B8 Methanol

King Lit Wong, Ph.D.

Johnson Space Center Toxicology Group

Biomedical Operations and Research Branch

Houston, Texas

PHYSICAL AND CHEMICAL PROPERTIES

Methanol is a colorless liquid (ACGIH, 1986).

Synonyms:

Methyl alcohol, wood alcohol

Formula:

CH3OH

CAS number:

67-56-1

Molecular weight:

32.0

Boiling point:

64.5°C

Melting point:

−97.8°C

Vapor pressure:

92 torr at 20°C

Saturated vapor concentration:

121,053 ppm at 20°C, 1 atm

Conversion factors at 25°C, 1 atm:

1 ppm = 1.31 mg/m3

1 mg/m3 = 0.76 ppm.

OCCURENCE AND USE

We are not aware of any use of methyl alcohol in the operation of spacecraft. Methyl alcohol, however, has been used in payload experiments in the space shuttle (Wong and Lam, 1990) and detected in off-gas tests of flight hardware (H. Leano, Johnson Space Center, personal commun., 1990). One potential source of methanol exposure is via the diet. Fruit juices contain an average of 140 mg of methanol per liter (Francot and



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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants B8 Methanol King Lit Wong, Ph.D. Johnson Space Center Toxicology Group Biomedical Operations and Research Branch Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Methanol is a colorless liquid (ACGIH, 1986). Synonyms: Methyl alcohol, wood alcohol Formula: CH3OH CAS number: 67-56-1 Molecular weight: 32.0 Boiling point: 64.5°C Melting point: −97.8°C Vapor pressure: 92 torr at 20°C Saturated vapor concentration: 121,053 ppm at 20°C, 1 atm Conversion factors at 25°C, 1 atm: 1 ppm = 1.31 mg/m3 1 mg/m3 = 0.76 ppm. OCCURENCE AND USE We are not aware of any use of methyl alcohol in the operation of spacecraft. Methyl alcohol, however, has been used in payload experiments in the space shuttle (Wong and Lam, 1990) and detected in off-gas tests of flight hardware (H. Leano, Johnson Space Center, personal commun., 1990). One potential source of methanol exposure is via the diet. Fruit juices contain an average of 140 mg of methanol per liter (Francot and

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants Geoffroy, 1956). Diet soda containing aspartame could release methanol, equivalent to 10% of its weight, when aspartame is hydrolyzed in the intestine (Stegink et al., 1981). A typical diet soda contains aspartame equivalent to 56 mg of methanol per liter, so drinking a 12-oz. can (355 mL) of such beverages could lead to the absorption of 20 mg of methanol. However, adult humans who ingested an amount of aspartame equivalent to that in 12 12-oz. cans of diet soda failed to increase the methanol concentration in blood during the 24 h after ingestion (Stegink et al., 1981). It took an amount of aspartame in 36 12-oz cans of diet soft drink to significantly elevate the blood methanol concentration. Therefore, oral intake of diet soda will not significantly contribute to methanol exposure in the astronauts. PHARMACOKINETICS AND METABOLISM The dog's respiratory system retains 81-88% of inhaled methanol in the first few minutes of an exposure at 300-550 ppm (Egle and Gochberg, 1975). In a human study, except for the first few minutes of exposure, the respiratory system consistently retained 58% of inhaled methanol throughout an 8-h exposure (Sedivec et al., 1981). The degree of retention also remained constant as the methanol concentration varied from 78 to 216 ppm or as the minute volume was increased 2.5 times when the individual exercised (Sedivec et al., 1981). After absorption, methanol is distributed rapidly throughout the dog's body in body water (Yant and Schrenk, 1937). Methanol is first metabolized to formaldehyde, which is very rapidly metabolized into formic acid, so that very little formaldehyde is detected in tissues (Tephly et al., 1979). Formic acid is then metabolized to CO2 (McMartin et al., 1977). The conversion rate of formic acid to CO 2 in primates is less than half of that in nonprimates (McMartin et al., 1977). Formic acid is, therefore, methanol's major metabolite in primates, but not in nonprimates (Clay et al., 1975). Formic acid is believed to be methanol's toxic metabolite (Clay et al., 1975), so toxicity data on nonprimates should not be relied on in setting methanol's SMACs. The species difference in methanol metabolism explains why Gilger and Pott (1955) found that methanol toxicity in monkeys differed from that in nonprimates. In addition to metabolism, methanol is also eliminated unchanged via the lung and in the urine (Jacobsen et al., 1983; Leaf and Zatman, 1952). The

