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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 11 Ethanol J. Torin McCoy Toxicology Group Habitability and Environmental Factors Division Johnson Space Center National Aeronautics and Space Administration Houston, Texas INTRODUCTION This document presents the results of an update and reassessment of the toxicity of ethanol as it relates to the establishment of appropriate spacecraft maximum allowable concentrations (SMACs). This reassessment refers to a chapter on ethanol published in Volume 3 of Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants (James 1996). Since publication of Volume 3, a number of research articles on ethanol have been published in the scientific literature. However, a large quantity of them focus on the health consequences of oral consumption and abuse of ethanol and have limited relevance to inhalation exposures in a spacecraft environment. As documented in Volume 3, the overall lack of information on inhalation exposures seems to be driven by the presumption that exposures to ethanol vapors are not widely applicable and that ethanol vapors have low toxicity and are a minimal health risk. A fairly recent development that somewhat catalyzed a renewed interest in the health consequences of exposure to ethanol by inhalation is the emergence of ethanol as a significant additive or replacement for motor vehicle fuels. For example, ethanol is often introduced into gasoline as an oxygenate (5-10%) to help limit emissions of carbon monoxide, ozone, and various volatile organic compounds (Ahmed 2001). Additionally, certain vehicles are equipped to use E85 fuels (85% ethanol blended with 15% unleaded gasoline). Although exposure assumptions for these routes can differ significantly from spacecraft applications, some useful data have been generated and were considered in this reassessment (Winebrake et al. 2001, Nadeau et al. 2003, Chu et al. 2005). This reassessment evaluates new data to determine whether the SMACs established in Volume 3 can still be supported as the most appropriate spacecraft exposure limits for ethanol. The toxicologic end points previously evaluated for which acceptable concentrations (ACs) were calculated in Volume 3 include neurotoxicity, irritation, hepatotoxicity, and flushing. New studies applicable to
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 these end points were reviewed and are incorporated in this reassessment. Any other relevant end points for which data emerged since publication of Volume 3 were addressed as they were identified. Another important aspect of this review is the need to set 1,000-d SMACs for longer-term crew exposures. Longer exposures would be of interest in assessing possible lengthy missions on the International Space Station (ISS) or in future lunar or Martian exploration efforts. The intent of this reassessment is not to revisit all the studies that were considered in the original Volume 3 chapter. Much of the foundation for this review (e.g., discussion on metabolism, rationale for not addressing fetal risks) was provided in Volume 3; thus, these two write-ups should be viewed as complementary. ISS MONITORING DATA Volume 3 was written before NASA’s full involvement with ISS and thus does not contain information on the relevance of ethanol in that environment or on monitored concentrations of ethanol in the ISS atmosphere. As a compound potentially used in a variety of spacecraft applications, ethanol can be introduced to the ISS atmosphere through many sources, including cleaning products such as alcohol wipes, payloads, substances in medical kits, and crew hygiene products. Other possible contributors to consider are the small amounts of ethanol that can be formed and released endogenously by humans. Ethanol is generally monitored (near-instantaneous readings) around 5-8 milligrams per cubic meter (mg/m3) in the ISS atmosphere, although measurements have approached 20 mg/m3 on occasion. Because of its extreme solubility in water, a main concern with ethanol in the ISS atmosphere is its potential to affect the processing of humidity condensate by the Russian water processing system. Recycled humidity condensate provides a significant percentage of potable water on ISS (50%+). Ethanol is a common organic component of ISS condensate, being measured at concentrations as high as 156 mg/liter (L), with average ethanol concentrations around 50-55 mg/L. For reasons that are not fully understood, U.S. Laboratory condensate frequently contains higher ethanol concentrations than condensate from the Russian Service Module (Figure 11-1). As