Life Sciences: Space Science in the Twenty-First Century -- Imperatives for the Decades 1995 to 2015 (1988)

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HUMAN BIOLOGY AND SPACE MEDICINE 77 6 Human Biology and Space Medicine INTRODUCTION The Space Science Board's recent report, A Strategy for Space Biology and Medical Science for the 19808 and 1990s (National Academy Press, 1987), proposes a broad program of biological, physiological, and psychological research for NASA into the next century. The report concludes that the field of space biology and medicine is in its infancy and emphasizes that the success of any long-term manned program is based upon the support of a well-balanced, vigorous program of research over the next 10 to 20 years. The task group supports these conclusions and notes that its own recommendations complement and extend those themes to the year 2015. This task group wishes to emphasize several of the conclusions contained in the Space Science Board report: • Basic and clinical research complement one another in that clinical observations often pose basic research problems. Conversely, solutions to medical problems usually depend on an understanding of the underlying biology. The design, execution, and interpretations of these experiments should honor this complementarity. 

HUMAN BIOLOGY AND SPACE MEDICINE 78 • Under the best of circumstances, opportunities for flight experiments will be infrequent and expensive. Extensive ground-based simulations and experiments must precede space experiments whenever possible. • Most of the experiments will require manned missions both because humans are frequently the subject of choice and because many experiments require observations and manipulations too complex to be performed remotely. We will be establishing the ranges of human physiological and behavioral responses to incrementally increased exposure to microgravity. All crew members should contribute to this data base without compromising their confidentiality, welfare, or performance. There must also be experiments on plants and animals. We should identify species suitable for the range of experiments and optimize our holding facilities for them. Ground studies should select desired mutants, explore their physiologies, and map and sequence relevant genes. • In order to interpret microgravity experiments, we must have adequate controls. Usually, these will involve parallel experiments performed at one-g in space, duplicating all of the biological and physical variables of the microgravity experiment. Building the required centrifuge is a major engineering challenge. • If the United States is to have the option of manned space-flight of several years' duration, we must define and ameliorate several potentially harmful effects of spaceflight. Beyond this, we must determine whether space provides opportunities better than those existing on Earth to study biology and medicine. Our past flight opportunities have been so restricted that we are not well prepared to project research strategies to 2015. • Men and women may be called upon to perform a broad range of jobs in construction, observation, and manipulation while in planetary orbit or interplanetary flight. We need to research the optimal interactions of the crew while working with under stressful conditions, while working with one another, and while working with a complex array of equipment and computers. EXPERIMENTAL USE OF ANIMALS Areas of special concern include animal use. There has been little substantial progress made in the development of animal holding units and research modules for the U.S. and Soviet space programs. The considered use of animals in space research is necessary 

HUMAN BIOLOGY AND SPACE MEDICINE 79 for an orderly, thorough program. In order to qualify humans for long-term flights or for repeated short-term flights, our scientific data base must be greatly extended. The uncertainties and potential dangers (from weightlessness, radiation, and so on) of long-term space missions underscore the need for carefully prepared animal flights in the period leading up to those missions. Gaining the experience and knowledge we need from animal research will demand a clearly enunciated commitment by NASA and the assignment of adequate priorities and resources. Approach to Scientific Questions Planning the research and development program for a space vehicle must incorporate factors considered in several sections of this and other chapters. A principal requirement for the advancement of the scientific objectives related to the vehicle is for a well-planned, carefully constructed, multipurpose, residential, ground-based vehicle simulator for intermediate and long-term investigations. While this would not permit study of critically important stresses (such as radiation and weightlessness), it would allow assessment of the structural features of the vehicle and the characteristics of their outgassing products; the utility and suitability of the arrangement of equipment; and the unique requirements for special research laboratories and animal holding and research facilities. Such a facility would also allow testing of modular design features and would be suited for long-term studies of nutrition, health care problems, and psychosocial interactions. Such design characteristics should be evaluated on short missions prior to a commitment to longer-term space missions. NEUROSENSORY PHYSIOLOGY Introduction Since its inception, NASA's neurosensory physiology research program has centered on the neurovestibular area largely because of the space motion sickness (SMS) problem that surfaced in the Apollo program. This focus is both appropriate and justifiable in view of the continued SMS incidence affecting over 50 percent of the crew on Shuttle flights, and in view of the resulting decreased 

HUMAN BIOLOGY AND SPACE MEDICINE 80 crew efficiency, as well as the potential impact on early extravehicular activity (EVA) requirements, and the potential problems for SMS-affected crew members during arrival and transfer at the Space Station. The goal of understanding the neural mechanisms of adaptation to microgravity is an enormous task requiring a broad-based program of investigation. Devising predictive SMS tests on Earth and rational therapies for the prevention or amelioration of SMS clearly rests on an intensive research effort aimed at understanding the mechanisms involved in human habituation to microgravity and readaptation on return to Earth. This broad-based neurosensory research program must emphasize a systematic, well-coordinated series of inflight experiments involving human and subhuman surrogates as research subjects. A relatively comprehensive ground-based research program is currently in place; however, a firm commitment for an extensive inflight program is mandatory if progress in this complex area is to be forthcoming. In this context, the validation of a suitable animal model for invasive experimentation would accelerate research progress. Extensive inflight experimentation will be required for several reasons: 1. SMS and other vestibular phenomena are unique to space (microgravity environment). 2. Microgravity cannot be simulated on Earth for sufficiently long time intervals (30 s in KC-135 parabolic flights). 3. SMS provocative stimuli (microgravity and head/body movements) are different from causative stimuli in motion sickness of one-g. Such movements at one-g do not result in motion sickness. 4. One-g motion sickness susceptibility tests do not predict susceptibility aloft. The correlation coefficient is low. 5. Habituation exercises such as gymnastics and acrobatics may have a salutary effect on performance in other one-g motion environments, but there is apparently no transfer to the microgravity environment, and such techniques have not been demonstrated to be effective in preventing or mitigating SMS symptoms. Very probably no "magic bullet" will be found to prevent SMS. In this case NASA's research strategy will have to rely on a coordinated, systematic approach to understanding the complex 

HUMAN BIOLOGY AND SPACE MEDICINE 81 operant neurosensory mechanisms. Even if the "magic bullet" for SMS were found, the requirement to do extensive neurophysiological (vestibular) research in space would still exist. The adaptations of this system are of great intrinsic interest. We have evolved on planet Earth for eons in a one-g environment. Only in microgravity can we remove this gravity vector and physiologically "dissect" the sensory nervous system in a nondestructive mode. For this reason alone, and for the immense benefits that will accrue to neurophysiological and medical knowledge and understanding of these complex phenomena, the systematic investigation of the vestibular/neurosensory system is a scientific imperative for the Space Station. Background Flight Experience For many reasons, progress in human physiological research in space has been limited. Experimental sample size has been and will continue to be small. In addition, experiments generally require at least two crew members (experimenter and subject). Finally, there has been a long hiatus inflight opportunities between Skylab and Shuttle programs. The dearth of flight research opportunities reflects the low priority given to life sciences research in general. The first dedicated Life Sciences Mission on the Shuttle (SLS-1) will carry experiments proposed in 1978. This is to be followed by SLS-2, carrying animal experiments also proposed in 1978. Data in the neurovestibular area have been measured by the European Space Agency (ESA) mission flown on the Shuttle, Spacelab 1 (SL-1), the German D-1 mission, detailed supplementary objectives (DSOs or mid-deck measurements), and limited preflight and postflight testing. These results will be referred to in the sections to follow. There is no current provision for a vestibular research facility on board the Shuttle, although time and space will be made available for single SMS / neurosensory experiments as these mature and are ready for flight. Given the formidable obstacles to inflight life sciences research outlined above, both reason and past experience indicate that the bulk of any proposed systematic, well-structured scientific research program in the neurophysiological discipline will have to await the Space Station era. All available Shuttle flight opportunities will 

HUMAN BIOLOGY AND SPACE MEDICINE 82 be utilized in the interim. These will be helpful, but inadequate to support the research program currently envisioned. Improved technologies for invasive and noninvasive experimental methods will doubtless be developed in the coming years. Some of these will lend themselves to relatively easy incorporation into the inflight investigative program; some will not. However, much vital information can be obtained using present state-of-the-art technology. Special facilities will be required for the execution of the research program detailed in this chapter; some of these will influence the design of the Life Science Research Module. These include: 1. A "space sled" (linear body accelerator) with triaxial seat capability. 2. A subject rotator (also with triaxial capability). 3. A multipurpose, variable-g centrifuge to accommodate animals, plants, and eventually humans. The latter facility would be of immense value in several disciplines. In neurosensory research it will permit observation and quantification of sensorimotor adaptation at various g levels during prolonged stays in microgravity. It would be invaluable in determining the optimal g level to prevent or reduce the adverse effects of microgravity such as cardiovascular deconditioning, bone demineralization, muscle atrophy, and abnormal plant growth. Research involving subhuman surrogates is detailed in A Strategy for Space Biology and Medical Science for the 1980s and 1990s. Space Motion Sickness As previously mentioned, neurosensory research efforts in the past have focused on space motion sickness (SMS). This is a special form of motion sickness that is experienced by some individuals during the first several days of exposure to microgravity. The syndrome may include such symptoms as depressed appetite, a nonspecific malaise, lethargy, gastrointestional discomfort, nausea, and vomiting. As in other forms of motion sickness, the syndrome may induce an inhibition of self-motivation, which can result in decreased ability to perform demanding tasks in those persons who are most severely affected. Table 6.1 gives the symptom incidence in 72 astronauts. The syndrome is self-limited. 

HUMAN BIOLOGY AND SPACE MEDICINE 83 TABLE 6.1 Space Motion Sickness Incidence and Symptom Complex Symptom Incidence Number Percent Vomiting 31 86 Anorexia 28 78 Headache 23 64 Stomach awareness 22 61 Malaise 21 58 Lethargy 19 53 Nausea 18 50 Drowsiness 8 22 Disequilibrium 7 19 Overall SMS Incidence: 36 of 72 astronauts (50%) Complete recovery from major symptoms—in other words, adaptation to the spaceflight environment—occurs within two to four days. After complete adaptation occurs, crew members appear to be immune to the development of further symptoms, although the Russians have reported repeat episodes. This development of immunity to further SMS symptoms was eloquently demonstrated by rotating chair tests, designed to provoke an SMS response, that were conducted inflight during Skylab missions. The etiology of SMS is currently under intensive investigation. There are two main hypotheses advanced to explain SMS: Sensory or neural mismatch (a variation of the sensory conflict theory) and the fluid shift model. Research data currently lend more credence to the former theory. Prediction of susceptibility has been an objective of the SMS research. Various approaches ranging from the use of questionnaires, psychodynamics or personality traits, vestibular function tests, physiological correlates, and tests in specific nauseagenic environments have been directed toward the question of SMS susceptibility. The correlations between the selected predictors and motion sickness have been of limited use in predicting susceptibility. Individual variations in preflight experience, medications, inflight tasks (i.e., mobility), and personal strategies for symptom management have further compounded the problem. Vestibulo-Spinal Reflexes Two of the more dramatic responses to orbital flight have 

