A New Approach to Reduce Uncertainties in Space Radiation Cancer Risk Predictions

The prediction of space radiation induced cancer risk carries large uncertainties with two of the largest uncertainties being radiation quality and dose-rate effects. In risk models the ratio of the quality factor (QF) to the dose and dose-rate reduction effectiveness factor (DDREF) parameter is used to scale organ doses for cosmic ray proton and high charge and energy (HZE) particles to a hazard rate for γ-rays derived from human epidemiology data. In previous work, particle track structure concepts were used to formulate a space radiation QF function that is dependent on particle charge number Z, and kinetic energy per atomic mass unit, E. QF uncertainties where represented by subjective probability distribution functions (PDF) for the three QF parameters that described its maximum value and shape parameters for Z and E dependences. Here I report on an analysis of a maximum QF parameter and its uncertainty using mouse tumor induction data. Because experimental data for risks at low doses of γ-rays are highly uncertain which impacts estimates of maximum values of relative biological effectiveness (RBE_max), I developed an alternate QF model, denoted QF_γAcute where QFs are defined relative to higher acute γ-ray doses (0.5 to 3 Gy). The alternate model reduces the dependence of risk projections on the DDREF, however a DDREF is still needed for risk estimates for high-energy protons and other primary or secondary sparsely ionizing space radiation components. Risk projections (upper confidence levels (CL)) for space missions show a reduction of about 40% (CL∼50%) using the QF_γAcute model compared the QFs based on RBE_max and about 25% (CL∼35%) compared to previous estimates. In addition, I discuss how a possible qualitative difference leading to increased tumor lethality for HZE particles compared to low LET radiation and background tumors remains a large uncertainty in risk estimates.     

Countermeasures against space radiation induced oxidative stress in mice

Of particular concern for the health of astronauts during space travel is radiation from protons and high atomic number (Z), high energy particles (HZE particles). Space radiation is known to induce oxidative stress in astronauts after extended space flight. In the present study, the total antioxidant status was used as a biomarker to evaluate oxidative stress induced by proton and HZE particle radiation in the plasma of CBA mice and the protective effect of dietary supplement agents. The results indicate that exposure to proton and HZE particle radiation significantly decreased the plasma level of total antioxidants in the irradiated CBA mice. Dietary supplementation with l-selenomethionine (SeM) or a combination of selected antioxidant agents (which included SeM) could partially or completely prevent the decrease in the total antioxidant status in the plasma of animals exposed to proton or HZE particle radiation. These findings suggest that exposure to space radiation may compromise the capacity of the host antioxidant defense system; this adverse biological effect can be prevented at least partially by dietary supplementation with agents expected to have effects on antioxidant activities.     

Updates to astronaut radiation limits: radiation risks for never-smokers

New epidemiology assessments of the life span study (LSS) of the atomic bomb survivors in Japan and of other exposed cohorts have been made by the U.S. National Academy of Sciences, the United Nations Committee on the Effects of Atomic Radiation, and the Radiation Research Effects Foundation in Japan. The National Aeronautics and Space Administration (NASA) uses a 3% risk of exposure-induced death (REID) as a basis for setting age- and gender-specific dose limits for astronauts. NASA's dose limits originate from the report of the National Council on Radiation Protection and Measurements (NCRP) in the year 2000 based on analysis of older epidemiology data. We compared the results of the recent analysis of the LSS to the earlier risk projections from the NCRP. Using tissue-specific, incidence-based risk transfer from the LSS data to a U.S. population to project REID values leads to higher risk and reduced dose limits for older astronauts (>40 years) compared to earlier models that were based on mortality risk transfer. Because astronauts and many other individuals should be considered as healthy workers, including never-smokers free of lifetime use of tobacco, we considered possible variations in risks and dose limits that would occur due to the reference population used for estimates. After adjusting cancer rates to remove smoking effects, radiation risks for lung and total cancer were estimated using a mixture model, with equal weights for additive and multiplicative transfer, to be 20% and 30% lower for males and females, respectively, for never-smokers compared to the average U.S. population. We recommend age- and gender-specific dose limits based on incidence-based risk transfer for never-smokers that could be used by NASA. Our analysis illustrates that gaining knowledge to improve transfer models, which entail knowledge of cancer initiation and promotion effects, could significantly reduce uncertainties in risk projections.     

