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Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 4 Methanol Hector D. García, Ph.D. Toxicology Group Habitability and Environmental Factors Division Johnson Space Center National Aeronautics and Space Administration Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Methanol, the simplest alcohol, is a colorless, volatile, highly flammable liquid with a mild, characteristic, agreeable odor. Its physical and chemical properties are shown in Table 4-1. TABLE 4-1 Physical and Chemical Properties of Methanol Formula CH3OH Chemical name Methanol Synonyms Methyl alcohol, wood spirit, carbinol, Columbian spirits, wood alcohol, wood naphtha, methyl hydroxide, hydroxymethane, methyl hydrate, methylol, monohydroxymethane CAS registry no. 67-56-1 Molecular weight 32.04 Density (H2O = 1) 0.79 Boiling point 65°C Melting point −98°C Vapor pressure 12.3 kPa at 20°C Explosive limits 5.5% to 44% in air Solubility Completely miscible in water, ethanol, ether, and many other organic solvents Conversion factor 1 part per million (ppm) = 1.31 milligrams per cubic meter (mg/m3)
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Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 OCCURRENCE AND USE Methanol occurs naturally in humans, animals, and plants, including fresh fruits and vegetables, and in fermented products, including wine and other spirits (see Tables 4-2 and 4-3). It is produced from the distillation of wood and is synthesized catalytically from crude petroleum. It is used industrially in the manufacture of other chemicals and as a solvent. It is added to various commercial and consumer products, including windshield washing solutions, deicing solutions, glass cleaners, duplicating fluids, solid canned fuels, paint thinners and removers, model airplane fuels, embalming fluids, lacquers, inks, and some formulations of gasohol motor fuel. Methanol has been found at concentrations up to 3.7 milligrams per liter (mg/L), with an average of <0.1 mg/L, in drinking water on the International Space Station (M. Hwang, J. Schultz, M. Hwang, and J. Schultz, National Aeronautics and Space Administration, Houston, TX, personal commun., 2005). TOXICOKINETICS AND METABOLISM In the early 1980s, measurements of the background concentration of methanol in human blood used available techniques that were limited by poor sensitivity (limit of detection = about 0.4 milligram per deciliter [mg/dL]) TABLE 4-2 Methanol Concentrations in Foods and Beverages Beverages and Food Concentration Beverages Fresh and canned fruit juices (orange and grapefruit juices) Average of 140 mg/L 1-43 mg/L 11-80 mg/L 12-640 mg/L Carbonated beverages ~56 mg/L Neutral spirits <1,500 mg/L Beer 6-27 mg/L Wines 96-329 mg/L Distilled spirits 16-220 mg/L Bourbon 55 mg/L Grain alcohol (50%) 1 mg/L Brandies (USA, Canada, and Italy) 6,000-7,000 mg/L Food Beans 1.5-7.9 mg/kg Split peas 3.6 mg/kg Lentils 4.4 mg/kg Abbreviation: mg/kg, milligram per kilogram. Source: NTP CERHR 2003.
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Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 TABLE 4-3 Background Blood Methanol and Formate Concentrations in Humans Subjects Methanol, mg/dL Mean ± SD (Range) Formate, mg/dL Mean ± SD (Range) Reference Twelve males on restricted diet (no methanol-containing or methanol-producing foods), 12 h 0.0570 ± 0.0305 (0.025-0.14) 0.38 ± 0.11 (0.22-0. 66) Cook et al. 1991 Twenty-two adults on restricted diet (no methanol-containing or methanol-producing foods), 24 h 0.18 ± 0.26 (no range data) 1.12 ± 0.91 (no range data) Chuwers et al. 1995, Osterloh et al. 1996 Three males who ate a breakfast with no aspartame-containing cereals and no juice 0.182 ± 0.121 (0.057-0.357) 0.908 ± 0.126 (0.731-1.057) Lee et al. 1992 Five males who ate a breakfast with no aspartame-containing cereals and no juice. (Second experiment) 0.193 ± 0.093 (0.054-0.315) 0.878 ± 0.182 (0.536-1.083) Lee et al. 1992 Twelve adults who drank no alcohol for 24 h 0.18 ± 0.07 (no range data) No data Batterman and Franzblau 1997 Twelve adults who drank no alcohol for 24 h 0.17 ± 0.09 (0.04-0.47) No data Batterman et al. 1998 Thirty adults who fasted for 10 h <0.4 (no range data) 1.91 (no range data) Stegink et al. 1981 Twenty-four infants who fasted for an unspecified time <0.35 (no range data) No data Stegink et al. 1983 Abbreviation: mg/dL, milligram per deciliter. Source: NTP CERHR 2003. (Stegink et al. 1981). As shown in Table 4-3, later (1992-1998) measurements with a superior limit of detection of about 0.05 mg/dL consistently showed background concentrations of methanol in blood of about 0.18 mg/dL in adults on methanol-restricted diets (Lee et al. 1992; Chuwers et al. 1995; Osterloh et al. 1996; Batterman and Franzblau 1997; Batterman et al. 1998). Absorption Gastrointestinal absorption of methanol is rapid and almost total after oral exposure. Inhalation studies with humans have shown a net absorption of methanol of 60% to 85% (NTP CERHR 2003). In autopsies of 28 humans who ingested lethal quantities of methanol, however, four had methanol in their stomach contents several days after the initial intoxication, possibly because it
