B7 Ethanol

John T. James, Ph.D.

Johnson Space Center Toxicology Group

Biomedical Operations and Research Branch

National Aeronautics and Space Administration

Houston, Texas

PHYSICAL AND CHEMICAL PROPERTIES

Ethanol is a clear, colorless, flammable liquid with an odor threshold of approximately 80 ppm (0.15 mg/L) (Amoore and Hautala, 1983) and a ''minimum identifiable odor level'' of approximately 350 ppm (0.66 mg/L) (Scherberger et al., 1958).

Synonym:

Ethyl alcohol

Formula:

CH3CH2OH

CAS number:

64-17-5

Molecular weight:

46.07

Boiling point:

78.5°C

Melting point:

-114.1 °C

Specific gravity:

0.789 at 20°C

Vapor pressure:

43 torr at 20°C

Solubility:

Miscible with water and most organic solvents

Conversion factors:

1 ppm = 1.88 mg/m3 = 0.00188 mg/L 1 mg/m3 = 0.531 ppm = 0.001 mg/L

OCCURRENCE AND USE

Ethanol is used as a fuel additive and in the manufacture of chemicals and medicines. It is used as a solvent in the manufacture of explo-



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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 B7 Ethanol John T. James, Ph.D. Johnson Space Center Toxicology Group Biomedical Operations and Research Branch National Aeronautics and Space Administration Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Ethanol is a clear, colorless, flammable liquid with an odor threshold of approximately 80 ppm (0.15 mg/L) (Amoore and Hautala, 1983) and a ''minimum identifiable odor level'' of approximately 350 ppm (0.66 mg/L) (Scherberger et al., 1958). Synonym: Ethyl alcohol Formula: CH3CH2OH CAS number: 64-17-5 Molecular weight: 46.07 Boiling point: 78.5°C Melting point: -114.1 °C Specific gravity: 0.789 at 20°C Vapor pressure: 43 torr at 20°C Solubility: Miscible with water and most organic solvents Conversion factors: 1 ppm = 1.88 mg/m3 = 0.00188 mg/L 1 mg/m3 = 0.531 ppm = 0.001 mg/L OCCURRENCE AND USE Ethanol is used as a fuel additive and in the manufacture of chemicals and medicines. It is used as a solvent in the manufacture of explo-

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 sives, plastics, resins, cosmetics, adhesives and preservatives. Ethanol is present in alcoholic beverages, which are widely consumed, and most toxicological concerns stem from the consequences of that consumption. Ethanol has been found in almost every sample of shuttle air, but at concentrations that seldom exceed 0.01 mg/L (James et al., 1994). Concentrations in the Mir space station are often above 0.01 mg/L; however, concentrations as high as 0.107 mg/L have been reported (James and Coleman, 1994). Ethanol enters the spacecraft atmosphere by off-gassing from hardware and from its use as a cleaner and disinfectant in operational procedures. Dilutions of liquid ethanol are frequently used in payload experiments; occasionally, it is used in undiluted form, and as such, it could pose a significant eye hazard upon escape. TOXICOKINETICS AND METABOLISM Absorption The absorption of ethanol has been most thoroughly studied by the oral ingestion route; however, absorption in the respiratory tract has been investigated in a few studies. It is important to compare the relative ability of the two routes of absorption to deliver ethanol to the bloodstream because that is where most of the distribution, metabolism, and excretion of ethanol occurs. Furthermore, specific toxic effects are often reported in terms of their probability of occurrence at known ethanol blood concentrations. Hence, it is important to know the efficiency of the inhalation route in delivering ethanol to the blood. Orally ingested ethanol is absorbed rapidly from the gastrointestinal tract by simple diffusion; peak blood concentrations are reached in 0.5 to 1.5 h after ingestion has ended. Food in the stomach delays gastric emptying and consequently delays the delivery of ethanol to the small intestine, where absorption is more rapid than it is in the stomach (Rall, 1990). In experimental animals, absorption of an oral dose of 6.4 g/kg has been shown to be much slower in rats than in guinea pigs (Strubelt et al., 1974). That absorption rate results in the maximum blood concentrations in rats being about one third the maximum in guinea pigs; this species difference is less pronounced at lower doses. In a human inhalation study, Lester and Greenberg (1951) showed

