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 of three to six astronauts for up to 180 days (d). 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-loop atmosphere and recycled water of the space station.

To protect space crews from contaminants in potable and hygiene water, 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 development of the 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 Committee on Spacecraft Water Exposure Guidelines to address this task. The Committee published its first report Methods for Developing Spacecraft Water Exposure Guidelines in 2000. A second report, Spacecraft Water Exposure Guidelines for Selected Contaminants, Volume 1 (2004a), used these guidelines to set exposure levels for nine chemicals: chloroform, dichloromethane, di-n-butyl phthalate, di(2-ethylhexyl) phthalate, 2-mercaptobenzothiazole, nickel, phenol, N-phenyl-beta-napthylamine, and silver.

Spacecraft water exposure guidelines (SWEGs) are to be established for exposures of 1, 10, 100, and 1,000 d. The 1-d SWEG is a concentration of a substance in water that is judged to be acceptable for the performance of specific tasks during rare emergency conditions lasting



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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 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 of three to six astronauts for up to 180 days (d). 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-loop atmosphere and recycled water of the space station. To protect space crews from contaminants in potable and hygiene water, 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 development of the 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 Committee on Spacecraft Water Exposure Guidelines to address this task. The Committee published its first report Methods for Developing Spacecraft Water Exposure Guidelines in 2000. A second report, Spacecraft Water Exposure Guidelines for Selected Contaminants, Volume 1 (2004a), used these guidelines to set exposure levels for nine chemicals: chloroform, dichloromethane, di-n-butyl phthalate, di(2-ethylhexyl) phthalate, 2-mercaptobenzothiazole, nickel, phenol, N-phenyl-beta-napthylamine, and silver. Spacecraft water exposure guidelines (SWEGs) are to be established for exposures of 1, 10, 100, and 1,000 d. The 1-d SWEG is a concentration of a substance in water that is judged to be acceptable for the performance of specific tasks during rare emergency conditions lasting

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 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 provided 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 performance 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 operating 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 spaceflights and habitation of the ISS, water reclamation, treatment, and recycling is required. Water for long spaceflights can be reclaimed from several on-board sources, including humidity condensate from the cabin, hygiene water (shower and wash water), and urine. Each of those sources will have a variety of contaminants. Humidity condensate will have contaminants released into the cabin from crew activities (for example, by-products of crew metabolism, food preparation, and hygiene activities) from routine operation of the air-revitalization system, from off-gassing of materials and hardware, from payload 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 metabolites 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 (such as silver and 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 the use of condensate from inside the cabin as a source of drinking water could introduce some unwanted substances into the water system.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 SUMMARY OF THE REPORT ON METHODS FOR DEVELOPING SWEGs Data In developing SWEGs, several types of data should be evaluated, including data on (1) the physical and chemical characteristics of the contaminant, (2) in vitro toxicity studies, (3) toxicokinetic studies, (4) animal toxicity studies conducted over a range of exposure durations, (5) genotoxicity studies, (6) carcinogenicity bioassays, (7) human clinical and epidemiology studies, and (8) mechanistic studies. All observed toxic effects should be considered, including mortality, morbidity, functional impairment, specific organ system toxicities (such as renal, hepatic, and endocrine), neurotoxicity, immunotoxicity, reproductive toxicity, genotoxicity, and carcinogenicity. Taste and odor thresholds are also relevant end points for setting SWEGs. 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 administration of a substance directly to the stomach within a brief period of time. 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 exposure from those routes occur when water is used for hygiene purposes. There are several important determinants for deriving a SWEG, including identifying the most sensitive target organ or body system affected; the nature of the effect on the target tissue; 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

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 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 process. For carcinogenic effects known to result from direct mutagenic events, no threshold dose would be assumed. However, when carcinogenesis results 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 (for example, 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 NOAEL and LOAEL risk assessment methods that are used to set carcinogenic and noncarcinogenic concentrations is the benchmark dose (BMD) approach. The BMD is the dose associated with a specified low level of excess health risk, generally in the risk range of 1-10% (BMDL01 and BMDL10), that can be estimated from modeled data with little or no extrapolation outside the experimental dose range. The BMDL01 and BMDL10 are defined as the statistical lower confidence limits of doses that correspond to excess risks of 1% and 10% above background concentrations, respectively. Use of the lower confidence limit provides a suitable method to incorporate experimental uncertainty. However, the use of a central estimate of the benchmark dose, with incorporation of an additional uncertainty factor to account for experimental variation, may be more appropriate for certain kinds of data. Like the NOAEL and LOAEL, the BMDL01 and BMDL10 are points of departure for establishing exposure guidelines 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 exposure guidelines. However, in the absence of sufficient data, or when

