4
Biomedical Research Issues

NASA’s biomedical program has been reviewed in a number of past NRC reports.1,2 A 2001 IOM review noted that “the three most important health issues that have been identified for long-duration missions are late effects of radiation, loss of bone mineral density, and behavioral adaptation.”3 More recently, the Bioastronautics roadmap, described by NASA as “the framework used to identify and assess the risks of crew exposure to the hazardous environments of space,” was reviewed.4 The review of that document reiterated the importance of the three areas cited in the 2001 IOM report and identified additional concerns, including food and nutrition and advanced life support. The relevance of ISS research to some of these critical research areas is discussed below.

RADIATION

The radiation encountered once one leaves Earth’s atmosphere consists of a mix of high-energy gamma rays, protons, electrons, neutrons, and high-Z charged particles that cannot be simulated on the ground. Positioned as it is in low Earth orbit, the ISS is exposed to all of these types of radiation, but the proportion of total exposure accounted for by exposure to high-Z particles is less than that expected on the lunar surface or in transit to Mars. Although a direct extrapolation of the radiation hazard from long-term animal experiments on the ISS to the radiation hazards encountered by humans during exploration missions in free space is problematic due to the differences in energy and mass spectrum of the galactic and solar cosmic rays, data obtained from animal experiments on the ISS are important because the mixed radiation field cannot be simulated on the ground, and adequately shielding the occupants in an exploration spacecraft is currently prohibitive due to the large upmass required.

For the proposed lunar sortie missions, present estimates of the radiation risk are likely valid because the total exposure is relatively low.5 The predominant risk is probably the induction of hematologic and solid malignancies, and no acute effects are expected. However, during 6-month stays at a lunar outpost on a 3-year round trip to Mars, the exposure to radiation has the potential to produce significant long-term effects that may not be limited to cancer induction.6,7

Classically, the radiation risk was predominantly thought to be associated with damage to the proliferating cells in organs whose function relied heavily on cell renewal systems to replace their damaged components.8,9 Recently, this concept has been called into question by a number of human and rodent studies.10-12 For example, 20 to 50 percent of brain tumor patients who receive fractionated large-field or whole brain irradiation and survive longer than 6 months have measurable cognitive deficits;13-15 of these, 10 to 15 percent progress to a condition similar to that seen in Alzheimer’s patients. In rodents, the late radiation effects produced by single dose or short fractionation schemes are not predictive of the late effects produced by prolonged fractionation schemes in brain, kidney, lung, and heart, where the functionality is predominantly the nondividing cells.16-19

Mechanistic studies have demonstrated that ionizing radiation produces a chronic increase in the intracellular reactive oxygen species, which leads to a chronic inflammatory response.20 Importantly, the level of reactive oxygen species and inflammation in nondividing cells never returns to its original level after irradiation, and so these cells, which do not die, function abnormally for months or years after