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 that the respiratory system absorbed about 62% of the ethanol from inspired air at concentrations ranging from 11 to 19 mg/L. This percentage appeared to be independent of ventilation rates, which ranged from 7 to 25 L/min. In the three test subjects, the blood alcohol concentrations averaged 4 mg/dL (0.004%) when inhaling ethanol at 15 to 16 mg/L for 3 h at a ventilation rate of 7 to 8 L/min. In two of the subjects tested at a ventilation rate of 15 L/min, the blood concentrations of ethanol after 3 h were approximately 9 mg/dL (0.009%). The concentration profiles suggested that the blood concentrations had reached equilibrium values during the 3 h of exposure. At a ventilation rate of 22 L/min, the blood concentrations, which averaged about 35 mg/dL (0.035%), did not appear to be at equilibrium after 3 h. The authors concluded that a ventilation rate above 14 L/min would be necessary to achieve a continuously increasing blood concentration of ethanol during an exposure at 15 mg/L for several hours. In an experiment designed to test the hypothesis that an individual inhaling ethanol vapors from an open liquid source could have significant blood concentrations of alcohol, Mason and Blackmore (1972) showed that, in a warm room with a maximum concentration of 17 mg/L (estimated from the amount of ethanol evaporated from the source), the ethanol concentration in the blood of the four subjects was below 5 mg/dL (0.005%) when tested at various intervals during the exposure. Although the subjects experienced no subjective symptoms of intoxication, those entering the room for the first time found the atmosphere intolerable at the end of the exposure. That information is consistent with the findings of Lester and Greenberg (1951) described above and underscores the difficulty in reaching significant blood concentrations in practical situations where inhalation is the only route of entry. It has been shown in vitro that rat lung tissue can metabolize ethanol to carbon dioxide at a capacity roughly one fifth of that of liver slices (Masoro et al., 1953). Some inhalation uptake data are available in rodents from experiments that were designed to develop models for evaluation of alcohol dependence and withdrawal. These inhalation models were developed to solve problems associated with variable blood alcohol concentrations after repeated oral or intravenous administrations. After the initial rise in blood ethanol concentration, continued inhalation of ethanol at a fixed concentration will result in gradually decreasing blood concentrations unless alcohol dehydrogenase (ADH) activity is inhibited (e.g., by

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 pyrazole) or the vapor concentration is increased during the exposure. Mice exposed to ethanol at 12 mg/L for 96 h, with daily injections of pyrazole, showed stable blood concentrations after about 20 h of exposure. The equilibrium blood concentration was approximately 170 mg/dL (0.17%) (Goldstein and Pal, 1971). A survey of rodent exposures to ethanol for up to 21 d suggested that the blood alcohol concentrations varied considerably with species, strain, and sex of the rodent (Goldstein, 1980). When exposures were conducted without an ADH inhibitor, the blood alcohol could be kept reasonably constant by doubling the exposure concentration progressively during the first 10 d of exposure. In rats exposed for 24 h at 28 mg/L, the blood concentration reached 340 mg/dL (0.34%). This exposure conferred tolerance to a hypothermia-inducing injection of ethanol administered 48 h after the exposure (Mullin and Ferko, 1981). Blood alcohol concentrations were stabilized at approximately 150 mg/dL (0.15%) by continuous exposures of rats that were individually exposed to air concentrations of 22 to 28 mg/L on the basis of their blood alcohol concentrations (Rogers et al., 1979). Distribution The arterial concentration of ethanol is significantly higher than the venous concentration during the absorption phase (Harger and Forney, 1967; Keiding, 1979). Ethanol diffuses slowly across cellular membranes but passes rapidly into the brain (Crone, 1965). The tissue-to-blood-concentration ratios in cat tissue were found to be about 0.85 in all tissues studied except in fat, where the ratio was only 0.2 (Eggleton, 1940, as cited in Rowe and McCollister, 1982). The placental transfer of ethanol is rapid in the many species studied, and the concentrations follow those in maternal blood (IARC, 1988). Excretion Once it reaches the blood, ethanol is removed at a constant rate in a given individual over a wide concentration range (zero-order kinetics); however, there is considerable evidence that the removal rate is lower at very low concentrations of ethanol. Above a peripheral blood con-

