The effects of proton radiation on UHMWPE material properties for space flight and medical applications

Ultra High Molecular Weight Polyethylene (UHMWPE) is a polymer widely used as a radiation shielding material in space flight applications and as a bearing material in total joint replacements. As a long chain hydrocarbon based polymer, UHMWPE’s material properties are influenced by radiation exposure, and prior studies show that gamma irradiation is effective for both medical sterilization and increased wear resistance in total joint replacement applications. However, the effects of space flight radiation types and doses on UHMWPE material properties are poorly understood. In this study, three clinically relevant grades of UHMWPE (GUR 1020, GUR 1050, and GUR 1020 blended with Vitamin E) were proton irradiated and tested for differences in material properties. Each of the three types of UHMWPE was irradiated at nominal doses of 0 Gy (control), 5 Gy, 10 Gy, 20 Gy, and 35 Gy. Following irradiation, uniaxial tensile testing and thermal testing using Differential Scanning Calorimetry (DSC) and Dynamic Mechanical Analysis (DMA) were performed. Results show small but significant changes in several material properties between the control (0 Gy) and 35 Gy samples, indicating that proton irradiation could have a effect on the long term performance of UHMWPE in both medical and space flight applications.     

Spaceflight-relevant types of ionizing radiation and cortical bone: Potential LET effect?

Extended exposure to microgravity conditions results in significant bone loss. Coupled with radiation exposure, this phenomenon may place astronauts at a greater risk for mission-critical fractures. In a previous study, we identified a profound and prolonged loss of trabecular bone (29–39%) in mice following exposure to an acute, 2 Gy dose of radiation simulating both solar and cosmic sources. However, because skeletal strength depends on trabecular and cortical bone, accurate assessment of strength requires analysis of both bone compartments. The objective of the present study was to examine various properties of cortical bone in mice following exposure to multiple types of spaceflight-relevant radiation. Nine-week old, female C57BL/6 mice were sacrificed 110 days after exposure to a single, whole body, 2 Gy dose of gamma, proton, carbon, or iron radiation. Femora were evaluated with biomechanical testing, microcomputed tomography, quantitative histomorphometry, percent mineral content, and micro-hardness analysis. Compared to non-irradiated controls, there were significant differences compared to carbon or iron radiation for only fracture force, medullary area and mineral content. A greater differential effect based on linear energy transfer (LET) level may be present: high-LET (carbon or iron) particle irradiation was associated with a decline in structural properties (maximum force, fracture force, medullary area, and cortical porosity) and mineral composition compared to low-LET radiation (gamma and proton). Bone loss following irradiation appears to be largely specific to trabecular bone and may indicate unique biological microenvironments and microdosimetry conditions. However, the limited time points examined and non-haversian skeletal structure of the mice employed highlight the need for further investigation.     

Haemopoietic cell renewal in radiation fields.

Space flight activities are inevitably associated with a chronic exposure of astronauts to a complex mixture of ionising radiation. Although no acute radiation consequences are to be expected as a rule, the possibility of Solar Particle Events (SPE) associated with relatively high doses of radiation (1 or more Gray) cannot be excluded. It is the responsibility of physicians in charge of the health of astronauts to evaluate before, during and after space flight activities the functional status of haemopoietic cell renewal. Chronic low level exposure of dogs indicate that daily gamma-exposure doses below about 2 cGy are tolerated for several years as far as blood cell concentrations are concerned. However, the stem cell pool may be severely affected. The maintenance of sufficient blood cell counts is possible only through increased cell production to compensate for the radiation inflicted excess cell loss. This behaviour of haemopoietic cell renewal during chronic low level exposure can be simulated by bioengineering models of granulocytopoiesis. It is possible to define a "turbulence region" for cell loss rates, below which an prolonged adaptation to increased radiation fields can be expected to be tolerated. On the basis of these experimental results, it is recommended to develop new biological indicators to monitor haemopoietic cell renewal at the level of the stem cell pool using blood stem cells in addition to the determination of cytokine concentrations in the serum (and other novel approaches). To prepare for unexpected haemopoietic effects during prolonged space missions, research should be increased to modify the radiation sensitivity of haemopoietic stem cells (for instance by the application of certain regulatory molecules). In addition, a "blood stem cell bank" might be established for the autologous storage of stem cells and for use in space activities keeping them in a radiation protected container.     

