8
Radiation Biology

INTRODUCTION

Concerns about the acute and chronic health effects of the radiation encountered in space (low Earth orbits and the International Space Station (ISS), and in extraterrestrial space) have been raised for many years. The risks arise from the interactions between high-energy charged particles, ranging from protons to iron nuclei, with the DNA, cells, and tissues of humans. Such interactions may kill cells; cause them to mutate; induce cancers; and injure the central nervous system (CNS), the immune system, and the reproductive system. Predicting the probability of such damaging effects requires a knowledge of dosimetry and radiation biology. Dosimetry is concerned with the type, energy, and number of particles in space; how their distribution changes in passing through spacecraft shielding; and how they depend on spacecraft location and time. Location in low Earth orbit (LEO) strongly affects the spatial distribution of the particles, and large solar particle events (SPEs) may increase the flux of protons by several orders of magnitude for many days (Badhwar, 1997). SPEs are associated with very strong increases in the Sun’s magnetic field, which result in highly significant decreases in the galactic cosmic-ray background. The SPEs are much more frequent during the period of solar maximum; hence the flux of galactic cosmic rays is larger during solar minimum. Radiation biology research deals with the effects of solar and cosmic-ray particles on suitable model biological systems that may be used to extrapolate risks to humans.

The 1998 Strategy report (NRC, 1998) gives estimates of the uncertainty in the carcinogenic risks from high-atomic-number, high-energy (HZE) particles that are between a factor of 4 and 15. The reason for the large uncertainty is that there is only one ground-based carcinogenesis experiment, on cancer induction in mice, that estimates the risk from HZE particles relative to gamma rays as appreciably greater than the risks determined for cell killing, mutation, or transformation of cells exposed in vitro (Alpen et al., 1993). Hence quantitative designs of appropriate countermeasures, such as shielding, and biochemical or biological schemes to reduce the damage from HZE particles or augment repair following radiation exposure, are very rudimentary. The Strategy report recommended a comprehensive research program to determine the risks from different types and energies of HZE particles and from



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Review of NASA’s Biomedical Research Program 8 Radiation Biology INTRODUCTION Concerns about the acute and chronic health effects of the radiation encountered in space (low Earth orbits and the International Space Station (ISS), and in extraterrestrial space) have been raised for many years. The risks arise from the interactions between high-energy charged particles, ranging from protons to iron nuclei, with the DNA, cells, and tissues of humans. Such interactions may kill cells; cause them to mutate; induce cancers; and injure the central nervous system (CNS), the immune system, and the reproductive system. Predicting the probability of such damaging effects requires a knowledge of dosimetry and radiation biology. Dosimetry is concerned with the type, energy, and number of particles in space; how their distribution changes in passing through spacecraft shielding; and how they depend on spacecraft location and time. Location in low Earth orbit (LEO) strongly affects the spatial distribution of the particles, and large solar particle events (SPEs) may increase the flux of protons by several orders of magnitude for many days (Badhwar, 1997). SPEs are associated with very strong increases in the Sun’s magnetic field, which result in highly significant decreases in the galactic cosmic-ray background. The SPEs are much more frequent during the period of solar maximum; hence the flux of galactic cosmic rays is larger during solar minimum. Radiation biology research deals with the effects of solar and cosmic-ray particles on suitable model biological systems that may be used to extrapolate risks to humans. The 1998 Strategy report (NRC, 1998) gives estimates of the uncertainty in the carcinogenic risks from high-atomic-number, high-energy (HZE) particles that are between a factor of 4 and 15. The reason for the large uncertainty is that there is only one ground-based carcinogenesis experiment, on cancer induction in mice, that estimates the risk from HZE particles relative to gamma rays as appreciably greater than the risks determined for cell killing, mutation, or transformation of cells exposed in vitro (Alpen et al., 1993). Hence quantitative designs of appropriate countermeasures, such as shielding, and biochemical or biological schemes to reduce the damage from HZE particles or augment repair following radiation exposure, are very rudimentary. The Strategy report recommended a comprehensive research program to determine the risks from different types and energies of HZE particles and from

