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PubMed1989

Cellular and subcellular effect of heavy ions: a comparison of the induction of strand breaks and chromosomal aberration with the incidence of inactivation and mutation.

Radiobiological effects of heavy charged particles are compared for a large variety of ions from Helium to Uranium and energies between 1 and 1000 MeV/u which correspond to LET values between 10 and 16000 keV/micrometers. The different cross section for the induction of strand breaks and chromosomal aberrations as well as for inactivation and mutation induction exhibit striking similarities when compared as function of the linear energy transfer (LET). At LET values below 100 keV/micrometers all data points of one specific effect form one single curve as a function of LET, independent of the atomic number of the ion. In this LET range, the biological effects are independ from the particle energy or track structure and depend only on the energy transfer. Therefore, LET is a good parameter in this regime. For LET values greater than 100 keV/micrometers, the curves for the different ions separate from the common curve in order of increasing atomic numbers. In this regime LET is no longer a good parameter and the physical parameters of the formation of particle tracks are important. The similarity of the sigma-LET curves for different endpoints indicates that the 'hook-structure' is produced by physical and chemical effects which occur before the biologically relevant lesions are formed. However, from the existing data of biological effects, it can be concluded that the efficiencies for cell killing are always smaller than those extrapolated from X-ray data on the basis of the energy deposition only. Therefore, cells which are directly hit by an HZE particle are not killed and undergo a finite risk of mutation and transformation.

Alpha Particles↗

PubMed1994

Monte Carlo track structure studies of energy deposition and calculation of initial DSB and RBE.

Estimation of exposure due to environmental and other sources of radiations of high-LET and low-LET is of interest in radiobiology and radiation protection for risk assessment. To account for the differences in effectiveness of different types of radiations various parameters have been used. However, the relative inadequacy of the commonly used parameters, including dose, fluence, linear energy transfer, lineal energy, specific energy and quality factor, has been made manifest by the biological importance of the microscopic track structure and primary modes of interaction. Monte Carlo track structure simulations have been used to calculate the frequency of energy deposition by radiations of high- and low-LET in target sizes similar to DNA and higher order genomic structure. Tracks of monoenergetic heavy ions and electrons were constructed by following the molecular interaction-by-interaction histories of the particles down to 10 eV. Subsequently, geometrical models of these assumed biological targets were randomly exposed to the radiation tracks and the frequency of energy depositions obtained were normalized to unit dose in unit density liquid water (l0(3) kg m-3). From these data and a more sophisticated model of the DNA, absolute yields of both single- and double-strand breaks expressed in number of breaks per dalton per Gray were obtained and compared with the measured yields. The relative biological effectiveness (RBE) for energy depositions in cylindrical targets has been calculated using 100 keV electrons as the reference radiation assuming the electron track-ends contribution is similar to that in 250 kV X-ray or Co60 gamma-ray irradiations.

Aluminum↗

PubMed1994

Effect of radiation quality on lesion complexity in cellular DNA.

Understanding the critical lesions induced by ionizing radiation in DNA and their relationship to cellular effects is an important challenge in radiation biology. Much evidence has suggested that DNA double-strand breaks (dsb) are important lesions. Establishing a cause and effect relationship between initial levels of DNA dsb, their repair rate or the level of residual unrepaired breaks, and cellular effects has proved difficult in mammalian cells. Several studies have measured yields of DNA dsb after irradiation with radiations of differing linear energy transfer (LET). In general the RBEs for dsb induction (20-100 keV/microns) have been lower than the RBEs measured for cell survival and in many cases are around 1.0. Several studies have shown differences in the rejoining of dsb with less dsb rejoined after high-LET irradiation in comparison with low-LET radiation. These results suggest that there may be differences in the types of lesions induced by different radiations and scored as DNA dsb using current techniques. Track structure modelling studies have suggested that some lesions induced will be clustered at the sites of energy depositions and that uniquely large energy deposition events are produced by high-LET radiations. Assays need to be developed to measure complex lesions in both model DNA and cellular systems. Different levels of complexity need to be considered such as clustering of radicals close to DNA, localized areas of DNA damage (1-20 bp) and lesions which may be induced over larger distances. Studies using new and existing assays of DNA damage, coupled with irradiation at various LETs, are directed at understanding the role of lesion complexity in relation to cellular effects.

