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Physiological Changes During *Z Space/light The general physiological effects of exposure to microgravity are better understood but much remains to be learned about the quan- titative impact of physiological changes on susceptibility to chemicals. Because a correlation appears to exist between the duration of expo- sure and the frequency and intensity of the effects, the issues of dura- tion of the spaceflights and of the microgravity environment remain the critical variables in attempting to establish safe levels of exposure to potentially toxic chemicals. Risk assessment of chemicals begins with biological studies conducted in animals and humans on earth. It is not clear how these data can be generalized to the space environ- ment. A variety of assumptions will be necessary. The quality of these assumptions can be substantially improved as more data from astronauts and cosmonauts are obtained. To date, of the effects ob- served in astronauts, space motion sickness and decreased immune function seem to be the effects having the most direct relevance to crew performance during spaceflights. SPACE MOTION SICKNESS Spatial disorientation and space motion sickness (SMS) occur early in spaceflight. SMS has been described since the Apollo 9 flight in the U.S. manned spaceflight program. The incidence of SMS among crew members has ranged from about 35% during Apollo to 60% during Skylab. During the four orbital flight tests of the shuttle, four of eight crew members described symptoms of SMS. SMS is a persistent operational medical problem and has been called the most clinically significant medical phenomenon during the first several days of spaceflight. SMS is characterized by increased sen- sitivity to motion and head movements, headache, malaise, lethargy, stomach awareness, loss of appetite, nausea, and episodic vomiting. 49
50 GUIDELINES FOR DEVELOPING SMACS Onset of symptoms usually occurs in the first 15 min to 6 hr of space- flight, although delayed symptoms have been reported up to 48 hr into the flight. Neural adaptive mechanisms respond, and within a few days, the symptoms disappear. These mechanisms are not well under- stood and further research is required. Symptom severity peaks during the first 2 days of flight, and recovery is usually complete by the third or fourth day. Results from the Soviet Salyut 6 flights show that symptom resolution occurred after 3-7 days in space, but one crew member reported having symptoms of SMS for 14 days. The high incidence, severity, and duration of SMS have limited some early flight crew activities. Extravehicular activity is now scheduled after the third flight day to allow symptomatic crew members to recover from SMS prior to extravehicular activity. A minimum-duration flight lasts at least three flight days to ensure that the crew has recovered sufficiently to permit all entry and landing activities. Until successful countermeasures or accurate preflight predictive tests can be developed, SMS will continue to have an impact on crew activities during the relatively short 5- to 10-day flights of the shuttle. The basic mechanisms of SMS should be defined so that drug therapy or other techniques for reducing SMS can be developed. BONE AND MINERAL METABOLISM A variety of studies of human beings during long-term bed rest, of humans in space, and of rats in space have shown that prolonged inac- tivity and weightlessness result in both significant and continuing losses of calcium from the skeleton and nitrogen from muscle and decreases in mass of both rats and humans (NRC, 1988b; Whedon, 1984). 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 measure- ments 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 poliomyelitis, calcium losses led to x-ray-visible os- teoporosis in the bones of the lower extremities as early as 3 months after paralysis. While the overall rate of calcium loss in Skylab astro- nauts was 0.4% of total body calcium per month, the loss was es- timated 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). That loss
PHYSIOLOGICAL CHANGES DURING SPACEFUGHT 51 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 9-12 months, espe- cially at gravities approaching 1 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 may occur earlier than bone fractures (Whedon, 1984). These risks are not likely to affect crew performance during flights, but they are serious considerations on return to earth after long flights or after landing on another planet, such as Mars. The cellular mechanisms of mineral loss are unknown. Excess ex- cretion of calcium associated with increased hydroxyproline in the urine in humans is indicative of increased bone resorption. Histologi- cal 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 countermeasures that could be ap- plied to astronauts in space to suppress or prevent calcium loss (NRC, 1988b; Schneider and McDonald, 1984). All mechanical procedures tested thus far have been ineffective including exercise with the Exer Genie pulley apparatus, static and intermittent compression of the length of the body from shoulders to feet, static and intermittent lower-body negative pressure, and impact loading up to 36 Ib to the bottom of the heel 40 times per minute for up to 8 hr daily. Cor- relative observations have indicated that a procedure would have to be derived for use in flight that would provide an equivalent force on the skeleton of 4 hr of walking per day. A high calcium and phosphorus diet reduced calcium loss for up to 90 days only; thereafter, increasing fecal excretion of calcium rendered a negative calcium balance and continued to do so for the remaining 17 weeks of the study. Sup- plementary dietary phosphate alone had no lasting beneficial effect to prevent calcium loss during bed rest. Salmon calcitonin at 100 MRC (Medical Research Council) units daily also did not prevent calcium loss. Promise in these countermeasure studies has come from bisphosphonate compounds, such as disodium etidronate, that bind to bone crystal and tend to inhibit bone resorption (Schneider and McDonald, 1984). Countermeasure studies are continuing particularly on the bisphosphonate leads.