these ethanol concentrations can double the system design limit for the Russian processing equipment (80 mg/L), significant efforts have been made to identify and limit releases of ethanol and other volatiles to the ISS atmosphere. The presence of excess volatiles in humidity condensate can affect the processing system in several ways. As the Russian system includes an oxidizing reactor and downstream multifiltration beds, system resources may be spent in oxidizing and removing relatively low-toxicity liquid components (e.g., ethanol). This has operational impacts for these limited life items and can impair performance when the system is also challenged with more toxic organic compounds.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 FIGURE 11-1 Ethanol concentrations (mg/L) measured in U.S. Lab Condensate (USL) and Russian Service Module (SM) condensate on ISS. Source: Data generated by NASA Johnson Space Center, Water and Food Analytical Laboratory. REVIEW OF ACS FOR ETHANOL IN VOLUME 3 (James 1996) In Volume 3, available toxicologic data on ethanol were presented and discussed in terms of specific end points. The review did not discuss the full range of toxicologic data on ethanol, as much of the data were not relevant to spacecraft applications or were deemed to be an issue only in association with chronic abuse (e.g., effects on skeletal or vascular smooth muscle). The document discussed adverse reproductive and developmental effects resulting from ethanol intake in some detail, but developing an AC was not deemed necessary given the lack of evidence that non-narcotic exposures could cause these effects (James 1996). Ultimately, ACs were developed for neurotoxicity, irritation, “flush response” (elevated skin temperature, pulse rate, and observable facial responses), and hepatotoxicity (Table 11-1). Most ACs were consistent across exposure time frames, as peak blood ethanol concentrations (BECs) are generally achieved in the first few hours of exposure (Pastino et al. 1997), and effects were not expected to be time dependent. For the irritation and flush response ACs, the 7- to 180-d ACs were set lower than the 1- and 24-h ACs not because of exposure time considerations but because a small margin of discomfort is allowable for the shorter-term ACs. CONSIDERATION OF NEW DATA The subsequent sections discuss new data available on the potential effects of inhalation exposure to ethanol. This includes studies not reviewed in Volume 3, and new studies published since 1996, as summarized in Table 11-2.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 TABLE 11-1 Acceptable Concentrations for Ethanol End Points in Volume 3 End Point Acceptable Concentration (mg/m3) 1 h 24 h 7 d 30d 180 d Neurotoxicity 7,000 7,000 7,000 7,000 7,000 Mucosal irritation (eye, nose) 10,000 10,000 2,000 2,000 2,000 Flush response 4,000 4,000 2,000 2,000 2,000 Hepatotoxicity N/Aa N/Aa 2,000 2,000 2,000 aFor hepatotoxicity, it was determined that non-narcotic exposures could not cause the relevant effects during these exposure time frames. Source: James 1996.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 TABLE 11-2 Toxicity Summary (For New Studies or Those Not Reviewed in Volume 3 SMAC Document) Concentration (mg/m3) Exposure Duration Species Results Referencea Inhalation 0, 500, 1,000, 2,000 (NOAEL) 6 h Human (n=5) No observable adverse neuromotor effects. BEC reached only 0.44 mg/dL (0.0004%). Nadeau et al. 2003 Inhalation 12,000 4 wk (6 h/d, 5 d/wk) SD rats (15 male, 15 female) Measured levels of certain neurochemicals (mediodorsal thalamus 5-hydroxyindoleacetic acid and hippocampal 5-hydroxytryptamine) were significantly reduced relative to controls in female but not in male rats. Chu et al. 2005 Inhalation 2,500 (NOAEL), 3,100, 3,900, 4,900, 6,100, and 7,600 Nasal lateralization evaluated with 1- to 10-s pulses. Human (n=6) None of the 6 volunteers could reliably lateralize ethanol at 2,500 mg/m3, but 4/6 (66%) could lateralize 3,100 mg/m3. Wise et al. 2006 Inhalation 19,000 (LOAEL) Nasal lateralization evaluated with 1- to 3-s pulses. Human anosmics (n=3) Identified nasal irritation threshold. Questions exist about exposure duration. Cometto-Muñiz and Cain 1990 Inhalation 90,000 (LOAEL) Nasal lateralization evaluated with 1- to 3-s pulses. Human (n=10) Identified eye irritation threshold. Questions exist about exposure duration and test method. Cometto-Muñiz and Cain 1996 Inhalation constant exposure 1,500 (NOAEL); Variable exposure 3,600 (NOAEL) Both conditions were 4-h exposures, but the variable exposure regime is not clearly defined. Human constant exposure (n=24); Variable exposure (n=16) Volunteers were asked to assess irritation of the eye, nose, throat, or skin and to rate it on a scale of 0 (not at all) to 5 (strong). For ethanol, the mean response at 1,500 mg/m3 remained about the same as the response for clean air. The mean response with variable exposures up to 3,600 mg/m3 was also consistent with clean air, but the authors do not adequately describe the regime. Seeber et al. 2002 aNone of these studies were used to set ACs or SMACs. Abbreviation: SD, Sprague-Dawley, LOAEL, lowest-observed-adverse-effect level; NOAEL, no-observed-adverse-effect level.