DNA↗

PubMed2004

Cell cycle arrest and aberration yield in normal human fibroblasts. I. Effects of X-rays and 195 MeV u(-1) C ions.

PURPOSE: To examine the relationship between cell proliferation and the expression of chromosomal damage in normal human skin fibroblasts after X-ray and particle irradiation. MATERIALS AND METHODS: Confluent G0/G1 AG1522B cells were exposed to X-rays or 195MeV u(-1) C ions with a linear energy transfer of 16.6 keV microm(-1) in the dose range 1-4 Gy. Directly after irradiation, cells were reseeded at a low density in medium containing 5-bromo-2'-deoxyuridine. At multiple time points post-irradiation, the cumulative BrdU-labelling index, mitotic index and aberration frequency were measured. Based on these data, the total amount of damage induced within the entire cell population was estimated by means of mathematical analysis. RESULTS: Both types of radiation exposure exert a pronounced effect on the cell cycle progression of fibroblasts. They result in delayed entry of cells into S-phase and into the first mitosis, and cause a dramatic reduction in mitotic activity. Measurement of chromosomal damage in first-cycle cells at multiple time points post-irradiation shows that the frequencies of aberrant cells and aberrations increase with time up to twofold for the lower doses. However, for the higher doses, this effect is less pronounced or even disappears. When the data for the whole cell population are analysed, it becomes evident that only a few damaged fibroblasts can progress to the first mitosis, a response attributable at least in part to a long-term arrest of injured cells in the initial G0/G1-phase. As observed in other investigations, the effectiveness of 195 MeV u(-1) C ions was similar or slightly higher than X-rays for all endpoints studied leading to a relative biological effectiveness in the range 1.0-1.4. CONCLUSIONS: Cell cycle arrests affect the aberration yield observable in normal human fibroblasts at mitosis. The data obtained for the cell population as a whole reveal that injured cells are rapidly removed from the mitotically active population through a chronic cell cycle arrest, which is consistent with other studies that indicate that this response is a specific strategy of fibroblasts to minimize the fixation and propagation of genetic alterations.

Apoptosis↗

PubMed2006

Contribution of indirect action to radiation-induced mammalian cell inactivation: dependence on photon energy and heavy-ion LET.

The contribution of indirect action mediated by OH radicals to cell inactivation by ionizing radiations was evaluated for photons over the energy range from 12.4 keV to 1.25 MeV and for heavy ions over the linear energy transfer (LET) range from 20 keV/microm to 440 keV/microm by applying competition kinetics analysis using the OH radical scavenger DMSO. The maximum level of protection provided by DMSO (the protectable fraction) decreased with decreasing photon energy down to 63% at 12.4 keV. For heavy ions, a protectable fraction of 65% was found for an LET of around 200 keV/microm; above that LET, the value stayed the same. The reaction rate of OH radicals with intracellular molecules responsible for cell inactivation was nearly constant for photon inactivation, while for the heavy ions, the rate increased with increasing LET, suggesting a reaction with the densely produced OH radicals by high-LET ions. Using the protectable fraction, the cell killing was separated into two components, one due to indirect action and the other due to direct action. The inactivation efficiency for indirect action was greater than that for direct action over the photon energy range and the ion LET range tested. A significant contribution of direct action was also found for the increased RBE in the low photon energy region.

Cell Survival↗

PubMed2002

Effect of LET on the yield and quality of chromosomal damage in metaphase cells: a time-course study.

