Protection by WR-2721 and WR-151327 against late effects of gamma rays and neutrons.

Two thiophosphoroate compounds WR-2721 and WR-151327 were assessed for their ability to modify the deleterious effects (life shortening and carcinogenesis) of fission-spectrum neutrons (kerma-weighted mean energy of 0.85 MeV) or gamma rays on B6CF1 hybrid mice. Male and female mice, 200 of each sex per experimental group, were irradiated individually at 110 days of age. Radioprotectors (400 mg/kg of WR-2721 or 580 mg/kg of WR-151327) were administered intraperitoneally 30 min prior to irradiation. Neutron doses were 10 cGy or 40 cGy and gamma ray doses were 206 cGy or 417 cGy. Animals were housed five to a cage; cage locations in the holding rooms were randomized by computer. Animals were checked daily and all deceased animals were necropsied. WR-2721 afforded protection against both neutron- and gamma-ray-induced carcinogenesis and subsequent life shortening. Cumulative survival curves for unirradiated mice of either sex were unaffectecd by protectors. WR-2721 protected irradiated groups against life shortening by approximately 10 cGy of neutrons or 100 cGy of gamma rays. WR-151327 was as effective as WR-2721 against neutron irradiation.     

Effects of exposure to different types of radiation on behaviors mediated by peripheral or central systems.

The effects of exposure to ionizing radiation on behavior may result from effects on peripheral or on central systems. For behavioral endpoints that are mediated by peripheral systems (e.g., radiation-induced conditioned taste aversion or vomiting), the behavioral effects of exposure to heavy particles (56Fe, 600 MeV/n) are qualitatively similar to the effects of exposure to gamma radiation (60Co) and to fission spectrum neutrons. For these endpoints, the only differences between the different types of radiation are in terms of relative behavioral effectiveness. For behavioral endpoints that are mediated by central systems (e.g., amphetamine-induced taste aversion learning), the effects of exposure to 56Fe particles are not seen following exposure to lower LET gamma rays or fission spectrum neutrons. These results indicate that the effects of exposure to heavy particles on behavioral endpoints cannot necessarily be extrapolated from studies using gamma rays, but require the use of heavy particles.     

Recent results form measurements of the energy spectrum of cosmic-ray induced neutrons aboard an ER-2 airplane and on the ground.

Crews of future high-altitude commercial aircraft may be significantly exposed to atmospheric cosmic radiation from galactic cosmic rays (GCR). To help determine such exposures, the Atmospheric Ionizing Radiation Project, an international collaboration of 15 laboratories, made simultaneous radiation measurements with 14 instruments on a NASA ER-2 high-altitude aircraft. The primary instrument was a sensitive extended-energy multisphere neutron spectrometer, which was also used to make measurements on the ground. Its detector responses were calculated for neutrons and charged hadrons at energies up to 100 GeV using the radiation transport code MCNPX. We have now recalculated the detector responses including the effects of the airplane structure. We are also using new FLUKA calculations of GCR-induced hadron spectra in the atmosphere to correct for spectrometer counts produced by charged hadrons. Neutron spectra are unfolded from the corrected measured count rates using the MAXED code. Results for the measured cosmic-ray neutron spectrum (thermal to >10 GeV), total neutron fluence rate, and neutron dose equivalent and effective dose rates, and their dependence on altitude and geomagnetic cutoff generally agree well with results from recent calculations of GCR-induced neutron spectra.     

The influence of dose, dose-rate and particle fragmentation on cataract induction by energetic iron ions.

Because activities in space necessarily involve chronic exposure to a heterogeneous charged particle radiation field it is important to assess the influence of dose-rate and the possible modulating role of heavy particle fragmentation on biological systems. Using the well-studied cataract model, mice were exposed to plateau 600 MeV/amu 56Fe ions either as acute or fractionated exposures at total doses of 5 - 504 cGy. Additional groups of mice received 20, 360 and 504 cGy behind 50 mm of polyethylene, which simulates body shielding. The reference radiation consisted of 60Co gamma radiation. The animals were examined by slit lamp biomicroscopy over their three year life spans. In accordance with our previous observations with heavy particles, the cataractogenic potential of the 600 MeV/amu 56Fe ions was greater than for low-LET radiation and increased with decreasing dose relative to gamma-rays. Fractionation of a given dose of 56Fe ions did not reduce the cataractogenicity of the radiation compared to the acute regimen. Fragmentation of the beam in the polyethylene did not alter the cataractotoxicity of the ions, either when administered singly or in fractions.     