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 Neurotoxicity The existing neurotoxicity AC (7,000 mg/m3 for all time frames) was based on observations (Lester and Greenberg 1951) that three individuals exposed to ethanol in air at 15,000 mg/m3 over 3-6 h did not report neurologic symptoms. Although lack of reported effects does not confirm the lack of performance detriments, it was noted that the BEC in this group reached only 10 mg/dL (0.01%), well below the level at which performance detriments have been observed in other studies reported in the scientific literature. Volume 3 noted one particularly applicable example in the work of Kennedy et al. (1993), which focused on the development of testing procedures that could be used to predict operational performance of air and space flight crew. The authors evaluated individual responses to a computer-based battery of performance tests (represented by the Armed Services Vocational Aptitude Battery) at different oral ethanol exposures (BECs of 150, 125, 100, 75, and 50 mg/dL). At each evaluated BEC except for 50 mg/dL (0.05%), the mean test score was below baseline performance, indicating various degrees of performance impairment. For example, the mean score at a BEC of 150 mg/dL was 17% lower than the baseline mean score. New Data Evaluation of the scientific literature since publication of Volume 3 found relatively few studies that specifically evaluated adverse neurologic impairment associated with inhalation exposures to ethanol. Nadeau et al. (2003) evaluated neuromotor effects in association with relatively low-level exposures to ethanol vapors. They exposed five volunteers to ethanol at 0, about 500, 1,000, and 2,000 mg/m3 for 6 h. Reaction time, body sway, hand tremor, and rapid alternating movements were evaluated before and after the exposures. Subjects were exposed for five consecutive days, although the exposures were separated by 24 h. The authors reported that exposures up to 2,000 mg/m3 did not result in significant neuromotor changes. Consistent with this conclusion, the BECs for test subjects exposed to ethanol at 500 and 1,000 mg/m3 were below detection limits, whereas exposure to ethanol at 2,000 mg/m3 resulted in a BEC of only 0.44 mg/dL (0.0004%). Chu et al. (2005) exposed 15 male and 15 female rats to ethanol at 12,000 mg/m3 for 4 wk (6 h/d, 5 d/wk) by inhalation. For the female rats, the authors noted that concentrations of certain neurochemicals (mediodorsal thalamus 5-hydroxyindoleacetic acid and hippocampal 5-hydroxytryptamine) were significantly reduced relative to controls. The biological significance of these results for humans in spaceflight is somewhat unclear, but it is worth noting that these compounds do relate to moods. However, the results do not outweigh the human data showing no adverse performance effects at similar ethanol concentrations.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 Pastino et al. (1997) evaluated the pharmacokinetics of inhaled ethanol in B6C3F1 mice and F344 rats to construct a physiologically based pharmacokinetic (PBPK) model of ethanol inhalation in humans. They exposed rats and mice to ethanol by inhalation of 100, 400, and 1,200 mg/m3 over 6 h and measured peak BECs. They developed a PBPK model to allow predictions of peak BECs in humans. The authors reported that the model accurately predicted the pharmacokinetics of ethanol in their inhalation study in mice and rats and was consistent with observed peak BECs for human males reported in the literature (primarily Lester and Greenberg 1951). The PBPK model predicted that the peak BEC in human males would reach a maximum of 293 μM (1.4 mg/dL or 0.001%) after inhalation of 1,200 mg/m3. The authors noted that this BEC was significantly lower than concentrations at which diminished fine motor skills and impaired judgment might begin to occur and was 1-2 orders of magnitude below legal blood ethanol limits. These studies suggest that the general range of BECs associated with mild performance impairment is 50-150 