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 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 differences, and differences in routes of exposure.1 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 BMDL10 instead of BMDL01 (or a LOAEL instead of a NOAEL); to account for experimental 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 can be physically, physiologically, and psychologically compromised include decreased muscle mass, decreased bone mass, decreased 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 sensitization to cardiac arrhythmias, 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. 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 nonpreg- 1 Two liters per day was used as the default for drinking water consumption, although this quantity may not be applicable in all situations.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 nant adults, the committee 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. These differences could be observed among astronauts who possess genetic polymorphisms for well-established genes. 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 astronauts and calculating exposure concentrations on the basis of those end points. The lowest exposure concentration is selected as the SWEG, because the lowest value would be expected to protect astronauts from manifesting other effects as well. To ensure that the SWEGs are developed in accordance with the NRC guidelines (2000b), NASA requested that the NRC committee independently review NASA’s draft SWEGs documents. NASA’s draft documents summarize data relevant to assessing risk from exposure to individual contaminants in water only; they are not comprehensive reviews of the available literature on specific contaminants. Furthermore, although the committee is mindful that contaminants will be present as mixtures in drinking water and the potential exists for interactions, the committee was asked to consider each chemical on an individual basis. The committee reviews NASA’s SWEG documents and provides comments and recommendations in a series of interim reports (see NRC 2000c,d,e; 2001; 2002; 2003; 2004b,c; 2005). The committee reviews

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 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 reports, the NRC committee cannot verify all the data used by NASA. The NRC committee relies on NASA for the accuracy and completeness of the toxicity data cited in the SWEG reports. This report is the second volume in the series Spacecraft Water Exposure Guidelines for Selected Chemicals. SWEG reports for acetone, alkylamines, ammonia, barium, cadmium, caprolactam, formate, formaldehyde, manganese, total organic carbon, and zinc are included in the appendix of this report. The committee concludes that the SWEGs developed in those documents are scientifically valid values based on the data reviewed by NASA and are consistent with the NRC (2000b) 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 of the Fourth Berkeley Symposium on Mathematical Statistics and Probability, J. Neyman, ed. Berkeley, CA: University of California Press. NRC (National Research Council). 1992. Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants. Washington, DC: National Academy Press. NRC (National Research Council). 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 1. Washington, DC: National Academy Press. NRC (National Research Council). 1996a. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 2. Washington, DC: National Academy Press. NRC (National Research Council). 1996b. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 3. Washington, DC: National Academy Press. NRC (National Research Council). 2000a. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 4. Washington, DC: National Academy Press. 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.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 NRC (National Research Council). 2000d. Interim Report 3 on Spacecraft Water Exposure Guidelines. Washington, DC: National Academy Press. NRC (National Research Council). 2000e. Interim Report 4 on Spacecraft Water 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. NRC (National Research Council). 2002. Interim Report 6 on Spacecraft Water Exposure Guidelines. Washington, DC: The National Academies Press. NRC (National Research Council). 2003. Interim Report 7 on Spacecraft Water Exposure Guidelines. Washington, DC: The National Academies Press. NRC (National Research Council). 2004a. Spacecraft Water Exposure Guidelines for Selected Contaminants. Volume 1. Washington, DC: The National Academies Press. NRC (National Research Council). 2004b. Interim Report 8 on Spacecraft Water Exposure Guidelines. Washington, DC: The National Academies Press. NRC (National Research Council). 2004c. Interim Report 9 on Spacecraft Exposure Guidelines. Washington, DC: The National Academies Press. NRC (National Research Council). 2005. Interim Report 10 on Spacecraft Exposure Guidelines. Washington, DC: The National Academies Press.