Early and late mammalian responses to heavy charged particles.

This overview summarizes murine results on acute lethality responses, inactivation of marrow CFU-S and intestinal microcolonies, testes weight loss, life span shortening, and posterior lens opacification in mice irradiated with heavy charged particles. RBE-LET relationships for these mammalian responses are compared with results from in vitro studies. The trend is that the maximum RBE for in vivo responses tends to be lower and occurs at a lower LET than for inactivation of V79 and T-1 cells in culture. Based on inactivation cross sections, the response of CFU-S in vivo conforms to expectations from earlier studies with prokaryotic systems and mammalian cells in culture. Effects of heavy ions are compared with fission spectrum neutrons, and the results are consistent with the interpretation that RBEs are lower than for fission neutrons at about the same LET, probably due to differences in track structure. Issues discussed focus on challenges associated with assessments of early and late effects of charged particles based on dose, RBE and LET, and with the concordance or discordance of results obtained with in vivo and in vitro model systems. Models for radiation damage/repair and misrepair should consider effects observed with in vivo as well as in vitro model systems.     

Relationships between neutron fluxes and rain flows

Registration of secondary cosmic ray neutrons is a convenient tool for investigation of primary cosmic ray variations and meteorological effects as well. At present a large network of neutron monitors exists, providing the studies of cosmic ray variations related to the interplanetary conditions and geomagnetic activity. At the same time cosmic ray variations may be caused by some atmospheric processes. In this connection, using the data from standard and lead-free neutron monitors, and gamma and muon detectors, we studied relations between rain flows and neutron, gamma and ionization component behavior. To explain observable results the calculations of neutron and gamma absorption and albedo neutron spectra have been performed on the basis of universal software package FLUKA-2006. In this study we used hourly data on the neutron flux, corrected for barometric pressure and data from local meteorological stations. It was shown that secondary neutron radiation, recorded by lead-free NM, and gamma radiation as well are strongly effected by meteorological factors. The neutron component behavior depends on the moisture content in the soil, and above its surface.     

Can late effects of neutron irradiation in man be estimated from early responses?1

Slowly-developing tissue changes after neutron irradiation should be more easily predicted from acutely-developing injury than is the case with X rays. The difference between tissue responses to neutrons and X rays is that cell survival in both rapidly and slowly responding tissues is a direct logarithmic function of neutron dose, at least up to about 3 Gy, whereas the X-ray dose-survival relationship differs between the two types of tissue: the target cells for late injury are more susceptible to killing from accumulation of sub-lethal X-ray injury and hence the survival curve diverges from its initial essentially linear region more rapidly than does that for the target cells for acute injury.     

Hematopoietic responses under protracted exposures to low daily dose gamma irradiation.

In attempting to evaluate the possible health consequences of chronic ionizing radiation exposure during extended space travel (e.g., Mars Mission), ground-based experimental studies of the clinical and pathological responses of canines under low daily doses of 60Co gamma irradiation (0.3-26.3 cGy d-1) have been examined. Specific reference was given to responses of the blood forming system. Results suggest that the daily dose rate of 7.5 cGy d-1 represents a threshold below which the hematopoietic system can retain either partial or full trilineal cell-producing capacity (erythropoiesis, myelopoiesis, and megakaryopoiesis) for extended periods of exposure (>1 yr). Trilineal capacity was fully retained for several years of exposure at the lowest dose-rate tested (0.3 cGy d-1) but was completely lost within several hundred days at the highest dose-rate (26.3 cGy d-1). Retention of hematopoietic capacity under chronic exposure has been demonstrated to be mediated by hematopoietic progenitors with acquired radioresistance and repair functions, altered cytogenetics, and cell-cycle characteristics. Radiological, biological, and temporal parameters responsible for these vital acquisitions by hematopoietic progenitors have been partially characterized. These parameters, along with threshold responses, are described and discussed in relation to potential health risks of the space traveler under chronic stress of low-dose irradiation.     