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants pulmonary clearance of methanol was determined to be 5.6 mL of blood per minute in a man poisoned with methanol (Jacobsen et al., 1983). Humans excreted 0.76% of an oral dose of methanol unchanged in the urine in 12 h (Leaf and Zatman, 1952). The major route of methanol elimination is via metabolism, which was estimated to account for 97% of the elimination in humans (Kavet and Nauss, 1990). In workers occupationally exposed to methanol at about 93 ppm for several months to 30 years, the venous methanol concentration reached 9 mg/L at the end of the working week, and the urinary methanol and formic acid concentrations were 22 and 30 mg/L, respectively (Heinrich and Angerer, 1982). Methanol elimination depends on the dose. In monkeys, at a high intraperitoneal dose of 1 g/kg, methanol elimination from the blood followed zero-order kinetics, with a hourly elimination rate of 0.44 mg/L (Eells et al., 1983). In 24 h, 60% of the administered methanol was eliminated (Eells et al., 1983). At lower doses, the elimination of methanol and its metabolites follows first-order kinetics. Methanol's half-life in blood is about 1.5-2.0 h in humans exposed to methanol vapor at 100-300 ppm (Sedivec et al., 1981). In monkeys, the half-lives of formaldehyde and formic acid in blood are about 1-1.5 min and 31-51 min, respectively (McMartin et al., 1977; Clay et al., 1975; McMartin et al., 1979). TOXICITY SUMMARY Acute Toxicity Metabolic Acidosis, Headaches, and Ocular Toxicity Methanol intoxication produces metabolic acidosis and ocular injuries in humans (Klaassen, 1990). With single oral exposure to methanol at a sufficient dose, headache, dizziness, nausea, abdominal pain, and blurred vision develop after a latent period of 8-36 h (Klaassen, 1990). An ingestion of as little as 15 mL of methanol is sufficient to cause blindness in humans (Klaassen, 1990). The latent period is thought to be due partly to the time for transformation of methanol to an active metabolite (Gosselin et al., 1984). Formic acid has been proposed to be the active metabolite because formic acid has been shown to produce both metabolic acidosis and ocular injuries (McMartin et al., 1977; Clay et al., 1975; Gilger and Potts, 1955).

