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Review of NASA's Human Research Program Evidence Books: A Letter Report (2008)

Chapter: C Committee Reviews of the Evidence Books

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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Suggested Citation:"C Committee Reviews of the Evidence Books." Institute of Medicine. 2008. Review of NASA's Human Research Program Evidence Books: A Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/12261.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

C Committee Reviews of the Evidence Books Sensorimotor Chapter 1 Impaired Ability to Maintain Control of Vehicles and Other Complex Systems Bone Chapter 2 Accelerated Osteoporosis Chapter 3 Bone Fracture Chapter 4 Renal Stone Formation Chapter 5 Intervertebral Disk Damage Muscle Chapter 6 Impaired Performance Errors Due to Reduced Muscle Mass, Strength, and Endurance Chapter 7 Operational Impact of Prolonged Daily Required Exercise Chapter 8 Compromised EVA Performance and Crew Health Due to Inadequate EVA Suit Systems Cardiovascular Chapter 9 Orthostatic Intolerance During Re-Exposure to Gravity Chapter 10 Cardiovascular Effects on Performance and Operational Limi- tations Chapter 11 Cardiac Rhythm Problems 31

32 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS Nutrition Chapter 12 Inadequate Nutrition Immunology Chapter 13 Crew Adverse Health Event Due to Altered Immune Response Behavioral Health and Performance Chapter 14 Performance Errors Due to Sleep Loss, Circadian Desynchro- nization, Fatigue, and Work Overload Chapter 15 Performance Errors Due to Poor Team Cohesion and Perform- ance, Inadequate Selection/Team Composition, Inadequate Training, and Poor Psychosocial Adaptation Chapter 16 Behavioral and Psychiatric Conditions Space Radiation Chapter 17 Acute Radiation Syndromes Due to Solar Particle Events Chapter 18 Degenerative Tissue or Other Health Effects from Radiation Exposure Chapter 19 Acute or Late Central Nervous System Effects from Radiation Exposure Chapter 20 Radiation Carcinogenesis Pharmacology Chapter 21 Therapeutic Failure Due to Ineffectiveness of Medication Exploration Medical Capabilities Chapter 22 Inability to Adequately Treat an Ill or Injured Crew Member Space Human Factors and Habitability Chapter 23 Lack of Human-Centered Design A. Sub-Risk of Reduced Safety and Efficiency Due to Poor Human Factors Design B. Sub-Risk of Error Due to Inadequate Information C. Sub-Risk Associated with Poor Task Design Chapter 24 Inadequate Food System Chapter 25 Adverse Health Effects from Lunar Dust Exposure

APPENDIX C 33 Chapter 1 Impaired Ability to Maintain Control of Vehicles and Other Complex Systems Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? Yes. Experimental and observational findings from prior missions, including Apollo, aviation, ground-experimental, and patient data are quite thoroughly described. Additional data and discussions would be helpful to add as described below. Is the text of the short description of the health risk provided in the PRD)clear (it should be Section I of the evidence book)? Provide suggestions of revised wording. Yes. However, an additional sentence relating the risk to existing Apollo data would be helpful. Does the evidence book make the case for the research gaps presented? Yes. The paper presents a comprehensive review of the literature. The implica- tions for future lunar and Mars missions are clearly spelled out. The documenta- tion in the appendix of apparently all U.S. and Russian neurological and sensorimotor experiments conducted in space is highly informative. Additional risks to be considered for review in this paper include the possible impact of alterations in cortical maps of motor control and somatosensation, and the physiologically relevant factors associated with cognitive and sensorimotor adaptations to abnormal force conditions. Are there any additional gaps in knowledge that should be considered for this specific risk? Yes, there should be some discussion of the relationship to the basic perform- ance measures (reaction time, short-term memory, etc.) in spaceflight. A discus- sion of fractional g-levels and sensorimotor adaptation is also needed. Does the evidence book address relevant interactions among risks? Yes. A consideration of sleep deprivation and stress effects on sensorimotor performance is indicated. Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? These are not relevant to this evidence book.

34 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed? • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed? • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered? The paper is highly readable, scholarly, and quite comprehensive in its coverage. The amount of material covered and the implications of the findings for future lunar and Mars missions are highly informative. The paper clearly specifies the potential risks in future space activities based on the sensorimotor deficit find- ings from previous studies. It would be helpful if the paper had a discussion of the caveats relevant to assessing the reliability of data from these types of space flight experiments that involve few subjects and lack adequate controls. A more thorough review of the literature on vestibulo-ocular reflex function could be added. The committee had concerns that the section on tilt translation and tilt gain illusions seems exceedingly long given the sparse information actu- ally available. Discussions of the issues regarding the theories that are proposed to explain these illusions should be added, as should a discussion of oculogravic illusions. The section on computer-based simulation information presents a number of the classic early studies in the field but more recent modeling data need to be described (data based on more biological considerations than on analogies with inertial guidance systems). Future reviews would benefit from a more diverse group of contributors that could add a focus on these additional topics. Minor issue: There is an error in the table of contents in which “Risk of Accelerated Osteopo- rosis” is listed as the title of the risk. Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. The paper provides a clear and succinct review of the space and other literature related to sensorimotor problems during and after spaceflight. The extrapolation of these data to potential risks in vehicle control for lunar and Mars missions is informative, particularly discussions about landing a vehicle on the Mars sur- face. The issue of predictors of astronaut performance from preflight measures is highly relevant.

APPENDIX C 35 Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) Space motion sickness should still be considered an unsolved risk, and there is ample reason to keep it on the gap and critical path lists. Chapter 2 Accelerated Osteoporosis Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? Generally, yes. The evidence book is an excellent review and analysis of the evidence. Some areas deserve additional comment, at least in part because they may lead to the identification of more knowledge gaps. 1. Although mentioned, the considerable heterogeneity in the rate of bone loss is of potentially huge importance, and should be further emphasized. Some flight personnel apparently experience particularly rapid bone loss, and these individuals may be at particular risk. Are flights imperiled more by the astronauts with greatest bone loss rather than the average bone loss of the crew? As the evidence book notes, there is also heterogeneity in the de- gree of recovery from bone loss after landing. 2. The evidence book mentions the lack of evidence concerning the effects of long-term flight (> 6 months) on bone, but fails to discuss the relevant data concerning long-term spinal cord injury (SCI). One of the potential failings of the comparison of bone loss in spaceflight to menopause is that it could lead to the assumption that the bone loss in space is self-limited. On the other hand, long-term SCI studies suggest that bone loss continues for long periods after immobilization begins and results in truly dramatic reductions in bone mass. Moreover, some data indicate that markers of bone resorption remain elevated for long periods, further raising the concern that accelerated bone loss could be prolonged with more impressive implications for long- term flights. These considerations seem important to discuss. See the re- views of SCI and bone by Giangregorio and Blimkie (2002) and Jiang et al. (2006). 3. The paper concentrates on the effects of the unloading that accompanies weightlessness, but little attention is given to known or possible effects of long-term reduced gravity environments such as those that might be experi- enced with future lunar missions. 4. A discussion of the potential biomechanical trauma anticipated on bone during flight and planetary/lunar stays seems important. Although it could also be presented in the evidence book on fractures (and just referenced in this section), the current evidence book does a good job of presenting finite

36 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS element analyses of the strength of bone, and the corollary of that discus- sion is that of the load-to-strength ratio (factor of risk). In other words, is the level of trauma risk anticipated (load) likely to be greater than the ability of the weakened bone to resist it (strength)? The issue of trauma would seem relevant given the possibility of flight turbulence, landing, and extra- vehicular excursions. Are there forms of trauma expected that might affect specific bones, and are those bones particularly weakened (e.g., hip)? In ad- dition to the possibility of trauma from factors such as turbulence, it may be worth mentioning the possibility of physical stresses from tasks requiring forceful movements and torque (although such tasks might be more likely to put stress on the upper extremities, where the bone changes are not as great). Should space suits or in-flight clothes contain force-mitigating pads during long flights? The degree of concern for in-flight fracture ultimately rests on the ability of the bones on the flight (and potentially the weakest bones) to resist the extant trauma. 5. The emphasis on unloading as the etiology of bone loss is necessary and appropriate, but the other potential causes of bone loss during missions may deserve more discussion. Although unloading is undoubtedly a dominant factor, other possible contributors to bone loss could be considered. These include chronic stress, weight loss, sleep disturbance, gonadal abnormali- ties, etc. Some of these are suspected to be problems, while others have not been examined. The possibility that unexpected effects on bone may be en- countered during spaceflight should not be ignored. More discussion is war- ranted. This may deserve special attention in light of the interindividual variation in bone loss. The factors mentioned, such as chronic stress and sleep disturbance, would be expected to vary substantially from person to person. 6. In the introduction, the authors appropriately point out that, despite their use of the menopausal and aging comparisons, that spaceflight is neither of those things. However, the possibility that spaceflight causes a distinct form of metabolic bone disease should be more carefully considered. For exam- ple, spaceflight is not like postmenopausal osteoporosis because there may be an absolute (or more marked) reduction in bone formation during flight whereas postmenopausal bone loss is characterized by increased bone for- mation (with an even more increased rate of resorption). If the nature of flight-induced bone loss is different from the aging or postmenopausal con- ditions, perhaps more akin to glucocorticoid-induced bone loss (where— like spaceflight—there is also a state of increased bone resorption and re- duced bone formation), it could result in an altered fracture threshold. An- other example of differences may be that hip bone loss seems to out of proportion to that seen in postmenopausal women, apparently indicating distinct pathophysiological mechanisms. Should these and other potential differences be examined to best understand how to mitigate risk?

APPENDIX C 37 7. Bone strength is the result of a number of factors, including the amount of bone, its structure, and its quality. The evidence book should mention the possibility that bone material properties could be altered by flight. Some data from the SCI literature indicate that bone formation is altered, poten- tially affecting material properties and strength. 8. Efforts undertaken so far to prevent bone loss during flight, and their effec- tiveness, should be discussed. 9. The recent occurrence of a hip fracture in a previous astronaut is potentially important, especially because traumatic fractures are highly related to lower bone mineral density (BMD) (Mackey et al., 2007). Perhaps this should be presented. Is the text of the short description of the health risk provided in the PRD clear (it should be Section I of the evidence book)? Provide suggestions of revised wording. 1. “…unloading of the skeleton. In moderate-duration flights (6 months) aver- age loss rates are approximately 1 percent per month, but some individuals lose at a greater rate. It is unclear whether this bone mineral loss will stabi- lize at a lower level or continue for the duration of longer flights. The cau- sation and specific nature of the loss are unknown. Efforts to devise methods to prevent loss during flight have not been successful. Mission- related bone loss…” 2. Also, the statement that “mission-related bone loss cannot be corrected by. . . ” may be too strong. Perhaps “ . . . cannot be reliably . . . ” or “ . . . cannot be completely . . . ” would be more correct. Does the evidence book make the case for the research gaps presented? Yes, there is an excellent presentation of research gaps. Are there any additional gaps in knowledge that should be considered for this specific risk? Additional gaps to be considered include: 1. Does the loss of bone during flight result in structural alterations that are unique (different from the aging or postmenopausal states) that have distinct biomechanical implications? 2. Apart from unweighting, the factors that contribute to bone loss are un- clear. 3. The effects of long-term flight on bone are unknown (the authors clearly note this, but it is not listed as a gap). 4. The preflight or during-flight factors that affect the rate of bone loss during flight are unknown.