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Review of NASA’s Biomedical Research Program high-energy protons for a number of biological end points and the efficacy of different types and thicknesses of shielding in reducing these risks. These recommendations are described in more detail in Appendix A. NASA’S CURRENT RESEARCH PROGRAM IN RADIATION BIOLOGY NASA’s Strategic Program Plan for Space Radiation Health Research (NASA, 1998) was approved in October 1998 by the associate administrator for the Office of Life and Microgravity Sciences and Applications. The budget breakdown for FY 1999 is given in Table 8.1. The program follows closely the principal recommendations of the Strategy report, which were given as experimental procedures designed to answer higher- and lower-priority research questions. The higher-priority recommendations were aimed at determining the carcinogenic risk and effects on the CNS of exposure to energetic protons and HZE particles; how the composition of the shielding would quantitatively ameliorate the biological effect of HZE particles; and whether there are studies on radiation-induced genetic changes that could increase confidence in extrapolating from rodents to humans and might enhance a similar extrapolation for cancer. Other high-priority recommendations were to determine if there were better analyses that could decrease the present uncertainties in the risks of HZE effects, to determine how the design of the space vehicle could affect the internal radiation levels, and to determine whether SPEs could be predicted with sufficient advance warning for astronauts to return to a shielded shelter. Low-priority recommendations were to estimate the effects of long-duration flight on fertility and on cataract formation, to TABLE 8.1 Summary of FY 1999 Funding for Radiation Research by Subdiscipline     NRA   NSBRI   NSCORT Subdiscipline Total ($) No. of Projects Total ($) No. of Projects Total ($) No. of Projects Dosimetry Instrumentation 460,000 2         Energy loss or scattering 75,000 1         Russian plutonium workers 150,000 —         Biological effects Carcinogenesis 200,000 1 523,819 3     Cataracts 297,000 1         Cell cycle 223,962 1         Mutagenesis 234,000 1         Cytogenetics 171,350 1 265,616 2     Genomic instabilitya 1,000,000 1         Radiation research 77,000 1     1,045,378 3 Total 2,888,312   789,435   1,045,378   NOTE: In addition to the values given in the table, the funding for radiation studies includes $3.5 million to begin construction of the BAF, $1.075 million to support the operation of the present HZE operations at the AGS, and $6.5 million of directed spending for operation of the proton facility (< 250 MeV) at Loma Linda University. a$1 million for cooperative research with the National Cancer Institute.

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Review of NASA’s Biomedical Research Program determine whether drugs could be used to protect against the carcinogenic effects of exposure to HZE particles, and to determine whether there are assays that might identify individuals with a predisposition for susceptibility to cancer, and whether biological responses to HZE particles depend only on the linear energy transfer (LET) or on the values of the atomic number and energy separately. Carrying out these experiments on molecules, on living cells in vitro and in vivo, and on animals so as to extrapolate to human risks requires ready access to energetic beams (up to several GeV per nucleon) of a number of nuclei that could mimic galactic cosmic rays. The major facility for these experiments is the Alternating Gradient Synchrotron (AGS) at Brookhaven National Laboratory, but it is available for only two to four weeks per year. At the present rate of progress it would take 20 or more years to complete the high-priority experiments recommended in the Strategy report, because of the limited accelerator time to carry out HZE particle and energetic proton irradiations at 1 GeV per nucleon. The Strategy report recommended that other sources of HZE particles be identified or constructed. NASA has followed this recommendation with the start of construction of a new accelerator beam line, the Booster Application Facility (BAF), to be built at Brookhaven National Laboratory with NASA funds. This facility will make available, for a significant fraction of the year, research time for HZE experiments on biological systems. Other useful accelerators in Japan and Germany will be recruited for similar efforts but at lower energies and atomic numbers. In future years, the essential increase in funding for construction of the BAF could seriously compromise the rest of the biomedical research program, unless additional monies are made available. NASA should make every effort to support appropriately both the research and the facilities to do this research. NASA’s Strategic Program Plan (NASA, 1998) is very clear in pointing out that “current knowledge of radiation effects in space is not adequate for the design of long-duration missions without incurring either unacceptable risks or excessive costs.” In 1998 and 1999, the total program in radiation biology and dosimetry included 35 NASA Research Announcements (NRAs), 3 NASA Specialized Centers of Research and Training (NSCORT), and 5 National Space Biomedical Research Institute (NSBRI) projects or subprojects. The First Biennial Space Biomedical Investigators’ Workshop (January 1999) included descriptions (abstracts) of 23 relevant projects, of which only three dealt with research on vertebrates—one on mutations of an exogenously incorporated gene in mice; one on behavioral effects of HZE particles on rats; and one on the induction of breast cancer in rats by HZE particles and gamma rays. The other projects dealt with dosimetry (seven projects); HZE effects on molecules, chromosomes, and cells in vitro (ten projects); and HZE effects on molecules, chromosomes, and cells in vivo (one project) (see NASA and USRA, 1999). There was a similar distribution in the Abstracts of the 10th Annual Space Radiation Health Investigators’ Workshop (June 13-16, 1999) (20 on dosimetry, 25 on cells in vitro, 5 on cells in vivo, and 3 on animals). This distribution of projects is not that envisaged in the Strategy report (see below). In addition, NASA holds annual 4-day workshops that bring together investigators on radiation effects to discuss the latest results in sessions of invited and proffered papers. NASA has made an excellent start in following the recommendations in the Strategy report and in starting construction of a dedicated beam line that will operate for a large fraction of the year to supply HZE particles for biological experiments.