HUMAN BIOLOGY AND SPACE MEDICINE 84 been postural disturbances and modified reflex activity in the major weight- bearing muscles. Monitoring the Hoffman A reflex, which takes advantage of the powerful and established anatomical pathways that link the otoliths and spinal motoneurons, has been selected as a method of monosynaptic spinal reflex testing when performed in conjunction with linear acceleration to assess otolith-induced changes in one group of major postural muscles (soleus). Second, extensive dynamic postural testing with a moving platform was performed before and after the flight of Spacelab 1. The Hoffman reflex amplitude, as reflected by the otolith-modulated motoneuron sensitivity, was low inflight after neurovestibular adaptation to spaceflight, and its postflight potentiation may have been dependent on rate of adaptation. The degree of inflight SMS symptoms was related to preflight and postflight Hoffman reflex amplitude. Dynamic posture tests revealed significant deviations from the results obtained before flight. The strategy used by the individuals for balance on the moving platform was modified, and their behavior indicated a decrease in awareness of the direction and magnitude of the motion. Proposed Research Overview Investigations using noninvasive methods and human subjects during long- duration orbital flight will be required for an understanding of human adaptability to microgravity and the return to Earth. Possible areas of investigation include: 1. Prediction of susceptibility. 2. Profiles of adaptability. 3. Training countermeasures. 4. Pharmacological countermeasures. 5. Physiological variables. 6. Neural mechanisms of SMS and adaptation to microgravity. 7. Vestibular function tests. 8. Vestibulo-spinal reflex mechanisms. Visual System The human visual system is addressed in the body of this 

HUMAN BIOLOGY AND SPACE MEDICINE 85 discussion principally in the context of its relationship to the vestibular system. Vision may compensate in large measure for modified otolith sensitivity. It helps in spatial orientation, and is essential to motor coordination. Other aspects of vision and the visual system must also be addressed. Visual acuity, contrast discrimination, and radiation effects must be investigated, particularly on long-duration missions. The former two functions have been studied on short-term Shuttle flights, and no significant decrements have been found. The effects of long-duration flights on these functions are unknown and must be determined. Visual ''light flashes'' were observed by Apollo astronauts and were more systematically studied on the Skylab 4 mission. During most of the Skylab 4 mission, these flashes averaged 20 per hour; however, flashes increased to 157 per hour when the Skylab orbit passed over the center of the South Atlantic anomaly. The flashes are believed to be due to high-energy heavy particles (cosmic rays) and have been reproduced in humans in the laboratory by exposure to high-energy ionizing particles at the Berkeley Bevalac facility. The flux of these particles may be expected to increase during any missions beyond the Earth's magnetosphere as well as during polar and high-inclination earth orbits. Thus, we must assess the effects of this radiation on nondividing cells of the retina and central nervous system before long-duration manned missions beyond Earth's magnetosphere are attempted. The radiation hazards to humans in space are addressed in greater detail in the "Radiation Effects" section of this chapter. Tactile and Proprioceptive Systems The gravity vector is a fundamental factor in human spatial orientation, which results from the integration of a complex of sensory inputs including visual, vestibular, tactile, and proprioceptive. The latter two systems are important both in spatial orientation and in postural control. In some individuals static visual cues become increasingly dominant in establishing spatial orientation in microgravity. Other subjects are more "body oriented" and align their exocentric vertical to be along their longitudinal body axis, and perceive the body axis relative to placement. Such individuals exhibit no problems in spatial orientation aloft even in the absence of visual cues 

HUMAN BIOLOGY AND SPACE MEDICINE 86 for vertical orientation. Further, these individuals appear able to strengthen their perception of subjective verticality by using localized tactile cues, especially by pressure exerted on the soles of their feet. It is evident that the nature of proprioceptive changes in microgravity must be addressed in detail, particularly neck and joint angle sensors and the role of localized tactile cues in the perception of body verticality. Perceptual and physiological data from Spacelab 1 underscore the need for additional systematic study. Early in a given spaceflight (before adaptation), sudden drops were perceived as falls or drops on Earth—linear translations— and felt much as they did preflight. Hoffman reflex changes at this time were similar to those observed preflight. Later, inflight drops were perceived as linear translations that were sudden, fast, and hard, with the crew not being aware of the position or location of their legs and feet and the absence of a falling sensation. They also exhibited difficulties in maintaining "balance" following the drop. In these late inflight drops, the Hoffman reflex was not potentiated. Finally, postflight drops were perceived as identical with the late inflight drops, namely, lack of awareness of position and location of feet. Again, the drops were perceived as sudden—not a falling sensation, but rather a feeling that "the floor came up to meet them." Experimental programs concerning spatial orientation must therefore identify and quantify the sensorimotor adaptation in microgravity as well as in the postflight "carryover" and readaptation to one-g periods. Such experiments will provide information regarding the psycho-physiological basis for establishing spatial orientation aloft. Postural mechanisms require investigation in long-duration space missions. Postural activity is the complex result of integrated orientation and motion information from visual, vestibular, and somesthetic sensory inputs. These inputs collectively contribute to a sense of body orientation and, additionally, coordinate body muscle activities that are largely automatic and independent of conscious perception and voluntary control. Changes in the adaptation of automatic postural systems to microgravity have not been studied systematically, but impairment of voluntary pointing accuracy and misperception of static limb and body position have been noted, as have postflight impairment in walking, standing (eyes closed), and negotiating rapid turns. Microgravity 

HUMAN BIOLOGY AND SPACE MEDICINE 87 is the only external environment condition in which segments of previous one-g postural control are no longer relevant and in which vestibular inputs are altered on a long-term basis. Microgravity affords a unique opportunity to investigate the adaptation of automatic postural control systems and to augment our understanding of adaptive mechanisms involved in the voluntary muscular system. BONE AND MINERAL METABOLISM Introduction Loss of calcium and phosphate from bone (osteopenia) continues at about 0.4 percent of total existing bone mass per month. The effect is especially marked in the weight-bearing bones of the legs and spine. There is no indication that this osteopenia abates with longer flights. The resorbed mineral may affect various organs, especially the kidneys. Bones could fracture under the extreme stress of heavy work or upon return to one-g. This poorly understood phenomenon is one of the major dangers posed by flights of several years. There are no immediate prospects for countermeasures based on exercise, diets, or drugs. Although empirical procedures may be found, they cannot be assured. The task group believes that a major research investment is mandatory before serious planning begins for spaceflights of several years' duration. Background Flight Experience A variety of studies of humans during long-term bed rest, of humans in space, and of rats in space have shown that prolonged inactivity and weightlessness result both in significant and continuing losses of calcium from the skeleton and nitrogen from muscle, and in notable atrophy of both body systems. These changes were consistent but quite different in degree from subject to subject. In the longest bed rest studies (7 months) and in the longest orbital spaceflight during which metabolic measurements were made (3 months), the rate of calcium loss was as great at the end of the studies as it was soon after the start. In the severe paralysis of 

HUMAN BIOLOGY AND SPACE MEDICINE 88 poliomyelitis, calcium losses led to x-ray visible osteoporosis in the bones of the lower extremities as early as 3 months after paralysis. While the overall rate of calcium loss in Skylab astronauts was 0.4 percent of total body calcium per month, the loss was estimated to be 10 times greater in the lower extremities than in the rest of the body (based on bed rest studies of calcium losses by metabolic balance compared with decrease in bone calcium density). This could lead in 8 months of flight to a decrease in bone density in the legs similar to that noted in paralytic poliomyelitis. In longer flights, if mineral loss were to continue at a similar rate the bones of the legs might fracture during physical work in as little as 9 to 12 months, especially at gravities approaching one-g. Studies of immobilized rabbits showed marked decrease in strength of tendons and ligaments after only 1 month. Thus, strains, sprains, and even ligament tears may be more likely to occur, and at an earlier time than bone fractures. Cellular Mechanisms The cellular mechanisms of mineral loss are unknown. Excess excretion of calcium associated with increased hydroxyproline in the urine in humans is indicative of increased bone resorption. Histologic examination of the bones of the rats on Cosmos showed suppressed bone formation; it is difficult, however, to apply these results directly to humans because of differences in rat bone physiology. In more recent research, bed rest studies under NASA sponsorship have been continued in search of so-called "countermeasures" that could be applied to astronauts in space to suppress or prevent calcium loss. All of the mechanical procedures tested thus far have been ineffective. Correlative observations have indicated that one would have to devise some procedure for use inflight that would provide the equivalent force on the skeleton of 4 hours of walking per day. A high calcium and phosphorus diet reduced calcium loss for up to 90 days only. Some promise has been noted in certain of the diphosphonates, compounds that bind to bone crystal and tend to inhibit bone resorption. These countermeasure studies are being continued. At the same time, with support from the National Institutes of Health, a variety of studies are being conducted on the basic mechanisms of the effects of mechanical forces on bone dynamics 

HUMAN BIOLOGY AND SPACE MEDICINE 89 and development. Such studies may give insight into the bone loss problem in space. Conversely, development of effective counter-measures to bone loss in space may contribute to improved therapy or management of osteoporosis, which is characterized by gradually decreasing bone mass and strength, and is the most prevalent clinical disorder of bone. Possibility of Urinary Tract Stone Formation The hypercalciuria associated with loss of mineral from bone in spaceflight might increase the potential for stone formation in the urinary tract. Although 75 to 80 percent of renal stones contain calcium, the likelihood of stone formation will depend not only on increased urinary concentration of calcium, but also on other factors such as urinary pH, concentration of inorganic elements (magnesium, potassium, and phosphorus), and concentrations of organic compounds (uric acid, citrate, and oxalate). Bed rest studies have shown a slight rise in urinary pH and a lack of change in urinary citrate, which in ambulatory states rises with increases in urinary calcium. Both of these factors, if also noted in spaceflight, would favor decreased solubility of calcium salts. These considerations suggest that research ought to be continued on urinary tract stone formation in relation to microgravity as a significant possibility during long spaceflight. The likelihood of such an occurrence may be small, especially if care is taken to maintain abundant urine volumes; nevertheless, such stone formation might be catastrophic to health and function for the astronaut involved, and thus to success of the particular flight. Proposed Research Characterization Over at least the next 10 years, research in bone physiology and metabolism related to space is likely to be involved primarily in the search for effective ways of protecting the skeleton from the decreases in mass associated with weightlessness and diminished physical activity. The initial phase will be a continuation of human bed rest studies and immobilization or suspension studies in primates and rats, respectively, as the only practical models for weightlessness. The principal "countermeasure" studies thus 

HUMAN BIOLOGY AND SPACE MEDICINE 90 far have been with humans subjected to bed rest. Thus far, in these studies no physical procedure tested has been helpful in preventing disuse osteoporosis. Among the biochemical modalities, trials of only two different diphosphonate compounds (EHDP and di-chloro) have suggested potential for usefulness. The rat and primate studies, including a number of rat studies on U.S.S.R.-Cosmos flights, have been mainly observational, but with the intent of obtaining data on the rate, degree, location, and pathophysiological processes of the bone loss occurring in inactivity and in weightlessness. While appropriate plans for Space Station research relative to the musculoskeletal system are being addressed, certain studies will be especially pertinent to learning more about the effects of long-term weightlessness, on the musculoskeletal system. The most obvious animal study to conduct in Space Station would be exposure of successive groups of rats to 30, 60, 90, or more days in weightlessness, followed by various biochemical, radiological, and histologic examinations of muscle and bone to determine the rate and course of bone loss and to obtain further insight into its basic mechanism. The rat is not the ideal model for such studies, however, because of its ever-growing skeleton. Plans should be made, therefore, to carry out similar studies on animals with skeletons that mature. These might include cats, dogs, small pigs, and—perhaps at a later date—primates. The task group again emphasizes the desirability of focusing research on a limited number of well-characterized species. In line with the NASA principle of extending knowledge of the effects of spaceflight by progressive extension of the duration of flight, the answer to the question of whether calcium loss will continue beyond some critical level of bone density needs to be obtained by studies of astronauts in longer exposure to microgravity. Payload specialists should be studied in space to at least 6 months, and depending on results, possibly on to 9 to 12 months. Such studies should include not just measurements of preflight and postflight bone density. Rather, they should include metabolic studies of certain individuals, analyzing dietary controls and total excreta. This would allow a rather precise assessment of the pattern and extent of continuing bone and muscle loss. The need for imaging techniques required to facilitate this research is discussed in Chapter 7. It is imperative that we progress with this research before 

