Air University Review, July-August 1968
We are living in an age of complex revolution in chemical technology, and we are daily reminded of its implications. We are becoming increasingly aware of the influence of this revolution on our everyday life and our health. At first, this awareness centered on air pollution because of some dramatic occurrences that emphasized its importance. Then came agricultural chemicals, pesticides, and insecticides. In a more subtle manner, they also found their way into our everyday life through the publicizing of the cranberry scare, and soon everybody was talking about “residuals” that may or may not be harmless when present in the food we eat. Meanwhile, the pharmaceutical industry was pursuing the game of structural roulette, synthesizing entirely new drugs to tranquilize the ruffed soul of a public deeply worried about air pollution, pesticides, and the arms race. Then, of course, came thalidomide and more pointing of fingers and looking for scapegoats. The arguments became more heated, pro and con, and, as human nature dictates, a period of overcompensation began. Some thought that the “Silent Spring” was imminent, and others concluded that the internal combustion engines would have to go. This attitude, of course, had to give way to more constructive thinking and the realization that scientific effort should not be restricted to the search for new chemical compounds but also must include development of adequate safety and precautionary measures so that we shall be able to afford both the progress and the price for it.
The United States Air Force has been fully aware of the impact of new
technology on the health and welfare of the people developing new missile and
space systems. In 1961 an accelerated research program was started in the areas
of toxicology, pharmacology, industrial hygiene, and occupational medicine, to
provide the necessary understanding and suitable control measures for handling
new propellants and other high-energy compounds by Air Force and contractor
personnel. While this program initially was directed toward the protection of
ground-based personnel, the rapid progress of the space age made it mandatory
that an equal emphasis be placed on the health of aerospace crews confined to
artificial atmospheric environments for extended periods. To expedite research
in this area, unique facilities were established in 1963 at the Aerospace
Medical Research Laboratories, Wright-Patterson Air Force Base,
The purpose of this discussion is to delineate the chemical hazards affecting the health of aerospace crews manning future systems capable of long mission duration and to forecast the operational implications of toxic hazards on the design of such systems. To be more specific, we are projecting ourselves into the 1975-85 era when mission durations of 100 to 1000 days should be feasible.
the environment
The space cabin environment is designed to sustain man as best we can for a long period of isolation from earth. Everything is artificial. To create a microcosmos capable of supporting life, new chemicals and new chemical processes had to be developed and incorporated into the life-support system. Our main concerns are the chemical composition and purity of the atmosphere and the partial pressures of oxygen and inert gases.
If these parameters are changed from the familiar earth atmosphere, the human organism must either learn to live with these changes or perish. In other words, as soon as we change the ratio of oxygen to nitrogen, or substitute another inert gas, or omit the inert gas, we are prevailing upon the organism to accommodate in order to survive. This process is called adaptation. We know from biological experience that, in general, adaptation is possible only if it is gradual. We can adapt easily to a slight change, but adaptation to considerable change in the environment is possible only where the rate of change is slow. There is a price for adaptation. Although the organism can adapt to the new environment, if the old environment were suddenly reestablished the organism again would have to readapt to the original conditions. The real danger is that adaptation can be pushed so far that readaptation may become very difficult or incomplete. Plausibly, there may be a number of artificial atmospheres (using various partial pressures of ingredients) to which the crew on a 1000-day mission could adapt completely and upon return find themselves in the untenable position of depending on a higher percentage of one or more ingredients of that atmosphere or perhaps dependent on a lesser or greater total pressure than our earth atmosphere.
We have already produced concrete evidence that this situation can occur in animals exposed to oxygen-enriched atmospheres. These animals survive the initial toxic effects of oxygen and can live in such environment indefinitely. The price they pay for this adaptation, however, is that upon return to the normal earth atmosphere, they die from lack of oxygen because their lungs underwent adaptive morphologic changes, such as thickening of the gaseous exchange surfaces, to protect them from the excess of oxygen in the artificial atmosphere. However, they can be saved by “weaning” them back to normal conditions if the oxygen content of the artificial atmosphere is decreased gradually over a period of weeks. Although this process saves their lives, the readaptation is incomplete, since much of the normal lung structure is destroyed and replaced by connective tissue that is nonfunctional for the purpose of respiration. The animals, although appearing healthy, have decreased pulmonary function and thus represent incomplete readaptation. This response suggests the possibility of occupational diseases in future spacecrews.
contaminants
Contaminants, by definition, are either toxic or annoying materials which inadvertently find their way into the cabin environment and the life-support system. They can be gases, vapors, aerosols, dusts, or other particulate matter such as fibers, microorganisms, etc. They may constitute a toxic hazard primarily because of the recirculation of the atmosphere in a very limited cabin volume. For the purpose of this discussion we will disregard problems concerning ionized particles, dusts, and microbial contamination.
