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Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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11
Toluene

This chapter summarizes relevant epidemiologic and toxicologic studies of toluene. 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 committee considered all that information in its evaluation of the Navy’s current and proposed 1-h, 24-h, and 90-day exposure guidance levels for toluene. The committee's recommendations for toluene exposure guidance levels are provided at the conclusion of this chapter with a discussion of the adequacy of the data for defining the levels and the research needed to fill the remaining data gaps.

PHYSICAL AND CHEMICAL PROPERTIES

Toluene is a flammable liquid at room temperature with a benzene-like odor (Budavari et al. 1989). The odor threshold has been reported to be 2.9 ppm (ATSDR 2000). Selected physical and chemical properties are presented in Table 11-1.

OCCURRENCE AND USE

Toluene is an important industrial chemical. It is used as a blending component for automotive fuels, as a chemical intermediate, and as a solvent primarily for paints and coatings and also for inks, adhesives, and pharmaceuticals.

Toluene is a common contaminant of outdoor and indoor air. The Agency for Toxic Substances and Disease Registry (ATSDR 2000) reported that toluene concentrations in suburban and urban air range from 1.3 to 6.6 ppb. Indoor air concentrations are often higher than outdoor air concentrations. The primary

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
×

TABLE 11-1 Physical and Chemical Properties of Toluene

Synonyms

Methylbenzene; phenylmethane

CAS registry number

108-88-3

Molecular formula

C7H8

Molecular weight

92.13

Boiling point

110.6°C

Melting point

−95°C

Flash point

4.4°C (closed cup)

Explosive limits

NA

Specific gravity

0.866 at 20°C/4°C

Vapor pressure

28.4 mm Hg at 25°C

Solubility

Very slightly soluble in water; miscible with alcohol, chloroform, ether, acetone, glacial acetic acid, carbon disulfide

Conversion factors

1 ppm = 3.77 mg/m3; 1 mg/m3 = 0.27 ppm

Abbreviations: NA, not available or not applicable.

Sources: Vapor-pressure data from HSDB 2006; all other data from Budavari et al. 1989.

source of toluene in outdoor air is motor-vehicle emissions; contributors to indoor air concentrations include emissions from household products and cigarette smoke. The toluene emission factor for cigarettes was reported as 80 µg/cigarette (ATSDR 2000).

Sources of toluene in a submarine include paints and coatings (Crawl 2003). The committee notes that cigarette-smoking is also a likely contributor to toluene concentrations in a submarine. Raymer et al. (1994) reported the results of air sampling conducted during the missions of two submarines. The fan room, galley, and engine room in each submarine were sampled over 6 h. Sampling indicated toluene concentrations of 11 ppb in the fan room, 11 ppb in the galley, and 19 ppb in the engine room of one submarine and 14 ppb in the fan room, 14 ppb in the galley, and 27 ppb in the engine room of the other submarine. A similar sampling exercise (two submarines, three locations, and sampling duration of 6 h) was reported by Holdren et al. (1995). Toluene concentrations in one submarine ranged from 122 to 137 ppb and from 241 to 342 ppb, depending on the sampling method, and in the other submarine from 14 to 21 ppb and from 17 to 23 ppb, depending on the sampling method. The committee notes that the results presented by Raymer et al. (1994) and Holdren et al. (1995) represent one-time sampling events in four submarines. Whether the reported concentrations are representative of the submarine fleet is not known, particularly inasmuch as few details were provided about the conditions in the submarines when the samples were taken.

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
×

SUMMARY OF TOXICITY

Toluene is a central nervous system (CNS) depressant and, at very high concentrations, can be irritating to the eyes. Consequences of accidental or intentional inhalation include renal toxicity, cardiac arrhythmias, blood dyscrasias, hepatomegaly, and developmental toxicity (ACGIH 1998, 2001, 2007). Sufficiently high concentrations of toluene vapor can produce euphoria; with increasing concentration, stupor, unconsciousness, or coma can occur with little accompanying irritation. The literature contains many descriptions of toluene narcosis and intoxication and the multiorgan sequelae of acute or chronic abuse. Deaths have occurred among abusers, who may expose themselves to acute toluene concentrations as great as 10,000 ppm (Press and Done 1967). Exposure to toluene at the high concentrations encountered in situations of abuse can lead to liver and kidney failure and multifocal leukoencephalopathy. In less affected people, toluene abuse has been reported to cause cognitive dysfunction. This review does not cover the topic of toluene abuse in great depth, because studies of persons known or suspected to have engaged in solvent abuse provide little quantitative information regarding dose-response relationships, and substance abuse is not a relevant model for exposure conditions expected onboard a modern submarine. For a review of the effects of exposure to toluene under conditions of abuse, see Schaumburg (2000).