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Review of NASA Plans for the International Space Station 4 Biomedical Research Issues NASA’s biomedical program has been reviewed in a number of past NRC reports.1,2 A 2001 IOM review noted that “the three most important health issues that have been identified for long-duration missions are late effects of radiation, loss of bone mineral density, and behavioral adaptation.”3 More recently, the Bioastronautics roadmap, described by NASA as “the framework used to identify and assess the risks of crew exposure to the hazardous environments of space,” was reviewed.4 The review of that document reiterated the importance of the three areas cited in the 2001 IOM report and identified additional concerns, including food and nutrition and advanced life support. The relevance of ISS research to some of these critical research areas is discussed below. RADIATION The radiation encountered once one leaves Earth’s atmosphere consists of a mix of high-energy gamma rays, protons, electrons, neutrons, and high-Z charged particles that cannot be simulated on the ground. Positioned as it is in low Earth orbit, the ISS is exposed to all of these types of radiation, but the proportion of total exposure accounted for by exposure to high-Z particles is less than that expected on the lunar surface or in transit to Mars. Although a direct extrapolation of the radiation hazard from long-term animal experiments on the ISS to the radiation hazards encountered by humans during exploration missions in free space is problematic due to the differences in energy and mass spectrum of the galactic and solar cosmic rays, data obtained from animal experiments on the ISS are important because the mixed radiation field cannot be simulated on the ground, and adequately shielding the occupants in an exploration spacecraft is currently prohibitive due to the large upmass required. For the proposed lunar sortie missions, present estimates of the radiation risk are likely valid because the total exposure is relatively low.5 The predominant risk is probably the induction of hematologic and solid malignancies, and no acute effects are expected. However, during 6-month stays at a lunar outpost on a 3-year round trip to Mars, the exposure to radiation has the potential to produce significant long-term effects that may not be limited to cancer induction.6,7 Classically, the radiation risk was predominantly thought to be associated with damage to the proliferating cells in organs whose function relied heavily on cell renewal systems to replace their damaged components.8,9 Recently, this concept has been called into question by a number of human and rodent studies.10-12 For example, 20 to 50 percent of brain tumor patients who receive fractionated large-field or whole brain irradiation and survive longer than 6 months have measurable cognitive deficits;13-15 of these, 10 to 15 percent progress to a condition similar to that seen in Alzheimer’s patients. In rodents, the late radiation effects produced by single dose or short fractionation schemes are not predictive of the late effects produced by prolonged fractionation schemes in brain, kidney, lung, and heart, where the functionality is predominantly the nondividing cells.16-19 Mechanistic studies have demonstrated that ionizing radiation produces a chronic increase in the intracellular reactive oxygen species, which leads to a chronic inflammatory response.20 Importantly, the level of reactive oxygen species and inflammation in nondividing cells never returns to its original level after irradiation, and so these cells, which do not die, function abnormally for months or years after

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Review of NASA Plans for the International Space Station irradiation.21 In nearly all the cases studied so far, these radiation-induced deficits occur with no gross histopathological evidence of disease.22-24 Given that (1) the dose, dose rate, and composition of a radiation field can drastically alter the biological outcome of exposure,25-28 (2) the results of short-term exposures do not predict the results of long-term exposures,29-32 (3) the biological effects of mixed-field radiation are generally worse than the sum of the biological effects of the individual types of radiation,33-35 and (4) microgravity and other environmental factors in the space vehicle are likely to have some influence on the final biological response, it would appear that experiments to assess the risk of prolonged exposure to space radiation can only be performed in the ISS or on the Moon. This would require both restoration of the capacity to perform long-term rodent experiments on the ISS or on the Moon and initiation of preflight and long-term postflight testing of humans for kidney, lung, heart, and brain function. Importantly, the low linear energy transfer (LET) radiation damage to the kidney and the brain, including cognitive impairment, appears to be modifiable in both humans and rodents using pharmacological interventions.36,37 Although there are no data on mitigating the late effects in liver, kidney, lung, and brain produced by high-LET radiation or mixed radiation fields, there are suitable pharmacological agents that could be tested on the ISS or on the Moon now.38,39 Finding: There is insufficient information about the mixed-beam radiation effects on biological systems to confidently derive risk estimates for a Mars mission. Based on current knowledge, it is dangerous to assume that carcinogenesis is the only long-term risk of extended-duration spaceflight. Recommendation: A high priority should be given to assessing the noncarcinogenic late effects of exposure to space radiation on the ISS or the Moon and to testing pharmacological interventions for ameliorating these late effects, because the results are critical for designing a Mars mission. BONE AND MUSCLE Existing countermeasures have failed to prevent deterioration of bone and muscle in astronauts during spaceflight. Current data based on 4- to 6-month spaceflights indicate that there is impressive bone loss at both the spine and hip.40 Observed losses at the spine and hip average 0.9 percent and 1.5 percent per month, respectively. Quantitative computer tomography studies indicate that loss of trabecular bone at the femoral neck (a frequent hip fracture site) is 2.7 percent per month.41 Although there is a wide spectrum of individual variation, linear extrapolation of these data suggests that approximately two-thirds (64 percent) of astronauts would experience more than a 25 percent loss of bone mineral at the hip during a 30-month Mars outpost-class mission. A 21 percent decline in peak force of slow muscle fibers has been observed after a 17-day spaceflight, and a 20 to 48 percent reduction in maximal voluntary contraction of the plantar flexors has been observed after 6 months in space.42 This level of deterioration will compromise motor performance and increase susceptibility to injury, changes unlikely to be acceptable for an outpost-class mission to Mars. Moreover, reversibility of tissue deterioration is unclear for long-duration flights, particularly in an environment of radiation exposure and suboptimal nutrition. The ability of fractional gravity environments (such as the 0.16-g and 0.38-g fields of the Moon and Mars, respectively) to maintain bone and muscle integrity has not been determined, and recent data indicate that bone density does not return to baseline within 12 months of returning to Earth.43,44 Muscle function appears to return to preflight levels within weeks. However, studies of long-term recovery have not been conducted to ascertain whether the deterioration involved nonpathological muscle cell shrinkage and postflight cell enlargement or a process of pathological cell degeneration followed by cell regeneration. Pathology is a concern, because tissue regeneration may be compromised by exposure to radiation in spaceflight.45,46 NASA has some human experiments planned and in progress to address the issue of bone loss. However, space-based clinical trials of antiosteoporotic therapies lag behind terrestrial applications by