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants CNS Effects Other Than Headaches Ingestion of high doses of methanol causes inebriation, but methanol is less potent than ethanol in causing inebriation (Klaassen, 1990). In addition to causing inebriation, methanol intoxication has been shown to cause a prolonged parkinsonian syndrome with lesions in the putamen in three human cases (Bourrat and Riboullard, 1986; Verslegers et al., 1988; LeWitt and Martin, 1988). In one of the cases, the intoxication was so severe that the individual developed permanent parkinsonism with visual impairment, increased dopamine beta-hydroxylase activity and decreased met-enkephalin levels in the cerebrospinal fluid (Verslegers et al., 1988). Brain hemorrhage was also documented in at least 13.5% of the cases of accidental methanol poisoning (Phang et al., 1988). Other than being toxic to the brain and eyes, methanol might also affect the heart. There has been one report of acute methanol intoxication causing severe reversible cardiac failure in a 55-year-old man (Cavalli et al., 1987). Because methanol's morphological effects on the brain and cardiac toxicity have been reported to occur after acute poisoning at high doses and they have not been reported to occur after inhalation exposures, the SMACs are not established according to the morphological effects on the brain and the cardiac toxicity. Subchronic Toxicity Headaches and Ocular Toxicity Kingsley and Hirsch (1955) reported that a number of workers complained of frequent, recurrent headaches in the offices of a plant where certain duplicating machines were operated for the major part of an 8-h working day. These machines used a duplicating fluid containing methanol and the airborne methanol concentration was 210-375 ppm in the winter, when most of the windows were shut. The methanol concentration reached 300 ppm at 1 h into the operation of a machine. These concentrations persisted for as long as 4 h following a machine operation. The headaches were more severe in the workers located close to the machine than those more remotely situated. The most severe symptom was detected in the machine operators. Because Kingsley and Hirsch did not report the number of employees involved in the study in that one plant, their results are not used in setting SMACs.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants Other than recurrent headaches, inhaled methanol could also cause visual disturbances (Frederick et al, 1984). However, Kingsley and Hirsch (1955) failed to report whether the workers, exposed to methanol at 210-375 ppm in that study, complained of any visual problems. In their paper, Kingsley and Hirsch did recognize that optic injury is a feature of methanol poisoning. An analysis of the data of a National Institute for Occupational Safety and Health (NIOSH) study provides evidence that 391 ppm is probably the lowest-observed-effect level (LOEL) for methanol to cause visual toxicity and headaches (Frederick et al., 1984). In this epidemiology study performed by NIOSH, the prevalence of symptoms in 66 female teacher aides and 66 female teachers of similar age were compared (Frederick et al., 1984). The percentage of work hours spent at spirit duplicating machines that used methanol in poorly ventilated areas ranged from 0 to 90% for the teacher aides and 0 to 20% for the teachers, so the teacher aides presumably were exposed to methanol more often than the teachers. During the month before the investigation, 22% more teacher aides complained of blurred vision than teachers and 17% more teacher aides complained of headaches than teachers (Frederick et al., 1984). Although the difference between the teacher aides and teachers in the prevalence of blurred vision was significant, there was no statistically significant difference in the prevalence of “trouble with or changes in vision” between the teacher aides and teachers (Frederick et al., 1984). The higher percentage of teacher aides with headaches than teachers was statistically significant. The higher prevalence of blurred vision in the teacher aides did not appear to be due to eye irritation because the increased prevalence of eye burning, itching, and tearing in the teacher aides was not statistically significant compared with that in the teachers (Frederick et al., 1984). These teacher aides worked from 1 h/w to 40 h/w. Measurements made in the breathing zone of the teacher aides at the duplicating machines showed that the methanol concentrations varied from 365 to 3080 ppm. The attack rates of methanol-related symptoms in the teacher aides and teachers were correlated with the percentage of time spent at the duplicating machines per week. Using the Chauvenet's criterion (Gad and Weil, 1988), the highest methanol concentration of 3080 ppm in table 1 of the NIOSH paper (Frederick et al., 1984) was found to be an outlier (the next two highest concentrations were 1440 and 1365 ppm). With the highest methanol concentration discarded, the mean and standard deviation were calculated to be 960