The database available for characterization of toluene toxicity is large and includes considerable quantities of human and animal data suitable for derivation of exposure guidelines. Many toxicologic reviews are available and include evaluations by the NRC (1966, 1978, 1987; Garcia 1996), ATSDR (2000), the International Agency for Research on Cancer (IARC 1989, 1999), the American Conference of Governmental Industrial Hygienists (ACGIH 1998, 2001, 2007), the National Toxicology Program (NTP 1990), CIIT (Gibson and Hardisty 1983), and the U.S. Environmental Protection Agency (EPA 2005, 2007a).

Toluene is readily absorbed from the respiratory and gastrointestinal tracts and distributed throughout the body, accumulating in tissues with high lipid content. Results of many of the older studies, earlier than about 1960, are now thought to be compromised because of impurities, such as benzene, in the toluene test articles and the limited accuracy of the analytic techniques in use at the time (Neubert et al. 2001a). More recent clinical and epidemiologic studies that involve a variety of toluene exposures are considered more relevant to guideline development. Numerous studies conducted with rodents address neurotoxicity, and data from well-conducted mouse and rat lethality studies are available.

CNS depression by and metabolism of inhaled toluene are well documented and understood. Specific sensitive populations are not identified in the literature, because the primary mechanism of toxicity (CNS depression) is the same in all mammalian species and the toluene vapor concentrations at which CNS depression occurs do not differ greatly among individuals.

Controlled studies with volunteers indicate that blood and brain concentrations reach a steady state rapidly. As a consequence, effects observed during the

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
×

first hour of an exposure do not increase in severity when the exposure extends over several hours.

Toluene is not a primary mucous membrane irritant, and adaptation to both the odor and the potential drying effects of toluene on mucous membranes occurs. Complaints of eye and nose irritation have been reported in some controlled studies in which subjects were exposed at concentrations of 100 ppm or more for several hours.

Available human and animal data are considered insufficient to support an estimation of carcinogenic potential in humans (IARC group 3 compound, “not classifiable as to its carcinogenicity to humans”; EPA class D compound, “not classified” as to its carcinogenicity). ACGIH (2007) has concluded that toluene is “not classifiable as a human carcinogen.” Extensive and well-conducted studies specifically designed to evaluate toluene carcinogenicity have found no association between cumulative toluene dose (as ppm-years) and standardized mortality ratios for multiple anatomic sites or respiratory tract cancers in humans or for carcinogenic activity by standard measures in chronic and subchronic studies of male and female mice and rats (NTP 1990).

Effects in Humans

Accidental Exposure

There are several case reports of accidental occupational exposure that resulted in intoxication, manifested as narcotic effects (muscular weakness, incoordination, and mental confusion). Early reports suggesting bone marrow toxicity were confounded by exposure to benzene. High exposures encountered in cases of intentional solvent abuse have caused deaths, usually associated with cardiac arrythmia and CNS depression. Severe renal acidosis has also been reported in those patients. The toxicity of toluene in humans has been reviewed by NRC (1981, 1987; Gracia 1996), Cohr and Stockholm (1979), the World Health Organization (WHO 1985), Cosmetic Ingredient Review (CIR 1987), ATSDR (2000), and EPA (1990).

Two men using toluene to remove excess glue from tiles in an empty swimming pool were exposed to toluene at greater than 1,842 ppm in air for 2 and 3 h (Meulenbelt et al. 1990). Toluene concentrations were measured at the pool edge with a Drager tube 3 h after the workers were rescued. It is assumed that toluene concentrations at the pool bottom, where the workers were found, exceeded 1,842 ppm in light of the vapor density (toluene vapor density relative to air) of 3.1. When found, both workers were disoriented; one was unable to walk or sit, and the other experienced difficulty when attempting to walk. Physical examinations 1 h after they were found revealed mucosal irritation of the eyes, slurred speech, headache, paresis, and amnesia. The patient exposed for 3 h had an excessive anion gap and sinus bradycardia. The second, exposed for 2 h, complained of headache, and clinical examination revealed sinus tachycardia

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
×

and a slightly excessive anion gap. Neither patient exhibited abnormalities in liver function or hematologic measures. Blood toluene concentrations 2 h after exposure were 4.1 and 2.2 mg/L in the 3-h and 2-h patients, respectively. The most striking effect was the increased anion gap in both patients, which the authors attributed to a high plasma concentration of toluene metabolites (benzoic or hippuric acid) or distal tubular acidosis. Both patients recovered without permanent sequelae.

