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Suggested Citation:"7 Methanol." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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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

Suggested Citation:"7 Methanol." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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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.

Suggested Citation:"7 Methanol." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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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

Suggested Citation:"7 Methanol." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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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

Suggested Citation:"7 Methanol." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

[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-

Suggested Citation:"7 Methanol." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

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

Suggested Citation:"7 Methanol." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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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.

Suggested Citation:"7 Methanol." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

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

Suggested Citation:"7 Methanol." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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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

Suggested Citation:"7 Methanol." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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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.

Suggested Citation:"7 Methanol." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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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

Suggested Citation:"7 Methanol." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

group). Exposures at up to 1,000 ppm were not associated with any evidence of optic nerve or retinal pathology (NEDO 1986). However, chronic exposures at 1,000 ppm were associated with basal ganglial astrocyte hyperplasia and metabolic acidosis. Chronic exposures at 100 ppm were associated with hematologic changes, altered electrocardiograms, and responsive stellate cells in the cerebral white matter. The shorter-term studies conducted by NEDO in monkeys indicate that the latter response is transient. For example, stellate cells were no longer observed in monkeys 6 months after the end of a 20-day near-continuous exposure to methanol at 3,000 ppm. The NEDO report (1986) indicates that 10 ppm was a NOAEL for chronic exposure.

Burbacher et al. (1999a,b; 2004a,b) conducted an extensive methanol inhalation study in cynomolgus monkeys. The study assessed whether subchronic methanol exposure at 200-1,800 ppm was associated with overt adult toxicity, female reproductive toxicity, or both and whether in utero exposure to methanol affected offspring development. Monkeys were exposed to air (n = 9) or to methanol at 200 (n = 12), 600 (n = 11), or 1,800 (n = 12) ppm for 2.5 h per day, 7 days per week through an initial 4-month exposure period, during breeding (ranging from 3 to 236 days), and throughout pregnancy (ranging from 150 to 178 days). Mean (± standard error of the mean) blood methanol concentrations observed in monkeys at the end of the initial 4-month period were 2.3 ± 0.1, 4.7 ± 0.1, 10.5 ± 0.3, and 35.6 ± 1.0 mg/L for the 0-, 200-, 600-, and 1,800-ppm exposure groups, respectively. Plasma formate concentrations were unaffected by methanol exposure. Blood methanol concentrations observed in the 600- and 1,800-ppm exposure groups did not fit a linear, one-compartment first-order model, suggesting that saturation of methanol metabolism occurred in the highest exposure group. Clinical signs consistent with methanol intoxication, such as CNS depression, ataxia, and blindness, were not observed in any of the exposed monkeys. Body-weight gain was unaffected by methanol exposure. Histopathologic evaluations were not performed in this study.

Reproductive Toxicity in Males

An NTP expert panel judged that there are insufficient human data to evaluate the reproductive toxicity of methanol (NTP 2003). The panel concluded that “adverse reproductive effects would not occur in male rats following inhalation exposure to ≤800 ppm.” In reaching that conclusion, the panel cited four studies that examined serum hormone concentrations

Suggested Citation:"7 Methanol." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

in male rats exposed to methanol by inhalation and two studies that included histologic evaluations of reproductive organs. The panel considered a study conducted by Lee et al. (1991) to be the definitive work and had high confidence in the results of that study. Lee et al. (1991) exposed 8-week-old Sprague-Dawley rats to methanol at 200 ppm for 8 h per day for 1-6 weeks and observed no effects on testosterone, weight of androgen-sensitive organs, capability of testes exposed in vivo to produce testosterone in vitro, or pathology. In the second part of the Lee et al. (1991) study, normal and folate-deficient methanol-sensitive Long-Evans rats were exposed to methanol at 800 ppm for 20 h per day, 7 days per week for 13 weeks. A higher incidence, but not severity, of age-related testicular degeneration was observed in the folate-deficient 18-month-old rats. However, the incidence of age-related testicular lesions in the normal 18-month-old treated rats was equal to that in control rats. Poon et al. (1995) found no lesions in the reproductive organs of 4 to 5-week-old male and female Sprague-Dawley rats that inhaled methanol at 2,500 ppm for 6 h per day for 4 weeks. The results of Poon et al. (1995) were consistent with the findings of Lee et al. (1991). The NTP panel concluded that “the blood levels of methanol associated with reproductive toxicity in rodents are 700 mg/L and greater. Blood methanol levels of this magnitude in humans would be associated with frank methanol (formate) toxicity.”

