The Biological Effects of Space Radiation During Long Stays in Space

The Biological Effects of Space Radiation during Long Stays in Space

Ken Ohnishi and Takeo Ohnishi

Department of Biology, Nara Medical University School of Medicine,Shijo-cho 840, Kashihara, Nara 634-8521, Japan.

Abstract Many space experiments are scheduled for the International Space Station (ISS). Completion of the ISS will soon become a reality. Astronauts will be exposed to low-level background components from space radiation including heavy ions and other high-linear energy transfer (LET) radiation. For long-term stay in space, we have to protect human health from space radiation. At the same time, we should recognize the maximum permissible doses of space radiation. In recent years, physical monitoring of space radiation has detected about 1 mSv per day. This value is almost 150 times higher than that on the surface of the Earth. However, the direct effects of space radiation on human health are currently unknown. Therefore, it is important to measure biological dosimetry to calculate relative biological effectiveness (RBE) for human health during long-term flight. The RBE is possibly modified by microgravity. In order to understand the exact RBE and any interaction with microgravity, the ISS centrifugation system will be a critical tool, and it is hoped that this system will be in operation as soon as possible. Key words; space, space radiation, biological effect, high-LET, ISS Characteristics of space and the composition of space radiation the radiation being composed of α-particles and heavy For several years, human beings have been particles. The sun changes its level of activity during an residing for long periods in the ISS where many space 11-year-cycle. Solar flares and solar winds, indicators of experiments are scheduled to be performed. In addition, solar activity, emit large quantities of charged particles, there are proposals for human to travel to Mars. electrons, protons, α-particles, X-rays, He, H and Fe Important characteristics of the environment in space which have much higher energies than galactic cosmic are the presence of microgravity and space radiation. rays. When the sun is producing solar flares and solar Radiation present in the space environment contains winds, astronauts are exposed to the particles emitted many components including low dose radiation, low from the solar flares and winds at a dose rate at more dose-rate radiation, and high-LET particles (Table 1). than an order of magnitude greater than normal. In The space environment produces microgravity- and/or addition, since the exposure to these particles outside of space radiation-induced physiological changes in the the space craft is several times higher than that inside of human body (e.g. calcium release from bone into the the space craft, astronauts can be seriously affected by urine, loss of muscular power, body fluid shifts, space or solar particles while working outside of the space craft. airsickness, reduced immunoreactivity and eye flashes). Geomagnetically trapped particles are particles which During a long-term stay in space, astronauts consist primarily of protons and electrons and which are will be constantly exposed to space radiation which trapped in the geomagnetic field layer. The high flux area contains various types of low dose-rate radiation. Space of geomagnetically trapped particles is called the Van radiation consists of galactic cosmic rays, solar particles Allen Belt and this is located over the Earthʼs equator. and geomagnetically trapped particles (Table 2). A An area of the Van Allen Belt over the South Atlantis is characteristic of galactic cosmic rays is their containing called the South Atlantic Anomaly (SAA) and this region high energy particles with energies over 10 GeV: contains an especially high flux of geomagnetically protons (90%), α-particles (9%) and heavy particles trapped particles. (1%). The origin of galactic cosmic rays is considered to be the explosion of supernovas. Solar particles are Biological effects of space radiation primarily protons and electrons with several percent of Space radiation contains high-LET radiation (α-particles, heavy particles and neutrons) derived from

Table 1 Characteristics of space radiation Review Received: January 4, 2005 Low dose Address for correspondence: Dr. Takeo Ohnishi Low dose-rate Department of Biology, Long-term exposure Nara Medical University School of Medicine, High-LET radiation Shijo-cho 840, Kashihara, Nara 634-8521, Japan. E-mail; [email protected] Interactions with microgravity

