chinese hamster V79 cells in vitro.

Model for Radial Dependence of Frequency Distributions for Energy Imparted in Nanometer Volumes from HZE Particles

Abstract Cucinotta, F. A., Nikjoo, H. and Goodhead, D. T. Model for Radial Dependence of Frequency Distributions for Energy Imparted in Nanometer Volumes from HZE Particles. This paper develops a deterministic model of frequency distributions for energy imparted (total energy deposition) in small volumes similar to DNA molecules from high-energy ions of interest for space radiation protection and cancer therapy. Frequency distributions for energy imparted are useful for considering radiation quality and for modeling biological damage produced by ionizing radiation. For high-energy ions, secondary electron (δ-ray) tracks originating from a primary ion track make dominant contributions to energy deposition events in small volumes. Our method uses the distribution of electrons produced about an ions path and incorporates results from Monte Carlo simulation of electron tracks to predict frequency distributions for ions, including their dependence on radial distance. The contribution from primary ion events is treated using an impact parameter formalism of spatially restricted linear energy transfer (LET) and energy-transfer straggling. We validate our model by comparing it directly to results from Monte Carlo simulations for proton and α-particle tracks. We show for the first time frequency distributions of energy imparted in DNA structures by several high-energy ions such as cosmic-ray iron ions. Our comparison with results from Monte Carlo simulations at low energies indicates the accuracy of the method.