38 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS 5. The expected forces (trauma) that may be exerted on bone during flight or extravehicular activity are unknown. The bones at particular risk are unknown. 6. The best methods for measuring bone structure and strength are not known. 7. The usefulness of new bone formation drugs are not known—either during flight or after return to Earth. 8. In-flight metabolic alterations that could affect bone are not known. Does the evidence book address relevant interactions among risks? Some possibilities are as follows: 1. The risk of renal stones from increased bone resorption is noted, but other possible problems may flow from alterations of bone metabolism. For instance, there are probably vitamin D reductions during flight, and muscle strength is reduced by vitamin D insufficiency. The danger of hypercalcemia is clearly increased in SCI (especially under certain cir- cumstances, such as dehydration). Hypercalcemia has been linked to nausea, mental status and mood abnormalities, cardiac arrhythmias, etc. 2. Nutrition is an area of potential overlap. 3. Human Factors Design and Task Design are areas of potential overlap. Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? These are not relevant to this evidence book. Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed? • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed? • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered? o Author expertise appropriate: The authors are outstanding. An ex- pert in mineral metabolism and related endocrine issues would be useful. A bone biomechanic would provide benefit, and an expert in human factors engineering may be useful. o Literature presented; generally very good. As noted previously, additional areas of interest would be the long term effects of SCI and bone/mineral endocrinology. o Overall readability: excellent. Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. Key issues raised include:

APPENDIX C 39 1. Concern about overreliance on the models of postmenopausal and age- related bone loss. 2. A minimal emphasis on the heterogeneity of bone loss, and the implica- tions of the “weakest link” consideration. 3. Need for linking the strength of bone to the trauma expected during flight. 4. The paucity of good data concerning the metabolic/environmental ab- normalities potentially contributing to bone loss (apart from unweight- ing). Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) Other risks: The possibility of metabolic disturbances resulting from accelerated bone remodeling/loss (vitamin D deficiency, hypercalcemia). REFERENCES CITED Giangregorio, L., and C. J. Blimkie. 2002. Skeletal adaptations to alterations in weight-bearing activity: A comparison of models of disuse osteoporosis. Sports Medicine 32(7):459-476. Jiang, S. D., L. Y. Dai, and L. S. Jiang. 2006. Osteoporosis after spinal cord injury. Osteoporosis International 17(2):180-192. Mackey, D. C., L. Y. Lui, P. M. Cawthon, D. C. Bauer, M. C. Nevitt, J. A. Cauley, T. A. Hillier, et al. 2007. High-trauma fractures and low bone min- eral density in older women and men. Journal of the American Medical As- sociation 298(20):2381-2388. Chapter 3 Bone Fracture Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? Yes. In general the evidence book is a scholarly and complete examination of the issue. There are additional knowledge gaps that should be considered. Is the text of the short description of the health risk provided in the PRD clear (it should be Section I of the evidence book)? Provide suggestions of revised wording. Yes, in general the short description is clear and complete. Consider a final sen- tence “Additional data is needed to understand the alterations in bone biology

40 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS that could increase the potential for stress fracture or impaired fracture healing in flight.” Does the evidence book make the case for the research gaps presented? Yes. The research gaps identified are well substantiated. Are there any additional gaps in knowledge that should be considered for this specific risk? Yes. Additional gaps in knowledge to be considered include: 1. The evidence book concentrates on fracture risk during flight. Although this is an appropriate concern, there is less attention paid to the risks of fracture after return from flight. As there have been several fractures now in previous astronauts, and the to-some-extent irreversible bone loss associated with flight is well known, post-flight fracture risk should be more prominently considered. 2. Fracture due to severe trauma is prominently considered (as it should be) but there may be additional mechanisms of potential importance (particularly in a situation associated with low bone formation). One is stress fracture due to repetitive lower level force. Unusual stress and impaired responses to it may be encountered during flight/EVA. An- other may be static forces and torque or torsional forces during mission activities such as construction tasks or EVAs. 3. In addition to the biomechanically oriented fracture risks considerations included in the evidence book, some attention should be paid to frac- ture healing in space. There is evidence to suggest that remodeling is altered, but little data concerning the adequacy of healing. Certainly, if a fracture occurs during flight, inadequate healing would add to the problem. Does the evidence book address relevant interactions among risks? Related risks that were not addressed. They might include: 1. Reduced muscle mass 2. Poor human factors design 3. Bone loss 4. Impact of prolonged exercise 5. Inability to provide clinical treatment 6. Nutrition 7. Poor task design 8. Orthostatic intolerance

APPENDIX C 41 Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? These are not relevant to this evidence book. Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed? • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed? • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered? Additional expertise in fracture biology and in human factors engineering (to give more full attention to the relationship between environmental design and physical stress on bones and joints) might be helpful. The literature search is complete. Readability is good. Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. In general the evidence book is excellent. Additional attention should be di- rected at postflight fracture risk, fracture healing during low-G situations, and the possibility of stress fracture. Although there are distinct features of this evidence book on fracture risk, it could be argued that it could be combined with that on bone loss. Two minor issues: 1. Figure 3-1 may have an error. The aBMD ascribed to the three bone ge- ometries is consistently 1, but in fact the aBMD is progressively lower going left to right. 2. On p. 3-9 it is noted that “ . . . planetary surfaces provide unique scenar- ios that may: - reduce the forces applied to bone structures.” In fact, planetary surfaces may increase forces when considered in comparison to previous 0 G conditions. That could be a critical consideration regarding frac- ture risk. Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) No additional comments.

42 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS Chapter 4 Renal Stone Formation Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? Yes. In general the evidence book is complete. A few additional gaps should be considered. Is the text of the short description of the health risk provided in the PRD clear (it should be Section I of the evidence book)? Provide suggestions of revised wording. Yes. The short description is clear and concise. Consider a change to the final sentence: “Alterations in hydration state (relative dehydration) and accelerated bone loss during exposure to microgravity may contribute to an increase in the risk of kidney stone formation. Other metabolic derangements may also contrib- ute. It is unclear which mitigation strategies would be most effective.” Does the evidence book make the case for the research gaps presented? Yes. The research gaps identified are well substantiated. Are there any additional gaps in knowledge that should be considered for this specific risk? Yes. Additional gaps in knowledge to be considered include: 1. Although increased bone resorption is likely to contribute to increased calcium excretion during flight, there may be other factors. This gap should be recognized. For instance: • Preflight renal stones suggest pre-existing propensity to stones, po- tentially on a genetic basis. • Dietary factors could influence calcium excretion (e.g., protein in- take). 2. From the data presented, it is clear that renal stones are not uncommon in astronauts before flight. This means other factors contribute to stones, and those factors could be exacerbated by flight. There may be a gap in understanding preflight contributors to renal stone propensity. This may influence the selection of mitigating measures (e.g., on the basis of preflight risk factors). 3. Although the evidence book refers to other potential causes of stones (e.g., hypocitraturia, urates), it concentrates on hypercalciuria. In fact the increases in urine calcium have been modest, and these other risk factors may be important. One of the gaps listed (“Data mining . . . ”) may address the need for additional data about the confluence of risk factors, but the need for more information about the nature and etiology of metabolic changes associated with flight should be more clearly identified as a gap.

APPENDIX C 43 4. An additional gap is that the real incidence of renal stones isn’t known because the only data are via symptomatic disease. Perhaps imaging studies (e.g., computerized tomography or CT) would help. 5. It is not currently known how genetic susceptibility to stone formation might be used to individualize preventative strategies. Samples should be collected and archived so that the information can be incorporated as genes become known. Does the evidence book address relevant interactions among risks? Related risks were not adequately addressed. They might include: 1. Bone loss/fracture risk. 2. Inability to provide clinical treatment. 3. Nutrition and hydration. 4. If a pharmacologic solution is planned, then there is potential for inter- action with “Risk of Therapeutic Failure Due to Ineffectiveness of Medication” for prolonged voyages (e.g., to Mars). Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? These are not relevant to this evidence book. Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed? • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed? • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered? Additional expertise in mineral metabolism might be helpful, but the literature search is complete and readability is good. One minor issue is that Figure 4-1 is said to illustrate calcium excretion, but in fact shows calcium balance. From that data alone, it is not possible to infer urine calcium excretion. Balance goes down, but calcium nutrition and absorption contribute as well. Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. In general the evidence book is good. Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) No additional comments.

44 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS Chapter 5 Intervertebral Disk Damage Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? No. The paper presents three facts, each of which is a valid concern that de- serves further consideration, but it does not combine these facts into a suffi- ciently clear argument that there is enough evidence to define an evidence book risk. The first fact is that 68 percent of surveyed astronauts reported generalized back pain during spaceflight. Although there are several possible explanations for this finding, the evidence book is too quick to state “at face value, the cause of the back pain in space appears to be associated to the elongation of the vertebral column by IVD expansion or other causes.” The second fact is that 3 astronauts developed cervical or lumbar herniated disks on landing day and another 11 developed herniated disks within 12 months of landing. The evidence book references an unpublished study comparing disk injuries among 321 astronauts with disk injuries among 482 age-matched, non- flying civil servants of NASA. The incidence of herniated disks among the as- tronauts was more than 15 times that of the control group. The evidence book seems to presume that this increased risk is causally related in some fashion to spaceflight. However, the evidence book also notes that astronauts with back- grounds as high-performance jet aviators were at the greatest risk and that ex- cessive G forces commonly experienced by such aviators may be an important risk factor for disk herniation. Without comparing the astronaut group with a control population having similar aviation experience except for spaceflight, it is premature to conclude that disk herniation is a risk of spaceflight. The third fact is that weightlessness and the associated absence of normal axial and muscular loading of the spine results in swelling of the intervertebral disks, elongation of the spine, and loss or lordotic curvature. The evidence book does make a plausible argument that this biomechanical distortion may predispose to back injury when crew members experience reloading during and after landing and when they undertake various physical mission tasks. However, the only pieces of evidence offered in support of this hypothesis are the back pain and herniated disk finding described above. The evidence book’s basic conclusion (that more evidence needs to be acquired “to establish whether the lengthening of the spinal column . . . exacerbates the risk for IVD damage with loading”) is both appropriate and necessary, but it is not sufficient. It is also necessary to evaluate other possible causes for back pain during spaceflights and for herniated disks after them.

