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
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 influence 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 hormone 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.
There are numerous known biomedical stressors associated with spaceflight and re-adaptation to gravity that may benefit from a translational approach.
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 CO2 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 sickness (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 O2 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.
No cases of hypobaric DCS have been reported on Apollo flights, the space shuttle, or the ISS. Decompression 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
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 medical 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 simulations 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 nitroglycerin8 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, astronauts 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 prebreathe is important for space exploration missions. Crews could live in an 8 psi, 32 percent O2 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 O2 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.
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, vocalization and heat transfer; and alternatives for hypoxia prevention and denitrogenation, such as perfluorocarbon therapeutic blood additives.
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 significantly 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 exposure 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
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
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. Ultimately, 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.
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 sickness 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
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 symptoms 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. Returning 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.
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 intramuscular 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 framework. 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 empirical. 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.
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.
More effective and operationally acceptable motion sickness countermeasures will soon be needed if commercial 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 containment, 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, vestibular, 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.
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” orientation 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.”
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.
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.
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.
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 establishing 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 percent 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 lacking 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 consistently 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-
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 study65 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 catabolic state. As blood glucose levels decline, muscle protein will be catabolized to supply amino acids for gluconeogenesis 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 astronauts 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 consequences 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
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 radiation 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 nutrient 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 development of an antioxidant “cocktail” to protect against increased production of reactive oxygen species during spaceflight. 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. Countermeasures 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
should be given to use of nutritional supplements and adjusting diets to meet nutrient requirements based on ~80 percent of energy requirements (i.e., a more nutrient dense diet). The current philosophy of basing diets on 100 percent of energy intake without supplements, commendable for Earth-based recommendations, may not be appropriate for space. An optimal nutritional status will require appropriate food intake. Further, a better estimation of the energy cost of exercise and EVAs is required to assess energy status and to design diets to meet energy requirements. Thus, activities requiring energy expenditure need to be coordinated with nutrition and food planning (see below the section “Physical Inactivity”).
Countermeasures Against Loss of Nutrient Potency Due to Storage,
Exposure to Microgravity, or Radiation in Space
Loss of nutrition potency is the most critical knowledge gap with respect to nutrition and the food supply for long-duration spaceflight. Lack of this knowledge for a semi-contained environment during a long-duration flight without the ability to replenish the food supply could have serious consequences, in particular as supplements will also be subject to decay over time. New methods of food processing and storage are therefore required. It is difficult to attract food scientists to focus on preserving nutrient stability in foods for 3 to 5 years when this is not an issue on Earth. In sum, the extent to which current processing techniques and subsequent space conditions affect nutrient potency needs to be ascertained before informed decisions for food selection, possible fortification, or reformulation can be made and before changes can be made to diet recommendations or new processing, packaging, and storage systems developed. Although optimal nutrition is always important for optimal health and function, it is critical for long-duration spaceflight. For example, at this time there is no evidence-based proposed system in place for how a 3-year trip to Mars and back will be able to sustain human life without replenishment of the food supply.
Research Models and Platforms Needed for New Research Directions
Excellent platforms for nutrition and food science research exist and are being exploited by the nutrition and food science scientists at NASA Johnson Space Center. These include use of bed rest facilities, which are now operated in a standardized manner; isolation venues such as NASA Extreme Environment Mission Operations; and outstanding facilities at Brookhaven National Laboratory to measure the effects of galactic cosmic radiation on animals, cells, and even foods. However, an integrative approach across all human studies in which nutrition and energy intake could be controlled or documented is missing. Valuable data are lost when, for example, human intervention studies are done on countermeasures to protect against muscle wasting, bone loss, cardiovascular effects, and immune response without any documentation as to what the subjects were eating or if they were meeting their energy requirements. As shown above, very different outcomes can occur depending on the nutrient and energy status of the subjects, and it is important to include such documentation in future studies. Use of isolation facilities is important with respect to food intake to evaluate food palatability, the effect of isolation on food intake, and how much variety, etc., is needed in the foods over time. Even if the overall goal of an isolation study is not primarily nutritional research, important information could be gained by controlling or documenting the foods eaten and the energy intake.
In basic food science, a new emphasis is needed at the molecular level to evaluate model foods and interactions of metals, oxidizing agents, lipids, etc., over time. The ability to test every astronaut food item under every condition of processing, exposure to radiation and microgravity, long-term storage, and every interaction of each essential nutrient clearly goes beyond the realm of the feasible. A better approach may be a translational approach to design food systems that can be based on experimentally validated model systems. This will require a new direction for NASA, as the Food Science and Nutrition areas have different reporting lines and until relatively recently have not worked together as a team.
Specific Recommendations for Fundamental and Applied Science Programs
1. The panel strongly recommends that food intake or at least energy intake be an outcome variable for human intervention trials supported by NASA or the National Space Biomedical Research Institute.
2. NASA should develop a strong basic food science program (most probably with external expertise) to evaluate the effects of a variety of conditions at the molecular level. This program should address nutrient-nutrient interactions and the effects of heat, storage, radiation, etc., over time. It should result in a set of principles that NASA can use to design food systems for the future.
3. NASA should consider designing diets that are more nutrient-dense to account for less than adequate energy intake.
4. NASA should develop a consistent and concerted effort across all stakeholders to emphasize the importance of maintaining energy balance during missions.
5. NASA should coordinate the design of diets and estimates of energy requirements with energy output (EVAs and exercise).
Summary and Concluding Comments
Optimal nutrition status affects every physiological system and impacts performance. At this time there is solid information on what nutrient needs are in space plus a good but not optimal understanding of energy needs. However, more effort needs to go into convincing astronauts and flight doctors of the importance of staying in energy balance. Also, there is minimal information on nutrient stability over time and as a function of food processing. Thus, it is critical that NASA:
• Address nutrient stability over time as part of planning for long-duration exploratory missions and
• Develop a food system that can support such a mission.
In addition, since nutrition is a crosscutting issue that affects all systems, it would be beneficial to have knowledge of the food and energy intake for human trials with primary outcome variables addressing different systems (bone, muscle, cardiovascular, immune response), since in most cases different outcomes can result as a function of diet or energy intake.
Space Radiation Biology Today
The area of space radiation biology has been studied in detail in recent years, with the NRC issuing several reports on the current status of the field, including strengths and weaknesses in the existing programs sponsored by NASA.83,84,85 Further, the most recent NRC report, Managing Space Radiation Risk in the New Era of Space Exploration,86 reviewed the current knowledge of the radiation environments likely to be experienced by astronauts; the effects of radiation on biological systems, electronics, and missions; and NASA’s current protection plans. The findings and recommendations from that report covered a number of issues relevant to the current report, including (1) the need for research on the biological effects of and responses to space radiation; (2) the need for continued attention to radiation protection strategies, such as use of surface habitat and spacecraft structure and components, provisions for emergency radiation shelters, implementation of active and passive dosimetry, scheduling of EVA operations, and proper consideration of the As Low As Reasonably Achievable principle; and (3) the importance of making experimental radiation data available to the scientific and engineering communities. Because there have been recent comprehensive reports on space radiation biology, the panel has not attempted to carry out a duplicative review. Readers should see the recommendations in the above referenced reports. The present report contains a brief overview of important gaps in knowledge and research needs in space radiation biology and presents related recommendations.
NASA’s current goals are focused predominantly on understanding the effects of space radiation on human beings in space and developing strategies to mitigate adverse effects. While there is a huge body of existing literature on the effects of low linear energy transfer (LET) radiation such as gamma rays and x-rays on biological samples, including data from long-term animal studies, clinical studies, and others, the information on radiation of the quality encountered in space (e.g., protons and high-LET radiation such as heavy charged ions) is much less detailed.87,88 NASA has worked to develop a cadre of scientists and facilities that can be used to study the effects on biological systems of these radiation types with unique qualities. Because the radiation types and effects are distinct from those found in exposure to more conventional radiation sources, it has been necessary to train biologists in the physics, dose-distribution features, and other unique properties of space radiation. The means of doing so have included a number of annual investigators’ meetings, special training workshops, and a course sponsored by NASA at the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory.89
In the general radiation biology field, there are currently some studies being done on the biological consequences of proton effects because protons have been shown to have medical applications. There are currently at least six proton facilities functioning in the United States, and several more are under construction.90 Protons have been shown to have depth-dose characteristics that make them a treatment option for prostate cancer, choroidal melanoma, chordoma, some brain cancers, and several other cancers. NASA’s radiation biology community has been tapped to aid and provide resources to the medical community in understanding normal tissue toxicities as a result of exposure to protons in cancer treatment. Nevertheless, the medical community is more focused on high-dose and partial-body exposures, while NASA is of necessity interested in risk issues associated with low-dose and total body exposures. Some of these cancer-based proton facilities (particularly those at Loma Linda University and the University of Pennsylvania) are also being used for NASA-based studies of space radiation effects on cells and animals.