PURPOSE: To investigate further the effect of linear energy transfer (LET) on the yield and quality of aberrations at different post-irradiation sampling times. MATERIALS AND METHODS: V79 G(1)-cells were exposed to either 10.6 MeV u-1 Ne ions (360 keV microm-1) or 11.1 MeV u-1 Kr ions (3980 keV microm-1) and chromosomal damage was measured in metaphase cells at several 2-h sampling intervals up to 30 h post-irradiation. To differentiate between cells in the first and second post-irradiation cycle, the fluorescence-plus-Giemsa technique was applied. RESULTS: In both experiments, an increase in the yield of aberrant cells as well as the number of aberrations per cell was observed in first- and second-cycle metaphases. Yet, the increase in the number of aberrations per cells was more pronounced for Kr ions and at comparable fluences Kr ions produced more aberrations than Ne ions. Because no sampling time was representative for the whole cell population, the total amount of Ne and Kr ion-induced chromosomal damage was determined by means of a mathematical approach and used for the comparison of data. Furthermore, in accordance with previous studies, LET-dependent changes in the spectrum of aberration types were detected, i.e. with increasing LET a higher fraction of chromatid-type aberrations was observed, although cells had been exposed in G1. In addition, more chromosomal breaks and less exchange-type aberrations were found. CONCLUSIONS: The observation that cell-cycle progression is related to the amount of aberrations harboured by a cell demonstrates that the routinely applied method to measure aberration frequencies in metaphase cells at only one post-irradiation sampling time will unavoidably result in an under- or overestimation of the cytogenetic effects of particles. Consequently, for a meaningful quantification of chromosomal damage, multiple fixation regimes should be used so that the complete time-course of aberrations can be taken into account. Moreover, to avoid bias, all aberration types should be recorded and included in the analysis since the aberration spectrum changes with LET.

Animals↗

PubMed1999

Monte Carlo mixture model of lifetime cancer incidence risk from radiation exposure on shuttle and international space station.

Estimating uncertainty in lifetime cancer risk for human exposure to space radiation is a unique challenge. Conventional risk assessment with low-linear-energy-transfer (LET)-based risk from Japanese atomic bomb survivor studies may be inappropriate for relativistic protons and nuclei in space due to track structure effects. This paper develops a Monte Carlo mixture model (MCMM) for transferring additive, National Institutes of Health multiplicative, and multiplicative excess cancer incidence risks based on Japanese atomic bomb survivor data to determine excess incidence risk for various US astronaut exposure profiles. The MCMM serves as an anchor point for future risk projection methods involving biophysical models of DNA damage from space radiation. Lifetime incidence risks of radiation-induced cancer for the MCMM based on low-LET Japanese data for nonleukemia (all cancers except leukemia) were 2.77 (90% confidence limit, 0.75-11.34) for males exposed to 1 Sv at age 45 and 2.20 (90% confidence limit, 0.59-10.12) for males exposed at age 55. For females, mixture model risks for nonleukemia exposed separately to 1 Sv at ages of 45 and 55 were 2.98 (90% confidence limit, 0.90-11.70) and 2.44 (90% confidence limit, 0.70-10.30), respectively. Risks for high-LET 200 MeV protons (LET=0.45 keV/micrometer), 1 MeV alpha-particles (LET=100 keV/micrometer), and 600 MeV iron particles (LET=180 keV/micrometer) were scored on a per particle basis by determining the particle fluence required for an average of one particle per cell nucleus of area 100 micrometer(2). Lifetime risk per proton was 2.68x10(-2)% (90% confidence limit, 0.79x10(-3)%-0. 514x10(-2)%). For alpha-particles, lifetime risk was 14.2% (90% confidence limit, 2.5%-31.2%). Conversely, lifetime risk per iron particle was 23.7% (90% confidence limit, 4.5%-53.0%). Uncertainty in the DDREF for high-LET particles may be less than that for low-LET radiation because typically there is very little dose-rate dependence. Probability density functions for high-LET radiation quality and dose-rate may be preferable to conventional risk assessment approaches. Nuclear reactions and track structure effects in tissue may not be properly estimated by existing data using in vitro models for estimating RBEs. The method used here is being extended to estimate uncertainty in spacecraft shielding effectiveness in various space radiation environments.

Adult↗

PubMed2005

Biological weighted effective dose in 205 MeV clinical proton beam.

The contribution of high linear energy transfer (L) charged particles to dosimetric and microdosimetric characteristics in a clinical proton beam was experimentally studied using an ionization chamber and track etched detectors. The particles mentioned are produced by proton nuclear interactions; at the Bragg peak region slowed down protons also contribute in the L region above several keV microm(-1). Due to these particles the biological weighted effective dose (BWED) of the beam changes with depth. The spectra of particles with L above 7 keV microm(-1) were established by means of track etched detectors, which permitted us to determine their contribution to dosimetric and microdosimetric characteristics of clinical proton beams. The studies were realized in the clinical proton beam of the JINR Dubna Phasotron, with a primary energy of 205 MeV. The relative contribution to the absorbed dose of the particles with L above 7 keV microm(-1) increases from several per cent at the beam entrance to several tens of per cent at the Bragg peak region. The relative biological weighted efficiency (RBWE) for radiotherapy has been calculated using a biological weighting function. It increases with depth from 1.02 at the beam entrance to about 1.25 at the Bragg peak region.