Longley et al. (1967) reported two cases of accidental occupational exposure to toluene at high concentrations. In one case, workers spraying an antirust paint in an enclosed space (ballast tank) aboard a commercial ship were overcome by toluene vapors from the paint formulation. During the incident and rescue operations, at least 17 men exhibited signs and symptoms of dizziness, collapse, unconsciousness, severe mental confusion, amnesia, and illogical behavior. All affected workers recovered fully within 30 min after breathing oxygen. No estimate of toluene exposure concentrations was reported. In the second case, the hold of a merchant ship was mistakenly sprayed with an undiluted insecticide mixture containing malathion (20%), piperonyl butoxide (8%), pyrethrum (1.5%), and toluene (to 100%) (Longley et al. 1967). Effects exhibited by workers and rescuers could not be attributed to toluene exposure alone. Everyone involved recovered without persistent effects after leaving the vessel.

Experimental Studies

Numerous studies have been conducted with healthy human subjects exposed in controlled settings to toluene at monitored concentrations for various periods. Studies performed in the 1940s are now considered compromised by impurities (for example, other solvents, including benzene) and poor analytic characterization of exposure concentrations, but multiple recent well-conducted clinical studies are eminently suitable for exposure guideline estimations (Table 11-2).

More than 300 people have been evaluated in clinical studies involving toluene exposure at 40-800 ppm, and several thousand have been surveyed in occupational monitoring studies involving toluene exposure at up to 1,500 ppm. Those populations were composed of healthy people and represent a broad spectrum of uptake rates (sedentary, working, and exercise conditions). Although many clinical studies used a concentration of 100 ppm, the addition of exercise to the protocol in the studies of Astrand et al. (1972), Baelum et al. (1990), and Rahill et al. (1996) more than doubled the blood concentration—to that greater than would result from exposure at 200 ppm with subjects at rest (Astrand et al. 1972; Veulemans and Masschelein 1978). Baelum et al. (1990) investigated peak exposures of 300 ppm (14 times during a 7-h exposure at a mean concentration of 100 ppm) with exercise (950-100 W) undertaken for 15 min during three of the peak exposures. Astrand et al. (1972) also incorporated exercise into 200-ppm exposures.

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
×

TABLE 11-2 Sensory and Neurobehavioral Effects of Toluene in Short-Term, Controlled Human Studies

Concentration (ppm)

Exposure Duration

Subjects and Effects

Reference

10, 40, 100

6 h

16 men, 21-32 years old

Slight irritation of eyes and nose at 100 ppm; no effect on mood, fatigue, or sleepiness; increase in occurrence of headache, dizziness, and feeling of intoxication, rated slight to moderate; no effect on lung function or nasal mucous flow; no significant effect on performance on 8 tests of visual perception, vigilance, psychomotor function, and higher cortical function (five-choice, rotary pursuit, screw-plate, Landolt’s rings, Bourdon Wiersma, multiplication, sentence comprehension, and word memory); 40 ppm is NOAEL for tested effects

Andersen et al. 1983

40

4 h (each of 2 sessions separated by 1 week)

12 men, 20-50 years old

No effects on measures of motor performance, attention, perceptual coding and memory, or mood and affect; positive correlation between results of finger-tapping test with alternate hands and blood toluene concentrations at end of 4 h

Lammers et al. 2004, 2005a

3, 30-min peaks to 110

Over 4 h (1 session)

50a

3 h

10 men, 20 women, 19-45 years old

No subjective symptoms; no abnormal episodic LH secretion profile in females or males; “subtle effects” on LH secretion in males and females in luteal phase (clinical significance unclear)

Luderer et al. 1999

50

4.5 h

20 nonsmoking men, 30.5 ± 5.2 years old

Sleepiness measured after exposure with Pupillographic Sleeping Test and Pupillary Unrest Index did not show a toluene-exposure effect (for example, no increased sleepiness); questionnaire scores for “unpleasant smell” significantly different from control; nonsignificant throat-irritation scores

Muttray et al. 2005

80

4 h

8 men, 22-50 years old

No impairment in neurobehavioral tasks

Cherry et al. 1983

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
×

Concentration (ppm)

Exposure Duration

Subjects and Effects

Reference

80

4 h

16 men, 23-38 years old

No differences in subjective symptoms between control and exposed group; no impairment in tests of simple reaction time, short-term memory, or choice reaction time; no effect on heart rate

Olson et al. 1985

80

4.5 h

12 men, 22-44 years old

Increase in subjective symptoms (nausea, headache, irritation) but rated negligible; no impairment in tests of simple and choice reaction time, color-word vigilance, or memory; no effect on EEG or sleep latency; “weak” depression of heart rate during sleep latency test (disappeared during performance testing)

Iregren et al. 1986

100

3.5 h

18

No behavioral deficits in psychomotor tests

Winneke 1982

100

4 h

30 men and women

No serious impairment in series of neurobehavioral tests (choice response time and pattern recognition); significant impairment in one measure of visual-vigilance test