HUMAN BIOLOGY AND SPACE MEDICINE 91 we commit to spaceflights of several years, as required for Mars exploration. Cellular Mechanisms The current models in bone research are bed rest for humans, tail suspension for rats, and immobilization for primates. An effort should be made to develop other animal models that are less expensive and more manageable than primates, and have a more appropriate skeletal system than rats. As for experimental techniques, relatively little has been done thus far among space physiology investigators in the area of kinetic studies for assessment of rates of bone formation and resorption and the effects thereon of various procedures or agents. Radioactive isotopes can be used in animal studies at proper dosages. Kinetic studies of humans in space will be more difficult. Use of stable isotopes is increasing generally despite their high cost, and presumably by 1995 appropriate studies can be designed for humans in microgravity. Some medical bone physiologists are increasingly interested in biophysical and biomechanical influences on bone (Kroc Conference in 1983 on "Functional Adaptation in Bone Tissue"). Development of bone cell and tissue cultures will also be required for progress in understanding bone and mineral metabolism in a microgravity environment. As they mimic hormonal and mechanical stresses, their various compositions and characteristics can be manipulated more readily than can intact animals. More precise measurements of magnetic and streaming potentials and of piezoelectric energies are becoming available for use in a wide variety of studies, including the interrelationships of mechanical and electrical forces and biochemical signals in bone cell cultures. Despite the steady development of more sophisticated techniques, the capabilities for diet control and specimen collections of metabolic balance studies will still be needed aboard space vehicles. Whatever the important insights we gain from organ, tissue, and cellular studies into mechanisms and how to influence them, there will still be the need to measure periodically changes in rates, masses, and patterns of flow of key elements in the whole animal or whole human being. 

HUMAN BIOLOGY AND SPACE MEDICINE 92 Nutrition Numerous previous studies unrelated to space have indicated that increasing the protein intake increases the urinary excretion of calcium. Therefore, the level of protein in the diets of astronauts, hitherto selected by them as quite high, needs to be reconsidered for its possible relationship to potential for urinary tract stone formation and to the rate of loss of mineral from the skeleton. At the same time, some degree of uncertainty exists as to whether or not the high phosphate content of meat is partially protective. The Space Station would be the logical clinical laboratory in which to settle the question of the best calcium, phosphate, and protein content and proportions in the diets of astronauts subject to months and years of weightlessness. The possible benefit of nutritional manipulation has been tried among various efforts to find a means of protecting the skeleton in weightlessness. In long bed rest studies sponsored by NASA (V. Schneider and Associates), high calcium and phosphate intakes kept calcium balance from going negative for the first three months of bed rest, but during the fourth month increasing fecal calcium excretion resulted in continuing losses of calcium (negative balance). A similar study of the effects of high calcium intake might be repeated in the Space Station, but it probably would not have high priority. Summary Review of the current state of knowledge regarding bone demineralization and the possibility of urinary calculi formation in space indicates that considerably more research will be needed in this area during the period 1995 to 2015. This well-known constellation of problems will require, at the least, careful monitoring during prolonged stays in space, even if countermeasures that are efficacious in missions of shorter duration have been developed. Bone demineralization is probably the most significant hazard for long residence in space at present. A fully effective countermeasure, or indeed a full understanding of the involved mechanisms, will not be available by 1995 and will require a major investment in understanding the fundamental biology of bone development, formation, and resorption. 

HUMAN BIOLOGY AND SPACE MEDICINE 93 MUSCLE METABOLISM Introduction After a few days of exposure to microgravity, the urinary excretion of nitrogen compounds increases and muscle atrophy begins. These effects may compromise the ability of astronauts to do their jobs. They may not be able to withstand the stress of one-g upon return to Earth; the continued excretion of nitrogen may have deleterious hormonal and nutritional effects. Although exercise, diet, or drugs may ameliorate these effects, the task group anticipates that a successful prophylaxis will be based on a fundamental understanding of the control of the expression of the genes encoding the structural and regulatory proteins of muscle. Background Flight Experience The increased urinary excretion of nitrogen by astronauts in Skylab reflected mainly muscle loss as is observed in bed rest, but was variable and generally greater in degree. At least a small part of this excess nitrogen excretion could reflect gluconeogenesis related to observed increased cortisol release, although the increases in plasma cortisol in both Skylab and a recent bed rest study were quite modest. The possibility of some other influence similar to the "toxic" factor of severe illness cannot be ruled out. However, most of the atrophy occurs in antigravity muscles, which are no longer load-bearing. Of these various possible factors contributing to the excess excretion of nitrogen, muscle atrophy is clearly the main one. In all nine Skylab astronauts, the high level of nitrogen excretion continued unabated for the duration of flight (up to 84 days). This indicates a serious malfunction not likely to reach a new steady state until an extreme degree of atrophy is reached. This nitrogen loss was accompanied by losses of 15 to 30 percent of muscle mass and strength in the lower extremities. This poses a significant handicap to vigorous work in the gravity of Mars or on return to Earth. The considerable and time-consuming exercise activity of the astronauts on Skylab 4 resulted in somewhat lesser losses of muscle mass and strength than on the earlier flights, but were obviously not adequate to be fully protective. 

HUMAN BIOLOGY AND SPACE MEDICINE 94 In spaceflight studies of rats in the U.S.S.R.-Cosmos series of flights, there was a differential atrophy of the various types of muscle fibers and many focal histopathologic changes with random deletion of myofibrillar filaments. There was a loss of muscle force and elasticity and some specific changes in enzyme activity. In the rats in these Cosmos studies that were subjected to centrifugation, these muscle changes were largely prevented. Ground-Based Studies Bearing directly on this human problem are NASA-sponsored animal studies of muscle atrophy due to disuse. These studies emphasize efforts to determine the physiological and biochemical mechanisms underlying muscle atrophy. They also are directed toward development of noninvasive methods of measuring muscle mass and toward searching for useful countermeasures. Although the mechanism of the process of atrophy remains unknown, certain aspects have become evident. Muscle atrophy is accompanied by decreased synthesis of muscle protein and by some degree of increased degradation. As shown in rats that are suspended (hind limb unloaded), loading and stretching of otherwise inactive leg muscles prevented muscle atrophy and stimulated protein synthesis; the addition of electrical stimulation increased protein synthesis markedly. As shown in muscle cell cultures, stretching stimulates protein syntheses. The uncertain value of physical exercise for suppressing muscle atrophy in human flight has been noted previously; no controlled studies of exercise inflight have been attempted. Proposed Research NASA-sponsored research is now addressing basic mechanisms relating muscle demand or load to hypertrophy, and decreased demand to atrophy. What is the signal and sequence of biochemical steps for initiating increased protein synthesis and deposition in muscle filaments, and what communicates a message to slow down protein synthesis? Answers to these questions would have an impact on muscle research far beyond spaceflight. Using various animal and human studies, we need to determine which muscles and fiber types are primarily affected in relation to 

HUMAN BIOLOGY AND SPACE MEDICINE 95 the duration of exposure to microgravity. The relationship of muscle fatigue to microgravity exposure and the usefulness of various exercise regimens in ameliorating the effects of microgravity need to be studied. What microanatomical, enzymic, and biochemical changes occur in myofilaments, in the muscle tissue of the walls of the veins, in myotendinous junctions, and in tendons and ligaments when subjected to microgravity? A variety of techniques are available for muscle research: electron microscopy, electromyography, CT scanning, and stable isotope etabolic studies. The effects of electrical stimulation of muscle have begun to be studied, but the possible combinations of frequency, voltage, and current are almost without limit. These are but a few of the permutations possible in undertaking to increase our knowledge of muscle physiology and biochemistry as influenced by microgravity. These existing technologies should be coupled with developing techniques in immunochemistry and in recombinant DNA and gene cloning. In order to understand changes of muscle mass and strength, we must understand their underlying cellular and molecular mechanisms. The genes encoding many major proteins of muscle, as well as their controlling elements, have been sequenced. Our goal is to relate mechanical stress, hormonal levels, and nutrition to the control of expression of these genes. CARDIOVASCULAR, PULMONARY, AND RENAL SYSTEMS Introduction Investigation of cardiovascular and pulmonary physiology in manned spaceflight will continue to be an important endeavor well beyond 1995. Clearly, the cardiovascular, pulmonary, and renal systems are crucial to health. At this writing, human cardiopulmonary and renal response to short-term exposure to microgravity seems to have been relatively free of major threats to well being and performance in spaceflight. However, we now have only a rudimentary glimpse of the total picture of optimal preparation for spaceflight, physiologic behavior during exposure to microgravity, and reaccommodation to a one-g environment. 

HUMAN BIOLOGY AND SPACE MEDICINE 96 Background The cardiopulmonary and renal systems readily adapt to microgravity. Adaptations to relatively short-duration flights (7 to 10 days) are quickly reversed upon return to the one-g environment. It now seems likely that flights of 28 to 237 days, the shortest Skylab and longest Salyut missions, respectively, result in somewhat more extensive although qualitatively similar adaptations, but demand a proportionately greater time for readaptation to one-g. Two examples of postflight problems are orthostatic intolerance and diminished exercise capacity. Orthostatic intolerance is characterized by a cluster of symptoms that follow standing: lightheadedness, resting tachycardia, labile blood pressure, narrowed pulse pressure, and presyncope or syncope (fainting). Diminished exercise capacity is the observed decrement in ability to perform given amounts of work and is usually measured by duration of treadmill or stationary bicycle exercise up to a maximum level of oxygen consumption. At current levels of experience, both orthostatic intolerance and diminished exercise capacity become more severe with longer exposure to microgravity and require more lengthy recovery times after returning to Earth. There appears to be no qualitative difference between short-and medium-term microgravity exposure with regard to cardiovascular well being and performance in space. For the Shuttle era, researchers remain concerned with devising and refining countermeasures to prevent or palliate cardiovascular problems associated with the return from microgravity to earth gravity (one-g). Current candidates for countermeasures include preflight and inflight exercise, application of lower body negative pressure (LBNP) during spaceflight, fluid loading prior to reentry, and rehabilitation after return to Earth. Low blood volume, fluid shifts, orthostatic and LBNP intolerance, reduced exercise capacity, and decreased heart size have all been observed after exposure to microgravity for up to 6 months. However, the effects of exposure to microgravity beyond 9 months are entirely unknown. This is of great concern, because such effects may involve not only amplification of reversible changes already known, but also the emergence of heretofore unrecognized and irreversible alterations in cardiopulmonary function. For example, some observers have speculated that there is a loss of cardiac mass 

HUMAN BIOLOGY AND SPACE MEDICINE 97 during prolonged microgravity exposure. Will lengthy missions render space travelers unfit for return to a one-g environment? Finally, it should be recognized that the microgravity environment may provide a unique laboratory for investigation of fundamental cardiovascular and pulmonary physiology and development. Basic observations in the microgravity environment may find practical applications to human health on Earth, perhaps in coping with the effects of prolonged bed rest. Proposed Research Cardiovascular Conditioning Several current issues in the area of cardiopulmonary function can be expected to continue to be of great interest 10 years from now, despite investigations now planned for Shuttle missions. Foremost among current topics is cardiovascular deconditioning. The mechanisms by which bodily fluid is shifted remain to be elucidated, and are undoubtedly not simple. In addition, renal and endocrine changes are likely upon exposure to microgravity, as are neuroregulatory alterations. We need to characterize all of the cardiovascular, renal, endocrine, and neuroregulatory forces at play during spaceflight, reentry, and post-reentry periods. Postflight orthostatic intolerance is due to more than just loss of fluid. We have evidence that both the autonomic nervous system and hormone secretion are altered. Their effects on the kidneys, blood vessels, and heart have yet to be fully understood and must be studied over varying durations of exposure to weightlessness. Elucidation of the mechanisms of these effects promises to shed light on some clinical, nonspaceflight problems such as high blood pressure and heart failure. The problem of long-term exposure to microgravity looms large; currently observed space effects may intensify or new ones may appear. All cardiovascular changes now appear to be relatively mild and entirely reversible upon resumption of one-g exposure. Might orthostatic intolerance become irreversible after long-term exposure? How will the time course of cardiovascular readaptation to one-g be affected by lengthier missions? There now appears to be no deleterious effect of spaceflight directly upon the heart; will long-term spaceflight bring irreversible, involutional myocardial degeneration or ''hypotrophy?'' 