Selenomethionine protects against adverse biological effects induced by space radiation

Ionizing radiation-induced adverse biological effects impose serious challenges to astronauts during extended space travel. Of particular concern is the radiation from highly energetic, heavy, charged particles known as HZE particles. The objective of the present study was to characterize HZE particle radiation-induced adverse biological effects and evaluate the effect of D-selenomethionine (SeM) on the HZE particle radiation-induced adverse biological effects. The results showed that HZE particle radiation can increase oxidative stress, cytotoxicity, and cell transformation in vitro, and decrease the total antioxidant status in irradiated Sprague-Dawley rats. These adverse biological effects were all preventable by treatment with SeM, suggesting that SeM is potentially useful as a countermeasure against space radiation-induced adverse effects. Treatment with SeM was shown to enhance ATR and CHK2 gene expression in cultured human thyroid epithelial cells. As ionizing radiation is known to result in DNA damage and both ATR and CHK2 gene products are involved in DNA damage, it is possible that SeM may prevent HZE particle radiation-induced adverse biological effects by enhancing the DNA repair machinery in irradiated cells.     

Cell science and protein crystal growth research for the International Space Station

The recent National Research Council report, Future Biotechnology Research on the International Space Station, evaluates NASA's plans for research in cell science and protein crystal growth to be conducted on the International Space Station. This report concludes that the NASA biotechnology programs have the potential to significantly impact relevant scientific fields and to increase understanding and insight into fundamental biological issues. In order to realize the potential impacts, NASA must focus its research programs by selecting specific questions related to gravitational forces' role in cell behavior and by using the microgravity environment as a tool to determine the structure of macromolecules with important biological implications. Given the time and volume constraints associated with space-based experiments, instrumentation to be used on the space station must be designed to maximize the productivity of researchers, and NASA's recruitment of investigators and support for space station experiments should aim to encourage and facilitate cutting-edge research.     

Space radiation research in Europe: flight experiments and ground-based studies

Exposure to space radiation has long been acknowledged as a potential showstopper for long-duration manned interplanetary missions. In an effort to gain more information on space radiation risk and to develop countermeasures, NASA initiated several years ago a Space Radiation Health Program, which is currently supporting biological experiments performed at the Brookhaven National Laboratory. Accelerator-based radiobiology research in the field of space radiation research is also under way in Russia and Japan. The European Space Agency (ESA) supports research in the field in three main directions: spaceflight experiments on the International Space Station; modeling and simulations of the space radiation environment and transport; and, recently, ground-based radiobiology experiments exploiting the high-energy SIS18 synchrotron at GSI in Germany (IBER program). Several experiments are currently under way within IBER, and so far, beams of C and Fe-ions at energies between 11 and 1,000 MeV/n have been used in cell and tissue targets.     

Effects of very low fluences of high-energy protons or iron ions on irradiated and bystander cells

In space, astronauts are exposed to radiation fields consisting of energetic protons and high atomic number, high-energy (HZE) particles at very low dose rates or fluences. Under these conditions, it is likely that, in addition to cells in an astronaut's body being traversed by ionizing radiation particles, unirradiated cells can also receive intercellular bystander signals from irradiated cells. Thus this study was designed to determine the dependence of DNA damage induction on dose at very low fluences of charged particles. Novel techniques to quantify particle fluence have been developed at the NASA Space Radiation Biology Laboratory (NSRL) at Brookhaven National Laboratory (BNL). The approach uses a large ionization chamber to visualize the radiation beam coupled with a scintillation counter to measure fluence. This development has allowed us to irradiate cells with 1 GeV/nucleon protons and iron ions at particle fluences as low as 200 particles/cm(2) and quantify biological responses. Our results show an increased fraction of cells with DNA damage in both the irradiated population and bystander cells sharing medium with irradiated cells after low fluences. The fraction of cells with damage, manifest as micronucleus formation and 53BP1 focus induction, is about 2-fold higher than background at doses as low as ～0.47 mGy iron ions (～0.02 iron ions/cell) or ～70 μGy protons (～2 protons/cell). In the irradiated population, irrespective of radiation type, the fraction of damaged cells is constant from the lowest damaging fluence to about 1 cGy, above which the fraction of damaged cells increases with dose. In the bystander population, the level of damage is the same as in the irradiated population up to 1 cGy, but it does not increase above that plateau level with increasing dose. The data suggest that at fluences of high-energy protons or iron ions less than about 5 cGy, the response in irradiated cell populations may be dominated by the bystander response.     

