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7
Methanol

This chapter summarizes the relevant epidemiologic and toxicologic studies on methanol. Selected chemical and physical properties, toxicokinetic and mechanistic data, and inhalation exposure levels from the National Research Council (NRC) and other agencies are also presented. The subcommittee considered all of that information in its evaluation of the Navy’s current and proposed 1-hour (h), 24-h, and 90-day exposure guidance levels for methanol. The subcommittee’s recommendations for methanol exposure levels are provided at the conclusion of this chapter along with a discussion of the adequacy of the data for defining those levels and the research needed to fill the remaining data gaps.

PHYSICAL AND CHEMICAL PROPERTIES

Methanol is a colorless, flammable liquid at ambient temperatures (Budavari et al. 1989; English et al. 1995). Selected physical and chemical properties are provided in Table 7-1.

OCCURRENCE AND USE

Methanol is used as a solvent, as an ethanol denaturant, as an antifreeze in windshield washer fluid, and as an intermediate in the synthesis of formaldehyde, methyl tertiary-butyl ether, and other chemicals (Hawley 1977; English et al. 1995). Methanol also can be used in automotive fuel and is sold in a blend of 85% methanol and 15% unleaded premium gasoline (“M85”) (IPCS 1997). Methanol can be used for fuel cells and is used



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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants 7 Methanol This chapter summarizes the relevant epidemiologic and toxicologic studies on methanol. Selected chemical and physical properties, toxicokinetic and mechanistic data, and inhalation exposure levels from the National Research Council (NRC) and other agencies are also presented. The subcommittee considered all of that information in its evaluation of the Navy’s current and proposed 1-hour (h), 24-h, and 90-day exposure guidance levels for methanol. The subcommittee’s recommendations for methanol exposure levels are provided at the conclusion of this chapter along with a discussion of the adequacy of the data for defining those levels and the research needed to fill the remaining data gaps. PHYSICAL AND CHEMICAL PROPERTIES Methanol is a colorless, flammable liquid at ambient temperatures (Budavari et al. 1989; English et al. 1995). Selected physical and chemical properties are provided in Table 7-1. OCCURRENCE AND USE Methanol is used as a solvent, as an ethanol denaturant, as an antifreeze in windshield washer fluid, and as an intermediate in the synthesis of formaldehyde, methyl tertiary-butyl ether, and other chemicals (Hawley 1977; English et al. 1995). Methanol also can be used in automotive fuel and is sold in a blend of 85% methanol and 15% unleaded premium gasoline (“M85”) (IPCS 1997). Methanol can be used for fuel cells and is used

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants in the treatment of wastewater and sewage (NTP 2003). Methanol is produced naturally as a by-product of anaerobic metabolism in many varieties of bacteria. Likewise, methanol is a by-product of mammalian carbon metabolism (IPCS 1997). Methanol is a natural component of fruits, vegetables, and fermented spirits (Soffritti et al. 2002). Ingestion of the food additive aspartame results in human exposures to methanol (Soffritti et al. 2002). The uses or sources of methanol on board submarines are unknown. NRC (1988) listed methanol as a possible air contaminant on board submarines and reported a concentration of 6 parts per million (ppm). No information was provided on sampling protocol, location, operations, or durations. More recent analyses of air samples from submarines did not report methanol as an air contaminant (Raymer et al. 1994; Holdren et al. 1995). TABLE 7-1 Physical and Chemical Properties of Methanola Synonyms and trade names Methyl alcohol, wood alcohol, carbinol, methylol, colonial spirits, columbian spirits, methyl hydroxide, monohydroxymethane, pyroxylic spirits, wood naphtha, and wood spirits CAS registry number 67-56-1 Molecular formula CH3OH Molecular weight 32.04 Boiling point 64.7°C Melting point −97.8°C Flash point 12°C (closed cup) Explosive limits 6.0% to 36.5% Specific gravity 0.7915 at 20°C/4°C Vapor pressure 127 mmHg at 25°C Solubility Miscible with water, ethanol, ether, benzene, and most organic solvents Conversion factors 1 ppm = 1.31 mg/m3 ; 1 mg/m3 = 0.76 ppm aData on vapor pressure are from HSDB (2004); all other data are from Budavari et al. (1989). Abbreviations: mg/m3, milligrams per cubic meter; mmHg, millimeters of mercury; ppm, parts per million.