HUMAN BIOLOGY AND SPACE MEDICINE 98 It is perhaps surprising that, to date, we have very little understanding of the exact physiologic effects—beneficial or harmful—of various types of exercise on the phenomenon of cardiovascular deconditioning. For example, some evidence suggests that the aerobically trained individual may be more vulnerable to orthostatic intolerance. Protocols for preflight, inflight, and postflight exercise must be designed and tested in a rigorous manner to determine what, if any, types of exercise may be the best countermeasures to deconditioning. Integrated into the problem of understanding the effects of exercise on cardiovascular deconditioning is also understanding the responses of blood gases, electrolytes, glucose, insulin, growth hormone, glucagon, and cortisol. The microgravity environment will be an ideal place to investigate the neurohumoral control of the cardiovascular system. It is well known that the bodies of upright primates, including human beings, have several "built-in" mechanisms to control blood volume and pressure during postural changes in the presence of gravity. These mechanisms include: (1) changing peripheral vascular tone, mediated by arterial baroreceptors, (2) regulating urine volume and electrolyte output, mediated through low-pressure baroreceptors in the atria, (3) matching of ventilation and perfusion in all lung segments, (4) autoregulating cerebral function, and (5) using check valves in the venous system. These neurohumoral mechanisms are complicated, and involve afferents from the sympathetic system and efferents originating in the hypothalamic and brainstem region and going to the heart, kidney, and peripheral vasculature. The neurotransmitters are numerous, and several hormones, such as the so-called "natriuretic factor," have not been fully characterized. Work on animals has delineated the importance of these regulatory systems. Dogs whose carotid sinus baroreceptors have been excised have a variation from 40 to 200 in their mean blood pressure. Manual compression of carotid sinuses can cause syncope and bradycardia (low heart rate) in healthy persons. In orbit or in free space, however, the carotid sinus would fire nerve impulses at a more or less constant rate, subject to accelerations generally much less than one-g. The extent to which the sensitivity of the baroreceptors may decrease with prolonged space travel, and their ability to regain the lost sensitivity, is unknown. Given the possibly disastrous consequences of loss of baroreceptor sensitivity, 

HUMAN BIOLOGY AND SPACE MEDICINE 99 which may have played a role in the syncope and prolonged incapacitation of the Russian astronauts following return from their 211-day mission, it is prudent to investigate the relationship between the duration of microgravity exposure and the magnitude and duration of the loss of baroreceptor sensitivity. Although we might expect Shuttle missions and earth-based modeling to help, in 1995 we will still need to understand more completely the actions of drugs that affect cardiopulmonary and renal systems in space. This will be essential for adequate health maintenance. Ordered in descending priority, the following classes of agents must be investigated: antiarrhythmics, bronchodilators, antiallergy / antianaphylactic drugs, analgesics (including narcotics), hypnotics / psychotropics, diuretics, and anticoagulants. Pulmonary Function Currently, there is little information on pulmonary function during spaceflight. However, it is possible that lengthy alterations in the relative flow distribution of blood and air in different lung regions might permanently affect right heart function. Dysbarism, the condition that results from exposure to decreased or changing barometric pressure, is a problem of increasing magnitude in the Shuttle period, but threatens to be of even greater importance during in-orbit, manned construction and repair of space stations and vehicles. It is likely that by 1995 we shall still require further, possibly urgent research into dysbarism. This is a problem involving several disciplines, but certainly appropriate to the pulmonary system. Renal Function The kidney is central to the above-mentioned physiologic questions. Renal problems may occur in the space environment. As discussed earlier, weightlessness causes a monthly 0.4 percent resorption of bone calcium, which is excreted in the urine. With increased concentration of urinary calcium and some other changes induced by weightlessness (such as urine alkalinity and possible reduction in urine volume), kidney stones may form more easily. In addition to debilitating pain, kidney stones might obstruct the urinary tract and precipitate infection—potentially quite dangerous. Thus, kidney function must be understood better with regard 

HUMAN BIOLOGY AND SPACE MEDICINE 100 to calcium metabolism as well as its relation to cardiovascular phenomena. Conclusions and Recommendation Cardiovascular mechanisms may be interlinked with problems in higher- priority systems: fluid volume shifts may be pivotal in the development of neurovestibular derangements, thus magnifying even further the need to fully investigate the circulatory deconditioning phenomenon and its physiology. In the next 10 years we will learn more about cardiovascular, pulmonary, and renal physiology in the microgravity environment. This will come about through ground-based as well as a limited number of inflight experiments. However, the new knowledge will not be sufficient to resolve most issues surrounding short- term exposure. In 1995, it is likely that virtually nothing will be known about the cardiopulmonary and renal effects of long-term spaceflight, particularly the potential for irreversible changes or adaptations. Thus, it is mandatory to incorporate cardiopulmonary-renal research into the general plan of research for 1995 to 2015, with special reference to long-term, incremental exposure. Methodology and instrumentation for measuring and imaging are expected to be more sophisticated by 1995. We shall continue to make significant strides in several areas including the following: (1) reliability, flexibility, and precision of instruments and methods, (2) miniaturization of instruments, (3) new and more powerful noninvasive imaging, and (4) ability to accumulate and process data on-line, on-board. The task group suggests several priorities for investigating cardiovascular, pulmonary, and renal systems: 1. We must understand more about exercise: What preflight conditioning or screening programs are really best? What is most effective for preventing and treating deconditioning? What is the optimum postflight reconditioning profile for resuming normal cardiopulmonary health and activity in one-g? What is the role of salt and water loading immediately before reentry, or the use of sodium-retentive drugs or other agents as countermeasures? What, in general, should we plan for the Earth rehabilitation of long-term space travelers? 

HUMAN BIOLOGY AND SPACE MEDICINE 101 2. We must validate to a much greater degree our ground-based models of weightlessness, determine their boundaries and validity, and examine their appropriateness with regard to duration of microgravity exposure. 3. We must characterize drug actions and metabolism in microgravity. The aforementioned list of agents must be fully studied to ensure their safe and effective use in space. 4. We must be prepared to conduct long-term experiments as soon as possible to study the possibility of extended or irreversible changes in cardiopulmonary systems. This will necessarily involve observation of animal subjects exposed to weightlessness under completely controlled conditions. It is important to emphasize that the above investigations will involve, in a crucial sense, the use of animal subjects in space. Such experiments cannot be done without a well-designed, smoothly functioning, and safe animal laboratory; the importance of this concept cannot be overestimated. INTEGRATED FUNCTIONS Introduction Every aspect of human physiology may be affected by space-flight or extraterrestrial habitation. The preceding four sections of this chapter have addressed systems that have already demonstrated the need for research. In this section, the task group considers nutrition and the immune system. Although every system or process must ultimately be viewed in the context of the entire person, the task group emphasizes the systemic importance of nutrition and immunology. Nutrition Background Prior to the start of the spaceflight program, there was speculation that the decreased effort of movement in weightlessness would result in a diminished caloric requirement compared to that on Earth. Diets were actually planned, however, at caloric levels close to those needed for normal activity on Earth. In practice this procedure has worked reasonably well. In the 1-to 3-month 

HUMAN BIOLOGY AND SPACE MEDICINE 102 flights of Skylab, modest degrees of body weight loss occurred, associated with body fluid shifts and losses in muscle mass, as astronauts consumed 2400 to 2800 calories per day. There was clearly no lessening of caloric requirements in space. In the past, many athletes and astronauts have been convinced that high protein intake builds muscle and strength. However, the physiological evidence indicates that protein is increased in muscle only when needed for the muscle hypertrophy required by continuing physical activity; excess calories of any kind are converted to and stored in the body as fat. In addition, numerous previous studies unrelated to space have indicated that increasing the protein intake increases the urinary excretion of calcium. The level of protein in the diets of astronauts, therefore, needs to be reconsidered for its possible relationship to the potential for urinary tract stone formation and possibly to the rate of loss of minerals from the skeleton. Some degree of uncertainty exists as to whether the high phosphate content of meat is partially protective against the effect of high protein intake to increase urinary calcium. At the same time, there must be concern not to accentuate the negative nitrogen balance associated with muscle atrophy in weightlessness by encouraging too low a protein intake. Since negative nitrogen balance in space has occurred at daily protein intakes of 85 to 95 g, the recommended intake should not fall below this level. Carbohydrates should be of special concern because of their effects on behavior. Abundant evidence supports the view that any dietary carbohydrate that elicits the secretion of insulin can, unless consumed with adequate amounts of protein, increase the synthesis and release of the brain neurotransmitter serotonin. This substance makes people drowsy and interferes with optimal performance. If this relationship is not recognized, menus and the time of consumption of particular items—specially snacks—might not be appropriate to the tasks required, particularly if they are complex and prolonged. It is possible that other food constituents will also be found that affect behavior, mood, and cognition. As carbohydrates are the likely products of future chemical synthetic systems, it is important to determine the type and maximum amount of carbohydrate that should be reasonably contained in a human diet. The current (1980) Recommended Dietary Allowances (RDAs) of the National Research Council's Food and Nutrition Board list 

HUMAN BIOLOGY AND SPACE MEDICINE 103 800 mg as the appropriate amount of calcium to be taken daily with the principal purpose of "protecting" the skeleton. A much higher level is currently under consideration by the committee working on the next edition of the RDAs. In anticipation of approval by the Food and Nutrition Board, 1000 mg is a reasonable base figure for calcium in diet formulation for spaceflight. Among the countermeasures tested by NASA have been high calcium and high phosphorus intake in both bed rest subjects and Skylab astronauts. The study showed that this procedure maintained calcium intake and excretion level in balance for up to 3 months, following which the gradually rising fecal excretion of calcium caused a negative calcium balance. Hence, there is no basis at this time for recommending a higher intake level than 1000 mg/day. Bed rest studies of the effects of high phosphorus intake showed some suppression of the tendency of urinary calcium to elevate, but overall phosphorus intake manipulation was ineffective because of gradually increasing fecal calcium excretion. Furthermore, the possible deleterious effect of a phosphorus intake higher than that in an approximate calcium to phosphorus ratio of 1:1.8 must be remembered. Too high an intake of phosphorus will exert some binding effect on calcium in the intestine and tend to inhibit calcium absorption. The current RDA level for magnesium is 350 mg/day for adult males. While studies of this element in relation to bone are far less numerous than studies of calcium, research to date indicates that deleterious effects apparently do not occur except possibly with low intake—as in an artificial diet—over a very long time. Since no studies have yet been made on the effects of space-flight on the metabolism of any of the trace elements, no comment can be made other than that care should be taken that space diets contain trace elements in the amounts recommended in the RDAs. The important vitamin in long spaceflights is vitamin D, the "sunshine vitamin." Enclosure in a space vehicle will prevent the normal conversion in the skin of the vitamin D precursor to vitamin D. This is normally accomplished by exposure of the face and arms to as little as 20 to 30 minutes of sunlight a day. Since vitamin D is essential for facilitating calcium absorption from the intestine, as well as other calcium-related effects in kidney and bone, this vitamin will need to be supplied to space travelers. 

