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Analysis of relative biological effectiveness of high energy heavy ions in comparison to experimental data.

We report that the relative biological effectiveness (RBE) of accelerated heavy ions for inactivation of cells can be analyzed by using the quadratic dependence on the linear energy transfer (LET) of the cellular effect. For high-LET radiation in low-dose regions, the inactivation cross section (sigma) can be approximately expressed as sigma max [1-exp[-k.(LET/Li)2]; here, k is the number of heavy-ions traversed in a cell nucleus and Li is a geometrical parameter related to the DNA structure, which depends on cell type. This original expression was first presented by Powers et al [Int. J. Radiat. Biol. 14 (1968)]. Using this expression and the Poisson distribution for the stochastic property of particle hitting, the mortality of cell populations was calculated. The numerical results were compared to the RBE values recently obtained with Chinese hamster V79 cells, and an Lt value of 152 keV/micron was found to give the best fit. At LETs of between 30 and 500 keV/micron, the D10 values (10% survival dose) agreed with the experimental data within an error range of -15%-(+8%).

Animals↗

Analysis of dose-LET distribution in the human body irradiated by high energy hadrons.

For the purposes of radiological protection, it is important to analyse profiles of the particle field inside a human body irradiated by high energy hadrons, since they can produce a variety of secondary particles which play an important role in the energy deposition process, and characterise their radiation qualities. Therefore Monte Carlo calculations were performed to evaluate dose distributions in terms of the linear energy transfer of ionising particles (dose-LET distribution) using a newly developed particle transport code (Particle and Heavy Ion Transport code System, PHITS) for incidences of neutrons, protons and pions with energies from 100 MeV to 200 GeV. Based on these calculations, it was found that more than 80% and 90% of the total deposition energies are attributed to ionisation by particles with LET below 10 keV microm(-1) for the irradiations of neutrons and the charged particles, respectively.

Body Burden↗

LET dependence of lethality in Arabidopsis thaliana irradiated by heavy ions.

To clarify the effect of heavy ions in plants, dry seeds of Arabidopsis were irradiated with carbon, neon, and argon ions with various linear energy transfer (LET) values. The relative biological effectiveness (RBE) for lethality peaked at LET values over 350 keV/microns for neon and argon ions. This LET giving the peak RBE was higher than the LET of 100-200 keV/microns which was reported to have a maximum RBE for other types of cells, such as mammalian cells. Furthermore, sterility showed a higher RBE at an LET of 354 keV/microns with neon ions than that at an LET of 113 keV/microns with carbon ions. Lethality and sterility are both considered to be caused by damage to DNA. The results indicate that the LET having a maximum of RBE for lethality is higher in Arabidopsis seeds than in other unicellular systems. The most likely explanation for this shift of LET is that the DNA in dry seeds has a different chemical environment and/or hydration state than the DNA in cells in culture.

Arabidopsis↗

Microdosimetric spectra and LET distributions on board the Mir space station obtained with a particle track detector.

A spectrometer measuring energy lost (deltaE) was used to determine linear energy transfer (LET) spectra on board the Mir orbital station during the period from 8 October 1997 to 16 June 2000, i.e. during the 24th, 26th, 27th and 28th basic expeditions. It was found that the LET spectra of secondary particles between 10 and 700 keV.microm(-1) in tissue do not depend on the external radiator, with the average quality factors for the region mentioned being about 6.4 with ICRP 26 quality factors or about 7.4 with ICRP 60 quality factors. Both differential and integral LET spectra are presented for some typical cases. The spectra permitted us to calculate the total doses and dose equivalents due to particles with the LET values in the mentioned region. It was found that these doses are higher when the detector was placed in a less shielded area. It was also found that these doses vary from one expedition to another. The correlation of these variations with the solar activity level was studied.

Aerospace Medicine↗

Neoplastic transformation of hamster embyro cells by heavy ions.

We have studied the induction of morphological transformation of Syrian hamster embryo cells by low doses of heavy ions with different linear energy transfer (LET), ranging from 13 to 400 keV/micrometer. Exponentially growing cells were irradiated with 12C or 28Si ion beams generated by the Heavy Ion Medical Accelerator in Chiba (HIMAC), inoculated to culture dishes, and transformed colonies were identified when the cells were densely stacked and showed a crisscross pattern. Over the LET range examined, the frequency of transformation induced by the heavy ions increased sharply at very low doses no greater than 5 cGy. The relative biological effectiveness (RBE) of the heavy ions relative to 250 kVp X-rays showed an initial increase with LET, reaching a maximum value of about 7 at 100 keV/micrometer, and then decreased with the further increase in LET. Thus, we confirmed that high LET heavy ions are significantly more effective than X-rays for the induction of in vitro cell transformation.