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants and 346 ppm, respectively, and the median is 1020 ppm. The scattergram of the methanol concentration data points shows that the concentration is monomodal and is relatively evenly distributed around the mean. The methanol concentration can be assumed to follow a normal distribution. One way to interpret the NIOSH study (Frederick et al., 1984) is that working in an environment with methanol at about 1000 ppm could result in blurred vision and headaches. Unfortunately, the NIOSH investigators did not present the methanol concentrations that the teacher aides afflicted with blurred vision or headaches were exposed to versus that of the nonresponding teacher aides. However, with three assumptions, the lowest-observed-adverse-effect level (LOAEL) based on visual disturbances and headaches can be estimated. First, assume that about equal number of the 66 teacher aides worked with each of the 21 duplicating machines that measured for methanol concentration (so that the percentage of teacher aides exposed to methanol at a concentration greater than or equal to a certain value can be estimated by the percentage of methanol-concentration measurements at or above that value). Second, assume that these teacher aides worked for equal amount of time with each of the duplicating machines (so that the amount of exposure, C × T, could be approximated by C alone). Finally, a normal distribution is assumed for the exposure concentration. The lower 90% confidence limit of the teacher aides' exposure concentration is calculated to be 391 ppm (mean − 1.645 × S.D. = 960 ppm − 1.645 × 346 ppm = 391 ppm) (Steel and Torrie, 1980). The National Research Council's subcommittee on SMACs agreed that the lower 90% confidence limit, i.e. 391 ppm, can be treated as the LOAEL on the basis of blurred vision and headaches. That way of estimating the LOAEL should be valid because only 23 % of the teacher aides complained of blurred vision and 17% complained of headaches (Frederick et al., 1984), and if methanol-induced toxicity follows a concentration response, the 23% and 17% responders (for blurred vision and headaches, respectively) were probably exposed to methanol concentrations at the upper half of the bell-shaped, concentration distribution curve. In a German study, it was reported that a 4-y occupational exposure to 1200 to 8000 ppm of methanol impaired the vision in one worker (Humperdinck, 1941). It appeared that the vision of other workers in the same plant was not affected. The vision of this apparently sensitive worker improved after exposures were stopped for 6 w.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants Chronic and Genetic Toxicity It should be noted that no carcinogenic data on methanol has been found. Methanol is not genotoxic as evidenced by negative findings in the Ames test, the methanol's inability to cause sister chromatid exchange in Chinese hamster ovary cells, and micronuclei in mice (Florin et al., 1980; Obe and Ristow, 1977; Gocke et al., 1981). Developmental Toxicity Unlike inhaled ethanol, which affects pregnant rats and is not teratogenic in fetuses at high concentrations, inhaled methanol affects both the fetuses and dams at high concentrations (Nelson et al., 1985). Inhalation exposure to methanol at 5000 ppm for 7 h/d on days 1-19 of gestation of pregnant rats had no effects on the fetuses and dams (Nelson et al., 1985). Exposure at 10,000 ppm, however, depressed fetal weight, but it did not affect maternal body weight, behavior, and water and feed consumption. Exposure at 20,000 ppm caused fetal malformation and slightly unsteady gait in the dams.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants TABLE 8-1 Toxicity Summarya Concentration Exposure Duration Species Effects Reference 160 to 780 ppm N.S.b Humanc No definite evidence of injury. TLV Committee, 1986 210 to 375 ppm N.S. Humanc Frequent and recurrent headaches. Kingsley and Hirsch, 1955 365 to 3080 ppm From 1 h/w to 40 h/w for unspecified number of w Humanc Headache, nausea, dizziness, blurred vision. Frederick et al., 1984 1200 to 8000 ppm 4 y Humanc Marked diminution of vision. Humperdinck, 1941 450 to 500 ppm 8 h/d, daily for 379 d Dog No visual impairment or ophthalmoscopic abnormalities, no gross or microscopic tissue injuries, no significant changes in formed elements and chemical compositions of blood. Sayers et al., 1942 500, 2000, or 5000 ppm 6 h/d, 5 d/w for 4 w Monkey No ophthalmoscopic or histopathological changes. Andrews et al., 1987 4800 ppm 8 h Rat No grossly observable signs of toxicity. Loewy and von der Heide, 1914 5000 ppm 6 h/d, 5 d/w for 4 w Rat Mucoid nasal discharge. Andrews et al., 1987 5000 ppm 7 h/d, d 1-19 of gestation Rat No effects on fetal weight and development. No effects on maternal body weight, behavior, water and feed consumption. Nelson et al., 1985 8800 ppm 8 h Rat Lethargy. Loewy and von der Heide, 1914

