7

Crosscutting Issues for Humans in the Space Environment

Translating knowledge from basic laboratory discoveries to human spaceflight is a challenging, two-fold task: Horizontal integration requires multidisciplinary and transdisciplinary approaches to complex problems; vertical translation requires meaningful interactions among basic, preclinical, and clinical scientists to translate fundamental discoveries into improvements in the health and well-being of crew members in space and in their re-adaptation to gravity. This chapter focuses on both aspects as a framework to expand human presence in space.

There are significant scientific gaps in a number of horizontal or crosscutting areas that span multiple physiological systems that can affect human health, safety, and performance. Specific examples discussed in this chapter include:

1. The physical stress of spaceflight and how it manifests physiological strain;

2. Optimization of nutrition, energy balance, and physical activity;

3. Enabling appropriate thermoregulation;

4. Issues related to radiation biology; and

5. Sex-specific effects.

Many of these interactions also involve interactions with behavioral factors, such as effects on cognitive function. These factors are discussed extensively in Chapter 5.

Although each area could be viewed as a relatively straightforward extension of human biology, in reality they represent crosscutting, thematic areas that require the collaboration of teams of experts representing different areas of physiological and engineering expertise. Accordingly, this chapter presents a new framework that builds on revolutionary approaches to health care research that have gained prominence in the past decade. The primary goal of these approaches is to mobilize fundamental and applied scientific knowledge and resources in a way that optimizes their utility for human spaceflight crews.

A research plan for vertical translation within individual physiological systems is well summarized in Chapter 6. So how does addressing the concepts of horizontal integration and vertical translation simultaneously complement the existing research enterprise? Consider the effects of reduced mechanical loading on bone and muscle loss in space. Whereas the effects of reduced loading per se on the individual systems are discussed thoroughly in Chapter 6 using a vertical translation strategy, detrimental changes in musculoskeletal mass and function in the space environment may be further influenced by horizontal integration of multiple factors that include, but are



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7 Crosscutting Issues for Humans in the Space Environment Translating knowledge from basic laboratory discoveries to human spaceflight is a challenging, two-fold task: Horizontal integration requires multidisciplinary and transdisciplinary approaches to complex problems; vertical translation requires meaningful interactions among basic, preclinical, and clinical scientists to translate fundamental discoveries into improvements in the health and well-being of crew members in space and in their re-adaptation to gravity. This chapter focuses on both aspects as a framework to expand human presence in space. There are significant scientific gaps in a number of horizontal or crosscutting areas that span multiple physi - ological systems that can affect human health, safety, and performance. Specific examples discussed in this chapter include: 1. The physical stress of spaceflight and how it manifests physiological strain; 2. Optimization of nutrition, energy balance, and physical activity; 3. Enabling appropriate thermoregulation; 4. Issues related to radiation biology; and 5. Sex-specific effects. Many of these interactions also involve interactions with behavioral factors, such as effects on cognitive function. These factors are discussed extensively in Chapter 5. Although each area could be viewed as a relatively straightforward extension of human biology, in reality they represent crosscutting, thematic areas that require the collaboration of teams of experts representing different areas of physiological and engineering expertise. Accordingly, this chapter presents a new framework that builds on revolutionary approaches to health care research that have gained prominence in the past decade. The primary goal of these approaches is to mobilize fundamental and applied scientific knowledge and resources in a way that optimizes their utility for human spaceflight crews. A research plan for vertical translation within individual physiological systems is well summarized in Chapter 6. So how does addressing the concepts of horizontal integration and vertical translation simultaneously comple - ment the existing research enterprise? Consider the effects of reduced mechanical loading on bone and muscle loss in space. Whereas the effects of reduced loading per se on the individual systems are discussed thoroughly in Chapter 6 using a vertical translation strategy, detrimental changes in musculoskeletal mass and function in the space environment may be further influenced by horizontal integration of multiple factors that include, but are 205

