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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants Volume 5
Introduction Construction of the International Space Station (ISS)âa multinational ef- fortâbegan in 1999. In its present configuration, it is expected to carry a crew of three to six astronauts for up to 180 days (d). Because the ISS is a closed and complex environment, some contamination of its internal atmosphere is un- avoidable. Several hundred chemical contaminants may be found in its closed- loop atmosphere, most at very low concentrations. Important sources of atmospheric contaminants include off-gassing of cabin materials, operation of equipment, and metabolic waste products of crew. Other potential sources of contamination are releases of toxic chemicals from experiments and from manufacturing activities performed on the ISS as well as accidental spills and fires. The water recycling system also produces chemical contaminants that can enter the cabin air. Astronauts potentially can be chroni- cally exposed to low concentrations of airborne contaminants and, in the event of an accidentâsuch as a leak, spill, or fireâto high concentrations of contaminants. The National Aeronautics and Space Administration (NASA) seeks to en- sure the health and safety of astronauts and to prevent their exposure to toxic amounts of spacecraft contaminants. Consequently, exposure limits need to be established for continuous exposure of astronauts to spacecraft contaminants for up to 180 d (for normal spacecraft operations) and for short-term (1 to 24 h) emergency exposures to high concentrations of contaminants. To protect space crews from air contaminants, NASA requested that the National Research Council (NRC) provide guidance for developing spacecraft maximum allowable concentrations (SMACs) and review NASAâs development of exposure guidelines for specific chemicals. The NRC convened the Commit- tee on Spacecraft Exposure Guidelines to address this task. The committee pub- lished Guidelines for Developing Spacecraft Maximum Allowable Concentra- 3
4 SMACs for Selected Airborne Contaminants tions for Space Station Contaminants (NRC 1992). A second report, Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Vol- ume 1 (NRC 1994), addressed 11 chemicals: acetaldehyde, ammonia, carbon monoxide, formaldehyde, freon 113, hydrogen, methane, methanol, octamethyl- trisiloxane, trimethylsilanol, and vinyl chloride. Volume 2 of the report (NRC 1996a) presented SMACs for acrolein, benzene, carbon dioxide, 2- ethoxyethanol, hydrazine, indole, mercury, methylene chloride, methyl ethyl ketone, nitromethane, 2-propanol, and toluene. Volume 3 (NRC 1996b) ad- dressed bromotrifluoromethane (halon 1301), 1-butanol, tert-butanol, diacetone alcohol, dichloroacetylene, 1,2-dichloroethane, ethanol, ethylbenzene, ethylene glycol, glutaraldehyde, trichloroethylene, and xylene. Volume 4 (NRC 2000a) reviewed acetone, C3 to C8 aliphatic saturated aldehydes, hydrogen chloride, isoprene, methylhyrazine, perfluoropropane and other aliphatic perfluoroal- kanes, polydimethylcyclosiloxanes, dichlorofluoromethane (freon 21), chlorodi- fluoromethane (freon 22), trichlorofluoromethane (freon 11), dichlorodifluoro- methane (freon 12), 4-methyl-2-pentanone, chloroform, furan, and hydrogen cyanide. This report (Volume 5) presents SMACs for acrolein, C3-C8 aliphatic saturated aldehydes, ammonia, benzene, n-butanol, C2-C9 alkanes, carbon diox- ide, carbon monoxide, 1,2-dichlorethane, dimethylhydrazine, ethanol, formalde- hyde, limonene, methanol, methylene chloride, propylene glycol, toluene, trimethylsilanol, xylenes. Most of these chemicals were reviewed in previous SMAC volumes, with the exception of C2-C9 alkanes, methylene chloride, di- methylhydrazine, limonene, and propylene glycol. The reason for the review of chemicals in Volume 5 is that many of them have not been examined for more than 10 years, and new research necessitates examining the documents to ensure that they reflect current knowledge. New knowledge can be in the form of toxicologic data or in the application of new approaches for analysis of available data. In addition, because NASA anticipates longer space missions beyond low Earth orbit, SMACs for 1,000-d exposures have also been developed. SMACs are defined as the maximum concentrations of airborne sub- stances that will not produce adverse health effects, cause significant discomfort, or degrade crew performance. SMACs are classified into 1- and 24-hour (h) emergency SMACs and 7-, 30-, and 180-d continuous SMACs. The SMACs for 1,000-d exposures are intended for longer space missions. The 1- and 24-h SMACs are to be used in emergency situations, such as accidental spills or fires. Temporary discomfort (such as mild skin or eye irritation) might occur, but if the 1- and 24-h SMACs are not exceeded, there should be no marked effect on judgment, performance, or the ability to respond to emergencies. The 7-, 30-, and 180-d SMACs are guidance concentrations intended to prevent adverse health effects, either immediate or delayed (over the course of a lifetime), and to avoid impairing crew performance after continuous exposures (which can last as long as 180 d) to contaminants in the ISS environment. These values are for normal operations of the ISS.