The effects of low-dose, high-LET radiation exposure on three models of behavior in C57BL/6 mice

To investigate the behavioral consequences of exposure to whole-body irradiation such as might occur for astronauts during space flight, female C57BL/6 mice were exposed to 0, 0.1, 0.5 or 2 Gy accelerated iron ions (56Fe, Z = 26, beta = 0.9, LET = 148.2 keV/microm) of 1 GeV per nucleon using the Alternating Gradient Synchrotron at the Brookhaven National Laboratory. Animal testing began 2 weeks after exposure and continued for 8 weeks. Under these conditions, there were few significant effects of radiation on open-field, rotorod or acoustic startle activities at any of the times examined. The lack of radiation effects in these behavioral models appears to offer reassurance to NASA mission designers. These results suggest that there may be negligible effects of HZE radiation on many behaviors during a 2-8-week period immediately after radiation.     

Initiation-promotion model of tumor prevalence in mice from space radiation exposures

Exposures in space consist of low-level background components from galactic cosmic rays (GCR), occasional intense-energetic solar-particle events, periodic passes through geomagnetic-trapped radiation, and exposure from possible onboard nuclear-propulsion engines. Risk models for astronaut exposure from such diverse components and modalities must be developed to assure adequate protection in future. NASA missions. The low-level background exposures (GCR), including relativistic heavy ions (HZE), will be the ultimate limiting factor for astronaut career exposure. We consider herein a two-mutation, initiation-promotion, radiation-carcinogenesis model in mice in which the initiation stage is represented by a linear kinetics model of cellular repair/misrepair, including the track-structure model for heavy ion action cross-sections. The model is validated by comparison with the harderian gland tumor experiments of Alpen et al. for various ion beams. We apply the initiation-promotion model to exposures from galactic cosmic rays, using models of the cosmic-ray environment and heavy ion transport, and consider the effects of the age of the mice prior to and after the exposure and of the length of time in space on predictions of relative risk. Our results indicate that biophysical models of age-dependent radiation hazard will provide a better understanding of GCR risk than models that rely strictly on estimates of the initial slopes of these radiations.Submitted paper presented at the International Symposium on Heavy Ion Research: Space, Radiation Protection and Therapy, Sophia-Antipolis, France, 21–24 March 1994     

Mechanism of cluster DNA damage repair in response to high-atomic number and energy particles radiation

Low-linear energy transfer (LET) radiation (i.e., γ- and X-rays) induces DNA double-strand breaks (DSBs) that are rapidly repaired (rejoined). In contrast, DNA damage induced by the dense ionizing track of high-atomic number and energy (HZE) particles is slowly repaired or is irreparable. These unrepaired and/or misrepaired DNA lesions may contribute to the observed higher relative biological effectiveness for cell killing, chromosomal aberrations, mutagenesis, and carcinogenesis in HZE particle irradiated cells compared to those treated with low-LET radiation. The types of DNA lesions induced by HZE particles have been characterized in vitro and usually consist of two or more closely spaced strand breaks, abasic sites, or oxidized bases on opposing strands. It is unclear why these lesions are difficult to repair. In this review, we highlight the potential of a new technology allowing direct visualization of different types of DNA lesions in human cells and document the emerging significance of live-cell imaging for elucidation of the spatio-temporal characterization of complex DNA damage. We focus on the recent insights into the molecular pathways that participate in the repair of HZE particle-induced DSBs. We also discuss recent advances in our understanding of how different end-processing nucleases aid in repair of DSBs with complicated ends generated by HZE particles. Understanding the mechanism underlying the repair of DNA damage induced by HZE particles will have important implications for estimating the risks to human health associated with HZE particle exposure.     