Dick et al. 1984

100

6 h

6 men and women, 27-38 years old

No significant effect on lung function (subjects exercised for 30 min); slight effects on some multitask and neuropsychologic tests (increased latency, but not accuracy, on neurobehavioral tasks)

Rahill et al. 1996

100

6.5 h

43 male printers and 43 male nonprinter referents, 29-50 years old; 4 groups tested: 2 exposed and 2 controls

Irritation of eyes, nose, and throat (no annoyance or nausea); sleepiness, fatigue, and lower performance on 4 of 10 tests (3 tests evaluated visual perseverance, and the other manual dexterity); complaints of low air quality and strong odor; no changes in kidney function

Baelum et al. 1985

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
×

100

1, 3, 7.5 h, over several days

10 men and 9 women

No decrement in psychomotor tests on first day of exposure; slight decrement in women on alertness test and deleterious change in 1 of 2 men in visual evoked response at 7.5 h/day, 5 days/week; increase in eye, nose, and throat irritation at 100 ppm 3 h/day, 5 days/week

Stewart et al. 1975

100

100 (TWA; varied with 15-min peaks to 300 ppm every 30 min)

7 h

(3 15-min exercise periods with load of 50-100 W; both exposures)

32 men and 39 women, 31-50 years old

Sensory irritation of nose and lower airways, but not eyes, in toluene-exposed groups; slight decrease on 1 of 4 psychomotor performance tests; no differences in symptoms or performances between groups exposed to constant and varied toluene concentrations

Baelum et al. 1990

75

150

7 h over 3 days

7 h over 3 days

42 male and female students, 18-35 years old

Mean 7% decrement on several neurobehavioral tests at 150 ppm; slight increases in headache and eye irritation exhibited dose-response relationship; sleepiness on first day; CNS effect demonstrated by dose-response relationship in number of times subjects slept; no clear pattern of neurobehavioral effects found; variation in control data across 3 days greater than solvent effect

Echeverria et al. 1989, 1991

100a, 200a

30, 60 min

11 men, 18-29 years old; 4 women, 27-46 years old

No difference in heart rate, pulmonary ventilation, oxygen consumption, or blood lactate either at rest or during a work load of 50 W

Astrand et al. 1972

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
×

Concentration (ppm)

Exposure Duration

Subjects and Effects

Reference

100, 200

3, 7 h with 1-h break

23 naive men, average 23 years old

Decrease in pulse rate at 200 ppm for 3 h; tendency to prolonged reaction time at 200 ppm; at 100 ppm, no significant change from control in pulse rate, diastolic or systolic blood pressure, flicker value, or reaction time; no clear dose-response relationship

Ogata et al. 1970

100a

300a

500a

700a

Successive 20-min exposure periods (one 5-min break); total 85 min

12 men, 20-35 years old

At 100 ppm, no effect on reaction time or perceptual speed; at 300 ppm, increase in simple reaction time; at 500 ppm, increase in complex reaction time; at 700 ppm, decrease in perceptual speed at end of exposure; no effect on heart rate during total exposure; 1 of 12 subjects able to distinguish between control and toluene exposures

Gamberale and Hultengren 1972

200, 400, 600, 800

7-8 h

2 subjects

Transitory mild throat and eye irritation and slight exhilaration at 200 ppm; metallic taste, transitory headache, lassitude, inebriation, and slight nausea at 800 ppm; threshold for “steadiness” task, 800 ppm

Carpenter et al. 1944

220b

427b

15 min

6 subjects

At 220 ppm, all subjects willing to work for 8 h, negligible sensory symptoms; at 427 ppm, 3 of 6 subjects willing to work for 8 h; 2 subjects reported slight “lightheadedness”; 1 reported “stuffy, drowsy feeling”

Carpenter et al. 1976

200

6 h

5 men, resting

Increase in pulse rate; no changes in respiration rate, galvanic skin reflex, or EEG.

Suzuki 1973

240

Three 30-min sessions

11 men, 20-21 years old

Impaired vigilance in third session; decreased fatigue during second session

Horvath et al. 1981

aSubjects exposed via mouthpiece.

bMeasured as toluene in “toluene concentrate.”

Abbreviations: CNS, central nervous system; EEG, electroencephalography; LH, luteinizing hormone; NOAEL, no-observed-adverse-effect level; TWA, time-weighted average.