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Review of NASA Plans for the International Space Station more than 10 years.47 Animal experiments could test whether antiresorptive drugs with or without other interventions would mitigate these risks. Animal studies would also allow for biomechanical studies (e.g., stress/strain curves) and bone histomorphometry, which would allow for better estimation of risks to astronauts and provide information to test maintenance of bone strength as well as bone density. Finally, an animal centrifuge (currently deleted because the JAXA-supplied centrifuge accommodation module has been removed from the flight manifest) would allow investigators to test (1) the potential bone-sparing effect of a fractional gravity environment such as that encountered on the Moon (0.16 g) or Mars (0.38 g), and (2) the effect of an intermittent centrifugal loading as a potential countermeasure. Finding: Current countermeasures have failed to mitigate significant progressive loss of bone and muscle mass during spaceflight. Recommendation: Long-duration experiments to characterize temporal muscle atrophy and bone loss in the spacecraft environment should be designed and conducted on the ISS. Restoration of the animal habitat and glove box are essential for these studies, and the probable utility of the animal centrifuge as a unique fractional gravity research tool and a potential countermeasure should be reevaluated in the context of a martian outpost scenario. BEHAVIOR The 2001 Safe Passage report noted that “human interactions aboard a spacecraft, isolated in time and space from Earth, may well be one of the more serious challenges to exploratory missions by humans.”48 Every recent examination of long-duration spaceflight has identified psychosocial (including cultural) issues as among the most likely, and potentially most damaging, inherent problems.49-53 Highly probable sources of adjustment difficulties include prolonged separation from one’s customary physical and social environment—in fact, from one’s home planet—under conditions of danger, dependence on complex life support technologies, noise, hygienic shortcomings, confinement, reduced privacy and personal space, significant changes to one’s body and physiological processes, difficulty of leaving in an emergency, enforced and monotonous closeness (both psychological and physical) with people of possibly very different, and possibly aversive, backgrounds and personalities, and the disorienting aspects of microgravity or reduced gravity. Previous reports have identified problems of adaptation to capsule living such as anxiety, depression, withdrawal, interpersonal hostility directed against crewmates and/or mission controllers and the home organization, sleep disturbances, psychosomatic symptoms, and counterdependence.54 A 2006 IOM and NRC report commented on the added difficulties of communicating and establishing positive relationships within groups that are diverse (with respect to ethnicity, gender, education, organizational norms, and general culture) and between spacefarers and their home organizations, and the tendency of these difficulties to exacerbate other problems.55 Although there is a sufficiency of data from spaceflight to establish the psychosocial realm as one that must be seriously considered, considerable corroborative evidence has been derived from research in simulated and analog environments.a Many of these environments involve isolation, confinement, and remoteness from “normal” social networks and accustomed sites; some are in locations where the outside environment is dangerous, life support systems are crucial, and access is limited. It is clear that both analog and simulated environments can be, and have been, useful in identifying many of the psychosocial problems that are likely to plague the crews of Moon outposts and Mars explorations. However, these terrestrial environmental approximations cannot duplicate the extreme physical conditions that space a   Simulated environments include bed-rest laboratories and mock-ups of a space vehicle or station in which volunteers live for weeks or months. Analog environments include small polar research stations, undersea habitats, and submersible vessels.