Animals↗

PubMed1996

Effects of target fragmentation on evaluation of LET spectra from space radiations: implications for space radiation protection studies.

We present calculations of linear energy transfer (LET) spectra in low earth orbit from galactic cosmic rays and trapped protons using the HZETRN/BRYNTRN computer code. The emphasis of our calculations is on the analysis of the effects of secondary nuclei produced through target fragmentation in the spacecraft shield or detectors. Recent improvements in the HZETRN/BRYNTRN radiation transport computer code are described. Calculations show that at large values of LET (> 100 keV/micrometer) the LET spectra seen in free space and low earth orbit (LEO) are dominated by target fragments and not the primary nuclei. Although the evaluation of microdosimetric spectra is not considered here, calculations of LET spectra support that the large lineal energy (y) events are dominated by the target fragments. Finally, we discuss the situation for interplanetary exposures to galactic cosmic rays and show that current radiation transport codes predict that in the region of high LET values the LET spectra at significant shield depths (> 10 g/cm2 of Al) is greatly modified by target fragments. These results suggest that studies of track structure and biological response of space radiation should place emphasis on short tracks of medium charge fragments produced in the human body by high energy protons and neutrons.

Aluminum↗

PubMed1997

Constancy of the relative biological effectiveness of 42 MeV (p-->Be+) neutrons among cell lines with different DNA repair proficiencies.

An important approach to understanding the role of the various DNA repair pathways in the cellular response to DNA-damaging agents is through the study of repair-deficient mutant cell lines. In the present study we used this strategy to assess the relative importance of four of these pathways for the repair of DNA damage induced by low-linear energy transfer (LET) gamma rays and intermediate-LET 42 MeV (p-->Be+) fast neutrons. The panel of hamster cell mutants that we characterized for their relative sensitivity to fast neutrons and gamma rays includes cell lines with defects in the nucleotide excision repair pathway; these can be further subdivided into mutants which are defective in nucleotide excision repair alone [UV5 (ERCC2-), UV24 (ERCC3-), UV135 (ERCC5-) and UV61 (ERCC6-)] compared to those which have an associated defect in the distinct but overlapping pathway for the repair of DNA crosslinks [UV20 (ERCC1-) and UV41 (ERCC4-)]. We also examined mutants with defects in the base excision repair pathway [EM9 (XRCC1-)] and the DNA-dependent protein kinase (DNA-PK)-mediated DNA double-strand break (DSB) repair pathway [xrs5 (XRCC5-)]. None of the mutants defective in nucleotide excision repair was differentially sensitized to fast neutrons or gamma rays; in fact, the slight radiosensitivity of these mutants under aerated conditions may be secondary to their defect in nucleotide excision repair. In contrast, deficiency in the base excision repair pathway resulted in a significant primary sensitization to both types of radiation (1.95-fold to gamma rays and 1.79-fold to neutrons). Deficiency in the DSB repair pathway mediated by DNA-PK resulted in a marked, but again similar, primary sensitization to gamma rays (4.2-fold) and neutrons (5.1-fold). Thus none of the repair pathways examined here exhibited a preferential role for the repair of damage induced by low-LET compared to intermediate-LET radiations; this resulted in an essentially constant relative biological effectiveness (RBE) of approximately 2 among the cell lines studied, independent of their DNA repair proficiency. However, consideration of these data along with data published previously for high-LET alpha particles suggests that, whereas the DNA-PK pathway is important for the repair of DSBs induced by low- and intermediate-LET radiations, it becomes less important as the LET increases beyond 100 keV/microm; thus this pathway may not be involved in repairing the more complex lesions induced by densely ionizing high-LET particles.

Animals↗

PubMed2005

The role of radiotherapy in the treatment of malignant salivary gland tumors.