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
×

Although slight irritation involving the eyes and nose in humans was reported in several studies at 80-200 ppm (Table 11-2), toluene is not a primary respiratory irritant, as evidenced by the high RD50 value (the concentration associated with a 50% depression in respiratory rate) of 5,300 ppm in male Swiss-Webster mice (Nielsen and Alarie 1982). Complaints increased among the controls, especially in studies with long exposure durations. Other studies reported exposures at 80-100 ppm to be nonirritating (Stewart et al. 1975; Cherry et al. 1983; Olson et al. 1985; Rahill et al. 1996). The value of 200 ppm is far below concentrations reported to cause frank CNS effects. No CNS effects were reported at 80-100 ppm in studies by Winneke (1982), Cherry et al. (1983), and Stewart et al. (1975); effects were minor in other studies at 100-700 ppm (Gamberale and Hultengren 1972; Dick et al. 1984; Baelum et al. 1990). There were no biologically significant pulmonary or cardiovascular effects at 100 and 200 ppm for up to 6 h (Astrand et al. 1972; Suzuki 1973) and no indications of kidney damage (Nielsen et al. 1985). Exposures at 100 ppm in the study by Stewart et al. (1975) were repeated for 5 days with no greater effects. Thus, the highest no-observed-adverse-effect levels (NOAELs) for more than mild sensory discomfort and other than subtle CNS effects were 100 ppm for 7.5 h (Stewart et al. 1975), 200 ppm for 60 min with exercise (Astrand et al. 1972), 300 ppm over 15 min with exercise (Baelum et al. 1990), and 700 ppm for 20 min (Gamberale and Hultengren 1972).

Muttray et al. (2005) assessed the potential for acute (4.5 h) toluene exposures to induce sleepiness in a two-period crossover design (50-ppm toluene alternating with air only) exposure-chamber experiment with 20 healthy non-smoking men (mean age, 30.5 ± 5.2 years). Quantitative measurement of the degree of “sleepiness” was performed with the Pupillographic Sleepiness Test and Pupillary Unrest Index, in which pupillary diameter oscillations were monitored (Muttray et al. 2005). Compared with the results of air-only exposure, parametric crossover analysis showed no effects of toluene exposure. Muttray et al. (2005) concluded that acute toluene exposure at 50 ppm did not increase sleepiness.

Studies of toluene exposure in combination with other solvents or alcohol reported delayed metabolism of toluene (Dossing et al. 1984), but there were no additive effects in neurobehavioral tests (Cherry et al. 1983).

Complaints of sensory irritation and differences in neurobehavioral tests have been reported in some occupational monitoring studies (Iregren 1982; Foo et al. 1990; Deschamps et al. 2001; Neubert et al. 2001a). Exposures in those situations were usually at or below the workplace guidelines (now 50-100 ppm but up to 200 ppm earlier) and have ranged up to 300-500 ppm for short durations during the workday (Deschamps et al. 2001). The 20-min NOAEL exposure at 700 ppm by Gamberale and Hultengren (1972) indicates that 700 ppm (after 20 min at 500 ppm, which itself followed successive 20-min exposures at 100 and 300 ppm) may be a threshold for CNS depression. Frank effects were reported at 800 ppm in the studies of von Oettingen et al. (1942a,b) and Carpenter et al. (1944), but the studies suffered from inferior analytic techniques and

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
×

potential benzene contamination of the test article. The clinical study of Gamberale and Hultengren (1972) with support from the clinical and occupational studies of von Oettingen et al. (1942a,b), Carpenter et al. (1944), and Wilson (1943) established that 700 ppm for a short duration (20 min) may be a threshold for decreased ability to complete complex tasks in a timely manner, whereas 800 ppm for 3-8 h may result in nausea and incoordination sufficient to impair escape (von Oettingen et al. 1942a,b; Carpenter et al. 1944).

Occupational and Epidemiologic Studies

Occupational studies have focused primarily on CNS impairment. Although exposure concentrations and durations are usually not well characterized, the studies provide information about the more common toxic effects. Interpretation of the results of many occupational studies is confounded by coexposure to other solvents, alcohol use, and age of participants (Table 11-3).

Wilson (1943) surveyed the effects of toluene at various concentrations in workers at a large industrial plant. About 1,000 workers were exposed at 50-1,500 ppm for 1-3 weeks. About 10% of the employees exhibited symptoms severe enough to require examination at a local hospital. Employees were grouped according to the concentration of toluene at their job sites as measured with a combustible-gas indicator. In workers exposed to toluene at 200 ppm, the most common complaints were headache, lassitude, and loss of appetite; workers exposed at 200-500 ppm complained of more pronounced headache, lassitude, and anorexia. The latter workers also complained of nausea, a “bad taste” in the mouth, loss of coordination, impaired reaction time, and momentary loss of memory. At measured concentrations greater than 500 ppm, the major complaints were nausea, headache, dizziness, anorexia, palpitation, and weakness. Physical and laboratory examinations of the roughly 60 workers exposed at 200 ppm were negative, and no significant physical or laboratory findings were noted in the 30 workers exposed at 200-500 ppm. On physical examination of the remaining 10% (exposed at measured concentrations greater than 500 ppm), loss of coordination, impaired reaction time, and skin petechiae were observed. Laboratory investigations of those patients revealed low red-blood-cell counts and leukopenia; in two of the patients, a bone-marrow biopsy revealed aplastic anemia. Workers who were hospitalized were treated symptomatically, and no deaths occurred. The Wilson (1943) results illustrate confounding by the presence of other workplace solvents or such contaminants as benzene; toluene alone is not known to cause hematopoietic toxicity.