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants SUMMARY OF TOXICITY The primary reviews used in this section include those prepared by the International Programme on Chemical Safety (IPCS) (1997), Kavet and Nauss (1990), and the National Toxicology Program (NTP) (2003). Methanol is an endogenously produced by-product of metabolism and is a natural constituent in animal blood, urine, saliva, and expired air. Exogenous exposures to methanol can occur by ingestion, inhalation, or dermal contact. Methanol is absorbed readily by those routes and is rapidly distributed to tissues. Methanol is metabolized sequentially, primarily in the liver, to formaldehyde, formic acid, and carbon dioxide. Formic acid dissociates to formate and hydrogen ions. Nearly all of the available information on methanol toxicity in humans relates to the consequences of acute, rather than chronic, exposures and is based on clinical cases of methanol poisoning. Those cases, as well as experimental studies in animals, have established that formate is the toxic metabolite of methanol. Formate accumulation accounts for the metabolic acidosis (reduced blood pH) and blindness observed in people diagnosed with methanol poisoning. Hepatic folate status governs the rate of formate detoxification. Central nervous system (CNS) depression, weakness, headache, vomiting, severe metabolic acidosis, optic disc edema, and bilateral necrosis of the putamen also occur in people during methanol intoxication. Other adverse effects of methanol exposure in humans include minor skin and eye irritation. Effects in Humans Accidental Exposures Some of the case studies reporting acute methanol intoxication in humans date back to the late 1800s. Historically, the majority of human poisoning cases involved adults and were related to the accidental or intentional consumption of alcoholic beverages in which methanol was substituted for ethanol. Although those types of exposures continue to occur, most contemporary poisoning cases in the United States involve children who have ingested methanol-based windshield wiper fluids or other automotive products (Davis et al. 2002). The minimum lethal oral dose in humans is about 0.3-1 gram per kilogram of body weight (g/kg) (Kavet and Nauss 1990). The oral methanol doses that have produced toxicity vary

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants widely and might reflect concurrent ingestion of ethanol, inadequate dietary folate intake, or other factors. Acute methanol poisoning occurs in three distinct clinical phases. The first phase resembles ethanol intoxication and initially is characterized by CNS depression, ataxia, and difficulty breathing (Tephly 1991). Intoxicated patients also might present with acute gastritis or pancreatitis, anorexia, intense abdominal pain, vomiting, and diarrhea. Toxicity observed during the first phase primarily is the result of direct toxicity from the parent alcohol. The second phase is usually a short (12-24 h), asymptomatic period. The third phase primarily is associated with the effects of formate accumulation. Visual disturbances and metabolic acidosis represent classical clinical findings associated with methanol intoxication. Visual disturbances can include blurred vision, altered visual fields, impaired pupil response to light, and permanent or temporary blindness. Ophthalmoscopic examinations of people with visual dysfunction often reveal the initial presence of optic disc hyperemia followed by persistent peripapillary edema. Optic disc pallor can occur 1-2 months after poisoning and is a sign of irreversible eye damage (Sharpe et al. 1982; Tephly 1991). Other signs and symptoms observed during the third phase include headache, dizziness, nausea, abdominal pain, vomiting, and dyspnea. Severe methanol intoxication might cause damage to the putamen, a brain structure linked with motor control (Ley and Galli 1983; Koopmans et al. 1988; Finkelstein and Vardi 2002). Other complications of severe acute methanol intoxication include coma, seizures, blindness, oliguric renal failure, cardiac failure, cerebral edema, cerebral or subarachnoid hemorrhage, and pulmonary edema (Davis et al. 2002). Death can be rapid or can occur several hours after coma. Death is associated with apnea and convulsions. Autopsies conducted on victims of methanol poisoning revealed gross pathologic effects consisting of edematous, hemorrhagic, and degenerative changes in visceral organs, liver, kidneys, lungs, and the CNS (McLean et al. 1980). Although methanol poisoning by ingestion is well documented, fewer cases of poisoning by inhalation exposure have been reported. The following case report illustrates important clinical features of the inhalation toxicity of methanol in humans. Frenia and Schauben (1993) described seven cases of suspected methanol poisoning in adults who intentionally inhaled a carburetor-cleaning fluid that contained about 23% methanol mixed with other solvents. Affected individuals developed CNS depression, nausea, vomiting, dyspnea, photophobia, and visual dysfunction. They also developed markedly elevated blood methanol (>50 milligrams per deciliter