APPENDIX C 45 Is the text of the short description of the health risk provided in the PRD clear (it should be Section I of the evidence book)? Provide suggestions of revised wording. No. The one-sentence description states a hypothesis, namely that extended ex- posures to microgravity may be a risk for spinal nerve compression and back pain. Although this is a legitimate issue deserving attention, it is stated so nar- rowly that it diverts attention from equally compelling questions. It would be more productive to frame the description around the findings of back pain dur- ing spaceflight and disk herniation following spaceflight and the need to identify their causes. The possible effect of IVD volume changes on back injury would then become one part of a comprehensive agenda rather than its dominant com- ponent. Does the evidence book make the case for the research gaps presented? No. The gaps are aimed principally at learning more about the characteristics and impacts of the IVD changes with gravitational unloading. These are real gaps, but it is hard to assess their importance without knowing more about the possible causes for the observed back pain and disk herniations among astro- nauts. Two additional gaps, described below, may have higher priority. Are there any additional gaps in knowledge that should be considered for this specific risk? Yes. Additional gaps in knowledge to be considered include: 1. Biomechanical and human factors evaluations of the physical stresses and forces required during mission-related activities that may be risk factors for back pain (e.g., prolonged awkward postures with excessive static muscle loading). 2. Epidemiological study of disk herniation following spaceflight, using a better control population than was used in the preliminary study. 3. The etiology of back pain during spaceflight is not clearly understood. Potential causes should be investigated. 4. The apparent increase in cervical events among astronauts merits evaluation. Does the evidence book address relevant interactions among risks? Other related risks that were not, but might be, addressed were the following: 1. Reduced muscle mass 2. Poor human factors design 3. Degenerative tissue 4. Bone fracture 5. Accelerated osteoporosis

46 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? These are not relevant to this evidence book. Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed? • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed? • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered? The team might be strengthened with additional experts who have specific re- search experience with the application of human factors engineering and epide- miology to back disorders. The readability is sufficient for a nonexpert audience. Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. The paper focused too narrowly on one possible cause of back pain and disk herniation experienced by astronauts. It would be more productive to organize the paper around the need to study the possible causes for these adverse events. The biochemical and biomechanical changes in intervertebral disks would then be set in a more meaningful context, instead of dominating the whole evidence book. Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) No additional comments. Chapter 6 Impaired Performance Errors Due to Reduced Muscle Mass, Strength, and Endurance Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? Yes. The paper provides strong evidence that human skeletal muscles undergo atrophy and loss of function during short-term and long-term spaceflight. Evi- dence is presented to indicate the atrophic response is exacerbated with increas- ing durations of spaceflight/unloading. The atrophic response is strongly linked to alterations in cell biology. To date, exercise has shown promise in mitigating these effects. However, more research is warranted to titrate the most effective

APPENDIX C 47 combination of the exercise countermeasure suite for long-duration missions. Good evidence is presented linking loss of muscle mass to health and task- related risks to humans while in space. Is the text of the short description of the health risk provided in the PRD clear (it should be Section I of the evidence book)? Provide suggestions of revised wording. No. The concept that human control subjects cannot be used due to ethical rea- sons in the microgravity of space is true, but for ground-based analogs this is not true. Several ground-based analog studies have included control subjects that have furthered our understanding of muscle loss with unloading. The concept needs to be revised with regard to feasibility and priority. Does the evidence book make the case for the research gaps presented? No. A more thorough overview of the progress that has been made in preventing muscle atrophy and functional deficits, especially in humans, is warranted. This will provide greater depth and direction to the gaps identified. Are there any additional gaps in knowledge that should be considered for this specific risk? Yes. Additional gaps in knowledge to be considered include: 1. Potential gender-related issues regarding muscle mass and function loss during unloading. 2. Effectiveness of various exercise modalities for preserving muscle. Does the evidence book address relevant interactions among risks? Yes. The interactions among exercise, partial-gravity environments, and EVAs for protecting skeletal muscle are highlighted. Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? These are not relevant to this evidence book. Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed? • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed? • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered? The expertise of the authors is outstanding. A number of the team members are leaders in the field of muscle biology and unloading. The background informa- tion on the space program and data obtained from the various eras of spaceflight

48 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS were excellent. The review of muscle biology as it pertains to functional loss was well defined. Generally, the paper was well structured and easy to read. Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. The summary of the muscle literature contained in the report was excellent. The limitations of spaceflight research and breadth of knowledge gained from ground-based analogs and animal models were highlighted. The report could be strengthened with a more in-depth review of human countermeasure develop- ment/progress (e.g., intensity, frequency, mode) that has been made for skeletal muscle using ground-based analogs (e.g., bed rest and unilateral lower limb sus- pension). This information is critical to further define the gaps for skeletal mus- cle during long-duration space missions. Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) A potential crosscutting issue is the interactive effects of nutrition on skeletal muscle properties with prolonged space travel. Chapter 7 Operational Impact of Prolonged Daily Required Exercise Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? No. The evidence book focuses almost exclusively on the time-consuming na- ture of exercise protocols and the lack of knowledge present in its effectiveness. Both of these findings are significant; however, the case for further research addressing this topic, which can and should be made, is not present. Additional areas where the evidence book could be improved include: 1. The concept of human health countermeasures and their impact on mis- sion operations has historically been a potential concern. As discussed, there is no strong evidence that physical exercise has negatively im- pacted mission operations. However, there has generally been a con- sensus to optimize the physical exercise program to protect crew health while minimizing the impact on crew time. A further challenge, as highlighted in the report, is that benchmarks for crew health/performance have not been established. 2. This report needs to be strengthened by the database from International Space Station (ISS) crew members and the limited data available in the literature. Several physical traits of human physiology/biology have been assessed before and after long-duration stays in space. Are the

APPENDIX C 49 current programs effective? Although the benchmarks have not been established, anchoring these physical capacities to preflight levels would provide a starting point to help establish performance bench- marks. Is the text of the short description of the health risk provided in the PRD clear (it should be Section I of the evidence book)? Provide suggestions of revised wording. No. Because benchmarks are not defined and there appears to be no negative impact on current mission operations; more justification is needed for this to be a major issue moving forward. The more significant risk lies in the inadequacy of this single countermeasure in preventing the deconditioning of bone, muscle, neurovestibular, and cardiovascular systems. Does the evidence book make the case for the research gaps presented? No, the research gaps seem reasonable, but are very limited in scope and loosely defined. The paper also does not address the supposed adequacy of exercise as present in the lunar EVA as sufficient to avoid deconditioning of bone, heart, and muscle during extended lunar stays. Are there any additional gaps in knowledge that should be considered for this specific risk? Yes. Exercise needs to be evaluated in conjunction with other countermeasures, such as artificial gravity, lower body negative pressure (LBNP), and pharmacol- ogical treatments. Does the evidence book address relevant interactions among risks? No. The relevant interactions are vaguely defined. The risk interactions need to be more closely linked to the EVA profile and potential risk to the microgravity tasks, partial-gravity environment tasks, and return to 1 G tasks. The evidence book should also discuss the interaction of prolonged exercise with bone and cardiovascular risks, which could be significant in missions of extended weight- lessness or lunar stays. Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? These are not relevant to this evidence book. Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed? • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed?

50 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered? Adding relevant data about the crew’s physical capacities preflight and post- flight as highlighted earlier would strengthen this report. As is currently written, the report lacks any relative or absolute data concerning benchmarks and meet- ing those targets. Additional insights may be gained from personnel involved with crewmember health (medical profession, crew members, trainers, etc.). Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. Exercise, as currently employed as a countermeasure on the ISS, is very time consuming and its effectiveness has not been quantified. It remains a centerpiece of future space missions, whether in microgravity or on the Moon, probably in conjunction with other methods of minimizing deconditioning. The most effec- tive combinations of exercise and other countermeasures can be studied in bed rest experiments as well as on orbit. As noted in the letter report, the committee suggests that the scope of this evi- dence book be expanded and changed to “Operational Impact of Countermea- sures.” Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) Several crosscutting areas here appear to be related to human health, human performance, and psychological aspects. Chapter 8 Compromised EVA Performance and Crew Health Due to Inadequate EVA Suit Systems Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? Yes. It underscores the vast increase in EVA suit use and exposure in the com- ing decades and supports the need for research regarding prebreathe and pres- sure requirements as well as the metabolic cost of walking in current suits. Mechanical difficulties in current boots and gloves are clearly identified. The case, however, would be stronger if the evidence book also discussed the risk of inadequate suit systems to crew safety. Is the text of the short description of the health risk provided in the PRD clear (it should be Section I of the evidence book)? Provide suggestions of revised wording.

APPENDIX C 51 No. The healthy risks described are adequate—but it has not dealt with the fol- lowing important concerns: 1. The risk of suit depressurization by a fall or impact with a protruding edge. 2. The risk of falling as increased by the absence of haptic and proprio- ceptive cues from the pressurized boots. 3. Crew safety. Does the evidence book make the case for the research gaps presented? Yes. There is an excellent summary of experience from earlier EVA suits, lack of oxygen reserves in Apollo, and problems with food and water as well as thermal control. Good treatment of the decompression sickness issue and choice of prebreathe protocols. Are there any additional gaps in knowledge that should be considered for this specific risk? Yes. Additional gaps in knowledge to be considered include: 1. Reduce the risk of falling through use of better boots, gloves, biosuit (skin-tight suits), auxiliary displays, and navigation and terrain infor- mation. 2. Study of alternate joint designs. 3. The detrimental effect of lunar dust, identified as a major problem in Apollo, is not treated. Does the evidence book address relevant interactions among risks? No. Two types of potential risk interactions are not explicitly addressed. One is the risk of poor task design. The design of tasks that necessitate EVA must nec- essarily consider the physical and other limitations created by the suit. The other is risks related to environmental threats. Two environmental threats that also have evidence papers but are not discussed here are radiation and lunar dust. Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? These are not relevant to this evidence book. Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed? • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed? • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered? This is a very good summary of highly relevant research, especially the meta- bolic costs of activities, including the “walk back” tests. The misuse of the Coo-

52 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS per Harper scale (specifically designed for aircraft-handling qualities) is easily correctable. The evidence book is highly readable and well illustrated. However, the literature cited is largely limited to that of the authors and their Houston col- leagues—ignoring the wealth of research outside of Johnson Space Center (JSC). Newer cooling methods and ease of food intake and outflow need consid- eration. Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. The current generation of suits is inadequate to meet the demands of the exten- sive use foreseen on the Moon. Both performance (ease of use and metabolic cost) and safety (decompression sickness, depressurization, and falls) are of concern. Damage to extremities and joints are common in current suits and the injury rate is unacceptable. Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) No additional comments. Chapter 9 Orthostatic Intolerance During Re-Exposure to Gravity Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? Yes. The report describes in detail past experiences with presyncope/orthostatic intolerance following spaceflight of varying durations. The risk is most promi- nent during transition states from microgravity to partial-gravity environments and is a particular concern for female astronauts, in whom the incidence of or- thostatic intolerance is much higher than in men. Although bed rest studies in humans and lower extremity unloading studies in animals help to elucidate the mechanisms of orthostatic intolerance related to microgravity, the complex eti- ology that has been revealed presents challenges to the development of coun- termeasures. The report also makes it clear that because there is no experience with long-term space missions, the risk of orthostatic intolerance in astronauts subjected to long-term spaceflight and long-term residence in reduced gravita- tional environments on the Moon and Mars are difficult to predict and may be very large. To date, exercise, volume loading, and pharmacological interven- tions have shown promise to partially mitigate the effects of orthostatic intoler- ance when returning to 1-G environments. The development of the Digital Astronaut Program may be helpful in clarifying the predictions of risk, but fur- ther studies of humans at fractional gravity exposures are clearly needed to fully assess the risk and develop useful countermeasures.