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206 RECAPTURING A FUTURE FOR SPACE EXPLORATION not limited to, low energy availability, micronutrient deficiencies, reduced physical activity, increased levels of glucocorticoids and other stress hormones, and reductions in gonadal hormones. Understanding the independent and combined effects of multiple stressors on multiple physiological systems, and how resultant changes influ - ence health, safety, and performance, should be viewed as an obligatory step for the development of effective countermeasures. For example, intensive exercise may effectively mitigate microgravity-related effects of reduced loading on muscle and bone loss but exacerbate the adverse effects of low energy availability and gonadal hor- mone suppression on the musculoskeletal system. Because of the small number of potential study subjects, it will probably not be possible in the foreseeable future to carry out human studies in space that effectively evaluate the independent and combined effects of multiple stressors. However, a comprehensive characterization of both the stressors and the responses of multiple biologic systems will generate important preliminary data for hypothesis- driven research on multiple stressors (e.g., ground-based human studies). Finally, this chapter emphasizes the need for effective coupling of biological and engineering problem- solving strategies. It is difficult, if not impossible, to replicate the multiple stressors of the space environment in a ground-based analog. However, creation of an effective exercise countermeasure for the preservation of bone, muscle, and cardiovascular function in a ground-based experiment is productive only if the countermeasure can be implemented in the space environment. This important translational step is heavily dependent on approaching the problem from a multidisciplinary perspective. SOLVING INTEGRATIVE BIOMEDICAL PROBLEMS THROUGH TRANSLATIONAL RESEARCH Stress—Physical and Physiological Considerations There are numerous known biomedical stressors associated with spaceflight and re-adaptation to gravity that may benefit from a translational approach. Decompression Sickness Human spaceflights in low Earth orbit or on exploration missions to the Moon, asteroids, or Mars all require many thousands of hours of extravehicular activity (EVA) and inherently carry a higher risk of decompression sickness.1 Suits are necessarily designed to operate at as low a pressure as practicable (e.g., Apollo, 3.8 psi; space shuttle/International Space Station (ISS), 4.3 psi; Russian Orlan, 5.7 psi) so as to maximize suit joint and glove flexibility while maintaining physiologically adequate oxygen and CO 2 partial pressures. During the airlock decompression from spacecraft to hypobaric suit pressure, nitrogen dissolved in blood and tissues comes out of solution, creating tiny bubbles (evolved nitrogen), which potentially can cause symptoms of decompression sick - ness (DCS), colloquially called “the bends.” DCS at 5 psia was not a problem on Apollo, because the spacecraft operated with a 100 percent O2 environment. Primarily for scientific reasons, the space shuttle and the ISS use an Earth-like 14.7 psia, 20.8 percent O2 atmosphere, although the space shuttle can be depressurized to 10.2 psia to shorten EVA prebreathing of pure oxygen. DCS during EVAs is avoided by prebreathing 100 percent O 2 to reduce evolved nitrogen. Exercise during prebreathing greatly accelerates denitrogenation. Staged decompression (e.g., to 10.2 psi) followed by a shorter prebreathe interval is sometimes used. Astronauts are also routinely exposed to hyperbaric environments during underwater “neutral buoyancy” EVA training. DCS upon ascent is avoided by limiting the depth and duration of underwater training and by the use of oxygen-enriched breathing gas. Known Effects No cases of hypobaric DCS have been reported on Apollo flights, the space shuttle, or the ISS. Decompres - sion using conventional staged protocols normally creates venous gas emboli (VGE or “silent bubbles”). 2,3 Small numbers of bubbles produce no symptoms, but in 1-g testing, large numbers of VGE are usually correlated with joint and muscle pain (Type I DCS). Exercise increases the number of venous bubble micronuclei and incidence of symptoms. Most VGE are believed trapped in the lungs. However intrapulmonary (pulmonary arterial to venous) connections exist4 that shunt blood to the systemic arterial side, particularly during exercise. VGE can be easily

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207 CROSSCUTTING ISSUES FOR HUMANS IN THE SPACE ENVIRONMENT detected using cardiac Doppler ultrasound, so the number of bubbles is used as a correlate of decompression stress during hypobaric chamber tests of astronaut oxygen prebreathe protocols. If a significant number of bubbles reach or form on the arterial side, more serious symptoms (Type II DCS) occur, ranging from headache, shortness of breath, impaired vision, fatigue, memory loss, and vomiting to seizures, paralysis, confusion, unconsciousness, and even death. Arterial gas emboli (AGE) can be detected using transcranial Doppler techniques, but so far this is practical only in laboratory settings. Fortunately, as compared to diving, there are few documented adverse medi - cal events of space EVA decompressive stress (e.g., neurologic signs or bone necrosis). 5 Severe hypobaric Type II DCS events are rare.6 Almost all symptoms encountered in 1-g hypobaric tests are Type I, and they frequently resolve with simple 100 percent O2 treatment. For the treatment of DCS in space, the ISS suit can deliver a total of 23 psi, 14.7 psi from station atmosphere, 4.3 psi from the suit pressure, and an additional 4 psi by overriding the positive pressure relief valve with the Bends Treatment Adapter. Effects of Countermeasures Astronaut candidates with a history of Type II DCS or uncorrected atrial septal defects are thought to be potentially at greater risk of AGE and are disqualified. Prebreathe protocols are designed using mathematical decompression stress models (e.g., two-phase tissue bubble dynamics models), prospective hypobaric simula - tions in altitude chambers, statistical analysis of data from ground and flight experience, and expert judgment. Test chamber DCS incidence must always be less than 15 percent, with less than 20 percent large VGEs and no serious DCS symptoms. Ground testing7 has shown that 10 min of exercise (75 percent of peak oxygen uptake) during a 1-h prebreathe is equivalent to a 4-h resting prebreathe. Among divers, administration of nitroglycerin 8 or intense predive exercise9 24 h previous reduces bubble formation. Modeling10 and animal11 studies indicate that recompression after a decompression step also reduces bubble formation. The latter findings suggest that multiple short sorties from a pressurized enclosure (e.g., a habitat or rover in a reduced-gravity environment) may reduce decompression stress relative to an equivalent single time exposure. Gaps in Fundamental and Applied Knowledge Operational incidence of Type I DCS in orbit has been far less than that anticipated based on ground tests. 12 It is not clear whether this is due to overreporting in ground studies or underreporting in orbit. Alternatively, astro - nauts may have fewer bubble micronuclei, VGE, and AGE in orbit, perhaps due to exertion or fluid shift effects on bubble nucleation or shunting. Further research on the cellular and molecular mechanisms of bubble formation and tissue interaction and on intrapulmonary shunting is needed. Determining whether gravity has an important effect on DCS mechanisms is obviously important. Should prebreathe protocols be designed more stringently for lunar and Mars partial gravity than for microgravity? VGE prevalence in microgravity could be experimentally assessed via cardiac Doppler ultrasound monitoring, but this important experiment has not yet been conducted during spaceflight. Currently, astronaut candidates are not evaluated for intrapulmonary shunting. 13 There may be individual differences in AGE formation due to exercise-induced intrapulmonary bubble shunting, which can only be detected via chamber testing using transcranial Doppler. Knowing the lowest suit pressure and compatible habitat atmospheres that would allow EVA without pre - breathe is important for space exploration missions. Crews could live in an 8 psi, 32 percent O 2 habitat and perform EVAs in a conventional 4.2 psi, 100 percent O2 suit without prebreathe. It has been suggested14,15 that, to promote suit joint and glove flexibility, crews could adapt to a slightly hypoxic 2.7 psia, 100 percent O 2 suit, and operate without prebreathe from a 6.2 psia, 36 percent O2 habitat. This suit pressure is equivalent to that at an elevation of 40,000 feet on Earth, and the pO2 is equivalent to breathing air at 11,000 feet. Maintaining a relatively low habitat oxygen partial pressure has fire safety advantages, but the resulting hypoxic, hypobaric environment may impair cognition and pose challenges for verbal communication and heat transfer. Higher operating pressures can mitigate the risk of DCS, but new risks for excessive fatigue and trauma may be created. Thus, an important technology challenge is to improve the design of EVA suit joints.16 Further research is also needed on operationally acceptable low suit pressures and hypobaric hypoxia levels. Novel perfluorocarbon therapeutic oxygen carriers, which are in human testing for stroke and brain injury,17 also enhance nitrogen offgassing. Use of such blood additives could eventually enable novel approaches to DCS and hypoxia management.