HUMAN BIOLOGY AND SPACE MEDICINE 104 However, amounts should not exceed about 800 to 1000 I.U. per day. Other vitamins are not so critical since it is expected that adequate amounts will be taken in the diet, provided it is "balanced" and the vitamins are not degraded by the methods of food preservation in use. It has become customary, however, to provide astronauts with daily vitamin supplements. The absence of natural light in spacecraft may have significant effects other than that on vitamin D synthesis. For most of man's evolutionary history he spent his days out-of-doors, exposed to 1000 to 8000 foot-candles of light provided by the Sun's rays (filtered through the ozone layer), including a small but important amount of mid-and near-ultraviolet light, and approximately equal portions of the various colors of visible light. Indoor lighting in most offices and, so far, in all spacecraft is of a much lower intensity (usually 60 to 100 foot-candles), and, if emitted by fluorescent "daylight" or "cool-white" bulbs, is deficient in ultraviolet light (and the blues and reds) and excessive in the light colors (yellow-green) that are best perceived as brightness by the retina. If light's only effect on humans was to generate subjective brightness, then this artificial light spectrum might be adequate. It has become abundantly clear, however, that light has numerous additional physiological and behavioral effects, and that the "action spectra" of these effects (i.e., the extent to which they are activated by different wavelengths) differ from the brightness spectrum. For example, light exerts direct effects on chemicals near the surface of the body, photoactivating vitamin D precursors (as noted above) and destroying circulating bilirubin and probably other photoabsorbent compounds. It also exerts indirect effects via the eye and brain on neuroendocrine functions, circadian rhythms, secretion frcm the pineal organ, and, most clearly, on mood. Many people exhibit major swings in mood seasonally, veering toward depression in the fall and winter when the hours of daylight grow short. Some cross into acknowledged depression, now known as the "seasonal affective disorder syndrome," a disease that may be related to excessive secretion of the pineal hormone, melatonin, and which also may be treatable with several hours per day of supplemental light. While not yet proved, it seems highly likely that prolonged exposure to inadequate lighting—that is, the wrong spectrum, or too low an intensity, or too few hours per day of light—may adversely affect mood and performance. Available information, 

HUMAN BIOLOGY AND SPACE MEDICINE 105 though not fully satisfactory, suggests that the lighting environment now provided in spacecraft may indeed be inadequate. The adequacy of lighting should be part of the planning for long-term spaceflights, and all physiological, biochemical, and behavioral effects of light should be studied extensively. In the early days of planning for manned spaceflight, many thought that diets should be low-residue in character so that bowel movements would be small and infrequent. It was observed especially in longer flights that bowel function in microgravity is essentially normal. Hence diets should be normal in residue, and adequate bulk should be available to afford relatively easy passage of stools once or twice a day. Proposed Research In spaceflights extending from many months to years, the acceptability of various currently available packaged, canned, freeze-dried, or heat-stable food items should be evaluated. As the capacity to carry and store frozen food items is likely to be limited in extremely long flights, space food technology research should be revived in planning for the Space Station era. To date, nutrition investigations (unrelated to space) suggest that individuals do not crave continual variety in foods but rather tend to select foods in the same small range or limited number over months, stretching out to a lifetime. Reduction in the total list of available food items should also simplify both the strategy of storage of multiple food packages in a long-flying spacecraft and the ability of travelers to pull out desired items with a minimum of difficulty and time. The Space Station will need to provide the function of testing the long-term durability and acceptability of both currently available and newly formulated items. There will also be a need to check out current calculations that there will be adequate and satisfactory food storage on long-flight vehicles for 3 years' flight duration. These studies should provide guidelines for the CELSS program. In turn, much of the research in nutrition should be guided by realistic projections of the characteristics and quantities of food to be produced by CELSS. 

HUMAN BIOLOGY AND SPACE MEDICINE 106 Immune System Background Although the reports to date are conflicting, some indicate that a microgravity environment may compromise the immune system's function. Studies on cell-mediated immunity of 21 crew members on Apollo missions showed that 7 did not reveal any consistent changes. In contrast, Cogoli et al. reported that cultures of human lymphocytes subjected to microgravity responded to concanavalin A, a lymphocyte stimulating agent, 97 percent less than ground-based controls. This is a standard test used to evaluate the competence of peripheral blood lymphocytes to multiply when stimulated with this agent. Studies on the astronauts of the first four STS flights revealed that the lymphocyte responses to photohemagglutinin, another lymphocyte stimulating agent, were reduced from 18 to 61 percent of normal following spaceflight. It has been suggested that the above changes were due to stress- related effects, but this has not been established and should be studied further. In an unmanned Russian spaceflight, it was reported that rats flown for 22 days had marked reduction in the weights of lymph nodes and spleens compared to controls on Earth, due to a marked decrease of lymphocytes in these organs. The effects were found to be reversible since the organs returned to normal by 27 days postflight. In another study, Mandel and Balish studied rats subjected to a 20-day flight aboard the unmanned U.S.S.R.-Cosmos 7820. They immunized groups of rats with formalin-killed Listeria monocytogenes 5 days before flight, and compared animals exposed to space conditions with one- g controls. They concluded that no deterioration of the acquisition cell-mediated immunity to L. monocytogenes could be detected in flown rats. In one study, mouse or human lymphocytes subjected to 2-g and 4-g, respectively, exhibited enhanced responses to concanavalin A compared to parallel cultures at one-g. In other investigations, hypergravity had little or no effect on the humoral response. On the other hand, graft survival time was increased in rats subjected to 2.5-g for 4 days preoperatively and 3-g post- operatively. These findings indicate that cell-mediated immunity against tissue grafts may be compromised in hypogravity. These 

HUMAN BIOLOGY AND SPACE MEDICINE 107 studies also emphasize the need for one-g inflight controls of immune system investigations. In view of the present uncertain status of the effect of hypogravity and hypergravity on immune function, the task group recommends that the basic components and function of the immunologic system be studied systematically at enhanced and diminished gravity. These studies assume added importance because, as discussed earlier, the concentrations of microorganisms in space vehicles may be significantly higher than normal. Proposed Research Specific questions to be answered by studies in microgravity include the following: 1. What are the effects of microgravity on the lymphoid organs— nodes, spleen, thymus, and bone marrow? 2. Is the response to antigen priming altered? 3. Is the response to antigen-induced secondary response altered? 4. What are the induced lymphocytic subsets? 5. What is the receptor density on macrophages including C3b, Fc, and Ia under conditions that activate macrophages? 6. Is the formation of the allergic granuloma and delayed hypersensitivity response using BCG strain of Mycobacterium tuberculosis altered? 7. What are the serum Ig and complement concentrations? 8. What are the interferon and interleukin 2 concentrations? Although there is need to answer these questions for the human system, some experiments must be done on small mammals. The conditions associated with space travel, space stations, and planetary colonies raise many new and important problems concerned with host-parasite interactions involving man and animals. Rotation of crew members on the Space Station will introduce different strains of fungi, bacteria, and viruses that could contribute to the emergence of ''new'' strains of opportunistic pathogens through mutation and genetic exchange. Investigations should also consider the dynamics of aerosol generation and microbial survival under weightless conditions. As discussed in Chapter 8, special equipment for these studies includes: an image 

HUMAN BIOLOGY AND SPACE MEDICINE 108 transmission microscope, a laser cytofluorograph, an immunoelectrophoresis device, and a small 20,000-g centrifuge. Other Systems At this time it is not possible to certify any physiological system to be unaffected by several years at microgravity or to preclude any as a fruitful area of research. Preliminary results indicate reduced hematocrit in some astronauts, but this may be a physiological readjustment that is appropriate. Whether hematopoesis or maturation of lymphocytes is compromised is yet to be established. The multiple stresses of spaceflight may lead to hormonal imbalances. Corticosteroid release may lead to immunosuppression. Oogenesis and spermatogenesis may be compromised. In any case, additional research is required to confirm or reject the presence of problems. At present, we cannot assume that as spaceflight increases from months to years unanticipated malfunctions will not appear. We must continue to establish a reliable data base so that we can recognize and research these new phenomena before proceeding to longer flights. To accomplish this, we must continue to employ the approach of incremental exposure of humans to microgravity with careful surveillance during and after exposure. RADIATION EFFECTS Introduction The importance of the radiation factor has been underscored by several committees of the National Research Council and other NASA-sponsored committees. The evolving interest in prolonged manned space travel beyond the Earth's protective magnetic field brings to the forefront uncertainties in the physical behavior and biological effects of the so-called "free space" radiation environment. It is generally agreed that these uncertainties must be resolved before we embark on the construction of a lunar base, the manned habitation of space platforms, manned flight to Mars, or lunar or martian habitation. 

