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Introduction Construction of the International Space Station (ISS) a multinational effort began in 1999. In its present configuration, the ISS is expected to carry a crew ofthree to six astronauts for up to 180 days. Because the space station will be a closed and complex environment, some contamination of its internal atmosphere and water system is unavoidable. Several hundred chemical contaminants are likely to be found in the closed-Ioop atmosphere and recycled water of the space station. To protect space crews from contaminants in potable and hygiene wa- ter, the National Aeronautics and Space Administration (NASA) requested that the National Research Council (NRC) provide guidance on how to develop water exposure guidelines and subsequently review NASA's devel- opment of exposure guidelines for specific chemicals. The exposure guidelines are to be similar to those established by the NRC for airborne contaminants (NRC 1992; 1994; 1996a,b; 2000a). The NRC was asked to consider only chemical contaminants, and not microbial agents. The NRC convened the Subcommittee on Spacecraft Water Exposure Guidelines to address this task, end the subcommittee's first report, MethocisforDeve11top- ing Spacecraft Water Exposure Guicle11tines, was published in 2000 (NRC 2000b). A summary of that report is provided below. Spacecraft water exposure guidelines (SWEGs) are to be established for exposures of 1, 10, 100, and 1,000 days Alp. The 1-d SWEG is the concen- tration of a substance in water that is judged acceptable for the performance 1

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2 Spacecraft Water Exposure Guidelines of specific tasks during rare emergency conditions lasting for periods up to 24 hours (h). The 1-d SWEG is intended to prevent irreversible harm and degradation in crew performance. Temporary discomfort is permissible as long as there is no effect on judgment, performance, or ability to respond to an emergency. Longer-term SWEGs are intended to prevent adverse health effects (either immediate or delayed) and degradation in crew perfor- mance that could result from continuous exposure in closed spacecraft for as long as 1,000 d. In contrast with the 1 -d SWEG, longer-term SWEGs are intended to provide guidance for exposure under the expected normal oper- ating conditions in spacecraft. WATER CONTAMINANTS Water used in NASA's space missions must be carried from Earth or generated by fuel cells. The water is used for drinking, food reconstitution, oral hygiene, hygienic uses (handwashing, showers, urine flushing), and oxygen generation. Because of plans for longer space flights and habitation of the ISS, water reclamation, treatment, and recycling is required. Water for long space flights can be reclaimed from several onboard sources, in- cluding humidity condensate from the cabin, hygiene water (shower and wash water), and urine. Each of those sources will have a variety of con- taminants. Humidity condensate will have contaminants released into the cabin from crew activities (e.g., by-products of crew metabolism, food preparation, and hygiene activities); from routine operation of the air revi- talizationsystem; from off-gassing ofmaterials end hardware; frompayload experiments; and from routine in-flight use of the crew health care system. Wash water will include detergents and other personal hygiene products. Urine contains electrolytes, small molecular weight proteins, and metabo- lites of nutrients and drugs. It is chemically treated and distilled before recycling, which causes a variety of by-products to be formed. Other sources of chemical contaminants include mechanical leaks, microbial metabolites, payload chemicals, biocidal agents added to the water to retard bacterial growth (e.g., silver, iodine), fouling of the filtration system, and incomplete processing of the water. It is also possible that contaminants in the spacecraft atmosphere will end up as toxic substances in the water system. The air and water systems of the ISS constitute a single life-support system, and using condensate from inside the cabin as a source of drinking water could introduce some unwanted substances into the water system.

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Introduction 3 NASA's current water exposure guidelines are based on standards from the U.S. Public Health Service and the U.S. Environmental Protection Agency (EPA) for public drinking water. Those standards were established to protect the general public, including the elderly, persons with disabilities or compromised immune systems, and infants and young children. Protect- ing sensitive individuals is necessary and appropriate for the safety of the public health, given the likelihood of lifetime exposures. However, expo- sure limits for the general public are not necessarily appropriate for space- craft flight crews. Many of the limits are likely to be overly conserv- ative much stricter than would be necessary to protect healthy adult astro- nauts even for several years away from Earth. Other limits could be inade- quate microgravity, increased radiation, or other unique attributes of spaceflight could make astronauts more sensitive to a given contaminant than they would tee on Earth. Moreover, water exposure guidance levels are not available for many contaminants that might be found in spacecraft water supplies. Data collected from space-shuttle and Mir missions indicate that organic compounds found in processed water samples are vastly different from the list of target compounds developed by EPA for protection of pub- lic drinking water supplies. SUMMARY OF THE REPORT ON METHODS FOR DEVELOPING SWEGs Data In developing SWEGs, several types of data should be evaluated, in- cluding data on (1) the physical and chemical characteristics ofthe contami- nant, (2) in vitro toxicity studies, (3) toxicokinetic studies, (4) animal toxic- ity studies conducted over a range of exposure durations, (5) genotoxicity studies, (6) carcinogenicitybioassays, (7) human clinical and epidemiology studies, and (~) mechanistic studies. All observed toxic effects should be considered, including mortality, morbidity, functional impairment, neuro- toxicity, immunotoxicity, reproductive toxicity, genotoxicity, and carcino- genicity. Data from oral exposure studies should be used particularly drinking water and feed studies in which the duration of exposure approximates anticipated human exposure times. Gavage studies can also be used, but they should be interpreted carefully because they involve the bolus adminis- tration of a substance directly to the stomach within a brief period of time.