52 GUIDELINES FOR DEVELOPING SMACS At the same time, with support from the National Institutes of Health and other sources, various studies are being conducted on the basic mechanisms of the effects of mechanical forces on bone dynam- ics 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 de- creasing bone mass and strength and is the most prevalent clinical disorder of bone. As another mineral metabolic effect, hypercalciuria associated with loss of mineral from bone in spaceflight might increase the potential for stone formation in the urinary tract (NRC, 1988b). Although 75-80% of renal stones contain calcium, the possibility of stone for- mation appears to depend not only on increased urinary concentration of calcium but also on other factors such as urinary pH, concentrations 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 in- creases in urinary calcium (Deitrick et al., 1948). Both of these fac- tors, 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 main- tain 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. Potential toxicants having an adverse effect on bone that might be introduced into the environment aboard the space station are alumi- num and fluoride. Aluminum, a component of antiperspirants, could be inhaled or absorbed through the skin and, if used in continuing substantial quantities, could be deposited in bone and inhibit bone formation. Fluoride has been under consideration as a possible in- hibitor of bone resorption in weightlessness, but it should not be used indiscriminately, because at only moderately high concentrations, its incorporation into bone makes bones brittle and at increased risk of fracture. Other cations and anions in the environment could have adverse effects on calcium and bone metabolism.
PHYSIOLOGICAL CHANGES DURING SPACEFUGHT 53 MUSCLE METABOLISM 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 1 g upon return to earth; the continued excretion of nitrogen may have deleterious hor- monal and nutritional effects. Exercise, diet, or drugs may ameliorate these effects, but a fully effective treatment is not likely to be devel- oped until impaired muscle function in prolonged microgravity is bet- ter understood. The increased urinary excretion of nitrogen by astronauts in Skylab reflected muscle loss such as that observed during bed rest, but the excretion was variable and generally greater than that seen during bed rest. Most of the atrophy occurred in antigravity muscles, which are no longer load-bearing. In all nine Skylab astronauts, the high level of nitrogen excretion continued unabated for the duration of the flight (up to 84 days) (Whedon et al., 1974). This response indicates a serious malfunction not likely to reach a new steady state until an extreme degree of atro- phy is reached. The nitrogen loss was accompanied by losses of 15-30% of muscle mass and strength in the lower extremities. The considerable exercise activity of the astronauts in Skylab 4 resulted in somewhat lesser losses of muscle mass and strength than on earlier flights but was obviously not fully protective. Although the mechanism of the process of atrophy remains un- known, certain aspects have become evident (NRC, 1988b). 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 syn- thesis markedly. As shown in muscle cultures, stretching stimulates protein synthesis. The uncertain value of physical exercise for suppressing muscle atrophy during spaceflight has been noted previously; no controlled studies of exercise in flight have been attempted.