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants [mg/dL]) and formate (2.6 millimoles [mmol]) concentrations and severe metabolic acidosis. Downie et al. (1992) reported a case of ocular toxicity following percutaneous exposure to methanol. The case involved a 31-year-old male worker who used methanol to clean a tanker. The cleaning took several hours to complete. The worker wore a positive-pressure breathing apparatus but no protective clothing during the activity. His clothes became saturated with methanol. About 8-10 h after the exposure, the worker developed CNS depression, blurred vision, dyspnea, metabolic acidosis, and semi-coma. Ophthalmoscopic examination revealed optic disc pathology consistent with methanol poisoning. This and the preceding case report confirm that the clinical signs and clinical pathology changes observed following methanol inhalation or dermal exposures are identical to those observed after methanol ingestion. Experimental Studies Several experimental human chamber studies and dermal absorption studies have been performed with methanol. Many of those studies exposed healthy men of an age range comparable to that of submariners. Limitations inherent in each of those studies include small sample size, limited numbers of exposure concentrations, relatively short exposure durations, and an inability to completely mask the odor of methanol from subjects and the experimenters. Most of the studies controlled for dietary sources of methanol and limited pre-exposure intake of ethanol. The studies are useful sources of data on background blood methanol and formate concentrations, and they provide important data on blood methanol and formate concentrations measured after methanol-exposure scenarios relevant to submariners (Table 7-2). Some of the studies also provide information about symptom reporting and neurobehavioral effects. Inhalation Exposure Cook et al. (1991) exposed 12 healthy nonsmoking young men (22-32 years of age) to methanol at 191 ppm for 75 minutes (min). The subjects did not describe any symptoms related to methanol exposure. End-of-exposure plasma formate concentrations were unaffected by methanol exposure, despite an about 3.3-fold increase in the mean plasma methanol concentra-

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants tion (Table 7-2). Subjects also were tested for an array of neurobehavioral end points. The majority of results were negative. Statistically significant effects and trends were found in brain wave patterns, particularly in response to light flashes and sounds (P-200 and N1-P2 components of event-related potentials); performances on the Sternberg memory task; and subjective measures of fatigue and concentration. The study authors noted that the effects were mild and did not exceed normal ranges. Chuwers et al. (1995) examined the neurobehavioral effects of 4-h inhalation exposures to either water vapor or methanol at 200 ppm in healthy men (n = 15) and women (n = 11), 21-51 years of age. Blood samples were collected before and after exposure, and a battery of neurobehavioral and neurophysiologic tests was performed. In general, there were no significant effects on visual, neurophysiologic, or neurobehavioral end points. Slight effects on P-300 brain wave amplitudes (in response to sensory stimuli) and performances on the Symbol Digit test (a test examining information processing and psychomotor skills) were observed. The study authors concluded that methanol exposure at 200 ppm had little effect on neurobehavioral performance. The authors also reported that subjects could not detect an odor during the methanol exposures. It should be noted that data reported by Osterloh et al. (1996) and d’Alessandro et al. (1994) describe similar subject characteristics and largely duplicate the findings reported by Chuwers et al. (1995). Thus, they do not represent new studies but different facets of a single study. Muttray et al. (2001) exposed 12 healthy subjects to methanol at either 20 or 200 ppm for 4 h. Electroencephalograph (EEG) activity was recorded before and after each exposure—once with the subjects’ eyes closed, once with the subjects’ eyes opened, and once during a choice reaction test (color word stress test). Subjective symptoms were assessed via questionnaires. Exposures at 200 ppm did not result in significant symptoms of narcosis or irritation compared with the reports from exposures at 20 ppm in the same subjects. Changes in the EEG theta-band at 200 ppm suggested a slight excitatory effect; however, the authors reported these effects to be weaker than those elicited by human circadian cycles. Lee et al. (1992) exposed six healthy male volunteers (29-55 years of age) to methanol at 200 ppm for 6 h. Subjects were either at rest or engaged in mild physical exercise (sessions consisted of 20 min at a work load of 50 watts on a bicycle ergometer, followed by 20 min at rest, repeated for 6 h) during the exposures. Pre- and post-exposure blood methanol and formate concentrations were determined. Blood methanol concentrations were increased following methanol inhalation (Table 7-2). Exercise did not