Greenberg et al. (1942) identified time-weighted average (TWA) toluene exposures at 100-1,100 ppm (most were at 500 ppm) in a workplace survey of 106 painters employed from 2 weeks to 5 years in an aircraft factory. Other solvents were present in the paint mixtures. A symptom survey for headache, sore throat, and weakness found no increase in complaints. In 30% of the workers,

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
×

TABLE 11-3 Effects of Toluene in Occupational Settings

Concentration (ppm)

Time

Subjects and Effects

Reference

≤200

200-500

>500

8 h/day, 1-3 weeks

Industrial-plant workers; results compromised by presence of other solvents

At ≤200 ppm, headache, lassitude, and loss of appetite observed; at 200-500 ppm, severe headache, nausea, anorexia, incoordination, increased reaction time, and memory loss; at >500 ppm, nausea, headache, weakness, anorexia, palpitation, low RBCs, leukopenia, and some aplastic anemia (indicative of nontoluene-solvent exposure) observed

Wilson 1943

100-1,100 (TWA); most ≤ 500

2 weeks-5 years

Aircraft-factory painters; results compromised by presence of other solvents

Enlarged liver, increased lymphocyte count, and increased mean corpuscular volume

Greenberg et al. 1942

≥ 101

8-h workshift monitoring (undefined exposure duration over working life)

Industrial workers in printing, paint production, surface coating, painting, and shoemaking facilities; 4 Chinese cities

Dizziness, floating sensations, nausea; no eye, nose, or throat irritation

Ukai et al. 1993

30.6 (average)

14.8 years

Auto painters

Deficits in intelligence, memory, and performance test battery

Hanninen et al. 1976

60-100

40 months

Female shoe workers

Neurologic and muscular deficits

Matshushita et al. 1975

117 (average)

22 years

Male rotogravure workers

No clinically significant neurophysiologic or autonomic nervous system deficits; some workers complained of “memory disturbance”

Juntunen et al. 1985

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
×

Concentration (ppm)

Time

Subjects and Effects

Reference

150 in 1974; 50 in 1979

Multiple years

Printers

No significant difference from control in 9 of 10 tests of mental and physical dexterity; increase in simple reaction time in toluene-exposed group

Iregren 1982

9-467 (workplace monitor: 9-48 ppm for 3.5-5 h, 50-300 ppm for 15 min)

≥ 5 years

Male and female workers not exposed to other solvents

Mucosal irritation significantly greater in toluene group; no differences from controls for such cognitive-function tests as simple reaction time; toluene-exposed workers scored significantly higher than controls on vocabulary tests

Deschamps et al. 2001

50-100 (TWA) at time of study; 6 h/shift

≥ 20 years

German rotogravure-factory workers

No alteration from referent group on standard tests of psychophysiologic and psychomotor functions; all scores of toluene-exposed group within referent range

Neubert et al. 2001a,b

Maximal (regulatory) concentrations of 200 in 1985; 100 (1985-1993), 50 (1993-present); median printer exposure measured in workplace, 25 at time of study (maximum, 216)

≥ 20 years

German rotogravure printers and helpers

Examined blood pressure, color vision, clinical chemistry, and hormone concentrations; no evidence that long-term occupational exposure was “convincingly associated” with chronic adverse health effects or altered surrogate markers

Gericke et al. 2001

45 ± 17

Work lifetime (average 21.2 years)

47 healthy adult workers in German rotary printing plants; average subject age, 42.9 years; sex not reported; 18 of 47 smokers

No health effects observed in self-reported diseases (such as loss of appetite and pain), sensory function (vibration and hearing thresholds and color discrimination), cognitive function (memory), psychomotor function (manual dexterity)

Seeber et al. 2005

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
×

9 ± 7

work lifetime (average 21.3 years)

39 healthy adult workers in German rotary printing plants; average subject age, 45.6 years; sex not reported; 19 of 39 smokers

No health effects observed in self-reported diseases (such as loss of appetite and pain), sensory function (vibration and hearing thresholds and color discrimination), cognitive function (memory), psychomotor function (manual dexterity)

Seeber et al. 2005

26 ± 19

5.5 years (average)

59 healthy adult workers in German rotary printing plants; average subject age, 31.4 years; sex not reported; 20 of 59 smokers

No health effects observed in self-reported diseases (such as loss of appetite and pain), sensory function (vibration and hearing thresholds and color discrimination), cognitive function (memory), psychomotor function (manual dexterity)

Seeber et al. 2005

2 ± 3

6.6 years (average)

47 healthy adult workers in German rotary printing plants; average subject age, 33.2 years; sex not reported; 11 of 47 smokers.