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Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 distributes in all body water, thus being resecreted to gastric fluids after the initial absorption (Mittal et al. 1991). In pregnant monkeys exposed for 2.5 h/d, 7 d/wk to 0, 200, 600, and 1,800 ppm of methanol vapor, average blood methanol concentrations 30 min postexposure were 5, 11, and 35 micrograms per milliliter (µg/mL) (0.5, 1.1, and 3.5 mg/dL) in the groups exposed to 200, 600, and 1,800 ppm, respectively (Burbacher et al. 2004a). Blood concentrations in the 200-ppm group were barely above the basal (preexposure) blood methanol concentrations or those observed in the control group (about 3 µg/ml; 0.3 mg/dL). Short-term inhalation exposure of adult volunteers to methanol vapors at 800 ppm for 0, 0.5, 1, 2, and 8 h produced maximal average blood methanol concentrations of 0.06, 0.53, 0.66, 1.40, and 3.07 mg/dL, respectively (Batterman et al. 1998). Distribution Absorbed methanol is distributed rapidly (peak blood concentrations were reached 30-90 min postexposure (Nashed and Fink 1994)) and uniformly to all organs and tissues in proportion to their water content (NTP CERHR 2003). In humans, the overall volume of distribution is 0.5-0.6 L/kg body weight (Liesivuori and Savolainen 1991; IPCS 1997). Thus, a 70-kg person would have 35-42 L of water in all tissues. Because microgravity causes fluid shifts to which the body responds by increasing the excretion of water into urine and, over a period of a few days after entering microgravity, results in a reduced blood volume, the lower value (35 L) of the range should apply to astronauts. Metabolism Humans and animals metabolize methanol primarily in the liver by sequential oxidative steps, first to formaldehyde by alcohol dehydrogenase (ADH) in humans and by catalase in rodents. Ethanol can act as a competitive inhibitor of ADH and is used therapeutically to slow the metabolism of methanol. Formaldehyde is rapidly oxidized (half-life, about 1 min) in humans and nonhuman primates to formic acid. In a tetrahydrofolate-dependent reaction, primates slowly metabolize formic acid to carbon dioxide, but nonprimates metabolize it about twice as rapidly (McMartin et al. 1977). The delayed toxicity of ingested methanol in humans appears to be due to the accumulation of the toxic metabolite, formate. The major route of formate metabolism in the rat, monkey, and presumably humans is oxidation to carbon dioxide via the folate biochemical pathway. Formate enters the pathway by combining with tetrahydrofolate. The susceptibility of various species to methanol toxicity is inversely related to the rate of tetrahydrofolate-dependent oxidation of formate to carbon dioxide (Black et al. 1985). Overall metabolism in humans proceeds with reported half-times of
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Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 24 h or more with doses greater than 1 g/kg and half-times of 2.5-3 h for doses less than 0.1 g/kg (IPCS 1997). Two mechanisms may be operative in explaining low formateoxidation in species susceptible to methanol toxicity: low hepatic tetrahydrofolate concentrations and reduced hepatic 10-formyltetrahydrofolate dehydrogenase activity (Johlin et al. 1987). The activity of 10-formyltetrahydrofolate dehydrogenase, the enzyme that catalyzes the final step of formate oxidation to carbon dioxide, has been reported to be markedly (4- to 5-fold) reduced in monkey and human liver compared with rodent liver, consistent with lower rates of formate oxidation in primates. Both mechanisms should apply to formate generated by metabolism of ingested methanol. Formate did not accumulate in the blood of volunteers exposed to methanol vapor at 200 ppm for 6 h (Lee et al. 1992), either at rest or with light exercise. The limit of detection for formate in that study was about 0.3 mg/dL. Blood concentrations of methanol increased from 1.8 µg/mL (0.18 mg/dL) before exposure to 7.0 µg/mL (0.70 mg/dL) after 6 h at rest and 8.1 µg/mL (0.81 mg/dL) after 6 h with light exercise. Excretion If there is no simultaneous exposure to ethanol, the kidneys excrete 2% to 5% of ingested methanol unchanged and the lungs eliminate a small amount. At blood concentrations below 15 mg/L (15 µg/ml; 1.5 mg/dL), the half-life of inhaled methanol in the blood of human volunteers has been reported to be 1.44 ± 0.33 h (Batterman et al. 1998), but, at blood concentrations above 300 mg/dL (3,000 µg/mL)—that is, after ingestion of a toxic dose—the enzymes that metabolize methanol become saturated, the half-life increases to 27 h (Tephly 1991), and the kidneys and lungs eliminate a larger proportion of unchanged methanol . Simultaneous exposure to ethanol (a therapeutic measure at a target ethanol concentration of 100-150 mg/dL in blood) increases the half-life of methanol to 30-52 h. TOXICITY SUMMARY Selected studies of various toxic effects of methanol are summarized in Table 4-4. Most of the available literature on methanol toxicity in humans concerns the effects of acute rather than chronic exposures and shows interindividual variability in the doses that produce toxic effects. Ingested doses as low as 25 mL of 40% methanol (= 7.9 g of methanol) have been reported to be lethal, but, in other cases, individuals have survived doses up to 500 mL of “moonshine” containing 40% methanol (Kavet and Nauss 1990; Nashed and Fink 1994).
