Countermeasures for space radiation induced adverse biologic effects

Radiation exposure in space is expected to increase the risk of cancer and other adverse biological effects in astronauts. The types of space radiation of particular concern for astronaut health are protons and heavy ions known as high atomic number and high energy (HZE) particles. Recent studies have indicated that carcinogenesis induced by protons and HZE particles may be modifiable. We have been evaluating the effects of proton and HZE particle radiation in cultured human cells and animals for nearly a decade. Our results indicate that exposure to proton and HZE particle radiation increases oxidative stress, cytotoxicity, cataract development and malignant transformation in in vivo and/or in vitro experimental systems. We have also shown that these adverse biological effects can be prevented, at least partially, by treatment with antioxidants and some dietary supplements that are readily available and have favorable safety profiles. Some of the antioxidants and dietary supplements are effective in preventing radiation induced malignant transformation in vitro even when applied several days after the radiation exposure. Our recent progress is reviewed and discussed in the context of the relevant literature.     

The effects of proton exposure on neurochemistry and behavior.

Future space missions will involve long-term travel beyond the magnetic field of the Earth, where astronauts will be exposed to radiation hazards such as those that arise from galactic cosmic rays. Galactic cosmic rays are composed of protons, alpha particles, and particles of high energy and charge (HZE particles). Research by our group has shown that exposure to HZE particles, primarily 600 MeV/n and 1 GeV/n 56Fe, can produce significant alterations in brain neurochemistry and behavior. However, given that protons can make up a significant portion of the radiation spectrum, it is important to study their effects on neural functioning and on related performance. Therefore, these studies examined the effects of exposure to proton irradiation on neurochemical and behavioral endpoints, including dopaminergic functioning, amphetamine-induced conditioned taste aversion learning, and spatial learning and memory as measured by the Morris water maze. Male Sprague-Dawley rats received a dose of 0, 1.5, 3.0 or 4.0 Gy of 250 MeV protons at Loma Linda University and were tested in the different behavioral tests at various times following exposure. Results showed that there was no effect of proton irradiation at any dose on any of the endpoints measured. Therefore, there is a contrast between the insignificant effects of high dose proton exposure and the dramatic effectiveness of low dose (<0.1 Gy) exposures to 56Fe particles on both neurochemical and behavioral endpoints.     

Estimates of HZE particle contributions to SPE radiation exposures on interplanetary missions.

Estimates of radiation doses resulting from possible HZE (high energy heavy ion) components of solar particle events (SPEs) are presented for crews of manned interplanetary missions. The calculations assume a model spectrum obtained by folding measured solar flare HZE particle abundances with the measured energy spectra of SPE alpha particles. These hypothetical spectra are then transported through aluminum spacecraft shielding. The results, presented as estimates of absorbed dose and dose equivalent, indicate that HZE components by themselves are not a major concern for crew protection but should be included in any overall risk assessment. The predictions are found to be sensitive to the assumed spectral hardness parameters.     

Effect of HZE particles and space hadrons on bacteriophages.

The effect of high energy (HZE) particles and high energy hadrons on T4Br+ bacteriophage was analyzed. The experiments were done in orbital flight, on high mountains, on an accelerator, and with an alpha particle source. We studied the survival rate of the bacteriophage, the mutation frequency, the mutation spectrum and the revertability under the action of chemical mutagens with a known mechanism of action on DNA. It was found that the biological efficiency of HZE particles and high energy hadrons is greater than that of gamma radiation. The spectra of mutations produced by these mutations and the mechanisms of their action are also different. These effects were local, because of the mode of interaction of the radiant energy with biological objects, and depended on the linear energy transfer (LET). The modes have now been experimentally defined.     

Adaptive response studies may help choose astronauts for long-term space travel.