PURPOSE: We analyzed the role of primary and postoperative low linear energy transfer radiotherapy in 538 patients treated for salivary gland cancer in centers of the Dutch Head and Neck Oncology Cooperative Group, in search for prognostic factors and dose response. METHODS AND MATERIALS: The tumor was located in the parotid gland in 59%, submandibular gland in 14%, oral cavity in 23%, and elsewhere in 5%. In 386 of 498 patients surgery was combined with radiotherapy, with a median dose of 62 Gy. Median delay between surgery and radiotherapy was 6 weeks. In the postoperative radiotherapy group, adverse prognostic factors prevailed. Elective radiotherapy to the neck was given in 40%, with a median dose of 50 Gy. Primary radiotherapy (n = 40) was given for unresectable disease or M(1), with a dose range of 28-74 Gy. RESULTS: Postoperative radiotherapy improved 10-year local control significantly compared with surgery alone in T(3-4) tumors (84% vs. 18%), in patients with close (95% vs. 55%) and incomplete resection (82% vs. 44%), in bone invasion (86% vs. 54%), and perineural invasion (88% vs. 60%). Local control was not correlated with interval between surgery and radiotherapy. No dose-response relationship was shown. Postoperative radiotherapy significantly improved regional control in the pN(+) neck (86% vs. 62% for surgery alone). A rating scale for different sites, T stage, and histologic type may be applied to calculate the risk of disease in the neck at presentation, and so indicate the need for elective neck treatment. A marginal dose-response was seen, in favor of a dose > or =46 Gy. A clear dose-response relationship was shown for patients treated with primary radiotherapy. Five-year local control was 50% with a dose of 66-70 Gy. CONCLUSIONS: Postoperative radiotherapy with a dose of at least 60 Gy is indicated for patients with T(3-4) tumors, incomplete or close resection, bone invasion, perineural invasion, and pN(+). In unresectable tumors, a dose of at least 66 Gy is advisable.

Adolescent↗

PubMed2001

p53-dependent thermal enhancement of cellular sensitivity in human squamous cell carcinomas in relation to LET.

PURPOSE: To investigate the dependence on p53 gene status of the thermal enhancement of cellular sensitivity against different levels of linear energy transfer (LET) from X-rays or carbon-ion (C-) beams. MATERIALS AND METHODS: Two kinds of human squamous cell carcinoma cell lines were used with an identical genotype except for the p53 gene. SAS/mp53 cells were established by transfection with mutated p53 (mp53) gene to SAS cells having functional wild-type p53 (wtp53). As the control, a neo vector was transfected to the SAS cells (SAS/neo cells). Both cells were exposed to X-rays or accelerated C-beams (30-150 KeV microm(-1)) followed by heating at 44 degrees C. Cellular sensitivity was determined by colony-forming activity. Induction of apoptosis was analysed by Hoechst 33342 staining of apoptotic bodies and agarose-gel electrophoresis for the formation of DNA ladders. RESULTS: It was found that (1) there was no significant difference in cellular sensitivity between SAS/neo and SAS/mp53 cells to LET radiation of >30 KeV microm(-1), although the radiosensitivity of SAS/neo cells to X-rays was higher (1.2-fold) than that of SAS/mp53 cells; (2) there was an interactive thermal enhancement of radiosensitivity below an LET of 70 KeV microm(-1) in SAS/neo cells, although only additive thermal enhancement was observed in SAS/mp53 cells through all LET levels examined; (3) low-LET radiation induced apoptosis only in SAS/neo cells; (4) high-LET radiation at an isosurvival dose-induced apoptosis of SAS/neo cells at a higher frequency compared with that with low-LET radiation; (5) high-LET radiation-induced p53-independent apoptosis in SAS/mp53 cells; and (6) thermal enhancement of cellular sensitivity to X-rays was due to induction of p53-dependent apoptosis. CONCLUSIONS: The findings suggest that thermal enhancement of radiosensitivity may result from p53-dependent apoptosis induced by inhibition of p53-dependent cell survival system(s) through either regulation of the cell cycle or induction of DNA repair. It is also suggested that the analysis of p53 gene status of cancer cells may predict response to combined therapies with low-LET radiation and hyperthermia.

Apoptosis↗

PubMed1996

Inactivation of V79 cells by low-energy protons, deuterons and helium-3 ions.