No health effects observed in self-reported diseases (such as loss of appetite and pain), sensory function (vibration and hearing thresholds and color discrimination), cognitive function (memory), psychomotor function (manual dexterity)

Seeber et al. 2005

Abbreviations: RBC, red blood cell; TWA, time-weighted average.

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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the liver was enlarged and both lymphocyte count and mean corpuscular volume were increased. Other solvents were present in the workplace, so those changes could not be attributed solely to toluene.

Juntunen et al. (1985) examined 43 male rotogravure printers with long-term (up to 22 years) occupational toluene exposure for clinical, neurophysiologic, neuropsychologic, and auditory effects and subjective symptoms. Results were compared with those in 31 matched control subjects. Neurologic examinations included physical coordination, reflexes, language and memory functions, computerized axial tomography of the brain, electrocardiography, and electroencephalography. The estimated average long-term workplace toluene concentration was 117 ppm. Of the symptoms tabulated, only the incidence of “memory disturbance” was significantly increased. Overall, the examinations failed to reveal any statistically significant differences between the groups. The authors concluded that there were no clinically significant adverse effects on the nervous system under the study conditions examined.

Ukai et al. (1993) conducted a factory survey in China, using personal sampling for workplace toluene exposure, questionnaires on subjective symptoms, and clinical evaluation of hematology, serum biochemistry, and urinary hippuric acid concentration. Workers were also given a neurologic evaluation. When they were compared with workers without toluene exposure, hematologic and clinical-chemistry measures were essentially normal. A dose-dependent increase in some subjective symptoms among toluene-exposed workers was observed with a threshold concentration at 100 ppm for 22 subjective symptoms. At 101 ppm, complaints of dizziness, “floating” sensations, and nausea (but not eye, nose, or throat irritation) were associated with a significant dose-response relationship.

Deschamps et al. (2001) tested cognitive function in 72 workers (42 men and 30 women) exposed to toluene (but no other solvent) at 9-467 ppm for at least 5 years. A general questionnaire on subjective symptoms was also administered. Personal samplers worn during the workshift indicated mean 3.5- to 5-h exposures at 9-48 ppm in several factories and mean exposures at 50-300 ppm in 15-min samples from pathology laboratories. Exposed workers were compared with 61 matched workers who had no known toluene exposure. The mean age of all workers was 43 years, and the mean duration of chronic exposure of the toluene-exposed workers was 20 years. Workers were tested 48 h after removal from exposure; the absence of toluene in the alveolar air of the subjects ensured that the solvent had been eliminated from the blood. Tests consisted of vocabulary, simple reaction time, digit symbol, digit span forward and backward, continuous tracking, color word vigilance, and switching attention. Except for the vocabulary test in which toluene-exposed workers scored significantly higher than the control group, there were no significant differences between groups in any of the tests. Of six subjective symptoms, only mucosal irritation had a significantly increased score (1.54 vs 1.37).

Iregren (1982) evaluated performance of a group of 34 toluene-exposed printers on a battery of psychologic tests and compared the results with test

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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scores from a group of spray painters exposed to a mixture of solvents and with a control group. The toluene-exposed printers differed significantly from the control group on only one of 10 tests addressing mental and physical dexterity. Simple reaction time was increased in the printer group compared with the control group (printers, 276 msec; controls, 238 msec). Although workplace air concentrations were not specifically stated, the authors indicated that exposures had decreased from about 150 ppm in 1974 to 50 ppm in 1979. The tests were administered at the end of the week that followed the last workday.

Neubert et al. (2001a) evaluated toluene-exposed employees at 12 German rotogravure factories. The study involved 1,290 exposed workers (1,178 males and 112 females) and 200 controls in a multicenter, controlled, blinded field study with the specific goal of evaluating dose-response relationships. Examinations included subjective self-rating of feeling and standard tests of psychophysiologic and psychomotor functions (verbal memory span, visuomotor performance, immediate visual memory, combined auditory and visual vigilance, and critical flicker-fusion frequency). Subjects were tested before and 0.5 h after a 6-h workday, and blood toluene concentrations were measured before and after the workshift. Air concentrations were monitored by continuous sample collection over the workshift with portable personal monitors. Age and alcohol consumption were recognized as confounding factors and were taken into account. Neither blood toluene concentrations of 0.85-1.70 mg/L nor TWA ambient-air concentrations of 50-100 ppm were clearly associated with alterations in results of psychophysiologic and psychomotor performance or increased subjective complaints in male volunteers. Compared with the referent group, no higher frequencies of headache or other unpleasant sensations were reported with toluene exposures up to 75-100 ppm. All test scores of toluene-exposed persons were within the reference range. There were too few subjects to support conclusions concerning males exposed at more than 100 ppm (blood toluene concentration, greater than 1.70 mg/L).