Radiobiological problems in space

Summary An overview is presented on radiation problems in space, with emphasis on aspects of major interest for manned space exploration. A classification of the radiation hazards is presented and strategies for their evaluation are discussed. Space radiation problems are compared with characteristic aspects of radiation research in other disciplines, in order to provide further insight into those aspects that are unique to space.The research described in this paper was carried out while the author was a NASA VisitingThe research described in this paper was carried out while the author was a NASA VisitingThe research described in this paper was carried out while the author was a NASA VisitingThe research described in this paper was carried out while the author was a NASA Visiting     

Relative Biological Effectiveness of HZE Particles for Chromosomal Exchanges and Other Surrogate Cancer Risk Endpoints

The biological effects of high charge and energy (HZE) particle exposures are of interest in space radiation protection of astronauts and cosmonauts, and estimating secondary cancer risks for patients undergoing Hadron therapy for primary cancers. The large number of particles types and energies that makeup primary or secondary radiation in HZE particle exposures precludes tumor induction studies in animal models for all but a few particle types and energies, thus leading to the use of surrogate endpoints to investigate the details of the radiation quality dependence of relative biological effectiveness (RBE) factors. In this report we make detailed RBE predictions of the charge number and energy dependence of RBE’s using a parametric track structure model to represent experimental results for the low dose response for chromosomal exchanges in normal human lymphocyte and fibroblast cells with comparison to published data for neoplastic transformation and gene mutation. RBE’s are evaluated against acute doses of γ-rays for doses near 1 Gy. Models that assume linear or non-targeted effects at low dose are considered. Modest values of RBE (<10) are found for simple exchanges using a linear dose response model, however in the non-targeted effects model for fibroblast cells large RBE values (>10) are predicted at low doses <0.1 Gy. The radiation quality dependence of RBE’s against the effects of acute doses γ-rays found for neoplastic transformation and gene mutation studies are similar to those found for simple exchanges if a linear response is assumed at low HZE particle doses. Comparisons of the resulting model parameters to those used in the NASA radiation quality factor function are discussed.     

Radiation protection: the NCRP guidelines and some considerations for the future.

The National Council on Radiation Protection and Measurements (NCRP) in the USA and the International Commission on Radiological Protection (ICRP), worldwide, were formed about 1928 and have since made recommendations on appropriate levels of protection from ionizing radiation for workers and for the public. These recommendations and much of the guidance provided by these organizations have usually been adopted by regulatory bodies around the world. In the case of the NCRP, the levels have fallen from 0.1 roentgen per day in 1934 to the current 5 rem per year (a factor of about 5). The present levels recommended by both the ICRP and the NCRP correspond to reasonable levels of risk where the risks of harm from ionizing radiation are compared with the hazards of other, commonly regarded, as safe, industries. Some considerations for the future in radiation protection include trends in exposure levels (generally downward for the average exposure to workers) and improvements in risk estimation; questions of lifetime limits, de minimis levels, and partial body exposures; plus problems of high LET radiations, acceptability of risk, synergisms, and risk systems for protection.     

