[Cell killing and chromosomal damage in primary human bronchial epithelial cells irradiated with accelerated 56Fe ions]
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NASA Discipline Radiation Health↗
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Neutron yields from 155 MeV/nucleon carbon and helium stopping in aluminum
Neutron fluences have been measured from 155 MeV/nucleon 4He and 12C ions stopping in an Al target at laboratory angles between 10 and 160 deg. The resultant spectra were integrated over angle and energy above 10 MeV to produce total neutron yields. Comparison of the two systems shows that approximately two times as many neutrons are produced from 155 MeV/nucleon 4He stopping in Al and 155 MeV/nucleon 12C stopping in Al. Using an energy-dependent geometric cross-section formula to calculate the expected number of primary nuclear interactions shows that the 12C + Al system has, within uncertainties, the same number of neutrons per interaction (0.99 +/- 0.03) as does the 4He + Al system (1.02 +/- 0.04), despite the fact that 12C has three times as many neutrons as does 4He. Energy and angular distributions for both systems are also reported. No major differences can be seen between the two systems in those distributions, except for the overall magnitude. Where possible, the 4He + Al spectra are compared with previously measured spectra from 160 and 177.5 MeV/nucleon 4He interactions in a variety of stopping targets. The reported spectra are consistent with previously measured spectra. The data were acquired to provide data applicable to problems dealing with the determination of the radiation risk to humans engaged in long-term missions in space; however, the data are also of interest for issues related to the determination of the radiation environment in high-altitude flight, with shielding at high-energy heavy-ion accelerators and with doses delivered outside tumor sites treated with high-energy hadronic beams.
NASA Discipline Radiation Health↗
Biological and genetic properties of the p53 null preneoplastic mammary epithelium
The absence of the tumor suppressor gene p53 confers an increased tumorigenic risk for mammary epithelial cells. In this report, we describe the biological and genetic properties of the p53 null preneoplastic mouse mammary epithelium in a p53 wild-type environment. Mammary epithelium from p53 null mice was transplanted serially into the cleared mammary fat pads of p53 wild-type BALB/c female to develop stable outgrowth lines. The outgrowth lines were transplanted for 10 generations. The outgrowths were ductal in morphology and progressed through ductal hyperplasia and ductal carcinoma in situ before invasive cancer. The preneoplastic outgrowth lines were immortal and exhibited activated telomerase activity. They are estrogen and progesterone receptor-positive, and aneuploid, and had various levels of tumorigenic potential. The biological and genetic properties of these lines are distinct from those found in most hyperplastic alveolar outgrowth lines, the form of mammary preneoplasia occurring in most traditional models of murine mammary tumorigenesis. These results indicate that the preneoplastic cell populations found in this genetically engineered model are similar in biological properties to a subset of precurser lesions found in human breast cancer and provide a unique model to identify secondary events critical for tumorigenicity and invasiveness.
NASA Discipline Radiation Health↗
Shedding light on proteins, nucleic acids, cells, humans and fish
I was trained as a physicist in graduate school. Hence, when I decided to go into the field of biophysics, it was natural that I concentrated on the effects of light on relatively simple biological systems, such as proteins. The wavelengths absorbed by the amino acid subunits of proteins are in the ultraviolet (UV). The wavelengths that affect the biological activities, the action spectra, also are in the UV, but are not necessarily parallel to the absorption spectra. Understanding these differences led me to investigate the action spectra for affecting nucleic acids, and the effects of UV on viruses and cells. The latter studies led me to the discovery of the important molecular nature of the damages affecting DNA (cyclobutane pyrimidine dimers) and to the discovery of nucleotide excision repair. Individuals with the genetic disease xeroderma pigmentosum (XP) are extraordinarily sensitive to sunlight-induced skin cancer. The finding, by James Cleaver, that their skin cells were defective in DNA repair strongly suggested that DNA damage was a key step in carcinogenesis. Such information was important for estimating the wavelengths in sunlight responsible for human skin cancer and for predicting the effects of ozone depletion on the incidence of non-melanoma skin cancer. It took experiments with backcross hybrid fish to call attention to the probable role of the longer UV wavelengths not absorbed by DNA in the induction of melanoma. These reflections trace the biophysicist's path from molecules to melanoma.