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Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 TABLE 4-4 Toxicity Summary Concentration/Dose, chemical form Route Exposure Duration Species/Strain Effects Reference Acute Exposures (<10 d) Unknown high dose Ingestion Single bolus Humans, n = 2 Severe metabolic acidosis, optic disc edema, death in 1 of 2 McMartin et al. 1980 Unknown high dose Ingestion Single bolus Humans, n = 2 Severe metabolic acidosis, optic disc edema, blindness Hayreh et al. 1977, 1980 Unknown high dose Ingestion Single bolus Humans, n=3 Severe metabolic acidosis, optic disc edema, blindness Jacobsen and McMartin 1986 192 ppm vapors Inhalation 75 min Humans, n = 12 NOAEL for sensory, neurobehavioral, and reasoning effects Cook et al. 1991 200 ppm vapors Inhalation 4 h Humans, n = 26 NOAEL for visual, neurophysiologic, and neurobehavioral effects Chuwers et al 1995 200 ppm vapors Inhalation 4 h Humans, n = 26 No significant increase in formate in serum or urine D’Alessandro et al. 1994 200 ppm vapors Inhalation 4 h Humans, n = 22 Serum methanol increased 4-fold to 6.5 mg/L; half-life of methanol in serum = 3.2 ± 2.3 h Osterloh et al. 1996 200 ppm vapors Inhalation 6 h Humans, n = 6 No increase in formate in blood; serum methanol increased to 0.7 mg/dL at rest and 0.81g/dL with light exercise Lee et al. 1992 200 ppm vapors Inhalation 2 h Humans, n = 4 No increase in urinary formic acid; methanol blood increased from 20 to 244 µM Ernstgard et al. 2005 800 ppm, vapors Inhalation 8 h Humans, n = 15 Measured methanol in breath, blood, and urin no toxic effects were examined Batterman et al. 1998
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Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 Concentration/Dose, chemical form Route Exposure Duration Species/Strain Effects Reference Aspartame, 200 mg/kg (equivalent to 20 mg of methanol / kg) Ingestion 3 times / d Humans, n=30 Blood methanol increased from <0.4 mg/dL to a peak of 2.58 mg/dL with no increase in formate in blood Stegink et al. 1981 Subchronic Exposures (11-100 d) 2,500 mg of methanol/kg/d Ingestion 90 d Rats, male and female, Sprague-Dawley, n = 30/sex/dose LOAEL for elevated SGPT and SAP and decreased brain weight EPA 1986 365-3,080 ppm vapors Inhalation 1 h/wk – 40 h / wk Teacher aids, female, n = 66 Dose-dependent incidence of blurred vision, headache, dizziness, and nausea Frederick et al. 1984 Chronic Exposures (≥100 d) 32.7 mg of methanol/dose (as metabolite of 900 mg aspartame/d) Ingestion 3 doses/d, 7 d/wk, 6 mo Human, n = 53 NOAEL for standard lab tests or symptoms Leon et al. 1989 Abbreviations: LOAEL, lowest-observed-adverse-effect level; NOAEL, no-observed-adverse-effect level; SAP, serum alkaline phosphatase; SGPT, serum glutamic-pyruvic transaminase (now called alanine amino transferase).