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 centration of about 2 mm (0.009%), the human liver eliminates ethanol at a constant rate; however, below that concentration, the rate of elimination decreases with concentration following Michaelis-Menton kinetics (Keiding, 1979; Bosron et al., 1988). Chronic alcoholics are able to eliminate ethanol from their blood almost twice as fast as the average person (Harger and Forney, 1967). Ethanol is mainly eliminated from the body by oxidation in the liver to acetate, which is distributed to other tissues and metabolized to carbon dioxide for excretion by the lungs (see Metabolism below). A small fraction of ethanol is excreted without change by the kidneys (0.5 to 2%), lungs (5%), and sweat (0.5%); elimination rates range from 70 to 180 mg/kg·h or 170 to 410 mg/kg·h, depending on the method of calculation (Haggard and Greenberg, 1934; von Wartburg, 1989). A small amount has been reported to be conjugated and excreted in the kidney as ethyl glucuronide (Kamil et al., 1953). Metabolism Understanding of Ethanol Metabolism Before 1900 Ethanol is certainly one of the most often studied toxicants and probably one of the earliest to receive serious toxicological evaluation and metabolic study. By 1900, it was known that nearly all of an ingested dose was metabolized by the test animal; this knowledge enabled use of ethanol as a source of energy (Jacobsen, 1952). The accumulation of fat in tissues of animals fed alcohol over long periods of time had also been demonstrated, even when the intake of food in the ethanol-fed animals and control animals was the same. Several investigators showed that the overall metabolic rate of an organism was not altered by ingestion of ethanol (Jacobsen, 1952). Understanding of Ethanol Metabolism by 1950 Investigations during the next half century resulted in much more detailed understanding of ethanol metabolism in experimental animals and humans. The state of knowledge at that time was reviewed by Jacobsen (1952), and most of the information below is from his review.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Although some controversy existed about the shape of the blood-concentration curve after ethanol administration, the majority of available data indicated a linear decrease in concentration with time. A relatively high preconditioning dose of alcohol causes a second smaller dose to be removed faster than a dose given without preconditioning. With blood alcohol levels in the range of 15 to 94 mg/dL (0.015-0.094%), constant infusion of ethanol was shown to maintain constant blood levels in humans. The capacity to metabolize alcohol appeared to vary less than 25% among individuals. The prevailing opinion at that time was that long-time use of alcohol does not increase the rate of metabolism and that exercise, except for increased evaporation, does not increase the removal rate of alcohol. Starved animals have a lower rate of alcohol metabolism than well-fed animals. Long before 1950, investigators conducted studies using hepatectomized dogs, liver slices, and perfused livers to show that the liver was the predominant organ to metabolize ethanol. Some metabolism of alcohol appeared to occur in muscles also (Bartlett and Barnet, 1949). Data were not consistent on whether the kidney could metabolize ethanol; however, it was apparent that little, if any, metabolism occurred in brain tissue. The biochemical pathway for ethanol metabolism was reasonably well demonstrated to be as follows: Acetaldehyde was found in the blood of animals and humans given sufficient doses of ethanol. Typically, the acetaldehyde concentration was less than 1% of the concentration of ethanol. Premedication with Anabuse was found to increase the blood concentrations of acetaldehyde up to 10 times over those in unmedicated animals after ethanol ingestion. Following up on evidence of the formation of acetate from ethanol, Bartlett and Barnet (1949) used 14C-labeled ethanol (1 g/kg) administered to rats to show that the acetate formed is rapidly oxidized to carbon dioxide, because 75% of the label was recovered in 5 h and 90% was recovered in 10 h. The enzymes involved in the first step of the pathway were known to be ADH and, to a much reduced extent, catalase. ADH catalyzes the transfer of hydrogen to nicotinamide adenine dinucleotide (NAD+).