Induction of genomic instability after an acute whole-body exposure of mice to Fe ions

The purpose of this study was to evaluate dose–response relationships for the in vivo induction of micronuclei (MN) as a measure of both initial radiation damage and the induction of genomic instability. These measurements were made in mouse blood erythrocytes as a function of radiation dose, radiation quality, time after irradiation, and the genetic background of exposed individuals. Blood samples were collected from two strains of mouse (CBA/CaJ and C57BL/6J) at different times up to 3 months following a whole-body exposure to various doses of 1 GeV/amu ⁵⁶Fe ions (0, 0.1, 0.5 and 1.0 Gy, at the dose rate of a 1 Gy/min) or ¹³⁷Cs gamma rays (0, 0.5, 1.0 and 3.0 Gy, at the dose rate of 0.72 Gy/min). Blood-smear slides were stained with acridine orange (AO). The frequencies of MN were measured in mature normochromatic-erythrocytes (MN-NCEs) and in immature polychromatic-erythrocytes (MN-PCEs). Effects of both types of radiation on erythropoiesis were also evaluated. As a measure of cell progression delay, a dose-dependent decrease in numbers of PCEs was observed at day 2 post-exposure in both strains, regardless of radiation quality. Subsequently, the levels of PCEs increased in all exposed mice, reaching control levels (or higher) by day 7 post-exposure. Further, at day 2 after the exposure, there was no increase in the frequency of MN-PCEs in CBA/CaJ mice exposed to ⁵⁶Fe ions while the frequency of MN-PCEs elevated as a function of dose in the C57BL/6J mice. At day 4, there was no dose related increase in MN-NCEs in either strain of mouse exposed to ¹³⁷Cs gamma rays. Additionally, at the early sacrifice times (days 2 and 4), ⁵⁶Fe ions were slightly more effective (per unit dose) in inducing MN-NCEs than ¹³⁷Cs gamma rays in CBA/CaJ mice. However, there was no increase in the frequency of MN-NCEs at late times after an acute exposure to either type of radiation. In contrast, both types of radiation induced increased MN-PCEs frequencies in irradiated CBA/CaJ mice, but not C57BL/6J mice, at late times post-exposure. This finding indicates the potential induction of genomic instability in hematopoietic cells of CBA/CaJ mice by both types of radiation. The finding also demonstrates the influence of genetic background on radiation-induced genomic instability in vivo.     

Effects of exposure to heavy particles on a behavior mediated by the dopaminergic system.

The effects of exposure to heavy particles on behaviors mediated by the central nervous system (CNS) are qualitatively different than the effects produced by exposure to other types of radiation. One behavior mediated by the CNS is the amphetamine-induced taste aversion, which is produced by pairing a novel tasting solution with injection of amphetamine. When the conditioning day is three days following irradiation, exposing rats to low doses of 56Fe particles (600 MeV/n or 1 GeV/n) eliminates the taste aversion produced by injection of amphetamine, which is dependent upon the integrity of the central dopaminergic system, but has no effect on the aversion produced by injection of lithium chloride which is mediated by the gastrointestinal system. In contrast to the effects obtained using heavy particles, exposing rats to 60CO gamma rays or to fission spectrum neutrons has no selective effect upon the acquisition of either amphetamine- or lithium chloride-induced taste aversions. When the conditioning day occurs four months following exposure to 1 GeV/n 56Fe particles, there is an enhancement of the amphetamine-induced taste aversion. The implications of these findings for approaches to risk assessment are considered.     

DNA fragmentation in mammalian cells exposed to various light ions.

Elucidation of how effects of densely ionizing radiation at cellular level are linked to DNA damage is fundamental for a better understanding of the mechanisms leading to genomic damage (especially chromosome aberrations) and developing biophysical models to predict space radiation effects. We have investigated the DNA fragmentation patterns induced in Chinese hamster V79 cells by 31 keV/micrometer protons, 123 keV/micrometer helium-4 ions and gamma rays in the size range 0.023-5.7 Mbp, using calibrated Pulsed Field Gel Electrophoresis (PFGE). The frequency distributions of fragments induced by the charged particles were shifted towards smaller sizes with respect to that induced by comparable doses of gamma rays. The DSB yields, evaluated from the fragments induced in the size range studied, were higher for protons and helium ions than for gamma rays by a factor of about 1.9 and 1.2, respectively. However, these ratios do not adequately reflect the RBE observed on the same cells for inactivation and mutation induced by these beams. This is a further indication for the lack of correlation between the effects exerted at cellular level and the initial yield of DSB. The dependence on radiation quality of the fragmentation pattern suggests that it may have a role in damage repairability. We have analyzed these patterns with a "random breakage" model generalized in order to consider the initial non-random distribution of the DNA molecules. Our results suggest that a random breakage mechanism can describe with a reasonable approximation the DNA fragmentation induced by gamma rays, while the approximation is not so good for light ions, likely due to the interplay between ion tracks and chromatin organization at the loop level.     