Animals↗

Genetic risks associated with radiation exposures during space flight.

The genetic risks associated with manned space flight are judged to be of little significance to the general population. The risks may be significant to the irradiated individual, particularly if one focuses attention on the incidence of dominant and chromosomal mutations that are expressed in the first generation offspring. Even so, the risk is not increased to a great extent by the low linear energy transfer (LET) component of the space radiations. It is the presumed high LET component, neutrons especially, that would make the major contribution to the risk, because the relative biological effectiveness (RBE) values for this component, relative to low dose-rate photon irradiation, are between 10 and 40, depending upon the particular genetic effect and dose-rate comparison. The appropriate RBE value would probably be 20 or greater, so that even small neutron doses become magnified in their contribution. Under the assumed condition of protracted exposure to 8 rads of low LET radiation and 2 rads of high LET radiation, or from 48 to 88 rem, the individual's risk of transmitting a new dominant mutation that will be expressed in his immediate offspring is estimated to increase by at least 4% and as much as about 40%. The HZE-particle component is not expected to make a significant contribution to the total risk.

Aerospace Medicine↗

Monte Carlo simulation of water radiolysis for low-energy charged particles.

The paper describes the development of chemical modules simulating the prechemical and chemical stages of charged particle tracks in pure liquid water. These calculations are based on our physical track structure codes for electrons and ions (KURBUC, LEPHIST and LEAHIST) which provide the initial spatial distribution of H2O+, H2O* and subexcitation electrons at approximately 10(-15) s. We considered 11 species and 26 chemical reactions. A step-by-step Monte Carlo approach was adopted for the chemical stage between 10(-12) s and 10(-6) s. The chemistry codes enabled to simulate the non-homogeneous chemistry that pertains to electron, proton and alpha-particle tracks of various linear energy transfers (LET). Time-dependent yields of chemical species produced by electrons and ions of different energies were calculated. The calculated primary yields (G values at 10(-6) s) of 2.80 for OH and 2.59 for e(aq)- for 1 MeV electrons are in good agreement with the published values. The calculated G values at 10(-6) s for a wide range LETs from of 0.2 to 235 keV microm(-1) were obtained. The calculations show the LET dependence for OH and H2O2. The electron penetration ranges were calculated in order to discuss the role of low energy electrons.

Computer Simulation↗

Radiation response of primary human skin fibroblasts and their bystander cells after exposure to counted particles at low and high LET.

PURPOSE: To investigate the dependence of bystander effects on linear energy transfer (LET) in the low dose region. MATERIALS AND METHODS: The single-ion microbeam of the Physikalisch-Technische Bundesanstalt (PTB) was used to irradiate confluent primary human skin fibroblasts. Cells plated on a special irradiation dish were targeted with 10 MeV protons (LET 4.7 keV/microm) and 4.5 MeV a-particles (LET 100 keV/microm). During exposure, the cells were confluent allowing signal transfers through both gap junctions and diffusion. RESULTS: For 10 MeV protons the clonogenic capability was significantly higher after exposure to 70 protons (0.31 Gy) compared with unirradiated cells. For higher doses the survival curve was exponential. Exposure of only 10% of all nuclei resulted in a similar radiation response in the low dose region. For higher doses up to 2.2 Gy no cell killing was observed. For 4.5 MeV alpha-particles an exponential survival curve was obtained. Irradiation of only 10% of all cell nuclei resulted in an survival curve as had been expected in the absence of any bystander effect. CONCLUSION: The type and extent of bystander effects turned out to be dependent on the particles' LET and are likely to depend also on the cell line used and the techniques applied.

Alpha Particles↗

Formation of plasmid DNA strand breaks induced by low-energy ion beam: indication of nuclear stopping effects.

Plasmid pGEM 3zf(+) was irradiated by nitrogen ion beam with energies between 20 and 100 keV and the fluence kept as 1x10(12)ions/cm2. The irradiated plasmid was assayed by neutral electrophoresis and quantified by densitometry. The yields of DNA with single-strand and double-strand breaks first increased then decreased with increasing ion energy. There was a maximal yield value in the range of 20-100 keV. The relationship between DNA double-strand breaks (DSB) cross-section and linear energy transfer (LET) also showed a peak-shaped distribution. To understand the physical process during DNA strand breaks, a Monte Carlo calculation code known as TRIM (Transport of Ions in Matter) was used to simulate energy losses due to nuclear stopping and to electronic stopping. It can be assumed that nuclear stopping plays a more important role in DNA strand breaks than electronic stopping in this energy range. The physical mechanisms of DNA strand breaks induced by a low-energy ion beam are also discussed.

DNA Damage↗

The variation in biological effectiveness of X-rays and gamma rays with energy.