mg/dL (0.05-0.15%) (Nadeau et al. 2003). Consistent with this range, many states in the United States set their legal driving limit at 100 mg/dL (0.1%) or less. AC Development Ideally, the ACs would be based on an inhalation study that specifically evaluated the neurotoxicity of ethanol, as in the Nadeau et al. (2003) study. However, as the highest concentration used in that study (2,000 mg/m3) resulted in a BEC of only 0.44 mg/dL, it would be an inappropriately low no-observed-adverse-effect level (NOAEL) to use. Accordingly, the approach taken in this reassessment was to use the same Kennedy et al. (1993) and Lester and Greenberg (1951) data that served as the basis for neurotoxicity ACs in Volume 3 but to evaluate them in a slightly different manner. Kennedy et al. (1993) reported a neurotoxicity NOAEL of 50 mg/dL. Applying an adjustment from this target BEC to account for the sample size (√27/10) provides a target BEC of 26 mg/dL. Lester and Greenberg (1951) demonstrated (n = 3) that inhalation of ethanol at 15,000 mg/m3 resulted in a BEC of only 10 mg/dL, less than half the target BEC cited above. Given this margin, further adjustments to account for the small sample size in the Lester and Greenberg (1951) study were not deemed to be necessary. Further, as recent data from the Nadeau et al. (2003) study (n = 5) observed a BEC of only 0.44 mg/dL after inhalation of ethanol at about 2,000 mg/m3, it appears that the Lester and Greenberg (1951) results provide a reasonably conservative BEC estimate. Accordingly, an AC of 15,000 mg/m3 was established for all time frames as peak BECs are expected to occur within the first few hours of exposure, and because adverse neurologic health effects are not acceptable for any exposure period. Although benchmark dose modeling was initially considered for this end point, the small difference between the
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 NOAEL (50 mg/dL) and the lowest-observed-adverse-effect level (LOAEL) (75 mg/dl) suggests that it would not significantly improve the risk estimate. Hepatotoxicity The Volume 3 SMACs were based on the work of Di Luzio and Stege (1979). The authors evaluated hepatotoxicity in Sprague-Dawley rats after 26 d of continuous exposure to ethanol at 20,000 mg/m3. The study observed transient changes in liver triglyceride concentrations and glutamic-pyruvic transaminase activity on days 3, 6, and 9 of testing. However, these changes were considered adaptive, and the same parameters did not differ from controls by the end of the 26-d study. With 20,000 mg/m3 used as a NOAEL for hepatotoxicity, ACs were set for the 7-, 30-, and 180-d time frames (2,000 mg/m3 after application of an uncertainty factor of 10 for animal-to-human extrapolation). No exposure time adjustments were considered to be necessary given that BECs and liver triglyceride levels were reached quickly in the testing and declined sharply by the end of the exposure period. Additionally, no short-term ACs were established, as hepatotoxicity over these time frames was not deemed to be credible without narcotic exposures. New Data No new studies were identified that specifically evaluated the hepatotoxicity of ethanol after inhalation exposures. AC Development Given that no new studies were identified, the Volume 3 ACs based on the Di Luzio and Stege (1979) findings were retained. Consistent with the rationale in Volume 3 for the lack of necessity for exposure time adjustments, a 1,000-d AC for hepatotoxicity was also established (2,000 mg/m3). Di Luzio and Stege (1979) noted that inhalation exposure concentrations would have to be increasing on a stepwise basis for BECs to be sustained to a point where sustained hepatic effects might be observed. The authors concluded that “the ethanol vapor inhalation technique does not induce the classical hepatic alterations associated with ethanol liquid formula diets or following the acute oral administration of