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Review of NASA Plans for the International Space Station explorers will face, particularly the loss of gravity and resultant physiological changes and disruptions of basic functions such as spatial perception and locomotion.56 The effects of these psychosocial and environmental factors are interactive. Further, unlike almost all analogs and simulations, spaceflight—especially Mars flight—poses the problem that crew members who experience serious psychological or psychiatric dysfunction cannot be spared from their job assignments. There will be no one who could administer psychotherapy, no facilities for providing sedation or other restraints until the end of the mission (unless it is imminent), and no chance of returning affected crew members immediately to Earth. Thus, such breakdowns are very likely to be dangerous to the mission and to the lives of the crew. Finding: Simulation and analog environments do not fully mimic the psychosocial and behavioral risks of long-term human spaceflight, especially those posed by a prolonged Mars mission, and are not adequate as testbeds for development and validation of effective countermeasures against these risks. Recommendation: Research should be carried out on the ISS (and/or the Moon) to establish how specific factors of the space environment might impair behavior, performance, interpersonal relationships, and psychological well-being and to develop effective countermeasures against potential adverse effects. DATA Life Sciences Data Archive and the Longitudinal Study of Astronaut Health The end points of all research are new knowledge, technologies, and products. In the realm of medical operations and biological responses to spaceflight, this information is codified in the Life Sciences Data Archive and the Longitudinal Study of Astronaut Health.57 These data will never be recreated and therefore constitute unique resources for future mission planners. The importance of these resources and issues related to their availability to investigators have been discussed in detail in previous reports.58,59 These resources are not mentioned in the ISS roadmap exercises. Recommendation: NASA should provide mechanisms to retain and readily access the scientific knowledge and data already obtained from previous space missions. Such information should be in a form (e.g., Internet-based) that is usable by members of the scientific and medical communities both within NASA and outside it. Individual Variability When deciding what amount of ISS resources should be directed to mitigate a medical/biological risk, individual differences (biological, psychological, cultural, social) pose a particular challenge. For example, preliminary data provided to the panel indicate that bone and muscle loss varied by a factor of 3 or more, and in many individuals these parameters had not returned to baseline. Although it has made considerable progress in representing biological variability in the permissible levels of exposure to radiation, NASA lacks a similar approach for musculoskeletal and cardiovascular deconditioning standards. Defining the probability that any crew members will exceed the proposed standard is a necessary part of safety decisions. If insufficient data exist to make medical and safety decisions (both go/no-go and mission modifying) in a probabilistic fashion, additional data collection or alternative statistical treatment is warranted.60 The panel concurs with a recent report recommending that NASA incorporate quality-of-evidence measurements and use standard-of-uncertainty analysis techniques to assess medical risk, particularly for human exploration missions.61 Reliance on expert opinion without an adequate evidence base is not an