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208 RECAPTURING A FUTURE FOR SPACE EXPLORATION Research Models and Platforms Needed Research models and platforms encompass animal and human research in altitude chambers and experimental ultrasound studies of incidence of VGE formation in microgravity, using operational denitrogenation protocols aboard the ISS. Findings and Recommendations After four decades of EVA experience, NASA views DCS as primarily an operational problem and in the past 20 years has supported little basic research on DCS mechanisms or countermeasures. However, the amount of surface EVA activity on exploration missions potentially far exceeds that on the space shuttle and the ISS, so the statistical likelihood of a DCS episode is higher. The effect of gravitational level on DCS incidence is not well understood. Previous National Research Council (NRC) reviews18,19 have recommended increased emphasis on advanced EVA research, with increased industry and university involvement. It is critical to understand whether gravity has a direct or indirect effect on microbubble nucleation. More research is also needed to understand VGE and AGE detection and tissue interaction; intrapulmonary right-to-left shunting; effects of exercise on DCS; effects of periodic recompression on DCS; the effects of hypobaric and hypoxic environments on DCS, cognition, vocal - ization and heat transfer; and alternatives for hypoxia prevention and denitrogenation, such as perfluorocarbon therapeutic blood additives. Rotation/Artificial Gravity Artificial gravity (AG)20 achieved by rotation was first proposed as a multisystem physiologic countermeasure by K. Tsiolkovsky more than 100 years ago. Small centrifuges have been flown on the space shuttle, the ISS, and Bion to provide 1-g controls for gravitational biology experiments. NASA’s planners have assumed that AG will not be required for 6-month lunar missions, although longer-term effects of living at lunar gravity remain unknown. Rotation of an entire exploration mission spacecraft to provide continuous AG for astronauts signifi - cantly complicates engineering design. Nonetheless, a 1-g, 4-rpm, 50-m-radius rotating truss design21 is under consideration for Mars missions. An alternative to rotating the entire spacecraft is to provide a facility within the spacecraft for intermittent, rather than continuous, AG exposure. Encouraging recent results from bone, muscle, and cardiovascular research on humans and animal models (see Chapter 6 of this report) suggest that intermittent rather than continuous expo - sure to hypogravic gravitational force levels may provide an adequate countermeasure. Intermittent AG could be provided using a short-radius centrifuge (2 to 5 m) mounted inside the vehicle and perhaps even human-powered. However, short-radius centrifuges require significant rotation rates and require that humans and animals adapt to initially unpleasant vestibular and biomechanical Coriolis effects. An alternative strategy to induce AG in humans is to use lower-body negative pressure to provide footward loading while walking or running on a treadmill.22 This approach has been tested extensively in bed rest studies involving both men and women, and it has shown significant beneficial effects for a multiplicity of systems. 23-32 Known Effects Graybiel and colleagues33 recognized that, because of the fluid mechanics of the vestibular semicircular canals, any head movement made out of the plane of rotation in a rotating system produces a strong tumbling illusion that quickly provokes motion sickness in a 1-g environment because of vestibular sensory cue conflict. Symptoms included fatigue, nausea, vomiting, and sensory after-effects. Most vertebrate animals exhibit similar symptoms. Rotating chair experiments on Skylab34 and in parabolic flight35 showed that provocativeness depends on both ambient gravitational force level and rotation rate. However, as ambient gravitational force approaches zero, subjects could make unlimited numbers of head movements in a rotating chair with their heads near the axis of rotation, even at 30 rpm, without becoming ill. In ground-based rotating rooms and centrifuges, where total gravitational force levels are inherently greater than 1, the sickness threshold is approximately 3 rpm. 36 However, when lying supine on short-radius centrifuges, many individuals can successfully adapt to significantly higher rotation rates, and the adaptation is partially retained.37,38 Susceptibility is expected to be lower if gravitational