Immunotoxicity

No relevant data on methanol immunotoxicity were found by the subcommittee. Natural killer-cell function was reduced in mice given a near lethal oral dose (0.8 times the dose lethal to 50% of subjects [LD50]) of methanol (Zabrodskii et al. 2003). Few details were provided, and the actual dose of methanol was not reported. Thus, that study has little utility in the subcommittee’s assessment.

Genotoxicity

IPCS (1997) conducted a thorough review of the genotoxicity information available for methanol. The majority of the findings were negative; however, some positive results were identified. IPCS (1997) stated that “the structure of methanol (by analogy with ethanol) does not suggest that it would be genotoxic.” IPCS (1997) reported negative findings in the Ames

Suggested Citation:"7 Methanol." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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test, cultured cell mutation assay in CH-V79 cells, and the micronucleus test performed by NEDO (1986). Negative findings were also reported for chromosome aberrations and sister chromatid exchange (IPCS 1997).

Inhaled methanol had no mutagenic effects in hamsters (Obe and Ristow 1979) or mice (Campbell et al. 1991). Fu et al. (1996) examined micronuclei formation in the reticulocytes of pregnant CD-1 mice fed diets containing adequate or marginal levels of folic acid (1,200 nanomoles per kilogram [nmol/kg] and 400 nmol/kg, respectively) and gavaged with methanol in water at 0 or 5,000 mg/kg per day on gestation days 6-10. Methanol exposure did not increase micronucleated cell frequency. Gattás et al. (2001) reported that methanol exposure was associated with increased incidence of oral mucosa micronuclei in fuel-pump operators in São Paulo, Brazil, after the introduction of a fuel composed of 33% methanol, 60% ethanol, and 7% gasoline.

Carcinogenicity

There is little evidence from animal studies to suggest that inhaled methanol is a carcinogen. The most comprehensive study of the carcinogenicity of methanol was conducted in rodents by NEDO (1986). Male and female Fischer 344 rats and B6C3F1 mice were exposed to methanol vapor at 10, 100, or 1,000 ppm for 20 h per day for 24 months. Increased incidence of papillary adenomas and adrenal pheochromocytomas was observed at the highest dose, but the increases were not statistically significant. The NEDO report indicates that there was no evidence of methanol-induced cancer.

Soffritti et al. (2002) conducted a chronic drinking water carcinogenicity study in male and female Sprague-Dawley rats. For 24 months, rats were exposed to drinking water that contained methanol at 0, 500, 5,000, or 20,000 ppm. Exposures to methanol in drinking water at 5,000 ppm or greater were associated with statistically significant increases in the incidence of carcinomas of the ear ducts. Those data were found to be of limited use to the subcommittee because inhalation was not the route of exposure.

TOXICOKINETIC AND MECHANISTIC CONSIDERATIONS

A lot is known about the chemical and biological behavior of metha-nol. Methanol is converted to formaldehyde by hepatic alcohol dehydro-

Suggested Citation:"7 Methanol." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

genase (Tephly and McMartin 1984). Formaldehyde is a very reactive compound with a very short life span in blood, and it does not contribute to the ocular toxicity of methanol (McMartin et al. 1979). Formaldehyde is metabolized to formic acid by a glutathione-mediated pathway involving formaldehyde dehydrogenase. Formic acid dissociates to formate and hydrogen ions (Tephly and McMartin 1984). Formate is detoxified to carbon dioxide by a multistep pathway (Jacobsen and McMartin 1986). In all species studied, the detoxification is achieved through a tetrahydrofolate-dependent pathway. When compared with rodents, humans and nonhuman primates have low hepatic tetrahydrofolate concentrations and metabolize formate to carbon dioxide relatively slowly. The rate at which methanol-derived formate accumulates to toxic levels following methanol exposures is primarily influenced by the rate at which formate is metabolized.