Long-term manned exploratory missions are planned for the future. Exposure to high-energy neutrons, protons and high charge and energy particles during a deep space mission, needs protection against the detrimental effects of space radiation. It has been suggested that exposure to unpredictable extremely large solar particle events would kill the astronauts without massive shielding. To reduce this risk to astronauts and to minimize the need for shielding, astronauts with highest significant adaptive responses should be chosen. It has been demonstrated that some humans living in very high natural radiation areas have acquired high adaptive responses to external radiation. Therefore, we suggest that for a deep space mission the adaptive response of all potential crew members be measured and only those with high adaptive response be chosen. We also proclaim that chronic exposure to elevated levels of radiation can considerably decrease radiation susceptibility and better protect astronauts against the unpredictable exposure to sudden and dramatic increase in flux due to solar flares and coronal mass ejections.     

Effects of heavy particle irradiation and diet on object recognition memory in rats

On long-duration missions to other planets astronauts will be exposed to types and doses of radiation that are not experienced in low earth orbit. Previous research using a ground-based model for exposure to cosmic rays has shown that exposure to heavy particles, such as ⁵⁶Fe, disrupts spatial learning and memory measured using the Morris water maze. Maintaining rats on diets containing antioxidant phytochemicals for 2 weeks prior to irradiation ameliorated this deficit. The present experiments were designed to determine: (1) the generality of the particle-induced disruption of memory by examining the effects of exposure to ⁵⁶Fe particles on object recognition memory; and (2) whether maintaining rats on these antioxidant diets for 2 weeks prior to irradiation would also ameliorate any potential deficit. The results showed that exposure to low doses of ⁵⁶Fe particles does disrupt recognition memory and that maintaining rats on antioxidant diets containing blueberry and strawberry extract for only 2 weeks was effective in ameliorating the disruptive effects of irradiation. The results are discussed in terms of the mechanisms by which exposure to these particles may produce effects on neurocognitive performance.     

A review and comparative analysis of the biological damage induced during space flight by HZE particles and space hadrons

We have studied the somatic and genetic effects of heavy ions (HZE particles) and the very high energy hadrons of space radiation on various organisms ranging in complexity from bacteriophage to man. Experimental data were obtained in space, on high mountains and in a proton accelerator at energies of 76 GeV. In all these experiments local micro- and macroradiational damage was observed. This damage was characterized by severity over large local regions and for the most part was due to cascades of secondary particle bundles resulting from the collosion of very high energy space hadrons with atomic nuclei rather than from cellular hits from relatively low energy single HZE particles. At present there does not appear to be any effective way to provide shielding against these cosmic hadrons.     

Unique biological aspects of radiation hazards--an overview.

Low orbit, geostationary, and deep-space flights differ from one another with respect to particle radiation environment, participating population size, mission duration, and biological risks other than radiation. It is proposed that all of these factors be considered in the setting of safety standards and, in particular, that the rem-dose concept is applicable only to radiations having low and intermediate linear energy transfer (electrons, protons, and helium ions), whereas the incidence of microlesions is a more meaningful indicator of the hazard due to higher-Z, high energy (HZE) particles. A microlesion is the biological injury inflicted in a specific tissue by a single HZE particle, and it is still in need of quantitative biological definition for specific mammalian tissues. If for example, a microlesion is taken as due to a HZE particle track 10 cell diameters long with LET > 200 KeV/micrometer in its core and > 25 rad dose in its penumbra at a distance of 10 micrometers, then the microlesion dose rate in geostationary orbit, for example, is about 9,000 microlesions per cm3 of tissue per month.     

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.     