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209 CROSSCUTTING ISSUES FOR HUMANS IN THE SPACE ENVIRONMENT force levels at the head are less than 1 g, but the dose-response relationship cannot be determined in ground-based laboratory centrifuges. Biomechanical Coriolis forces also cause reaching errors and other limb movement control problems, although humans rapidly adapt if body orientation remains constant. Gaps in Fundamental and Applied Knowledge There are three basic reasons to incorporate AG in orbital studies: 39 1. To explore the feasibility and the parameter space (e.g., gravity level, exposure duration, exposure frequency, and whether concurrent exercise is used) for this potentially universal countermeasure; 2. To allow study of the biological and physical effects of partial-gravity environments at less than 1 g that are not otherwise available through scientific investigations of reduced-gravity environments on Earth; and 3. To serve as a 1-g control for microgravity experiments on human and nonhuman subjects. Science-based decisions on whether to use AG on very long duration missions and whether to use short-radius, intermittent rotation (e.g., via an onboard centrifuge) or long-radius, continuous rotation (e.g., by rotating all or part of the spacecraft) can be made when it becomes clear whether AG is required for medical or habitability reasons and after the necessary gravitational force level and the frequency and duration of exposure, rotation rate, and gravity gradient limits are determined from dose-response studies. Research Models and Platforms Needed Only plant and animal studies can be accomplished using centrifuges aboard free-flying satellites (e.g., Bion). The Japanese Aerospace Exploration Agency, JAXA, developed a 2.5-m animal and plant centrifuge for the ISS and initiated ground studies in humans using head-down bed rest and intermittent short-radius centrifugation. Ulti - mately, flight experiments on humans and animals will be required, especially to resolve questions about partial gravity that cannot be addressed on the ground. However, both NASA’s ground-based and flight AG research was suspended in 2005 when the U.S. program was refocused on lunar missions. The 2.5-m centrifuge was dropped from the ISS. Fortunately, AG research is continuing in ground laboratories elsewhere (France, Germany, Japan, China, and Belgium). Several small centrifuges remain aboard the ISS to support blood sample separation and control experiments on very small animals, plants, and other biologicals, but no facilities or logistical support exist for AG experiments on rats or small primates. The next generation of crew taxi vehicles lack sufficient interior space for a human short-radius centrifuge. Conceivably a larger habitat, tether, or truss systems could be developed to provide AG for missions otherwise involving very long duration exposures to microgravity. Recommendations Resolution of the gaps in fundamental knowledge of partial gravity on human physiology may require a decade or more of research in ground laboratories and eventually aboard the ISS. In collaboration with international partners, NASA should reinitiate a vigorous program of ground research, develop small animal AG experimental facilities for the ISS, and develop a simple short-radius human centrifuge for eventual countermeasure evaluation experiments aboard the ISS. Space Motion Sickness Of all the physiological difficulties astronauts encounter during their first days in orbit, space motion sick - ness has been the most overt and prevalent. Symptoms are often triggered by head and body movements or visual disorientation in the microgravity environment.40,41 There were no reports of space sickness in the Mercury or Gemini program, probably because the cabins were so small that the crew had limited ability to move around. More than 70 percent of space shuttle crew members report some symptoms, with moderate to severe symptoms in 30 percent of cases. These symptoms usually involve multiple vomiting episodes, but as crews adapt to microgravity, symptoms usually abate within 2 to 4 days.42,43 Crew members who have flown previously typically have milder symptoms. Nonetheless the operational impact is initially high on space shuttle flights: crews limit their movements

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210 RECAPTURING A FUTURE FOR SPACE EXPLORATION and avoid all EVA, since suits have no vomitus containment capability. As crews adapt, symptoms abate within several days, mitigating the overall operational impact on long-duration flights. Apollo crews reported no symp - toms in 1/6 g on the Moon. However, when microgravity-adapted crews return to Earth, they almost universally experience head-movement-contingent vertigo for at least several hours, which causes mild ataxia and frequently triggers recurrence of motion sickness symptoms. Long-duration space station crews typically experience more severe after-effects, which limit their vehicle egress ability, and these after-effects can last several days. Return - ing Apollo crews landed in the ocean, and many experienced symptoms. Existing anti-motion sickness drugs are sedating and only partially effective, so they are used primarily for treatment in orbit, rather than prophylaxis. Space sickness will doubtless affect passengers and crews on commercial orbital and suborbital flights and during the early microgravity and post-return days of future transportation system options. Mars exploration crews may experience symptoms in 3/8 g and again upon Earth return. Known Effects Symptoms resemble those of familiar forms of chronic motion sickness, superimposed on those caused by fluid shift, and include drowsiness, yawning, and sometimes headache. Some individuals experience sudden vomiting, but many have prodromal nausea, at least during the first several attacks. Once nausea develops, the causal link with head and body movements and disorientation becomes unambiguous. Nausea causes impaired concentration, loss of initiative, gastric stasis, and anorexia and triggers hypothalamic-pituitary-adrenal stress hormone release. Repeated vomiting leads to loss of fluid, glucose, and electrolytes. Unless those are replaced, individuals become ketotic and prostrate. The smell or sight of vomitus can trigger nausea in others. Effects of Countermeasures Crews routinely restrict head and body movements and remain visually upright. Some choose to take single doses of prophylactic oral promethazine-dexedrine before launch or entry. Treatment of severe cases with intra - muscular injection of 25 to 50 mg promethazine followed by sleep has been judged operationally effective, but the injections are painful and drug cognitive side effects remain a concern. Potential interaction with promethazine has prevented use of midodrine as an orthostatic countermeasure. Countermeasure effectiveness has proven difficult to determine, since crew often deny prodromal symptoms; head and body movements cannot be standardized, so formal susceptibility testing is operationally impractical. Even on Earth, individual susceptibility to motion sickness stimuli can vary considerably from day to day. For all these reasons, it has not been possible to predict an individual’s susceptibility to space sickness under operational conditions on the basis of a single susceptibility test on the ground. Gaps in Fundamental and Applied Knowledge Although NASA has made a significant investment in neurovestibular research over the past three decades, most work has focused on eye movements, perception, and posture control, rather than fundamental emetic physiology or pharmacology. It seems clear that space sickness is a form of motion sickness, with symptoms that superimpose on discomforts associated with fluid shift (e.g., headache, head fullness, visceral elevation). Sensory conflict theories for motion sickness and space sickness44,45,46 have provided a useful conceptual etiologic frame- work. However, conflict neurons and the neural or chemical linkage between neurovestibular and emetic centers posited by sensory conflict theory have not yet been identified. Much has been learned about emetic physiology in the context of managing nausea after anesthesia, cancer chemotherapy, and radiation treatment. 47 However, drugs that are effective against these stimuli have proven relatively ineffective against motion sickness. 48 Lacking knowledge of which receptors to target, pharmacologic approaches to motion sickness prevention remain empiri - cal. Some drugs (e.g., baclofen, lorazepam, diazepam) are effective but are sedating or have other side effects that prevent operational use. Drugs believed most effective against motion sickness generally have antihistaminic (e.g., promethazine) and/or antimuscarinic (e.g., scopolamine) actions. Furthermore, promethazine is sedating, while scopolamine causes detectable short-term memory loss and therefore may interfere with neurovestibular adaptation as well as cognition.