Introduction 5 SUMMARY OF REPORT ON METHODS FOR DEVELOPING SMACS In developing SMACs, several types of data should be evaluated, includ- ing (1) the physical and chemical characteristics of the contaminant, (2) in vitro toxicity studies, (3) toxicokinetic studies, (4) mechanistic studies, (5) animal toxicity studies conducted over a range of exposure durations, (6) genotoxicity studies, (7) carcinogenicity bioassays, and (8) human clinical and epidemiology studies. All observed toxic effects should be considered, including mortality, morbidity, functional impairment, specific organ system toxicities (such as re- nal, hepatic, and endocrine), neurotoxicity, immunotoxicity, reproductive toxic- ity, genotoxicity, and carcinogenicity. Toxicity data from human studies are most applicable and are used when available in preference to data from animal studies and in vitro studies. The toxicity data from animal species most repre- sentative of humans in terms of pharmacodynamic and pharmacokinetic proper- ties are used for determining SMACs. Toxicity data from inhalation exposures are most useful for setting SMACs for airborne contaminants because inhalation is the most likely route of exposure. There are several important determinants for deriving a SMAC, including identifying the most sensitive target organ or body system affected, the nature of the effect on the target tissue, the exposure duration in relation to the SMAC being developed, the dose-response relationship for the target tissue, the rate of recovery, the nature and severity of the injury, cumulative effects, pharma- cokinetic data, interactions with other chemicals, and effects of microgravity. Derivation of the SMACs in this report is informed by NRC (1992, 2000b) guidelines. Risk Assessment Several risk assessment methods can be used to derive SMACs. Risk as- sessments for exposure to noncarcinogenic substances traditionally have been based on the premise that an adverse health effect will not occur below a spe- cific 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 uncer- tainty factors. This method requires making judgments 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. Estimating car- cinogenic risk involves fitting mathematical models to experimental data and extrapolating to predict risks at doses that are usually well below the experimen-
6 SMACs for Selected Airborne Contaminants tal range. A linearized form of the multistage model has historically been used in cancer risk assessment. According to multistage theory, a malignant cancer cell develops from a single stem cell as a result of several biologic events (for exam- ple, mutations) that must occur in a specific order. Other models, such as two- stage clonal expansion models, have been used in cancer risk assessment. EPAâs Guidelines for Carcinogen Risk Assessment (EPA 2005) also introduce modifi- cations to the assessment process. 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% to 10%, that can be estimated from modeled data with little or no extrapolation outside the experimental dose range. 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, and these are often used as a point of departure for estimating doses thought to be of negligible risks. Use of the lower confidence limit provides a suitable method to account for sampling variability. However, the use of a point estimate of the BMD, with incorporation of an additional uncertainty factor to account for experimental variation, may be more appropriate for certain types of data. There are many ways to apply BMD models. Ideally, mechanistic information about a com- poundâs toxic action can guide the choice of a model. In the absence of this in- sight, model averaging approaches can be used to estimate points of departure. Like the NOAEL and LOAEL, BMDL01 and BMDL10 are points of departure for establishing exposure guidelines and should be modified by appropriate expo- sure 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 special circum- stances dictate, the other, more traditional approaches should be used. Special Considerations for NASA When deriving SMACs, by either the NOAEL/LOAEL or the BMD ap- proach, it is 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. 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 in- stead of a NOAEL); to account for experimental variation; and to adjust for
Introduction 7 spaceflight factors that could alter the toxicity of 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 psy- chologically compromised include decreased muscle mass, decreased bone mass, decreased red blood cell mass, depressed immune systems, altered nutri- tional 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 toxic- ity resulting from spaceflight environmental factors. Thus, spaceflight uncer- tainty factors should be used when available information on a substance indi- cates that it could affect one or more aspects of an astronautâs condition that might already be compromised in space. Another commonly used uncertainty factor is one that accounts for vari- able 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 popula- tion is typically composed of healthy nonpregnant adults, the committee consid- ers that an uncertainty factor for intraspecies differences should be used