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants TABLE 7-2 Blood Methanol and Formate Concentrations Observed in Humans Following Experimental Methanol Exposures Methanol Concentration (ppm) Exposure Duration (h) Plasma/serum formate Concentration (mg/L)a Plasma/Serum Methanol Concentration (mmol/L)   Pre-exposure Post-exposure Pre-exposure Post-exposure Reference 190 1.25 0.57 ± 0.31 1.88 ± 0.47 0.08 ± 0.03 0.08 ± 0.02 Cook et al. 1991 200 4 1.8 ± 2.6 6.5 ± 2.7 0.24 ± 0.18 0.30 ± 0.19 Chuwers et al. 1995 200 6 1.82 ± 1.21(rest) 1.93 ± 0.93 (exercise) 6.97 ± 1.24 (rest) 8.13 ± 1.49 (exercise) 0.20 ± 0.03 (rest) 0.19 ± 0.04 (exercise) 0.19 ± 0.05 (rest) 0.21 ± 0.02 (exercise) Lee et al. 1992 400 8 2.65 ± 1.8 (rest) 13.4 ± 4.8 (rest) ND ND Franzblau et al. 1995 800 1 1.3 ± 0.6 6.6 ± 1.2 ND ND Batterman et al. 1998 800 8 1.8 ± 0.9 30.7 ± 6.9 ND ND Batterman et al. 1998 aMean ± standard deviation. Abbreviations: h, hours; mg/L, milligrams per liter; mmol/L, millimoles per liter; ND, not determined; ppm, parts per million.

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants influence end-of-exposure blood methanol concentrations, even though pulmonary ventilation was increased (10.5 L/min at rest vs 18.6 L/min while exercising). Methanol exposures did not result in altered blood formate concentrations (Table 7-2). The authors of this study did not report symptoms; thus, the study could not be used to establish submarine exposure guidance levels for methanol. Batterman et al. (1998) examined the relationships between methanol concentrations in blood, urine, and exhaled breath in people exposed to methanol vapor. Exposure scenarios and group characteristics are provided in Table 7-3. Periodic breath, blood, and urine samples were collected. Pre-and post-exposure blood methanol and formate concentrations were determined (Table 7-2). Because the study authors failed to report whether any symptoms were observed, this study could not be used to establish exposure guidance levels for methanol. Franzblau et al. (1995) exposed three men (31-55 years of age) and one woman (49 years of age) to methanol at 0, 100, 200, 400, and 800 ppm for 8 h. Subjects completed each exposure either at rest or while performing light exercise on a bicycle ergometer that served to increase minute ventilation by about 50% over baseline. Blood and breath samples were collected before exposure and after 6 and 8 h of exposure. Blood methanol concentrations were significantly increased after 6 and 8 h of exposure (Table 7-2). Franzblau stated that none of the methanol-exposed subjects reported symptoms (A. Franzblau, University of Michigan, personal commun., June 14, 1999, and October 3, 2000). Dermal Exposure For 60 min, Dutkiewicz et al. (1980) exposed six human volunteers (ages not specified) to methanol at 0.19-0.21 mL applied to an area of the forearm 11.2 square centimeters (cm2) large. Dermal absorption was examined 15-60 min after application, and the mean calculated absorption rate was 11.5 mg/cm2/h. The absorption rate peaked between 20 and 30 min after application. The authors estimated that immersion of one hand in liquid methanol for 2 min would result in a body burden of about 170 mg, which is similar to the body burden that results from inhaling methanol at about 40 ppm for 8 h. Franzblau et al. (1995) used the three men (31-55 years of age) and one woman (49 years of age) who participated in their aforementioned inhalation study and four additional men (26-33 years of age) in a dermal