HUMAN BIOLOGY AND SPACE MEDICINE 109 Background Space Radiation Environment There are basically three sources of naturally occurring space radiation that can be hazardous to manned spaceflight: the geomagnetically trapped proton and electron environment (Van Allen belts), galactic cosmic radiation (GCR), and solar particulate radiation. The Van Allen belts consist of high-energy protons (approximately 1 keV to several hundred MeV) and electrons (approximately 1 keV to several Me V) trapped in the geomagnetic field. The proton belt extends to an altitude of approximately 20,000 km, with peak intensities occurring at approximately 5,000 km. The electron belts extend to an altitude of 30,000 km, with peaks at about 3,000 and 15,000 km. Models of the trapped proton and electron environments have been developed from satellite measurements. Galactic cosmic radiation (GCR) consists of extremely energetic (up to 1013 MeV) ionized nuclei ranging from hydrogen to uranium and originating outside the solar system (so-called HZE particles). Models of the GCR environment have been generated from geostationary satellite and high-altitude balloon measurements. Current knowledge of the GCR hazard, however, is inadequate because of the poor understanding of the effects of HZE particles on biological tissue. Solar particulate radiation (solar particle events) consists of high-energy particles (predominately protons) ejected from the Sun, usually during solar flares. Solar activity has an 11-year cycle, during which a tenfold variation in the frequency of particle events has been observed. No reliable physical model can predict the timing or magnitude of solar particle event (SPE) occurrence with acceptable accuracy. This feature makes SPEs a significant hazard in long- duration space travel. Additionally, solar flare activity can substantially increase the fluence of HZE particles, at least up to energies of a few hundred MeV per nucleon. The high-altitude IMP 8 satellite, for example, observed 28 solar flares during solar cycle 21 in which the flux of heavy ions was substantial. At 100 Me V/nucleon the fluxes of carbon and oxygen ions were approximately 10 times the ambiance of the GCR flux. Occasionally flares are observed to be iron rich, and a flare in 1977 

HUMAN BIOLOGY AND SPACE MEDICINE 110 produced a fluence of 200 MeV/nucleon iron ions 10 to 20 times the GCR fluence. As will be mentioned presently, the absorbed dose in biological tissue in these events is not negligible, and the effects on spacecraft electronics could be significant. Radiation exposure in low earth orbit (LEO), where Shuttle orbits lie and the Space Station orbit will lie, is primarily from the proton and electron belts and GCR. Trapped-radiation exposure increases with altitude and varies with orbital inclination. GCR exposure varies with orbital inclination: from approximately 5 mrad / day at 28° to approximately 20 mrad / day for polar orbit during solar minimum, and approximately 3 mrad / day at 28° to approximately 15 mrad / day for polar orbit during solar maximum. The geomagnetic field provides some degree of protection from solar particle events, depending on the orbital inclination; flux is almost totally eliminated for a 28° orbit and reduced to about 30 percent of the free space flux for polar orbit. Exposure at geosynchronous (GEO) altitude will be primarily from bremsstrahlung (x rays) created by the trapped electrons as they interact with spacecraft shielding. The electron environment at GEO has a diurnal fluctuation, and intensities can increase by several orders of magnitude with magnetic storm activity. GEO is susceptible to the full exposures from GCR and solar particle events, as are lunar and interplanetary missions. Spacecraft Radiation Environment Incoming radiation from space is modified as it passes through the body of a spacecraft and any additional shielding that may be present. The biological effects of radiation must be determined, therefore, by starting with this modified spectrum. The physical principles by which radiation interacts with matter are well known, but the way to combine these principles to form a good model of the resulting secondary spectrum is not. Models for the magnitude of the trapped radiation in certain energy ranges have uncertainties ranging from a factor of 2 for the inner belt to a factor of 10 or more for the outer belt. In addition, the trapped radiation models were developed in the early 1970s and are in need of refinement. Nuclear fragmentation cross sections for heavy ion constituents of the GCR are, in some cases, completely unknown. A substantial amount of data obtained from various forms of dosimetry onboard Apollo, Skylab, and STS missions has provided measurements of 

HUMAN BIOLOGY AND SPACE MEDICINE 111 radiation exposures, but these data cannot be extrapolated to free space. Nevertheless, with available models and limited spacecraft data, the daily exposure for various mission configurations has been estimated. For the Space Station, the dose to the blood-forming organs (BFO) has been estimated to be approximately 100 mrad / day, of which approximately 90 percent will be from trapped protons. During as SPE, the absorbed dose would be mainly from high- energy protons. The SPE of August 1972 would have produced approximately 150 rad to the BFO for a mission in free space assuming reasonable shielding, such as that provided by the STS orbiter. (The exposure would have been uniformly lethal without shielding.) High charge and energy ions (HZE) from the GCR contribute about 30 mrad/day in free space, independent of the amount of shielding. Indeed, the inability to shield effectively against the GCR in free space will be a persistent problem for long-duration missions to planets, for platform habitation, and at a lunar or martian colony. As stated previously, solar flare activity can result in heavy ion fluences at a few hundred MeV per nucleon that are up to 10 times higher than the background GCR flux. This fluence may result in a 24-h exposure of up to 300 mR of high linear energy transfer (LET) radiation. Depending on the relative biological effect of these ions, the dose could be significant. Biological Effects The biological effects of ionizing radiation have been extensively studied for almost a century. The data come from studies of controlled irradiation of cell cultures, small and large animals, and nonhuman primates, as well as from retrospective studies of humans exposed to nuclear weapons blasts, radiation used for medical treatment, and nuclear occupational hazards. Most of the information has been obtained with so-called low-LET radiation such as x, gamma, and electron radiation. Low-LET radiation is sparsely ionizing—it is characterized by separated clusters of ionizations along the path of the primary photon or electron. In contrast, high-LET radiation, such as stopping protons, secondary stopping protons from neutrons, alpha particles, and energetic heavy multicharged particles, is densely ionizing. It has been known for decades that a given amount of energy deposited by high-LET radiation could be several times more damaging than the same amount of energy deposited by low-LET 

HUMAN BIOLOGY AND SPACE MEDICINE 112 radiation. Because of the higher relative biological effectiveness (RBE) of high- LET radiation, a quality factor (Q) is applied to occupational doses (in physical units) to obtain a weighted unit for assessment of radiological health risk (dose equivalent). For example, the Q for neutrons from a nuclear reactor would be about 10. The International Commission on Radiation Protection (ICRP) has a long-pending recommendation that calls for a Q ranging from 1 to 20 depending on the LET of the particle. In recent years, however, evidence is mounting that under certain practical circumstances, RBEs can be 40 to 100. These circumstances include neutron radiation, low doses at low dose rates; and certain biological endpoints, such as effects related to cancer induction (chromosomal abnormalities and rearrangements). This recent information has led to a ferment in the radiological health community, and Q values higher than 20 are currently being proposed. More generally, the assumed linear relationship between absorbed dose and observed biological effect has come into question for HZE particles or high-LET particles in general. Since the manner in which energy is deposited in tissue by HZE particles is so different from that of low-LET particles, this linearity may not apply to HZE particles. Individual physical circumstances in the way in which these particles interact with various biological tissues must be considered, rather than including all such interactions in a single ratio called "relative biological effect." This opinion has been expressed both by the National Council on Radiation Protection and Measurements and by prominent high-energy particle research groups. Of current interest has been the "microlesion" concept. This theoretical model of the interaction of heavy particles with biological tissue has raised the question of a whole new spectrum of biological damage, including damage to nondividing cells, particularly the central nervous systems. It appears that the microlesion concept is worthy of further investigation, as there may be significant consequences in long-duration spaceflight (> 3 years) if an accidental underestimation of the effect of HZE particles is made. The assessment of the radiological health risks for various future missions (Space Station, polar orbit, GEO sorties, lunar base, and Mars missions) and thus the operational limits for such missions are dependent on Q, which in turn will be greatly dependent on the evaluation of RBE using relevant biological criteria (life 

HUMAN BIOLOGY AND SPACE MEDICINE 113 shortening, tumor induction, chromosome abnormalities, mutation, teratogenesis, and so on). The data base using space-type radiation for such assessments is disturbingly small. Estimates of carcinogenic risk have been made by the National Institutes of Health Ad Hoc Working Group to Develop Radioepidemiological Tables. These risk values have been expanded upon for use in the report of Scientific Committee 75 of the National Council on Radiation Protection and Measurements (NCRP) entitled Guidance on Radiation Received in Space Activities. Table 6.2 (extracted from the NCRP report) shows the best currently available estimates for the effects of 1 sievert (Sv)* of radiation spread over 10 years. Although the values are presented to three significant figures, it should be emphasized that there are large uncertainties. As further statistics on the Hiroshima-Nagasaki survivors become available, these values are expected to change somewhat. NASA must continue to monitor developments in such radioepidemiological efforts. Nonetheless, these radiogenic cancer risk estimates given in Table 6.2 have served in part as the basis for the new set of astronaut radiation exposure limits being recommended to NASA by NCRP. These new limits are shown in Table 6.3. The limit of greatest importance for future space activities is the career dose-equivalent for the BFO. For example, the BFO career dose-equivalent limit for a 30-year-old male or a 38-year-old female is 2 Sv. In practice, it will be unlikely that any astronaut will receive 1 Sv over a career (barring exposure to an unanticipated dose from a large and unexpected solar particle event). However, the 1 Sv value will be approached during a 2-to 3-year Mars mission, given currently used quality factors. If the Q for GCR heavy ions increased, the 1-Sv level may very likely be exceeded. The career limits are not expected to be raised, because the risk estimates are based on radioepidemiological data from humans exposed to low-LET radiation for which the Q is unity. In other words, the report of Scientific Committee 75 of the NCRP entitled Guidance on Radiation Received in Space Activities did not give any consideration to the effect of HZE particles. As we move into the future toward lunar colonization and long-term * A sievert (Sv) is the SI unit for dose-equivalent, which is the physical dose in Gray (Gy: 1 joule/kilogram) multiplied by a quality factor (Q) to account for the increased biological effectiveness of some radiations. The Sv is equivalent to 100 rem; the Gy is equivalent to 100 rad. 

HUMAN BIOLOGY AND SPACE MEDICINE 114 TABLE 6.2 Cancer Morbidity and Mortality by Age Group and Sex, With and Without Radiation Sex Age Lifetime Additional Lifetime Additional Incidence (%) Incidence Mortality (%) Mortality Unirradiated (%) from 1 Unirradiated (%) from 1 Sva Sva Male 25 34.9 3.10 18.5 1.99 35 35.2 1.84 18.7 1.20 45 35.5 1.38 18.9 0.92 55 35.4 1.12 18.7 0.75 Female 25 35.6 6.24 15.7 2.93 35 35.2 3.50 15.5 1.70 45 33.9 2.22 15.1 1.19 55 30.8 1.73 13.9 0.99 a1 Sv at 0.1 Sv/year for 10 years starting at indicated age (1 Sv = 100 rem). TABLE 6.3 Astronaut Ionizing Radiation Exposure Limitsa Depth (5 cm), cSvb Eye (0.3 cm), cSvb Skin (0.01 cm), cSvb 30 Days 25 100 150 Annual 50 200 300 Career 100–400c 400 600 aThese dose-equivalent limits are being recommended to NASA by NCRP Scientific Committee 75 on Guidance on Radiation Received in Space Activities. bcSv = centisievert, which is based on the SI unit of dose equivalent, the sievert (Sv); 1 Sv = 100 rem; 1 cSv = 1 rem. cThe career depth dose equivalent is based upon a maximum-3 percent lifetime risk of cancer mortality. The total dose equivalent yielding this risk depends on sex and on age at the start of exposure. The career dose equivalent limit is approximately equal to 200 + 7.5 (age 30) cSv, for males, up to 400 cSv maximum; and 200-7.5 (age 38) cSv, for females, up to 400 cSv maximum. interplanetary travel, which might involve entire lifetimes or perhaps even generations of lifetimes in space, entirely new standards will have to be devised to account for this dominating source of radiation. The possibilities of modifying the biological damage by radiation deserve further attention. Recent evidence obtained by 