Previous work by ourselves and by others has demonstrated that protons with a linear energy transfer (LET) about 30 keVmum(-1)are more effective at killing cells than doubly charged particles of the same LET. In this work we show that by using deuterons, which have about twice the range of protons with the same LET, it is possible to extend measurements of the RBE of singly charged particles to higher LET (up to 50 keVmum(-1). We report the design and use of a new arrangement for irradiating V79 mammalian cells. Cell survival measurements have been made using protons in the energy range 1.0-3.7 MeV, deuterons in the energy range 0.9-3.4MeV and 3He2+ ions in the energy range 3.4-6.9 MeV. This corresponds to volume-averaged LET (within the cell nucleus) between 10 and 28 keVmum(-1) for protons, 18-50 keVmum(-1) for deuterons, and 59-106 keVmum(-1) for helium ions. Our results show no difference in the effectiveness of protons and deuterons matched for LET. However, for LET above about 30 keVmum(-1) singly charged particles are more effective at inactivating cells than doubly-charged particles of the same LET and that this difference can be understood in terms of the radial dose distribution around the primary ion track.

Animals↗

PubMed1985

Charged particle cytogenetics: effects of LET, fluence, and particle separation on chromosome aberrations.

Induced rearrangements of chromosomes, disrupting the orderly sequence and/or separation of the genetic material, are responsible for a significant proportion of cellular lethality, genetic mutation, and, as has become increasingly apparent in recent years, human cancer. The quantitative observation of chromosomal aberrations induced by ionizing radiations led early to the realization that as linear energy transfer (LET) increased, curvilinear dose responses became increasingly linear. Those few studies that examined aberrations as a function of LET found that the optimally effective LET was about 100 keV per micrometer, results consistent with those observed for other end points. The majority of chromosomal aberrations originate from molecular interaction between pairs of lesions (misrepair), with differences in sensitivity to aberration induction through the cell cycle. In Chinese hamster V-79 cells for all LET values studied, aberrations are most frequent in G2, then G1, then S phase of the cell cycle. The variation in sensitivity through the cell cycle changes from a factor of about 5 for 10 keV/micron particles to about 3 for 80 keV/micron particles. In the G2 phase a curvilinear dose response (G1 and S being linear) is found for all LETs occurring at fluences where there are substantial distances (greater than or equal to 3 micron) between particles. It is possible that for this one phase of the cell cycle a saturation of repair capabilities occurs as a function of both fluence and LET. When cells were irradiated with associated charged particles (molecular ions) it was found that even when two particles were separated by distances of less than 100 nm their effect was much less than one particle of twice the LET (the equivalent of 0 distance separation). This implies that the vast majority of molecular interactions which result in chromosomal aberrations occur as a consequence of interaction between damaged sites formed only a few nanometers from each other. It is clear that an analysis of chromosomal aberrations produced by charged particles can provide considerable insight into basic radiobiological mechanisms and into the organization of the mammalian genome.

Alpha Particles↗

PubMed2000

Assessment of DNA damage induced by high-LET ions in human lymphocytes using the comet assay.

The alkaline single-cell gel electrophoresis assay (comet assay) was used to analyze DNA damage induced in human lymphocytes by irradiation with high linear energy transfer (LET) ions. Our aim was to measure DNA breaks and to demonstrate the heterogeneity of the damage levels in a lymphocyte population irradiated with ions of different energies and LETs. Four experiments with heavy ions (Ar, C and U), as well as gamma-ray exposure, were conducted to enable comparisons. We demonstrated that the comet assay is able to assess the variability in DNA damage induced at the single cell level. The amount of DNA damage and its heterogeneity increased with particle fluence and LET, but saturated at high LETs. However, when expressed in terms of the mean dose, gamma-rays were more efficient than most of the ions used. The comet assay also allowed the detection of highly damaged cells (HDC), which were previously described as cells in late apoptotic stages. The rapid emergence of HDC in this study suggests that they were generated following ion irradiation-induced creation of DNA break clusters induced by ion exposure. Another clue was that the proportion of HDC increased with LET and fluence. We hypothesized that the LET threshold observed and the higher efficiency of low-LET radiation might be linked to the impossibility of measuring small DNA fragments in HDC.

Comet Assay↗

PubMed1997

Chromosomal aberrations induced in human lymphocytes by high-LET irradiation.