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants TABLE 7-3 Experimental Parameters of Batterman et al. (1998) Exposure Concentration (ppm) Duration (h) Gender Age (years) Sample Size 800 0.5, 1, 2 Female 41-60 4 800 8 Male Unknown 12 800 8 Female Unknown 7 Abbreviations: h, hours; ppm, parts per million. study. One hand of each volunteer was placed in a beaker containing neat methanol for 0, 2, 4, 8, or 16 min. Blood and breath methanol samples were taken immediately after the exposures and at 12 additional time points during the first 8 h after exposure. Blood methanol concentrations peaked at about 45-60 min post-exposure and averaged 11.3 mg/L. Breath methanol concentrations peaked at about 15 min post-exposure and averaged 9.3 ppm. The authors stated that exposure to one hand (440 cm2, <3% of body surface area) for 16 min resulted in blood methanol concentrations similar to those observed following inhalation at 400 ppm for 8 h. Batterman and Franzblau (1997) exposed seven men (22-54 years of age) and five women (41-63 years of age) to methanol. One hand of each volunteer was placed in a beaker containing neat methanol for 0, 2, 4, 8, or 16 min. Blood samples were taken immediately after the exposures and at 11 additional time points during the first 7 h post-exposure. Methanol delivery into the blood began during or immediately after exposure and reached a maximum rate at 30 min post-exposure. Peak blood methanol concentrations occurred about 2 h after exposure and ranged from 2.7 ± 0.9 mg/L following the 2-min exposure to 11.5 ± 2.3 mg/L following the 16-min exposure. The area under the curve (AUC) correlated highly with duration of exposure and peak blood methanol concentration. The average derived dermal absorption rate was 8.1 ± 3.7 mg/cm2/h. The authors reported that the exposed hand was often temporarily whitened in color and appeared very dry. That effect was most marked after the longer exposures. Occupational and Epidemiologic Studies Several studies have examined human exposures to methanol in occupational settings. One of the first studies was conducted by Tyson and Schoenberg (1914) who described about 100 cases of methanol intoxication resulting from occupational inhalation exposures. A much more recent

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants study of occupational inhalation exposures by Frederick et al. (1984) was considered by Kavet and Nauss (1990) to be the most definitive. In that study, 84 teachers’ aides working near paper duplicators reported headaches, dizziness, blurred vision, and nausea. The aides used a 99% methanol fluid for 1 h per day, 1 day per week or for 8 h per day, 5 days per week over a period of 3 years. Methanol concentrations measured in the breathing zone of a subset of the workers (n = 21) ranged from 365 to 3,080 ppm. Dermal exposures to methanol also might have occurred; however, those exposures were not determined. A study by Kawai et al. (1991) examined subjective complaints and clinical findings in 22 workers exposed to high concentrations of methanol (mean = 459 ppm) and 11 workers exposed to lower concentrations (mean = 31 ppm). Breathing-zone exposures to methanol (time-weighted averages) were determined during representative shifts. The most common complaints in workers exposed at the highest concentration included dimmed vision (not considered to be related to retinal toxicity), nasal irritation, headache, forgetfulness, and increased skin sensitivity. Three workers exposed to methanol at 119-3,577 ppm exhibited slow pupil response to light or mild mydriasis. The optic discs were unaffected, and there were no indications of permanent eye damage in those individuals. The study authors did not believe that the ocular effects were the result of formate poisoning. Effects in Animals Several animal models have been used to evaluate methanol toxicity. The animal studies have clearly demonstrated that nonhuman primates are the most appropriate model for humans. Like humans, monkeys exposed to methanol develop increased blood formate concentrations, metabolic acidosis, and blindness (Roe 1982; Tephly and McMartin 1984). Conversely, rats, mice, dogs, and other resistant species exposed to methanol neither accumulate formate nor develop metabolic acidosis or blindness (Roe 1982; Tephly and McMartin 1984). Therefore, the subcommittee focused its review on studies conducted in nonhuman primates. Acute Toxicity No relevant studies on the acute toxicity of methanol in monkeys or sensitive animal species were available.

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants Repeated Exposures and Subchronic Toxicity The Japanese New Energy Development Organization (NEDO) conducted inhalation toxicity studies in cynomolgus monkeys (Macaca fascicularis) (NEDO 1986). The monkeys were exposed to air (n = 1) or to methanol vapor at 3,000 (n = 1), 5,000 (n = 2), 7,000 (n = 1), or 10,000 (n = 1) ppm for 21 h per day for 21, 21, 14, 6, and 6 days, respectively. Exposures at >5,000 ppm were associated with metabolic acidosis, reduced movement, vomiting, and dyspnea. Clinical signs were severe enough to warrant early termination of the study. The monkey exposed at 3,000 ppm exhibited astrocyte hyperplasia in the basal ganglia, fatty hepatic degeneration, and a transient decrease in food consumption. The study report indicates that 3,000 ppm represented a lowest-observed-adverse-effect level (LOAEL). It should be noted that this study had inadequate sample sizes for statistical evaluations. NEDO also exposed cynomolgus monkeys to methanol at 1,000 (n = 3), 2,000 (n = 3), 3,000 (n = 3), or 5,000 (n = 2) ppm for 21 h per day for 7 months and 20, 20, and 12 days, respectively (NEDO 1986). Animals were held for various times to evaluate whether recovery occurred. Exposures at 5,000 ppm were associated with metabolic acidosis, reduced movement, vomiting, dyspnea, and mild optic nerve atrophy. Exposures at 2,000 ppm were associated with metabolic acidosis. Andrews et al. (1987) exposed three male and three female cynomolgus monkeys per group to either air or to methanol vapors (99.85% purity) at 500, 2,000, or 5,000 ppm for 6 h per day, 5 days per week for 4 weeks. Weekly measurements of body weight revealed no differences between control and treated animals. Absolute adrenal weights were significantly decreased in female monkeys in the 5,000-ppm exposure group, but the authors indicated that the effect was not considered to be biologically significant. Gross and histopathologic examination revealed no other effects in any of the examined organs. No ocular abnormalities were noted during an ophthalmoscopic examination. The study authors concluded that 5,000 ppm represented a no-observed-adverse-effect level (NOAEL) for repeated methanol exposure in monkeys. Chronic Toxicity NEDO exposed female cynomolgus monkeys (eight per group) to methanol vapor at 0, 10, 100, or 1,000 ppm for 22 h per day for 7 months (two per group), 19 months (three per group), or 29 months (three per