NASA Discipline Radiation Health↗
Gene conversion is strongly induced in human cells by double-strand breaks and is modulated by the expression of BCL-x(L)
Homology-directed repair (HDR) of DNA double-strand breaks (DSBs) contributes to the maintenance of genomic stability in rodent cells, and it has been assumed that HDR is of similar importance in DSB repair in human cells. However, some outcomes of homologous recombination can be deleterious, suggesting that factors exist to regulate HDR. We demonstrated previously that overexpression of BCL-2 or BCL-x(L) enhanced the frequency of X-ray-induced TK1 mutations, including loss of heterozygosity events presumed to arise by mitotic recombination. The present study was designed to test whether HDR is a prominent DSB repair pathway in human cells and to determine whether ectopic expression of BCL-x(L) affects HDR. Using TK6-neo cells, we find that a single DSB in an integrated HDR reporter stimulates gene conversion 40-50-fold, demonstrating efficient DSB repair by gene conversion in human cells. Significantly, DSB-induced gene conversion events are 3-4-fold more frequent in TK6 cells that stably overexpress the antiapoptotic protein BCL-X(L). Thus, HDR plays an important role in maintaining genomic integrity in human cells, and ectopic expression of BCL-x(L) enhances HDR of DSBs. This is the first study to highlight a function for BCL-x(L) in modulating DSB repair in human cells.
NASA Discipline Radiation Health↗
Genomic instability and bystander effects: a paradigm shift in radiation biology?
A basic paradigm in radiobiology is that, following exposure to ionizing radiation, the deposition of energy in the cell nucleus and the resulting damage to DNA, the principal target, are responsible for the radiation's deleterious biological effects. Findings in two rapidly expanding fields of research--radiation-induced genomic instability and bystander effects--have caused us to reevaluate these central tenets. In this article, the potential influence of induced genomic instability and bystander effects on cellular injury after exposure to low-level radiation will be reviewed.
NASA Discipline Radiation Health↗
Space radiation dosimetry in low-Earth orbit and beyond
Space radiation dosimetry presents one of the greatest challenges in the discipline of radiation protection. This is a result of both the highly complex nature of the radiation fields encountered in low-Earth orbit (LEO) and interplanetary space and of the constraints imposed by spaceflight on instrument design. This paper reviews the sources and composition of the space radiation environment in LEO as well as beyond the Earth's magnetosphere. A review of much of the dosimetric data that have been gathered over the last four decades of human space flight is presented. The different factors affecting the radiation exposures of astronauts and cosmonauts aboard the International Space Station (ISS) are emphasized. Measurements made aboard the Mir Orbital Station have highlighted the importance of both secondary particle production within the structure of spacecraft and the effect of shielding on both crew dose and dose equivalent. Roughly half the dose on ISS is expected to come from trapped protons and half from galactic cosmic rays (GCRs). The dearth of neutron measurements aboard LEO spacecraft and the difficulty inherent in making such measurements have led to large uncertainties in estimates of the neutron contribution to total dose equivalent. Except for a limited number of measurements made aboard the Apollo lunar missions, no crew dosimetry has been conducted beyond the Earth's magnetosphere. At the present time we are forced to rely on model-based estimates of crew dose and dose equivalent when planning for interplanetary missions, such as a mission to Mars. While space crews in LEO are unlikely to exceed the exposure limits recommended by such groups as the NCRP, dose equivalents of the same order as the recommended limits are likely over the course of a human mission to Mars. c2001 Elsevier Science B.V. All rights reserved.