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211 CROSSCUTTING ISSUES FOR HUMANS IN THE SPACE ENVIRONMENT Research Models and Platforms Needed Ground research is required on physiological mechanisms associated with sensory conflict and the emetic linkage in motion sickness. Rodents do not vomit, so primate, ferret, dog, and cat models are preferred. ISS studies are needed of cognitive side effects of anti-motion sickness drugs under operational conditions. Recommendations More effective and operationally acceptable motion sickness countermeasures will soon be needed if com - mercial suborbital and orbital flights are to succeed. There is a strong need to re-educate the new generation of astronauts on this almost universal problem, so as to take advantage of what is already known and to improve in-flight reporting. Flight surgeons should resume systematic and complete collection of data on symptoms and drug use. Tests of the cognitive side effects of existing pharmacologic therapies should be conducted on the ISS, in parallel with similar research on sleep-aid side effects. New EVA suits must be designed for vomitus contain - ment, so early mission EVAs can be safely undertaken and suits remain reusable. A new program of basic research on the physiology of the emetic linkage should be initiated, soliciting pharmaceutical industry collaboration for development of targeted drugs. Performance Decrements Due to Launch/Entry Acceleration and Vibration Human performance during Earth launch accelerations and vibrations and the ability of deconditioned crews to tolerate entry and landing accelerations and touchdown shocks, particularly in off-nominal conditions, remain major constraints on mission design.49 Performance depends on a variety of cardiovascular, pulmonary, vestibu- lar, neuromuscular, and biomechanical factors. Apollo crews normally experienced 4.5 gx,* launch accelerations, but 6.5 to 10 gx was possible in some abort scenarios. Space shuttle and Soyuz launch accelerations (3 to 4 gx) are slightly more benign. However, oscillations produced by resonant burning in solid rocket motor stages could produce 12 Hz oscillations up to 3.8 gx, exceeding the 0.1 to 0.2 g oscillation levels specified for space shuttle and Apollo launches. The effects of combined acceleration and vibration on crew visual acuity and performance in cockpits with electronic displays are uncertain and also depend on seat and suit design. 50 Lunar orbit and landing maneuvers involve relatively low acceleration levels; the Apollo crews landed and launched standing up. However, acceleration levels that exploration crews will encounter during atmospheric entry to Mars and on return to Earth are a concern, because of the relatively high spacecraft entry velocity, as compared to an entry from low Earth orbit. Mars mission architecture studies51 suggest that deconditioned crews could experience Mars aerocapture decelerations at up to 5 gx and will therefore need to be supine. When Apollo crews returned from the Moon, 5.5 to 7.2 peak gx was typical, and returning Orion lunar mission crews will likely encounter comparable levels. Seated space shuttle crews normally experience several minutes of +1.5 gz (“eyeballs down”) acceleration during approach and landing. ISS crews returning on the space shuttle lie supine. Soyuz crews lie supine on couches also designed to dissipate touchdown shock. Immediately after landing, crews typically experience head movement contingent vertigo, oscillopsia, locomotor ataxia, and motion sickness symptoms. Known Effects Humans can tolerate higher sustained linear accelerations for longer durations along the positive transverse (“eyeballs in”) gx axis than in other directions, since the hydrostatic gradient reducing brain blood flow is minimized and the position is more comfortable.52,53 Physiological symptoms can include respiration difficulty, dimming and * Subscripts are used with the unit of force due to gravity and/or acceleration to indicate the direction of the force vector relative to the body orientation of an astronaut during the flight maneuver under discussion. The positive x-axis direction is with the force vector transverse to the head and trunk of an astronaut and pointing forward, as when astronauts are essentially lying on their backs during launch. This “ gx” orienta- tion is also called “transverse,” or more colloquially, “eyeballs in.” The positive z-axis direction, gz, is with the astronaut’s head-trunk axis oriented parallel to the force vector, with the vector pointing in the direction from feet to head, as in the acceleration force felt when riding in an ascending elevator. Colloquially, this orientation is called “eyeballs down.”