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Review of NASA’s Biomedical Research Program PROGRAMMATIC BALANCE Balance of Subdiscipline Areas There is adequate balance in the radiation program between dosimetry and biology. Extensive work is being done at JSC on real-time dosimetry in LEO, external and internal to a spacecraft. This work also supports a recommendation made in a recent NRC report (NRC, 2000), which also recommends implementaion, by the space physics community, of steps to predict SPEs and their intensities and locations using real-time data. Retrospective personal dosimetry is being carried out using measurements of chromosome translocations in lymphocytes of astronauts following spaceflight, compared to a baseline of aberrations before flight (Yang et al., 1997). Chromosome translocations in peripheral blood lymphocytes are excellent estimates of cumulative exposure. However, translocations as a function of dose depend on both the dose rate and the nature of the incident charged particles—their charges, energies, and linear energy transfers in tissue (Straume and Bender, 1997). Thus, for chromosome dosimetry that will give the dose equivalent of the radiation field in the space environment, one must know the nature of the particles as a function of time in flight and the translocation yields for these particles, measured on Earth at high dose rates and extrapolated to the dose rates observed in space. Data to be used for extrapolating from high dose rates to low dose rates cannot be obtained by exposing lymphocytes in vitro because of the short lifespan of these cells in vitro. The data will have to be obtained by exposing lymphocytes in vivo using a suitable animal model, probably monkeys. At present there is no provision for extrapolating from the acute experimental calibrations on Earth to the chronic exposures usually experienced in space. Experiments at ground-based accelerators are being carried out to determine the effectiveness of various types and thicknesses of shielding in reducing doses from HZE particles, for various biological end points. The written plan ( NASA, 1998) is similar to the Strategy report, but there is a marked difference in emphasis. The report emphasizes carcinogenic end points and molecular, chromosomal, and cellular effects from in vivo exposures to HZE particles and high-energy protons. Only one experiment is being carried out with a relevant cancer end point—breast cancer induction in rats (the report recommends mice as the more appropriate species). Although the biological research uses state-of-the-art techniques in molecular and cellular effects, it is not clear how data from these experiments will be used to estimate the relative biological effectiveness (RBE) of HZE particles for cancer induction. These molecular and cell biology experiments were proposed in the Strategy report as a way to validate the general biological effects of radiation fields behind shielding, but no such shielding experiments have yet been carried out. Only one project deals with the effect of HZE particles on the CNS, in terms of changes in the behavior of rats following exposure. This type of research was a high priority in the Strategy report, and it was estimated that such a project could take 5 to 7 years if 3 months of beam time were available per year. This is probably an underestimate given that a recent study, not related to radiation effects, that involved mouse behavior and was carried out in three separate laboratories with genetically identical mice and the same experimental protocols, gave three different results (Crabbe et al., 1999). Hence, NASA should increase its efforts in CNS effects and in the use of state-of-the-art molecular and brain-scanning techniques, such as positron emission tomography, to measure the effect of energetic nuclei on brain chemistry. The main and overriding issue to be solved before a spacecraft is designed is the appropriate shielding necessary to minimize the effects of exposure to radiation. The shielding design depends on HZE particle effects on the high-priority end points of carcinogenesis and CNS effects. Low-priority