HUMAN BIOLOGY AND SPACE MEDICINE 115 the cancer research community indicates that the multiphase process of carcinogenesis can be interrupted at various stages. For example, at the DNA damage or initiation phase, free radical scavengers, such as vitamin E and possibly vitamins A and C, can protect. Some data indicate that the promotion phase, in which a radiation-damaged cell changes to a potentially cancerous cell cluster and then goes on to the progression phase yielding a tumor, can be interrupted by agents such as dimethylsulfoxide (DMSO) or protease inhibitors. Implementation of the results of studies directed toward early detection of cancer could help improve the prognosis for crew members unfortunate enough to contract cancer. Before a commitment to a lunar or martian colony is made, mutagenesis and teratogenesis by high-LET radiation must be extensively studied. Mutation and developmental abnormalities are, like cancer induction, stochastic effects: the severity of the effect is independent of dose, but the probability of occurrence increases with dose. The mutation risk to future generations from expected space radiation doses is apparently fairly low, but the available information is woefully inadequate for assessing the teratogenic risks to fetuses. Although most space radiation doses will be low and received at low dose rates, a very large solar particle event can expose astronauts in polar orbit, in GEO, or in free space to high-dose and high-dose-rate radiation, which can produce clinically significant effects. These effects are nonstochastic: the severity of the effect increases with dose above some effective threshold. The acute radiation syndrome (ARS) at sublethal doses is characterized early on by transient anorexia, nausea, vomiting, and diarrhea. Later, the survivors may suffer temporary or permanent sterility and cataracts, as well as cancer. Lethal doses lead to bone marrow suppression and immune system compromise, which leads to hematopoietic death in 30 to 60 days. These high doses lead to severe gastrointestinal disturbances in 1 day to 1 week. Extreme doses can produce central nervous system derangement in a matter of hours. The ARS has been studied extensively over the past four decades and continues to be studied in animal models by, for example, the Armed Forces Radiobiology Research Institute (AFRRI). The human clinical experience, however, has been extremely limited. It is important to stress that the treatment of ARS has 

HUMAN BIOLOGY AND SPACE MEDICINE 116 been largely supportive. This limitation implies the need for a "critical case" of an astronaut exposed to potentially lethal doses of radiation in a solar flare or onboard nuclear containment accident. Onboard provisions for such management must be based on the philosophical decision to treat severe illness in space travel—a decision that has not yet materialized in the U.S. space program. In the prevention of high-dose acute radiation exposure, special shielding is the most commonly considered modality. In situations where it is not possible to deorbit or lower the altitude to a protected region of space, a storm shelter with adequate shielding must be provided. For example, a water-filled collapsible cocoon has been proposed. For added protection in case a very large solar event occurs, partial body shielding of a small amount of bone marrow stem cells can be very effective in raising the lethal threshold: for example, in one study monkeys that had 1 percent of their stem cells protected survived a dose that killed all unshielded animals. In the future, ex vivo cell storage techniques may allow a bank of shielded autologous bone marrow to accompany astronauts on a long-duration mission. Proposed Research As we embark on an era of the U.S. space program in which lunar colonies and manned Mars missions are being seriously discussed, we are largely unaware of the possibly serious consequences of both long-term exposure to the free space GCR and short-term exposure to an SPE. The task group recommends the following major research, beginning now and continuing in the years 1995 to 2015: 1. The biological dosimetry of high-LET radiation should be developed and formalized to allow for studies of comparative risks. 2. Shielding models applicable to the GCR spectrum should be further developed. Emphasis should be given to realistic shielding materials and thickness suitable for manned spacecraft. 3. A free space satellite carrying GCR detectors should be sent with the intent of fully characterizing the spectrum behind a realistic shield in free space. 4. Terrestrial studies of the biological effects of low-level, high-LET irradiation on cell cultures and animals (using particle accelerators) should be expanded, with particular attention paid to the space radiation problem. 

HUMAN BIOLOGY AND SPACE MEDICINE 117 5. Characterization and prediction of solar particle events should continue, with an awareness by solar physicists and astronomers of the biological relevance to the future of the U.S. space program. In particular, the directionality of particles in low-altitude polar orbits needs characterization in order to optimize the use of available spacecraft mass for shielding. 6. Methods for the critical care of acute radiation injury should be addressed, with a focus on manned space mission application. In the spacecraft setting, additional innovations are possible, such as carrying onboard shielded, frozen, autologous bone marrow or partial body shielding of blood stem-cell-rich body regions. 7. Studies of drug interventions should proceed. BEHAVIOR AND PERFORMANCE Introduction Nearly all essential human functions during long-term space missions will depend critically upon individual and group behavior. To date, selection, training, and organizational functions have been the focus of human behavioral initiatives. A program of fundamental scientific research treating behavior interactions is as essential to ensure the success of long-duration human operations in space as are the physical science and engineering investments that make such initiatives possible. Before the long-term occupancy of space environments can be safely and productively assured, we must address the historical problems of individual behavioral adjustment, interpersonal conflict, and group performance effectiveness. That such obstacles are typically exacerbated in isolated and confined microsocieties has been repeatedly documented in operational settings such as remote stations in the Antarctic, undersea habitats, and most pertinently, in spacecraft. To some extent, these earth-based experiences provide relevant data to questions regarding human behavior and performance in space. However, the fact that observations are made and observed by people who actually share the experience limits the reliability of data. The conditions that will exist in long-duration space missions increase the potential for adverse effects already reported during relatively short-term missions (e.g., 

HUMAN BIOLOGY AND SPACE MEDICINE 118 irritability, depression, sleep disturbances, and poor performance of both group and individual). It is essential that we develop the scientific foundation for the provision of adequate individual, social, and organizational environments. Long-term space travel will require establishing and maintaining effective, stable interactions between individuals in small groups that are under microgravity conditions and are isolated and confined for prolonged periods. However, the research data base pertaining to these conditions is extremely limited. Behavioral and social problems are regarded among those who have been involved in extended space missions to date as formidable obstacles to long-term voyages. Even more important from a life science perspective, it seems likely that entirely new principles of human interaction and group dynamics will emerge as a result of such research to ensure effective human behavior in space environments. Background The current status of knowledge in the field of human behavior has provided for substantial progress toward the goal of extended space occupancy. Careful attention to selection, training, and organizational functions has permitted small groups of individuals to live and work effectively in space for continuous periods of several months. But there are enormous gaps in our understanding of how the multiple, complex behavioral factors operate independently to influence the behavior of individuals and groups. While these deficiencies are generally recognized, it seems unlikely that substantial progress in this important field will be under way, much less achieved, by 1995. Deficiencies in understanding the dynamics of the performance and psychosocial health of groups, and especially the integrative factors that ensure the effective function of the system, will be particularly evident. Proposed Research Overview A description of the research required in the realm of human behavior encompasses a range of experimental questions related 

HUMAN BIOLOGY AND SPACE MEDICINE 119 to the establishment, maintenance, and enhancement of human productivity under progressively autonomous conditions. Many construction and observation tasks will be done under extremes of pressure, temperature, and radiation hostile to the human body. Human judgment and ingenuity are often indispensible to the completion of some of these jobs. This will demand optimal interactions between humans, machines, and computers. This should not be seen as a choice between man and robot, but as a challenge to integrate judiciously their respective capabilities. Specifically, the primary research objectives of the human behavior studies the task group recommends are: 1. To analyze the environmental factors and associated task requirements that determine completion of mission objectives and enhancement of creative accomplishment. 2. To understand the individual factors and the interactive physiological / behavior processes. 3. To characterize the group factors that influence maintenance of performance effectiveness and enhancement of behavioral competence in space environments. 4. To determine the integrative factors that ensure the most effective systems management of essential environmental, individual, and group requirements in space. 5. To evaluate the design of robots with a goal of optimizing human performance in unique conditions. Environmental Factors If long-term space missions are to become a reality, automation, robotics, artificial intelligence, and other advanced computer technologies will increasingly dominate both the physical and the behavior features of space environments. This will necessitate empirical determinations of optimal ''mixes'' between human control and control by computerized management systems over the entire range of life support, work task, and general performance functions. The development of an experimental base to ensure effective workplace designs under confined, microgravity conditions and to provide for creative integration of living accommodations should be the first step in this program of research. 

HUMAN BIOLOGY AND SPACE MEDICINE 120 Individual Factors Perhaps the most important research priority in considering the impact of individual factors upon personal adjustment to occupancy of space environments is the screening and selection of prospective participants. For the most part, screening efforts have emphasized identification and elimination of potentially disruptive individuals and selection of those individuals evidencing the highest proficiency. The dilemma of choice between achievement and interpersonal harmony is likely to become particularly prominent in the isolated and confined microsociety of the space environment. Of primary concern must be the development of more valid and reliable methods for observing and recording the effect of space stresses upon complex performance processes. The scientific literature has documented the effectiveness of trained participant observers. A closely related area of research focuses upon the development and refinement of behavioral procedures for physiological self-regulation (e.g., biofeedback techniques). Important questions surround the general health performance effects of shifting circadian periodicities and extended exposure to drastically modified sensory environments. A host of specific research questions have been raised documenting the intimate relationship between biological rhythms and behavioral interactions. A rapidly emerging behavioral pharmacology data base suggests that highly specific drug performance interactions hold promise for the facilitation and stabilization of behavior under a broad range of environmental conditions. A determination of the extent to which pharmacological interventions can be of benefit in the management of such space-related adaptational problems requires experimental analysis. Sensorimotor and perceptual functions of long-term isolation and confinement also require concentrated investigation. Training and testing procedures with advanced subhuman primates have been documented. They suggest that one of the more fruitful applications of an animal experimental flight program would be obtaining reliable behavioral measures of sensory thresholds and motor function over extended periods of up to several years. This is one of the most difficult research questions associated with the long- term effects of continuous exposure to space environments. Perhaps the area of greatest long-range scientific promise is that of an experimentally derived, functional account of individual 

HUMAN BIOLOGY AND SPACE MEDICINE 121 behavioral variability over time. Without such knowledge, a natural science of behavior cannot exist. Without a natural science of behavior, the social sciences, to which we turn for guidance in the establishment and maintenance of stable behavioral ecosystems in space, will continue to be of limited use. Also of prime importance are the motivational issues raised by the prospect of long-term space occupancy. Motivation plays a critical role in maintaining individual performances and amicable social interactions over extended intervals of isolation and confinement. It is essential that behavioral research explore the extent to which such motivational processes can be identified in the restricted environment of space travel. This investigation will require that the fundamental structure and function of the human biological and behavioral repertoire be monitored, measured, and analyzed experimentally under simulated conditions involving small groups in isolation and confinement. Group Factors Despite an extensive literature on small group structure and function, it has become clear that our understanding of in these important areas is not adequate for spaceflight program planning. There is increasing evidence that groups are, in fact, small social systems shaped by multiple determinants no one of which, considered in isolation, can necessarily account for the variations in behavioral interactions or performance effectiveness. Much remains to be learned about the partitioning of authority and autonomy among (1) group managers at the base of operations, (2) group leaders internal to the operation, and (3) individual group members. Existing research findings are unambiguous in showing that a clear, engaging set of objectives that "stretch" a group is a powerful means for orienting members toward achieving overall organizational goals. Little is known, however, about the relative effectiveness of alternative strategies for "charging" a group, or about the means of reinforcing overall direction in the course of actual performances, particularly for groups that are physically distant from the central base of operations for extended periods of time. Moreover, additional research is needed on the appropriate exercise of authority in managing the inevitable problems and disputes that occur in real time and that threaten the overall integrity of the group. 