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212 RECAPTURING A FUTURE FOR SPACE EXPLORATION tunneling of vision, changes in smooth-pursuit eye movements, pain, loss of consciousness, convulsions, post- acceleration, and confusion and disorientation. Tolerance is a function of magnitude, duration, and external factors such as previous training/exposure and deconditioning. Impact on human performance also depends on interface design (required reach, arm support, etc.). Little is known about the effects of multi-axis gravitational force loads, which would be experienced primarily during launch, abort, aerocapture, or entry. Less is known about human tolerance to rotation. Yaw is generally tolerated at higher rates than pitch. Tolerance to rotational velocities is reduced when translational accelerations are superimposed. Tumbling through multiple axes leads to vestibular disorientation and performance degradations and interferes with a crew’s ability to take corrective actions. These accelerations could occur in abort scenarios and off-nominal situations. Landing impact acceleration (duration <0.5 s) exposure limits are based primarily on aircraft ejection data and do not consider the possible effect of bone loss due to prolonged exposure to microgravity. Exposures to whole-body vibration for up to several minutes may cause discomfort (headache and pain) and manual, visual, and cognitive performance decrements, but usually do not cause injury.54 Acceptable limits depend on performance criteria, seat orientation, and biomechanics of the human-equipment interface and must be investigated on a case-by-case basis. Minimal tolerance usually occurs between 4 and 8 Hz, the range in which the body exhibits abdominal mechanical resonance. Countermeasures Primary countermeasures have included limiting launch, abort, and entry accelerations and orienting the seats so crew members are supine. However, this is not always possible in piloted vehicles where direct forward view is required. Anti-gravity compression garments covering the abdomen and legs are used on space shuttle and other high-performance aircraft and improve “eyeballs down” linear acceleration tolerance of seated pilots by 1 to 1.5 g. Astronauts and pilots undergo centrifuge training to learn the anti-gravity straining maneuver (tensing arm, leg, and abdominal muscles and exhaling against the glottis), which temporarily provides up to 3 gz of additional tolerance. Returning astronauts are typically volume depleted, and so fluid/salt loading prior to entry has proven somewhat effective. Supine and seated crews must eventually stand up after landing, and even with fluid loading the prevalence of orthostatic hypotension on the day of landing has been 20 to 30 percent after 1- to 2-week space shuttle missions and at least 80 percent after long-duration flights. The origin of individual differences in postflight orthostatic tolerance and neurovestibular vertigo and ataxia is not well understood. The ability of long-duration crews to egress quickly after Orion landings on the ocean remains a concern. Pharmacologic agents (midodrine, octreotide) have been evaluated to improve orthostatic tolerance, but concerns about drug interactions (e.g., with promethazine administered to prevent motion sickness) have so far limited their use. 55 AG centrifuges and lower- body negative-pressure devices have also been considered. Gaps in Fundamental and Applied Knowledge There is effectively no knowledge of the effects of elevated gx forces and high vibration on crew performance in a cockpit with electronic displays, where electronic crew-vehicle interfaces require novel methods of crew-vehicle interaction not encountered in earlier vehicle designs. Virtually all existing acceleration and vibration tolerance data were obtained from Earth-normal-conditioned subjects. Although sustained gravitational force-load limits for abort and nominal exposures for conditioned and deconditioned crews for durations up to 1,000 s are specified in NASA Standard 3000 and in the new NASA Human Interface Design Handbook, no vibration limits have yet been included for normal or deconditioned subjects. Similarly there are few data on the interaction between vibration and prolonged transverse acceleration or the interaction between rotational and translational accelerations. There are no data on performance effects in deconditioned subjects in simulated launch, abort, entry, or ocean emergency egress situations. Relatively little is known about the physiology of the head movement contingent vertigos, which complicate emergency egress and locomotion, or the cause of individual differences. Research Models and Platforms Needed • Human head-down bed rest studies are needed of deconditioning effects on acceleration and vibration tolerance and performance, using cockpit-equipped centrifuge simulators. • Early post-flight studies are needed on head-movement-contingent vertigo and the ability of returning ISS crews to perform emergency egress. Also needed are studies of tolerance to Earth and Mars entry accelerations. • Mathematical models of cardiovascular system response56,57 will continue to provide important insights.