short duration↗
Total-body irradiation with high-LET particles: acute and chronic effects on the immune system
Although the immune system is highly susceptible to radiation-induced damage, consequences of high linear energy transfer (LET) radiation remain unclear. This study evaluated the effects of 0.1 gray (Gy), 0.5 Gy, and 2.0 Gy iron ion (56Fe(26)) radiation on lymphoid cells and organs of C57BL/6 mice on days 4 and 113 after whole body exposure; a group irradiated with 2.0 Gy silicon ions (28Si) was euthanized on day 113. On day 4 after 56Fe irradiation, dose-dependent decreases were noted in spleen and thymus masses and all major leukocyte populations in blood and spleen. The CD19(+) B lymphocytes were most radiosensitive and NK1.1(+) natural killer (NK) cells were most resistant. CD3(+) T cells were moderately radiosensitive and a greater loss of CD3(+)/CD8(+) T(C) cells than CD3(+)/CD4(+) T(H) cells was noted. Basal DNA synthesis was elevated on day 4, but response to mitogens and secretion of interleukin-2 and tumor necrosis factor-alpha were unaffected. Signs of anemia were noted. By day 113, high B cell numbers and low T(C) cell and monocyte percents were found in the 2.0 Gy 56Fe group; the 2.0 Gy 2)Si mice had low NK cells, decreased basal DNA synthesis, and a somewhat increased response to two mitogens. Collectively, the data show that lymphoid cells and tissues are markedly affected by high linear energy transfer (LET) radiation at relatively low doses, that some aberrations persist long after exposure, and that different consequences may be induced by various densely ionizing particles. Thus simultaneous exposure to multiple radiation sources could lead to a broader spectrum of immune dysfunction than currently anticipated.
NASA Discipline Radiation Health↗
Modulation of lens cell adhesion molecules by particle beams
Cell adhesion molecules (CAMs) are proteins which anchor cells to each other and to the extracellular matrix (ECM), but whose functions also include signal transduction, differentiation, and apoptosis. We are testing a hypothesis that particle radiations modulate CAM expression and this contributes to radiation-induced lens opacification. We observed dose-dependent changes in the expression of beta 1-integrin and ICAM-1 in exponentially-growing and confluent cells of a differentiating human lens epithelial cell model after exposure to particle beams. Human lens epithelial (HLE) cells, less than 10 passages after their initial culture from fetal tissue, were grown on bovine corneal endothelial cell-derived ECM in medium containing 15% fetal bovine serum and supplemented with 5 ng/ml basic fibroblast growth factor (FGF-2). Multiple cell populations at three different stages of differentiation were prepared for experiment: cells in exponential growth, and cells at 5 and 10 days post-confluence. The differentiation status of cells was characterized morphologically by digital image analysis, and biochemically by Western blotting using lens epithelial and fiber cell-specific markers. Cultures were irradiated with single doses (4, 8 or 12 Gy) of 55 MeV protons and, along with unirradiated control samples, were fixed using -20 degrees C methanol at 6 hours after exposure. Replicate experiments and similar experiments with helium ions are in progress. The intracellular localization of beta 1-integrin and ICAM-1 was detected by immunofluorescence using monoclonal antibodies specific for each CAM. Cells known to express each CAM were also processed as positive controls. Both exponentially-growing and confluent, differentiating cells demonstrated a dramatic proton-dose-dependent modulation (upregulation for exponential cells, downregulation for confluent cells) and a change in the intracellular distribution of the beta 1-integrin, compared to unirradiated controls. In contrast, there was a dose-dependent increase in ICAM-1 immunofluorescence in confluent, but not exponentially-growing cells. These results suggest that proton irradiation downregulates beta 1-integrin and upregulates ICAM-1, potentially contributing to cell death or to aberrant differentiation via modulation of anchorage and/or signal transduction functions. Quantification of the expression levels of the CAMs by Western analysis is in progress.
NASA Discipline Radiation Health↗
Mechanisms of mutagenesis in human cells exposed to 55 MeV protons
Protons represent the major type of charged particle radiation in spaceflight environments. The purpose of this study was to assess mutations arising in human lymphoid cells exposed to protons. Mutations were quantitated at the thymidine kinase (TK1) locus in cell lines derived from the same donor: TK6 cells (wt TP53) and WTK1 cells (mutant TP53). WTK1 cells were much more susceptible to mutagenesis following proton exposure than TK6 cells. Intragenic deletions were observed among early-arising TK1 mutants in TK6 cells, but not in WTK1 cells where all of the mutants arose by LOH. Deletion was the predominant mode of LOH in TK6 cells, while allelic recombination was the major mode of LOH in WTK1 cells. Deletions were of variable lengths, from <1 cM to 64 cM, while mutations that arose by allelic recombination often extended to the telomere. In summary, proton exposures elicited many types of mutations at an autosomal locus in human cells. Most involved large scale loss of genetic information, either through deletion or by recombination.