APPENDIX C 53 Is the text of the short description of the health risk provided in the PRD clear (it should be Section I of the evidence book)? Provide suggestions of revised wording. Yes. This is very clear and appropriately emphasizes the importance of develop- ing and evaluating countermeasures to combat orthostatic intolerance during space missions. Does the evidence book make the case for the research gaps presented? Yes. The evidence book emphasizes the lack of information about the effects of exposure to microgravity followed by partial gravity on orthostatic tolerance and also emphasizes the lack of full evaluation of suggested countermeasures, such as midodrine and somatostatin. It also emphasizes the importance of developing and testing more effective antigravity suits. Are there any additional gaps in knowledge that should be considered for this specific risk? No. Does the evidence book address relevant interactions among risks? No. The risks of orthostatic intolerance are related to the reduced muscle-mass strength and endurance and possibly to the central nervous system (CNS) effects of radiation exposure that could be experienced by astronauts during prolonged spaceflight. Countermeasures, such as formal exercise programs, designed to preserve or prevent the loss of muscle mass could clearly improve orthostatic tolerance at the end of spaceflight and should be considered in the context of reduced orthostatic tolerance. Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? These are not relevant to this evidence book. Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed? • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed? • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered? The expertise of the authors was very good. The literature review was appropri- ate and extensive. The background information on the space program and data obtained from the various eras of spaceflight and analog-related research were excellent. Generally, the paper was well structured and easy to read.

54 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. Key issues raised are that postflight orthostatic intolerance is likely to be nearly universal in astronauts after long-duration spaceflight, and the need for develop- ing effective countermeasures is urgent. The key areas identified for moving forward relate to gender and transition states (from microgravity to partial- gravity environments). A particular concern is the total lack of information about whether partial-gravity exposure (1/6 G on the Moon and 3/8 G on Mars) will exacerbate or mitigate effects against orthostatic intolerance following pro- longed spaceflight. Ground-based studies directed toward answering these ques- tions are underway, but it is not clear that these can fully reproduce the effects of prolonged exposure to microgravity in space. To date, an effective countermea- sure for orthostatic intolerance has not been fully identified. Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) Additional risks that should be included in their report include the possibility of cardiovascular events, including ischemic events and arrhythmias resulting from volume depletion and dysautonomia/disorders of peripheral vascular regulation resulting from prolonged exposure to microgravity. A potential crosscutting issue relates to drug delivery/pharmacokinetics as a countermeasure due to the possibility of interactive effects with other physio- logical systems. Chapter 10 Cardiovascular Effects on Performance and Operational Limitations Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? Yes. The paper provides a good deal of support for cardiovascular decondition- ing during short-term and long-term exposure to microgravity. Although some controversy remains regarding the degree of in-flight deconditioning, the post- flight reduction in cardiovascular capacity is compelling. Strong evidence is also given for alterations in submaximal responses to exercise. Although a host of potential mechanisms have been studied to help explain the cardiovascular changes as a result of spaceflight, hypovolemia is perhaps the strongest candi- date, with several secondary alterations contributing to this reduction in aerobic performance.

APPENDIX C 55 Is the text of the short description of the health risk provided in the PRD clear (it should be Section I of the evidence book)? Provide suggestions of revised wording. No. The risk generally pertains to potential emergency contingencies (e.g., egress, safety). To date, it appears that crew members have not been challenged with activities that would exceed cardiovascular capacity. However, little data from long-term spaceflight are available, with no in-flight data (long term) on aerobic capacity. This is an open issue for long-duration spaceflight. Finally, defining the operational requirements related to cardiovascular capacity for planetary exploration is needed. Does the evidence book make the case for the research gaps presented? No. All the gaps appear to have merit. However, they are very general and sweeping in nature. Given the extensive literature on this topic, it is suggested that the gaps be framed in a more focused and directed fashion. Are there any additional gaps in knowledge that should be considered for this specific risk? Yes. The gaps should include preflight fitness requirements for cardiovascular capacity relating to prolonged space travel. Gender should also be considered as a potential gap. Although gender-related data are limited, it does point to a po- tential issue. Gaps 4 and 6 should include cardiac and skeletal muscle mass as potentially important contributors to cardiovascular performance. Does the evidence book address relevant interactions among risks? Yes, for emergency egress situations (more related to 1G). Links to several physiological systems are highlighted and appropriate. Because benchmarks for cardiovascular performance are not presented, the risk assessment during long- term space travel and planetary exploration cannot be adequately determined. Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? These are not relevant to this evidence book. Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed? • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed? • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered? The expertise of the authors was appropriate. The literature review was exten- sive. The background information on the space program and data obtained from

56 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS the various eras of spaceflight and analog related research were good. Generally, the paper was well structured and easy to read. Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. The summary provided a good overview of cardiovascular deconditioning with spaceflight. Although the data gathered from short-term spaceflight were exten- sive, fewer data are available from long- duration missions. The data generally support an initial and rapid decrease in cardiovascular capacity that may be tied more closely to hypovolemia. Thereafter, there is a more gradual decay in car- diovascular performance, with secondary mechanisms related to muscle remod- eling (cardiac and skeletal) and several central and peripheral adaptations that appear to be linked and contribute to a decreased aerobic capacity. Although no strong evidence was presented for a gender-related aspect for cardiovascular performance, it was an underlying issue that deserves attention for the future. As noted in the letter report, the committee found that the topic of this evidence book is a subset of the broader issue of the effects of decrements in work capac- ity on operational performance. The committee suggests that this risk should be redefined to “Physiological Limits on Performance and Operations” to include effects such as cardiovascular, metabolic, strength, and thermal limits that might cause operational tasks to be limited or redefined. Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) No additional comments. Chapter 11 Cardiac Rhythm Problems Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? No. The difficulty with making this assessment is that there is little research on the risk of cardiac arrhythmias during spaceflight. The only supportive evidence comes from observational reports that have shown some evidence of non-life- threatening arrhythmias during or after spaceflight. It is not clear that these did not arise simply by chance. Two potential mechanisms are put forth, prolonga- tion of the QTC and cardiac atrophy. There is little solid research to connect these dots.

APPENDIX C 57 Is the text of the short description of the health risk provided in the PRD clear (it should be Section I of the evidence book)? Provide suggestions of revised wording. Yes. The text makes it clear that potential cardiac rhythm disturbances could be related to underlying cardiovascular disease, to cardiovascular disease that de- velops over time and would have developed in the same way if the subjects had remained on Earth, and to effects of prolonged exposure to microgravity that have not yet been defined. It could, however, be strengthened by inserting the main recommendation. Does the evidence book make the case for the research gaps presented? No. The statement of required action is “systematic evaluation of cardiac struc- ture and function on the International Space Station.” A more straightforward approach might be constant telemetric monitoring of subjects on the Interna- tional Space Station and a more thorough evaluation of cardiac function and anatomy before the subjects enter space. The evidence book could go much fur- ther in suggesting experiments and monitoring that should be done. Are there any additional gaps in knowledge that should be considered for this specific risk? Yes. Additional gaps to be considered include: 1. Are astronauts screened for family histories of sudden death? 2. Are astronauts screened for various forms of underlying heart disease, that is, for coronary disease with fast CT for calcium; with echocardio- grams or cardiac magnetic resonance imaging (MRI) for cardiomyopa- thy; or with genomic techniques for genes that have been related to arrhythmias? Does the evidence book address relevant interactions among risks? Not directly, although the evidence book does suggest that in persons with un- derlying occult heart disease, arrhythmias may be precipitated by the stress of working in space or of microgravity. Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? These are not relevant to this evidence book. Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed? • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed? • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered?

58 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS The literature search is adequate and the overall readability of the evidence book is sufficient. However, it would be strengthened with the addition of experts in myocardial imaging, that is, fast CT for coronary calcium and cardiac MRI as well as additional expertise in clinical electrophysiology. Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. The paper emphasizes that the risk of cardiac rhythm problems in persons ex- posed to microgravity for prolonged periods of time is hypothetical. Only a few cases of astronauts developing arrhythmia during or following spaceflight have been reported, and it is not clear if these abnormalities occurred as a result of chance or as a result of some aspect of exposure to a microgravity environment. Key issues deal with the necessity of more rigorous screening of astronauts for occult cardiovascular disease prior to spaceflight and more sophisticated moni- toring techniques to determine the prevalence of cardiac arrhythmias in persons exposed to prolonged weightlessness. This should be feasible with contemporary telemetry techniques and is needed to assess the magnitude of the problem. Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) No additional comments. Chapter 12 Inadequate Nutrition Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? Yes. The document makes a compelling case for the importance of proper nutri- tion. Perhaps most important, the opening material documents in considerable detail evidence from prior space missions to indicate that astronauts often ex- perience reduced dietary intake. Is the text of the short description of the health risk provided in the PRD clear (it should be Section I of the evidence book)? Provide suggestions of revised wording. Yes. The authors have described this particular risk quite clearly and succinctly. Does the evidence book make the case for the research gaps presented? Yes. In most cases, the evidence is quite clear. This is one area in which sub- stantial data are available from previous missions, and the data are reviewed thoroughly. The arguments are thoughtful. Not all issues are as developed as others. The paper reviews 31 specific nutrients. Most have already been studied

APPENDIX C 59 with regard to spaceflight and analog environments, but some have not (e.g., Vitamin A, niacin, pantothenic acid). In the latter cases, the statements with re- gard to gaps simply say, “This issue should be studied.” Although the document covers evidence regarding 31 nutrients, it does not ex- plain how this list was generated. Therefore it is difficult to know whether these 31 factors were selected from a larger list or if these are all the possible nutrients that could be considered. From the lay perspective, the list would be exhaustive and possibly unnecessary due to the varying levels of strength in the arguments for each. This could be partially clarified by including a review of the current nutritional guidelines used for astronauts and relevant gaps in knowledge associ- ated with each standard. Are there any additional gaps in knowledge that should be considered for this specific risk? No. This paper seems to cover all of the relevant ground with regard to nutrition. Does the evidence book address relevant interactions among risks? Yes. The paper does raise important issues regarding connections between nutri- tion and other important risks, such as loss of bone density, radiation, and (to a lesser extent) behavioral health. Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? These are not relevant to this evidence book. Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed? • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed? • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered? The authors have a sufficient level of expertise on the issues and the literature review seems to be completely exhaustive. In fact, the background sections for each of the 31 nutrients might be considered to be too long and detailed. They read a bit like excerpts taken from a textbook on nutrition. The paper is well organized and nicely written, but it is so long and detailed that it is easy to miss the main points. Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. This is a thorough and nicely written summary of many important issues related to the possible impact of inadequate nutrition. The primary concern with the