While protons are one quality of radiation encountered in space, galactic cosmic rays include most of the elements in the periodic table; about 90 percent of the nuclei are protons (hydrogen nuclei), but the remaining 10 percent include helium, carbon, oxygen, magnesium, silicon, and iron. The proton facilities noted above can be used to study the effects of protons, but not the other heavy ions. Protons have biological effects similar to those of low-LET x-rays and gamma rays, whereas the radiation properties and biological consequences of heavier ions are distinctly different. In particular, heavy ions have a much greater relative biological effectiveness per unit dose than do x-rays.91 Experiments on the biological effects of heavy charged ions are therefore essential to understanding the consequences of prolonged exposure to space radiation. High-LET radiobiology is an area that is not well studied in the general radiation community because it has lacked relevance to medical therapies (although this may be changing). Facilities for performing high-LET exposures for clinical applications exist only in Germany and Japan. In the United States, only the NSRL is capable of providing high-LET radiation for biological experiments.
Ground-Based Space Radiation Studies
As noted in Chapter 3, the NSRL is the result of cooperation between the Department of Energy (DOE), which runs Brookhaven National Laboratory, and NASA, which uses the facility to generate protons and heavy charged ions that can be used for irradiation.92 While there is one proton facility used by NASA at Loma Linda University, the NSRL is the only facility in the United States that can generate appropriate heavy ions and mixed field beams for NASA’s studies requiring simulated space radiation. Thus, this facility—and as a consequence the partnership with DOE—is essential for NASA’s space radiation biology endeavors not only now but also well into the future; assurance of this continued cooperation is therefore important. The current contract between NASA and DOE was due to expire in June 2011, but it has already been renewed for an additional 3 years, until June 2014. There is some concern that NASA is entirely dependent on this one facility for space-radiation-relevant biological studies. DOE and NASA also cosponsor several research activities related to low-dose effects. DOE manages a low-dose program with a focus on understanding consequences of low-dose exposure to low-LET radiation, and NASA co-funds some proposals that overlap with its interests in this program, permitting a leveraging of funding.
NASA’s focus on radiation risks to be encountered in space has also limited most experiments to ground-based studies. The doses currently encountered by astronauts on the ISS or on any space shuttle mission are so low that
it is difficult if not impossible with today’s science to detect any biological consequence using end points that are available in the research laboratory; this does not mean, however, that no consequences exist, since it has been shown clearly that low-dose radiation induces cell signal transduction changes, gene expression changes, and other end points in cell systems, and some studies in cells and animals have suggested that exposure to low-dose radiation may result in cancer.93-97 The usual approach used by radiation biologists is to examine effects at multiple doses, starting with very high doses and then moving to lower doses, so that low-dose effects that would normally be considered marginal can be verified by more significant effects at higher doses. In addition, doses that would be encountered in compromising situations such as exposure to a solar particle event on the Moon or to constant radiation bombardment on a trip to Mars will not be mimicked by a short trip in the space shuttle or on the ISS.
The ground-based experiments have been confined largely to studies of cells or whole animals (mostly mice) exposed to radiation in the absence of other stresses such as microgravity, lack of exercise, etc., which astronauts are likely to encounter in space.98 The NSRL is able to provide charged particles over a wide range of doses (fluences) and dose rates, including approaching those of galactic cosmic radiation in space, and with simulated solar particle events, also at relevant dose rates. Furthermore, the NSRL is positioned to allow expansion of space-like radiation research into combinations with other stressors (e.g., microgravity) and into radiation countermeasures.
Space Radiation Biology in the Next Decade
The heart of NASA’s radiation biology program during the coming decade will be the development of a better understanding of radiation risks associated with spaceflight. Some of these risks are being explored now, including biological consequences of high-LET radiation, extrapolation of low-dose effects from high-dose effects, and biological consequences for noncancer end points. One unknown currently of considerable importance to the space radiation community is the definition of the dose and dose rate effectiveness factor (DDREF), a term that defines the risks associated with low-dose and low-dose-rate exposures. This factor is based on the idea that, as the dose rate decreases, repair occurs and reduces the negative consequences of an exposure to radiation.99 Most current experimental work is based on high-dose-rate exposures, but a trip to Mars will involve a constant low-dose-rate exposure. Most exposures to radiation on the Moon are at low dose rates, not high, just as in interplanetary space. Only in the infrequent event of a solar particle event would there be higher-dose irradiation, and that would occur both on the Moon and if astronauts are in interplanetary space. Travel to Mars and other interplanetary long-term trips will therefore include primarily low-dose-rate exposures, which the DDREF will influence. There is little work being done in this area now, but during the coming decade additional low-dose-rate work will be necessary. If radiation doses in space are an uncertainty, then all approaches toward understanding effects and eventual mitigation are equally uncertain. While much work has been done on dosimetry in space, there are still unknowns. A precise understanding of the radiation qualities and doses to be encountered in the atmosphere of Mars, or on its surface, for example, is not clearly in hand. While some work has been done with dosimetry in space and also on the Moon, radiation quality questions remain.
At the current funding level, NASA programs may require significant time to assess risks from radiation exposure in space. Much work in radiation biology during the past several decades has focused on radiation as an inducer of cancer, and NASA work has not been an exception to that focus. In addition to cancer, other late tissue toxicities that have been examined include neurologic dysfunction, cataract induction, heart disease, and others. Induction of cataracts is currently being studied in the astronaut population and in human lens epithelial cells,100 as well as in rodent models.101,102 These results suggest that high-LET space radiation may induce cataracts at lower doses than was previously reported. In addition, in rodents cataract induction has been shown to have sex-specific differences, a finding that is worthy of continued investigation regarding mechanisms. Controversy over radiation-induced cardiac and blood vessel toxicities has also been found in the literature. Previous studies have supported the idea that long-term consequences of exposure of Hodgkin’s disease patients to high-dose gamma radiation can lead to a variety of cardiac toxicities, including damage to the vasculature.103,104 These are high doses not likely to be encountered in space, and gamma rays are low LET, unlike the high-LET radiation encountered in space. Investigations by Virmani et al.105 suggest a relationship between exposure to radiation (via stents or external beam) and the development of atherosclerotic plaques. In long-term studies of atomic bomb survivors
Shumizu et al. demonstrated that long-term survivors of the atomic bomb radiation may be at higher risk than non-exposed populations for developing heart disease,106,107 even when the doses are as low as 1 Gy. Again, the quality of radiation from the atomic bombs dropped on Japan is not high-LET space radiation, and the doses may be higher than those predicted from space radiation exposure. In addition, the risks associated with these exposures are long-term risks and should not affect astronauts during spaceflight. Nevertheless, concerns about the effects of underlying disease in astronauts and the uncertainties in what is known suggest that this area is a high priority for continued research.
More recently, additional programs have focused not only on the examination of high-LET radiation effects on cancer and late-tissue toxicities as end points but also on acute radiation consequences, such as neurologic effects, skin toxicities, and nausea, that could hamper functioning in space.108 Because this work is at the cutting edge of the field, it is not always clear even which end points should be examined, and so the projects are focused less on mechanisms and directed more at a descriptive approach. While a large number of cellular studies lead into this work, most of these recent experiments require animals for assessing biological consequences in appropriate model systems. Animal work necessarily takes much longer to complete than cellular studies, and the experimental conditions often require long-duration experiments to assess precise consequences. These studies will no doubt continue through the present decade into the next and will probably not be completed during the 10 years following release of this report.
NASA is doing little work on countermeasures and mitigators at this point. Work done on shielding has been severely reduced in recent years. NASA will need to augment its countermeasures research in order to meet its goal of reducing biological consequences of exposure to radiation. A partnership with the Countermeasures program of the National Institute of Allergy and Infectious Diseases (NIAID) within the National Institutes of Health (NIH) could be very useful and productive since the goal of the NIAID program is to develop countermeasures in the same dose range that is of interest to NASA. Ongoing countermeasure work at the Department of Defense is also of interest. It will be important to assess whether those mitigators are capable of working in association with high-LET radiation. Additional work on radioprotectors (taken before radiation exposure) may also be of benefit, since astronauts on the Moon are likely to have some warning before a solar particle event occurs.
The radiation biology program is likely to be highly affected by informatics approaches to biology that have revolutionized the biomedical community. There are several investigators in the NASA community who are generating and integrating informatics approaches for studies of gene and protein expression, assessment of genetic contributions to radiation toxicities, and other purposes.109,110,111 This work not only will enhance a basic understanding of radiation consequences but also will facilitate work toward understanding individual variation in response to radiation effects and inform modeling approaches for development of paradigms to explain radiation injury at the molecular, cellular, and organismal levels. Throughout all of biology, systems biology approaches are being used to understand the interactions of different factors on a particular biological response—multiple tissues interacting together, cytokines and other factors released in response to a stimulus, three-dimensional organization of the tissue, etc. This is likely to impact space radiation biology significantly in the coming decade. Continued interaction of NASA with other agencies such as DOE will facilitate this transition within NASA, since DOE has a well-developed systems biology group for studying radiation effects.