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Review of NASA Plans for the International Space Station acceptable method for making decisions related to crew health and safety. The tacit assumption that risk values and associated medical decision making can be extrapolated from current data obtained from limited sources, such as anecdotal reports from previous crew members and short-duration animal and human studies in the actual space environment, raises concerns. Recommendation: NASA should critically analyze both disaggregated and aggregated data (such as that in the Longitudinal Study of Astronaut Health and the Life Sciences Data Archive) to derive confidence bands for medical risks. The quality of the data and the difference between best-case and worst-case scenarios should be assessed and analyzed. Additional, hypothesis-driven, long-duration research on the ISS may be necessary to refine confidence bands such that there is a reasonable statistical likelihood that the adaptation of crew members during a long-duration mission will fall within a clinically acceptable range. Research into predictors of individual responses to conditions on the ISS or during extended-duration spaceflight is needed to allow tailoring of individual countermeasures. Recommendation: NASA should utilize previous recommendations (e.g., those of the IOM and NRC bioastronautics roadmap review committee) to select and sequence additional needed experiments and address in a timely fashion those critical issues that could affect important decisions on the design of architecture for future missions. REFERENCES 1. National Research Council (NRC). 1987. A Strategy for Space Biology and Medical Science. National Academy Press, Washington, D.C. 2. NRC. 1998. A Strategy for Research in Space Biology and Medicine in the New Century. National Academy Press, Washington, D.C. 3. Institute of Medicine (IOM). 2001. Safe Passage: Astronaut Care for Exploration Missions. National Academy Press, Washington, D.C., p. 3. 4. IOM and NRC. 2006. A Risk Reduction Strategy for Human Exploration of Space: A Review of NASA’s Bioastronautics Roadmap. The National Academies Press, Washington, D.C. 5. Brenner, D.J., and E.J. Hall. 1992. Commentary 2 on Cox and Little: Radiation-induced oncogenic transformation: The interplay between dose, dose protraction, and radiation quality. Adv. Radiat. Biol. 16: 167-179. 6. Curtis, S.B. 1994. Importance of dose rate and cell proliferation in the evaluation of biological experimental results. Adv. Space Res. 14: 989-996. 7. Curtis, S.B. 1996. Possible effects of protracted exposure to the additivity risks from space radiations. Adv. Space Res. 18: 41-44. 8. Withers, H.R., L.J. Peters, and H.S. Kogelnik. 1980. The pathobiology of late effects in irradiation. Pp. 439-448 in Radiation Biology in Cancer Research (R.E. Meyn and H.R. Withers, eds.). Raven Press, New York, N.Y. 9. Rubin, P., and G.W. Casarett. 1968. Clinical radiation pathology as applied to curative radiotherapy. Cancer 22: 767-778. 10. Denham, J.W., and M. Hauer-Jensen. 2002. The radiotherapeutic injuryA complex “wound.” Radiother. Oncol. 63: 129-145. 11. Coleman, C.N., H.B. Stone, J.E. Moulder, and T.C. Pellmar. 2004. Modulation of radiation injury. Science 304: 693-694. 12. Stone, H.B., C.N. Coleman, M.S. Anscher, and W.H. McBride. 2003. Effects of radiation on normal tissue: Consequences and mechanisms. Lancet Oncol. 4: 529-536.