Chromosome aberrations in human lymphocytes induced by 250 MeV protons: effects of dose, dose rate and shielding.

Although the space radiation environment consists predominantly of energetic protons, astronauts inside a spacecraft are chronically exposed to both primary particles as well as secondary particles that are generated when the primary particles penetrate the spacecraft shielding. Secondary neutrons and secondary charged particles can have an LET value that is greater than the primary protons and, therefore, produce a higher relative biological effectiveness (RBE). Using the accelerator facility at Loma Linda University, we exposed human lymphocytes in vitro to 250 MeV protons with doses ranging from 0 to 60 cGy at three different dose rates: a low dose rate of 7.5 cGy/h, an intermediate dose rate of 30 cGy/h and a high dose rate of 70 cGy/min. The effect of 15 g/cm2 aluminum shielding on the induction of chromosome aberrations was investigated for each dose rate. After exposure, lymphocytes were incubated in growth medium containing phytohemagglutinin (PHA) and chromosome spreads were collected using a chemical-induced premature chromosome condensation (PCC) technique. Aberrations were analyzed using the fluorescence in situ hybridization (FISH) technique with three different colored chromosome-painting probes. The frequency of reciprocal and complex-type chromosome exchanges were compared in shielded and unshielded samples.     

Neutron spectra in the atmosphere from interactions of primary cosmic rays

Spectra of neutrons from interactions of primary cosmic rays in the earth's atmosphere are calculated with the Monte Carlo model fluka for various depths down to sea level. We discuss the environmental models describing the primary cosmic ray spectrum and details of the calculations. Neutron energy spectra are presented for different depths in the atmosphere and for different geographical locations. By comparing results of calculations to measurements on neutron spectra it is shown that fluka may serve as an important tool for the estimation of the radiation environment in the atmosphere.     

Flight safety implications of the extreme solar proton event of 23 February 1956

There is considerable speculation about the effects at aircraft altitudes resulting from extreme solar proton events. The ground level event (GLE) of 23 February 1956 (GLE 5), remains the largest solar proton event of the neutron monitor era in terms of its influence on count rates at monitors near sea level. During this GLE the count rate was increased by as much as 4760% (15-min average) at the Leeds monitor relative to the count rate from galactic cosmic radiation (GCR). Two modern models of the event cumulative solar proton spectrum for this event, a 6-parameter fit in energy and a 4-parameter Band fit in rigidity, are compared with 1-h of GCR at solar minimum. While effective doses calculated with CARI-7A for both models at low geomagnetic cutoff rigidities are indeed high when compared with GCR and can exceed recommended exposure limits, both GLE spectra exhibit a much stronger dependence on cutoff rigidity than GCR, and a larger fraction of the dose from neutrons. At locations with cutoff rigidities above 4.2 and 6.4?GV, respectively, the GLE effective doses are smaller than the GCR hourly dose. At locations with cutoff rigidities above about 4?GV, GCR was the dominant source of exposure in 10?h or less at all altitudes examined. This suggests that if a similar event occurs in the future, low- and mid-latitude flights at modern jet flight altitudes could be well-protected by Earth’s magnetic field.     

Radiation exposures during space flight and their measurement.

The paper reviews radiation exposures recorded during space flights of the US and USSR. Most of the data are from manned missions and include discussion of absorbed dose and dose rates as a function of parameters such as altitude, inclination, spacecraft type and shielding. Preliminary data exist on the neutron and HZE-particle component, as well as the LET spectra. For low Earth-orbit missions, the dose encountered is strongly altitude-dependent, with a weaker dependence upon inclination. The doses range from about 6 millirad per day for the Space Transportation System No. 3 flight to about 90 mrad per day for Skylab. The effective quality factor (QF) for the near-Earth orbits and free space has been estimated to be about 1.5 and about 5.5 respectively. Complete shielding from the galactic cosmic rays does not appear practical because of spacecraft weight limitations.     