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Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 The initial toxic effect of methanol is inebriation within the first 1-2 h after ingestion. After a delay of 6-30 h following ingestion, more serious toxic effects are associated with methanol: headaches, dizziness, nausea, blurred vision, gastric and muscle pain, metabolic acidosis, blindness due to optic nerve injury, and, in extreme exposures, death. The severity and kinetics of toxic effects depend on the rate of metabolism in the liver, which can vary substantially among individuals, depending on the hepatic concentration of folate, a cofactor needed to convert formate to carbon dioxide, and depending on concurrent exposure to (treatment with) substances such as ethanol and fomepizole (4-methyl pyrazole), which can inhibit ADH and slow production of the toxic metabolite, formic acid or formate. Interpretation of toxicity data from animal experiments involving exposures to methanol is complicated by interspecies as well as nutritional status-dependent differences in the rate of metabolism of methanol. In rodents, the initial oxidation of methanol to formaldehyde is catalyzed by catalase, rather than by ADH as in humans. Because catalase is saturated at low concentrations of methanol, the blood concentrations of methanol increase in rodents, whereas in humans, the conversion of formate to carbon dioxide is the rate-limiting step in metabolism and formate accumulates in the blood, in addition to methanol. The developmental toxicity (Nelson et al. 1985; Rogers et al. 1993; Weiss et al. 1996) reported in rodents is of doubtful relevance to humans because it occurs only at doses (mg/kg) severalfold above the lethal dose in humans (Methanol Institute 2002). Acute Exposures (≤10 d) Symptoms of acute methanol toxicity begin with narcosis followed by a symptom-free period of several hours to about a day, followed by visual disturbances and central nervous system (CNS) effects, including headache; dizziness; abdominal, back, and leg pain; nausea; and delirium that can lead to coma (Gosselin et al. 1984). Many of the delayed toxic effects can be attributed to the accumulation of formate, which also leads to metabolic acidosis. Neurobehavioral Effects Potential CNS effects of inhalation of 192 ppm of methanol vapor for 75 min were tested in 12 young male volunteers (Cook et al. 1991). A battery of 20 neurobehavioral tests was administered before, during, and after each exposure. No detectable effects were seen except for two tests in which minor effects were within the range of test values seen in control subjects exposed to air. No significant neurobehavioral effects were seen in 26 volunteers exposed once for 4 h to 200 ppm of methanol vapors and tested for color discrimination (Stroop test and Lanthony 15), contrast sensitivity (Visitech), auditory evoked
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Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 potentials, visual scanning, symbol-digit substitution, memory scanning (Sternberg), and event-related potential (P-300), unless certain between-subject variables were considered (Chuwers et al. 1995). Specifically, significant effects were seen on only two outcomes: the P-300 amplitude when alcohol consumption and smoking accounted for between-subject variability (P = 0.01) and the symbol-digit test with age accounting for between-subject variability (P = 0.05). In agreement with previous reports (D’Alessandro et al. 1994), formate concentrations in serum were not affected after exposure to 200 ppm of methanol for 4 h, but serum methanol concentrations were increased (peak = 0.65 mg/dL, which was 0.56 mg/dL greater than in controls). CNS Degeneration The sensitivity of the CNS to degenerative changes after exposure to methanol is supported by a case report of putaminal necrosis seen in computed tomography scans of the head of a 26-y-old woman with degenerating mental status after recovery from acute methanol intoxication (Fontenot and Pelak 2002). An autopsy study of 28 fatal cases of methanol poisoning, in which shrinkage and degeneration of neurons in the parietal cortex were seen in 86% of the cases and putaminal degeneration and necrosis were seen in 7.1% of the cases, provided further evidence of the CNS toxicity of methanol (Mittal et al. 1991). Ocular Effects Ocular toxicity is commonly seen in cases of human exposure to methanol. McMartin et al. reported severe metabolic acidosis and optic disc edema in two patients whose blood concentrations were 11.1 and 26.0 milliequivalents of formate/mL when measured after hospitalization for methanol intoxication (McMartin et al. 1980). The patient with the higher blood formate concentration died despite aggressive treatment (bicarbonate, intravenous 10% ethanol, and hemodialysis) of both patients. In humans, permanent visual damage has been associated with prolonged exposures (>24 h) to blood formate concentrations >7 mM (31.5 mg/dL) produced during methanol intoxication (Hayreh et al. 1980; Hayreh et al. 1977; Jacobsen and McMartin 1986). Clinical observations in methanol-intoxicated humans have shown that, in its initial stages, developing ocular toxicity can be reversed, even >24 h after methanol ingestion, by treatments such as bicarbonate, fomepizole or ethanol, intravenous folinic acid, and dialysis, which reduce blood formate concentrations and metabolic acidosis (Barceloux et al. 2002). Such reversibility is consistent with a mechanism of formate toxicity involving gradual optic nerve toxicity due to prolonged metabolic hypoxia and with the reversibility of formateinhibition of cytochrome c oxidase (Nicholls 1975).