Enhanced intestinal tumor multiplicity and grade in vivo after HZE exposure: mouse models for space radiation risk estimates

Carcinogenesis induced by space radiation is considered a major risk factor in manned interplanetary and other extended missions. The models presently used to estimate the risk for cancer induction following deep space radiation exposure are based on data from A-bomb survivor cohorts and do not account for important biological differences existing between high-linear energy transfer (LET) and low-LET-induced DNA damage. High-energy and charge (HZE) radiation, the main component of galactic cosmic rays (GCR), causes highly complex DNA damage compared to low-LET radiation, which may lead to increased frequency of chromosomal rearrangements, and contribute to carcinogenic risk in astronauts. Gastrointestinal (GI) tumors are frequent in the United States, and colorectal cancer (CRC) is the third most common cancer accounting for 10% of all cancer deaths. On the basis of the aforementioned epidemiological observations and the frequency of spontaneous precancerous GI lesions in the general population, even a modest increase in incidence by space radiation exposure could have a significant effect on health risk estimates for future manned space flights. Ground-based research is necessary to reduce the uncertainties associated with projected cancer risk estimates and to gain insights into molecular mechanisms involved in space-induced carcinogenesis. We investigated in vivo differential effects of γ-rays and HZE ions on intestinal tumorigenesis using two different murine models, ApcMin/+ and Apc1638N/+. We showed that γ- and/or HZE exposure significantly enhances development and progression of intestinal tumors in a mutant-line-specific manner, and identified suitable models for in vivo studies of space radiation–induced intestinal tumorigenesis.     

EVA dosimetry in manned spacecraft

Extra Vehicular Activity (EVA) will become a large part of the astronaut's work on board the International Space Station (ISS). It is already well known that long duration space missions inside a spacecraft lead to radiation doses which are high enough to be a significant health risk to the crew. The doses received during EVA, however, have not been quantified to the same degree. This paper reviews the space radiation environment and the current dose limits to critical organs. Results of preliminary radiation dosimetry experiments on the external surface of the BION series of satellites indicate that EVA doses will vary considerably due to a number of factors such as EVA suit shielding, temporal fluctuations and spacecraft orbit and shielding. It is concluded that measurement of doses to crew members who engage in EVA should be done on board the spacecraft. An experiment is described which will lead the way to implementing this plan on the ISS. It is expected that results of this experiment will help future crew mitigate the risks of ionising radiation in space.     

Effects of dietary supplements on space radiation-induced oxidative stress in Sprague-Dawley rats

Of particular concern for the health of astronauts during space travel is radiation from protons and high-mass, high-atomic-number (Z), and high-energy particles (HZE particles). Space radiation is known to induce oxidative stress in astronauts after extended space flight. In the present study, the total antioxidant status was used as a biomarker to evaluate oxidative stress induced by gamma rays, protons and HZE-particle radiation. The results demonstrate that the plasma level of total antioxidants in Sprague-Dawley rats was significantly decreased (P < 0.01) in a dose-dependent manner within 4 h after exposure to gamma rays. Exposure to protons and HZE-particle radiation also significantly decreased the serum or plasma level of total antioxidants in the irradiated animals. Diet supplementation with L-selenomethionine alone or a combination of selected antioxidant agents was shown to partially or completely prevent the decrease in the serum or plasma levels of total antioxidants in animals exposed to gamma rays, protons or HZE particles. These findings suggest that exposure to space radiation may compromise the capacity of the host antioxidant defense and that this adverse biological effect can be prevented at least partially by dietary supplementation with L-selenomethionine and antioxidants.     

How Safe Is Safe Enough? Radiation Risk for a Human Mission to Mars

Astronauts on a mission to Mars would be exposed for up to 3 years to galactic cosmic rays (GCR) — made up of high-energy protons and high charge (Z) and energy (E) (HZE) nuclei. GCR exposure rate increases about three times as spacecraft venture out of Earth orbit into deep space where protection of the Earth''s magnetosphere and solid body are lost. NASA''s radiation standard limits astronaut exposures to a 3% risk of exposure induced death (REID) at the upper 95% confidence interval (CI) of the risk estimate. Fatal cancer risk has been considered the dominant risk for GCR, however recent epidemiological analysis of radiation risks for circulatory diseases allow for predictions of REID for circulatory diseases to be included with cancer risk predictions for space missions. Using NASA''s models of risks and uncertainties, we predicted that central estimates for radiation induced mortality and morbidity could exceed 5% and 10% with upper 95% CI near 10% and 20%, respectively for a Mars mission. Additional risks to the central nervous system (CNS) and qualitative differences in the biological effects of GCR compared to terrestrial radiation may significantly increase these estimates, and will require new knowledge to evaluate.     