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants 10,000 ppm 3 min/d, daily for 100 d Dog No detectable adverse effects. Sayers et al., 1944 10,000 ppm 6 h/d, 5 d/w for 6 w Rat No detectable effects in lungs. White et al., 1983 10,000 ppm 7 h/d, d 1-19 of gestation Rat Depressed fetal weight. No effects on the mother's body weight, behavior, water and feed consumption. Nelson et al., 1985 13,000 ppm 24 h Rat Prostration. Loewy and von der Heide, 1914 20,000 ppm 7 h/d, d 1-19 of gestation Rat Congenital malformations of the brain, skeletal, cardiovascular and urinary systems. Slightly unsteady gait in the dams. Nelson et al., 1985 22,500 ppm 8 h Rat Narcosis. Loewy and von der Heide, 1914 a Only the results from inhalation studies were included. b N.S. = not specified. c Human subjects in workforce.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants TABLE 8-2 Exposure Limits Set by Other Organizations Organization Concentration, ppm ACGIH's TLV 200 (TWA) ACGIH's STEL 250 OSHA's PEL 200 (TWA) NIOSH's REL 200 (TWA), 800 (15-min ceiling) NIOSH's IDLH 25,000 NRC's 1-h EEGL 200 NRC's 24-h EEGL 10 TLV = threshold limit value. TWA = time-weighted average. PEL = permissible exposure limit. STEL = short-term exposure limit. REL = recommended exposure limit. IDLH = immediately dangerous to life and health. EEGL = emergency exposure guidance level. TABLE 8-3 Spacecraft Maximum Allowable Concentrations Duration ppm mg/m3 Target Toxicity 1 h 30 40 Visual disturbances 24 h 10 13 Visual disturbances 7 da 7 9 Visual disturbances 30 d 7 9 Visual disturbances 180 d 7 9 Visual disturbances a Current 7-d SMAC = 40 ppm. RATIONALE Methanol's SMACs are set to protect the astronauts against headaches and ocular injury, the two major toxic end points of methanol poisoning. For each desired exposure duration, an acceptable concentration (AC) for each of the toxic end point is derived from the toxicity data. At the end, the lowest AC is chosen as the SMAC for that exposure duration.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants Headache 1-h AC In a study by Kingsley and Hirsch (1955) and in a NIOSH study (Frederick et al., 1984), workers complained of headaches when they worked in the vicinity of duplicating machines in which methanol was used. As described in “Toxicity Summary,” the LOAEL for headaches is estimated to be 391 ppm according to the data in the NIOSH study. Since some degree of headache is acceptable during emergencies, the LOAEL in an occupational setting is chosen to be the 1-h AC based on headaches. 1-h AC based on headaches = occupational LOAEL = 391 ppm. 24-h AC In an emergency that lasts up to 24 h, it is not acceptable for the crew to have to endure recurrent headaches for 24 h. So the 24-h SMAC should be set lower than the 1-h SMAC. Unfortunately, there are no data on the level of methanol that does not cause headaches. The American Conference of Governmental Industrial Hygienists (ACGIH) cited a study performed by the Massachusetts Division of Occupational Hygiene in 1937 that detected no definite evidence of injury at 160-780 ppm (TLV Committee, 1986). Because two more recent reports showed that methanol could produce headaches at less than 780 ppm (Kingsley and Hirsch, 1955; Frederick et al., 1984), the apparently negative finding in the Massachusetts study was disregarded. Instead, to estimate a concentration that might not cause headaches, an extrapolation factor of 5 is applied to the LOAEL, 391 ppm, based on headaches in an occupational study (Kingsley and Hirsch, 1955). The factor of 5 is chosen because minor headaches are acceptable in a 24-h contingency, as a factor half the size of the traditional factor of 10 is used to estimate a no-observed-adverse-effect level (NOAEL) from a LOAEL. Time adjustment is needed to account for the potential difference be-

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants tween an 8-h workday exposure and a 24-h continuous exposure. The time adjustment for headaches is performed with the assumptions that headaches are dependent on the blood concentration of methanol's active metabolite, formic acid, and that there is a threshold blood concentration below which no headaches would occur. According to classical pharmacokinetics, during a continuous exposure at a constant dose rate of a chemical that follows a one- or two-compartment model, the blood concentration will reach 99% of the steady state seven elimination half-lives into the exposure (Gibaldi and Perrier, 1975). Since methanol distributes rapidly throughout the body in body water (Yant and Schrenk, 1937), one can assume that methanol follows a one-compartment model. However, the findings of Leaf and Zatman (1952) tend to indicate that methanol follows either a one-or a two-compartment model. They showed that the urinary methanol concentration declined monoexponentially from 1 to 14 h after an ingestion of up to 7 mL of methanol in adult males and the urinary methanol concentrations closely reflected the changes in blood concentration. That means the methanol concentration in blood declined monoexponentially from 1 to 14 h following an ingestion. Because Leaf and Zatman did not collect any data in the first hour after methanol ingestion, they might have missed an early exponential phase, so it is possible that methanol follows a two-compartment model. Regardless of whether a one- or two-compartment model is used, with a half-life of 1.5-2 h in humans (Sedivec et al., 1981), it only takes 14 h for the methanol blood level to essentially reach equilibrium. We need to estimate the time the blood level of methanol's active metabolite, i.e., formic acid, takes to reach equilibrium. As summarized above, methanol is metabolized first to formaldehyde, which is further metabolized to formic acid. Because formaldehyde is very rapidly metabolized to formic acid (Tephly et al., 1979) and because the elimination half-life of formaldehyde is only about 1/30th of that of formic acid (McMartin et al., 1977, 1979; Clay et al., 1975), kinetically we can assume that the metabolism of methanol to formic acid consists of only one step. It has been shown that, for a metabolite with a elimination half-life less than the elimination half-life of the parent compound, the blood level of the metabolite follows that of the parent compound after an initial period (Gibaldi and Perrier, 1975). Formic acid's elimination half-life is 31 min in monkeys (McMartin et al, 1977) and that of methanol is 1.5-2 h in humans (Sedivec et al., 1981). Assuming that formic acid's half-life in humans resembles that in monkeys, the blood level of formic acid should, therefore, follow the blood level of methanol after an initial period. Formic acid started to