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Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 Subchronic and Chronic Exposures (≥10 d) A National Institute for Occupational Safety and Health (NIOSH) epidemiology study of adverse health effects in 66 female teacher aides exposed to methanol vapors from duplicating fluid (99% methanol) found that aides exposed to 365-3,080 ppm of methanol reported significantly more blurred vision, headache, dizziness, and nausea than a comparison group of 66 unexposed female teachers randomly selected from 287 respondents to the questionnaire (Frederick et al. 1984). Exposure durations ranged from 1 h/d, 1 d/wk to 8 h/d, 5 d/wk. Fifteen of 21 measurements exceeded the (1984 relevant) NIOSH-recommended 15-min exposure limit of 800 ppm. The NIOSH recommended exposure limit (REL) is currently 200 ppm, time-weighted average (TWA). The incidence of symptoms related to methanol toxicity was positively correlated with the percentage of time spent per week at the duplicator. Aides who spent an average of 85% of their time (based on a 40-h wk) at or near a duplicating machine had a 50% incidence of reported methanol toxicity, which Frederick et al. defined as having any one of four aggregations of symptoms from a list chosen by an independent NIOSH physician. Only about 15% of aides who spent about 5% of their time (about 2 h) near a duplicator reported symptoms of methanol toxicity. The minimum and maximum daily doses the aides potentially inhaled can be estimated from the given ranges of atmospheric concentrations and exposure durations: An earlier study (Kingsley and Hirsch 1955) reported frequent headaches and dizziness, but no blurred vision, in workers exposed to methanol vapors at concentrations of 15-375 ppm (20-490 mg/m3). In a recent study, serum methanol concentrations in volunteers inhaling 200 ppm of methanol for 4 h were 0.65 ± 0.27 mg/dL, and serum methanol concentrations in controls were 0.09 ± 0.06 mg/dL (Osterloh et al. 1996). A case report was found attributing progressive parkinsonism in a young experimental physicist to long-term exposure to methanol vapors in the laboratory, with no episodes of acute intoxication (Finkelstein and Vardi 2002). No estimate was provided of the dose or exposure concentration of methanol, and it appears that there was simultaneous exposure to methyl bromide. A study of the safety of 6 mo of exposure to 300 mg of aspartame (an artificial sweetener that is rapidly and completely metabolized to methanol and its constituent amino acids) three times/d (equivalent to 32.7 mg of methanol/dose or 98.1 mg of methanol/d) reported no elevation in blood methanol concentra-
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Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 tion (most concentrations were below the level of detection, 0.992 mg/dL), no significant increases in blood formate or mean urinary formate concentrations, and no adverse effects associated with the exposure (Leon et al. 1989). The Environmental Protection Agency (EPA)-sponsored 90-d gavage study in rats, tested at methanol concentrations of 0, 100, 500, and 2,500 mg/kg of body weight/d (10 rats/sex/dose group), found increases in liver enzymes (serum glutamic pyruvic transaminase (SGPT) and serum alkaline phosphatase (SAP)) and decreases in brain weight at the highest dose but no histopathologic lesions in the liver (EPA 1986). A dose rate of 500 mg/kg/d was considered a no-observed-adverse-effect level (NOAEL) in rats. No consistent treatment-related effects were found for organ or body weights or for histopathologic or ophthalmoscopic examinations in a subchronic inhalation study of rats and monkeys exposed to 0, 500, 2,000, and 5,000 ppm of methanol for 6 h/d, 5 d/wk for 4 wk (Andrews et al. 1987). Genotoxicity Methanol was negative for cell transformation in Syrian hamster embryo cells (clonal assay and viral enhanced), for sister chromatid exchange in vitro, and for aneuploidy and chromosome aberrations in Neurospora crassa (EPA 1994). The micronucleus test and the assay for chromosome aberrations in mammalian polychromatic erythrocytes were inconclusive (EPA 1994). Reproductive Toxicity No studies of the potential reproductive toxicity of methanol in humans were found. In male Sprague-Dawley rats, inhalation of 200 ppm of methanol for 8 h/d, 5 d/wk for 6 wk reduced serum testosterone concentrations to 32% that of controls, although similar exposure to 10,000 ppm of methanol had no significant effect on testosterone concentration but increased serum levels of luteinizing hormone about 3-fold (Cameron et al. 1984). In female monkeys, exposures for 2.5 h/d, 7 d/wk to 0, 200, 600, and 1,800 ppm of methanol vapor did not alter their menstrual cycles, the number of breedings to conception or the conception rate, or the birth weight or health status of the offspring but decreased the length of pregnancy by 6 to 8 d compared with controls (Burbacher et al. 2004b). Developmental and Fetal Toxicity No studies were found of the potential developmental or fetal toxicity of methanol in humans. In CD-1 mice, inhaled methanol vapors caused developmental abnormalities (neural and ocular defects, cleft palate, hydronephrosis,