Radiation protection in space

The challenge for planning radiation protection in space is to estimate the risk of events of low probability after low levels of irradiation. This work has revealed many gaps in our knowledge that require further study. Despite investigations of several irradiated populations, the atomic-bomb survivors remain the primary basis for estimating the risk of ionizing radiation. Compared with previous estimates, two new independent evaluations of available information indicate a significantly greater risk of stochastic effects of radiation (cancer and genetic effects) by about a factor of three for radiation workers, including space travelers. This paper presents a brief historical perspective of the international effort to assure radiation protection in space.Invited paper presented at the International Symposium on Heavy Ion Research: Space, Radiation Protection and Therapy, Sophia-Antipolis, France, 21–24 March 1994     

Technical developments at the NASA Space Radiation Laboratory

The NASA Space Radiation Laboratory (NSRL) located at Brookhaven National Laboratory (BNL) is a center for space radiation research in both the life and physical sciences. BNL is a multidisciplinary research facility operated for the Office of Science of the US Department of Energy (DOE). The BNL scientific research portfolio supports a large and diverse science and technology program including research in nuclear and high-energy physics, material science, chemistry, biology, medial science, and nuclear safeguards and security. NSRL, in operation since July 2003, is an accelerator-based facility which provides particle beams for radiobiology and physics studies (Lowenstein in Phys Med 17(supplement 1):26–29 2001). The program focus is to measure the risks and to ameliorate the effects of radiation encountered in space, both in low earth orbit and extended missions beyond the earth. The particle beams are produced by the Booster synchrotron, an accelerator that makes up part of the injector sequence of the DOE nuclear physics program’s Relativistic Heavy Ion Collider. Ion species from protons to gold are presently available, at energies ranging from <100 to >1,000 MeV/n. The NSRL facility has recently brought into operation the ability to rapidly switch species and beam energy to supply a varied spectrum onto a given specimen. A summary of past operation performance, plans for future operations and recent and planned hardware upgrades will be described. Work performed under the auspices of the auspices of the US National Aeronautics and Space Administration and the US Department of Energy.     

Effects of 28Si Ions, 56Fe Ions,and Protons on the Induction of Murine Acute Myeloid Leukemia and Hepatocellular Carcinoma

Estimates of cancer risks posed to space-flight crews by exposure to high atomic number, high-energy (HZE) ions are subject to considerable uncertainty because epidemiological data do not exist for human populations exposed to similar radiation qualities. We assessed the carcinogenic effects of 300 MeV/n ²⁸Si or 600 MeV/n ⁵⁶Fe ions in a mouse model for radiation-induced acute myeloid leukemia and hepatocellular carcinoma. C3H/HeNCrl mice were irradiated with 0.1, 0.2, 0.4, or 1 Gy of 300 MeV/n ²⁸Si ions, 600 MeV/n ⁵⁶Fe ions or 1 or 2 Gy of protons simulating the 1972 solar particle event (1972SPE) at the NASA Space Radiation Laboratory. Additional mice were irradiated with ¹³⁷Cs gamma rays at doses of 1, 2, or 3 Gy. All groups were followed until they were moribund or reached 800 days of age. We found that ²⁸Si or ⁵⁶Fe ions do not appear to be substantially more effective than gamma rays for the induction of acute myeloid leukemia. However, ²⁸Si or ⁵⁶Fe ion irradiated mice had a much higher incidence of hepatocellular carcinoma than gamma ray irradiated or proton irradiated mice. These data demonstrate a clear difference in the effects of these HZE ions on the induction of leukemia compared to solid tumors, suggesting potentially different mechanisms of tumorigenesis. Also seen in this study was an increase in metastatic hepatocellular carcinoma in the ²⁸Si and ⁵⁶Fe ion irradiated mice compared with those exposed to gamma rays or 1972SPE protons, a finding with important implications for setting radiation exposure limits for space-flight crew members.