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Table 2 Composition of space radiation 2003), and about 2.0 for 100 keV/µm (Takahashi 1) Galactic cosmic rays: protons (90%), α-particles (9%), et al., 2001). In accepting these high RBE heavy particles (1%) values for mutation and cell lethality induced by 2) Solar particles: primarily protons and electrons, α-particles (several %), high-LET radiation, it is assumed that this high- heavy particles (several %) LET radiation could cause DNA damage which 3) Geomagnetically trapped particles: protons, electrons can be repaired by the non-homologous end- joining repair processes. In recent experiments, galactic cosmic rays, solar particles and geomagnetically the indirect biological effects of radiation were studied: trapped particles. The RBE of the high-LET radiation is these indirect effects are called the “bystander effect”: higher than the RBE of X-rays or γ-rays. The RBE value non-irradiated cells are affected by their neighboring depends on the LET values, the size of the dose, and irradiated cells through cell to cell junctions and by the biological indicator analyzed, and thus it is difficult radicals generated by radiation. In the case of a space to estimate a value for the RBE based on a simple environment, the bystander effect probably should not physical parameter such as the absorbed dose. High- be neglected, because heavy particles such as α-particles LET radiation causes a larger amount of damage to DNA and carbon-ion beams were able to induce bystander than X-rays or γ-rays. DNA strand breaks induced by effect in chromatin damage through cell to cell junctions space radiation were detected as grains in fixed human (Suzuki et al., 2004) and in experiments observing cell cultured cells in Mir Space Station- and Space Shuttle- proliferation and micronuclei mediated by NO (Shao et experiments (Ohnishi et al., 2002). The number of grains al., 2002). visualized with in situ enzymatic post-labeling method Some space experiments reported that there increased with the increase of the length of the stay in appeared to be interactions between space radiation and space. DNA damage induced by radiation is known to microgravity. Abnormal differentiation was observed cause cell death, mutations, chromosomal aberrations, more frequently in one kind of insect, Carausius developmental abnormalities and senescence. In the morosus, under microgravity conditions than when central nervous systems of mice irradiated with high subjected to one gravity force generated by a centrifuge energy heavy particles using the Heavy Ion Medical in space (Bucker et al., 1986). Recessive lethal mutations Accelerator in Chiba (HIMAC), cell death was induced were induced by space radiation at low, supposedly non- in microglia but not in astrocytes (Nojima et al., 2000). effective doses in the progeny of fruit flies taken into Such selective cell death in the brain may also be induced space (Ikenaga, et al., 1997). These space experiments by space radiation. The death of an individual has not suggested the possibility that microgravity may have been reported after acute exposure to space radiation. In elevated the frequency of mutations induced by space contrast to an acute exposure, chronic exposure to space radiation. Some possible suggestions to explain the effect radiation may induce late effects such as central nervous of microgravity have been offered. One suggestion is system damage, cataracts and carcinogenesis. Effects of that a microgravity environment may inhibit the repair of heavy particles on the functioning of the central nervous DNA damage induced by space radiation. Another is that system (learning and memory) have been examined in metabolic changes induced by microgravity indirectly ground-based experiments using water maze analysis in modify biological processes. For example, microgravity mice. Mutations induced by space radiation could lead may lead to the accumulation of stress-related proteins to carcinogenesis. The types of chromosomal aberrations which then might modify cellular sensitivity to space induced by space radiation were translocations and radiation. This possibility is supported by investigations complex exchanges seen in the cytogenetic analysis of observing accumulated heat shock protein 72 or tumor lymphocytes of astronauts (Durante et al., 2003, 2004; suppressor gene product p53 in the muscle and spleen George et al., 2002). Large individual differences in the of goldfish, and in the skin and muscle of rats examined frequency of these types of chromosomal aberrations after space flight (Ohnishi et al., 1996, 1998). were observed among astronauts. Thus, individual In contrast, some space experiments have shown that differences in sensitivity to space radiation must be mutation frequencies and DNA repair activity are not expected. Since space radiation consists of different affected by microgravity in E. coli (Harada et al., 1998; types of particles having different energies and dose- Horneck et al., 1996), B. subtillis (Yatagai et. al., 2000), D. rates, it is difficult to determine an exact RBE value for discoideum (Takahashi et al., 1997), S. cerevisiae (Pross space radiation. Several studies on high-LET radiation et al., 1999; Fukuda, et al., 2000), human cells (Horneck have reported an RBE for the mutation frequencies of et al., 1996) and with in vitro assays (Takahashi et al., α-particles of about 20 (Kiefer, 2002) and those for 2000). carbon-ion beams were 3.6 and 7.3 for 68 keV/µm and 120 keV/µm beams, respectively (Suzuki et al., 2003). Estimation of the maximum permissible dose of The RBEs for carbon beams with cell lethality as an space radiation endpoint were estimated to be 2.3 and 4.1 for 68 keV/ To protect the human body from the harmful or lethal µm and 120 keV/µm beams, respectively (Suzuki et al., effects of space radiation, it is necessary to determine