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants TABLE 7-4 Selected Inhalation Exposure Levels for Methanol from NRC and Other Agenciesa Organization Type of Level Exposure Level (ppm) Reference Occupational       ACGIH TLV-TWA 200 ACGIH 2002   TLV-STEL 250   NIOSH REL-TWA 200 (skin) NIOSH 2004   REL-STEL 250 (skin)   OSHA PEL-TWA 200 29 CFR 1910.1000 Spacecraft       NASA SMAC   NRC 1994   1 h 30     24 h 10     30 days 7     180 days 7   Submarine       NRC EEGL   NRC 1985   1 h 200     24 h 10     CEGL       90 days 50b   General Public       NAC/NRC Proposed AEGL-1 (1 h) 530 EPA 2004   Proposed AEGL-2 (1 h) 2100     Proposed AEGL-1 (8 h) 270     Proposed AEGL-2 (8 h) 510   aThe comparability of EEGLs and CEGLs with occupational and public health standards or guidance levels is discussed in Chapter 1, section “Comparison to Other Regulatory Standards or Guidance Levels.” bProposed in 1968. No value was proposed in 1985. Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; AEGL, acute exposure guideline level; CEGL, continuous exposure guidance level; EEGL, emergency exposure guidance level; h, hour; NAC, National Advisory Committee; NASA, National Aeronautics and Space Administration; NIOSH, National Institute for Occupational Safety and Health; NRC, National Research Council; OSHA, Occupational Safety and Health Administration; PEL, permissible exposure limit; ppm, parts per million; REL, recommended exposure limit; SMAC, spacecraft maximum allowable concentration; STEL, short-term exposure limit; TLV, Threshold Limit Value; TWA, time-weighted average.

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants SUBCOMMITTEE RECOMMENDATIONS The subcommittee’s recommendations for EEGL and CEGL values for methanol are summarized in Table 7-5. The current and proposed U.S. Navy values are provided for comparison. 1-Hour EEGL Health effects of concern following an acute 1-h inhalation exposure to methanol include narcosis, delayed neuro-ocular toxicity, headaches, and mucous membrane irritation. Andrews et al. (1987) reported that cynomolgus monkeys developed neither narcosis nor histopathologic evidence of optic nerve or retinal pathology following inhalation exposures to methanol at 5,000 ppm for 6 h per day, 5 days per week for 4 weeks. Studies conducted by Burbacher et al. (1999a,b; 2004a,b) in cynomolgus monkeys failed to produce any evidence of visual toxicity or narcosis in monkeys exposed to methanol at 1,800 ppm for 2.5 h per day, 7 days per week through an initial 4-month exposure period, during breeding, and throughout pregnancy. The weight of evidence from the two studies suggests that short-term (1 h) exposure to methanol vapors at 1,800 ppm does not produce neuro-ocular toxicity in monkeys and that 1,800 ppm represents an acute NOAEL in that species. A 3-fold uncertainty factor to account for intraspecies differences was applied. That uncertainty factor accounts for possible differences in either methanol or formate metabolism among people. Metabolic differences are most pronounced at high exposure concentrations, such as 1,800 ppm, where metabolism can become saturated. Application of the intraspecies uncertainty factor to the monkey NOAEL of 1,800 ppm yields a 1-h EEGL of 600 ppm. The recommended 1-h EEGL is supported by methanol exposure studies conducted in humans. Franzblau et al. (1995) exposed four people to methanol at 800 ppm for 8 h. The authors indicated that none of the subjects developed symptoms (A. Franzblau, University of Michigan, personal commun., June 14, 1999, and October 3, 2000). Batterman et al. (1998) reported a mean peak blood methanol concentration of 6.6 ± 1.2 mg/L for the subjects in the Franzblau et al. (1995) study. That concentration is about 150-fold lower than the mean blood methanol concentration seen in humans poisoned with methanol (1,000 mg/L) (Kostic and Dart 2003).