NASA Discipline Radiation Health↗
Evidence for factors modulating radiation-induced G2-delay: potential application as radioprotectors
Manipulation of checkpoint response to DNA damage can be developed as a means for protecting astronauts from the adverse effects of unexpected, or background exposures to ionizing radiation. To achieve this goal reagents need to be developed that protect cells from radiation injury by prolonging checkpoint response, thus promoting repair. We present evidence for a low molecular weight substance excreted by cells that dramatically increases the duration of the G2-delay. This compound is termed G2-Arrest Modulating Activity (GAMA). A rat cell line (A1-5) generated by transforming rat embryo fibroblasts with a temperature sensitive form of p53 plus H-ras demonstrates a dramatic increase in radiation resistance after exposure to low LET radiation that is not associated with an increase in the efficiency of rejoining of DNA double strand breaks. Radioresistance in this cell line correlates with a dramatic increase in the duration of the G2 arrest that is modulated by a GAMA produced by actively growing cells. The properties of GAMA suggest that it is a low molecular weight heat-stable peptide. Further characterization of this substance and elucidation of its mechanism of action may allow the development of a biological response modifier with potential applications as a radioprotector. GAMA may be useful for protecting astronauts from radiation injury as preliminary evidence suggests that it is able to modulate the response of cells exposed to heavy ion radiation, similar to that encountered in outer space.
NASA Discipline Radiation Health↗
Clustered DNA damages induced by high and low LET radiation, including heavy ions
Clustered DNA damages--here defined as two or more lesions (strand breaks, oxidized purines, oxidized pyrimidines or abasic sites) within a few helical turns--have been postulated as difficult to repair accurately, and thus highly significant biological lesions. Further, attempted repair of clusters may produce double strand breaks (DSBs). However, until recently, there was no way to measure ionizing radiation-induced clustered damages, except DSB. We recently described an approach for measuring classes of clustered damages (oxidized purine clusters, oxidized pyrimidine clusters, abasic clusters, along with DSB). We showed that ionizing radiation (gamma rays and Fe ions, 1 GeV/amu) does induce such clusters in genomic DNA in solution and in human cells. These studies also showed that each damage cluster results from one radiation hit (and its track), thus indicating that they can be induced by very low doses of radiation, i.e. two independent hits are not required for cluster induction. Further, among all complex damages, double strand breaks comprise--at most-- ~20%, with the other clustered damages being at least 80%.
NASA Discipline Radiation Health↗
Fibroma induction in rat skin following single or multiple doses of 1.0 GeV/nucleon 56Fe ions from the Brookhaven Alternating Gradient Synchrotron (AGS)
Rat skin was exposed to the plateau region of the 1.0 GeV/nucleon 56Fe beam at the Brookhaven AGS. Rats were irradiated or not with single of split doses of 56Fe or argon; some 56Fe-exposed rats were fed 250 ppm retinyl acetate continuously in the lab chow beginning 1 week before irradiation. All lesions were noted, photographed and identified for eventual histological diagnosis. The preponderance of the tumors so far are fibromas. The data show that single doses of 56Fe ions are 2 or 3 fold more effective than argon in producing tumors at 4.5 Gy but are about equally effective at 3.0 Gy and 9.0 Gy. The presence of 250 ppm retinyl acetate in the lab chow reduced the incidence of tumors by about 50-60% in comparison to groups exposed only to the radiation. These are preliminary findings based on only about one-fourth the eventual number of tumors expected.
NASA Discipline Radiation Health↗
Recent measurements for hadrontherapy and space radiation: nuclear physics
The particles and energies commonly used for hadron therapy overlap the low end of the charge and energy range of greatest interest for space radiation applications, Z=1-26 and approximately 100-1000 MeV/nucleon. It has been known for some time that the nuclear interactions of the incident ions must be taken into account both in treatment planning and in understanding and addressing the effects of galactic cosmic ray ions on humans in space. Until relatively recently, most of the studies of nuclear fragmentation and transport in matter were driven by the interests of the nuclear physics and later, the hadron therapy communities. However, the experimental and theoretical methods and the accelerator facilities developed for use in heavy ion nuclear physics are directly applicable to radiotherapy and space radiation studies. I will briefly review relevant data taken recently at various accelerators, and discuss the implications of the measurements for radiotherapy, radiobiology and space radiation research.