HUMAN BIOLOGY AND SPACE MEDICINE 122 While a reasonable knowledge base exists in the areas of selection, placement, and training of individuals for solo task assignments, the data on group composition and task design are rudimentary. For collective operations, the right people, well trained and properly configured (that is, with the right mix of skills, personal characteristics, task requirements, and work setting), are essential. An important yet poorly defined area bearing upon an understanding of group performance effectiveness concerns competent leadership. A promising new approach to leadership research involves focusing on the identification of those functions that leaders perform in enhancing effectiveness and efficiency. Integrative Factors The goal of providing a scientific foundation for human behavioral transactions in space environments requires integration of the separately considered environmental, individual, and group factors within an organizational and systems management context. It is becoming clear that these problems are both interrelated and interactive. We must develop a research analysis model specifying the major integrative features of organizational management systems that foster high performance effectiveness. One of the more important integrative problems is the relationship between formal organizational structures and the emergent social structures that serve as the milieu for daily life in an isolated and confined microsociety. The accommodation of leisure time activities and the need for individual privacy are but two of the more salient integrative issues deserving research in this regard. Technology and Scientific Resource Requirements The task group recommends the development of methods and instruments for the structural and functional analysis of vocal utterances of crew members. This may be especially valuable in evaluating the moods of astronauts or as an early warning system of performance degradation and interpersonal conflict. The task group also proposes the creation of a long-term residential laboratory providing for the study of behavior under continuous environmental control. The laboratory must simulate the 

HUMAN BIOLOGY AND SPACE MEDICINE 123 anticipated requirements of future long-duration space operations by incorporating the following features or activities: 1. Environmental design: the facility must contain at least some approximation of the physical features of anticipated space vehicles, space stations, or extraterrestrial colonies. 2. Programmable control of environmental resources, such as temperature, light, food, and recreational facilities. 3. Inventory of essential behavioral activities, such as sleep and waking, eating and drinking, personal hygiene, work, recreation, and social interaction. 4. Biochemical, physiological, and behavioral monitoring of certain biological functions, such as changes in endocrine, autonomic, and skeletal processes. The task group recommends that analogue research settings, where it is possible to manipulate environmental, group, and organizational factors that bear on spaceflight success, be vigorously supported as an important source of data on human behavior science. Perhaps the closest operational analogue of space occupancy is the undersea habitat, where aquanaut divers live and work on the ocean floor with a degree of isolation similar to that in space. Under these circumstances, and in Antarctic stations and submarine operations as well, observational measurements have focused upon critical individual and group factors that influence performance effectiveness and interpersonal relations. While these analogue studies lack the control of laboratory experiments, the behavioral interactions involved have much in common with space habitation. Thus, these studies can be one of several elements in the vigorous ground-based program in human behavioral research necessary to support any manned mission of long duration. HEALTH MAINTENANCE Introduction As humans establish a permanent presence in space, whether it be on a space platform or in lunar or martian colonies, it is imperative that health care be provided to workers, scientists, and astronauts. The required facilities, procedures, and expertise will demand development of new technologies that pay special heed 

HUMAN BIOLOGY AND SPACE MEDICINE 124 to the constraints and unique stresses of space, and to the new findings anticipated in the preceding chapters. Another essential aspect of a health maintenance facility is its interrelation to other life sciences activities. Experience over the past century in the development of modern medicine has shown a strong correlation between optimal medical care and scientific investigation. This concept should be extended into extraterrestrial medicine. To do so should positively affect not only the quality of care but also the quality of life sciences research. Types of Care The types of care that a health maintenance facility must provide on a minimal basis fall into four categories: prevention, treatment of disease, treatment of injury, and rehabilitation. One of the most important components of a health maintenance program is prevention, that is, the maintenance of physical and mental health. Considerations include: physiological status monitoring, nutrition and stress management, safe waste management, hygiene, medical record keeping, environmental monitoring, exercise machinery and facilities, assurance of a suitable sleep environment, recreation and entertainment, social support aids, and communication with family and friends. We must establish physiological norms for both a space station and long-term missions. For missions of a few months' duration, the trade-off between the capability for emergency transportation back to Earth and the capability for emergency treatment in space must be studied. If emergency rescue is found to be impossible or impractical, then emergency care capability must be improved. It may be necessary to provide a physician for inflight care. Such a person could also be a trained astronaut capable of performing other duties including life sciences research. On long-duration missions, e.g., at a lunar base or on a Mars mission, the need for such personnel will increase greatly. It is imperative that these physicians have access to consultation with other medical specialists on Earth. Cross-trained individuals could provide surgical assistance, anesthesia support, and diagnostic capability, such as in the laboratory or imaging areas. The concept of a "safe haven" is imperative in planning any 

HUMAN BIOLOGY AND SPACE MEDICINE 125 health maintenance facility. Such safe havens could provide temporary protection against fire, environmental toxins, decompression, and radiation. In addition to prevention and treatment, rehabilitation should be considered so as to enhance optimal crew productivity and return to operational capability. Although space health care should ideally equal terrestrial care in quality, the cost of this care and the expected evolution of what is currently an untested endeavor must be considered. Previous studies at the Johnson Space Center have outlined a four-tiered system of health care that would be adaptable to a space station or even a lunar or Mars colony. The first system in health care can be roughly categorized as a facility that would provide simple first aid, with one or all members of the crew trained in basic care. Equipment would be minimal and would not include integration of life sciences research with the health maintenance facility. A second-tier health maintenance facility would be a dedicated area for first aid and exercise. In addition, equipment for treatment of hypobarism might be considered. The objectives would be to stabilize the injured patient until rescue could occur, treat minor injury, and even carry out some minimal invasive diagnostic studies and simple diagnostic testing. Such a facility would require extended training of a crew member. Symptoms and clinical signs could be described to physicians on the Earth, who would direct treatment giving instruction to the paraprofessional in the space station or space colony. This seems to be a minimum requirement for a space station. Injury is the most likely debilitating or potentially life-threatening process, if personnel are young, healthy individuals. There are, however, certain medical and surgical emergencies that affect even young people, such as appendicitis, perforated ulcer, renal stones, and subarachnoid hemorrhage. In the Polaris submarine missions there have been approximately 21 cases of appendicitis—17 of which were successfully treated with antibiotics and 4 of which resulted in death. Surgery is the only alternative when antibiotics fail and is the primary treatment on Earth in a nonremote setting. If the health maintenance facility is incapable of providing surgical care, the workers and scientists, as well as the public must be aware of such a conscious decision. 

HUMAN BIOLOGY AND SPACE MEDICINE 126 Unique Environmental Stresses The closed environment and limited resources of a space station or space colony introduce special health problems in addition to those already discussed in the context of microgravity, radiation, and human behavior. The task group addresses a few that demand additional investigation. Others can be expected to arise. Microorganisms The fungi, bacteria, and viruses carried inflight will experience the unique stresses and opportunities of a small, closed environment. The microbial populations carried inflight by man and animals will be subjected to unknown and highly variable fields of mutagenic radiation. Rotation of crew members on the Space Station will introduce different strains of microorganisms that could contribute to the emergence of new strains of opportunistic pathogens through mutation and genetic exchange. Experience involving Apollo and Skylab indicates that microbial exchange commonly occurs among crew members. Although inflight infections were neither unusual nor increased during the Apollo missions, several bacterial- associated diseases were experienced by the crew in Skylab 1. In this case, the environment became heavily contaminated with bacteria, reaching 4350 bacterial colony-forming units per cubic meter in the cabin air two days before mission termination. In the course of eight STS flights, numbers of bacteria in the spacecraft air ranged from 200 to 1300 colony forming units per cubic meter of air. Staphlyococcus aureus and Aspergillus species were commonly isolated from air and surface samples in these flights. No information is available with respect to viruses. We have little information about the survival of microorganisms in droplet nuclei in microgravity. It is likely that microorganisms will not sediment in microgravity as occurs at one-g. This would result in persisting aerosols and high microbial densities in cabin air, especially with inefficient air filtering systems. Aerosols and Particulates Aerosols and particulates contribute to the dissemination of microorganisms and of toxic compounds. On the Skylab 3 mission, particulates reached 35,000 per cubic meter on day one in 

HUMAN BIOLOGY AND SPACE MEDICINE 127 the mid-deck. In the flight deck, the particulate count reached 24,000 per cubic meter. More effective systems to filter air and water and to remove microbial aerosols and particulates must be developed. Increased quality of housekeeping, hygiene, and waste management must be developed. Relatively few skin-related problems have been encountered thus far in manned spaceflight in spite of the difficult conditions for the maintenance of skin hygiene imposed by the relative lack of water in space. The skin has a high level of cellular turnover, with significant shedding of tiny particulates into the environment. Bathing facilities, personal hygiene procedures, and clothing should not contribute to the particulate load. Toxic Volatiles Crew exposure to several categories of toxic substances may be anticipated from several sources: (1) leaks and spills from storage tanks, chemical reagent stoves, and life support/flight control systems; (2) volatile waste products from crew, experimental animals and plants, as well as from nutrients necessary for their support; (3) pyrolytic products derived from excessive heating or combustion, as in small electrical fires; and (4) outgassing of spacecraft materials such as electrical insulation, paints, lubricants, and solvents, and degradation of nonmetallic materials. The release of any toxic substance into the spacecraft is more serious and hazardous than similar incidents on Earth for a number of reasons. The closed spacecraft atmosphere with its finite volume and low gas exchange rate allows for greater than normal concentrations of toxic materials and thus greater crew exposure with time. Exposure will be continuous, permitting increased accumulation and greater hazard. NASA's current approach to the spacecraft toxicology problem includes careful initial materials selection as well as outgassing testing for toxic volatiles prior to approving use of these materials in the spacecraft. In addition, inflight "grab" air samples are obtained periodically and returned for postflight analysis. These procedures have proven adequate for Skylab and the shorter Shuttle flights thus far. A large number of volatile chemicals have been detected during flight, mostly within threshold limit values (TLVs) and NASA spacecraft maximum allowable concentration (SMAC) limits. These values, however, are based on modified Occupational 

HUMAN BIOLOGY AND SPACE MEDICINE 128 Safety and Health Administration (OSHA) limits for short-term exposures. Although helpful, they should be reexamined in the context of long-term space missions. Much ground-based information must be obtained regarding the long- term, cumulative effect of representative families of toxic chemical products and their subtle effects on behavior and performance. Water, Air, and Temperature In future long-term space habitats, including the Space Station, water from Earth will have to be reclaimed and recycled from urine, spent wash water, and habitat humidity condensate. In Skylab, waste water was not reclaimed. Potable water was merely stored, yet it was considered tasteless because it had a reduced level of dissolved gases as well as excess residual iodine required to meet bacteriological standards. Reasonable standards regarding concentrations of dissolved gas, organic compounds, inorganics, and microorganisms in water must be established. A major goal of the CELSS program is to meet these standards. In addition to the potability of water is the related question of atmospheric water (humidity) and the key parameter of temperature. The task group has already emphasized that air quality must be controlled in terms of toxic volatiles, aerosols and particulates, and microorganisms. In addition, humidity and temperature are fundamental to human performance and comfort; while extremes of both can be tolerated for a short time, long-term performance and well-being require the definition of a comfort zone and the control of these two parameters. Lack of such control can quickly produce debilitating and even dangerous conditions. Proposed Research Although the health maintenance problems discussed in this section are primarily technical, their solutions require an understanding of biology and medicine often lacking in an engineering group. The task group stresses that these problems should be addressed early in the design of spacecraft and in frequent consultation with the biomedical community. Problems that merit special collaboration include: 

HUMAN BIOLOGY AND SPACE MEDICINE 129 1. Screening materials for outgassing and pyrolytic products. 2. Developing a sophisticated onboard atmosphere-monitoring system. 3. Developing air scrubbers, filters, and catalytic detoxicants. 4. Developing decontamination procedures to deal with spills of toxics and of radioactive materials. 5. Designing safe havens and oxygen face masks. 6. Evaluating appropriate medications to inactivate toxic substances within the body. 7. Completing the research required to establish new NASA spacecraft maximum allowable concentration (SMAC) limits in the context of the Space Station and other long-duration missions.