only if there is evidence that some individuals could be especially susceptible to the contaminant. These differences could be observed among astronauts who have 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 SMACs 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 NASAâs guidelines and to assess whether those differences are reasonable in light of NASAâs spe- cial needs. REVIEW OF SMAC REPORTS NASA is responsible for selecting the contaminants for which SMACs will be established and for developing documentation on how SMAC values were determined. As described above, the procedure for developing SMACs involves identifying toxicity effects relevant to astronauts and calculating expo- sure concentrations on the basis of those end points. The lowest concentration is selected as the SMAC, because the lowest value would be expected to protect astronauts from manifesting other effects. To ensure that the SMACs are developed in accordance with the NRC guidelines (NRC 1992), NASA requested that the NRC committee independ-
8 SMACs for Selected Airborne Contaminants ently review NASAâs draft SMAC documents. NASAâs draft documents sum- marize data relevant to assessing risk from exposure to individual contaminants in air only; they are not comprehensive reviews of the available literature on specific contaminants. Furthermore, although the committee is mindful that con- taminants will be present as mixtures and the potential exists for interactions, it was asked to consider each chemical on an individual basis. The committee re- views NASAâs SMAC documents and provides comments and recommenda- tions in a series of interim reports (see NRC 2004a,b, 2005a,b, 2006a,b, 2007a,b, 2008). The committee reviews NASAâs documents as many times as necessary until it is satisfied that the SMACs are scientifically justified. Because of the enormous amount of data presented in the SMAC reports, the NRC committee cannot verify all the data NASA used. The NRC committee relies on NASA for the accuracy and completeness of the toxicity data cited in the SMAC reports. This report is the fifth volume in the series Spacecraft Maximum Allow- able Concentrations for Selected Airborne Contaminants. The SMACs pre- sented here supersede values presented in earlier volumes; however, the older volumes often contain a more complete review of the literature. Volume 5 sup- plements the earlier volumes by describing new data relevant to setting SMACs and by showing how new approaches can be applied to both older and newer data. SMAC reports for acrolein, C3-C8 aliphatic saturated aldehydes, ammonia, benzene, n-butanol, C2-C9 alkanes, carbon dioxide, carbon monoxide, 1,2- dichlorethane, dimethylhydrazine, ethanol, formaldehyde, limonene, methanol, methylene chloride, propylene glycol, toluene, trimethylsilanol, xylenes are in- cluded in the appendix of this report. The committee concludes that the SMACs developed in those documents are scientifically valid based on data reviewed by NASA and are consistent with the guideline reports (NRC 1992, 2000). REFERENCES EPA (U.S. Environmental Protection Agency). 2005b. Guidelines for Carcinogen Risk Assessment. EPA/630/P-03/001F. Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC. March 2005 [online]. Available: http://cfpub. epa.gov/ncea/cfm/recordisplay.cfm?deid=116283 [accessed August 1, 2008]. NRC (National Research Council). 1992. Guidelines for Developing Spacecraft Maxi- mum Allowable Concentrations for Space Station Contaminants. Washington, D.C.: National Academy Press. NRC (National Research Council). 1994. Spacecraft Maximum Allowable Concentra- tions for Selected Airborne Contaminants, Vol. 1. Washington, D.C.: National Academy Press. NRC (National Research Council). 1996a. Spacecraft Maximum Allowable Concentra- tions for Selected Airborne Contaminants, Vol. 2. Washington, D.C.: National Academy Press. NRC (National Research Council). 1996b. Spacecraft Maximum Allowable Concentra- tions for Selected Airborne Contaminants, Vol. 3. Washington, D.C.: National Academy Press.
Introduction 9 NRC (National Research Council). 2000a. Spacecraft Maximum Allowable Concentra- tions for Selected Airborne Contaminants, Vol. 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). 2004. Interim Report 9 on Spacecraft Exposure Guidelines. Washington, DC: National Academy Press. NRC (National Research Council). 2005a. Interim Report 10 on Spacecraft Exposure Guidelines. Washington, DC: National Academy Press. NRC (National Research Council). 2005b. Interim Report 11 on Spacecraft Exposure Guidelines. Washington, DC: National Academy Press. NRC (National Research Council). 2006a. Interim Report 12 on Spacecraft Exposure Guidelines. Washington, DC: National Academy Press. NRC (National Research Council). 2006b. Interim Report 13 on Spacecraft Exposure Guidelines. Washington, DC: National Academy Press. NRC (National Research Council). 2007a. Interim Report 14 on Spacecraft Exposure Guidelines. Washington, DC: National Academy Press. NRC (National Research Council). 2007b. Interim Report 15 on Spacecraft Exposure Guidelines. Washington, DC: National Academy Press. NRC (National Research Council). 2008. Interim Report 16 on Spacecraft Exposure Guidelines. Washington, DC: National Academy Press.