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Review of NASA’s Biomedical Research Program effects such as synergism with other variables and identification of in-flight markers of exposure (rather than determinations made on the ground) should not receive any emphasis. Radiation limits to satisfy the principle of ALARA (as low as reasonably achievable) for LEO are currently being revised by the National Council on Radiation Protection and Measurements. The anticipated new career limits will be significantly lower than the current ones (NASA, 1998, p. 41). No such limits are currently available for travel beyond LEO. The results of the HZE experiments on molecules, cells in vitro, cells in vivo, and animals must be synthesized so as to predict the extrapolated risks to astronauts, as emphasized in the Strategy report. Such a synthesis procedure should be put in place in order to recommend radiation limits for astronauts exposed to HZE particles. These recommendations, plus knowledge of the types and energies of HZE particles, should guide the design of shielding. Balance of Ground and Flight Investigations The overwhelming majority of radiobiological experiments are, and will be, carried out on the ground and, of necessity, will use animals. The flux rate of HZE particles in space is low, and although the particles, if not appropriately shielded, could over a long period of time produce deleterious effects in humans, the use of such radiation for radiobiological experiments on small vertebrates in space is impractical because it is not possible to transport an HZE accelerator into space. Some radiation experiments in space, using sparsely ionizing radiation, have been carried out on human lymphocytes, microorganisms, and the small roundworm Caenorhabditis elegans. The radiation sources used were radioisotopes emitting β-particles. None of these experiments have shown any significant synergistic or antisynergistic effect of radiation and microgravity. Similar experiments on mice on the ISS would require an x-ray or γ-ray source to irradiate animals at 1 g and at microgravity. Since there is no compelling theoretical reason to expect that hypogravity will affect radiation end points in vertebrates, the committee’s view is the same as that in the Strategy report—such experiments “with all their logistical difficulties, will not be rewarding and may not be worth the effort” (p. 190). Hence, it is not clear how one might validate ground-based risk prediction in space by ISS utilization as suggested in NASA’s Strategic Program Plan (NASA, 1998, pp. 17, 18, 20). The biological dosimetry behind shielding may be validated by ground-based experiments (see “Development and Validation of Countermeasures” below). On the other hand, the validation of biological risk estimates, behind shielding, of HZE nuclei and energetic protons cannot be done in space but must be done at a ground-based facility. Emphasis Given to Fundamental Mechanisms The effects of HZE particles on humans cannot be measured directly for ethical and practical reasons. The effects must be extrapolated from the results of animal experiments using fundamental knowledge of the mechanisms of radiation damage and repair. NASA strongly supports basic experiments on the effects of HZE particles on molecules, chromosomes, cells, and tissues so as to derive the necessary extrapolation rules to estimate risks to humans from exposure to HZE particles, as recommended in the Strategy report. Utilization and Validation of Animal Models The presumed important effects of HZE particles are possible carcinogenic and CNS effects. Estimates of the magnitudes of these effects must come from extrapolations from animal experiments as

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Review of NASA’s Biomedical Research Program outlined in the previous two subsections of this chapter and in the Strategy report. The principal species used are mice and rats, for which typical measurement end points are chromosomal changes, cell killing, cellular apoptosis, mutations, cancer induction, CNS responses, and brain metabolic abnormalities. There is a good balance between dosimetry and molecular and cellular radiobiology. However, more emphasis should be placed on carcinogenesis and CNS end points, using animal models. Such experiments must be carried out in ground-based facilities so as to estimate the risks to astronauts of exposure to HZE particles and develop guidelines for limits on exposure to these particles. DEVELOPMENT AND VALIDATION OF COUNTERMEASURES The proven countermeasures are shielding and operational parameters (especially in LEO), such as orbit paths and warnings of SPEs. However, calculated shielding (composition and thickness) must be validated, as described in the high-priority research questions in the Strategy report, by measuring the distribution and fluxes of particles behind shielding and then calculating and measuring their effects on simple biological end points such as cell killing and chromosome aberrations. Presumably, because of the limited time now available at HZE accelerators, such validation experiments have not been attempted or scheduled. Other possible countermeasures, which are currently impractical, are (a) identification of individuals with high radiation resistance; (b) the use of chemical radioprotectors; (c) genetic methods to enhance the repair of radiation damage; and (d) interventions following unexpected radiation exposures that might enhance repair or induce apoptosis of damaged cells. These countermeasures are among the low-priority research questions of the Strategy report. NASA in collaboration with the National Cancer Institute should stimulate research in these areas. Biodosimetry, by measuring chromosome translocations in lymphocytes, gives only retrospective doses and is not a countermeasure. Autologous bone marrow transplants have been used on Earth to counteract acute radiation exposure. The proposal, in the NASA Strategic Program Plan, to use this as a countermeasure (NASA, 1998, p. 24) is of questionable feasibility. Presumably, exposed individuals will have to return to Earth for the procedure. Major emphasis should be given to determining the types and thicknesses of shielding necessary to reduce astronaut risks to acceptable levels. EPIDEMIOLOGY AND MONITORING Measurements of chromosome translocations and their translation into dose equivalents (in sieverts) should be required for all long-term space travelers as indicated in NASA’s Countermeasure Evaluation and Validation Project Plan (NASA, 1999). Data on translocations and on the methods used to calculate dose equivalents from these translocations should be available to compare with the subsequent monitored health of astronauts, as emphasized in the discussion of human flight in the Strategy report. SUPPORT OF ADVANCED TECHNOLOGIES NASA is a strong supporter of advanced and innovative technologies in radiation dosimetry, biodosimetry, and molecular and cellular biology as applied to radiation effects, as indicated by