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Table 3 Averaged absorbed dose rate (D) recorded by dosimetry badge dose-rates (D) and averaged dose equivalent-rates (H) in and estimates of averaged dose equivalent rate (H) in the blood-forming the hematopoietic tissues of astronauts who participated organ received by astronauts who participated in NASA Programs (Cucinotta et al., 2002 modiﬁed by Yasuda). in space mission programs organized by NASA (Cucinotta et al., 2002). The values of D and H depend on the orbit Program Orbit angle Altitude D rate H rate angle and altitude of a space craft. When the orbit angle (deg.) (km) (mGy/d) (mSv/d) becomes higher, space crafts will pass through the SAA Gemini - - 0.49 0.87 and thus be exposed to high doses of radiation. It will be Apollo - - 0.43 1.20 necessary to know the dose distribution throughout the Shuttle 28.5 >400 1.20 2.10 body to estimate the effective dose which is an important Shuttle 28.5 <400 0.10 0.18 parameter needed to design radiation protection systems Shuttle >50 >400 0.44 1.10 for travel in space. For this reason, the measurement of Shuttle >50 <400 0.20 0.45 space radiation in order to calculate the effective dose Shuttle-Mir 51.6 390 0.37 0.84 was performed in the Shuttle-Mir mission 9 (STS-91) which had an orbit similar to that of the ISS. Until these measurements were made, it was not known what dose each organ and tissue of the human body received what the maximum permissible dose of space radiation in space. Table 4 shows the effective doses measured is. Exposure to space radiation increases rapidly with a for each organ or tissue of a phantom replicating the gain in elevation above the Earthʼs surface because the human body (Yasuda et al., 2000). The received dose atmosphere becomes attenuated and the geomagnetic differed between tissues and organs of the human body field becomes weaker at higher altitudes. The ISS is with effective doses varying by 10% to several times. scheduled to fly at an altitude of 400 km and an orbit There appears to be a tendency to have a high dose angle of 51.6 degrees. When the ISS passes through on the surface of the body (skin) and protruding near the SAA, it will be exposed to space radiation such as surface elements (e.g. bone surfaces corresponding to low-LET radiation (γ-rays and protons) and high-LET the shoulder), and to have low doses in internal regions radiation. The exposure dose in the inside of the space (e.g. bone marrow and colon). Although the bone shuttle or ISS is estimated to be about 1mSv/day (Doke marrow and colon are sensitive to radiation, it appears et al., 1995). This value is about 150 times higher than that these organs are protected from space radiation by that on the Earth. Table 3 summarizes averaged absorbed

Table 4 Values of absorbed dose, dose equivalent, effective quality factor of each organ and tissue and effective dose equivalent measured using small integrating dosimeters in the 9th Shuttle-Mir mission. (Yasuda et al., 2000)