Overview on experience to date on human exposure to space radiations.

The human exposure in space depends on the three factors: the flight trajectory, its date and duration and the cyclogram of the cosmonaut's activities. In the near-Earth orbits the daily dose varies within the limits of (1.5-5.0) 10(-4) Gy day-1 and greatly increases if the altitude increases. The mean daily quality factor is 1.6-2.0. Strong solar proton events in the orbits with the inclination of < 52 degrees result in the dose rate increase up to 2-3 cGy day-1. On the surface of the orbital spacecrafts the daily dose reaches 2 Gy. The neutron dose depends on the shielding mass distribution varying within the limits of 6%-30% of the charged particles dose. In deep space the dose is mainly formed by the galactic and solar cosmic rays(GCR,SCR). Behind the shielding of 2-3 g cm-2 Al the GCR dose varies in the range of (20-30) 10(-5) Gy day-1. The SCR dose can reach hundreds of cSv.     

Chromosomal data relevant for Q values.

It has been known for many years that relationships between absorbed dose and biological effect vary with the type of radiation. In particular, neutrons and alpha particles are more damaging than x or gamma radiations. This applies to a range of biological effects such as cell killing, chromosome aberrations, cell mutation, cell transformation as well as life shortening and cancer induction in animals. The application of this knowledge to devise a scheme for specifying the quality factor (Q) in radiological protection has been the subject of much debate. There are no tumour data in humans from which the quality factor may be derived. The problems of using animal and cell transformation data which are probably the next best choice are discussed. The extensive data base on chromosomal aberrations in human lymphocytes is described and discussed in terms of relevance to deducing quality factors. Particular emphasis is placed on data obtained at low doses and low dose rates.     

Neoplastic cell transformation by energetic heavy ions and its modification with chemical agents.

For many years we have been interested in understanding the potential carcinogenic effects of cosmic rays. We have studied the oncogenic effects of cosmic rays with accelerator-produced heavy particle radiation and with a cultured mammalian cell system--C3H10T1/2 cells. Our quantitative data obtained with carbon, neon, silicon, and iron particles showed that RBE is both dose and LET dependent for neoplastic cell transformation. RBE is higher at lower dose, and RBE increases with LET up to about 200 keV/micrometer. In nonproliferation confluent cells, heavy-ion induced transformation damage may not be repairable, although a dose modifying factor of about 1.7 was observed for X-ray radiation. Our recent studies with super-heavy high-energy particles, e.g., 960 MeV/U U235 ions (LET = 1900 keV/micrometer), indicate that these ions with a high inactivation cross-section can cause neoplastic cell transformation. The induction of cell transformation by radiation can be modified with various chemicals. We have found that the presence of DMSO (either during or many days after irradiation) decreased the transformation frequency significantly. It is, therefore, potentially possible to reduce the oncogenic effect of cosmic rays in space through some chemical protection.     

G2-chromosome aberrations induced by high-LET radiations.

We report measurement of initial G2-chromatid breaks in normal human fibroblasts exposed to various types of high-LET particles. Exponentially growing AG 1522 cells were exposed to gamma rays or heavy ions. Chromosomes were prematurely condensed by calyculin A. Chromatid-type breaks and isochromatid-type breaks were scored separately. The dose response curves for the induction of total chromatid breaks (chromatid-type + isochromatid-type) and chromatid-type breaks were linear for each type of radiation. However, dose response curves for the induction of isochromatid-type breaks were linear for high-LET radiations and linear-quadratic for gamma rays. Relative biological effectiveness (RBE), calculated from total breaks, showed a LET dependent tendency with a peak at 55 keV/micrometer silicon (2.7) or 80 keV/micrometer carbon (2.7) and then decreased with LET (1.5 at 440 keV/micrometer). RBE for chromatid-type break peaked at 55 keV/micrometer (2.4) then decreased rapidly with LET. The RBE of 440 keV/micrometer iron particles was 0.7. The RBE calculated from induction of isochromatid-type breaks was much higher for high-LET radiations. It is concluded that the increased production of isochromatid-type breaks, induced by the densely ionizing track structure, is a signature of high-LET radiation exposure.