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Catalase facilitates the transfer of hydrogen from ethanol by reduction of peroxide to water. Jacobsen (1952) speculated that the second step in the pathway was catalyzed by either a flavoprotein or another dehydrogenase, but no evidence indicated which type of aldehyde-oxidizing enzyme might actually be involved. Present Understanding of Ethanol Metabolism In general, the view of ethanol metabolism has not fundamentally changed from the pathway illustrated above. There have been significant new insights into ethanol's metabolism that have facilitated an understanding of the pathogenesis of ethanol-induced liver injury and carcinogenesis. Data now available on the location and enzymatic function of subcellular organelles in hepatocytes and how they respond to repeated insults from ethanol present a complex picture; the major features of that picture are described below. In addition, some of the early concepts about ethanol metabolism, especially the degree of variability among individuals, have been corrected by new data. Genetic variations in the enzymes involved in ethanol metabolism control the immediate response to ingested ethanol; however, no studies could be found in which differences in susceptibility to inhaled ethanol were evaluated. The cascade of effects induced by ethanol can be partially understood by refinements in the pathway shown above. Many of the effects occur as a result of the changed redox state (NADH/NAD ratio). The excess of hydrogen equivalents from ethanol metabolism are used by mitochondria instead of those equivalents originating from the citric-acid cycle by metabolism of 2-carbon fragments from fatty acids. This process facilitates decreased fatty-acid metabolism and causes deposition of dietary fat in the liver. Chronic administration of ethanol to rats or baboons results in attenuation of this change in redox state, so continued accumulation of fat must depend on another mechanism, possibly one involving changes in the mitochondria (Lieber, 1979). The first reaction in the metabolic pathway is primarily catalyzed by ADH in the cytosol. This step is affected by the presence of acetaldehyde, the transport of reducing equivalents, and the ability of the mitochondria to oxidize those reducing equivalents. ADH activity is affected by hormonal status, dietary status, and age of the subject (IARC, 1988). ADH is a dimer with multiple molecular forms determined by

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 at least five gene loci (ADH1 to ADH5). An atypical form (ADH2*2) has been identified at a high frequency (33 % to 81%) in Asian populations compared with a much lower frequency (1% to 12%) in Caucasian populations (Agarwal and Goedde, 1992). The atypical subunit of ADH2 has a 20-fold higher capacity than the ADH2*1 subunit to oxidize ethanol. That difference might explain the two-to threefold variability in alcohol elimination observed in humans given identical ethanol doses (Bosron et al., 1988). Two other enzymes have been shown to be capable of catalyzing the first step in the pathway. Cytochrome P-450 (the microsomal ethanol-oxidizing system) depends on nicotinamide adenine dinucleotide phosphate (NADPH), oxygen, and hydrogen to oxidize ethanol to acetaldehyde. One isoenzyme of cytochrome P-450, IIE1, is induced by ethanol, and that induction might explain ethanol's ability to act as a cocarcinogen (see below). In addition, it has been argued that this enzyme is important in ethanol oxidation at high concentrations and may become more important with chronic ingestion (Lieber, 1984). Catalase, a hemoprotein located in the peroxisomes of many tissues, can also catalyze the first reaction, but it depends on a hydrogen peroxide generating system to control the rate (IARC, 1988). When ethanol is present at low concentrations, neither of these enzymes appears to be nearly as important as ADH in ethanol oxidation. In vitro studies of ethanol metabolism in rat and monkey liver slices have shown that more than 89% of the metabolism is due to ADH alone (Havre et al., 1977). The second step in the pathway is catalyzed by aldehyde dehydrogenase (ALDH), an enzyme present primarily in mitochondria with broad specificity for aldehydes. The mitochondrial form (ALDH2) is thought to be most important in oxidizing acetaldehyde, and because approximately 50% of the Japanese and Chinese lack an active form of this enzyme, they experience much higher blood acetaldehyde concentrations after ethanol ingestion (Bosron and Li, 1986). It was suggested that Asian individuals who exhibit the "flush" reaction to ethanol have the highly active ADH2 and the deficient ALDH2 enzymes (Yoshida et al., 1983). In fact, Shibuya et al. (1989) showed that of nine Japanese who flushed, all were at least heterozygous for the atypical allele (ALDH1*2 or ALDH2*2), and of six who did not flush, five were homozygous for the usual allele (ALDH1*1). Thomasson et al. (1993) showed that the atypical ALDH2*2 in a large population of Chinese men was associated with the most intense flushing (as measured by in-