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 ethanol.” Given that only one dose was used in the critical study, benchmark dose modeling was not pursued for this end point as part of this reevaluation. Mucosal Irritation The Volume 3 ACs for mucosal irritation were based on the findings of Lester and Greenberg (1951). In their study, the five volunteers reported only mild irritation (coughing and smarting of the eyes and nose) when exposed to ethanol at 10,000 mg/m3, and the effects dissipated so that no irritation was noted after 5-10 min of exposure. In contrast, there was continuous lacrimation at 30,000 mg/m3, and 40,000 mg/m3 was reported as intolerable. On the basis of these results, short-term ACs were set at 10,000 mg/m3, with long-term ACs set at 2,000 mg/m3 based on incorporation of an adjustment factor to account for the small sample size. New Data Several studies evaluated the nasal pungency associated with ethanol through nasal lateralization techniques (Wise et al. 2006, Cometto-Muñiz and Cain 1990). In these studies, both ethanol and clean air were introduced into a subject’s nostrils, and the concentration at which the subject could consistently identify which nostril received the ethanol exposure (through interaction with nerve endings and reports of burning, stinging, or other signs of irritation) was recorded. A limitation of these studies for SMAC purposes is that the developed detection thresholds may correspond to a relatively minor degree of irritation, and it is difficult to evaluate the impact of exposure duration. The exposure duration may have not been long enough to elicit a maximum response; conversely, any observed nasal sensation may dissipate with time. Using these techniques, Wise et al. (2006) found that none of the six volunteers could reliably lateralize ethanol at concentrations of 2,500 mg/m3, whereas four of six (66%) could lateralize about 3,000 mg/m3. These results support the long-term AC of 2,000 mg/m3 for ethanol set in Volume 3. Using similar lateralization techniques, Cometto-Muñiz and Cain (1990) reported that the threshold for nasal pungency (irritation) was about 19,000 mg/m3 in a group of three anosmics. These results are consistent with the upper end of the 10,000-20,000 mg/m3 proposed as an irritation threshold range by Lester and Greenberg (1951). With regard to eye irritation, Cometto-Muñiz and Cain (1996) observed that irritation did not occur until about 90,000 mg/m3, although the degree to which the test method (a specialized bottle cap) influenced the study findings is not clear. Seeber et al. (2002) also evaluated sensory irritation associated with inhalation exposures to ethanol. They exposed volunteers to ethanol under two test conditions: (1) 4 h of constant exposure to 0, 150, 760, and 1,500 mg/m3, and (2) 4 h of variable concentration exposure at 0, 200, 2,000, and 3,600 mg/m3. The volunteers (n = 24 for the constant exposure group, n = 16 for the
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 variable exposure group) were asked to assess irritation of the eye, nose, throat, or skin and to rate it on a scale between 0 (not at all) and 5 (strong). With constant exposures, the mean evaluated response to ethanol at 1,500 mg/m3 remained approximately the same as the response reported for clean air. For variable exposures, the mean response at 3,600 mg/m3 was also consistent with the clean air response, although the authors did not adequately describe how the variable exposure regime was implemented. AC Development Available study results support the existing Volume 3 short- and long-term ACs for ethanol, which are based on the Lester and Greenberg (1951) observations. Benchmark dose analysis was not pursued for this end point because of the qualitative nature of the response measurement with irritation (presence or absence of irritant effect). With regard to setting a 1,000-d AC for irritation, the same long-term AC (2,000 mg/m3) can be applied, as solvent irritation is expected to peak within an hour or less (Hempel-Jorgensen et al. 1999) and not to demonstrate time dependency beyond that point. Flush Response In Volume 3, ACs were developed that were protective against the flush response that is frequently observed in alcohol-sensitive subpopulations. This flush response is evidenced by visible facial flushing, an increase in pulse rate, blood pressure changes, elevated skin temperature, and other physical symptoms (Shibuya et al. 1989). These effects are believed to be related to a buildup of acetaldehyde, a main metabolic product of ethanol (Chan et al. 1986), as peak BECs do not differ among flushing and nonflushing subjects (Mizoi et al. 1979). Due to genetic differences related to differences in aldehyde dehydrogenase activity, 50-80% of Asians are susceptible to this adverse response to ethanol, compared with only 5-10% of Caucasians (Wolff 1972, Zeiner et al. 1979). Given these statistics, a fair percentage of crew members may exhibit this sensitivity, and final ACs should ensure that the potential for these adverse effects is minimized. Volume 3 set the flush response ACs by using breath acetaldehyde concentrations observed in a study by Zeiner et al. (1979) in which Caucasian and Asian volunteers were exposed to ethanol at 0.7 mL/kg of body weight (about 40 g of ethanol for a 70-kg individual). As Shibuya et al. (1989) reported that ethanol exposures from 0.3 to 0.5 mL/kg were sufficient to induce the flush re-