NASA Discipline Radiation Health↗
BNL accelerator-based radiobiology facilities
For the past several years, the Alternating Gradient Synchrotron (AGS) at Brookhaven National Laboratory (USA) has provided ions of iron, silicon and gold, at energies from 600 MeV/nucleon to 10 GeV/nucleon, for the US National Aeronautics and Space Administration (NASA) radiobiology research program. NASA has recently funded the construction of a new dedicated ion facility, the Booster Applications Facility (BAF). The Booster synchrotron will supply ion beams ranging from protons to gold, in an energy range from 40-3000 MeV/nucleon with maximum beam intensities of 10(10) to 10(11) ions per pulse. The BAF Project will be described and the future AGS and BAF operation plans will be presented.
NASA Discipline Radiation Health↗
Genomic instability, bystander effect, cytoplasmic irradiation and other phenomena that may achieve fame without fortune
The possible risk of induced malignancies in astronauts, as a consequence of the radiation environment in space, is a factor of concern for long term missions. Cancer risk estimates for high doses of low LET radiation are available from the epidemiological studies of the A-bomb survivors. Cancer risks at lower doses cannot be detected in epidemiological studies and must be inferred by extrapolation from the high dose risks. The standard setting bodies, such as the ICRP recommend a linear, no-threshold extrapolation of risks from high to low doses, but this is controversial. A study of mechanisms of carcinogenesis may shed some light on the validity of a linear extrapolation. The multi-step nature of carcinogenesis suggests that the role of radiation may be to induce a mutation leading to a mutator phenotype. High energy Fe ions, such as those encountered in space are highly effective in inducing genomic instability. Experiments involving the single particle microbeam have demonstrated a "bystander effect", ie a biological effect in cells not themselves hit, but in close proximity to those that are, as well as the induction of mutations in cells where only the cytoplasm, and not the nucleus, have been traversed by a charged particle. These recent experiments cast doubt on the validity of a simple linear extrapolation, but the data are so far fragmentary and conflicting. More studies are necessary. While mechanistic studies cannot replace epidemiology as a source of quantitative risk estimates, they may shed some light on the shape of the dose response relationship and therefore on the limitations of a linear extrapolation to low doses.
NASA Discipline Radiation Health↗
Shielded Heavy-Ion Environment Linear Detector (SHIELD): an experiment for the Radiation and Technology Demonstration (RTD) Mission
Radiological assessment of the many cosmic ion species of widely distributed energies requires the use of theoretical transport models to accurately describe diverse physical processes related to nuclear reactions in spacecraft structures, planetary atmospheres and surfaces, and tissues. Heavy-ion transport models that were designed to characterize shielded radiation fields have been validated through comparison with data from thick-target irradiation experiments at particle accelerators. With the RTD Mission comes a unique opportunity to validate existing radiation transport models and guide the development of tools for shield design. For the first time, transport properties will be measured in free-space to characterize the shielding effectiveness of materials that are likely to be aboard interplanetary space missions. Target materials composed of aluminum, advanced composite spacecraft structure and other shielding materials, helium (a propellant) and tissue equivalent matrices will be evaluated. Large solid state detectors will provide kinetic energy and charge identification for incident heavy-ions and for secondary ions created in the target material. Transport calculations using the HZETRN model suggest that 8 g cm -2 thick targets would be adequate to evaluate the shielding effectiveness during solar minimum activity conditions for a period of 30 days or more.
NASA Center LaRC↗
Biomarkers of exposure and dose: state of the art
Biomarkers provide methods to measure changes in biological systems and to relate them to environmental insults and disease processes. Biomarkers can be classified as markers of exposure and dose, markers of sensitivity, and markers of disease. It is important that the differences and applications of the various types of biomarkers be clearly understood. The military is primarily interested in early biomarkers of exposure and dose that do not require high levels of sensitivity but can be used to rapidly triage war fighters under combat or terrorist conditions and determine which, if any, require medical attention. Biomarkers of long-term radiation risk represent the second area of interest for the military. Biomarkers of risk require high sensitivity and specificity for the disease and insult but do not require rapid data turnaround. Biomarkers will help provide information for quick command decisions in the field, characterise long-term troop risks and identify early stages of radiation-induced diseases. This information provides major positive reassurances about individual exposures and risk that will minimise the physical and psychological impact of wartime radiation exposures.
Review, Tutorial↗