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 creased facial blood flow). In individuals with the usual allele, the metabolic rate is very fast, so little acetaldehyde accumulates to reach the blood; however, in those who flush, the concentration of acetaldehyde may reach 100 µm (Bosron et al., 1988). Several isoenzymes of ALDH have been identified, and ALDH is present in tissues other than the liver (IARC, 1988). Acetaldehyde produced in the mitochondria during chronic ethanol intake appears to cause the biochemical changes and ultrastructural damage apparent in test animals and alcoholics (Lieber, 1979). According to several reviews, the third step occurs mostly outside the liver when acetate is released into the circulation and delivered to peripheral tissues (Lieber, 1979; Weiner et al., 1988; Bosron et al., 1988). No specific data are cited by any of the reviewers to support this conclusion. Early studies using liver slices from rats and 14C-labeled ethanol suggested that the liver alone converted a sizable portion of ethanol to carbon dioxide (Bartlett and Barnet, 1949). A later study in 10 human subjects infused to an average plasma concentration of ethanol at 3.6 mm (0.017%) showed that the output of acetate from the splanchnic area was 50% to 100% of the ethanol disappearance rate (Lundquist et al., 1962); that result was confirmed in another human study (Tygstrup et al., 1965). TOXICITY SUMMARY The number of toxicity studies involving ethanol is enormous; however, the goal of this document is to provide a rationale for setting inhalation exposure limits. With this goal in mind, my focus will be on the few inhalation studies conducted with ethanol and on studies by other routes of administration if those studies provide insight into how inhaled ethanol could adversely affect living systems. It is beyond the scope of this document to provide a comprehensive review of ethanol's toxicity by all routes. For example, adverse effects of ethanol on skeletal, cardiac, and vascular smooth muscle (Altura and Altura, 1982; Urbano-Marquez et al., 1989) and on the kidney (Ponticelli and Montagnino, 1979) will not be considered in detail because such effects are seen only in chronic alcoholics, and there is no indication that inhalation exposure would injure these tissues. Also, reports of responses to ethanol vapor at 0.5 ppm (0.001 mg/L) by 3 of 47 chemically sensi-