NASA will also need to consider examining more integrative work examining the effects not only of mixed fields of radiation but also multiple stressors (microgravity, etc.). While some work has begun on radiation effects on hindlimb loading/unloading systems in rodents, the effects of radiation on bone metabolism and other biochemical effects of microgravity have not been studied. This is especially difficult since many of the stressors (such as microgravity) are not well mimicked in a ground-based situation, and NASA’s space radiation studies are designed to be almost exclusively ground-based at this point. In fact, it would be difficult to imagine a space-based study that could be guaranteed to achieve the doses needed to observe biological consequences and not at the same time be a threat to the astronauts themselves. This difficulty is likely to pose a considerable challenge for the future.
Major cuts in funding of radiobiology and radiation sciences in most federal agencies have led to a reduction in the number of programs providing radiation training and thus also a reduction in trained radiation scientists, especially radiation biologists. A plan for long-term assurance of research funding is needed for projects that require multiple years for completion, for example, carcinogenesis studies in animals, and to encourage investigators to feel invested in the NASA program, by fostering reasonable expectations of continued funding availability. As
seasoned radiation scientists enter retirement, there are likely to be difficulties in finding sufficient qualified scientists in the field to meet NASA’s radiation needs. Increased development of training programs in the radiation sciences generally, and space radiation specifically, are needed for junior investigators, as well as for investigators from other fields who are moving into space radiation studies.
The inclusion of training programs for graduate students, postdoctoral fellows, and junior faculty members will be essential for ensuring a proper cadre of personnel trained in radiation biology and radiation sciences and able to address questions relevant to NASA’s space radiation needs. The relationship with NIAID (counterterrorism and countermeasures) will be extremely important to this educational and training mission for NASA. NIAID is already expending large resources in the radiation countermeasures area. NASA cannot afford to, and should not, “re-invent the wheel.” It should capitalize on other funded projects ongoing in the area.
1. Continued research on the effects of space-quality radiation is essential to explaining the consequences for human health of exposure to radiation in space. Emphasis should be placed on increasing information comparing biological effects at various LET values and at low doses (low particle fluences) and low dose rates (fluxes). To enhance an understanding of whole-body and whole-organism effects, studies in cellular systems need to continue to progress to animal studies.
2. Radiation studies should include the development of an understanding not only of short-term effects that might hamper a mission (acute radiation toxicities) but also of long-term consequences (carcinogenesis, heart disease, neurologic dysfunction, and others) that might affect astronauts after they return.
3. A clearer understanding is needed of the effects of mixed fields composed of radiation of varying LETs, mixed effects of radiation and other stressors, and possible use of countermeasures.
4. NASA should enhance its relationship with other governmental programs (at NIH, DOE) to facilitate incorporation of radiation knowledge gained from other programs into the NASA information base.
5. NASA should ensure the continued availability of space radiation exposure facilities to its investigators through either a continuing relationship with Brookhaven National Laboratory or the availability of new facilities.
During the past decade, there has been a remarkable evolution of our understanding of the role of physical activity in human health. Much recent research has shown that the human genome is predisposed to health when physical activity is maintained. Physical inactivity of the kind that might be encountered during prolonged periods of exposure to microgravity facilitates the expression of a different genotype more commonly associated with chronic diseases such as coronary artery disease, neoplasms, diabetes, and osteoporosis.112 Thus, a threshold of physical activity is required to normalize gene expression that suppresses disease.113 Because spaceflight represents an abrupt change in physical activity level, a systematic evaluation of genomic changes during spaceflight will advance the understanding of gene-environment interactions that influence chronic disease risk.
Gaps in the Knowledge Base
The concept of gene-environment interaction has rarely been applied to the spaceflight environment from the standpoint of physical activity. Although microgravity alters gene expression quite dramatically114 and, at least in skeletal muscle, produces a pattern of gene expression similar to hindlimb unloading,115 the expression of genes associated with disease has not been fully determined.
An important focus of the next decade’s work should include a systematic examination of mammalian gene expression in the microgravity environment for prolonged periods, focusing on genes associated with predisposition to disease. A second issue is to determine how these genes can be suppressed. At least three types of interventions
are possible: genetic, pharmacologic, and addition of activity. While much of this work may be associated with ground-based research, verification from long-duration flight experiments will be necessary. Finally, a limitation of this particular route of study needs to be recognized: most chronic diseases are polygenic; changing a single gene may not produce a clinical phenotype.
Approximately 500 people have orbited Earth since Gagarin’s first orbital flight in April 1961.116 Of this number, only about 12 percent (60 people) have been women.117 Of the 92 astronauts currently classified as active in the NASA astronaut corps, 25 percent are women.118 Only 8 women have spent 6 months or longer in microgravity, and of the 334 passengers on space shuttle flights, only 44 have been women.119
In 1998, the NRC report A Strategy for Research in Space Biology and Medicine into the Next Century120 included a one-paragraph section mentioning that gender-specific space physiology has been neglected. That study committee’s recommendation was that “NASA should continue to examine data from in-flight and ground-based model experiments, for gender differences in the response to microgravity” (p. 146). In the 11 years since that report was published, 38 flight slots have been filled by women, 8 of them conducting long-duration stays on the ISS. During this time, three reviews have addressed gender-specific health issues in spaceflight121,122,123 and a number of investigations specifically employing women subjects in spaceflight analogs have been conducted.124-132 These publications complement a relatively modest earlier literature of reviews and scientific studies of the physiology of women in space.133,134,135
Although men and women differ physically, there is considerable overlap between the sexes, which makes prediction of differences on the basis of biological sex inaccurate, particularly within a small elite subgroup (i.e., astronauts). For example, as identified in the next subsection, “Effects of Spaceflight,” men and women experience the same general decrements in function, such as orthostatic intolerance, loss of fitness, musculoskeletal weakness, etc. However, studies of large population groups have found gender differences in anthropometry, exercise capacities, and sensory function. Women tend to have a higher percentage of body fat, less muscle mass, more flexibility, and lower blood pressure.136 Women may have a more aggressive immune response to an infectious challenge, but are thought to be more susceptible to autoimmune diseases.137 Women tend to be more sensitive to pain138 and have better hearing and olfactory abilities.139 Importantly, because astronauts represent such a small fraction of the population and because there is considerable overlap between women and men in all gender-related characteristics, it is not clear what differences attributable to gender have existed within the astronaut corps.
Effects of Spaceflight
For the most part, the physiological responses of men and women during spaceflight have been similar, but there may be potential differences. The following list should be considered preliminary and in need of further study because there is a void of well-controlled gender-difference observations.
• Cardiovascular deconditioning (lower orthostatic tolerance in women, especially following short-duration spaceflights [5-16 days] where there was a four times higher incidence of orthostatic intolerance [28 percent versus 7 percent] during a 10-min head-up tilt test than in males);140
• Reproductive health (increased risk of endometriosis in microgravity);147
• Pharmacokinetics (women may be more susceptible to some toxins);150
• Renal stone formation (although there have been no marked gender differences in renal stone formation, men produce more calcium-containing stones while women produce more struvite stones [composed of magnesium ammonium phosphate]);151
• Nutrition (additional supplements may be needed, such as iron for menstruating women);
• Immune response (women have a more aggressive immune response but are more susceptible to autoimmune diseases);152
• Neurovestibular health (no obvious gender differences in susceptibility to space adaptation sickness);153
• Decompression risk (increased risk in women requires confirmation).157
Current Status of the Knowledge Base
Mechanisms underlying gender differences in orthostatic tolerance are not yet completely understood, but may involve possible sex-specific hormone effects on neurovascular regulation of arterial pressure,158 splanchnic vasoconstriction,159 or physical differences such as a smaller and less distensible heart.160 The study of the causes and prevention of post-flight orthostatic tolerance may lead to an improved diagnosis and treatment of ground-based cases of clinical orthostatic hypotension.
Spacesuit design for lunar and martian surface activity has received some recent attention. Many preliminary suit designs have been modifications from the Apollo-era EVA suit, which was designed for men. During EVA work, handgrip strength is essential to maintain stability, and the average woman’s handgrip strength is only about 60 percent of a man’s.161 However, the importance of this difference is diminished in routine EVA practice by the extensive use of foot restraints at worksites and of robotic arms for many mobile tasks. However, the use of a fixed-mass life support system sized for maximal metabolic demands is likely to be a major gender difference working against generally smaller female space explorers. The fixed-mass life support system dimensions and interfaces place constraints on spacesuit design that may compromise achievable mobility for small astronauts for some joints and motions. In terms of aerobic capacity, it is estimated that physical effort in the U.S. EVA suit requires approximately 28 percent aerobic capacity for a male and 44 percent aerobic capacity for a female.162 On the Moon and Mars with partial gravities, the metabolic cost of EVA work will be even greater.163 Thus, an average woman working at a higher relative aerobic capacity and upper body strength will fatigue sooner. New suit-design efforts should meet individual needs for crew members164 of both sexes. Objective requirements for strength, aerobic capacity, and flexibility are needed to select individuals optimally for an EVA-intensive mission. With the current EVA suit design and pressure, more women than men are likely to be excluded. An effort should be made to address this issue, to be certain that physics and not legacy determines who can participate in EVA.
