5
Other Issues

The research questions and strategies discussed in Chapter 4 describe the higher-and lower-priority research that is necessary to improve the risk estimate for adverse biological effects of exposure to radiation in a space environment. The scientific requirements of the experiments proposed include the need to use animal models as surrogates for humans in assessing cancer risk and effects in the central nervous system. It is also important to consider how new techniques, already developed or currently being developed, might affect the collection of data to be used in risk assessment. In particular, the use of molecular biology techniques will enhance the ability to characterize mutations and chromosomal aberrations in cellular systems and tumors. Both as a practical and fiscal issue, it is necessary to consider the relative benefits of conducting research in space versus on the ground. In addition, the effects of radiation on plants, which would constitute a major part of the food supply in extended spaceflight, should be noted. These issues are briefly discussed below.

Need for Animal Use

There are no estimates for the risk of cancer induction in humans exposed to protons, the major component of galactic cosmic radiation and solar radiation, or to heavy ions such as iron. Therefore, risk estimates currently must be based either on (1) information on the risks incurred by exposure to low-LET radiation modified by radiation weighting factors (WR) or quality factors (Q) to allow for the different relative biological effectiveness (RBE) values for the different types of radiation involved or (2) data from animal experiments used in conjunction with some method of extrapolating the risk estimates to humans. The first approach relies on experimental data because the WR and Q factors are based on RBE values obtained from animal experiments and, to some extent, studies of chromosomal aberrations. The values for WR (Table 2.1) are based on the judgment of a National Council on Radiation Protection and Measurements task group that examined the available relevant data.1 Quality factors are based on the relationship of RBE to the linear energy transfer (LET) of the dose.

Both approaches to estimating the risk of adverse biological effects for humans exposed to various types of radiation suffer because of insufficient experimental data. For example, it is essential to have adequate data on the induction of cancer by radiation at a sufficient range of LET values to obtain the RBE values or Q factors needed to estimate the risk from exposure to GCR in deep space. Obtaining such data involves use of animals and to a lesser extent in vitro studies on human chromosomes and cells. As indicated in Chapter 2, specific deterministic effects such as reduction in fertility, cataractogenesis, and damage to the central nervous system are important in assessing the total risk posed by prolonged sojourns in the radiation environments in space. The effects of heavy ions on the central nervous system are of particular importance. While



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--> 5 Other Issues The research questions and strategies discussed in Chapter 4 describe the higher-and lower-priority research that is necessary to improve the risk estimate for adverse biological effects of exposure to radiation in a space environment. The scientific requirements of the experiments proposed include the need to use animal models as surrogates for humans in assessing cancer risk and effects in the central nervous system. It is also important to consider how new techniques, already developed or currently being developed, might affect the collection of data to be used in risk assessment. In particular, the use of molecular biology techniques will enhance the ability to characterize mutations and chromosomal aberrations in cellular systems and tumors. Both as a practical and fiscal issue, it is necessary to consider the relative benefits of conducting research in space versus on the ground. In addition, the effects of radiation on plants, which would constitute a major part of the food supply in extended spaceflight, should be noted. These issues are briefly discussed below. Need for Animal Use There are no estimates for the risk of cancer induction in humans exposed to protons, the major component of galactic cosmic radiation and solar radiation, or to heavy ions such as iron. Therefore, risk estimates currently must be based either on (1) information on the risks incurred by exposure to low-LET radiation modified by radiation weighting factors (WR) or quality factors (Q) to allow for the different relative biological effectiveness (RBE) values for the different types of radiation involved or (2) data from animal experiments used in conjunction with some method of extrapolating the risk estimates to humans. The first approach relies on experimental data because the WR and Q factors are based on RBE values obtained from animal experiments and, to some extent, studies of chromosomal aberrations. The values for WR (Table 2.1) are based on the judgment of a National Council on Radiation Protection and Measurements task group that examined the available relevant data.1 Quality factors are based on the relationship of RBE to the linear energy transfer (LET) of the dose. Both approaches to estimating the risk of adverse biological effects for humans exposed to various types of radiation suffer because of insufficient experimental data. For example, it is essential to have adequate data on the induction of cancer by radiation at a sufficient range of LET values to obtain the RBE values or Q factors needed to estimate the risk from exposure to GCR in deep space. Obtaining such data involves use of animals and to a lesser extent in vitro studies on human chromosomes and cells. As indicated in Chapter 2, specific deterministic effects such as reduction in fertility, cataractogenesis, and damage to the central nervous system are important in assessing the total risk posed by prolonged sojourns in the radiation environments in space. The effects of heavy ions on the central nervous system are of particular importance. While