Radioprotection by metals: selenium.

The need exists for compounds that will protect individuals from high-dose acute radiation exposure in space and the agents that might be less protective but less toxic and longer acting. Metals and metal derivatives provide a small degree of radioprotection (dose reduction factor < or = 1.2 for animal survival after whole-body irradiation). Emphasis is placed here on the radioprotective potential of selenium (Se). Both the inorganic salt, sodium selenite, and the organic Se compound, selenomethionine, enhance the survival of irradiated mice (60Co, 0.2 Gy/min) when injected IP either before (-24 hr and -1 hr) or shortly after (+15 min) radiation exposure. When administered at equitoxic doses (one-fourth LD10; selenomethionine = 4.0 mg/kg Se, sodium selenite = 0.8 mg/kg Se), both drugs enhanced the 30-day survival of mice irradiated at 9 Gy. Survival after 10-Gy exposure was significantly increased only after selenomethionine treatment. An advantage of selenomethionine is lower lethal and behavioral toxicity (locomotor activity depression) compared to sodium selenite, when they are administered at equivalent doses of Se. Sodium selenite administered in combination with WR-2721, S-2-(3-aminopropylamino)ethylphosphorothioic acid, enhances the radioprotective effect and reduces the lethal toxicity, but not the behavioral toxicity, of WR-2721. Other studies on radioprotection and protection against chemical carcinogens by different forms of Se are reviewed. As additional animal data and results from human chemoprevention trials become available, consideration also can be given to prolonged administration of Se compounds for protection against long-term radiation effects in space.     

Estimation of a cosmonaut's radiation hazard during long-term space missions on the basis of a generalized dosimetric function.

This paper presents a new concept of radiation hazard assessment for spacecraft crew members during long term space missions on the basis of a generalized dosimetric function. This new dosimetric function enables a complicated nature of space radiation exposure to be reduced to the conditions of a standard irradiation. It can be obtained on the basis of mean-tissue equivalent dose values calculated for each space radiation source and transmission coefficients describing the influence of the complex spatial and temporal distribution of the absorbed dose in the cosmonaut's body on the radiobiological effects. The combination of cosmic ionizing radiation with other non-radiation nature factors in flight can also be accounted for. In terms of the generalized dose, it is possible to assess the nature and extent of lowering a crew working capacity, as well as radiation risk, both during a flight and post flight period.     

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.     

Comparison of genotoxic damage in monolayer cell cultures and three-dimensional tissue-like cell assemblies

Assessing the biological risks associated with exposure to the high-energy charged particles encountered in space is essential for the success of long-term space exploration. Although prokaryotic and eukaryotic cell models developed in our laboratory and others have advanced our understanding of many aspects of genotoxicity, in vitro models are needed to assess the risk to humans from space radiation insults. Such models must be representative of the cellular interactions present in tissues and capable of quantifying genotoxic damage. Toward this overall goal, the objectives of this study were to examine the effect of the localized microenvironment of cells, cultured as either 2-dimensional (2D) monolayers or 3-dimensional (3D) aggregates, on the rate and type of genotoxic damage resulting from exposure to Fe-charged particles, a significant portion of space radiation. We used rodent transgenic cell lines containing 50–70 copies of a LacI transgene to provide the enhanced sensitivity required to quantify mutational frequency and type in the 1100-bp LacI target as well as assessment of DNA damage to the entire 45-kbp construct. Cultured cells were exposed to high-energy Fe charged particles at Brookhaven National Laboratory’s Alternating Gradient Synchrotron facility for a total dose ranging from 0.1 to 2 Gy and allowed to recover for 0–7 days, after which mutational type and frequency were evaluated. The mutational frequency was found to be higher in 3D samples than in 2D samples at all radiation doses. Mutational frequency also was higher at 7 days after irradiation than immediately after exposure. DNA sequencing of the mutant targets revealed that deletional mutations contributed an increasingly high percentage (up to 27%) of all mutations in cells as the dose was increased from 0.5 to 2 Gy. Several mutants also showed large and complex deletions in multiple locations within the LacI target. However, no differences in mutational type were found between the 2D and the 3D samples. These 3D tissue-like model systems can reduce the uncertainty involved in extrapolating risk between in vitro cellular and in vivo models.     