54 GUIDELINES FOR DEVELOPING SMACS CARDIOVASCULAR FUNCTION AND BODY FLUID CHANGES In the Space Science Board's publication Life Beyond the Earth's Environment (NRC, 1979), the Cardiovascular Panel summarized their review of studies up to that date in this area of space physiology as follows: The experience hitherto gained from manned spaceflight demonstrates that the cardiovascular system can adapt promptly to weightlessness and that man can maintain an excellent functional capacity in space for prolonged periods of time. However, an impressive body of data indicates that sudden exposure to 0 g is associated with a rapid shift of a considerable amount of interstitial fluid and blood from the lower toward the cephalad pans of the body. Most of the trans- located fluid is accommodated in the intrathoracic compartment, distending its vascular structures and presumably inducing significant changes in central hemo- dynamics. The increase of the intrathoracic blood volume is apparently "interpreted" by the body as a "total body" intravascular volume expansion and elicits compensatory mechanisms (i.e., natriuresis and diuresis), which reduce total blood volume. The lack of any impairment in inflight physical work (aero- bic) capacity indicates that the contracted blood volume is an appropriate adap- tation to the zero environment. However, this adaptation becomes inap- propriate upon return to normal gravity. Postflight circulatory studies demon- strate decreased orthostatic tolerance, decreased physical work capacity, and lowered exercise stroke volume and cardiac output in the sitting position. All of these postflight phenomena are consistent with a state of relative hypo- volemia. The fluid shift from the legs into the thorax as seen in Skylab crew members occurred within the first few days of flight and amounted to more than 2 L of extravascular fluid, as determined by a series of accurately located limb-girth measurements (Thornton et al., 1974). Related Skylab studies showed an apparent increase in leg venous compliance during the first 2 weeks of flight and a later decrease thought to be primarily related to the decrease in leg musculature (Thornton and Hoffler, 1974). In addition to the apparent decrease in plasma volume in weightlessness, red-blood-cell volume in Skylab crew members decreased by a mean of 11%, or 232 mL. Although some hemolysis occurred in Gemini astronauts, neither hemolysis nor hemorrhage occurred in Skylab members, and current interpretation is that splenic entrapment associated with slight inhibition of bone-marrow red-blood-cell formation occurred, as indicated by an observed decrease in reticulocyte counts (Johnson et al., 1974).
PHYSIOLOGICAL CHANGES DURING SPACEFUGHT 55 IMMUNE SYSTEM Although reports to date are conflicting, some indicate that a microgravity environment may alter the immune system's function. Cogoli et al. (1980) reported that cultures of human lymphocytes sub- jected to microgravity responded to concanavalin A, a lymphocyte- stimulating agent, 97% less frequently than ground-based controls did. Studies of the astronauts of the first four space-travel-system flights revealed that the lymphocyte responses to phytohemagglutinin, another lymphocyte-stimulating agent, were reduced by 18-61% of normal following spaceflight (Taylor and Dardano, 1983). Stress has been suggested as the cause of these changes, but that cause has not been established and should be studied further. In an unmanned Russian spaceflight, the weights of lymph nodes and spleens of rats flown for 22 days were reported to be markedly reduced, compared with those of controls on earth, because of a marked decrease of lymphocytes in these organs. The effects were found to be reversible since the organs returned to normal 27 days postflight(Durnovaetal., 1977). In another study, Mandel and Balish (1977) 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 \-g controls. They concluded that no deterioration of the acquired cell-mediated immunity to L. monocytogenes could be detected in flown rats. NUTRITION Prior to the start of the spaceflight program, there was speculation that decreased effort of movement in weightlessness would result in diminished caloric requirements compared with those 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 flights of Skylab, modest loss of body weight occurred, associated with body-fluid shifts and losses in muscle mass, as astronauts consumed 2,400-2,800 calories per day. Clearly, caloric requirements were not lessened in space (NRC, 1988b).