Absorbed dose Organ or Tissue Effective Tissue b Organ or tissue (DT) dose equivalent quality factor weighting HT x wT b b c [mGy(H2O)] (HT) [mSv] (Qe) factor (wT) Skin 2.2±0.17 4.5±0.05 2.0±0.16 0.01 0.05±0.001 Thyroid 2.2±0.12 4.0±0.21 1.9±0.16 0.05 0.20±0.011 Bone surface 2.7±0.24 5.2±0.22 1.9±0.12 0.01 0.05±0.002 Esophagus 2.1±0.13 3.4±0.49 1.7±0.17 0.05 0.17±0.024 Lung 2.1±0.31 4.4±0.76 2.1±0.20 0.12 0.53±0.091 Stomach 2.4±0.30 4.3±0.94 1.8±0.50 0.12 0.52±0.113 Liver 2.3±0.33 4.0±0.51 1.7±0.33 0.05 0.20±0.026 Bone marrow 1.8±0.10 3.4±0.40 1.9±0.14 0.12 0.41±0.048 Colon 1.7±0.22 3.6±0.42 2.2±0.44 0.12 0.43±0.050 Bladder 1.8±0.16 3.6±0.24 2.0±0.25 0.05 0.18±0.012 Gonad (Testis) 2.0±0.05 4.7±0.71 2.4±0.37 0.2 0.94±0.142 Breast (Chest) 2.3±0.16 4.5±0.11 1.9±0.13 0.05 0.23±0.006 Remaindera 2.1±0.15 4.0±0.57 1.9±0.22 0.05 0.20±0.029 Effective dose equivalent [mSv]: 4.1±0.22

a) Remainder comprises brain, heart, spinal column, and rectum. Bone surface is at the shoulder. The dose at the breast was measured in a Nomex-suit pocket on the chest; the skin dose was measured in another pocket on the abdomen. b) Value shows the mean (m) ± one standard deviation (s); the s indicates a statistical error (type-A) only. Systematic errors (type-B) of the detector system were conservatively incorporated into the values in keeping with radiological protection practices, by using conservative calibration curves for both, the correction of TDMS efﬁciency and the determination of LET using PNTD. c) The Q-LET relationship and the WT values were adopted from the 1990 recommendation of the ICRP, although the concept of dose equivalent was introduced in 1977.