From limited ground-based comparisons, exercise countermeasures are similarly effective in men and women in terms of maintaining aerobic capacity165 and muscle strength.166 A critical area of research is to develop countermeasures for bone loss during spaceflight, because low bone mass (more common in women) may increase susceptibility to fractures. Preliminary bed rest data suggest that exercise may be less effective in preventing bone loss in women than in men.167 Investigations are needed of pharmacological countermeasures against bone loss (e.g., bisphosphonates) during spaceflight and to determine whether there are gender differences in efficacy.
NASA has focused on radiation risk assessment rather than on radiation countermeasures. Countermeasures to radiation exposure should be developed to protect against prolonged low levels of exposure or higher levels in the event of a significant accidental exposure. In addition, information from NIAID’s Radiation Countermeasures program168 may facilitate NASA’s work in this direction. While it is likely that countermeasures that are useful in one sex will be applicable in the other, there are some concerns that mechanisms responsible for gender-specific differences (e.g., the role of hormone levels in cataract induction or breast cancer induction following radiation exposure) may be important in developing countermeasures. Studies of mechanisms of gender-based differences and their possible role in countermeasure development/utilization will be important factors for protection against radiation in the space environment.
Gaps in Knowledge
A gap in knowledge exists regarding the effect of spaceflight on normal hypothalamic, pituitary, and gonadal axis function. Also, flight studies are needed to measure hormones at intervals during long-duration flight to correlate with energy balance (nutrition and exercise data), reproductive function, and bone-loss and bone-gain markers.
One critical issue that needs to be understood for men and women who perform long-duration spaceflights involves bone loss. At this time it is unknown whether women are at greater risk of bone loss and fracture in space than men. Women generally have a smaller bone mineral content than men and, after menopause, have an accelerated bone loss that can reach 1 to 5 percent per year, which translates into an increased prevalence of osteoporosis. In bed rest studies, women with normal reproductive function exposed to simulated microgravity frequently become oligomenorrheic.169 Such menstrual cycle disruptions accelerate bone loss and increase the risk of fracture. Whether the effects of microgravity and disruptions in reproductive function have additive effects on bone loss in astronauts is unknown. A common practice of women astronauts is to take hormones to regulate in-flight menstrual cycle function. Although the controlled estrogen and progesterone levels during such treatment may attenuate bone loss during spaceflight, there is no evidence to demonstrate the efficacy of this treatment. Moreover, hormone therapy may not be an option for astronauts at risk for certain cancers170 or blood clots. In ground-based studies, some hormone therapies, such as selective estrogen-receptor modulators, protect against bone loss with less cancer risk,171,172 but they have not been studied in a microgravity or simulated microgravity environment. The use of bisphosphonates in post-menopausal women to reduce bone loss has led to the implementation of an experiment currently underway on the ISS to test this drug’s effectiveness in astronauts.173 However, potential side effects of this treatment in patients, such as osteonecrosis of the jaw and over-suppression of bone turnover resulting in skeletal fragility, albeit rare, require caution with long-term use.174 Atrial fibrillation has been reported in women with low blood calcium levels who take bisphosphonates,175 although these findings have not been consistent.176,177
From both studies of Japanese atomic bomb casualties and survivors and radiotherapy studies of patients exposed to low-LET radiation, gender differences in tumor incidence178 have been reported in the years following exposure to radiation. For example, there may be gender differences in development of cancer following exposure to radiation, and the types of cancers may be different. There are insufficient numbers of humans exposed to space-quality radiation to make an assessment of gender differences, and so NASA has relied on animal studies for this work. There are a few ongoing NASA projects examining cancer risk in animals following exposure to space radiation (protons and high-LET radiation). However, to date these studies have been able to use only a relatively small number of animals. More studies, with larger numbers of animals, are in progress, particularly using the resources of the NSRL, although little attention has yet been paid to gender differences. DOE conducted a series of large-scale animal studies from the 1960s to the1990s examining gender effects in mice and dogs exposed to high-LET neutrons (which have biological properties similar, although not identical, to those of heavy charged particles in space radiation and can be produced by interactions of charged particles in spacecraft and in astronauts’ bodies). These studies also pointed to an increased risk among female animals and a difference in the spectrum of tumors observed between the sexes.179-182 Recent studies183 have also pointed to gender differences in cataract incidence in rats exposed to cosmic (high-LET) radiation. Therefore, defining gender differences in responses to space radiation exposure is an important knowledge gap.
Research Models and Platforms
Mathematical models, such as the digital astronaut program,184 may be useful in predicting or verifying gender differences in physiological responses to spaceflight. However, more experimental data are needed to make such models useful.
Ground-based and flight studies should be used to evaluate effects of microgravity simulation on reproductive function and to draw correlations between altered reproductive hormones and changes in body composition
and health status. Additional studies should be used to evaluate radiation risks because space exposures in general cannot provide the doses needed to test radiation effects in a reasonable sample size.
Bed rest studies should be continued that allow direct gender comparisons and an understanding of the effects of microgravity simulation on reproductive function, and potential bone countermeasures (continuous estrogen/progesterone use, bisphosphonates, nutritional supplements, etc.).
Analog environments (see Chapter 5) with small groups can be used to study single-gender and mixed-gender behavioral interactions.
Recommendations and Priorities
There is a critical lack of information about the effects of spaceflight on gonadal function and bone loss, as well as about effects of cosmic radiation on women’s health. Basic information is needed about the effects of microgravity and circadian disruption on gonadotropin release and on estrogen and progesterone concentrations. In general, development of countermeasures should account for gender differences. Also, whenever feasible, modifications to the EVA suit design should accommodate smaller individuals or crew members with less upper body strength, to enhance mobility during EVA tasks.
Summary and Conclusions
The most significant gender issues that should be addressed in the next decade include an understanding of possible differences in bone loss and radiation risks and development of effective countermeasures. For crew selection, the most important consideration should be to choose the people most qualified to perform the required tasks. A critical issue is to select crews that work well together. Antarctic studies have found that mixed-gender teams may experience sexual jealousies and rivalries but often are more stable than all-male teams.185,186
The importance of maintaining body temperature is well understood by both clinicians and lay persons. The normal resting core temperature is tightly controlled around 37°C. For survival, the degree of overheating is more critical than overcooling. Although core temperature is tightly regulated, it fluctuates normally in a daily, 24-h circadian rhythm. This small, approximately 1°C, rise and fall in temperature is associated with hormonal cues that are important in regulating food intake, sleep, cognitive function, and immune surveillance.
Effects of Spaceflight
The effect of microgravity on thermoregulation usually is not viewed as an issue as critical as the effects of microgravity on the cardiovascular or musculoskeletal systems. During normal spaceflight, astronauts are enclosed in an artificial environment that maintains ambient conditions within a narrow temperature range to which they can easily adapt. However, to develop more efficient and effective environmental systems and to understand the consequences of environmental failures, the effects of spaceflight on human thermoregulation must be fully understood.
Physical heat exchange between the human body and the environment occurs through four main channels—radiation, conduction, convection, and evaporation—and the sum of heat transfer by all four must balance body heat production. In microgravity there may be significant alterations to each channel of heat transfer, compared with Earth environments.
Resting heat production for an average man is approximately 1,824 kcal/day and approximately 18 percent lower for a woman. Heat production measurements obtained during flights have shown that average metabolic
rates are similar to preflight rates.187,188 However, with longer flights it is possible that resting metabolic rates may be reduced if there are large decreases in metabolically active tissue (e.g., with muscle atrophy).
Thermal risk is particularly great during EVA, when radiant heat may be gained on the surface of the EVA suit exposed to the Sun or lost from the surface exposed to the lower temperature of open space (−270°C). Astronauts are protected from radiant energy fluctuations by the selection of a material and color (white) of the outer EVA suit that will insulate the crew member while reflecting radiant heat.
Conductive heat exchange occurs between two objects of different temperature that are in direct contact. During spaceflight, conductive heat loss becomes an issue when the insulative property of the EVA suit is insufficient to prevent heat exchange between the astronaut and a surface in contact with the astronaut. For example, due to insufficient glove insulation a crew member experienced frostbite while training for an EVA to repair the Hubble Space Telescope.189
Convective heat exchange refers to the exchange of thermal energy between hot and cold objects by the physical transfer of matter such as a liquid or gas. In humans, convective heat transfer occurs at two levels. First, body heat is transferred from the body core to the skin by dilating skin blood vessels to increase blood flow to the skin. This regulation of blood flow is under the control of the autonomic nervous system and has been found to be impaired after spaceflight or simulated microgravity.190,191 Second, heat is lost by convection from the surface of the skin via the air circulating near the skin and from the respiratory tract to the expired air. At very low airflows (<0.12 m·s-1) heat loss occurs by natural or free convection, in which the air nearest the skin surface becomes warmer and lighter than the surrounding air. In a 1-g environment, the warm air rises away from the skin, removing heat. However, in a microgravity environment, this warm air does not rise but remains close to the skin.192 Novak and coworkers193 confirmed that at airflows less than 2 m·s-1, convective heat loss from an artificially heated metal cylinder is impaired during spaceflight.