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 tive patients are not considered evidence of toxicity in this report. The responses were not applicable to nonsensitive populations, and the effects are hardly adverse (e.g., increased pulse rate) (Rea et al., 1991). Acute and Short-Term Exposures Short-term exposures to ethanol are known to induce irritation of mucosal surfaces, central-nervous-system (CNS) depression, and possibly a flush response in certain individuals. The first two effects have been demonstrated by inhalation exposure; however, the flush reaction has only been demonstrated by oral ingestion. The first two effects are thought to be mediated by ethanol, whereas the flush reaction is almost certainly due to acetaldehyde, which accumulates to unusually high concentrations in susceptible individuals. Neurotoxicity The mechanism of toxic action of ethanol on the nervous system is believed to depend on its ability to fluidize the bulk lipid in membranes. A correlation between the severity of intoxication and the magnitude of ethanol-induced fluidization of brain membranes has been demonstrated in vitro, and long-sleep strains of mice show greater ethanol-induced fluidization of membranes than short-sleep strains (Wood and Schroeder, 1988). In a refinement of the bulk lipid effect, some of the membrane effects may be explained by differential effects in domains of the membrane defined by their degree of hydrophobicity, orientation (lateral or vertical) or composition (e.g., protein and phospholipid). Changes in membrane fluidity and lipid composition might be related to ethanol sensitivity and tolerance, but that relation has not been convincingly demonstrated (Wood and Schroeder, 1988). Ethanol causes CNS depression in animals and humans exposed to air concentrations on the order of 10 mg/L and above. Table 55.4 in Rowe and McCollister (1982) summarizes mouse, guinea pig, and rat exposures to ethanol at 6 to 94 mg/L for 1 to 24 h that induce drowsiness, ataxia, narcosis, and death. Most of the data are from Loewy and von der Heide (1918) and suggest that guinea pigs are somewhat less

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 susceptible than rats. In rats, the no-observed-adverse-effect level (NOAEL) for a 6-h exposure was 6.1 mg/L, whereas in guinea pigs, the NOAEL was 12 mg/L for an exposure of 8 h. The table shows that in mice, guinea pigs, and rats exposed for 7 to 10 h, the concentration × time needed to induce death is about 400 h·mg/L. Quantifying the effect of inhaled ethanol on the human nervous system depends on correlating inhalation exposures with blood alcohol levels (BALs) and then correlating those BALs with specific nervous system effects. This correlation is necessary because the assessment of nervous-system effects in the human inhalation studies is inadequate as compared with the extensive work that has been reported on the effects after oral ingestion. For example, Loewy and von der Heide (1918) reported headache after 33 min of exposure at 2.6 mg/L and a slight daze after leaving the chamber, whereas Lester and Greenberg (1951) reported no CNS effects during 3 to 6 h exposures at 15 mg/L, even in subjects breathing at 24 L/min. The authors of the latter paper, in which subjects were exposed with a head-only hood, attribute the differences in their findings and those of Loewy and von der Heide (1918) to fatigue caused by confinement in the exposure chamber. As discussed in the section Rationale for Acceptable Concentrations, the data from Loewy and von der Heide (1918) are not that different from Lester and Greenberg's (1951) data. The older study was conducted in a sealed static chamber of 8000-L capacity, and the apparent concentrations of ethanol decreased far more rapidly than the authors expected. They attributed the rapid decrease to wall condensation (Loewy and von der Heide, 1918). Both studies suffer from having few test subjects, subjective end points, and no control exposures. Fortunately, Lester and Greenberg (1951) measured BALs and found that, at a light load (15 L/min), the BAL reached 9 mg/dL (0.009%). They reported no CNS effects at that concentration, but their methods to detect such effects were subjective. It appears that minimal to no effects are detectable in humans with BALs of 50 mg/dL (0.05%), which is compatible with the report of Lester and Greenberg (1951). Flury and Klimmer (1943) indicated that the ''beginning of uncertainty'' is 0.06%. Small performance decrements (< 10%) were demonstrated in grammatical reasoning, code substitution, choice reaction, and tapping in 18 subjects with BALs of 0.06% after ingestion of 95% ethanol mixed with juice (Kennedy et al., 1993a). In another study with the same group, 20 males with BALs of