203 Biological Effects of Space Radiation the body itself. The human body seems to be able to References generate an extensive amount of protection for itself in Bucker, H., Horneck, G., Reitz, G., Graul, E.H., Berger, H., an environment exposed to space radiation. Hoffken, H., Ruther, W., Heinrich, W. and Beaujean, R. The International Commission on Radiological (1986) Embryogenesis and organogenesis of Carausius Protection (ICRP) regulations restrict the annual morosus under spaceflight conditions. Naturwissenschaften, permissible dose to radiation workers to less than 50 73, 433-434. mSv. According to this regulation, human beings should Cucinotta, F.A., Badhwar, G.D., Saganti, P., Schimerling, not be able to stay over 50 days in the ISS. However, W., Wilson, J.W., Peterson, L.E. and Dicello, J.F. (2002) NASA and the Japan Aerospace Exploration Agency Space radiation cancer risk projections for exploration (JAXA) plan long-term stays in the ISS for up to 90 days missions: Uncertainty reduction and mitigation. NASA/ TP-2002-210777, NASA: Houston, TX. which would not conform with ICRP regulations. A trip to Mars will require a much longer stay in space (up to Doke, T., Hayashi, T., Kikuchi, J., Hasebe, N., Nagaoka, S., 1.5 years). The exposure dose acquired for a trip to Mars Kato, M. and Badhwar, G.D. (1995) Real time measurement is estimated to be about 1 Sv. This seems to mean that of LET distribution in the IML-2 Space Lab (STS-65). Nucl. Inst. Methods Phys. Res., A365, 524-532. the current ICRP regulations will not permit long-term stays in space. In order to allow crews to remain in space Durante, M., Ando, K., Furusawa, Y., Obe, G., George, for prolonged periods the total dose must be decreased, K. and Cucinotta, F.A. (2004) Complex chromosomal rearrangements induced in vivo by heavy ions. Cytogenet. and dosimetry and radiation protection studies must be Genome Res., 104, 240-244. considered. However, the dose rate is a very important factor in considering exposure to space radiation, Durante, M., Snigiryova, G., Akaeva, E., Bogomazova, A., Duzhinin, S., Fedorenko, B., Greco, O., Novitskaya, N., because space radiation includes neutrons. Generally, Rubanovich, A., Shevchenko, V., Von Recklinghausen, U. γ when cells are exposed to -rays at a low dose-rate, the and Obe, G. (2003) Chromosome aberration dosimetry in biological effects decrease when compared to high dose- cosmonauts after single or multiple space flights. Cytogenet. rate radiation (the so-called dose-rate effect). In contrast Genome Res., 103, 40-46. to this finding, Elkindʼs group reported that the biological Fukuda, T., Fukuda, K., Takahashi, A., Ohnishi, T., Nakano, effects of neutrons become more pronounced when T., Sato, M. and Gunge, N. (2000) Analysis of deletion cultured mammalian cells were exposed to neutrons at mutations of the rpsL gene in the yeast Saccharomyces a low dose-rate (Hill et al., 1984). This phenomenon cerevisiae detected after long-term flight on the Russian is called the opposite dose-rate effect. Taking these space station Mir. Mutat. Res., 470, 125-132. characteristics into account, we have to correctly estimate George, K., Wu, H., Willingham, V. and Cucinotta, F.A. (2002) the biological effects of space radiation during a long- Analysis of complex-type chromosome exchanges in term stay in space. To cope with the above mentioned astronauts' lymphocytes after space flight as a biomarker of problem, the National Space Development Agency of high-LET exposure. J. Radiat. Res., 43 (Suppl.), S129-S132. Japan (NASDA) considered the maximum permissible Harada, K., Nagaoka, S., Mohri, M., Ohnishi, T. and Sugahara, dose based on the exposure dose during a total lifetime T. (1998) Lethality of high linear energy transfer cosmic exposure, and proposed permissible lifetime exposure radiation to Escherichia coli DNA repair-deficient mutants dose of 1.0 Sv for a male approximately 35 years old, during the 'SL-J/FMPT' space experiment. FEMS Microbiol. and 0.9 Sv for a female approximately 35 years old. This Lett., 164, 39-45. would correspond to a lifetime cancer death probability Hill, C.K., Han, A. and Elkind, M.M. (1984) Possible error- of 3%, and this would be the acceptable level of risk prone repair of neoplastic transformation induced by fission- for astronauts (NASDA, 2001). The ICRP and National spectrum neutrons. Br. J. Cancer, 6 (Suppl.), 97-101. Council of Radiation Protection and Measurements Horneck, G., Rettberg, P., Baumstark-Khan, C., Rink, H., (NCRP) proposed 3.6% and 3% lifetime cancer death Kozubek, S., Schafer, M. and Schmitz, C. (1996) DNA probabilities, respectively. NASA proposes similar repair in microgravity: studies on bacteria and mammalian permissible lifetime exposure doses (1.0 Sv in male, 0.6 cells in the experiments REPAIR and KINETICS. J. Sv in female) (NCRP, 2000). Biotechnol., 47, 99-112. It is hoped that this review provides useful Ikenaga, M., Yoshikawa, I., Kojo, M., Ayaki, T., Ryo, H., information for understanding the problems involved in Ishizaki, K., Kato, T., Yamamoto, H. and Hara, R. (1997) maintaining and protecting the health of crew members Mutations induced in Drosophila during space flight. Biol. working in space and in the ISS. Sci. Space, 11, 346-350. Kiefer, J. (2002) Mutagenic effects of heavy charged particles. J. Acknowlegements Radiat. Res., 43 (Suppl), S21-S25. This work was partially supported by grants from NASDA (2001) Report by Manned Space Technology Support “Ground Research for Space Utilization” promoted by Committee, Space Radiation Health Subcommittee (in JAXA and the Japan Space Forum. Japanese). NCRP (2000) Report No. 132, Radiation protection guidance for activities in low-earth orbit, National Council on