60 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS evidence book is that it provides an excessive amount of detail, particularly with regard to background on the 31 nutrients. It also does not explain to a novice why these particular 31 nutrients were selected for inclusion in this report. An enormous amount of evidence is reviewed regarding nutrition and previous spaceflights, and it seems likely that that information could be condensed and summarized. Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) No additional comments. Chapter 13 Crew Adverse Health Event Due to Altered Immune Response Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? Yes. Evidence provided relative to cellular and humoral immunity alterations associated with spaceflight do make the case that this risk is relevant, though the evidence book appropriately observes that no clear evidence of disease associ- ated with these alterations has yet been observed. Is the text of the short description of the health risk provided in the PRD clear (it should be Section I of the evidence book)? Provide suggestions of revised wording. No. The short description is clear, but to be more generalizable it would be rea- sonable to change the wording from “Further research may elucidate whether microgravity exposure impairs the immune system, and whether this change represents a health risk to crews” to “Further research may elucidate whether microgravity exposure or other characteristics of spaceflight impair the immune system, and whether this change represents a health risk to crews.” Does the evidence book make the case for the research gaps presented? Yes. Are there any additional gaps in knowledge that should be considered for this specific risk? Yes. The lack of correlation between observed changes in cell-mediated and humoral immunity and clinically evident disease suggests that an important gap is the ability to assess which changes are functionally significant. Simply doing more in-flight measurements of existing immune tests may not be particularly useful in the absence of predictive biomarkers that have a validated relationship

APPENDIX C 61 to clinically overt immune disorders. Identifying such biomarkers might be con- sidered another gap. Does the evidence book address relevant interactions among risks? No. A discussion of known effects of different types and doses of radiation would be appropriate. Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? These are not relevant to this evidence book. Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed? • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed? • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered? Some text in the evidence book is unclear, as follows: 1. Introduction, paragraph 1: “The specific functions of these cell popula- tions can vary widely, and in some cases they are counter regulatory.” The meaning of the term “counter regulatory” is unclear. Beginning this Introduction with a brief overview of the components of the im- mune system (humoral and cellular) may be more useful than starting with an assertion about white cells trafficking around the body. 2. P. 4: “Dysregulation detected individual immune assays may be either hyper-activity or hypo-activity.” Overall, the paper would leave a nonspecialist unable to interpret its detailed observations. It is readable only by a specialist conversant with the meaning of the various (and somewhat arcane) assays of immune function. The addition of an author (or assignment of existing authors) to create an explanatory context for each detailed finding in the evidence book would be helpful, in addition to the creation of an introductory overview on human immune function as noted above. Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. The evidence for alterations of immune function appears overall to have a somewhat opportunistic gestalt to it, as if measurements were made because it was possible to do a variety of assays and not because of a coherent plan to iden- tify functionally important alterations of immune systems. The majority of data relates to cell-mediated immunity, and little attention is given to antibody

62 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS classes and titers—which in theory might have equally important effects on al- teration of host defenses—nor to other molecules such as cytokines that modu- late immune response. Similarly, the research gaps seem quite tactical and not strategic, as closing the gaps might still leave NASA without an understanding of the most meaningful and predictive assessments of immune function. A conceptual framework for understanding which parts of the immune system, when altered, have real prog- nostic significance might emerge from a comparison of the reported findings in the evidence book and the growing terrestrial literature on the molecular biology of disease states of over- and underactive immunity. Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) No additional comments. Chapter 14 Performance Errors Due to Sleep Loss, Circadian Desynchronization, Fatigue, and Work Overload Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? Yes. The paper makes a strong and clear case that this risk is highly relevant to long-duration space missions. It provides a clear review of the evidence from ground-based studies on the effects of sleep loss, circadian desynchronization, fatigue, and work overload on alertness, cognitive performance, reaction time, and to a lesser extent, motor behavior. There is a clear discussion of the biologi- cal and behavioral mechanisms through which each of these factors affect per- formance, and the relevance of this risk to long-duration space missions. The review of the research findings is informative for short-duration missions, and has applications as well for long-duration missions to the Moon and Mars. The discussion of different light intensities on the Moon and Mars and possible ef- fects on sleep and performance is also informative. Is the description of the health risk provided in the PRD clear? Provide sug- gestions of revised wording. Yes. It is precise and nicely written. Does the evidence book make the case for the research gaps presented? Yes. The issues identified are interesting and well presented. They are well de- fined and clearly lend themselves to further empirical investigation. One con-

APPENDIX C 63 cern, however, is the extent to which these research gaps fit into determining overall priorities for research. Some issues to consider include: 1. The research is elegant and thorough; more work can be done and no doubt will be done well. What additional level of precision and types of research are needed to address mission-related sleep and fatigue con- cerns? 2. How can the importance or potential impact of these risk factors be compared to or balanced against the need for additional research on other behavioral and psychiatric risk factors? 3. The quality of the work in the area of sleep research is clearly superior, but does the benefit justify the relative lack of attention being paid to other important concerns? Are there any additional gaps in knowledge that should be considered for this specific risk? Yes. The evidence book states that motor performance has not been affected substantially by sleep loss, fatigue, etc. More information on this point would be interesting because EVA as well as onboard activities require skilled motor functioning. Does the evidence book address relevant interactions among risks? Yes. This is a very positive point in the paper, pointing to the interaction of sleep loss, fatigue, etc., on the risk of performance errors. Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? These are not relevant to this evidence book. Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed? • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed? • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered? The expertise of the authors is very strong. A number are leaders in the field of sleep and performance. The literature search is also sufficient and the table documenting the findings from spaceflights is very helpful. Apparently the au- thors have covered the available studies in the English- language literature. Where available, it would also be informative to report findings from the So- viet/Russian space program. The text readability is good, but editing would be beneficial to reduce the amount of repetition in the document. The same infor- mation and phrases are presented in a number of places throughout the evidence book.

64 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. The paper is clear and, on the whole, well written. The review of the literature on different amounts of sleep loss and effects on performance as well as the in- teraction among sleep loss, circadian desynchronization, fatigue, and effects on performance is informative and well presented. The description of research find- ings from a range of ground-based laboratory and “real-life” situations, as well as evidence from spaceflights, is also helpful in obtaining a perspective of risk. The designation of research gaps applicable for planning for planetary missions is well thought out and compelling. A highly positive feature of this paper is the discussion of individual differences in the effects of sleep loss and fatigue on human performance. In addition, the description of current research, particularly the development of two different biomathematical models showing the temporal dynamics and effectiveness of cognitive performance as predictors of perform- ance decrement, may prove to be a highly important countermeasure enabling astronauts to self-monitor their performance readiness. The only major reservation about this evidence book is the difficulty that is in- volved in comparing efforts devoted to this topic relative to the sparse number of studies devoted to other significant behavioral and psychiatric risks. Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) A crosscutting issue is the effect of sleep loss and fatigue on psychosocial adap- tation. Chapter 15 Performance Errors Due to Poor Team Cohesion and Performance, Inadequate Selection/Team Composition, Inadequate Training, and Poor Psychosocial Adaptation Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? Yes. The existing evidence is covered in considerable detail. However, in part the case is made based on non-flight information because, unfortunately, empiri- cal evidence from space is extremely sparse and often anecdotal. Is the text of the short description of the health risk provided in the PRD clear (it should be Section I of the evidence book)? Provide suggestions of revised wording. Yes. It is clear and succinct, and again points to the lack of systematic research in this area.

APPENDIX C 65 Does the evidence book make the case for the research gaps presented? In part. Gaps 1 and 2 are based on the literature review and are presented with accompanying information about how JSC personnel and other investigators are attempting to deal with these gaps. Gap 3, regarding methods and tools for se- lecting and composing crews for optimal team performance, would be strength- ened by a fuller prior discussion covering empirical research in this area along with the authors’ recommendations. Are there any additional gaps in knowledge that should be considered for this specific risk? Yes. The approach of this paper is to focus on how to optimize human perform- ance during long-duration missions, rather than simply how to eliminate errors. A strong case is made that the best way to reduce risk is to achieve optimal per- formance. This conceptual framework is positive and provides a context for the research that needs to be carried out that ultimately will reduce the risk of per- formance errors. However, more information is needed based on empirical re- search in space, and on heterogeneous small groups performing in arduous extreme environments or in simulation chambers. Additional attention should also be given to the definition of teams and of cohesiveness, including potential impacts of the broader “mission team” that includes both astronauts and earth- based support staff. A potential consideration is the distinction between group cohesion and individual morale and how personality, demographic, and situ- ational variables influence the manner in which emotional reactions may affect the individual’s and the crew’s performance.. More comprehensive research in analog environments with greater fidelity to the space voyage or planetary ex- ploration, including simulations of a space vehicle, will advance information obtained from teams interacting via computer on specific tasks. This program of research will supplement the lesser amount of information that can be obtained studying the relatively small number of flight crews. Further, the issue of leader- ship is absent, including the interaction between leadership style and situational demands on impact on a mission. Does the evidence book address relevant interactions among risks? Yes. The relationship between team performance and individual adaptation is presented. However, there is almost no coverage of the impact of specific behav- ioral problems such as personality disorders and mood disorders (poor psycho- social adaptation) on team cohesion and performance. This information is relevant to the risk of performance errors, particularly if certain types of behav- ior problems have a specific impact on various team factors, and in turn per- formance. Moreover, individual adaptation is relevant to team selection and the development of countermeasures. Finally, additional focus is needed to address the lack of specific criteria that define what constitutes optimal, outstanding, adequate, or inadequate performance and the external validity of analogue tasks (not only analogue environments).

66 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? These are not relevant to this evidence book. Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed? • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed? • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered? The literature review on issues such as team cohesion and selection is of interest. A great deal of relevant information is presented, with a summary and recom- mendations at the end of each section for the type of research that needs to be carried out to mitigate risk. However, the coverage is uneven. At times, the pa- per does not go beyond a somewhat superficial discussion of the literature, mak- ing points that are quite obvious, or not following through with more in-depth analysis. For example, with regard to selection, what are the various options that might be taken for measuring personality or attitudes toward teamwork, and so on? The section on Training (pp. 12-13) mentions previous studies that show different kinds of training have an impact on “performance.” But the issues are treated in a very general way. What kind of training? For what kinds of indi- viduals? Conducted by whom? How was performance measured? In addition, the literature on single- and mixed-gender expedition teams as an analog for spaceflight and planetary exploration is not covered, although these studies were specifically designed to inform about individual and team processes in space. A more thorough review of data that originates from international space agencies, including the Shuttle/MIR and ISS studies of team process is also needed. The evidence book could also be strengthened with a review of issues related to ex- tended cohesion, i.e., promoting positive interactions beyond the contexts of selection, training, and flight to the post-flight period. Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. The paper presents a considerable breadth of topics and research findings. How- ever, greater attention to empirical studies in space and of small groups perform- ing in arduous extreme and simulation environments is needed. Editing is required to clarify some of the comments that are vaguely presented or repeat the obvious. The recommendations for research on selection and countermea- sures for dealing with the risk of performance errors due to team performance need to be expanded. Furthermore, coverage of the effects of particular behavior problems on team functioning is lacking.