The effect of microgravity on evaporative heat loss is unclear at this time, but it appears that both sensible and insensible water loss are reduced Thermotolerance, which is the ability to tolerate a given level of core temperature without symptoms of heat illness, depends on the individual’s level of aerobic conditioning and heat acclimation.194 Before flight, most astronauts are relatively fit and have attained some level of heat acclimation. However, after spaceflight most crew members undergo a significant degree of aerobic deconditioning195,196,197 and have become deacclimated to heat. This may result in a faster rise in core temperature during exercise or heat exposure, reducing productivity and increasing the risk of heat-related illness.
Another well-documented effect of spaceflight is a decrease in blood volume, due to a rapid, 10-20 percent loss of plasma and a more gradual decrease in red blood cell mass.198 A loss of plasma volume of this magnitude on Earth severely compromises skin blood flow and sweating responses during body heating.199 In two crew members after a 115-day spaceflight, a faster rise in core temperature during submaximal cycle exercise was attributed to a “reduced sensitivity” of both the skin blood flow and sweating responses.200
Crew members orbiting Earth experience complete day/night cycles approximately every 90 min. This change in light cycling or the overall lower lighting conditions during spaceflight have been postulated to produce a dampening and delay in circadian temperature fluctuations.201 In ground-based studies, circadian desynchronization causes disruption of sleep and eating cycles, altered insulin regulation, and elevated levels of stress hormones such as cortisol and catecholamines.202 During the first couple of weeks of spaceflight, circadian changes in body temperature have shown only minor changes in phase or amplitude,203,204 although there is a reduced quality of sleep, which becomes shorter in duration and more disturbed. In one crew member during a long-duration spaceflight, circadian rhythm was well maintained during the first 100 days of flight, but then there was almost complete flattening of circadian temperature fluctuations, which was associated with sleep disruption.205
The thermoregulatory responses to cold during spaceflight have been even less studied than responses to heat. However, results from ground-based studies (see bed rest section below) suggest that physiological defenses against cold stress also are impaired, including delayed vasoconstriction and less-effective shivering response.206 Altered vasomotor responses in the hands and feet may increase thermal discomfort and increase susceptibility to frostbite.
In the field of thermoregulation, technology always will be crucial for preventing thermoregulatory stress. Further refinement of environmental control systems, to perhaps include feedback and assessment of the thermal status of the crew members, may be needed as space vehicles and crew members are exposed to different and
possibly more challenging environmental and work scenarios. Emergency procedures in the event of a loss of environmental control should be considered.
Historically, thermoregulation issues during spaceflight have been addressed by engineering solutions. Under normal spaceflight conditions, cabin temperature is maintained in a thermoneutral range. On the ISS, for example, the environmental control system was designed to maintain cabin temperature between 18°C and 27°C and relative humidity from 25 to 70 percent.207 However, there have been many incidents where the engineering solutions have failed and crew members were exposed to extreme thermal environments. For example, after the explosion of oxygen tanks during the Apollo 13 mission, the crew lived in the lunar module, which cooled rapidly to approximately 11°C. In another example, during the launch of Skylab a solar array and a meteoroid shield were lost and a piece of the shield inhibited opening of the second solar array. This led, among other things, to the temperature in the laboratory stabilizing at 58°C. When the first crew arrived, they had to rotate at intervals between the hot Skylab laboratory and their cooler command module until they could deploy a solar shade.
Since the Challenger accident, crew members are required to wear a pressure garment during space shuttle launch and landing that consists of an antigravity suit, a cooling garment, and an outer impermeable shell.208 Despite the liquid cooling garment, crew members report feeling hot during re-entry;209 this is a concern because increasing body temperature could reduce their orthostatic tolerance during re-entry.210 Even mild elevations in core temperature during landing could result in cognitive and manual performance deficits.211
During EVA, crew members wear a pressurized suit to reduce the risk of decompression sickness and to sustain a pressurized environment essential for normal gas exchange through the lungs.
After observations of thermal discomfort during EVA in the Gemini program, a liquid cooling garment has been included in all EVA suit systems starting with Apollo. The current EVA suit has an upper heat-removal limit of 504 kcal/h (2,000 Btu/h) for 15 min or 252 kcal/h (1,000 Btu/h) for up to 7 h.212 In a recent report estimating the heat removal requirements for a future lunar EVA in which the crew members would ambulate over the surface wearing their EVA suits, the average heat production while performing a 10-km “walkback” was 598 kcal/h (2,374 Btu/h). The subjects in this test unanimously reported inadequate cooling, and their core temperatures rose by an average of 1°C.213 Thus, improvements in the cooling system of the EVA suit are required to prevent hyperthermia and possible impaired work performance of EVA crew members in future lunar or exploratory missions. This will require the development of smart EVA suits, with automatic regulation of cooling based on physiological input, a higher cooling capacity, and possibly an ability to modify the heat transfer characteristics of the spacesuit skin.
Gaps in Knowledge
Since the physiological consequences of long-term spaceflight for human thermoregulation are still unknown, engineering solutions to control thermal stress may be inadequate. The current thermal models to predict human thermoregulation during and after exposure to microgravity and partial gravity require validation for long-duration flights.
Evaporative cooling normally is the primary channel for humans to dissipate heat during heat exposure. Yet the effect of microgravity on evaporative heat loss is unknown.
Convective heat loss is a major channel for heat loss under resting conditions. Because of changes in blood flow distribution and increased peripheral blood flow after adaptation to microgravity, there may be an accumulation of heat near the surface of the skin and under clothing. Changes in convective heat exchange may alter thermal comfort and must be considered when choosing clothing and environmental conditions in the spacecraft or EVA suit.
The effects of adaptation to microgravity on heat and cold thermotolerance are not understood. It is likely that loss and redistribution of body fluids, decreased vascular reactivity, and reduced physical transfer of heat may limit the range of tolerable body temperature and increase risk of temperature-induced injuries and illnesses.
No data currently are available regarding the effects of spaceflight on cold thermoregulation. There is even a paucity of ground-based data on the effects of reduced-gravity exposure on cold response or tolerance to cold.
This is an important gap in knowledge for prevention of frostbite or other cold-related injuries during EVA or in the event of a prolonged power outage.
Finally, the consequences of altered thermoregulation on alertness, cognitive performance, food intake, sleep, and immune function require further study.
Research Models and Platforms
Mathematical Models of Thermoregulation
Mathematical models are used to predict human thermal responses during spaceflight.214-217 However, none of the current models accurately incorporates physiological adaptations to microgravity. Fundamental research is required to understand the effects of microgravity on physical heat transfer, physiological responses, and possible changes in thermal tolerance. Multisystem models should be employed to probe the consequences of other microgravity-induced adaptations—for example, impaired baroreceptor function—on human tolerance for hot or cold environments.
Altered circadian control of body temperature during spaceflight has been demonstrated in primates, rats, beetles, and even fungi.218 In constrained primates, spaceflight is associated with an early drop in core temperature,219 a dampening of circadian temperature fluctuation, and desychronization of circadian rhythm.220,221,222 Animal models in microgravity or simulated microgravity may be required to study physiological responses and molecular pathways that determine thermotolerance.
Bed rest simulates cardiovascular changes and fluid shifts thought to impair thermoregulation in microgravity.223 Thermoregulatory changes during bed rest concur with many of the changes reported during and after spaceflight, including a gradual reduction in resting metabolic rate,224 lower resting skin temperatures, hyporeactive vasomotor responses to thermal stress, and changes in circadian rhythm. Bed rest is thus an excellent model to study specific mechanisms and potential countermeasures for the impaired thermoregulatory responses during a microgravity exposure. Bed rest impairs thermoregulatory responses to heat during exercise,225 whereas supine exercise (for 90 min each day at 75 percent of pre-bed rest maximal heart rate) preserved the skin blood flow and sweating responses226 and maximal capacities.227 The effect of bed rest on thermoregulatory responses to cold was examined by immersing male subjects in cold water (28°C) for 100 min. After 35 days of bed rest, the fall in rectal temperature during a cold water immersion was more rapid than after 5 weeks of recovery from bed rest. Whether exercise countermeasures can prevent these changes in response to cold is unknown. Mekjavic and coworkers attributed the greater and more rapid fall in body temperature to a less pronounced vasoconstrictor response and a delayed-onset and less vigorous shivering response.228 An impaired vasoconstrictor response also was reported after 14 days of bed rest, when a cold stimulus was applied by immersing one foot in ice water while the forearm blood flow was dilated by reactive hyperemia.229
Recommendations and Prioritization in Fundamental Research
1. Flight studies are needed to quantify the effects of microgravity on human thermoregulation. Overestimation of human thermal tolerance may result in an increased risk of heat injury during EVA, landing, or emergency egress. Such flight studies will be aided by the development of non-encumbering methods to accurately measure and record body temperatures over 72-h periods during spaceflight.
Thermoregulatory measures should be obtained in at least 10 astronauts during a prolonged spaceflight. Measurements should be obtained during rest and during exercise before flight, approximately every 30 days during flight, and post-flight. Measurements should include core and skin temperatures, heat production (indirect calorimetry), sweat loss, and blood flow distribution.