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants TABLE 7-5 Emergency and Continuous Exposure Guidance Levels for Methanol (ppm) Exposure Level U.S. Navy Values NRC Recommended Current Proposed Values EEGL           1 h 200 200 600   24 h 10 10 50 CEGL           90 days 10 7 10 Abbreviations: CEGL, continuous exposure guidance levels; EEGL, emergency exposure guidance level; h, hour; NRC, National Research Council; ppm, parts per million. 24-Hour EEGL Health effects of concern following a 24-h inhalation exposure to methanol would include narcosis, delayed neuro-ocular toxicity, headaches, mucus membrane irritation, and impaired neurobehavioral function. Several chamber studies conducted in humans have evaluated whether a 4-h exposure to methanol at 200 ppm could result in neurobehavioral or electro-physiologic changes (Chuwers et al. 1995; Muttray et al. 2001). The authors of those studies concluded that methanol exposure at 200 ppm for 4 h had little effect on neurobehavioral performance or EEG activity. Exposures to methanol at 200 ppm did not result in increased symptoms of narcosis or irritation compared with exposures at 20 ppm in the same subjects (Muttray et al. 2001). Moreover, human exposures at 200 ppm for 4 h (Chuwers et al. 1995) or 6 h (Lee et al. 1992) did not result in statistically or toxicologically significant increases in blood formate concentrations. Peak blood methanol concentrations observed in the studies were <10 mg/L and were much lower than blood methanol concentrations measured in humans poisoned with methanol (1,000 mg/L) (Kostic and Dart 2003). The weight of evidence from these studies (Chuwers et al. 1995; Muttray et al. 2001) suggests that short-term (4-6 h) exposure to methanol vapors at 200 ppm does not produce headaches, irritation, neuro-ocular toxicity, or significant neurobehavioral toxicity in humans. A 4-fold adjustment to account for the shorter duration was applied to the 6-h data to yield a 24-h EEGL of 50 ppm. That adjustment was reasonable because the average end-of-exposure blood methanol concentration observed in people exposed at 200 ppm for 4 h (6.5 ± 2.7 mg/L; Chuwers et al. 1995) was similar to that seen in people

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants exposed at 800 ppm for 1 h (6.6 ± 1.2 mg/L; Batterman et al. 1998) and was about 2-fold lower than that seen in people exposed at 400 ppm for 8 h (13.4 ± 4.8 mg/L; Franzblau et al. 1995). The 24-h EEGL value is further supported by the results of repeated-exposure studies that failed to produce any evidence of visual toxicity, narcosis, or metabolic acidosis in monkeys exposed to methanol at 1,000 ppm for 21 h per day for 21 days (NEDO 1986). The subcommittee did not apply uncertainty factors to account for differences in methanol or formate metabolism among humans. Alcohol dehydrogenase activity measurements can differ up to about 3-fold among people (Norberg et al. 2003). However, even susceptible people would not be expected to develop blood methanol concentrations high enough to result in neurotoxicity following exposure at the recommended 24-h EEGL of 50 ppm. Data collected in cynomolgus monkeys—a species that, like humans, metabolizes formate more slowly than rodents—indicate that toxicologically significant accumulations of formate did not occur in folate-deficient monkeys exposed to [14C]methanol at 900 ppm for 2 h (Dorman et al. 1994). Therefore, no adjustment was deemed necessary to account for differences in formate metabolism due to folate deficiency. Moreover, many foods have been fortified with folate to reduce the incidence of birth defects. Thus, the incidence of folate deficiency has decreased during the past decade. 90-Day CEGL Health effects of concern following a continuous 90-day inhalation exposure to methanol would include ocular toxicity, hepatotoxicity, and neurotoxicity. The subcommittee used the NEDO (1986) study in cynomolgus monkeys to determine the recommended 90-day CEGL. The monkeys were exposed to methanol vapor at 0, 10, 100, or 1,000 ppm for 22 h per day for 7 months (two monkeys per group), 19 months (three monkeys per group), or 29 months (three monkeys per group). Exposures at up to 1,000 ppm were not associated with any evidence of optic nerve or retinal pathology (NEDO 1986). The NEDO report (1986) indicated that 10 ppm was a study NOAEL, whereas exposures at 100 ppm were associated with reversible hematologic changes, altered electrocardiograms, and subtle neuropathology (increased numbers of responsive stellate cells in the cerebral white matter) that might represent adverse responses. Chronic exposures at 1,000 ppm were associated with astrocyte hyperplasia in the basal ganglia