Modeling of the radiation exposure during the flight of the second Bulgarian cosmonaut on board the Mir Space Station.

An experiment involving active detection of space radiation was carried out in the Space Research Institute (SRI) of Bulgarian Academy of Sciences, in preparation of the flight of the second Bulgarian cosmonaut. The radiations that would be encountered on the flight were modelled including solar and galactic cosmic rays and the particle radiation in the Earth's radiation belts. The dose rate was calculated for these different radiations behind the shielding of the space station. The variations in dose rates over the period of the flight were calculated and compared with measurements made during the orbit of the Mir Space Station. The calculated and measured dose rates agreed within 15-35%.     

Deterministic pion and muon transport in Earth’s atmosphere

An accurate understanding of the physical interactions and transport of space radiation is important for safe and efficient space operations. Secondary particles produced by primary particle interactions with intervening materials are an important contribution to radiation risk. Pions are copiously produced in the nuclear interactions typical of space radiations and can therefore be an important contribution to radiation exposure. Charged pions decay almost exclusively to muons. As a consequence, muons must also be considered in space radiation exposure studies. In this work, the NASA space radiation transport code HZETRN has been extended to include the transport of charged pions and muons. The relevant transport equation, solution method, and implemented cross sections are reviewed. Muon production in the Earth’s upper atmosphere is then investigated, and comparisons with recent balloon flight measurements of differential muon flux are presented. Muon production from the updated version of HZETRN is found to match the experimental data well.     

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.     

航天员受银河宇宙线辐射的剂量计算

在近地空间(LEO)和深空探测中,航天员遭受的辐射风险主要来自于银河宇宙线(GCR)照射.银河宇宙线的辐射剂量是航天员辐射风险评价的基础.国际放射防护委员会(ICRP)于2013年提出了新的航天员空间辐射剂量估算方法,以更准确给出空间重离子辐射的剂量.基于此方法,开发了宇宙线粒子在物质中输运的蒙特卡罗程序,并在程序中实现用中国成年男性人体数字模型来仿真航天员.采用该程序计算了粒子(Z=1~92)各向同性照射航天员时器官的通量-器官剂量转换因数,并估算出航天员在近地轨道空间受银河宇宙线辐射的剂量.     

Space environmental factors affecting responses to radiation at the cellular level.

Previous space experiments suggest a high value for the RBE of cosmic radiation. A possible explanation could be a change in cell radiosensitivity due to a combined effect of radiation and other factors related to the space environment and to the space flight. Results of the EXOBLOC II experiment support this assumption. On earth, vibrations or accelerations applied before or after irradiation can change the responses to radiation. Microgravity could be the main factor affecting the radiosensitivity and DNA repair but this hypothesis must be confirmed by additional experiments.     

Radiation-induced apoptosis in scid mice spleen after low dose irradiation.

To assess the radioadaptive response of the whole body system in mice, we examined the temporal effect of low dose priming as an indicator of challenging irradiation-induced apoptosis through a p53 tumor suppressor protein- mediated signal transduction pathway. The p53 protein also plays an important role both in cell cycle control and DNA repair through cellular signal transduction. Using severe combined immunodeficiency mice defective in DNA-dependent protein kinase catalytic subunit, we examined the role of DNA-dependent protein kinase activity in radioadaptation induced by low dose irradiation. Specific pathogen free 5-week-old female severe combined immunodeficiency mice and the parental mice (CB- 17 Icr +/+) were irradiated with X-ray at 3.0 Gy at 1, 2, 3 or 4 weeks after the conditioning irradiation at 0.15, 0.30, 0.45 or 0.60 Gy. The mice spleens were fixed for immunohistochemistry 12 h after the challenging irradiation. The p53-dependent apoptosis related Bax proteins on formalin-fixed paraffin-embedded sections were stained by the avidin-biotin peroxidase complex method. The apoptosis incidence in the sections was measured by hematoxylin-eosin staining. The frequency of Bax- and apoptosis-positive cells increased up to 12 h after the challenging irradiation in the spleen of both mice. However, these cells were not observed after a low dose irradiation at 0.15-0.60 Gy. When pre-irradiation at 0.45 Gy 2 weeks before the challenging irradiation at 3.0 Gy was performed, Bax accumulation and apoptosis induced by challenging irradiation were depressed in the spleens of CB-17 Icr +/+ mice, but not in severe combined immunodeficiency mice. These data suggest that DNA-dependent protein kinase might play a major role in radioadaptation induced by pre-irradiation with a low dose in mice spleen. We expect that the present findings will provide useful information in the health care of space crews.     