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants appear in blood as soon as 2 h after monkeys ingested methanol (Tephly et al., 1979). It follows that formic acid's blood level probably lags behind that of methanol by no more than 2 h during an inhalation exposure of methanol. So formic acid's blood level should reach steady state at 14 h + 2 h, i.e. 16 h, in a continuous methanol inhalation exposure. That means the time adjustment for any exposure longer than 16 h, e.g. 24 h, 7 d, 30 d, and 180 d, could be done using 16 h in place of the actual exposure duration. So the time-adjustment factor becomes 8 h/16 h. Such a time-adjustment factor is conservative because it implies that the blood concentration of formic acid increases linearly with exposure time for 16 h into a methanol exposure. Actually, the blood concentration of formic acid will probably increase in some exponential function to 16 h, but because the data available do not allow for an accurate estimation of the exponential function, a linear function is used instead. 24-h AC based on headaches = occupational LOAEL × 1/extrapolation factor × time adjustment = 391 ppm × 1/5 × 8 h/16 h = 39 ppm. 7-d, 30-d, and 180-d ACs Since formic acid reaches steady state in 16 h, the time adjustment for a 7-d, 30-d, or 180-d continuous exposure is all done using 16 h. To estimate the NOAEL, a safety factor of 10 is applied onto the LOAEL. Because the LOAEL is derived from a NIOSH study based on only 66 teacher aides, an adjustment for “small n” is used to derive the 7-d, 30-d, and 180-d ACs. The adjustment for small n is not needed for the 1-h and 24-h ACs based on headaches because a small degree of headache is acceptable for 1 h or 24 h, so a wide safety margin is not needed. 7-d, 30-d, and 180-d AC based on headaches = occupational LOAEL × 1/NOAEL factor × time adjustment × 1/small-n factor = 391 ppm × 1/10 × 8 h/16 h × (square root of n)/10 = 391 ppm × 1/10 × 8 h/16 h × (square root of 66)/10 = 16 ppm,