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Review of NASA Plans for the International Space Station 13. Roman, D.D., and P.W. Sperduto. 1995. Neuropsychological effects of cranial radiation: Current knowledge and future directions. Int. J. Radiat. Oncol. Biol. Phys. 31: 983-998. 14. Surma-aho, O., M. Niemalä, J. Vilkki, M. Kouri, A. Brander, O. Salonen, A. Paetau, M. Kallio, J. Pyykkönen, and J. Jääskeläinen. 2001. Adverse long-term effects of brain radiotherapy in adult low-grade glioma patients. Neurology 56: 1285-1290. 15. Shaw, E.G., and M.E. Robbins. 2005. Central nervous system. In Radiation Toxicity: A Practical Guide (W. Small and G.E. Woloschak, eds.). Kluwer Academic Publishers, New York, N.Y. 16. Tofilon, P.J., and J.R. Fike. 2000. The radioresponse of the central nervous system: A dynamic process. Radiat. Res. 153: 357-370. 17. Gaber, M.W., O.M. Sabek, K. Fukatsu, H.G. Wilcox, M.F. Kiani, and T.E. Merchant. 2003. Differences in ICAM-1 and TNF-α expression between large single fraction and fractionated irradiation in mouse brain. Int. J. Radiat. Biol. 79: 359-366. 18. Jaenke, R.S., M.E.C. Robbins, T. Bywaters, E. Whitehouse, M. Rezvani, and J.W. Hopewell. 1993. Capillary endothelium: Target site of renal radiation injury. Lab. Invest. 57: 551-565. 19. Rubin, P., J. Finkelstein, and D. Shapiro. 1992. Molecular biology mechanisms in the radiation induction of pulmonary injury syndromes: Interrelationship between the alveolar macrophages and the septal fibroblast. Int. J. Radiat. Oncol. Biol. Phys. 24: 93-101. 20. Robbins, M.E.C., and W. Zhao. 2004. Chronic oxidative stress and radiation-induced late normal tissue injury: A review. Int. J. Radiat. Biol. 80: 251-259. 21. Robbins, M.E.C., and W. Zhao. 2004. Chronic oxidative stress and radiation-induced late normal tissue injury: A review. 22. Yoneoka, Y., M. Satoh, K. Akiyama, K. Sano, Y. Fujii, and R. Tanaka. 1999. An experimental study of radiation-induced cognitive dysfunction in an adult rat model. Br. J. Radiol. 72: 1196-1201. 23. Hodges, H., N. Katzung, P. Sowinski, J.W. Hopewell, J.H. Wilkinson, T. Bywaters, and M. Rezvani. 1998. Late behavioral and neuropathological effects of local brain irradiation in the rat. Behav. Brain Res. 91: 99-114. 24. Brown, W.R., C.R. Thore, D.M. Moody, M.E. Robbins, and K.T. Wheeler. 2005. Vascular damage after fractionated whole-brain irradiation in rats. Radiat. Res. 164(5): 662-668. 25. Brenner, D.J., and E.J. Hall. 1992. Commentary 2 on Cox and Little: Radiation-induced oncogenic transformation: The interplay between dose, dose protraction, and radiation quality. Adv. Radiat. Biol. 16: 167-179. 26. Curtis, S.B. 1994. Importance of dose rate and cell proliferation in the evaluation of biological experimental results. 27. Curtis, S.B. 1996. Possible effects of protracted exposure to the additivity risks from space radiations. 28. Hall, E.J. 1994. Radiobiology for the Radiologist, 4th Edition. J.B. Lippincott Co., Philadelphia, Pa. 29. Tofilon, P.J., and J.R. Fike. 2000. The radioresponse of the central nervous system: A dynamic process. Radiat. Res. 153: 357-370. 30. Gaber, M.W., O.M. Sabek, K. Fukatsu, H.G. Wilcox, M.F. Kiani, and T.E. Merchant. 2003. Differences in ICAM-1 and TNF-α expression between large single fraction and fractionated irradiation in mouse brain. Int. J. Radiat. Biol. 79: 359-366. 31. Jaenke, R.S., M.E.C. Robbins, T. Bywaters, E. Whitehouse, M. Rezvani, and J.W. Hopewell. 1993. Capillary endothelium: Target site of renal radiation injury. Lab. Invest. 57: 551-565. 32. Rubin, P., J. Finkelstein, and D. Shapiro. 1992. Molecular biology mechanisms in the radiation induction of pulmonary injury syndromes: Interrelationship between the alveolar macrophages and the septal fibroblast.