2. There have been few, if any, molecular studies of the effect of microgravity on thermotolerance. This gap can begin to be addressed by genomic studies to identify specific molecular pathways altered by microgravity
that might enhance or reduce thermal tolerance. This information may be useful for predicting which astronauts might be most susceptible to heat intolerance and for developing pharmacological countermeasures to prevent heat injuries and improve thermal tolerance.
Studies should be conducted in animals and humans during ground-based and flight studies. This objective may be met by obtaining blood, tissue, or saliva measurements during the studies outlined above and comparing specific molecular markers (e.g., heat shock proteins) against physiological responses.
3. Heat tolerance should be assessed in ground-based studies using animals and humans to assess the physiological mechanisms by which microgravity might alter thermal tolerance. This information may be used in the prevention and treatment of heat illness during a mission. Also, specific cooling countermeasures for use in microgravity can be evaluated.
Measurements should include assessment of gut permeability, endotoxin and inflammatory markers after an exertional heat stress in humans, and markers of tissue damage and inflammation in specific body tissues (skeletal muscle, brain, heart) in rats or mice.
4. Human circadian rhythm measurements are needed in a larger sample of humans during long-duration spaceflight, with continuous rather than intermittent measurement of core temperature. This information may be useful in preventing decrements in astronaut performance resulting from increased stress and sleep disruption caused by circadian dysrythmia.
Bed rest studies (with simulated flight-like light/dark cycling) and flight research should be undertaken to obtain core temperature, blood pressure and heart rate, stress (e.g., insulin, cortisol, urinary norepinephrine) and inflammatory markers (e.g., cytokines, C reactive protein), sleep, performance, and cognitive measurements to assess interactions between circadian dysfunction and overall health, performance, and cognitive function.
5. Cold studies should be continued to assess thermoregulatory responses to passive, prolonged cold exposure after bed rest or spaceflight. Studies should focus on susceptibility, awareness, and prevention of hypothermia and local tissue injuries (frostbite).
Measurements should include core and skin temperatures and vasoconstriction and shivering responses. Effects of prolonged bed rest with and without exercise countermeasures to maintain sympathetic, cardiovascular, and body fluid responses on cold tolerance should be explored. Effective methods for rewarming that could be applied in spaceflight could be developed and evaluated during these studies.
Summary and Conclusions
Maintaining a safe level of body temperature is critical for the health and productivity of the crew during spaceflight. Normally, humans thermoregulate within an approximately 5°C range of core temperature (35°C to 40°C). However, during spaceflight behavioral responses are limited, cooling and heating systems may fail, and it is suspected that thermotolerance to cold or hot conditions may be reduced. Fundamental research is required to understand the effects of spaceflight on human thermoregulation. Applied research is needed to develop countermeasures and emergency treatments for hyperthermia and hypothermia. Such applied research could lead to the development of rapid whole body cooling and heating methodologies that would be practical and effective in a microgravity environment. It could also enable the identification of personal cooling or heating methods that would permit crew members to perform their normal activities in a spacecraft or habitat in which the ambient temperature control is not functioning.
Biomedical research is carried out in a continuum that begins at discovery and ends with documentation that an intervention improves health or function. Such a discovery may occur through research at the bench, in an animal laboratory, or at the clinical level, deriving from a physiological investigation, a controlled clinical trial, or from a serendipitous observation in a single subject or group of subjects. If gaps impede this process of moving from discovery to deliverable, this process may founder. In spite of much insightful basic and clinical space sci-
ence research by scientists over many years, the extent to which the products of this discovery process have led to interventions or countermeasures that are now routinely employed has been limited.
Progress from Fundamental to Applied Knowledge
When an important biomedical discovery is made, it should ideally set in motion an orderly sequence of studies that take the discovery to achievement of a deliverable such as a drug, an intervention, or a countermeasure that addresses a health concern. The totality of this process is sometimes referred to as clinical and translational science,230 which is best viewed as a way of organizing the research process. In 2006, the progression of these principles was developed at NIH and began to permeate the biomedical research community in both NIH intramural research and, with the inauguration of the Clinical and Translational Science Awards (CTSAs), the extramural research community in the academic health centers and universities. In some ways, elements of NASA’s publicized philosophy of “better, faster, cheaper” influenced the CTSA conceptual development. After 4 years of deployment across 49 academic medical centers encompassing perhaps 8,000 individual research projects, with a mandate to expand to a system of 60 centers, this program has in fact become the largest functionally integrated research network in biomedicine. The CTSAs support Clinical Research Units (formerly called General Clinical Research Centers), which now represent the nation’s major capability for intensive patient-oriented research—for example, as might be required in microgravity models such as bed rest, nutritional interventions, exercise interventions, energy balance, drug trials, and imaging capabilities that permit visualization of human physiology in real time.
Findings and Recommendations
The reorganization of the nation’s biomedical research infrastructure into a clinical translational science network represents a substantial opportunity for NASA to emulate and to partner in this 21st century approach to applying new biomedical knowledge. Two major changes are recommended.
1. Implementation of a clinical and translational framework for space life sciences research. In spite of the large number of studies of countermeasures that have been carried out over the years, the results that have actually reached implementation are quite limited. This translation failure might best be addressed by systematic analysis of where in the translational process inefficiencies might be occurring. Overcoming or at least minimizing such gaps or obstacles has been a hallmark of the NIH CTSA program. Although this program is only entering its fifth, the longest existing awards have just gone through renewal review and were generally considered to be doing well. The kinds of interventions currently being undertaken to improve the process of clinical and translational research in the CTSA network should be generalizable to some aspects of NASA’s research enterprise. Increased research investment by NASA in basic science and in the discovery phase of this process, including studies of animal models, might be a means to prime the process of NASA research.
One important aspect of this process is the deployment of informatics capabilities addressing all aspects of the research process so that captured information about all transactions—whether research, contractual, bureaucratic, laboratory, facility, etc.—are monitored to examine inefficiencies that may be delaying or in some cases sidelining a rapid and orderly discovery process. Hallmarks of this approach include:
A. Focusing on investigator needs first;
B. Collecting and analyzing metrics to assist in the evaluation of the success of projects;
C. Inclusion of auditing to ensure evaluation metrics are available to support program review and future prioritization; and
D. Leveraging existing resources whenever possible to avoid duplication of effort.
2. A refocus on research as a priority to enable NASA to move forward with the best possible science. To improve NASA’s research enterprise, important changes will need to be implemented. Since the retirement of
Spacelab, in which many sophisticated experiments took place in the context of dedicated research missions implemented by a highly trained and supportive crew, the priority for research has been reduced to levels that compromise the research endeavor. For example, individual astronauts may elect not to participate in research projects for reasons such as concerns about confidentiality or simply a lack of interest, with no clear link to flight status or mission objectives. Communication between investigators and the actual subjects (the crew) is kept to a minimum, and misunderstandings and miscommunications about the goals, objectives, and risk/benefit ratios of specific studies are common. Mission managers, who are not uniformly well grounded in research, sometimes control crew availability, making decisions about crew scheduling that can compromise research studies. Even when non-advocate review committees provide outside consultation and peer review, their recommendations may not be followed, with attendant costs in terms of quality of research. To fix these systemic problems and improve NASA’s research programs over the next decade, the panel offers the following suggestions.
A. A change of attitude should be implemented concerning research within NASA. Although it seems obvious that in order to improve research, research must be a priority, this truth is not always reflected in day-to-day NASA decisions. Every employee from management through crew needs to subscribe to the view that one of the key objectives of the organization is to support and conduct research. The designation of an ISS crew science officer is a positive step, but it does not achieve the goal in its entirety.
B. Human research is an obligatory component of spaceflight operations. Most crew members are fantastic advocates for research and go to extraordinary lengths to do a superb job for ground-based investigators. However, if a crew member does not want to participate, that individual should understand that not being assigned to a flight is the implication of that decision. These decisions should therefore be made before specific flight assignments as part of crew selection and indeed as part of the astronaut selection process from the beginning. The panel understands that this perspective might raise issues of compulsion to participate. Of course, no individual should ever be forced to participate in research against his or her will. However, it seems reasonable and ethical that, if participating in research is part of the job, then not participating may lead to a different type of assignment. This recommended philosophy is consistent with the occupational medicine model recommended in previous reports.231 Difficulties inherent in this approach exist, but the panel encourages NASA to partner with other entities to find a workable solution. Furthermore, the panel recognizes that not all ethicists will agree with the prescriptive approach outlined above, and NASA should engage a variety of individuals with expertise in addressing ethical concerns to advise it on these issues.
The ISS is now essentially complete and is beginning to realize the goal of serving as a U.S. National Laboratory.232 This will present opportunities for NASA as well as for public, private, and governmental entities such as NIH. Such a laboratory can be of inestimable value in addressing scientific as well as practical issues in basic and human physiology, pathophysiology, pharmacology, and discovery-based translational science.
It is fortunate that the full ISS capability comes when NIH is rolling out its national CTSA network. There is, at one level, an analogy between the CTSA Clinical Research Units, which provide the capability for complex and intensive clinical studies of basic and clinical physiology and pathophysiology, and the U.S. National Laboratory on the ISS, with its goal of providing a facility where compelling biomedical research of the highest importance for understanding space physiology can be carried out.