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4 Spacecraft Water Exposure Guidelines Such exposure could result in blood concentrations of contaminants and attendant effects that might not be observed if the administration were spread out over several smaller doses, as would be expected with the normal pattern of water consumption. Dermal absorption and inhalation studies should also be evaluated, because exposures from those routes occur when water is used for hygiene purposes. There are several important determinants for deriving a SWEG, includ- ing identifying the most sensitive target organ or body system affected; the nature of the effect on the target tissue; the dose-response relationships for the target tissue; the rate of recovery; the nature and severity of the injury; cumulative effects; toxicokinetic data; interactions with other chemicals; and the effects of microgravity. Risk Assessment There are several risk assessment methods that can be used to derive SWEGs. Risk assessments for exposure to noncarcinogenic substances traditionally have been based on the premise that an adverse health effect will not occur below a specific threshold exposure. Given this assumption, an exposure guidance level can be established by dividing the no- observed-adverse-effect level (NOAEL) or the lowest-observed-adverse- effect level (LOAEL) by an appropriate set of uncertainty factors. This method requires making judgements about the critical toxicity end point relevant to a human in space, the appropriate study for selecting a NOAEL or LOAEL, and the magnitudes of the uncertainty factors used in the pro- cess. For carcinogenic effects known to result from direct mutagenic events, no threshold dose would be assumed. However, when carcinogenesis re- sults from nongenotoxic mechanisms, a threshold dose can be considered. Estimation of carcinogenic risk involves fitting mathematical models to experimental data and extrapolating to predict risks at doses that are usually well below the experimental range. The multistage model of Armitage and Doll (1960) is used most frequently for low-dose extrapolation. According to multistage theory, a malignant cancer cell develops from a single stem cell as a result of several biologic events (e.g., mutations) that must occur in a specific order. There also is a two-stage model that explicitly provides for tissue growth and cell kinetics. An alternative to the traditional carcinogenic and noncarcinogenic risk assessment methods is the benchmark dose (BMD) approach. The BMD is the dose associated with a specified low level of excess health risk, gener-

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Introduction s ally in the risk range of 1%-10% (BMDLo, and BMDL,o), that can be esti- mated from modeled data with little or no extrapolation outside the experi- mental dose range. Like the NOAEL and LOAEL, respectively, the BMDLo~ and BMDL~o are starting points for establishing exposure guide- lines and should be modified by appropriate exposure conversions and uncertainty factors. Scientific judgment is often a critical, overriding factor in applying the methods described above. It is recommended that when sufficient dose- response data are available, the BMD approach be used to calculate expo- sure guidelines. However, in the absence of sufficient data, or when special circumstances dictate, the other, more traditional approaches should be used. Special Considerations for NASA When deriving SWEGs, either by the traditional or BMD approach, it will be necessary to use exposure conversions and uncertainty factors to adjust for weaknesses or uncertainties about the data. When adequate data are available, exposure conversions that NASA should use include those to adjust for target tissue dose, differences in exposure duration, species differ- ences, and differences in routes of exposure. Uncertainty factors should also be used to extrapolate animal exposure data to humans when human exposure data are unavailable or inadequate; to extrapolate data from subchronic studies to chronic exposure; to account for using BMDL~o in- stead of BMDLo~ (or a LOAEL instead of aNOAEL); to account for experi- mental variation; and to adjust for spaceflight factors that could alter the toxicity of water contaminants. The latter factors are used to account for uncertainties associated with microgravity, radiation, and stress. Some of the ways astronauts canbe physically, physiologically, andpsychologically compromised include decreased muscle mass, decreased bone mass, de- creased red blood cell mass, depressed immune systems, altered nutritional requirements, behavioral changes, shift of body fluids, altered blood flow, altered hormonal status, altered enzyme concentrations, increased sensitiza- tion to cardiac arrhythmia, and altered drug metabolism. There is generally little information to permit a quantitative conversion that would reflect altered toxicity resulting from spaceflight environmental factors. Thus, spaceflight uncertainty factors should be used when available information on a substance indicates that it could compound one or more aspects of an astronaut's condition that might already be compromised in space.