The sources of contamination are manifold and extremely hard to eliminate. Those contaminants of biological origin produced by the crew are controlled only in the waste disposal processes and by the oxygen reclamation systems. Since no such process operates with 100 percent efficiency, there will be a gradual accumulation of such contaminants on missions of long duration. Another major source is the air purification and disposal equipment, together with the chemicals used in the reactions, specific reaction by-products, and specific chemical processes. Finally, all materials used in the construction of the cabin and its maze of instrumentation contribute significantly by outgassing volatile materials that were used during manufacture or installation. This outgassing phenomenon is greatly enhanced in the cabin’s reduced pressure.
Since all these sources continuously supply many different types of contaminants, the end result is a highly complex mixture of contaminants made up of minute quantities of primarily organic chemicals representing all major classification categories. They are generally referred to as trace contaminants.
toxic effects from trace
contaminants
This article will not dwell on the toxicological characteristics of individual contaminants for two reasons. First, such information is readily available in the literature on those chemicals which have been extensively used in industry. Second, many of these trace contaminants have never posed a problem in industrial operations, and therefore no specific toxicological information is available. Rather, they should be regarded and classified according to groups possessing similar mechanisms of toxic action, irritation, or mere nuisance value.
The main reason trace contaminants must be taken seriously is the complexity of the mixture contaminating the atmosphere and the long mission duration, which constitutes a truly long-term continuous exposure. Continuous exposure per se seldom, if ever, occurs in anybody’s life under normal earth conditions. The industrial worker, although exposed to certain toxic contaminants in the milieu of his job, is seldom exposed for more than 8 hours a day, 5 days a week. When he leaves his site of occupation, he is removed from the noxious atmosphere for the rest of the day or for the weekend. This allows a period of recuperation from any incipient damage to his health. In a continuous-exposure situation, there are no recuperative periods, and the increments of damage, however slight per 24-hour period, accumulate without opportunity for repair. This is often referred to as a “summation of interest” type of situation. There is a role for adaptation in this instance, too, but it is much more limited than physiological adaptation to an artificial atmosphere. Here, we are dealing not with one mode of toxic damage and one target organ but with many modes of action affecting every organ. Consequently, we should consider the deleterious effects of trace contaminants as a nonspecific toxic stress affecting the whole organism. Thus, as the exposure continues and damage mounts upon damage, eventually the proverbial straw that breaks the camel’s back arrives.
The absence of recuperative periods poses another real danger to health. Beyond the fact that trace contaminants affect all vital organ functions, classes of contaminants having different target organs or modes of action can exert additive and even synergistic toxic effects. This compound mechanism is a real detriment to any potential adaptive response. For example, while adaptive processes can increase tolerance to pulmonary irritants, the end result is a decrease in the efficiency of pulmonary function, ventilation, and compliance of pulmonary tissues. This is a highly undesirable course of events in an artificial atmosphere. Poor lung ventilation will lead to atelectasia first and to emphysema in the long run. As a direct consequence, the pulmonary defense mechanisms are impaired, the residence time of toxic substances in the lung increases, resulting in more complete absorption and, hence, a more severe toxic effect. If, in addition, there are contaminants present which affect the cardiovascular system, the heavier load imposed on the heart by the pulmonary changes will establish the classic vicious circle of cardiopulmonary decompensation.
Similar additive and/or synergistic effects can be postulated for an infinite variation of mechanisms, target organs, and classes of contaminants. Many organic chemicals do have a depressive effect on the central nervous system (CNS). In their more subtle manifestation of toxicity, these affect only performance without causing overt clinical symptomatology or neurological deficit. It is quite easy to see how the presence of carbon monoxide as a contaminant could complicate the effects from CNS depressants. Any interference with oxygen transfer mechanism will lead to relative hypoxia in all tissues. If the CNS is already depressed, a relatively small decrease in tissue oxygen availability caused by carbon monoxide could have precipitous results.