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 sponse in flush-sensitive individuals, flushing was expected in the Zeiner et al. (1979) subjects. Among Asian volunteers, 6 of 7 experienced flushing symptoms, whereas only 1 of 10 Caucasians reported these effects. In Volume 3, a NOAEL was estimated from this study by observing that peak breath acetaldehyde concentrations below 10 ng/mL (Figure 11-2) did not correspond with flushing in either exposure group. As the peak individual breath acetaldehyde concentration for any test subject was 60 ng/mL, the ethanol dose was downwardly adjusted by a factor of 6 to estimate an oral NOAEL. With standard exposure assumptions, this dose was extrapolated to an inhalation exposure that resulted in an AC of 2,000 mg/m3 for the 7-, 30-, and 180-d time frames. A doubling of the exposure concentration was deemed acceptable for short-term exposures (1- and 24-h ACs of 4,000 mg/m3). As part of this reevaluation it was determined that there was an error in the calculation for flush response ACs in Volume 3 (p. 196). In determining the ACs, the assumed inhalation absorption percentage (62%) was applied in the numerator rather than in the denominator of the AC equation, which resulted in an underestimation of the allowable air concentration by a factor of 2.5. Recalculating the ACs based on the correct application of the absorption fraction yields long-term ACs of 5,000 mg/m3 and corrected 1- and 24-h ACs of 10,000 mg/m3. FIGURE 11-2 Breath acetaldehyde concentrations (ng/mL) in Asian (left) and Caucasian (right) volunteers. Source: Zeiner et al. 1979. Reprinted with permission; copyright 1979, Alcoholism: Clinical and Experimental Research.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 New Data As stressed in Volume 3, it would be preferable to have a study that demonstrates that flushing is relevant to inhalation exposures to ethanol. Unfortunately, an inhalation study that evaluated the induction of the flush response in sensitive and nonsensitive populations was not located in the scientific literature as part of this reevaluation. Tardif et al. (2004) evaluated breath acetaldehyde concentrations (although the flush response was not specifically evaluated) in five nonsmoking Caucasian volunteers exposed to ethanol at 50, 200, and 2,000 mg/m3. In evaluating inhalation exposures (2-6 h) to ethanol at 2,000 mg/m3, the authors observed a maximum breath acetaldehyde concentration of 2.6 ng/mL among the five volunteers (Robert Tardif, University of Montreal, personal communication, October 11, 2006). Although this level is well below the NOAEL of 10 ng/mL of Zeiner et al. (1979), the Tardif et al. (2004) group did not appear to include any flush-sensitive individuals, and it is not unusual for flush-sensitive populations to exhibit breath acetaldehyde concentrations 3-5 times higher than nonflushers (Zeiner et al. 1979, Jones 1995). Thus, it is reasonable to conclude that flush-sensitive individuals may approach the 10-ng/mL NOAEL in association with inhalation exposure to ethanol at 2,000 mg/m3. AC Development With joint consideration of the Tardif et al. (2004) breath acetaldehyde measurements and the NOAEL estimated from Zeiner et al. (1979), an AC of 2,000 mg/m3 is established. Given that data for multiple doses are not available for the critical study, benchmark dose analysis was not pursued for this end point. With regard to the short-term ACs (1 and 24 h), mild flushing should be tolerable during temporary off-nominal situations. Where flushing is induced in the scientific literature (ethanol dose of 0.3-0.5 mL/kg per Shibuya et al. (1989)), the level of discomfort most test subjects experienced appears to be consistent with the degree of impairment allowable for short-term SMACs. Thus, the short-term ACs were set at the lower end of the ethanol dose used to elicit the flushing effect in sensitive individuals (0.3 mL/kg or 17 g for a 70-kg person). A short-term AC is calculated by making the same route-to-route extrapolation assumptions as in Volume 3.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 UPDATED RECOMMENDATIONS Literature not reviewed in Volume 3, in addition to new literature published since 1996, was considered in the preceding sections. This was done in an effort to update, if necessary, the recommendations for acceptable concentrations for ethanol inhalation exposure. These updated recommendations are summarized in Table 11-3. Also included in Table 11-3 are NASA’s proposed SMACs. These values were determined based on the lowest AC for the endpoints in consideration: neurotoxicity, sensory irritation, flush response, and hepatotoxicity.