The ICRP has attributed the same relative risk for all low-LET (linear energy transfer) radiations, including X and gamma radiations of all energies. However, very low energy X-rays are expected to be more biologically effective, per unit absorbed dose, than high energy X-rays or gamma rays due to the production of lower energy secondary electrons, with a correspondingly higher LET. This increase in relative biological effectiveness (RBE) is also seen experimentally for a range of biological end-points, however, a wide range of RBE values have been reported. The assessment of risks is particularly important due to the use of low energy X-rays for mammography screening. A review of the published data on the variation in biological effectiveness with energy is presented here.

Animals↗

Heavy ion-induced DNA double-strand breaks in yeast.

Induction of DSBs in the diploid yeast, Saccharomyces cerevisiae, was measured by pulsed-field gel electrophoresis (PFGE) after the cells had been exposed on membrane filters to a variety of energetic heavy ions with values of linear energy transfer (LET) ranging from about 2 to 11,500 keV/microm, (241)Am alpha particles, and 80 keV X rays. After irradiation, the cells were lysed, and the chromosomes were separated by PFGE. The gels were stained with ethidium bromide, placed on a UV transilluminator, and analyzed using a computer-coupled camera. The fluorescence intensities of the larger bands were found to decrease exponentially with dose or particle fluence. The slope of this line corresponds to the cross section for at least one double-strand break (DSB), but closely spaced multiple breaks cannot be discriminated. Based on the known size of the native DNA molecules, breakage cross sections per base pair were calculated. They increased with LET until they reached a transient plateau value of about 6 x 10(-7) microm(2) at about 300-2000 keV/microm; they then rose for the higher LETs, probably reflecting the influence of delta electrons. The relative biological effectiveness for DNA breakage displays a maximum of about 2.5 around 100-200 keV/microm and falls below unity for LET values above 10(3) keV/microm. For these yeast cells, comparison of the derived breakage cross sections with the corresponding cross section for inactivation derived from the terminal slope of the survival curves shows a strong linear relationship between these cross sections, extending over several orders of magnitude.

Alpha Particles↗

Initiation of oncogenic transformation in human mammary epithelial cells by charged particles.

Experimental studies have shown that high linear-energy transfer (LET) charged particles can be more effective than x-rays and gamma-rays in inducing oncogenic transformation in cultured cells and tumors in animals. Based on these results, experiments were designed and performed with an immortal human mammary epithelial cell line (H184B5), and several clones transformed by heavy ions were obtained. Cell fusion experiments were subsequently done, and results indicate that the transforming gene(s) is recessive. Chromosome analysis with fluorescence in situ hybridization (FISH) techniques also showed additional translocations in transformed human mammary epithelial cells. In addition, studies with these cell lines indicate that heavy ions can effectively induce deletion, break, and dicentrics. Deletion of tumor suppressor gene(s) and/or formation of translocation through DNA double strand breaks is a likely mechanism for the initiation of oncogenic transformation in human mammary epithelial cells.

Breast↗

Issues in protection from galactic cosmic rays.

Radiation risks to astronauts depend on the microscopic fluctuations of energy absorption events in specific tissues. These fluctuations depend not only on the space environment but also on the modifications of that environment by the shielding provided by structures surrounding the astronauts and the attenuation characteristics of the astronaut's body. The effects of attenuation within the shield and body depends on the tissue biological response to these microscopic fluctuations. In the absence of an accepted method for estimating astronaut risk, we examined the attenuation characteristics using conventional linear energy transfer (LET)-dependent quality factors (as one means of representing relative biological effectiveness, RBE) and a track-structure repair model to fit cell transformation (and inactivation) data in the C3H10 T1/2 mouse cell system obtained for various ion beams. Although the usual aluminum spacecraft shield is effective in reducing dose equivalent with increasing shield thickness, cell transformation rates are increased for thin aluminum shields. Clearly, the exact nature of the biological response to LET and track width is critical to evaluation of biological protection factors provided by a shield design. A significant fraction of biological injury results from the LET region above 100 keV/mu m. Uncertainty in nuclear cross-sections results in a factor of 2-3 in the transmitted LET spectrum beyond depths of 15 g/cm2, but even greater uncertainty is due to the combined effects of uncertainty in biological response and nuclear parameters. Clearly, these uncertainties must be reduced before the shield design can be finalised.

Animals↗

Radiogenic cell transformation and carcinogenesis.