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 below the typical lowest dose of 0.3 mL/kg used to elicit a flush response. Hence, the 1-h and 24-h ACs were set at 4 mg/L.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 TABLE 7-4 Acceptable Concentrations   Uncertainty Factors Acceptable Concentrations, mg/L Effect, Data, Reference Species Species Time Small n 1 h 24 h 7 d 30 d 180 d Neurotoxicity   NOAEL, 15 mg/L, 6 h (Lester and Greenberg, 1951; Kennedy et al., 1993b) Human (n = 20) 1 √20/10 1 7 7 7 7 7 Irritation   NOAEL, 10 mg/L (Lester and Greenberg, 1951; Loewy and von der Heide, 1918) Human (n = 5) 1 √5/10 1 10 10 2 2 2 Flush response   NOAEL, 0.2 mL (Shibuya et al., 1989) Human 1 1 1 4 4 2 2 2 Hepatotoxicity   NOAEL, 20 mg/L, 26 d continuous (Di Luzio and Stege, 1979) Rat 10 1 1 - - 2 2 2 SMACs         4 4 2 2 2 —, Data not considered applicable to the exposure time.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 RECOMMENDATIONS Despite the general consensus that inhaled ethanol is not harmful except in very high concentrations, no toxicity studies appear to have been conducted according to modern protocols to substantiate this conclusion. Only two studies involving human exposure were found, and they involved very few subjects, were uncontrolled, and relied on subjective reporting of symptoms. A carefully structured human inhalation study, including both flush response and nonflush response subjects, would provide a valuable addition to the data base. REFERENCES Abel, E. L., and R. J. Sokol. 1987. Incidence of fetal alcohol syndrome and economic impact of FAS-related anomalies. Drug Alcohol Depend. 19:51-70. ACGIH. 1991. Guide to Occupational Exposure Values-1991. American Conference of Governmental Industrial Hygienists, Cincinnati, Ohio. ACGIH. 1995. 1995-1996 Threshold Limit Values and Biological Exposure Indices. American Conference of Governmental Industrial Hygienists, Cincinnati, Ohio. Agarwal, D. P., and H. W. Goedde. 1992. Pharmacogenetics of alcohol metabolism and alcoholism. Pharmacogenetics 2:48-62. Ainley, C. C., A. Senapati, I. M. H. Brown, C.A. Iles, B. M. Slavin, W. D. Mitchell, D. R. Davies, P. W. N. Keeling, and R. P. H. Thompson. 1988. Is alcohol hepatotoxic in the baboon? J. Hepatol. 7:8592. Altura, B. M., and B. T. Altura. 1982. Microvascular and vascular smooth muscle actions of ethanol, acetaldehyde, and acetate . Fed. Proc. 41:2447-2451. Amoore, J. E., and E. Hautala. 1983. Odor as an aid to chemical safety: Odor thresholds compared with threshold limit values and volatilities for 214 industrial chemicals in air and water dilution. J. Appl. Toxicol. 3:272-290. Baarson, K. A., and C. A. Snyder. 1991. Evidence for the disruption of the bone marrow microenvironment by combined exposures to inhaled benzene and ingested ethanol. Arch. Toxicol. 65:414-420.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Badr, F. M., and R. S. Badr. 1975. Induction of dominant lethal mutation in male mice by ethyl alcohol. Nature 253:134-136. Bartlett, G. R., and H. N. Barnet. 1949. Some observations on alcohol metabolism with radioactive ethyl alcohol. Q. J. Stud. Alcohol. 10:381-397. Bosron, W.F., and T.-K. Li. 1986. Genetic polymorphism of human liver alcohol and acetaldehyde dehydrogenases and their relationship to alcohol metabolism and alcoholism. Hepatology 6:502-510. Bosron, W. F., L. Lumeng, and T.-K. Li. 1988. Genetic polymorphism of enzymes of alcohol metabolism and susceptibility to alcoholic liver disease . Mol. Aspects Med. 10:147-158. Browning, E. 1953. Pp. 217-223 in Toxicity of Industrial Organic Solvents. New York: Chemical Publishing. Browning, E. 1965. Pp. 324-331 in Toxicity and Metabolism of Industrial Solvents. Amsterdam: Elsevier. Coon, R. A., R. A. Jones, L. J. Jenkins, Jr., and J. Siegel. 