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 TABLE 11-3 Updated Acceptable Concentrations for Ethanol End Point, Data Species Uncertainty Factor Acceptable Concentration (mg/m3) Species Time Small n Space-flight 1 h 24 h 7 d 30 d 180 d 1,000 d Neurotoxicity Estimated NOAEL of 15,000 mg/m3 (Lester and Greenberg 1951); based on target BEC of 26 mg/dL (Kennedy et al.1993) Human 1 1 √27/10 (applied to target BEC) 1 15,000 15,000 15,000 15,000 15,000 15,000 Sensory Irritation NOAEL of 10,000 mg/m3 (Lester and Greenberg 1951) Human 1 1 √3/10 1 10,000 10,000 2,000 2,000 2,000 2,000 Flush Response LOAEL of 0.3 mL/kg (Shibuya et al. 1989) Human 1 1 1 1 15,000 15,000 - - - - NOAEL of 2,000 mg/m3 (Tardif et al. 2004) based on 10 ng/dL target breath acetaldehyde level (Zeiner et al. 1979) Human 1 1 1 1 - - 2,000 2,000 2,000 2,000 Hepatotoxicity NOAEL, 20,000 mg/m3, (Di Luzio and Stege 1979) Rat 10 1 1 1 - - 2,000 2,000 2,000 2,000 SMACs 10,000 10,000 2,000 2,000 2,000 2,000 -, Flush Response: Mild flushing should be tolerable during temporary off-nominal situations, so short-term ACs were set at the lower end of the ethanol dose used to elicit the flushing effect in sensitive individuals. -, Hepatotoxicty: Non-narcotic exposures could not cause the relevant effects during these exposure timeframes.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 REFERENCES Ahmed, F.E. 2001. Toxicology and human health effects following exposure to oxygenated or reformulated gasoline. Toxicol. Lett. 123(2-3):89-113. Chan, A.W.K. 1986. Racial difference in alcohol sensitivity. Alcohol Alcoholism 21(1):93-104. Chu, I., R. Poon, V. Valli, A. Yagminas, W.J. Bowers, R. Seegal, and R. Vincent. 2005. Effects of an ethanol-gasoline mixture: Results of a 4-week inhalation study in rats. J. Appl. Toxicol. 25(3):193-199. Cometto-Muniz, J.E., and W.S. Cain. 1990. Thresholds for odor and nasal pungency. Physiol. Behav. 48(5):719-725. Cometto-Muniz, J.E., and W.S. Cain. 1996. Relative sensitivity of the ocular trigeminal, nasal trigeminal, and olfactory systems to airborne chemicals. Chem. Senses. 20(2):191-198. Di Luzio, N.R., and T.E. Stege. 1979. Influence of chronic ethanol vapor inhalation on hepatic parenchymal and Kupffer cell function. Alcohol Clin. Exp. Res. 3(3):240-247. Hempel-Jorgensen, A., S.K. Kjaergaard, L. Molhave, and H.K. Hudnell. 1999. Time course of sensory irritation in humans exposed to N-butanol and 1-octene. Arch. Environ. Health 54(2):86-94. James, J.T. 1996. Ethanol. Pp. 171-207 in Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Vol. 3. Washington, DC: National Academy Press. Jones, A.W. 1995. Measuring and reporting the concentrations of acetaldehyde in human breath. Alcohol Alcoholism 30(3):271-285. Kennedy, R.S., W.P. Dunlap, J.J. Turnage, and J.E. Fowlkes. 1993. Relating alcohol-induced performance deficits to mental capacity: A suggested methodology. Aviat. Space Environ. Med. 64(12):1077-1085. Lester, D., and L. Greenberg. 1951. The inhalation of ethyl alcohol by man. I. Industrial hygiene and medicolegal aspects. II. Individuals treated with tetraethylthiuram disulfide. Q.J. Stud. Alcohol 12(2):167-178. Mizoi, Y., I. Ijiri, Y. Tatsuno, T. Kijima, S. Fujiwara, J. Adachi, and S. Hishida. 1979. Relationship between facial flushing and blood acetaldehyde levels after alcohol intake. Pharmacol. Biochem. Behav. 10(2):303-311. Nadeau, V., D. Lamoureux, A. Beuter, M. Charbonneau, and R. Tardif. 2003. Neuromotor effects of acute ethanol inhalation exposure in humans: A preliminary study. J. Occup. Health 45(4):215-222. Pastino, G.M., B. Asgharian, K. Roberts, M.A. Medinsky, and J.A. Bond. 1997. A comparison of physiologically based pharmacokinetic model predictions and experimental data for inhaled ethanol in male and female B6C3GF1 mice, F344 rats, and humans. Toxicol. Appl. Pharmacol. 145(1):147-157. Seeber, A., C. van Thriel, K. Haumann, E. Kiesswetter, M. Blaszkewicz, and K. Golka. 2002. Psychological reactions related to chemosensory irritation. Int. Arch. Occup. Environ. Health 75(5):314-325. Shibuya, A., M. Yasunami, and A. Yoshida. 1989. Genotypes of alcohol dehydrogenase and aldehyde dehydrogenase loci in Japanese alcohol flushers and nonflushers. Hum. Genet. 82(1):14-16. Tardif, R., L. Liu, and M. Raizenne. 2004. Exhaled ethanol and acetaldehyde in human subjects exposed to low levels of ethanol. Inhal. Toxicol. 16(4):203-207.
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