Neuroimmune response and sleep studies after whole body irradiation with high-LET particles

In order to investigate the biological effects of galactic rays on astronaut cerebral functions after space flight, mice were exposed to different heavy ions (HZE) in whole-body conditions at doses comparable to the galactic flux: ¹²C, ¹⁶O and ²⁰Ne (95 MeV/u, at 42–76 mGy). Animals were also exposed to 42 mGy of ⁶⁰Co radiation for comparison with HZE. The neuroimmune response, evaluated by interleukin-1 (IL-1) measurement, showed that this cytokine was produced 3 h after irradiation by ¹⁶O or ⁶⁰Co. In contrast, neither ¹²C (56.7 mGy) nor ²⁰Ne (76 mGy) induced IL-1 production. However, immunohistochemical staining of ¹²C-irradiated mouse brain tissue showed 2 months later a marked inflammatory reaction in the hippocampus and a diffuse response in parenchyma. Sleep studies were realized before and after exposure to 42 mGy of ¹⁶O and 76 mGy of ²⁰Ne: only the ²⁰Ne radiation displayed a small effect. A slight decrease in paradoxical sleep, corresponding to a reduction in the number of episodes of paradoxical sleep, was manifested between 8 and 22 days after exposure. Exposure to ¹²C and ¹⁶O induced no changes either in cellularity of spleen or thymus, or in caspase 3 activity (as much as four months after irradiation). Taken together, these data indicate that the CNS could be sensitive to heavy ions and that responses to HZE impact depend on the nature of the particle, the dose threshold and the time delay to develop biological processes. Differences in responses to different HZE highlight the complex biological phenomena to which astronauts are submitted during space flight.     

Approaches to radiation guidelines for space travel.

There are obvious risks in space travel that have loomed larger than any risk from radiation. Nevertheless, NASA has maintained a radiation program that has involved maintenance of records of radiation exposure, and planning so that the astronauts' exposures are kept as low as possible, and not just within the current guidelines. These guidelines are being reexamined currently by NCRP Committee 75 because new information is available, for example, risk estimates for radiation-induced cancer and about the effects of HZE particles. Furthermore, no estimates of risk or recommendations were made for women in 1970 and must now be considered. The current career limit is 400 rem to the blood forming organs. The appropriateness of this limit and its basis are being examined as well as the limits for specific organs. There is now considerably more information about age-dependency for radiation effects and this will be taken into account. In 1973 a committee of the National Research Council made a separate study of HZE particle effects and it was concluded that the attendant risks did not pose a hazard for low inclination near-earth orbit missions. Since that time work has been carried out on the so-called microlesions caused by HZE particles and on the relative carcinogenic effect of heavy ions, including iron. A remaining question is whether the fluence of HZE particles could reach levels of concern in missions under consideration. Finally, it is the intention of the committee to indicate clearly the areas requiring further research.     

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.     

Nonlinear processes in cosmic-ray precursor of strong supernova shock: Maximum energy and average energy spectrum of accelerated particles

The instability in the cosmic-ray precursor of a supernova shock is studied. The level of turbulence in this region determines the maximum energy of accelerated particles. The consideration is not limited by the case of weak turbulence. It is assumed that the Kolmogorov type nonlinear wave interactions together with the ion-neutral collisions restrict the amplitude of random magnetic field. As a result, the maximum energy of accelerated particles strongly depends on the age of a SNR. The average spectrum of cosmic rays injected in the interstellar medium in the course of adiabatic SNR evolution takes the approximate form E⁻² at energies larger than 10–30 GeV/nucleon with the maximum energy that is close to the position of the knee in cosmic-ray spectrum at 4 × 10¹⁵ eV. At an earlier stage of SNR evolution – the ejecta-dominated stage, the particles are accelerated to higher energies and have a rather steep power-law distribution. These results suggest that the knee may mark the transition from the ejecta-dominated to the adiabatic evolution of SNR shocks which accelerate cosmic rays.     