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6 Spacecraft Water Exposure Guidelines Another commonly used uncertainty factor is one that accounts for variable susceptibilities in the human population. That uncertainty factor is used to protect sensitive members of the general population, including young children, pregnant women, and the immune compromised. Because the astronaut population is typically composed of healthy, nonpregnant adults, the subcommittee believes that an uncertainty factor for intraspecies differences should only be used if there is evidence that some individuals could be especially susceptible to the contaminant. Exposure Guidelines Set by Other Organizations Several regulatory agencies have established exposure guidance levels for some of the contaminants of concern to NASA. Those guidance levels should be reviewed before SWEGs are established. The purpose of this comparison would not be simply to mimic the regulatory guidelines set elsewhere, but to determine how and why other exposure guidelines might differ from those of NASA and to assess whether those differences are reasonable in light of NASA's special needs. REVIEW OF SWEG REPORTS NASA is responsible for selecting the water contaminants for which SWEGs will be established and for developing documentation on how SWEG values were determined. As described above, the procedure for developing SWEGs involves identifying toxicity effects relevant to astro- nauts and calculating exposure concentrations on the basis of those end points. The lowest exposure concentration is selected as the SWEG, be- cause the lowest value would be expected to protect astronauts from mani- festing the other effects as well. To ensure that the SWEGs are developed in accordance with the NRC guidelines (2000b), NASA requested that the NRC subcommittee independ- ently review NASA's draft SWEGs documents. NASA's draft documents summarize data relevant to assessing risk from exposure to individual con- taminants in water only; they are not comprehensive reviews of the avail- able literature on specific contaminants. Furthermore, although the sub- committee is mindful that contaminants will be present as a mixture in drinking water and the potential exists for interactions, the subcommittee was asked to consider each chemical on an individual basis. The subcom- mittee reviews drafts of NASA's SWEG documents and provides comments

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Introduction and recommendations in a series of interim reports (see NRC 1999; 2000c,d,e; 2001~. The subcommittee reviews NASA's documents as many times as necessary until it is satisfied that the SWEGs are scientifically justified. Because of the enormous amount of data presented in the SWEG re- ports, the NRC subcommittee cannot verify all the data used by NASA. The NRC subcommittee relies on NASA for the accuracy and completeness of the toxicity data cited in the SWEG reports. This report is the first volume in the series Spacecraft Water Exposure Guicle1/tines for Se1/tectec! Contaminants. SWEG reports for chloroform, di- chioromethane, di-n-buty! phthalate, di(2-ethy~hexyI) phthalate, 2-mer- captobenzothiazole, nickel, phenol, N-phenyI-beta-naphthylamine, and silver are included in the appendix of this report. The subcommittee con- cludes that the SWEGs developed in those documents are scientifically valid values on the basis of the data reviewed by NASA and are consistent with the NRC guideline report. SWEG reports for additional chemicals will be presented in subsequent volumes. REFERENCES Armitage, P., and R. Doll. 1960. Stochastic models for carcinogenesis. Pp.19-38 in Proceedings ofthe Fourth Berkeley Symposium on Mathematical Statistics end probability, Vol.4, J. Neyman, ed. Berkeley, CA: University ofCalifornia Press. NRC (National Research Council). 1992. Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants. Wash- ington, DC: National Academy Press. NRC (National Research Council). 1994. Spacecraft Maximum Allowable Con- centrations for Selected Airborne Contaminants, Volume 1. Washington, DC: National Academy Press. NRC (National Research Council). 1996a. Spacecraft Maximum Allowable Con- centrations for Selected Airborne Contaminants, Volume 2. Washington, DC: National Academy Press. NRC (National Research Council). 1996b. Spacecraft Maximum Allowable Con- centrations for Selected Airborne Contaminants, Volume 3. Washington, DC: National Academy Press. NRC (National Research Council). 1999. Letter Report 1 on Spacecraft Water Exposure Guidelines. Washington, DC: National Academy Press. NRC (National Research Council). 2000a. Spacecraft Maximum Allowable Con- centrations for Selected Airborne Contaminants, Volume 4. Washington, DC: National Academy Press.

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8 Spacecraft Water Exposure Guidelines NRC (National Research Council). 2000b. Methods for Developing Spacecraft Water Exposure Guidelines. Washington, DC: National Academy Press. NRC (National Research Council). 2000c. Letter Report 2 on Spacecraft Water Exposure Guidelines. Washington, DC: National Academy Press. NRC (National Research Council). 2000d. Interim Report 3 on Spacecraft Wa- ter Exposure Guidelines. Washington, DC: National Academy Press. NRC (National Research Council). 2000e. Interim Report 4 on Spacecraft Wa- ter Exposure Guidelines. Washington, DC: National Academy Press. NRC (National Research Council). 2001. Interim Report 5 on Spacecraft Water Exposure Guidelines. Washington, DC: National Academy Press.