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Radiation Protection and Measurements. Nojima, K., Ando, K., Fujiwara, H. and Ando, S. (2000) Effects of carbon ions on primary cultures of mouse brain cells. Adv. Space Res., 25, 2051-2056. Ohnishi, T., Inoue, N., Matsumoto, H., Omatsu, T., Ohira, Y. and Nagaoka, S. (1996) Cellular content of p53 protein in rat skin after exposure to the space environment. J. Appl. Physiol., 81, 183-185. Ohnishi, T., Ohnishi, K., Takahashi, A., Taniguchi, Y., Sato, M., Nakano, T. and Nagaoka, S. (2002) Detection of DNA damage induced by space radiation in Mir and space shuttle. J. Radiat. Res., 43, S133-S136. Ohnishi, T., Tsuji, K., Ohmura, T., Matsumoto, H., Wang, X., Takahashi, A., Nagaoka, S., Takabayashi, A. and Takahashi, A. (1998) Accumulation of stress protein 72 (HSP72) in muscle and spleen of goldﬁsh taken into space. Adv. Space Res., 21, 1077-1080. Pross, H.D. and Kiefer, J. (1999) Repair of cellular radiation damage in space under microgravity conditions. Radiat. Environ. Biophys., 38, 133-138. Shao, C., Furusawa, Y., Aoki, M., Matsumoto, H. and Ando, K. (2002) Nitric oxide-mediated bystander effect induced by heavy-ions in human salivary gland tumour cells. Int. J. Radiat. Biol., 78, 837-844. Suzuki, M., Tsuruoka, C., Kanai, T., Kato, T., Yatagai, F. and Watanabe, M. (2003) Qualitative and quantitative difference in mutation induction between carbon-and neon-ion beams in normal human cells. Biol. Sci. Space, 17, 302-306. Suzuki, M., Zhou, H., Geard, C.R. and Hei, T.K. (2004) Effect of medium on chromatin damage in bystander mammalian cells. Radiat. Res., 162, 264-269. Takahashi, A., Ohnishi, K., Fukui, M., Nakano, T., Yamaguchi, K., Nagaoka, S. and Ohnishi, T. (1997) Mutation frequency of Dictyostelium discoideum spores exposed to the space environment. Biol. Sci. Space, 11, 81-86. Takahashi, A., Ohnishi, K., Ota, I., Asakawa, I., Tamamoto, T., Furusawa, Y., Matsumoto, H. and Ohnishi, T. (2001) p53- Dependent thermal enhancement of cellular sensitivity in human squamous cell carcinomas in relation to LET. Int. J. Radiat. Biol., 77, 1043-1051. Takahashi, A., Ohnishi, K., Takahashi, S., Masukawa, M., Sekikawa, K., Amano, T., Nakano, T., Nagaoka, S. and Ohnishi, T. (2000) The effects of microgravity on ligase activity in the repair of DNA double-strand breaks. Int. J. Radiat. Biol., 76, 783-788. Yasuda, H., Komiyama, T., Badhwar, G.D. and Fujitaka, K. (2000) Effective dose equivalent in the ninth Shuttle-Mir Mission (STS-91). Radiat. Res., 154, 705-713. Yatagai, F., Saito, T., Takahashi, A., Fujie, A., Nagaoka, S., Sato, M. and Ohnishi, T. (2000) rpsL mutation induction after space ﬂight on MIR. Mutat. Res., 453, 1-4.

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