These few examples are cited to emphasize the serious consequences of continuous exposure to bizarre mixtures of trace contaminants. It is well to remember that the chemical stress is only one burden of life in a space cabin, but it could be enough of a burden to undermine the health of the crew in a long duration mission. Unfortunately, there are other stresses which also can act in an additive fashion. Weightlessness and resultant deconditioning affect the cardiovascular status. The dynamic stresses during re-entry require a great deal of physiological reserve in the crew. The heat stress during extravehicular activity could play havoc with an already unbalanced cellular energy metabolism caused by toxic action from some contaminants. Tolerance to radiation can be greatly reduced by contaminants that have a radiomimetic effect; i.e., act through the mechanism of free radical formation in the body. Ozone is a classic example.
For the sake of brevity, I will not consider the many other stresses which also play an important role in taxing the general status of health, such as toxic effects from microbial organisms and radiation and the entire area of psychological stress. Many of these stresses are inherent in the nature of space missions, and many of them cannot be controlled entirely or at all. The chemical stress is the most amenable to control, provided sufficient care and foresight are exercised during the design phase of the system.
philosophy of contaminant
control
The design goal of zero contamination is desirable but probably unattainable within the time period with which we are dealing. Fortunately, there are very few toxic substances that would require the assignment of a zero tolerance limit. Still, this ideal goal should be adhered to as closely as possible in the initial design phase so that the sizing of air-purification and waste-disposal equipment, with the attendant power consumptive figures, will be taken into consideration by the engineers. In the process of prototype design and testing of life-support systems and subsystems, whatever contamination is functionally inherent in these units must be carefully identified and remedied if possible. But even before this stage, we should be certain that no materials were used in the construction and assembly processes which would impart an undue contaminant burden to the system. Only when engineering remedial action is unsatisfactory should we be concerned with setting mission-oriented tolerance limits for specific contaminants.
materials selection
This is an area where an ounce of prevention is worth a pound of cure. Fortunately, the crucial importance of material selection has recently been recognized, and standard testing procedures have been established for materials acceptability from the standpoints of both fire and toxic hazards. Their mogravimetric analysis, coupled with mass spectrometry, gas chromatography, and infrared spectroscopy where necessary, is used to identify volatile contaminants emanating from cabin materials. As a result, cabin construction materials are being catalogued for acceptability and the engineers will have a suitable reference list for selecting or substituting materials for specific applications.
To complement the analytical screening effort, biological test methods are al1 employed in qualifying cabin materials. Small animals are exposed to the gas-off products from cabin materials in a recirculating support system to test for overt signs of toxicity and for chronic effects. To avoid unpredictable surprises from potential additive or synergistic effects between contaminants, these tests also include large mixtures of typical cabin materials for a specific system.
human tolerance limits
For control of the most common undesirable contaminants, tentative tolerance limits have been established by the ad hoc Committee on Air Standards of the Space Science Board. These are for preliminary engine purposes and consider mission duration of 100 and 1000 days. Development of more definite limits requires extensive biological experimentation, which has already been initiated. The same is true in establishing physical limits for alert or abort situations. The importance of animal experimentation in the development of valid human tolerance limits cannot be overemphasized. Because of the many uncertainties and dangers of long-term continuous exposure objective estimates of tolerance, adaptation, and readaptation must first be established in various animal species to facilitate extrapolation to man. Since many of the attending changes must be quantittated in tissues and at the subcellular level, the necessity for animal experimentation is quite obvious. In this respect the procedures required to declare a specific concentration of contaminant safe are closely related to those routinely employed in the safety evaluation of new drugs, food additives, pesticides, and insecticides.