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Review of NASA Plans for the International Space Station 33. Ngo, F.Q., E.A. Blakely, and C.A. Tobias. 1981. Sequential exposures of mammalian cells to low- and high-LET radiations: I. Lethal effects following X-rays and neon-ion irradiation. Radiat. Res. 87: 59-78. 34. Iliakis, G., F.Q. Ngo, W.K. Roberts, and K. Youngman. 1985. Evidence for similarities between radiation damage expressed by beta-ara-A and damage involved in the interaction effect observed after exposure of V-79 cells to mixed neutrons and gamma irradiation. Radiat. Res. 104: 303-316. 35. Ngo, F.Q., E.A. Blakely, C.A. Tobias, P.Y. Chang, and L. Lommel. 1988. Sequential exposures of mammalian cells to low- and high-LET radiations. II. As a function of cell cycle stage. Radiat. Res. 115: 54-69. 36. Coleman, C.N., H.B. Stone, J.E. Moulder, and T.C. Pellmar. 2004. Modulation of radiation injury. Science 304: 693-694. 37. Moulder, J., M.E.C. Robbins, E.P. Cohen, J.W. Hopewell, and W.F. Ward. 1998. Pharmacologic modification of radiation-induced late normal tissue injury. Pp. 129-151 in Radiation Therapy (B.B. Mittal, J.A. Purdy, and K.K. Ang, eds.). Kluwer, Norwell, Mass. 38. Coleman, C.N., H.B. Stone, J.E. Moulder, and T.C. Pellmar. 2004. Modulation of radiation injury. 39. Moulder, J., M.E.C. Robbins, E.P. Cohen, J.W. Hopewell, and W.F. Ward. 1998. Pharmacologic modification of radiation-induced late normal tissue injury. 40. Lang, T., A. LeBlanc, H. Evans, Y. Lu, H. Genant, and A. Yu. 2004. Cortical and trabecular bone mineral loss from the spine and hip in long-duration spaceflight. J. Bone Miner. Res. 19: 1006-1012. 41. Lang, T., A. LeBlanc, H. Evans, Y. Lu, H. Genant, and A. Yu. 2004. Cortical and trabecular bone mineral loss from the spine and hip in long-duration spaceflight. 42. Fitts, R.H., D.R. Riley, and J.J. Widrick. 2001. Functional and structural adaptations of skeletal muscle to microgravity. J. Exp. Biol. 204: 3201-3208. 43. Sibonga, J.D., H.J. Evans, H. Sung, E.R. Spector, V.S. Oganov, A.V. Bakulin, L.C. Shackelford, and A.D. LeBlanc. 2005. Skeletal recovery following long-duration spaceflight missions as predicted by preflight and postflight dual x-ray absorptiometry (DXA): Scans of 49 crewmembers. J. Bone Miner. Res. 20: S44. 44. Lang, T.F., A. LeBlanc, H. Evans, and Y. Lu. 2005. Recovery of proximal femoral density and geometry after long-duration spaceflight. J. Bone Miner. Res. 20: S44. 45. Mozdziak, P.E., Q. Truong, A. Macius, and E. Schultz. 1998. Hindlimb suspension reduces muscle regeneration. Eur. J. Appl. Physiol. Occup. Physiol. 78: 136-140. 46. Kirchen, M.E., K.M. O’Connor, H.E. Gruber, J.R. Sweeney, I.A. Fras, S.J. Stover, A. Sarmiento, and G.J. Marshall. 1995. Effects of microgravity on bone healing in a rat fibular osteotomy model. Clin. Orthop. Relat. Res. 318: 231-242. 47. Strewler, G.J. 2004. Decimal point—Osteoporosis therapy at the 10-year mark. N. Engl. J. Med. 350(12): 1172-1174. 48. IOM. 2001. Safe Passage: Astronaut Care for Exploration Missions, p. 3. 49. Harrison, A.A. 2001. Spacefaring: The Human Dimension. University of California Press, Berkeley, Calif. 50. IOM. 2001. Safe Passage: Astronaut Care for Exploration Missions, p. 3. 51. Kanas, N., and D. Manzey. 2003. Space Psychology and Psychiatry. Kluwer, Dordrecht, and Microcosm Press, El Segundo, Calif. 52. National Aeronautics and Space Administration (NASA). 2004. Bioastronautics Critical Path Roadmap. NASA, Washington, D.C. 53. NRC. 1998. A Strategy for Research in Space Biology and Medicine in the New Century. 54. Suedfeld, P., and G.D. Steel. 2001. The environmental psychology of capsule habitats. Annual Review of Psychology 51: 227-253. 55. IOM and NRC. 2006. A Risk Reduction Strategy for Human Exploration of Space.

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Review of NASA Plans for the International Space Station 56. NRC. 1998. A Strategy for Research in Space Biology and Medicine in the New Century, p. 198. 57. IOM. 2001. Safe Passage: Astronaut Care for Exploration Missions, p. 3. 58. NRC. 1998. A Strategy for Research in Space Biology and Medicine in the New Century. 59. IOM. 2001. Safe Passage: Astronaut Care for Exploration Missions. 60. IOM. 2001. Small Clinical Trials: Issues and Challenges. National Academy Press, Washington, D.C. 61. IOM and NRC. 2006. A Risk Reduction Strategy for Human Exploration of Space.