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Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 deformed tails, and limb (paw and digit) anomalies) at doses of 10,000 and 15, 000 ppm for 6 h/d, 3 d (Bolon et al. 1993). The highest concentration was mildly to moderately neurotoxic to up to 20% of the dams but would yield a dose that would be potentially lethal in humans (about 98 g/d). Similar results were reported in an EPA study of CD-1 mice, with a NOAEL of 1,000 ppm, 7 h/d on days 6-15 of gestation (Rogers et al. 1993). Plasma methanol concentrations in this study were approximately 9.7, 53.7, 165.0, 317.8, 420.4, and 733.0 mg/dL in the 1,000-, 2,000-, 5,000-, 7,500-, 10,000-, and 15,000-ppm exposure groups, respectively. In pregnant rats and their newborn pups, exposure to 4,500 ppm of methanol vapor produced only isolated, subtle performance decrements in a battery of neurobehavioral tests (Weiss et al. 1996). Further testing is needed to establish whether the observed differences are reproducible and significant. Offspring of rats consuming 2% methanol (an average of 2.5 g/kg of body weight) in drinking water during gestational days 15-17 or 17-19 required longer than controls consuming distilled water to begin suckling on postnatal day 1; they also required more time than the controls to locate nesting material from their home cages on postnatal day 10 (Infurna and Weiss 1986). No other overt toxicity was observed in dams or pups. Neither the Clean Air Act (CAA), Clean Water Act (CWA), nor the Safe Drinking Water Act (SDWA) require methanol monitoring. Some current standards for methanol exposures for workers and the general public are listed in Tables 4-5 and 4-6. Basis for EPA’s Reference Dose Calculation In an EPA-sponsored study, Sprague-Dawley rats that were gavaged daily with methanol at 0, 100, 500, or 2,500 mg/kg/d for 90 d showed elevated SGPT and SAP concentrations and small, but not statistically significant, increases in liver weight. Brain weights were significantly decreased in males and females at the highest dose. A dose rate of 500 mg/kg/d was considered a NOAEL in rats. An oral reference dose (RfD) of 0.5 mg/kg/d was calculated from the NOAEL by applying uncertainty factors of 10 for interindividual variations, 10 for species extrapolation, and 10 for subchronic to chronic extrapolation. However, rodents are poor models for methanol toxicity in humans. In addition, for a given daily dose rate, the use of gavage treatments would be expected to result TABLE 4-5 Drinking Water Standards for Methanol Set by Other Organizations Organization, Reference Standard Amount Concentration EPA 1993 Reference dose (oral, chronic) 0.5 mg/kg/d 12.5 mg/La aThe calculated concentration is based on a body weight of 70 kg and 2.8 L of water/d.
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Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 TABLE 4-6 Air Standards for Methanol Vapors Set by Other Organizations Organization, Standard Amount Reference NIOSH NIOSH 2005 IDLH 6,000 ppm REL-TWA 200 ppm (260 mg/m3) ST 250 ppm (325 mg/m3) (skin) OSHA NIOSH 2005 PEL-TWA 200 ppm (260 mg/m3) ACGIH ACGIH 2008 TLV-TWA 200 ppm, skin TLV-STEL 250 ppm, skin Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; IDLH, immediately dangerous to life and health; NIOSH, National Institute for Occupational Safety and Health; OSHA, Occupational Safety and Health Administration; PEL, permissible exposure limit; REL, recommended exposure limit; ST, short-term exposure limit (15 min); STEL, short-term exposure limit; TLV, Threshold Limit Value; TWA; time-weighted average. in higher peak blood methanol concentrations compared with what would be expected from smaller fractionated doses throughout the day for drinking water exposures. RfD values are meant to be protective of the entire population, including the elderly, children, and unusually sensitive individuals. NIOSH does not state the basis of its REL value of 200 ppm but based its immediately-dangerous-to-life-and-health value of 6,000 ppm on a Russian report of a 2-h LCLo (the lowest tested concentration that killed any mice after two hours of exposure) in mice of 37,594 ppm (Izmerov et al. 1982). The Occupational Safety and Health Administration does not state the basis of its value of 200 ppm for the permissible exposure limit (PEL), but it often uses the Threshold Limit Values (TLVs) of the American Conference of Governmental Industrial Hygienists (ACGIH) in setting PEL values. ACGIH did not state the specific studies or reports used as the basis for setting a TLV of 200 ppm but states that “Based on the human and animal toxicological responses, the TLV Committee recommends a TLV-TWA of 200 ppm and a STEL [short-term exposure limit] of 250 ppm for methanol” (ACGIH 1991). Since exposure scenarios for spacecraft crews differ significantly from those of workers or the general public, NASA calculates exposure guidelines for specific exposure durations on the basis of the lowest acceptable concentration for the various adverse effects as listed in Table 4-7 and described in the section below.