Using high-energy proton fluence to improve risk prediction for consequences of solar particle events

The potential for exposure to large solar particle events (SPEs) with high energy levels is a major concern during interplanetary transfer and extra-vehicular activities (EVAs) on the lunar and Mars surface. Previously, we have used data from the last 5 solar cycles to estimate percentiles of dose to a typical blood-forming organ (BFO) for a hypothetical astronaut in a nominally shielded spacecraft during a 120-d lunar mission. As part of this process, we made use of complete energy spectra for 34 large historical SPEs to calculate what the BFO mGy-Eq dose would have been in the above lunar scenario for each SPE. From these calculated doses, we then developed a prediction model for BFO dose based solely on an assumed value of integrated fluence above 30 MeV (Φ₃₀) for an otherwise unspecified future SPE. In this study, we reasoned that since BFO dose is determined more by protons with higher energies than by those with lower energies, more accurate BFO dose prediction models could be developed using integrated fluence above 60 (Φ₆₀) and above 100 MeV (Φ₁₀₀) as predictors instead of Φ₃₀. However to calculate the unconditional probability of a BFO dose exceeding a pre-specified limit (“BFO dose risk”), one must also take into account the distribution of the predictor (Φ_30,Φ₆₀, or Φ₁₀₀), as estimated from historical SPEs. But Φ₆₀ and Φ₁₀₀ have more variability, and less available historical information on which to estimate their distributions over many SPE occurrences, than does Φ₃₀. Therefore, when estimating BFO dose risk there is a tradeoff between increased BFO dose prediction at a given energy threshold and decreased accuracy of models for describing the distribution of that threshold over future SPEs as the threshold increases. Even when taking the second of these two factors into account, we still arrived at the conclusion that overall prediction improves as the energy level threshold increases from 30 to 60 to 100 MeV. These results can be applied to the development of approaches to improve radiation protection of astronauts and the optimization of mission planning for future space missions.     

Summary of current radiation dosimetry results on manned spacecraft.

Measurements of radiation exposures aboard manned space flights of various altitudes, orbital inclinations and durations were performed by means of passive radiation detectors, thermoluminescent detectors (TLD's), and in some cases by active electronic counters. The TLD's and electronic counters covered the lower portion of the LET (linear energy transfer) spectra, while the nuclear track detectors measured high-LET produced by HZE particles. In Spacelab (SL-1), TLD's recorded a range of 102 to 190-millirad, yielding an average low-LET dose rate of 11.2 mrad per day inside the module, about twice the dose rate measured on previous space shuttle flights. Because of a higher inclination of the SL-1 orbit (57 degrees versus 28.5 degrees for previous shuttle flights), substantial fluxes of highly ionizing HZE particles were also observed, yielding an overall average mission dose-equivalent of about 135 millirem, about three times higher than measured an previous shuttle missions. A dose rate more than an order of magnitude higher than for any other space shuttle light was obtained for mission STS-41C, reflecting the highest orbital altitude to date of 519 km.     

Trapped particle energy spectrum in shuttle middeck

We describe the differential energy spectrum of trapped particles measured by a solid-state charged particle telescope in the mid-deck of the Space Shuttle during the period of solar maximum. The telescope was flown in two high altitude flights at 28.5° and 57° inclination. Assuming, as is normally done, that the variations of Shuttle orientation during the missions lead to average isotropic incident spectra, the observed spectrum disagrees significantly from AP8 model calculations. This indicates the need to take into consideration the variations of solid-angle direction relative to the magnetic field. The measurements show that there is a very significant flux of secondary light ions. The energy spectra of these ions does not agree with the production spectrum from radiation transport calculations based on omni-directional AP8 Max model as an input energy spectrum.

We also describe measurements of linear energy transfer spectra using a tissue equivalent proportional counter (TEPC) flown both in the mid-deck and the payload bay of the Space Shuttle. Comparisons are made between linear energy transfer spectral measurements AP8 model-based radiation transport predictions, and thermoluminescent dosimeter (TLD) measurements. The absorbed dose-rate measurements using TLD's are roughly 25% lower than the TEPC-measured dose rate measurements.     

Analysis of radiation risk from alpha particle component of solar particle events.