The effects of heavy particle irradiation on exploration and response to environmental change.

Free radicals produced by exposure to heavy particles have been found to produce motor and cognitive behavioral toxicity effects in rats similar to those found during aging. The present research was designed to investigate the effects of exposure to 56Fe particles on the ability of male Sprague-Dawley rats to detect novel arrangements in a given environment. Using a test of spatial memory previously demonstrated to be sensitive to aging, open field activity and reaction to spatial and non-spatial changes were measured in a group that received a dose of 1.5 Gy (n=10) of 56Fe heavy particle radiation or in non-radiated controls (n=10). Animals irradiated with 1.5 Gy of 56Fe particles exhibited some age-like effects in rats tested, even though they were, for the most part, subtle. Animals took longer to enter, visited less and spent significantly less time in the middle and the center portions of the open field, independently of total frequency and duration of activity of both groups. Likewise, irradiated subjects spend significantly more time exploring novel objects placed in the open field than did controls. However, irradiated subjects did not vary from controls in their exploration patterns when objects in the open field were spatially rearranged. Thus, irradiation with a dose of 1.5 Gy of 56Fe high-energy particle radiation elicited age-like effects in general open field exploratory behavior, but did not elicit age-like effects during the spatial and non-spatial rearrangement tasks.     

Long term effects of low doses of 56Fe ions on the brain and retina of the mouse: ultrastructural and behavioral studies.

Eight month old male C57BL6 mice were exposed without anesthesia to whole-body irradiation in circular holders. The mice were tested for behavioral decrements after 0.5 and 50 rads of Fe particle irradiation at 6 and 12 months post irradiation to obtain long term results. A standard maze was used and the animals were timed for completion thereof. A string test also was administered to the mice, testing their ability to grasp and move along a string to safety. The results from animals exposed to 50 rads were significantly different from [correction of fron] control results to p = < .001 in both systems of testing. The hippocampus (believed to be the location of environmental interaction in the brain) and the retina were examined for ultrastructural changes. The ultrastructural changes were similar to those we found in our Cosmos 782, 936 and in our Argon experiments. The mouse data indicate that iron particles were able to induce long term changes in the central nervous system which lead to behavioral impairment.     

Radiation hazards on space missions outside the magnetosphere.

Future space missions outside the magnetosphere will subject astronauts to a hostile and unfamiliar radiation environment. An annual dose equivalent to the blood-forming organs (BFOs) of approximately 0.5 Sv is expected, mostly from heavy ions in the galactic cosmic radiation. On long-duration missions, an anomalously-large solar energetic particle event may occur. Such an event can expose astronauts to up to approximately 25 Gy (skin dose) and up to approximately 2 Sv (BFO dose) with no shielding. The anticipated radiation exposure may necessitate spacecraft design concessions and some restriction of mission activities. In this paper we discuss our model calculations of radiation doses in several exo-magnetospheric environments. Specific radiation shielding strategies are discussed. A new calculation of aluminum equivalents of potential spacecraft shielding materials demonstrates the importance of low-atomic-mass species for protection from galactic cosmic radiation.     

In vivo and in vitro measurements of complex-type chromosomal exchanges induced by heavy ions.