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213 CROSSCUTTING ISSUES FOR HUMANS IN THE SPACE ENVIRONMENT Recommendations 1. For exploration missions, since fundamental data are lacking, NASA must perform the appropriate ISS, bed rest, and centrifuge studies to determine appropriate acceleration and vibration tolerance, task performance, and emergency egress capability of deconditioned astronauts, with and without anticipated countermeasures. Vehicle launch, abort, Earth/Mars entry acceleration, and vibration profiles must be designed appropriately. 2. The prevalence of orthostatic hypotension immediately following long-duration spaceflight has never been determined in an operational context (i.e., not in a clinical tilt-table or stand test). It is essential to identify the mechanism underlying the practical incapacitation of crews after long-duration spaceflight prior to developing pharmacological countermeasures. Research should be designed to elucidate multifactorial mechanisms, which are hypothesized to include some combination of cardiovascular deconditioning, neurovestibular vertigo and ataxia, muscle weakness, and kinesthetic abnormalities. Food, Nutrition, and Energy Balance As described more fully below, inadequate nutrition affects all aspects of long-duration spaceflight, from accelerating bone loss and reducing muscle function to diminishing cognitive ability and depressing immune response. To protect against inadequate nutrition, it is important to: 1. Fully understand nutrient needs under space conditions compared to terrestrial conditions; 2. Develop appropriate diets for space use and ensure their palatability; and 3. Ensure that the nutrients within a food remain bioactive for the duration of the mission. NASA has done an excellent job in parsing out specific nutrient needs for spaceflight and a fair job in estab - lishing a climate where 100 percent consumption of supplied foods is encouraged, but gaps remain in tracking the bioactivity of essential nutrients in foods as a function of food processing, storage, exposure to radiation, etc. Because nutrient deficiencies are rare, and overweight and obesity have reached epidemic levels in the general population, issues related to nutrient stability over time or food consumption patterns among astronauts have not been a focus. However, whenever an individual is totally dependent on a limited number of foods to meet 100 per- cent of his/her nutrient needs (e.g., infants fed formula, patients being fed intravenously, or astronauts in space), it is critical that the diet provided be nutritionally complete. For the success of long-duration space missions, it is also essential that the diet remains nutritionally complete for the prescribed amount of time and that steps are taken to ensure that individuals consume appropriate amounts of the diet’s elements to meet their nutrient and energy needs. Impact of Spaceflight on Nutritional Status, Nutrient and Energy Intake, and Nutrient Stability in the Food Supply Nutritional Status in Space A substantial amount of information has been generated about nutrient status in space, although data are lack - ing on the mechanisms by which nutrient status in space differs from that on Earth. A thorough and continuously updated review is provided in the Human Research Program Evidence Book,58 which highlights risk factors of inadequate nutrition and of an inadequate food system. Each of these risks is categorized as being a risk with substantial evidence rather than one which is not yet fully supported or refuted.59 A complete reiteration of the current understanding of nutrient status in space is not possible in this section, but a synopsis can be given of the most important differences between Earth and space. In particular, several deficiencies or insufficiencies are con - sistently reported, including inadequate energy intake (see below), depressed vitamin D and K and folate status, and diminished antioxidant capacity. Data from individual Skylab missions show that length of mission is a factor in vitamin D status; the longer the mission, the more depressed the vitamin D status. For example, a study of 11 astronauts showed an average decrease of ~25 percent (P < 0.01) in serum 25-hydroxycholecalciferol (25-OH vitamin D3) after flight (128-195 d).60 Similarly, a decrease of 32 to 36 percent in 25-OH vitamin D3 concentrations in serum was found in Mir crew members during and after 3- to 4-month missions.61,62 Bone resorption was increased after flight, as indicated by several markers. Vitamin D is required for calcium absorption, and bone loss is a clearly documented nega -

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214 RECAPTURING A FUTURE FOR SPACE EXPLORATION tive consequence of spaceflight.63 There is considerable debate at this time as to whether the Dietary Reference Intake for vitamin D is adequate. Recent data suggest that an optimal serum level of 25-OH vitamin D3 is ~80 nmol/L.64 Using these criteria, 80 to 90 percent of the subjects in the ISS study 65 had suboptimal vitamin D status. An important difference between vitamin D status on Earth and in space is that vitamin D can be synthesized from a precursor under the skin that is activated by ultraviolet (UV) light excitation. However, because astronauts are not exposed to UV light in flight, they require a vitamin D supplement (the only nutrient that is routinely supplemented in spaceflight). Folate status is also compromised in space. In addition to a reduction in 25-OH vitamin D3, red blood cell folate concentrations were approximately 20 percent lower (P < 0.01) after landing. 66 The number of multivitamins consumed per week was positively correlated (r = 0.62, P < 0.05) with red blood cell folate levels, suggesting that intake from the prescribed diet was insufficient to maintain blood folate levels. Folate deficiency, with neurological and hematological manifestations, can occur in a matter of 2 to 3 months on inadequate diets. Cell populations with rapid turnover rates (such as absorptive cells lining the small intestine) require adequate folate to replicate, and folate deficiency may result in diminished absorptive capacity. Clearly, a diminished absorptive capacity would decrease availability of all nutrients to the body. Vitamin K status has been shown to be decreased after spaceflight, 67 which again has negative implications for bone health.68 Vitamin K is required for the formation of gamma-carboxyglutamate in specific bone proteins such as osteocalcin and matrix Gla-protein, which are necessary for appropriate calcium binding. During the 6-month spaceflight of the EUROMIR-95 mission, both bone resorption markers and urinary calcium excretion increased about two-fold immediately after launch. A major negative factor of long-duration spaceflight is exposure of crews to ionizing radiation. Solar radiation and galactic cosmic radiation can produce reactive oxygen species, which can cause oxidative damage to DNA measurable by urinary levels of 8-hydroxy-2’-deoxyguanosine. Levels of this biomarker have increased after long-duration flight, suggesting an inadequate response to an oxidative challenge. 69 Nutrient and Energy Intake Nutrient intake is closely linked to an adequate energy intake. Crew members on the ISS have been reported to consume a mean of 80 percent of their recommended energy intake,70 whereas reports from other missions show intakes around 60 percent of recommendations.71 Energy intake is typically 30 to 40 percent below the World Health Organization recommendation, but energy expenditure is typically unchanged or even increased. 72,73 The functional consequences of inadequate energy intake are not fully appreciated, because in the current Earth environment, many see weight loss as a desirable end point. Inadequate energy intake in space results in a cata - bolic state. As blood glucose levels decline, muscle protein will be catabolized to supply amino acids for gluco - neogenesis and dietary amino acids will be used for energy, rather than protein synthesis. Loss of muscle mass during spaceflight74 and during bed rest75 is well documented. A bed rest study has documented that an essential amino acid supplement, which protects against loss of muscle mass when subjects have sufficient energy intake, is no longer protective when energy intake is intentionally reduced to 80 percent of the requirement. 76 Another consequence of a catabolic state is formation of ketone bodies from lipolysis, promoting metabolic acidosis, a known consequence of an astronaut diet of high quantities of animal protein (which supplies acidic sulfur amino acids) combined with low amounts of fruits and vegetables (and thus a low intake of potassium, which helps to alkalinize pH). Acidotic conditions promote bone loss and kidney stone formation because of release of calcium as part of a compensatory mechanism.77 Nutrient Stability in the Astronaut Food Supply Under space conditions, nutrients are obtained from food, with the single exception being supplementation for vitamin D. Beyond nutrient stability in the food supply, other issues that relate to providing food to astro- nauts include food safety; food preparation and storage; packaging; and mass, volume, and waste. These issues are described elsewhere.78 Inadequate intake of any one essential nutrient over time has critical functional con - sequences including blindness (vitamin A), dementia (niacin), neurological dysfunction (folate), hemorrhaging (vitamin K), compromised immune function (protein), and ultimately death. In fact, most of the essential nutrients