The validity of extrapolation from animal data to human often been questioned by engineers and technical personnel from other than the biological area. Without going into lengthy polemics, suffice it to say that these procedures have been all worked out and that the safety record in marketing such new drugs and chemicals is both extensive and impressive. Besides the ethical considerations involved in experimentation with human volunteers, the difficulties in obtaining human experimental subjects for 100-day confinement are great enough. Let alone for 1000 days! In any case, animal experimentation must precede the exposure of humans to either a simulated contaminant atmosphere or to an actual one occurring during a space mission. The area where human experimentation may become necessary is that of relatively short-duration continuous exposure for the purpose of verifying intactness of performance in an alert or abort situation.
in-flight control of contaminants in the
cabin
Assuming that everything possible has been done to eliminate volatile contaminants during the design and construction phase, one still may find certain contaminants when all stems and subsystems become integrated to a functional spacecraft. In many instances systematic search for the origin of these contaminants will also reveal potential methods control by slightly changing performance characteristics or efficiency of such air-purification devices as catalytic burners, filter flow rates, etc. If all this fails, as a last resort the leak rate of the cabin toward the vacuum of space can be increased at the expense of either mission duration or weight of stored oxygen supplies. A word of caution is in order here. Any such manipulations should be thoroughly tested for efficacy in space simulators on the ground, and a careful analytical survey of the cabin atmosphere should be made to insure that the shifts in operating parameters of certain systems have not led to the production of previously unencountered contaminants. Previous experience with a number of life-support system simulators shows that indeed this can occur very frequently. This type of testing is important because it can also reveal unexpected toxic hazards that might occur during emergency phases of the mission when the crew must attempt alternate methods of repair on the life-support system which have not been originally planned. As a matter of fact, a complete mode-of-failure analysis is an absolute necessity to define well in advance the consequences of failing parts or processes, with concomitant effects on other parts and other processes within the system.
For very long-duration missions, several engineering trade-offs should be considered. As our exploration of space progresses and carries us farther and farther away from earth, the spacecraft logistics and resupply aspects become more and more difficult. In relatively short-duration missions, increasing the leak rate of the cabin can decrease atmospheric contaminants to tolerable levels. This approach is not practical logistically when mission length requires resupply, because of the premium price on payload. At any rate, there must be sufficient oxygen reserve aboard to allow for complete dumping and repressurization of the cabin atmosphere in emergency situations, such as generation of noxious gases from fires or fire extinguishants and contaminants produced by malfunctioning life-support equipment.
Air-filtering and purification equipment must always have sufficient redundancy and capacity to allow for alternate modes of operation during repair or emergency periods. Inflight periodic maintenance will be an absolute must in long-duration flights. Devices and media that can be regenerated to prolong their service life are preferable. But even regenerative devices have a limited useful life cycle. If too many spares are provided, they also represent an added weight penalty on takeoff. Extraterrestrial materials suitable for absorbent beds probably could be found on the moon and other planets or their satellites and might be processed into usable form with relatively little effort. This approach may also be useful for replenishment of media for waste disposal and trickling filters.
Extraterrestrial materials may also be found which will serve as energy sources for the operation of the life-support system. Other possible uses include shielding materials for extraterrestrial shelters and germination media for growing seedlings for dietary supplements.
The use of extraterrestrial material must be preceded by systematic physical/chemical and toxicological characterization so that no new contaminates are introduced into the spacecraft.
toxicology research needed
The gaps in knowledge concerning response to very long-term continuous exposure to a mixture of contaminants and the effects of combined stress during such exposures must be closed in the next ten to fifteen years. Without this closure, extended aerospace flight would present unpredictable toxicological risks, and contamination of the cabin atmosphere could become one of the most serious limiting factors in the overall safety aspects of space flight. Mathematical models of chronic toxicity must be developed and tested in a systematic manner to evaluate the effect of absorption and clearance rates of toxic contaminants on specific target organs and on the entire organism. This will require the development of new methodology in assaying “half lives” for typical contaminant categories. To perform such studies, tagged contaminants should be used which embody radioisotopes that have as little radiobiological effect as possible. This will require the modification of existing exposure facilities to accommodate the use of low-activity radioactive materials.
As a next logical step, better methods must be found for the evaluation of nonspecific chemical stress. In conjunction with the development and testing of mathematical models, a statistically significant number of animals from each exposure group should be subjected to meaningful terminal stress tests to assess biological reserve. These terminal stress methods should approximate, both qualitatively and quantitatively, the combined stresses of the space mission. Special emphasis should be placed on the re-entry profile and the attendant thermal and biodynamic stress, to insure detection of subliminal biological decompensation resulting from the exposure to toxic chemicals. With such new tools as the dynamic escape simulator nearing completion, this type of terminal stress testing can be optimized and made quite realistic.