High linear energy transfer (LET) particles are more efficient than sparsely ionizing radiations in inducing chromosomal aberrations, in particular complex rearrangements. We analysed R-banded chromosome rearrangements in human lymphocytes irradiated with several ions having a wide range of LET (31.3-1435 keV/micron). The frequency of chromosome breaks unrejoined or inferred from observed rearrangements, and of complex rearrangements induced by a single particle, increased with the LET up to about 100-150 keV/micron and seemed to level off for higher LET values. Additional study was focused on damage induced by oxygen ions of three different energies. Significant cell cycle delay, and multiple chromosome rearrangements and breaks were demonstrated using Giemsa and Fluorescence-plus-Giemsa stainings, coupled with chromosome painting. Damage increased with the fluence and the LET, but at the higher LET damage decreased for fluences > 10(7) particles/cm2. Cell death and G2 block might be involved in this phenomenon. Chromosome 1 painting exhibited a high frequency of breaks and complex rearrangements, which would not have been detected using a standard staining. Complex rearrangements were induced by as few as one particle per cell nucleus and may be considered as a biological fingerprint of high-LET irradiation.

Azure Stains↗

PubMed1999

Complex hprt deletion events are recovered after exposure of human lymphoblastoid cells to high-LET carbon and neon ion beams.

Hypoxanthine phosphoribosyltransferase gene (hprt) mutations were induced in human TK-6 lymphoblastoid cells by irradiation at a linear energy transfer (LET) of 250 or 310 keV/micron for carbon and neon ions, respectively. At such a high level of LET, ions will lose most of their total energy and stop shortly after passing through the cell. The hprt mutations were analyzed by multiplex PCR, long-PCR and DNA sequencing of both genomic and cDNA. Over half of the C ion-induced hprt mutations (10 of 19) were point mutations, in contrast to 15% of the mutations induced by Ne ions (three of 20). The remaining 47 and 85% of the C and Ne ion-induced mutants, respectively, are deletion events. The latter events include three complex losses of multiple non-contiguous exon regions in both ion irradiation collections. We note that mutations involving the exon 6 region are frequent in the Ne ion collection: all three of the complex events retained the exon 6 region with flanking deletion of sequence and three other mutants involved deletion of this region. It may be concluded that these high-LET C and Ne ion irradiations produce different mutational spectra.

Carbon↗

PubMed2004

Options for the modified radiation weighting factor of neutrons.

The recent ICRP Report 92 has noted that the current radiation weighting factor, wR, depends on the energy of the incident neutrons in a manner that differs substantially from the dependence, which results from the current convention, QL. At all neutron energies, but most conspicuously below 1 MeV, the values of wR exceed those of the effective quality factor, qE. The discrepancy is largely due to the fact that--in the absence of computed values of the effective quality factor for neutrons--wR has been patterned after the values of the ambient quality factor, which accounts insufficiently for the low-linear energy transfer (LET) gamma ray component from neutron capture in the human body. There are different options to remove the discrepancy. Option 1 is to reduce wR substantially at all neutron energies to make it equal to qE for a standard condition, such as isotropic incidence of the neutrons. Since such a reduction may cause problems in those countries where the current wR values are already legally implemented, ICRP 92 has proposed what is here termed Option 2. It recommended to replace QL by the increased value 1.6 QL - 0.6 and, accordingly, to make the radiation weighting factor equal to 1.6 qE - 0.6. With Option 2 the radiation weighting factor needs to be decreased appreciably at low neutron energies, but for fission neutron spectra the overall changes are minor. To guide--regardless which option is chosen--the selection of the numerical values, the effective quality factor, qE, is computed here for different directional distributions of neutrons incident on the anthropomorphic phantoms ADAM and EVA. None of the sex averaged numerical values is found to deviate much from those for isotropic incidence. Isotropic incidence can, thus, be used as an adequate standard condition. A numerical approximation is proposed for the standard qE that is nearly equivalent to a formula invoked by ICRP 92, but is somewhat simpler and provides realistic values of qE even for the extremely high neutron energies in space. In line with ICRP 92, it is emphasised that wR needs to be seen as a derived quantity related to the LET-dependent weighting factor.

Dose-Response Relationship, Radiation↗