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Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 TABLE 4-7 Spacecraft Water Exposure Guidelines for Methanol Duration Concentration, mg/L Target Toxicity 1 d 40 Neurobehavioral effects 10 d 40 Neurobehavioral effects 100 d 40 Neurobehavioral effects 1,000 d 40 Neurobehavioral effects RATIONALE Acceptable concentrations (ACs) (Table 4-8) were determined following the guidelines of the National Research Council (NRC 2000). ACs were calculated as described below assuming consumption of 2.8 L of water/d. This includes an average of 800 mL/d used to prepare or reconstitute food in addition to 2.0 L/d for drinking. A value of 70 kg was used as the mass of an average astronaut. Spaceflight Effects None of the reported adverse effects of methanol exposures are known to be affected by spaceflight, but the 1.7% to 12% reduction in total body water associated with prolonged microgravity would proportionately increase the blood concentration of any methanol ingested. This effect is too small to significantly change the spacecraft water exposure guideline (SWEG) calculations. One-Day SWEG Immediate and delayed adverse effects of acute exposures to toxic, but not life-threatening, doses of methanol, such as those reported by teacher’s aids and other workers intermittently exposed to methanol vapors, include narcosis, headaches, dizziness, nausea, and blurred vision. More subtle neurobehavioral effects in humans (e.g., slight effects on P-300 amplitude and symbol-digit substitution tests) have been detected in controlled exposures to low (200 ppm) concentrations of methanol vapors. The available evidence suggests that acute exposures that produce such effects but do not produce symptoms of metabolic acidosis are not usually associated with permanent sequelae. Calculation of a concentration of methanol in drinking water that will keep blood methanol concentrations from accumulating to toxic levels when exposure is intermittent requires knowing the half-life of methanol in the blood. The published data on the half-life of methanol at low doses are sparse—only four papers (Haffner et al. 1992, 1997; Osterloh et al. 1996; Batterman et al. 1998), in addition to the study of Chuwers et al. (1995), were found, involving a total of
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Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 28 healthy subjects. The reported range of half-lives in individuals ranged from 1.2 to 3.6 h. A similar narrow range of half-lives was found in reviews of the literature for the metabolism of ethanol, despite the existence of marked genetic polymorphisms in some of the ADH enzymes, which metabolize both methanol and ethanol. This masking of the genetic variability may be explained by the contributions of multiple ADH enzymes and CYP2E1 to alcohol elimination. Note that the longer half-lives (e.g., 20 h) for blood methanol that have been reported occur only at concentrations above 300 mg/dL, such as those produced after ingestion of large doses of methanol. Thus, in calculating an acceptable concentration of methanol in drinking water, the use of the longest half-life (3.6 h) seen in any tested individual at low doses should provide a high level of confidence that methanol concentrations that do not exceed the calculated concentrations will not produce methanol toxicity in astronauts. Because Chuwers’ study involved fewer than 100 volunteers, the observed NOAEL of 0.65 mg/dL = 650 µg/dL should be adjusted by a factor of √n/√100 = √26/√100 = 0.51 to account for potential interindividual variations (NRC 2000). Thus, the target peak concentration of blood methanol should be 0.65 mg/dL × √26/√100 = 0.33 mg/dL. The maximum allowable concentration of methanol in drinking water that will produce a concentration of 0.33 mg/dL in the blood can be calculated as follows. If the half-life of methanol in the blood at low concentrations is ≤ 3.6 h, we can calculate the time course of methanol concentration in the blood during a typical day when drinking water contains a specified low concentration of methanol. Astronauts consume about 2.8 L of water per day. The pattern of consumption varies somewhat from individual to individual and from day to day, but for the purposes of this calculation we can assume that the 2.8 L is consumed in volumes equivalent to that of a canned soft drink (about 670 mL, including water used to reconstitute food) at meal times (assume 8 AM, noon, and 7 PM) with additional drinks of about 400 mL at around 3 PM and 9 PM. This pattern of drinking water consumption was used previously in calculating SWEG values for formate. Plots of the blood methanol concentration at each hour during a typical day can be used to determine the maximum concentration of methanol in drinking water that will maintain a blood methanol concentration of ≤0.33 mg/dL. Figure 4-1 shows that drinking water containing methanol at 40 mg/L will maintain blood methanol concentrations below 330 µg/dL of blood when the half-life is 3.6 h. The hourly calculated concentration of methanol in the blood is shown in Figure 4-1.
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Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 TABLE 4-8 Acceptable Concentrations for Methanol End Point Exposure Data Uncertainty Factor Acceptable Concentrations, mg/L Species Inter-individual LOAEL to NOAEL Interspecies Time Spaceflight 1 d 10 d 100 d 1,000 d NOAEL for neurobehavioral toxicity 200 ppm, 4 h Human, n = 26 0.51 1 1 PK model 1 40 40 40 40 SWEG 40 40 40 40
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Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 FIGURE 4-1 Calculated 24-h blood methanol kinetics for a 70-kg person ingesting water containing methanol at 40 mg/L. The pattern of ingestion was assumed to be 670 mL at 8 h (e.g., 8:00 AM), 670 mL at 12 h, 400 mL at 15 h, 670 mL at 19 h, and 400 mL at 21 h. Chuwers et al. measured a baseline of blood methanol at 0.18 mg/dL (Chuwers et al. 1995). Ten-, One-Hundred-, and One-Thousand-Day SWEGs Because the toxic effects of methanol do not follow Haber’s rule but instead depend on the concentration of methanol (or its metabolite, formate) in the blood, SWEG values for exposures >1 d should be set to ensure that methanol does not accumulate in the blood—that is, the peak methanol concentration does not increase during a multiday exposure. Thus, the methodology used to calculate blood methanol kinetics for a 1-d SWEG of 40 mg/L can also be applied to calculating SWEG values for 10, 100, and 1,000 d. Extending the exposure to examine the blood methanol concentration over multiple days reveals that the peak methanol concentration does not increase from day to day, but each day it achieves the same peak concentration and remains below the calculated target NOAEL concentration of 0.33 mg/dL (Figure 4-2). This pattern repeats for all exposure durations of ≥1 d.