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Review of NASA’s Biomedical Research Program the NSBRI and NSCORT programs and in their competitive, peer-reviewed research projects, which are reported at annual space radiation health investigators’ workshops. SUMMARY At the present rate of progress it would take 20 or more years to complete the high-priority experiments recommended in the Strategy report, because of the limited accelerator times available to carry out HZE particle and energetic proton irradiations at 1 GeV per nucleon. NASA understands this problem and, to address it, has allocated initial funds to begin construction of a dedicated accelerator facility (the Booster Application Facility (BAF)) that, when completed, will supply the necessary energetic particles for the following decade and longer. Arrangements have been made to use other lower-energy facilities (Loma Linda: 250-MeV protons; HIMAC in Japan: 0.4 GeV per nucleon of HZE nuclei). The high costs of building and operating facilities could seriously deplete the funds for fundamental research in the many relevant and important biological, biomedical, physiological, and behavioral areas associated with long-term spaceflight. The projects in high-priority radiation research areas—carcinogenesis and CNS—are at present poorly represented in the area of biological end points as determined in animals. The majority of projects are related to determinations of changes in cells, following exposure to HZE nuclei, in parameters such as turning genes on or off, cell cycle alterations, production of chromosome aberrations, mutation, and transformation. These experiments are state of the art, but it is not clear how the results will translate into helping estimate the radiation risks to astronauts. Radiation dosimetry and computations and measurements of the radiation fluxes behind various types and thicknesses of shielding are well carried out, but they have to be validated by ground-based experiments on simple in vitro systems. The risk to astronauts of exposure to galactic cosmic radiation, estimated from ground-based experiments on molecules, cells, and animals, cannot be validated experimentally but could be approached by using several independent methods to calculate risks as proposed in the Strategy report. REFERENCES Alpen, E.L., P. Powers-Risius, S.B. Curtis, and R. DeGuzman. 1993. Tumorigenic potential of high-Z, high-LET charged-particle radiations. Radiat. Res. 136:382-391. Badhwar, G.D. 1997. The radiation environment in low-Earth-orbit. Radiat. Res. 148:S3-S10. Crabbe, J.C., D. Wahlsten, and B.C. Dudek. 1999. Genetics of mouse behavior: Interactions with laboratory environment. Science 284:1670-1672. National Aeronautics and Space Administration (NASA). 1998. Strategic Program Plan for Space Radiation Health Research. Life Sciences Division, Office of Life and Microgravity Sciences and Applications. Washington, D.C.: NASA. NASA. 1999. Countermeasure Evaluation and Validation Project Plan. Houston, Tex.: Johnson Space Center. NASA and Universities Space Research Association (USRA). 1999. Proceedings of the First Biennial Space Biomedical Investigators’ Workshop, January 11-13, 1999, League City, Texas. Houston, Tex.: NASA and USRA. National Research Council (NRC), Space Studies Board. 1998. A Strategy for Research in Space Biology and Medicine in the New Century. Washington, D.C.: National Academy Press. National Research Council (NRC), Space Studies Board. 2000. Radiation and the International Space Station: Recommendations to Reduce Risk. Washington, D.C.: National Academy Press. Straume, T., and M.A. Bender. 1997. Issues in cytogenetic biological dosimetry: Emphasis on radiation environments in space. Radiat. Res. 148:S60-S70. Yang, T.C., K. George, A.S. Johnson, M. Durante, and B.S. Federenko. 1997. Biodosimetry results from spaceflight Mir-18. Radiat. Res. 148:S17-S23.