New instrumentation must also be developed, both in the biological monitoring area and for the generation and detection of contaminants. Various organ function tests are highly desirable during long-term continuous exposure. Pulmonary and cardiac function should be evaluated on a day-to-day basis, and improved psychopharmacological test methods are sorely needed to detect deterioration of higher mental functions and decision-making processes. By the judicious application of such function tests, the intactness of the integrated organic functions of the experimental animals can be ascertained. Very likely, many of these methods to be developed will be applicable to medical monitoring of the crew itself.
Contaminant generation equipment for animal exposures is still quite primitive, and few advances have been made in the past 50 years. To study highly complex mixtures one will need equipment that can generate, in various proportions, 50 to 100 contaminant species with great reliability for long time periods. The advantage of such equipment employing a fixed-ratio principle is obvious from the monitoring standpoint. Anyone of the easy-to-monitor components can be selected for quality control purposes with assurance that the concentration of contaminants will be maintained at the intended level.
Contaminant detection and monitoring in the spacecraft require other approaches. On board high-resolution analytical capability can cope with the appearance of unexpected contaminants only if a sufficient number of different sensing principles is incorporated. While some form of readout capability must be aboard for quick interpretation of dynamic changes, the more detailed information can be transmitted back to the operational bas for data processing and final identification.
Assuming that the proper mathematical models are successfully developed, a small special computer should be built to aid the medical monitoring personnel onboard and on the ground in decision-making. Since the contaminant profile of the atmosphere will be continually changing as a result of accumulation and removal of old contaminants an the appearance of new ones, the crew’s tolerance will have to be computed repeatedly Such computations should take into consideration the previously discussed phenomena of adaptation, tolerance, additive and synergistic effects on target organs, and the physiological reserve needed for the rest of the mission and re-entry. This computer should also be able to trade off increased contaminant levels wit mission duration if such trade-offs are feasible and meaningful.
Much fundamental research must be carried out concurrently with the applied program. Once we start to delineate the deleterious effects of continuous exposure, approaches will become apparent for counteracting some of them. Probably periodic interruption of the exposure by respiratory protective devices or by special clean-atmosphere compartments can counteract the “summation of interest” type of damage mechanism. The optimum length of such recuperative periods must be determined experimentally and concurrently with the continuous-exposure studies. This will both save lead time and also shed further light on the nature and degree of adaptive cellular and subcellular mechanisms, if properly supported by electron microscopic studies of the ultrastructure and concurrent biochemical determination of energy metabolism in mitochondrial and microsomal preparation
The latter area alone has a significant impact on the entire field of safety evaluation of new drugs, cosmetics, food additives, pesticides, and agricultural chemicals. The morphological changes at the cellular and subcellular levels must be correlated with functional biochemistry in order to be meaningful. Indeed, the demarcation between adaptation, tolerance, and degeneration is a very thin line and must be described thoroughly and quantitated accurately.
spin-off benefits from
space-cabin
toxicology research
As has been demonstrated with other areas of the expanding space technology, toxicology research will have several major benefits in the area of medical research. The most prominent of these will apply to occupational medicine, industrial hygiene, air pollution, and the safety evaluation of new chemicals. The better understanding of biological response to toxic agents in general and to chronic exposures in particular will have a revolutionary effect on concepts governing the control of occupational exposures and the development of protective methodology. The quantitative evaluation of residual toxic effects will have great impact not only on the protection of the industrial worker from the chemical environment but also on the medical-legal assessment of disabilities occurring as a result of lifetime chronic exposures. The developments in the biological and contaminant monitoring areas will undoubtedly find immediate applicability to clinical medicine and industrial hygiene. The tolerance limits in space-cabin atmosphere can be extrapolated easily and safely to shorter-duration continuous exposure, such as occurs in severe air pollution episodes, and will supply the basis for calculating community air standards. The development of a valid mathematical model alone will eliminate the guesswork in experimental planning and in selecting of dose rates for the safety evaluation of new chemicals. The relationship of changes between ultrastructure and biochemistry at the subcellular level will further increase the overall safety and validity in the evaluation of new drugs. In general, the entire area of toxicology and pharmacology will gain from almost every bit of new knowledge that is generated as the result of an intensive research program dedicated to the protection of the health of aerospace crews during extended missions.
Aerospace Medical Research
Laboratories, AFSC
Dr. Anthony A. Thomas (M.D.,
Disclaimer
The conclusions and opinions expressed in this
document are those of the author cultivated in the freedom of expression,
academic environment of
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