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215 CROSSCUTTING ISSUES FOR HUMANS IN THE SPACE ENVIRONMENT were discovered as a result of morbidity or mortality of individuals who were lacking in a specific nutrient—e.g., sailors who developed scurvy from lack of citrus fruit, prisoners who were switched from brown rice to white rice and developed beriberi, hospitalized patients who developed essential fatty acid deficiency during parenteral nutrition, and infants fed formula lacking essential nutrients. These examples underscore the critical need to assess the stability of essential nutrients in the astronaut food supply over time. NASA Johnson Space Center has developed a wide portfolio of space foods that have been analyzed for their nutrient content based on published data. However, although it is well known that processing and long-term storage of food on Earth can lead to loss or even destruction of nutrients, there is currently insufficient knowledge about whether food processing in space affects nutrient activity, or whether nutrient potency is affected by in-flight radia - tion or storage under space conditions (e.g., temperature, humidity, and effects of radiation). Two ongoing projects address nutrient stability. In one study, ground-based shelf life testing is performed on five thermostabilized food items placed in storage for up to 3 years at three different temperatures. The other study is designed to determine stability of certain nutrients in five space foods and two supplements by testing content before and after spaceflight on the ISS.79 A set of space foods and supplements that remain on Earth are matched with the space-flown foods for humidity, time, and temperature. A recent report from the latter study suggests that storage conditions are more important than exposure to microgravity, because both ground controls and space-flown foods decreased in nutri - ent potency over time.80 However, the ISS may provide limited information related to exposure to space radiation that would occur on the Moon or Mars. Thus, to date NASA has had to rely on published data from external shelf life studies as guidance in designing diets and optimizing processing conditions for long-duration spaceflight. Known Effects and Knowledge Gaps Countermeasures Against Negative Effects on Nutritional Status and Knowledge Gaps A decrease in nutritional status as a function of spaceflight can be due to one or more of several factors: 1. A lack of understanding of nutrient needs in space as compared to those on Earth; 2. An inappropriate diet design that does not provide the required intake of nutrients; 3. A lack of nutrient intake; or 4. A lack of nutrient stability. As noted above, supplementation with vitamin D is necessary. Similarly, supplementation with folic acid and vitamin K improved their status.81 This appears to indicate that the food supplied lacked adequate amounts of these nutrients, there was insufficient consumption of supplied foods containing these nutrients, or the potency of these nutrients in the supplied diet had declined. It is important to understand the reason for observed negative changes in nutritional status during and after flight in order to properly correct them. There is a considerable database documenting the association of spaceflight with depressed nutritional status, but information is insufficient as to the specific causes of depressed nutritional status. Considerable attention has been given, recently, to the develop - ment of an antioxidant “cocktail” to protect against increased production of reactive oxygen species during space - flight. However, there are knowledge gaps about the efficacy and overall design of such a supplement. A potential countermeasure against loss of antioxidant capacity of foods needs to be based on experimental data. Processing can actually enhance antioxidant capacity in some situations and depress it in others, and antioxidants can even become pro-oxidants.82 Before any recommendations can be made, it is critical to understand how astronaut food antioxidant capacity changes as a function of processing and “space conditions.” Countermeasures Against Lack of Energy Intake and Knowledge Gaps Lack of sufficient energy intake is an ongoing problem with multifactorial causes, including nausea, lack of time for food preparation, lack of a social environment for eating, and boredom with foods over time. Coun - termeasures that have proven useful are increasing emphasis on communal dining (cosmonauts) and one-on-one counseling with astronauts as to the importance of consuming their food allotment. If a significant proportion of individuals in space continue to consume below their recommended energy requirement, strong consideration

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