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Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 FIGURE 4-2 Calculated multiday blood methanol kinetics for a 70-kg person ingesting water containing methanol at 40 mg/L. The pattern of ingestion was assumed to be 670 mL at 8 h (e.g., 8:00 AM), 670 mL at 12 h, 400 mL at 15 h, 670 mL at 19 h, and 400 mL at 21 h, repeating each 24-h period. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 1991. Methanol. Pp. 903-905 in Documentation of the Threshold Limit Values and Biological Exposure Indices, 6th Ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists. ACGIH (American Conference of Governmental Industrial Hygienists). 2008. Methanol. Pp. 113 in Guide to Occupational Exposure Values. Cincinnati, OH: American Conference of Governmental Industrial Hygienists. Andrews, L.S., J.J. Clary, J.B. Terrill, and H.F. Bolte. 1987. Subchronic inhalation toxicity of methanol. J. Toxicol. Environ. Health 20(1-2):117-124. Barceloux, D.G., G.R. Bond, E.P. Krenzelok, H. Cooper, J.A. Vale, and American Academy of Clinical Toxicology Ad Hoc Committee on the Treatment Guidelines for Methanol Poisoning. 2002. American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning. J. Toxicol. Clin. Toxicol. 40(4):415-446. Batterman, S.A., and A. Franzblau. 1997. Time-resolved cutaneous absorption and permeation rates of methanol in human volunteers. Int. Arch. Occup. Environ. Health 70(5):341-351. Batterman, S.A., A. Franzblau, J.B. D'Arcy, N.E. Sargent, K.B. Gross, and R.M. Schreck. 1998. Breath, urine, and blood measurements as biological exposure indices of
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Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 Methanol Institute. 2002. Comments on Final Draft, NTP-CERHR Expert Panel Report on Reproductive and Developmental Toxicity of Methanol. Washington, DC: Methanol Institute. Mittal, B.V., A.P. Desai, and K.R. Khade. 1991. Methyl alcohol poisoning: An autopsy study of 28 cases. J. Postgrad. Med. 37(1):9-13. Nashed, A., and G. Fink. 1994. Methanol [online]. Available: http://www.embbs.com/cr/alc/alc6.html [accessed March 30, 2005]. Nelson, B.K., W.S. Brightwell, 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(4):727-736. Nicholls, P. 1975. Formate as an inhibitor of cytochrome c oxidase. Biochem. Biophys. Res. Commun. 67(2):610-616. NIOSH (National Institute for Occupational Safety and Health). 2005. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) No. 2005-151. National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, Cincinnati, OH. NRC (National Research Council). 2000. Methods for Developing Spacecraft Water Exposure Guidelines. Washington, DC: National Academy Press. NTP-CERHR (National Toxicology Program–Center for the Evaluation of Risks to Human Reproduction). 2003. NTP-CERHR Expert Panel Report on Reproductive and Developmental Toxicity of Methanol. National Toxicology Program-Center for the Evaluation of Risks to Human Reproduction, U.S. Department of Health and Human Services, Research Triangle Park, NC. Osterloh, J.D., A. D'Alessandro, P. Chuwers, H. Mogadeddi, and T.J. Kelly. 1996. Serum concentrations of methanol after inhalation at 200 ppm. J. Occup. Environ. Med. 38(6):571-576. Rogers, I.M., M.L. Mole, N. Chernoff, B.D. Barbee, C.I. Turner, T.R. Logsdon, and R.J. Kavlock. 1993. The developmental toxicity of inhaled methanol in the CD-1 mouse, wiht quantitative dose-response modeling for estimation of benchmark doses. Teratology 47(3):175-188. Stegink, L.D., M.C. Brummel, K.E. McMartin, G. Martin-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(2):281-290. Stegink, L.D., M.C. Brummel, L.J. Filer, and G.L. Baker. 1983. Blood methanol concentrations in one-year-old infants administered graded doses of aspartame. J. Nutr. 113(8):1600-1606. Tephly, T.R. 1991. The toxicity of methanol. Life Sci. 48(11):1031-1041. Weiss, B., S. Stern, S.C. Soderhohn, C. Cox, A. Sharma, G.B. Inglis, R. Preston, M. Balys, K.R. Reuhl, and R. Gelein. 1996. Developmental Neurotoxicity of Methanol Exposure by Inhalation in Rats. Reseach Report No. 73. Health Effects Institute, Boston, MA.