Formate is the metabolic product of methanol thought to be responsible for the acute toxic effects of methanol exposure (McMartin et al. 1980; Tephly and McMartin 1984). Blood formate concentrations at 10 mmol/L or greater have been reported in humans diagnosed with neuro-ocular toxicosis following methanol exposures by ingestion (Kavet and Nauss 1990). Formate contributes to metabolic acidosis, and it acts as an inhibitor of cytochrome c oxidase activity in intact rat liver mitochondria (Nicholls 1975). Reduced cytochrome c oxidase can result in decreases in cellular adenosine triphosphate production and might subsequently lead to neurotoxicity.

Methanol is rapidly absorbed after oral, inhalation, or dermal exposure. In a group of 22 human volunteers exposed to methanol at 200 ppm for 4 h, the mean absorption half-life was 0.80 ± 0.55 h (Osterloh et al. 1996). Only a fraction of inhaled methanol is absorbed across the respiratory tract epithelium into the systemic circulation (Perkins et al. 1995; Fisher et al. 2000). Inhalation studies in humans have shown net absorptions of methanol of 60-85% (Sedivec et al. 1981). Studies conducted in nonhuman primates show similar percentages of absorption (Fisher et al. 2000).

Like that of ethanol, methanol metabolism follows saturable zero-order kinetics at low concentrations. Studies conducted in monkeys have provided some indication of when methanol metabolism becomes saturated. In studies conducted by Horton et al. (1992), rhesus monkeys were exposed to methanol concentrations at 200, 1,200, or 2,000 ppm for 6 h. End-of-exposure blood methanol and formate concentrations were determined for up to 12 h after the end of the 6-h exposure, and they were directly proportional at 1,200 and 2,000 ppm. The 200-ppm exposure concentration resulted in blood methanol concentrations that were lower than those that would be proportional to the measurements at the two higher doses. The

Suggested Citation:"7 Methanol." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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nonlinearity observed in the blood methanol concentrations suggested that methanol elimination proceeds by a saturable pathway and that monkeys demonstrate dose-dependent kinetics at exposure concentrations between 200 and 2,000 ppm. Although blood formate concentrations varied considerably among the individual monkeys, the authors were unable to detect any changes in total blood formate concentrations following 6-h methanol exposures at 200, 1,200, or 2,000 ppm.

Clinical case reports have confirmed that blood methanol concentrations poorly predict ocular toxicity. Although maximal blood methanol concentrations following acute lethal methanol exposures in humans are often undetermined, blood methanol concentrations in excess of 1,000 mg/L are commonly reported within 24-48 h of methanol ingestion (Kostic and Dart 2003).

Methanol is excreted unchanged in urine or expired air or as formate in urine. Methanol elimination is dose dependent. The half-life of methanol elimination in blood in highly exposed humans who do not receive ethanol treatment or dialysis treatment ranges from 17 to 27 h, and the half-life of methanol elimination in expired air after moderate oral or dermal exposure is 1.5 h. The amount of formate excreted in the urine varies greatly among species and ranges from 1% in rabbits to 20% in dogs; humans excrete formate in intermediate amounts (Kavet and Nauss 1990).