APPENDIX C 67 Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) No additional comments. Chapter 16 Behavioral and Psychiatric Conditions Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? Yes. The case is made, but not in a strong and persuasive fashion. Unfortu- nately, most of the evidence that is provided is either intuitive or based on anec- dotes and personal testimonials. Specific findings from analog environments as well as space missions are presented, including a small amount of information from the Russian space program, primarily the book by one cosmonaut. Numer- ous statistical analyses are presented projecting behavioral and psychiatric risks based on data primarily from analog environments. Is the text of the short description of the health risk provided in the PRD clear (it should be Section I of the evidence book)? Provide suggestions of revised wording. No. The writing is clear, but it would be helpful to provide more details regard- ing the specific types of psychiatric and behavioral conditions that are expected and the impact they might have on the health of the crew and the success of the mission. Information beyond Safe Passage (IOM, 2001) should be included, commenting on data from more recent space missions. Does the evidence book make the case for the research gaps presented? The gaps presented are somewhat vague (e.g., what are the best assessment measures to detect behavioral and psychiatric disorders?). There is an enormous amount of literature on this topic. This evidence book, however, does not connect the exist- ing literature on the assessment of psychopathology to the specific circum- stances and special problems involved in spaceflight. The paper moves from this very general issue (assessment of psychopathology) to an extremely specialized and somewhat narrow topic that involves cognitive changes following exposure to isolated, confined, and extreme environments. The report should make this connection more explicitly and further investigate the decline in cognitive per- formance during long-duration missions, but this is mentioned only in the Gaps section. The risk of behavioral problems due to monotony and boredom should also be considered in depth. The final gap mentioned involves countermeasures to maintain behavioral health (presumably including both psychological and pharmacological interventions). Again, this is a reasonable statement at the most

68 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS general level, but it is not connected to a more specific set of goals that might motivate a systematic research program. Are there any additional gaps in knowledge that should be considered for this specific risk? Yes. The section on personality factors is extremely sparse and does not cover adequately the many personality studies of personnel in extreme environments including simulation studies, as well as data from astronaut selection. Moreover, the described methodology of the Ursin et al. (1992) paper is imprecise, as their paper is a review article with speculations about long-duration flight. The comment in the Executive Summary, that the select-in procedures used thus far have not been able to predict “whether an astronaut would be adversely af- fected by the stresses of spaceflight” (p. 4) and thus countermeasures remain the primary focus of risk mitigation, needs further clarification. NASA has collected a huge body of data via various personality and other assessment measures. NASA should make these data accessible, while taking into consideration in- formed consent and guarding confidentiality, to retrospectively assess possible predictors of later functioning. In addition, given the limited availability of data, NASA may wish to examine “anecdotal” sources including archival literature, such as astronaut memoirs and the NASA oral history series. Although counter- measures are clearly crucial, there is still much research that could be carried out that would inform about select-in personality traits, and an examination of the predictive effectiveness of different personality assessment instruments. This is a highly important issue because the traits adaptive for long-duration missions may be quite different from those adaptive for shorter missions. Greater atten- tion to selecting out those with personality disorders versus clear Axis I clinical disorder psychopathology is also important. The authors may also wish to make more of a point about how valid different analogues may be—e.g., an Antarctic station where 100-200 people winter over is not all that comparable to a ten-day Shuttle mission with a dozen or fewer, or a 2+-year trip to Mars and back with half a dozen astronauts.” Other gaps that should be considered include outcome research on the most ef- fective countermeasures for training coping skills, etc., preflight; countermea- sures for behavioral and psychiatric problems during and after a flight; computer-based counseling; on-board presence of a crewmate trained in coun- seling; telepsychiatry; and evaluation of the effectiveness of countermeasures for families before, during, and after flight. Greater research attention is needed to understand the cause and phenomenon of asthenia reported by the Russians as a problem or disorder manifested by an unknown number of cosmonauts during spaceflights. This apparently psycho- physiological state would constitute a high risk during long-duration missions.

APPENDIX C 69 Does the evidence book address relevant interactions among risks? Yes. Coverage of sleep problems is informative. However, the review may be strengthened by a consideration of environmental design. For example, the abil- ity to control and vary the environment of the capsule would be important to combat boredom. Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? These are not relevant to this evidence book. Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed? • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed? • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered? The paper is highly readable, although some editing is indicated. Several sec- tions in the paper are redundant. It reads as though it was written in several smaller sections by different authors, and these sections were not carefully inte- grated. The reliance on “personal communication” interspersed throughout the paper detracts from its overall scientific quality. It would be helpful to add experts on topics such as the treatment of depression. Will conversations with ground- based professionals be effective, especially given communication delays? Can crew members be trained to help each other with psychosocial interventions? There is little information in this paper on empirical findings from the Russian space program. Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. The paper makes a strong case for the risk of behavioral problems and psychiat- ric disorders occurring during long-duration missions. However, there are two primary problems with the content of the paper. One is that the evidence used to develop the argument does not move much beyond statements from previous Institute of Medicine reports, references to unpublished papers, and anecdotes attributed to specific staff members and astronauts. The other problem is that the gaps identified are so general and vague that they do not lend themselves to em- pirical evaluation. More attention to personality and behavioral predictors of problems and psycho- pathology in space or postflight is indicated, as well as potential impact on as- tronaut families. There is a need for more comprehensive understanding of the

70 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS types of disorders experienced in space as reported by the Soviet/Russian space program, based on their considerable experience in long-duration missions. Greater attention needs to be paid to research on the effectiveness of the coun- termeasures used to deal with the various risks covered, and in particular, the development and evaluation of countermeasures for dealing with postflight problems by astronauts and their families. Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) Missing: prevention and treatment of postflight behavior/psychiatric disorders. Chapter 17 Acute Radiation Syndromes Due to Solar Particle Events Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? Yes. Is the text of the short description of the health risk provided in the PRD clear (it should be Section I of the evidence book)? Provide suggestions of revised wording. No. Replace “atmosphere” with “magnetosphere” or “magnetosphere and earth shadow.” Does the evidence book make the case for the research gaps presented? Not entirely. The description of the acute gap #1 is confusing both in wording and with respect to intent. The goal would seem to be to develop probabilistic uncertainty distributions for certain acute effects associated with galactic cosmic radiation (GCR) and solar particle events (SPEs); the unspoken assumption is that we now have such information for gamma rays and X-rays (or perhaps, the only information we now have pertains to these types of radiation), and need more information about relative biological effectiveness (RBE) of proton and high charge and energy (HZE) nuclei in particular for extrapolating to GCR and SPE. On the other hand, the problem may not be just a matter of RBE. If the mechanisms of tissue damage differ, which is suggested by Figure 20-3 in the radiation carcinogenesis paper, extrapolation from low linear energy transfer (LET) radiation like gamma and X-ray may not be direct. In general, the discussion in the text should prepare the reader for each of the research gaps; this does not always occur. Acute Gap #5 (which is important) is an example of this.

APPENDIX C 71 Acute Gap #11 is somewhat surprising: Fertility and heredity impairment are not usually considered to be acute effects that would damage the mission as laid out in the initial paragraph of the evidence book. Like increased cancer risk, they certainly are matters of concern, but do they belong here? (Of course, techni- cally the effect is “acute” as opposed to “stochastic,” but the initial paragraph uses the word in a somewhat different way.) Are there any additional gaps in knowledge that should be considered for this specific risk? Some effort might be expended in expanding on the “etc.” in Acute Gap #5 (in general, “etc.” isn’t appropriate for a scientific paper unless one is sure the reader can readily supply the details). Does the evidence book address relevant interactions among risks? See comments about Acute Gap #5. Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? These are not relevant to this evidence book. Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed? • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed? • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered? The evidence book would benefit from a good editor with knowledge of the field. Sometimes the wording is confusing. For example, on p. 17-4: “In contrast to the constant presence of galactic cosmic rays in space, SPE exposures are sporadic and without sufficient shielding protection.” Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. Overall, the paper would benefit from editing. Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) No additional comments.

72 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS Chapter 18 Degenerative Tissue or Other Health Effects from Radiation Exposure Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? Yes. Is the text of the short description of the health risk provided in the PRD clear (it should be Section I of the evidence book)? Provide suggestions of revised wording. Yes. Does the evidence book make the case for the research gaps presented? Yes. Are there any additional gaps in knowledge that should be considered for this specific risk? Yes. Additional gaps in knowledge to be considered include: 1. Genetic susceptibility and its influence on individual response? 2. ISS currently operates at Earth normal except during prebreathe; how- ever, some Constellation class missions may be operating with elevated oxygen concentrations (30-34 percent). Because response to radiation is in part mediated by generation of oxygen-free radicals, will this poten- tiate degenerative effects of radiation exposure? 3. Because the CNS effects are of such potential concern, consider briefly listing these here with crossreference to relevant document. Does the evidence book address relevant interactions among risks? Yes. Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? Appropriate. Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed? • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed? • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered?

APPENDIX C 73 This is an excellent and comprehensive review of the state of knowledge about degenerative tissue effects and the need to improve that state. However, the lack of search information about genetic susceptibility and potential interaction with oxygen concentration should be addressed or dismissed as literature search would reveal. Small correction: pp. 18-19, line 4: it’s an arithmetic (not geometric) average— see NCRP 132, eq. 7.6 (p. 246). Note that geometric averages, although con- venient for lognormal model calculations, are biased toward the lesser of risk projections according to two transport models. Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. The primary concern is a lack of recognition (this is pervasive throughout the evidence books) that individual gene profiles might inform and influence risks. For example, to use a CNS example, genes have been identified that correlate with early-onset Alzheimer’s disease; would such mutations render an individ- ual more susceptible to degenerative CNS effects (either acute or late)? A sec- ond area of concern is about the interaction with ambient oxygen levels. Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) See above. REFERENCE CITED Hirsch, D. B., J. H. Williams, S. A. Harper, H. Beeson, and M.D. Pedley. 2007. Oxygen concentration flammability thresholds of selected aerospace mate- rials considered for the Constellation program. NASA Technical Report #20070018178, http://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/2007001 8178_2007017304.pdf (accessed April 13, 2008). Chapter 19 Acute or Late Central Nervous System Effects from Radiation Exposure Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? Yes. The paucity of human evidence, the small sizes of relevant animal studies, the apparent lack of studies of nonhuman primates, and the possibility of acute effects that could degrade crew performance make this a potentially serious risk