1970. Animal inhalation studies on ammonia, ethylene glycol, formaldehyde, dimethylamine, and ethanol. Toxicol. Appl. Pharmacol. 16:646-655. Cornish, H., and J. Adefuin. 1966. Ethanol potentiation of halogenated aliphatic solvent toxicity. Am. Ind. Hyg. Assoc. J. 27:57-61. Crone, C. 1965. The permeability of brain capillaries to non-electrolytes. Acta Physiol. Scand. 64:407-417. de Raat, W. K., P. B. Davis, and G. L. Bakker. 1983. Induction of sister chromatid exchanges by alcohol and alcoholic beverages after metabolic activation by rat-liver homogenate. Mutat. Res. 124:85-90. 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. Echeverria, D., L. Fine, G. Langolf, T. Schork, and C. Sampaio. 1991. Acute behavioral comparisons of toluene and ethanol in human subjects. Br. J. Ind. Med. 48:750-761. Ernhart, C. B., R. J. Sokol, S. Marrier, P. Moron, D. Nadler, J. W. Ager, and A. Wolf. 1987. Alcohol teratogenicity in the human: A detailed assessment of specificity, critical period, and threshold. Am. J. Obstet. Gynecol. 156:33-39. Flury, F. and O. Klimmer. 1943. Alcohols. Pp. 196-216 in Toxicology and Hygiene of Industrial Solvents, E. King and H. F. Smyth, Jr., translators, K. B. Lehmann and F. Flury, eds. Baltimore: Williams & Wilkins.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Forsander, O. A. 1979. Effects of ethanol on the liver—New questions and old. Pp. 345-353 in Metabolic Effects of Alcohol, P. Avogaro, C. R. Sirtori, and E. Tremoli, eds. Amsterdam: Elsevier/North-Holland. French, S. W., and J. R. Morris. 1972. Ethanol dependence in the rat induced by non-intoxicating levels of ethanol. Res. Commun. Chem. Pathol. Pharmacol. 4(1):221-233. Garro, A. J., and C. S. Lieber. 1990. Alcohol and cancer. Annu. Rev. Pharmacol. Toxicol. 30:219-249. Gavaler, J. S., and D. H. Van Thiel. 1987. Reproductive consequences of alcohol abuse: Males and females compared and contrasted. Mutat. Res. 186:269-277. Goldstein, D. B. 1980. Inhalation of ethanol vapor. Pp. 81-92 in Alcohol Tolerance and Dependence, H. Rigter and J. C. Crabbe, eds. Amsterdam: Elsevier/North-Holland. Goldstein, D. B. and N. Pal. 1971. Alcohol dependence in mice by inhalation of ethanol: Grading the withdrawal reaction. Science 172:288-290. Haggard, H. W., and L. A. Greenberg. 1934. Studies in the absorption, distribution, and elimination of ethyl alcohol. II. The excretion of alcohol in urine and expired air; and the distribution of alcohol between air and water, blood, and urine. J. Pharmacol. 52:150-166. Harger, R. N., and R. B. Forney. 1967. Pp. 1-61 Aliphatic Alcohols in Progress in Chemical Toxicology, A. Stolman, ed. New York: Academic. Havre, P., M. A. Abrams, R. J. M. Corrall, L.C. Yu, P. A. Szczepanik, H. B. Feldman, P. Klein, M. S. Kong, J. M. Margolis, and B. R. Landau. 1977. Quantitation of pathways of ethanol metabolism. Arch. Biochem. Biophys. 182:14-23. IARC. 1988. Evaluation of Carcinogenic Risks to Humans: Alcohol Drinking, Vol. 44. Lyon, France: International Agency for Research on Cancer. Ikatsu, H., and T. Nakajima. 1992. Hepatotoxic interaction between carbon tetrachloride and chloroform in ethanol treated rats. Arch. Toxicol. 66:580-586. Jacobsen, E. 1952. The metabolism of ethyl alcohol. Pharmacol. Rev. 4:107-135. James, J. T., and M. E. Coleman. 1994. Toxicology of Airborne Gaseous and Particulate Contaminants in Space Habitats . Pp. 37-60 in

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