Radiation carcinogenesis is one of the major biological effects considered important in the risk assessment for space travel. Various biological model systems, including both cultured cells and animals, have been found useful for studying the carcinogenic effects of space radiations, which consist of energetic electrons, protons and heavy ions. The development of techniques for studying neoplastic cell transformation in culture has made it possible to examine the cellular and molecular mechanisms of radiation carcinogenesis. Cultured cell systems are thus complementary to animal models. Many investigators have determined the oncogenic effects of ionizing and nonionizing radiation in cultured mammalian cells. One of the cell systems used most often for radiation transformation studies is mouse embryonic cells (C3H10T1/2), which are easy to culture and give good quantitative dose-response curves. Relative biological effectiveness (RBE) for heavy ions with various energies and linear energy transfer (LET) have been obtained with this cell system. Similar RBE and LET relationship was observed by investigators for other cell systems. In addition to RBE measurements, fundamental questions on repair of sub- and potential oncogenic lesions, direct and indirect effect, primary target and lesion, the importance of cell-cell interaction and the role of oncogenes and tumor suppressor genes in radiogenic carcinogenesis have been studied, and interesting results have been found. Recently several human epithelial cell systems have been developed, and ionizing radiation have been shown to transform these cells. Oncogenic transformation of these cells, however, requires a long expression time and/or multiple radiation exposures. Limited experimental data indicate high-LET heavy ions can be more effective than low-LET radiation in inducing cell transformation. Cytogenetic and molecular analyses can be performed with cloned transformants to provide insights into basic genetic mechanism(s) of radiogenic transformation of human epithelial cells.

Animals↗

Heavy-ion effects on cellular and subcellular systems: inactivation, chromosome aberrations and strand breaks induced by iron and nickel ions.

A broad spectrum of particles and energies has been used in the last years to study the influence of the radiation quality i.e. of the physical parameters of the particle beam on the biological effectiveness ¿2¿12¿. In these measurements a common structure of the functional dependence of the induction probability per particle (cross section) from the linear energy transfer is observed for different biological endpoints. Because of the relevance for space research, we present in this report our data from experiments with iron and nickel particles, in particular. Our experiments were designed to investigate the relationship between the inactivation and chromosome aberration in mammalian cells and the induction of single and double strand breaks in SV40 DNA in respect to the parameters of the track formation like LET and particle energy.

Animals↗

Response of thermoluminescent detectors to charged particles and to neutrons.

Thermoluminescent detectors (TLDs) are widely used for the dosimetry of photons and electrons. They are less used for the radiation with higher linear energy transfer (LET). One of the reasons for that is that their TL relative efficiency eta decreases for the most of them with increasing LET. The paper presents first a review of author's experimental results in which eta was established for charged particles having LET of the order from 1 to 100 keV/micrometers in tissue. Among TLDs studied were known materials like LiF:Mn; Ti; Al-P glass; CaSO4:Dy; Al2O3:Na; and Al2O3:C. It was found that the dependence of their eta on LET is not the same for all TLDs studied. The response of the same materials to neutrons was also studied. It was found that both eta as the relative response (RR) defined in terms of absorbed dose in tissue are different, they depend critically also on the composition. When a TLD contains nuclei like 6Li and 10B, their RR would be rather high. As far as eta is concerned, the same tendencies were observed as for charged particles, i.e. when average LET of secondary particles formed in a TLD increases, their eta generally decreases.

Body Burden↗

Bystander effect on cell growth stimulation in neoplastic HSGc cells induced by heavy-ion irradiation.

The bystander effect on unirradiated neoplastic human salivary gland (HSGc) cells was investigated by co-culturing them with HSGc cells that had been irradiated with 290 MeV/u carbon beams of different linear energy transfer (LET) values. It was found that the plating efficiency and proliferation of the unirradiated recipient cells were increased and that these increases were related to the LET as well as the radiation dose. Exposure of HSGc cells to higher LET and higher dose was much more effective in enhancing the plating efficiency and proliferation of the unirradiated cells than exposure to lower LET and lower dose. However, when PTIO, a nitric oxide (NO)-specific scavenger, was present in the co-culture medium, the cell growth capacity of the unirradiated recipients was reduced to control level, indicating that NO is involved in the bystander response. As an oxidation product of NO, nitrite was detected in the co-culture medium and its concentration depended on the LET and dose of irradiation. Using a NO-generator sper/NO, it was verified that NO at low concentrations indeed enhanced cell proliferation. Accordingly, NO plays an important role in medium-mediated bystander effects.

Bystander Effect↗

A TLD-based personal dosemeter system for aircrew monitoring.

Evaluation of LiF:Mg,Ti thermoluminescence dosemeters (TLDs) according to the high-temperature ratio (HTR) method enables the determination of the dose-average linear energy transfer (LET), the mean quality factor and the dose equivalent in mixed radiation fields of unknown composition. The neutron contribution is assessed by the Extended Pair method calibrated in the CERN-EU High-Energy Reference Field (CERF). The advantages of the small passive detectors as an easy-to-handle monitoring system for in-flight surveillance are demonstrated by measurements on-board north-bound and trans-equatorial flights. The experimental results are compared with calculations by the well-established CARI code.

Aircraft↗