The solar particle events (SPE) will contain a primary alpha particle component, representing a possible increase in the potential risk to astronauts during an SPE over the often studied proton component. We discuss the physical interactions of alpha particles important in describing the transport of these particles through spacecraft and body shielding. Models of light ion reactions are presented and their effects on energy and linear energy transfer (LET) spectra in shielding discussed. We present predictions of particle spectra, dose, and dose equivalent in organs of interest for SPE spectra typical of those occurring in recent solar cycles. The large events of solar cycle 19 are found to have substantial increase in biological risk from alpha particles, including a large increase in secondary neutron production from alpha particle breakup.     

Theoretical model of HZE particle fragmentation by hydrogen targets.

The fragmenting of high energy, heavy ions (HZE particles) by hydrogen targets is an important, physical process in several areas of space radiation research. In this work quantum mechanical optical model methods for estimating cross sections for HZE particle fragmentation by hydrogen targets are presented. The cross sections are calculated using a modified abrasion-ablation collision formalism adapted from a nucleus-nucleus collision model. Elemental and isotopic production cross sections are estimated and compared with report measurements for the breakup of neon, sulphur, and iron, nuclei at incident energies between 400 and 910 MeV/nucleon. Good agreement between theory and experiment is obtained.     

Fluence-related risk coefficients using the Harderian gland data as an example.

The risk of radiation-induced cancer to space travelers outside the earth's magnetosphere will be of concern on missions to the Moon and beyond to Mars. High energy galactic cosmic rays with high charge (HZE particles) will penetrate the spacecraft and the bodies of the astronauts, sometimes fragmenting into nuclear secondary species of lower charge but always ionizing densely, thus causing cellular damage which may lead to malignant transformation. To quantitate this risk, the concept of dose equivalent (in which a quality factor Q as a function of LET is assumed) may not be adequate, since different particles of the same LET may have different efficiencies for tumor induction. Also, RBE values on which quality factors are based depend on response to low-LET radiation at low doses, a very difficult region for which to obtain reliable experimental data. Thus, we introduce a new concept, a fluence-related risk coefficient (F), which is the risk of a cancer per unit particle fluence and which we call the risk cross section. The total risk is the sum of the risk from each particle type: sigma i integral Fi(Li) phi i(Li) dLi, where Li is the LET and phi i(Li) is the fluence-LET spectrum of the ith particle type. As an example, tumor prevalence data in mice are used to estimate the probability of mouse Harderian gland tumor induction per year on an extra-magnetospheric mission inside an idealized shielding configuration of a spherical aluminum shell 1 g/cm2 thick. The combined shielding code BRYNTRN/GCR is used to generate the LET spectra at the center of the sphere. Results indicate a yearly prevalence at solar minimum conditions of 0.06, with 60% of this arising from charge components with Z between 10 and 28, and two-thirds of the contribution arising from LET components between 10 and 200 keV/micrometers.     

Effects of prolonged exposure of lettuce seeds to HZE particles on orbital stations.

In a study of the biological effects of cosmic HZE particles, lettuce (Lactuca sativa) seeds were flown on the orbital stations Salyut 6 and 7 for varying periods of time (from 40 to 457 days). The dependence of the biological damage on flight duration, physical parameters and the fact of passage of an HZE particle through the seed was estimated using the criterion of the frequency of aberrant cells. The arrangement of the flight biological container Biobloc made it possible to trace the location of tracks of individual HZE particles with Z > or = 6 and LET 200 keV/um. In seeds hit by HZE particles, for all exposure times, a statistically significant much higher yield of aberrant cells and also of cells containing multiple chromosome aberrations was observed than in the control material. The frequency of aberrant cells is markedly higher (by a factor of 1,5) in seeds hit than in non-hit ones. The changes of the yield of aberrant cells as a function of the absorbed dose (3.2-63.4 mGy) and the fluence (4.8-44.2 particles/cm2) are linear for the exposure duration ranging from 40 to 457 days.