Rodent studies have indicated that folate deficiency might alter the rate at which formate is metabolized. Rats maintained on a folate-deficient diet develop increased blood formate concentrations following high-dose (4 g/kg) intraperitoneal methanol exposures (Makar and Tephly 1976). Dorman et al. (1994) examined the pharmacokinetics of inhaled [14C]methanol in normal and folate-deficient cynomolgus monkeys. Four normal female monkeys were initially exposed to [14C]methanol at 10, 45, 200, or 900 ppm for 2 h. Average (± standard deviation) peak blood [14C]formate concentrations were 0.07 ± 0.02, 0.25 ± 0.09, 2.3 ± 2.9, and 2.8 ± 1.7 micromolar (M) following methanol inhalation at 10, 45, 200, and 900 ppm, respectively. The monkeys were then fed a folate-deficient diet supplemented with 1% succinylsulfathiozole for 6-8 weeks to reduce their serum and erythrocyte folate concentrations to <3 nanograms per milliliter (ng/mL) and 120 ng/mL, respectively. Finally, the monkeys were exposed to [14C]methanol at 900 ppm for 2 h. End-of-exposure methanol concentrations, AUC, and total amounts of [14C]methanol and [14C]CO2 exhaled were linearly and significantly related to inhaled methanol concentrations indicating that dose-dependent methanol metabolism and pharmacokinetics did not

Suggested Citation:"7 Methanol." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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occur. The average (± standard deviation) peak blood [14C]formate concentration was 9.5 ± 4.7 μM. Despite folate deficiency, peak [14C]formate concentrations remained a small fraction of the endogenous formate blood concentrations seen in the monkeys (0.28-0.56 millimolar [mM]) or in healthy humans (see Table 7-2).

Conditions that can predispose humans to folate deficiency include gastrointestinal disorders that reduce folate absorption (such as Crohn’s disease and adult gluten enteropathy), chronic alcoholism, pernicious anemia, and psychiatric disorders, such as depression. Smoking and use of methotrexate, sulfasalazine, trimethoprim, or other medications that are folic acid antagonists also increase susceptibility to folate deficiency. Those factors are unlikely to be of concern in the healthy submariner population. The methylenetetrahydrofolate reductase polymorphism 677T mutation that decreases folate activity is common among the general population. Homozygosity was found in 21% of a Hispanic population sampled in California and in 12% of Caucasians sampled in the United States (Botto and Yang 2000). Genetic differences in folate receptor activity and in enzymes involved in folic acid metabolism are, at this time, theoretical causes of folate deficiency (Antony and Hansen 2000).

Polymorphisms in human alcohol dehydrogenase and P450 2E1 (CYP2E1) genes have been described (Fairbrother et al. 1998; McCarver et al. 1998) and could influence the rates at which methanol is metabolized. Polymorphisms in the alcohol dehydrogenase allele might lead to greater susceptibility to the direct effects of methanol in affected individuals, and decreased metabolism could result in higher blood methanol concentrations. Conversely, those individuals would be expected to exhibit lower blood formate concentrations.

INHALATION EXPOSURE LEVELS FROM THE NRC AND OTHER ORGANIZATIONS

A number of organizations have established or proposed inhalation exposure limits or guidelines for methanol. Selected values are summarized in Table 7-4.

Suggested Citation:"7 Methanol." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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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.

Suggested Citation:"7 Methanol." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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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).

Suggested Citation:"7 Methanol." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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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

Suggested Citation:"7 Methanol." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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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

Suggested Citation:"7 Methanol." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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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.

Suggested Citation:"7 Methanol." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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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.

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Suggested Citation:"7 Methanol." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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U.S. Navy personnel who work on submarines are in an enclosed and isolated environment for days or weeks at a time when at sea. Unlike a typical work environment, they are potentially exposed to air contaminants 24 hours a day. To protect workers from potential adverse health effects due to those conditions, the U.S. Navy has established exposure guidance levels for a number of contaminants. The Navy asked a subcommittee of the National Research Council (NRC) to review, and develop when necessary, exposure guidance levels for 10 contaminants.

Overall, the subcommittee found the values proposed by the Navy to be suitable for protecting human health. For a few chemicals, the committee proposed levels that were lower than those proposed by the Navy. In conducting its evaluation, the subcommittee found that there is little exposure data available on the submarine environment and echoed a previous recommendation from an earlier NRC report to conduct monitoring that would provide a complete analysis of submarine air and data on exposure of personnel to contaminants.

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