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--> no information about such effects on humans in available that is suitable for setting radiation limits, it is essential that the possibility of effects on the central nervous system be adequately assessed. Because the ideal of obtaining data from primates exposed to heavy ions is unlikely to be realized, critical animal experiments must be carefully crafted and executed. Experimental Techniques and New Data Required This section touches on new techniques being used for the qualitative assessment of mutations and chromosomal aberrations, and the characterization of molecular events involved in tumor development. It is assumed that significant progress in the next few years will be made in the above broad areas. As pointed out in previous chapters, estimates of cancer risk posed by low-LET radiation are quite well founded and are based on fairly extensive animal but limited human studies (those of atomic bomb survivors). Testing the reliability of the extrapolation of results from rodent studies to humans would require a better understanding of the mechanism of formation of specific tumor types, both background and x ray induced, for both human and animal models (with the same tumor type). Although rather little information is available on the genetic alterations associated with radiation-induced tumors, the methods exist and candidate genes such as p53 have been proposed. 2 What remains to be developed are sufficiently sensitive assays for detecting mutations in nonselectable genes that could be markers of early stages in tumor development. While specific polymerase chain reaction (PCR) methods are becoming more sensitive, they are still 1 or 2 orders of magnitude away from being able to detect induced mutations at the needed frequencies of occurrence, typically at mutation frequencies of 1 in 107 cells. Limited data are available on cancer induction in rodents exposed to high-LET radiation; information on other biological effects is also sparse. It will be necessary to conduct additional cancer studies in rodents exposed to different types of high-LET radiation and to characterize the resulting tumors at the molecular level. In fact, for high-LET radiation, the conversion of DNA lesions into mutations is not well understood. In order to better simulate conditions of exposure during spaceflight, it is necessary to consider the effectiveness of induction of mutations by low-dose-rate exposure to both high-and low-LET radiation. The use of fluorescence in situ hybridization allows reciprocal translocations to be assessed following protracted exposure. A translocation is a significant chromosomal end point when considering genomic alterations that are associated with adverse health effects. Assays are also under development for detecting low-frequency aberrations in genes above background. Although currently available only for selectable genes such as that for HPRT (hypoxanthine phosphoribosyl transferase), for which mutants have a growth advantage (i.e, they are selected for their ability to grow faster than non-mutants), it is anticipated that new assays will be available for nonselectable tumor genes and genes such as p53 and other tumor suppressor genes in the future. The identification of populations that are genetically susceptible to cancer development is also of considerable importance. Uncovering the mechanisms involved in tumor formation is critical for this purpose but despite considerable progress is still a distant goal. A more attainable goal may be development of surrogate assays for predicting increased sensitivity for tumor induction. The G2 chromosomal aberration assay described by Jones et al.3 is promising. It appears to be able to identify individuals who have at least increased radiosensitivity of lymphocytes, and in one case, this increase was quite marked in about 40% of breast cancer patients.4 More work and probably a number of modifications to the technique are in order before it can be used as a predictor of radiation sensitivity. Ground-vs. Space-Based Research. The influence of microgravity on the effects of low-LET radiation have been reviewed by Horneck and by Nelson.5,6 Most experiments showed negligible or small effects of microgravity on radiation-induced changes. Typical changes observed had to do with increased chromosomal alterations in fruit flies and in Tradescantia (the spiderwort plant) following irradiation before lift-off. Horneck suggests that changes in chromosomal structure or position in microgravity could have prevented effective rejoining of chromosomes. On the other hand, there was no control in such experiments for vibration or acceleration during lift-off or return of the satellites. In another example cited in these reviews, an experiment measuring viability in yeast,

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--> survival was lower for microorganisms irradiated before lift-off compared to survival for ground-based controls treated in the same way. It was noted that the difference in survival did not seem to be dose dependent. These results were interpreted as indicating that DNA repair was less efficient in microgravity. No experiments were carried out in space using a 1-g centrifuge for controls. Recent ground-based experiments, summarized by Kronenberg, on radiation-induced DNA fragmentation, neoplastic transformation of cells plated 24 hours after irradiation, and the effects of a chemical radioprotector on mutation induction showed that DNA repair and cell recovery take place readily after low-LET radiation, but not following exposure to HZE particles.7 Since the only reported significant effect of microgravity may be on DNA repair and cell recovery following low-LET exposure and there seems to be no DNA repair/cell recovery following high-LET exposure, microgravity should not be important for HZE particle effects. The above considerations indicate that HZE particles are a very important factor in the damage resulting from long space missions and that the effects of microgravity probably will not alter the cellular response to HZE particles but might actually increase the effect of low-LET radiation. Hence, the task group concluded that the majority of the useful information on radiation effects and risks will come from ground-based experiments described in Chapter 4 and that radiation experiments in space, with all their logistical difficulties, will not be rewarding and may not be worth the effort. Plants and Food Supply Since any interplanetary spaceflight will be of long duration (up to 3 years), it will be necessary not only to have packaged food available, but also to grow additional plant food. The very high doses of radiation used to sterilize food do not significantly affect food quality. Hence, no significant effects of irradiation are plausible for packaged food, and given the predicted magnitude of exposure during spaceflight, no effect is likely on growing plants. In general, plants are relatively radiation resistant when growing and extremely resistant as dormant seeds. The most sensitive response of plants to irradiation would be overall growth, and this occurs at doses above those predicted during spaceflight. References 1. National Council on Radiation Protection and Measurements (NCRP). 1995. Radiation Exposure and High Altitude Flight. NCRP Commentary No. 15. National Council on Radiation Protection and Measurements, Bethesda, Md. 2. Culotta, E., and Koshland, R.D.E. 1993. p53 sweeps through cancer research. Science 262:1958–1961. 3. Jones, L.A., Scott, D., Cowan, R., and Roberts, S.A. 1995. Abnormal radiosensitivity of lymphocyte from breast cancer patients with excessive normal tissue damage after radiotherapy: Chromosome aberrations after low-dose-rate irradiation. Int. J. Radiat. Biol. 67: 519–528. 4. Jones et al., 1995, Abnormal radiosensitivity of lymphocyte from breast cancer patients with excessive normal tissue damage after radiotherapy. 5. Horneck, G. 1992. Radiobiological experiments in space: A review. Int. J. Radiat. Appl. Instrum. 20: 82–205. 6. Nelson, G. 1995. Space-based radiation biology. Presentation to the Task Group on the Biological Effects of Space Radiation, November 13, 1995, Washington, D.C. 7. Kronenberg, A. 1995. NASA space radiation health program: Ground-based radiobiology research program. Presentation to the Task Group on the Biological Effects of Space Radiation, Washington, D.C.

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