However, there are enormous differences in logistical issues and costs of research in circumstances as disparate as the ISS and a Clinical Research Unit. Also, there are special issues of research opportunity on the ISS, given the necessarily circumscribed and targeted mission equipment. Nevertheless, comparison of the ISS’s potential function in scientific discovery with a CTSA Clinical Research Unit should prompt discussions about how NASA and NIH might be able to cooperate in research selection and implementation. Indeed, NASA could interact with NIH and its National Center for Advancing Translational Science (which oversees the CTSAs) to explore some of the following ways to interact and strengthen relationships between these agencies:
1. Knowledge sharing. At the simplest level, knowledge sharing might take the form of comparative sharing of best practices and analysis of research metrics, but at a more substantive level it should include a genuine collaborative effort between NASA and NIH to jointly evaluate, fund, and place the most compelling biomedical research in the U.S. National Laboratory. NIH Program Announcement 09-120, “Biomedical Research on the International Space Station,” is a notable example of such cooperation, but it is limited to cell biology and molecular biology experiments. Building on this model, the facilities of the CTSA Clinical Research Units could be made available to NASA as a research capability for bed rest studies and complex land-based protocols that could provide preliminary data for future research on the U.S. National Laboratory. With experience, cooperative evaluation and review of proposed research might enable even greater future collaboration.
2. Establishment of standing research prioritization panels or committees that include flight medicine, NASA and NIH science staff, and the external research community. The NIH style of peer review has withstood the test of time. Standing committee members are invited to defined terms of service, with an experienced panel chair and SRA (scientific review administrator). A specific NASA study section, perhaps created within the NIH Center for Scientific Review system, as opposed to the current system where every NASA review panel is constituted ad hoc, would create a cadre of experienced reviewers who could review proposals consistently. However, NASA and the National Space Biomedical Research Institute should retain the programmatic right to focus on research areas of high priority. This approach would help ensure that highly reviewed science would be implemented based on both scientific and programmatic priorities, simultaneously expanding knowledge sharing between the agencies.
3. Collaboration in ground-based research. The CTSA effort establish a network of Clinical Research Units that is the ideal infrastructure to increase opportunities for research on circadian rhythms and for postural and bed rest analog studies. With dedicated nursing and dietetic staff and a national coordinating network, a strong CTSA partnership could increase the number of NASA translational researchers and the annual participation rate in announced research opportunities in areas relevant to space biology and biomedicine.
Astronaut Health and Genomic Medicine
The Human Genome Project has accelerated scientific discovery. While variation in the human genome has long been the cornerstone of human genetics, the diverse set of novel molecular tools now available is radically altering how we think not only about genetics but also about the essence of disease and diagnosis. By comparing genetic differences at the nucleotide and haplotype level, coupled with sophisticated phenotyping and genome-wide association studies (GWAS), the complementary approach of medical resequencing for rare variants, and searching for somatic mutations, new insights into interindividual differences and the susceptibilities that distinguish individuals are emerging and are leading to the new discipline of personalized medicine.233
Known Effects and Gaps in Fundamental and Applied Knowledge
Personalized medicine has penetrated many fields, including oncology,234 cardiovascular disease.235 and sleep loss. With respect to sleep loss, the large phenotypic interindividual differences in neurobehavioral vulnerability to acute and chronic partial sleep deprivation236 might compromise astronaut health and safety in spaceflight due to loss of circadian entrainment, abrupt sleep shifts for logistical reasons, high-tempo work schedules, and the effects of the microgravity environment.
Despite this progress elsewhere, the vision of personalized medicine has been delayed in the current NASA Human Research Program science portfolio. This delay may relate to concerns that genetic information would be used for job selection in the United States.
Findings and Recommendations
NASA can benefit from the rapid scientific advances in personalized medicine. An era is emerging when these unusually rapid advances are not only expanding our knowledge of human health but also altering the fundamental basis of the health care equation. Reorganizing NASA’s approach by aligning it more with this new paradigm
has important advantages for both science and the health of astronauts, although appropriate implementation may require a cultural change within NASA. A somewhat different issue, but one of considerable importance, is obtaining phenotypic analysis and physiological information on individual astronauts. Privacy issues have driven an understandable reluctance to make such data available to investigators. However encryption and de-identification methods for medical records are progressing rapidly, and NASA should explore recent advances in the de-identification of data such as the approach described in the synthetic derivative developed by Masys.237
Clinical Pharmacology in the Microgravity Environment
The body’s absorption of and response to medications are generally perceived to be relatively unaffected by the microgravity environment. This view reflects the paucity of reports of serious deviations from expected drug effect in space. However a recent in-depth report238 based on evidence from spaceflight experience calls attention to the possibility of alterations in clinical pharmacology in the microgravity environment that may have escaped previous recognition. Policies to better document deviations from land-based norms have been put in place.
There is evidence that, in some circumstances, there may be changes in the individual pharmacodynamic and/or pharmacokinetic profile of certain drugs caused by physiological adjustments or other factors in the microgravity environment.239 Some of the effects observed have been related to drug-drug interactions, for example altered drug handling related to agents whose metabolism depends on the enzyme CYP2D6. A specific example has been the concomitant use of midodrine (the alpha agonist administered to increase vascular tone) and promethazine (an agent commonly used by astronauts for its antiemetic and sedative effect). While this specific interaction has received the greatest attention, there are 14 drugs in the current space shuttle and ISS formularies that have CYP2D6 effects. Other differences in drug effect may relate to less well studied phenomena such as alterations in gastrointestinal transit time and gastrointestinal absorption,240 microgravity-induced alterations in blood and plasma volume,241 and altered intestinal microflora (e.g., bacterial hyperproliferation).
Gaps in Fundamental and Applied Knowledge
A better understanding is needed of the consequences of physiological variables and how they alter drug absorption and handling at the kidney. Also it is important to understand if there are systematic alterations in the expression of key gene products of importance in drug disposition in the microgravity environment. These studies need to be conducted in the space microgravity environment, as well as in analog environments.
Findings and Recommendations
Efforts should be made using both ground-based microgravity analogs and experiments in the microgravity environment to determine if alterations in volume of distribution, drug metabolism, and hepatic and renal clearance occur in microgravity. If these effects occur and are of a magnitude that might have consequences for the health of astronauts, consideration of drugs with less extensive metabolism or more stable metabolism might be of value in selecting the drugs for future use in space.
Only an estimated 14 percent of new scientific discoveries are successfully translated to routine clinical practice, and the time for those translations to occur has averaged 17 years.242 If this translation rate remains similar for the life and microgravity science disciplines, then the research progress based on decadal survey recommendations will be very small. Returning to the analogy of the CTSA, that reorganization of the U.S. biomedical research enterprise expands the emphasis on education and training programs for target audiences ranging from practitioners to researchers to students as one way to expedite the translation of discoveries to practice. One ancillary goal of
these programs is to increase the number and quality of collaborations among practitioners, scientists, patients and administrators.243 This model of expanded education offers clues to the design of unique educational programs that improve translation in the space life sciences, including one or both of the following elements:
• A curriculum-based program focused on existing flight surgeons and physician-astronauts that will seek to expand their research knowledge and skill set (such programs are comparable to the NIH’s K30 awards) and
• Mentored research training, similar to the NIH K12 awards.
An essential element of these programs is that they demand that a majority of the trainee’s time be protected for instruction and research. When such expectations are not feasible or practical, CTSA institutions often provide continuing and professional education in specific areas of research. Such programs, if tailored to the biological concerns of extended-duration spaceflight, could provide meaningful opportunities for management personnel, physicians, and astronauts to expand their understanding of the research payloads for which they are responsible. Moreover, they could include combinations of virtual and traditional modes of instruction.
Procurements of flight hardware by NASA space life sciences have sometimes been characterized by noncompetitive bidding by contractors, lack of consultation or involvement of experienced commercial developers of similar equipment, and inadequate ground-based testing prior to flight operations. Under these conditions, the design-development-testing-evaluation process is shortened or improperly completed, causing loss of data, extensive additional work, and increased costs to correct the problems. For example, the flight treadmill has undergone several iterations whereby the science requirements (ability to apply and quantify foot-ward loading, motorized control of treadmill speed, and speed range) have not been met. Once these treadmills were in orbit, the deficiencies were recognized, resulting in increased cost and development of a new treadmill by the same hardware developers. The interim resistance exercise device (iRED) is another example of the inefficiencies of this type of procurement processing.
When specialized equipment is needed that is commercially available, NASA should use or modify an off-the-shelf device. Such commercial hardware is usually thoroughly tested, often meets science requirements, and often can be modified for flight. When a commercial device is not appropriate for spaceflight, NASA should encourage collaboration between developers of commercial equipment and engineers who build flight hardware. There are several notable examples of integrative design strategies that result in hardware that functions well. Important features of these approaches include:
• Strong NASA reliance on science working groups whose members are potential customers of flight hardware;
• Regular inclusion of users (especially scientists and flight personnel) in the design process from the earliest planning stages through completion of the hardware;
• When possible, use of commercially available devices to develop and manufacture flight hardware;
• Rigorous ground-based testing to failure; and
• Sufficient time to iterate design cycles.