Heavy ions are more efficient in producing complex-type chromosome exchanges than sparsely ionizing radiation, and this can potentially be used as a biomarker of radiation quality. We measured the induction of complex-type chromosomal aberrations in human peripheral blood lymphocytes exposed in vitro to accelerated H-, He-, C-, Ar-, Fe- and Au-ions in the LET range of approximately 0.4-1400 keV/micrometers. Chromosomes were analyzed either at the first post-irradiation mitosis, or in interphase, following premature condensation by phosphatase inhibitors. Selected chromosomes were then visualized after FISH-painting. The dose-response curve for the induction of complex-type exchanges by heavy ions was linear in the dose-range 0.2-1.5 Gy, while gamma-rays did not produce a significant increase in the yield of complex rearrangements in this dose range. The yield of complex aberrations after 1 Gy of heavy ions increased up to an LET around 100 keV/micrometers, and then declined at higher LET values. When mitotic cells were analyzed, the frequency of complex rearrangements after 1 Gy was about 10 times higher for Ar- or Fe- ions (the most effective ions, with LET around 100 keV/micrometers) than for 250 MeV protons, and values were about 35 times higher in prematurely condensed chromosomes. These results suggest that complex rearrangements may be detected in astronauts' blood lymphocytes after long-term space flight, because crews are exposed to HZE particles from galactic cosmic radiation. However, in a cytogenetic study of ten astronauts after long-term missions on the Mir or International Space Station, we found a very low frequency of complex rearrangements, and a significant post-flight increase was detected in only one out of the ten crewmembers. It appears that the use of complex-type exchanges as biomarker of radiation quality in vivo after low-dose chronic exposure in mixed radiation fields is hampered by statistical uncertainties.     

Experimental simulation of proton space radiation environments: a dosimetric perspective.

Three-dimensional dose calculation techniques developed for radiotherapy treatment planning were used to calculate dose distributions from unidirectional, planar rotational and omnidirectional incident radiation (experimental proton beams and solar flares). The calculations predicted regions of high dose within primate heads exposed to 55-MeV protons, supporting the postulate of radiation-induced brain tumors within this population. Comparisons among predicted doses to the human head from solar flares of three different energies demonstrated differences between unidirectional and omnidirectional irradiation in the space environment. The results can be used to estimate dose distributions based on a) limited phantom measurements, or b) nonuniformly incident radiation in orbit; both situations are difficult to replicate under laboratory exposure conditions.     

Protective effects of melatonin against C beam irradiation-induced oxidative stress and DNA injury in the mouse brain

The purpose of this experiment was to estimate the protective effects of melatonin against radiation-induced brain damages in mice induced by heavy ion beams. Kun-Ming mice were randomly divided into five groups: normal control group, irradiation control group, and three different doses of melatonin (5, 10, and 20 mg/kg, i.p.) treated groups. Apart from the normal control group, the other four groups were exposed to whole-body 4.0 Gy carbon ion beam irradiation (approximately 0.5 Gy/min) after i.p. administration of normal saline or melatonin 1 h before irradiation. The oxidative redox status of brain tissue was assessed by measurement of malondiadehyde (MDA) levels, total superoxide dismutase (T-SOD), cytosolic superoxide dismutase (Cu/ZnSOD, SOD1) and mitochondrial superoxide dismutase (MnSOD, SOD2) activities at 8 h after irradiation. DNA damages were determined using the Comet assay and apoptosis and cell cycle distribution were detected by flow cytometric analyses. A dramatic dose-dependent decrease in MDA levels, tail moment, rates of tailing cells, and apoptosis, and a dose-dependent increase in T-SOD and SOD2 activities, in brain tissues in the melatonin-treated groups were detected compared with the irradiation only group. Furthermore, flow cytometric analysis demonstrated that the percentage of brain cells in the G0/G1 phase decreased significantly, while those in the S and G2/M stage increased dramatically, with mice pretreated with melatonin compared to the irradiation control group. These data indicate that melatonin has protective effects against irradiation-induced brain injury, and that its underlying protective mechanisms may relate to modulation of oxidative stress induced by heavy ionirradiation.     

Development of human epithelial cell systems for radiation risk assessment.

The most important health effect of space radiation for astronauts is cancer induction. For radiation risk assessment, an understanding of carcinogenic effect of heavy ions in human cells is most essential. In our laboratory, we have successfully developed a human mammary epithelial cell system for studying the neoplastic transformation in vitro. Growth variants were obtained from heavy ion irradiated immortal mammary cell line. These cloned growth variants can grow in regular tissue culture media and maintain anchorage dependent growth and density inhibition property. Upon further irradiation with high-LET radiation, transformed foci were found. Experimental results from these studies suggest that multiexposure of radiation is required to induce neoplastic transformation of human epithelial cells. This multihits requirement may be due to high genomic stability of human cells. These growth variants can be useful model systems for space flight experiments to determine the carcinogenic effect of space radiation in human epithelial cells.