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants where the NOAEL factor is the uncertainty factor used to estimate a NOAEL from a LOAEL. Visual Disturbances 1-h AC As discussed in “Toxicity Summary,” the LOAEL for visual disturbances is estimated to be 391 ppm in an occupational exposure setting on the basis of data from the NIOSH study of 66 teacher aides (Frederick et al., 1984). 1-h AC based on visual disturbances = occupational LOAEL × 1/NOAEL factor × 1/small-n factor = 391 ppm × 1/10 × (square root of n)/10 = 391 ppm × 1/10 × (square root of 66)/10 = 32 ppm. 24-h AC Unlike headaches, methanol's occular toxicity might not be entirely dependent on the blood concentration of formic acid and might not have a threshold. Methanol's occular toxicity is prudently assumed to be dependent on the product of exposure concentration and exposure duration. Because it is difficult to find a representative workday for the teacher aides in the NIOSH study, the time adjustment used to derive the 24-h AC is based on an occupational exposure of 8 h, so the time-adjustment factor is 8 h/24 h. Considering the fact that some of the teacher aides were exposed for 1 h/w and others were exposed for years at 40 h/w, a time-adjustment factor of 8 h/24 h seems to be an appropriate compromise. 24-h AC based on visual disturbances = occupational LOAEL × 1/NOAEL factor × time adjustment × 1/small-n factor = 391 ppm × 1/10 × 8 h/24 h × (square root of n)/10 = 391 ppm × 1/10 × 8 h/24 h × (square root of 66)/10 = 11 ppm.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants 7-d, 30-d, and 180-d ACs A similar rationale is used in deriving the longer-term ACs. As a compromise for the facts that some workers were exposed to less than 40 h/w for less than a year, while others were exposed for years at 40 h/w, all time adjustments are done on a per-week basis regardless of whether the AC is for 7, 30, or 180 d. 7-d, 30-d, and 180-d ACs based on visual disturbances = occupational LOAEL × 1/NOAEL factor × time adjustment × 1/small-n factor = 69 ppm × 1/10 × (40 h/w)/(24 h/d × 7 d/w) × (square root of n)/10 = 69 ppm × 1/10 × (40 h/w)/(24 h/d × 7 d/w) × (square root of 66)/10 = 7 ppm. The data of a subchronic exposure of monkeys to methanol can be used to check if the 180-d AC of 7 ppm can prevent ocular damage in a 180-d exposure. Andrews et al. (1987) showed that an exposure of monkeys to methanol at 500, 2000, or 5000 ppm, 6 h/d, 5 d/w for 4 w failed to produce any eye injury on the basis of microscopic and ophthalmoscopic examinations (Andrews et al., 1987). Therefore, 5000 ppm is considered the NOAEL in this 4-w study. Haber's rule is used in adjusting for the differences in exposure durations. 180-d acceptable concentration derived from data in monkeys = 4-w NOAEL × species extrapolation factor × time adjustment = 5000 ppm × 1/10 × (6 h/d × 5 d/w × 4 w)/(24 h/d × 180 d) = 5000 ppm × 1/10 × 0.03 = 14 ppm. Since the 180-d AC derived from the human data of NIOSH is lower than the acceptable methanol exposure concentration based on the data in monkeys, the 180-d AC appears to be appropriate. With a preference of human data over animal data, the 180-d acceptable concentration derived from data in monkeys is not adopted in setting the 180-d SMAC. Because methanol's toxicity in primates differs from that in nonprimates