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants and metabolic acidosis. The subcommittee used the study NOAEL of 10 ppm as the 90-day CEGL. The subcommittee did not apply uncertainty factors to account for interspecies differences or time extrapolation because monkeys are a sensitive animal species and the exposure duration was much longer than 90-days. Application of uncertainty factors to account for differences in methanol and formate metabolism among people was likewise unnecessary because subtle differences in metabolism are unlikely to be a factor at 10 ppm. Pharmacokinetic considerations can be used to support the subcommittee’s decisions and the proposed 90-day CEGL value. A 24-h exposure at 10 ppm (13.1 milligrams per cubic meter [mg/m3]) would yield an aggregate daily exposure of about 2.2 mg/kg per day assuming a 70-kg human breathing at a rate of 20 m3 per day (twice the resting ventilation rate) and an absorption fraction of 60% (Sedivec et al. 1981; Kavet and Nauss 1990; Fisher et al. 2000). That upper-limit burden results in an estimated tissue concentration of about 0.05 mM, a value that is nearly 100-fold lower than the Michaelis-Menten constant (Km)1 observed by Makar et al. (1968) in monkeys (8.7 mM). Actual tissue concentrations would be lower than that because of ongoing metabolism and pulmonary and renal excretion. Makar et al. (1968) estimated that primates metabolize methanol at a rate (Vmax) of about 48 mg/kg/h. The hourly rate at which an individual would metabolize methanol is greater than the anticipated rate of intake from inhalation exposures at 10 ppm. The margin between elimination and intake rates at 10 ppm is also greater than the anticipated variability in elimination rates among humans. The 90-day CEGL is also supported by repeated-exposure studies that failed to produce any evidence of visual toxicity, narcosis, or metabolic acidosis in monkeys exposed to methanol at 1,000 ppm for 21 h per day for 21 days (NEDO 1986). Studies by Andrews et al. (1987) and Burbacher et al. (1999a,b; 2004a,b) further support the subcommittee’s recommended 90-day CEGL. 1The Km, or Michaelis-Menten constant, describes the affinity of an enzyme for a substrate and is defined as the substrate concentration that produces one-half the enzyme’s maximum velocity.

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants DATA ADEQUACY AND RESEARCH NEEDS The data available on methanol toxicity were deemed sufficient to derive EEGL and CEGL values. The subcommittee in part relied on the subchronic inhalation studies in monkeys performed by NEDO. The subcommittee recognizes that there were some weaknesses in those studies. The report produced by NEDO (1986) is often fragmentary and lacks full descriptions of the raw data from the experiments. Moreover, some of the histologic descriptions in that report are incomplete and inadequately documented. Other studies were available to support the validity of the NEDO studies. When considered collectively, the relevant studies provided an adequate database for the subcommittee’s deliberations. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 2002. TLVs & BEIs: Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. 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. Antony, A.C., and D.K. Hansen. 2000. Hypothesis: Folate-responsive neural tube defects and neurocristopathies. Teratology 62(1):42-50. 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 short-term inhalation exposure to methanol. Int. Arch. Occup. Environ. Health 71(5):325-335. Botto, L.D., and Q. Yang. 2000. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: A review. Am. J. Epidemiol. 151(9):862-877. Budavari, S., M.J. O’Neil, A. Smith, and P.E. Heckelman, eds. 1989. Methanol. Pp. 939 in the Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, 11th Ed. Rahway, NJ: Merck and Co., Inc. Burbacher, T., K. Grant, D. Shen, D. Damian, S. Ellis, and N. Liberato. 1999a. Part II: Developmental effects in infants exposed prenatally to methanol. Pp. 69-117 in Reproductive and Offspring Developmental Effects Following Maternal Inhalation Exposure to Methanol in Nonhuman Primates. Research Report No. 89. Health Effects Institute, Cambridge, MA. October 1999.

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