To ensure that flight hardware is robust and operates according to scientific or operational specifications, development timelines should not circumvent scientific feedback and re-engineering efforts.
There is a need to reinvigorate international scientific cooperation, specifically the International Space Life Sciences Working Group. Such cooperation worked well in the decades before 2000 and will undoubtedly reduce costs to NASA. New partnerships with India, Russia, Australia, and China should be encouraged. Expansion of
this working group and joint research announcements will aid discovery and internationalize space life sciences, offering opportunities for collaboration in ground studies prior to flight experiments.
There is no lack of space life sciences research to be completed in the next decade. Critical to completing this work in the most useful fashion will be setting research priorities according to the most sensible sequence, the most frequent or severe risk to be mitigated, and the availability of resources. The following are the highest-priority research recommendations selected from the previous sections of this chapter.
To ensure the safety of future commercial orbital and exploration crews, post-landing vertigo and orthostatic intolerance should be quantified in a sufficiently large sample of returning ISS crews, as part of the immediate post-flight medical exam. The effects of mission duration should be determined, and the causes of individual differences in egress performance identified. It is also important to assess the effectiveness and side effects of anti-motion sickness drugs on memory, cognition, sensory-motor adaptation, urinary retention, and sleep under operational conditions on the ISS. (CC1)
Engineering design of exploration spacecraft for multiyear missions depends on whether artificial gravity (AG) is needed as a multisystem (bone, muscle, cardiovascular, vestibular, and immune systems) countermeasure and whether continuous large-radius AG is needed or intermittent exercise within lower-body negative pressure or short-radius AG is sufficient. If NASA determines that AG is required, human bed rest/centrifuge studies in ground laboratories are essential to establish dose-response relationships and determine what gravitational force level, gradient, rate of revolution, duration, and frequency are adequate. This research will require several years and should be resumed as soon as possible. The European Space Agency and the French Centre National d’Etudes Spatiales have active human and ground-based AG research programs, and NASA should forge a collaborative relationship with them. A short-radius centrifuge for rodents and, if possible, for humans on the ISS will ultimately be essential to validate effectiveness and operational acceptability. (CC2)
Because human space exploration involves significant EVA activity, the risk of decompression sickness must be mitigated. Doppler ultrasound studies on several human subjects in the ISS airlock and in ground chambers are needed to determine whether there is an effect of gravity on micronucleation and/or intrapulmonary shunting, or whether the unexpectedly low prevalence of decompression sickness on the space shuttle and the ISS is due to underreporting. Altitude chamber studies (1- to 2-year effort) are needed to determine operationally acceptable low suit pressure and hypobaric hypoxia limits. Lower habitat pressures could potentially eliminate prebreathe requirements, and lower suit pressure could improve glove and joint flexibility in advanced suits. However, use of such pressures would complicate the interpretation of scientific data. The decision to employ hypobaric and/or hypoxic habitat and suit environments thus involves significant scientific versus engineering tradeoffs and will depend on mission objectives. (CC3)
Recent data indicate that crews on long-duration spaceflights are at risk for nutrient deficiency, particularly deficiencies in vitamins E and K, folate, and antioxidants. The next decade’s work should focus on optimizing dietary strategies for crews (especially when UV exposure is limited) and food preservation strategies that will maintain bioavailability for 12 or more months. This work can be conducted in analog or spaceflight environments. (CC4)
If a crewed mission to Mars becomes a NASA priority, one of the first research programs that should be initiated is a robust food science program focused on preserving nutrient stability for 3 or more years. (CC5)
Because the energy requirements for long-duration exploration are still not fully defined, intervention trials (ground-based laboratory studies, ground-based spaceflight analog field studies, and spaceflight) should include food and energy intake as an outcome variable. (CC6)
The fundamental question in space radiation biology is, What will be the health consequences of exposure of astronauts to radiation in space? The radiation in question is high-LET radiation, which has been studied only infrequently to date. To understand the health risks associated with spaceflight, identification of the effects (short-term and long-term) of such radiation exposure is essential. The current studies in this field are predominantly at the molecular-cellular level and to a lesser extent at the whole-animal level. Continuation of these studies during the coming decade is essential for a full understanding of the consequences of exposure to radiation and a better estimate of radiation risk in space. Once risks have been determined, development of mitigators will be essential.
Longer-duration missions on the Moon or to Mars, where risks of exposure to solar particle events and galactic cosmic rays are higher, could result in exposures higher than astronauts have previously encountered. The only detrimental consequence of irradiation that has been shown in astronauts to date that is considered to be radiation-dose-dependent is the induction of cataracts.244,245 The induction may be stochastic (with no dose threshold), and the pattern may be somewhat different from that with cataracts induced by lower-LET radiation (which usually begin in the subcapsular posterior region of the eye). Thus, continued study and follow-up of astronauts for cataract incidence, quality, and pathology related to radiation exposures is essential not only for understanding risk from cataracts but also for understanding radiation-induced late tissue toxicities in humans in general. The cataract studies should continue for the next 10 years and beyond in order to develop the largest database possible, since the sample size is so small. (CC7)
Much of the ongoing work in the field of space radiation biology is being done at the molecular and cellular levels in order to identify end points that should be examined in whole animals. Major questions to be resolved include risks from cancer, cataracts (which show sex-specific differences in mice), cardiovascular disease, neurologic dysfunction, degenerative diseases, and acute toxicities such as fever, nausea, bone marrow suppression, and others. Animal studies inform an important knowledge base to extrapolate human risks since voluntary exposure of humans to radiation at such doses is neither possible nor prudent. While much is known about the effects of the low-LET radiation (gamma rays, x-rays) used in conventional radiotherapy, little is known about the consequences of exposure to high-LET space radiation. It is not likely that the needed information will be acquired in 10 years but, as studies continue, they are likely to influence decisions about risks posed by exposure to radiation in space. At present, most of the studies being conducted by NASA involve rodents (mice and rats), although additional animal models are being added for particular purposes. The next 10 years should expand the use of animal models that mimic human disease, including nonhuman primates, based on how well they mimic human disease. (CC8)
Continued cellular studies during the next 10 years are essential for developing end points and markers that can be used to define acute and late radiation toxicities. The work requires continued ground-based studies using radiation facilities that are able to mimic space radiation exposures, such as the NASA Space Radiation Laboratory at Brookhaven National Laboratory. Ground-based exposures are highly recommended because space exposures are of insufficient dose to induce detectable biological consequences. This constraint hampers studies of the combined effects of microgravity and radiation, which thus require either reliance on ground-based models (such as hindlimb unloading) or the installation of a radiation facility on the ISS.
Recently Brookhaven National Laboratory has done much to improve its ability to generate mixed field radiations that mimic solar particle events and is working to develop additional mixed field capabilities; studies using this facility or one comparable to it will be important for space radiobiology in the coming decade. (CC9)
A renewed emphasis on expanding our understanding of gender differences in adaptation to the spaceflight environment should be part of future flight and ground-based research solicitations. Of particular interest are potential differences in bone, muscle, and cardiovascular function that might be amenable to targeted, gender-specific therapy.
Ground-based animal studies should be performed during the next 10 years to evaluate long-term radiation risks in male and female animals (mice, rats, and primates). Large-scale, multidecade animal studies, results from studies of atomic bomb casualties, and radiotherapy studies of patients exposed to low-LET radiation should report sex differences in the type and incidence of tumors following exposure to radiation. Future research should focus on the mechanisms responsible for sex-specific differences that may aid in the development and utilization of countermeasures for protection against radiation in the space environment. (CC10)
Human studies that systematically investigate the biophysical principles of thermal balance should be performed to determine whether microgravity reduces the threshold for thermal intolerance. This research area is highly relevant for safe spaceflight, especially during EVA and times of heavy work loads. Without an understanding of whether thermal tolerance is altered by microgravity, risk assessment is not possible. This research could be conducted in bed rest studies over the next 5 to 10 years, and may include rarified-gas environments to alter thermal exchange with the environment. Thermotolerance tests should be performed in male and female subjects before and after microgravity deconditioning and should include measurements of body temperature, gut permeability, blood endotoxins, and inflammatory and anti-inflammatory markers. Furthermore, methods to produce rapid, sustained, and physiologically appropriate cooling should be evaluated first during ground-based studies and then during parabolic flight, followed by spaceflight validation studies. (CC11)
Research is needed to develop and test integrated countermeasures, including exercise, for periods exceeding 180 days in microgravity with and without artificial gravity. On-orbit measurements of loads and exercise histories are also important. This research is needed to maintain crew health and well-being during prolonged existence in microgravity and could require a decade to achieve a reasonable sample of human subjects.
Ground-based (e.g., bed rest) studies are needed to test and optimize integrated exercise countermeasures (both hardware and protocol), especially those that include an artificial gravity component. National and international cooperative studies utilizing the existing CTSA network may promote greater resource sharing and accelerate research. Effective use of the International Space Life Sciences Working Group and joint research announcements will promote efficient use of resources and internationalize space life sciences, offering opportunities for collaboration in ground studies prior to flight experiments.
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