74 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS factor, possibly equal or greater in importance to that of radiation-related cancer risk. Is the text of the short description of the health risk provided in the PRD clear (it should be Section I of the evidence book)? Provide suggestions of revised wording. Yes. The PRD is clear and succinct. Does the evidence book make the case for the research gaps presented? Yes. The gaps enumerated are more or less self-evident. There is some urgency because of the possibility of severe consequences to mission performance. Are there any additional gaps in knowledge that should be considered for this specific risk? New gaps are likely to emerge as we learn more about the problem. Does the evidence book address relevant interactions among risks? Yes. Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? These are not relevant to this evidence book. Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed? • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed? • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered? The evidence book has the great advantage of information provided by NCRP Report No. 153, which was commissioned by NASA. That report includes a comprehensive literature survey. The expertise provided by the NCRP commit- tee and the senior author of the evidence book is considerable. The evidence book is accessible to a science professional not familiar with the specific area covered, but some effort is required. Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. The evidence book addresses a possibly serious risk factor for which the epide- miological literature in particular is not very informative because of important differences between the radiation environments inside and outside the Earth’s magnetic field. Information from experimental studies and medical case reports

APPENDIX C 75 is limited by small numbers. A greatly expanded research program would seem to be required. Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) No additional comments. Chapter 20 Radiation Carcinogenesis Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? Yes. The case is an easy one to make, and it is made very well. Is the text of the short description of the health risk provided in the PRD clear (it should be Section I of the evidence book)? Provide suggestions of revised wording. No. The phrase “is likely to increase” risk should be changed to “may increase.” because “risk” refers to probabilities and because the case is a strong one. The following change is suggested: “Occupational radiation exposure from the space environment may increase cancer morbidity or mortality in astronauts.” Does the evidence book make the case for the research gaps presented? Yes. As stated in the PRD, the main conclusion, that we have to find a practica- ble way to reduce the risk, trumps everything not directly related to that goal. Are there any additional gaps in knowledge that should be considered for this specific risk? No. The list of gaps seems comprehensive. It would be helpful if they were pri- oritized in terms of probable importance for risk and likelihood of achieving useful results in the next decade or two (a kind of cost–benefit analysis for re- search on identified gaps). Does the evidence book address relevant interactions among risks? No. There are many potential for interactions between radiation and other risks that should be considered. One example is the potential interaction between ra- diation and immune dysfunction incurred during space travel (see Farrell et al., 2000, and accompanying editorial). Also, given that the full program may take decades, NASA should be archiving material for genetic testing related to possi- ble new developments with respect to genetic susceptibility to radiation-related cancer.

76 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? The latency periods are such that any radiation-related cancer would most likely appear after the completion of the mission. On the other hand, predicted lifetime excess cancer risk, which would be uncertain and should be represented by an estimated probability distribution, would provide full information for a decision about acceptability of risk. The approach of Figure 20-2 comes close to that ideal. Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed? • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed? • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered? Author expertise is high, especially with respect to understanding of radiation physics, epidemiology, and risk estimation. Some cited references do not appear in the reference list, suggesting that the document was submitted before it could be fully proofed, but the overall quality of the evidence book is high. Readers not quantitatively inclined will probably skip the mathematical parts, but they should remain in the paper. Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. Overall, the evidence book provides a very good and comprehensive review of the issue of radiation-related cancer associated with space activities. Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) This comment is a general one, not limited to the specific evidence book: The approach using separate evidence books could be too compartmentalized, unless the next phase is to integrate them. It would make sense to classify risks and risk factors in terms of (1) effect on ability to successfully complete the mission (e.g., acute effects) and (2) long-term effects on health and well-being following the mission (e.g., cancer risk). The next step would be to carry out quantitative uncertainty analyses, using objective data where available and expert subjective uncertainty information where necessary. The process should be transparent and open. The analyses would be designed to provide estimates of the implications of the various sources of information for the two types of effects, with uncertain-

APPENDIX C 77 ties. Such analyses might be expected to identify areas for which more informa- tion is most needed because of possible or likely consequences for mission suc- cess and long-term health effects. REFERENCE CITED Farrell, R. J., Y. Ang, P. Kileen, D. S. O’Briain, D. Kelleher, P. W. Keeling, and D. G. Weir. 2000. Increased incidence of non-Hodgkin’s lymphoma in in- flammatory bowel disease patients on immunosuppressive therapy but overall risk is low. Gut 47(4):514-519; editorial commentary by L. J. Kinlen, pp. 462-463. Chapter 21 Therapeutic Failure Due to Ineffectiveness of Medication Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? Yes. The evidence book makes a convincing case for risks associated with medication use. The title is somewhat misleading, as the evidence book clearly demonstrates that there are risks related to self-medication, and inaccurate re- cordkeeping in addition to “ineffectiveness of medication.” It is striking that the largest indication for self-medication is pain relief, yet debriefings suggest that pain is inadequately addressed in flight. Similarly, the evidence book appropri- ately warns against the “un-counseled polypharmacy trend of medication use in space.” We suggest changing the title to: “Risk of therapeutic failure or adverse effect due to ineffectiveness of medication, medication interaction, or unantici- pated idiosyncratic reaction.” Is the text of the short description of the health risk provided in the PRD clear (it should be Section I of the evidence book)? Provide suggestions of revised wording. Yes. Does the evidence book make the case for the research gaps presented? Yes. The evidence book is comprehensive, although a bit difficult to read. Are there any additional gaps in knowledge that should be considered for this specific risk? Yes. Additional gaps in knowledge to be considered include: 1. How does genetic variation contribute to differences in drug effective- ness and side effects in the space environment?

78 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS 2. What potential interactions with alcoholic beverages might be antici- pated (if the crew is international and if alcohol is allowed in-mission)? 3. How will the natural degradation associated with long storage periods be mitigated for long-duration space travel? 4. What classes of drugs should be taken on a mission, what quantities should be taken, and how can the risk of inability to treat be minimized, especially during long-duration exploration-class mission? 5. The decision on which classes of therapeutic agents and which drugs to take will impact which conditions can be treated. A methodology for decision making should be included. Does the evidence book address relevant interactions among risks? Yes. Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? Merging is appropriate. No risks appear to have been omitted. Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed? • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed? • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered? The expertise is appropriate and the literature review is comprehensive. The evidence book is extremely thorough. This will make it a bit difficult for the average “science professional” to wade through. The case for Gap #3 could be improved, including the consideration of technologic solutions. Gap #4, as worded, is overly broad and overarching and Gap #5 is vague. Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. The evidence book makes a convincing argument for significant gaps in knowl- edge and need for additional research. It does not appear to adequately address the following issues, listed as gaps above: 1. It is now recognized that genetic polymorphisms influence drug me- tabolism significantly (e.g., warfarin, tamoxifen, codeine). In clinical practice, testing for known mutations that affect drug metabolism is rapidly becoming part of the standard of care. Ongoing research should include archiving samples for future testing as new genes are identified. Use of drugs may need to be optimized to individual astronauts’ genetic profiles.

APPENDIX C 79 2. When long-duration exploration-class missions are undertaken, a deci- sion will need to be made about taking alcoholic beverages or not. If alcoholic beverages are to be flown, potential interactions of drugs and alcohol in the space environment must be considered. 3. Because of the duration of exploration-class missions, drugs will need to be stored for considerable time. Degradation occurs with time, even on Earth. Storage periods may exceed current recommendations. Loss of potency and potential for toxicity may result. The time factor needs to be addressed as one of the unique factors in these classes of mis- sions. Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) No additional comments. Chapter 22 Inability to Adequately Treat an Ill or Injured Crew Member Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? Yes. The synthesis of in-mission experience and incidence of illness derived from analog environments makes a strong case for the importance of autono- mous health care capability for exploration-class missions, and the probability that some health emergencies may not be treatable. Is the text of the short description of the health risk provided in the PRD clear (it should be Section I of the evidence book)? Provide suggestions of revised wording. Yes. The wording conveys the essence of the issue. Does the evidence book make the case for the research gaps presented? No. The evidence book states: “Identification of the ‘gaps’ between anticipated in-mission medical conditions and abilities to mitigate or treat these conditions adequately is currently being conducted.” No list of gaps is presented, nor is the basis on which anticipated conditions will be included or excluded. Are there any additional gaps in knowledge that should be considered for this specific risk? Yes. A gap exists not only for specific medical conditions identified, but also for a published and widely understood algorithm or method for including or exclud- ing any particular condition for in-mission treatment consideration. An approach

80 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS based solely on existing in-mission and analog environment experience is likely to be insufficiently effective, and should be enhanced by best available synthesis of the other health risk categories. For example, although altered immunity has yet to be associated with clinically evident disease, consideration of treatments of conditions that might result from altered immunity, such as disseminated viral reactivation, should be included in planning for long-term missions. Does the evidence book address relevant interactions among risks? No. Inability to provide treatment is interlinked with “risk of error due to inade- quate information.” Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? These are not relevant to this evidence book. Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed? • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed? • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered? The paper is quite readable and well formulated, with adequate citations to pub- lished and unpublished findings. Author expertise appears to be appropriate to the task. Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. This evidence book seems to be in an early stage of development. The addition of a detailed list of gaps will do much to illuminate the directions in which re- search and development will be going within NASA. As written, it describes a necessary, but not sufficient, overall approach to the provisioning of autono- mous health care resources and, at least as importantly, the enumeration of con- ditions that will be left untreated during exploration-class missions. Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) No additional comments.

APPENDIX C 81 Chapter 23A Lack of Human-Centered Design: Sub-Risk of Reduced Safety and Effi- ciency Due to Poor Human Factors Design Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? Yes. The case is made largely on the basis of anecdotal incidents that are con- vincing, but not a thorough scientific evaluation. The numerous examples are compelling, but it would be a stronger case if they were limited to the space ac- cidents rather than the ground-based accidents (e.g., aviation, ship, power plant) as well. It is far more important to demonstrate the problems that exist in long- duration spaceflight and the research required to address those problems than it is to describe the effects of general human accidents in recent history. Is the text of the short description of the health risk provided in the PRD clear (it should be Section I of the evidence book)? Provide suggestions of revised wording. No. Although the case is strong, the description is inadequate. It is filled with jargon and is not specific. Does the evidence book make the case for the research gaps presented? Yes. Are there any additional gaps in knowledge that should be considered for this specific risk? Yes. Additional gaps in knowledge to be considered include: 1. Manual control 2. Advanced displays 3. Workload assessment 4. Training, both initial and in-mission 5. Use of artificial intelligence for malfunctions 6. Spatial disorientation as it affects performance Does the evidence book address relevant interactions among risks? Yes. With human factors, everything is connected to everything else. A fatigued astronaut will need a redundant checklist. A disoriented one will need a more compelling display. Further, the authors may wish to address the potential over- lap associated with the impact of environmental design on psychosocial and behavioral adjustment issues, e.g., issues discussed in Chapters 15 and 16. Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? These are not relevant to this evidence book.