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants (Gilger and Potts, 1955), the data from the long-term study in dogs (Andrews et al., 1987) are not used to set the long-term SMACs. Establishment of SMACs The ACs based on headaches and visual disturbances for each of the exposure durations are listed in Table 10-4. The lowest ACs for each exposure duration are chosen to be the corresponding SMACs. The 1-h, 24-h, 7-d, 30-d, and 180-d SMACs are set at 30, 10, 7, 7, and 7 ppm, respectively. Finally, these SMACs are not adjusted for microgravity effects, because microgravity-induced changes are not expected to affect methanol 's ocular toxicity and its propensity to produce acidosis. TABLE 8-4 Acceptable Concentrations   Acceptable Concentrations, ppm Toxic End Points 1 h 24 h 7 d 30 d 180 d Headaches 391 39 16 16 16 Visual Disturbances 32 11 7 7 7 SMAC 30 10 7 7 7 REFERENCES ACGIH. 1986. Methanol. In Documentation of TLVs and BEIs. American Conference of Governmental Industrial Hygienists, Cincinnati, Ohio. Andrews, L.S., J.J. Clary, J.B. Terrill, and H.F. Bolte. 1987. Subchronic inhalation toxicity of methanol. J. Toxicol. Environ. Health 20:117-124. Bourrat, C. and L. Riboullard. 1986. Voluntary methanol poisoning. Severe regressive encephalopathy with anomalies on x-ray computed tomography. Rev. Neurol. (Paris) 142:530-534.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants excretion of methanol in man. Scand. J. Clin. Lab. Invest. 43:377-379. Kavet, R. and K.M. Nauss. 1990. The toxicity of inhaled methanol vapors. Crit. Rev. Toxicol. 21:21-50. Kingsley, W.H. and F.C. Hirsch. 1955. Toxicologic considerations in direct process spirit duplicating machines. Compen. Med. 40:7-8. Klaassen, C.D. 1990. Solvents and vapors. P. 1624 in Goodman and Gilman's The Pharmacological Basis of Therapeutics. A.G. Gilman , et al. , eds. Macmillan, New York. Leaf, G. and L.J. Zatman. 1952. A study of the condition under which methanol may exert a toxic hazard in industry. Br. J. Ind. Med. 9:19-31. LeWitt, P.A. and S.D. Martin. 1988. Dystonia and hypokinesis with putaminal necrosis after methanol intoxication. Clin. Neuropharmacol. 11:161-167. Loewy, A. and R. vonder Heide. 1914. Uber die aufnahme des methylalkohls durch die atmung. Biochem. Z. 65:230-252. Mahieu, P., A. Hassoun, and R. Lauwerys. 1989. Predictors of methanol intoxication with unfavourable outcome. Hum. Toxicol. 8:135-137. McMartin, K.E., G. Martin-Amat, A.B. Makar, and T.R. Tephly. 1977. Methanol poisoning. V. Role of formate metabolism in the monkey. J. Pharmacol. Exp. Ther. 201:564-572. McMartin, K.E., G. Martin-Amat, P.E. Noker, and T.R. Tephly. 1979. Lack of a role of formaldehyde in methanol poisoning in the monkey. Biochem. Pharmacol. 28:645-649. Nelson, B.K., W.S. Brithwell, D.R. Mackenzie, A. Khan, J.R. Burg, W.W. Weigel, and P.T. Goad. 1985. Teratological assessment of methanol and ethanol at high inhalation levels in rats. Fundam. Appl. Toxicol. 5:727-736. Obe, G. and H. Ristow. 1977. Acetaldehyde, but not ethanol, induces sister chromatid exchanges in Chinese hamster cells in vitro. Mutat. Res. 56:211-213. Phang, P.T., L. Passerini, B. Mielke, R. Berendt, and E.G. King. 1988. Brain hemorrhage associated with methanol poisoning. Crit. Care Med. 16:137-140. Sayers, R.R., W.P. Yant, H.H. Schrenk, J. Chornyak, S.J. Pearce, F.A. Patty, and J.G. Linn. 1942. P. 1 in Methanol poisoning—I. Exposure of dogs to 450-500 ppm methanol vapor in air. Rep. Invest. No. 3617. U.S. Department of the Interior, Bureau of Mines, Washington, D.C. Sayers, R.R., W.P. Yant, H.H. Schrenk, J. Chornyak, S.J. Pearce, F.A.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants Patty, and J.G. Linn. 1944. Methanol poisoning II. Exposure of dogs for brief periods eight times daily to high concentrations of methanol vapor in air. J. Ind. Hyg. Toxicol. 26:255-259 . Sedivec, V., M. Mräz, and J. Flek. 1981. Biological monitoring of persons exposed to methanol vapors. Int. Arch. Occup. Environ. Health 48:257-271. Steel, R.G.D. and J.H. Torrie. 1980. Pp. 55-56 in Principles and Procedures of Statistics. A Biomedical Approach. McGraw-Hill, New York. Stegink, L.D., M.C. Brummel, K. McMartin, G. Matin-Amat, L.J. Filer, G.L. Baker, and T.R. Tephly. 1981. Blood methanol concentrations in normal adult subjects administered abuse doses of aspartame. J. Toxicol. Environ. Health 7:281-290 . Tephly, T.R., A.B. Makar, K.E. McMartin, S.S. Hayreh, and G. Martin-Amat. 1979. Methanol: Its metabolism and toxicity. Pp. 145-164 in Biochemistry and Pharmacology of Ethanol. Vol. I . E. Majchrowicz and E.P. Noble , eds. Plenum, New York. Verslegers, W., M. Van den Kerchove, R. Crols, W. De Potter, B. Appel, and A. Lowenthal. 1988. Methanol intoxication. Parkinsonism and decreased met-enkephalin levels due to putaminal necrosis. Acta Neurol. Belg. 88:163-171 . White, L.R., A.B. Marthinsen, R.J. Richards, K.B. Eik-Nes, and O.G. Nilsen. 1983. Biochemical and cytological studies of rat lung after inhalation of methanol vapour. Toxicol. Lett. 17:1-5 . Wong, K.L. and C.-W. Lam. 1990. STS-31 Orbiter Payload, DSO and Utility Chemicals. Toxicologic Information and Risk Assessments. JSC 24227. Toxicology Group, Biomedical Operations and Research Branch, Medical Sciences Division , Johnson Space Center, NASA, Houston, Tex. Yant, W.P. and H.H. Schrenk. 1937. Distribution of methanol in dogs after inhalation and administration by stomach tube and subcutaneously. J. Ind. Hyg. Toxicol. 19:337-345 .

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