56 GUIDELINES FOR DEVELOPING SMACS In the past, many athletes and astronauts have been convinced that high intake of protein 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 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, should be reconsidered because of its potential relationship to urinary tract stone formation and, possibly, loss of minerals from the skeleton. The high phosphate content of meat may partially protect against the effect of high protein intake increasing urinary calcium. At the same time, the negative nitrogen balance associated with muscle atrophy in weightlessness should not be accen- tuated by encouraging too low a protein intake. Since negative nitro- gen balance in space has occurred at daily protein intakes of 85-95 g, the recommended intake should not fall below this level (NRC, 1988b). 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 increase the syn- thesis and release of the brain neurotransmitter serotonin unless con- sumed with adequate amounts of protein. This substance makes people drowsy and interferes with optimal performance. If this rela- tionship is not recognized, menus and the time of consumption of particular itemsâespecially snacksâmight not be appropriate for the tasks required, particularly if they are complex and prolonged. It is possible that other food constituents will be found that affect behav- ior, mood, and cognition (NRC, 1988b). Among the countermeasures tested by NASA have been high in- takes of calcium and phosphorus by bed-rest subjects. The study showed that this procedure maintained calcium intake and excretion level in balance for up to 3 months, after which the gradually rising fecal excretion of calcium caused a negative calcium balance. Hence, there is no basis at this time for recommending calcium intake during spaceflight at a higher level than 1,000 mg/day. It is obvious, how- ever, that a low intake of calcium favors loss of this mineral from the skeleton, adding to the deleterious effect of microgravity. Therefore, the recommendation of the Life Sciences Task Group of the Space Science Board is 1,000 mg/day (NRC, 1988b).
PHYSIOLOGICAL CHANGES DURING SPACEFLIGHT 57 Bed-rest studies of the effects of high intake of phosphorus 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 pos- sible deleterious effect of phosphorus intake higher than an ap- proximate calcium/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. Since no studies have been done on the effects of spaceflight 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 U.S. Recommended Dietary Allowances (RDAs). The important vitamin in long spaceflights is vitamin D. Enclosure in a space vehicle will prevent the normal conversion in the skin of the vitamin D precursor to vitamin D. Conversion is normally ac- complished by exposure of the face and arms to as little as 20-30 min 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. However, amounts should not exceed 800-1,000 lU/day (Holick, 1986). The RDA of vitamin D is 200 IU (5 jtg) (NRC, 1989a); however, there is evidence that in the absence of any exposure to sunlight, the RDA for healthy young adults, such as astronauts, is closer to 600 IU (15 Mg) (Holick, 1987). The lighting environment, including the spectral distribution and intensity of the lighting, needs to be carefully engineered for the space station. Adding a small component of UVB (290-320 nm) radiation in an area where astronauts exercise or eat would promote vitamin D in the skin. The intensity of the lighting also should be evaluated to help maintain the biological clock and decrease the incidence of "seasonal affective disorder syndrome." Other vitamins are not as critical since adequate amounts will be taken in the diet provided it is balanced and the vitamins are not de- graded by the methods of food preservation in use. It has become customary, however, to provide astronauts with daily vitamin supple- ments at RDA levels, which is a reasonable procedure. In the early days of planning for manned spaceflight, many thought that diets should be low in residue so that bowel movements would be small and infrequent. However, bowel function in microgravity, espe- cially in longer flights, was observed to be essentially normal. Hence,
5* GUIDELINES FOR DEVELOPING SMACS diets should be normal in residue, and adequate bulk should be avail- able to afford relatively easy passage of stools once or twice a day. With regard to research and development at the practical level, the acceptability of various currently available packaged, canned, freeze- dried, or heat-stable food items should be evaluated for spaceflights extending many months to years. Because the capacity to carry and store frozen food items is likely to be limited in extremely long flights, research in space-food technology should be revived in plan- ning for the space-station era. To date, nutrition investigations (unrelated to space) suggest that individuals do not crave a continuous variety of foods, but rather they tend to select from a small range or limited number of foods over a period of months, and these periods continue throughout life. Reduction in the total list of available food items should simplify both the strategy of storage of multiple food packages in a long-flying spacecraft and the ability of travelers to retrieve desired items with a minimum of difficulty and time. The space station will need to provide for testing of currently available and newly formulated items for long-term durability and acceptability.