82 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed? • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed? • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered? The literature should be divided into the specific accounts associated with the Human Factors examples, and the broader references dealing with space experi- ences and human factors methodology. The expertise and examples are ade- quate, though not all are directly applicable. The overall readability is poor because of too much jargon and too much repetition. The evidence book list of authors includes many from “inside” the NASA system, and may be improved with additional external academic perspectives. Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. This section is a full and provocative primer on the general issue of dangers as- sociated with the various aspects of human-centered design, and what can hap- pen if the principles are ignored. It suffers from being too long—but especially in not distinguishing between the dangers associated with the failure to follow known procedures, and the absence of information about what procedures to employ for long-duration spaceflight. The first is a matter of training and the second is the subject for NASA’s Human Research Program (HRP) research. Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) 1. Manual control 2. Displays 3. Spatial disorientation 4. Fatigue Chapter 23B Lack of Human-Centered Design: Sub-Risk of Error Due to Inadequate Information Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? Yes. As discussed below; however, the case could be made more compelling. Is the text of the short description of the health risk provided in the PRD clear (it should be Section I of the evidence book)? Provide suggestions of revised wording.

APPENDIX C 83 Yes. It is clear. but incomplete. “Lack of information can be a problem, but so can too much information if the means of separating the important information are inadequate or poorly designed.” A suggested revision follows: “Task errors can be due to lack of, or inadequate ability to dis- cern, appropriate information, which in turn may be due to any of the following: [(a), (b), (c), (d) as shown] (e) excessive information, with unclear or otherwise inade- quate demarcation between the information that is important or useful for the situation and the information that is not.” Does the evidence book make the case for the research gaps presented? Yes. The supporting evidence from spaceflight is very strong, and NASA is cer- tainly one of the world’s leading experts. However, the categorization of the spaceflight examples could have been more logically presented in some in- stances. The ground-based supporting evidence is not adequate. For example, using an occurrence that is nearly 30 years old (the Three Mile Island nuclear accident in Pennsylvania) as an example of inadequate displays and controls certainly raises the question of whether there are more recent examples. If so, these should be cited as examples, and if not, query whether a problem still ex- ists. In addition, because the risk definition does not adequately address having too much information, none of the examples relates to that issue. There is a large amount of supporting ground-based evidence that is available concerning every category enumerated in the evidence book, involving both inadequate and too much information. The evidence book would be stronger if such issues were also included. Are there any additional gaps in knowledge that should be considered for this specific risk? Yes. There are undoubtedly gaps associated with the issue of too much informa- tion, which is not adequately discussed in the report. Does the evidence book address relevant interactions among risks? Yes. Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? These are not relevant to this evidence book. Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed?

84 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed? • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered? No additional comments. Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. The paper satisfactorily addresses issues associated with inadequate information, but the paper should also address issues associated with too much information, which can also lead to undesirable outcomes. Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) No additional comments. Chapter 23C Lack of Human-Centered Design: Sub-Risk Associated with Poor Task Design Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? Yes. As discussed below, however, the case could be more compelling. Is the text of the short description of the health risk provided in the PRD clear (it should be Section I of the evidence book)? Provide suggestions of revised wording. Yes. It is clear but incomplete. Focusing solely on reducing operator error is politically popular, but can result in serious inefficiencies when applied in actual operation. Moreover, the issue relates to all tasks, not just critical tasks. A sug- gested revision to the second sentence follows: “All tasks, especially critical tasks, must be designed to minimize human error in a way that improves effi- ciency as much as possible, or at least minimally degrades efficiency.” Does the evidence book make the case for the research gaps presented? Yes. Similar to Chapter 23B: Inadequate Information, the supporting evidence from spaceflight is very strong, and NASA is certainly one of the world’s lead- ing experts. However, the categorization of the spaceflight examples could have been more logically presented in some instances. The ground-based supporting evidence is not adequate. For example, using an occurrence that is more than 60 years old (a cargo ship explosion in 1947) as an example of which cargo com- partments should and should not be adjacent to each other (not to mention the

APPENDIX C 85 issue of why this is an example of poor task design) certainly raises the question of whether there are better and more recent examples. If so, why aren’t more recent examples cited, and if not, query whether this is still a problem. Are there any additional gaps in knowledge that should be considered for this specific risk? Yes. There are gaps associated with determining the impact on efficiency of an error-reducing task design. Does the evidence book address relevant interactions among risks? No. The design of tasks that necessitate EVA must consider the physical and other limitations created by the EVA suit. Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? These are not relevant to this evidence book. Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed? • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed? • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered? No additional comments. Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. The paper should address not only the error potential of task designs, but also the impact on efficiency. In addition, task design of activities that involve EVA must also consider the physical and other limitations of the EVA suit. Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) No additional comments. Chapter 24 Inadequate Food System Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? Yes.

86 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS Is the text of the short description of the health risk provided in the PRD clear (it should be Section I of the evidence book)? Provide suggestions of revised wording. No. The last sentence suggests that an allocation of resources for food has al- ready been made, which is unlikely at this early stage. The following is a sug- gested replacement for the last sentence: “Furthermore, careful attention must be paid to the resources allocated to creating a satisfactory food system in order to avoid unduly depriving other systems of needed resources.” Does the evidence book make the case for the research gaps presented? Yes. Are there any additional gaps in knowledge that should be considered for this specific risk? Yes. One gap that is not mentioned is whether acceptable food will grow on Mars, the Moon, or enroute, given the reduced gravity, reduced sunlight, avail- able water, radiation, and other aspects of the growing environment. This uncer- tainty may necessitate carrying enough on-board food to provide adequate and acceptable nutrition in case biogeneration is not successful. If enough on-board nutrition has to be carried, as a contingency, a potential query is whether bio- generation should be part of the overall nutrition plan. Does the evidence book address relevant interactions among risks? No. The paper addresses several interactions, most notably the relation between adequate and acceptable food and the crew’s physical and mental well-being, but at least one risk interaction is missing. The evidence book on central nervous system effects from radiation exposure mentions some dietary countermeasures, but there is no indication in this food system paper regarding giving any special consideration to those dietary items. Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? These are not relevant to this evidence book. Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed? • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed? • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered? No additional comments.

APPENDIX C 87 Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. The paper provides a good description and analysis of the many difficult issues involved. Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) No additional comments. Chapter 25 Adverse Health Effects from Lunar Dust Exposure Does the evidence book make the case (sufficient evidence) that this risk is relevant to long-term space missions? No. 1. The evidence book would be strengthened by the addition of a system- atic introduction to the toxicology of airborne particulates, so that the reader would have a set of benchmarks against which the evidence re- garding lunar dust can be considered. As a related consequence, the document jumps from one topic to another, including some examples (e.g., Hawks Nest tunnel disaster) that have little relevance for the task at hand. It makes the assumption that activation/passivation is the key issue, but does not adequately justify this. The draft does not do an adequate job of presenting and discussing the potential health effects of dust exposure. These would include at least fibrogenicity, carcinogenic- ity, allergic sensitization, and respiratory/dermal irritant properties. 2. This evidence book should include a more complete and systematic presentation concerning what is known about the characteristics of lu- nar dust in order to consider adequately the potential health risks. This is another prerequisite for an evaluation of risk and gaps. The human health risks from airborne dust exposure vary according to chemical composition, particle size, physical characteristics (e.g., crystalline structure, particle shape, fibrous character), and a variety of human fac- tors (e.g., pre-existing illness, respiratory rate). As an example, the draft paper seems to presume that lunar dust is respirable (see first sen- tence of executive summary), but there is no discussion about the parti- cle size distribution of lunar dust and not all evidence supports this assumption. More attention is necessary for this important issue. 3. Similarly, the current draft fails to consider potential allergic/immune consequences of lunar dust. Indeed, terms such as “airborne allergen” and “IgE” never appear, and the word “immune” (or related) appears only once. This is despite the evidence that two individuals who were

88 REVIEW OF NASA’S HUMAN RESEARCH PROGRAM EVIDENCE BOOKS exposed to lunar dust reported allergic symptoms or findings. The first, an Apollo astronaut, described his response as “hay fever” (i.e., pollen allergy); the second, a ground-based physician-scientist, described an “allergic-type” reaction, apparently supported by changes in basophil and eosinophil counts. This oversight should be considered and ad- dressed to ensure the development of effective countermeasures. 4. The draft offers two Earth-based analogs (silicosis among miners and volcanic ash exposure) without convincingly explaining how these compare with possible lunar dust exposures. It fails to explore another body of evidence that may be relevant—environmental exposure to PM10 particulate dust (10µM-diameter particulate matter) and its effect on respiratory and cardiovascular function. Is the text of the short description of the health risk provided in the PRD clear (it should be Section I of the evidence book)? Provide suggestions of revised wording. No. The text is not an affirmative statement describing the problem. Rather it is simply a critique of the risk statement in the PRD. It is suggested that it be re- written, not just revised. Does the evidence book make the case for the research gaps presented? Yes. Most of the gaps identified seem reasonable; however, the paper may be strengthened if it begins to establish relative importance to each. Are there any additional gaps in knowledge that should be considered for this specific risk? Yes. Additional gaps in knowledge to be considered include: 1. Respiratory dynamics under conditions of reduced gravity or weight- lessness. Does particle distribution and deposition in the respiratory tract differ from Earth-based conditions? 2. Effectiveness of available control methods to reduce exposure. 3. Role of lunar dust as a possible airborne allergen. 4. Countermeasure development, ranging from physical to pharmaceuti- cal, to deal with the airborne allergen potential. Does the evidence book address relevant interactions among risks? No. Only EVA suits are mentioned. Other topics for consideration include im- pact of prolonged exercise, poor human factors design, and cognitive errors. Comment if relevant to the specific evidence book: Is the merging of some risks in the Bioastronautics Roadmap into a single risk appropriate? Is the omission of some risks in the Bioastronautics Roadmap appropriate? These are not relevant to this evidence book.

APPENDIX C 89 Comment on other issues regarding the evidence book, including: • Is the author expertise sufficient? Other disciplines needed? • Literature search: Is the breadth of the search sufficient? Is informa- tion on the search strategy needed? • Overall readability: Is it appropriate for a “science professional” who is not familiar with the specific area covered? See comments above regarding the literature base. The authors seem highly skilled and knowledgeable in a variety of areas, but the draft suggests the need for more input from the clinical, epidemiological, and environmental health sci- entists who are familiar with the occupational and environmental health risks of long-term, low-level exposures to a variety of airborne particulates. Overarching comments on the evidence book: Provide a short paragraph summary of the key issues raised in your review of the paper. No additional comments. Please note: • Crosscutting issues and ideas for broader recommendations • Additional risks that should be added to the list (missing risks) No additional comments.

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Planning for long-duration space flights requires consideration of complex disease prevention, behavioral health, and clinical treatment issues-issues resulting from the hazards of the space environment and from limitations to in-mission medical care. These research and development needs have prompted NASA to seek and coordinate assessment from both national and international space medicine practice as well as biomedical research communities. Review of NASA's Human Research Program Evidence Books: A Letter Report examines NASA's plans to assemble the available evidence on human health risks of spaceflight and moves forward in identifying and addressing gaps in research. Recommendations to strengthen the content, composition, and dissemination of the evidence books are intended to improve future versions of these critical documents. These evidence books should be the continuously updated knowledge base of best evidence regarding risks to human health associated with spaceflight, particularly spaceflight beyond low Earth orbit and of long duration. Such a knowledge base will serve the interests of mission planners, researchers, and ultimately the individuals who accept those risks in their role as space travelers.

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