A subgroup of the printers and their helpers (1,077 male subjects) that participated in the Neubert et al. (2001a) study described above was further evaluated after long-term exposure to toluene (Gericke et al. 2001). The referent group (109 subjects) was selected from the paper industry. The length of exposure of some of the toluene-exposed and referent workers was 20 years. Exposure duration and gross extent of exposure were taken into account. Blood pressure, pulmonary function, color vision, clinical chemistry, hormone concentrations, and subjective symptoms were tallied. Trends showing reduced performance in the digit-symbol and visual-reproduction tests were correlated with age in both the printers and the referents. Although insomnia, dry mucous membranes, and allergies were higher in the toluene-exposed group than in the referent group, the frequency of these complaints and complaints of headache, nausea, loss of appetite, and gastrointestinal distress did not correlate with the duration or extent of toluene exposure. There was no association between circulating liver glutamine oxaloacetic transaminase and glutamic pyruvic transaminase with the length or extent of toluene exposure or age. A small upward trend

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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was observed for serum cholesterol, but it appeared to be age-related. Renal function as measured by creatinine clearance was unaffected. Follicle stimulating hormone, luteinizing hormone, and testosterone concentrations were not affected by exposure. Higher systolic blood pressure correlated weakly with toluene exposure of longer than 20 years, but confounding factors associated with hypertension were not taken into account. Overall, no clear adverse effects could be verified in this study of long-term occupational exposure. The authors point out the limitations of their study, including the reversibility of effects that may have occurred during past exposures at higher concentrations and the healthy-worker effect.

Seeber et al. (2005) studied 192 workers in German rotary-printing plants who had undergone “long” (about 20 years) or “short” (5.5-6.6 years) exposure to toluene in various portions of the plants. The authors pointed out that the long-term workers had been historically exposed at much higher concentrations (140 ppm vs about 40 ppm currently for the “high” group; and 20 ppm vs about 5 ppm currently for the “low” group). The resulting four exposure-duration groups were made up of people exposed at 45 ppm for 21.2 years, 9 ppm for 21.3 years, 26 ppm for 5.5 years, and 2 ppm for 6.6 years. Smoking was represented in each subject population (see Table 11-3), as was alcohol consumption. Odds ratios were used to evaluate a number of measures: sensory function (vibration and hearing thresholds and color discrimination), cognitive function (memory), and psychomotor function (manual dexterity). For all measures evaluated, results do “not support the hypothesis that there are health effects of toluene at current exposures of about 25 ppm or lifetime weighted exposures of about 46 ppm” (Seeber et al. 2005). Furthermore, “evidence for neurobehavioral effects due to long-term toluene exposure below 50 ppm was not established” (Seeber et al. 2005).

Monitoring studies indicate that workers have been historically and routinely exposed at 32 ppm (range, 0.1-457 ppm; Neubert et al. 2001b), at 26 and 45 ppm (26 ± 19 ppm and 45 ± 17 ppm; Seeber et al. 2005), at a TWA of 63-118 ppm (range, 5-353 ppm; Ovrum et al. 1978), at 132 ppm (range, 66-250 ppm; Zavalic et al. 1998), at 100-440 ppm with peaks at 200-500 ppm (Eller et al. 1999), at 200 ppm (Forni et al. 1971), and at 200-800 ppm (Parmeggiani and Sassi 1954). In most cases in which psychomotor tests were administered, tests were given before the workday began, so acute changes were not measured. In most of the studies, only subtle differences in neurologic measures, such as alterations in the visual evoked response, or small impairments of reaction time were found in comparisons with controls (Abbate et al. 1993; Boey et al. 1997; Eller et al. 1999; Murata et al. 1993; Vrca et al. 1995; 1997a,b; Yin et al. 1987; Zavalic et al. 1998). No changes from baseline in any sensory measure, cognitive function, or psychomotor function were noted by Seeber et al. (2005). Irritation of the conjunctiva and upper respiratory tract was found in one of 11 workers exposed at 200-800 ppm (Parmeggiani and Sassi 1954). In some studies, the incidence of sore throat was greater than in matched control groups. Chronic occupational exposure to toluene at routine concentrations in workplace air has

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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not resulted in serious kidney damage (ATSDR 2000). An acute exposure of flexoprint workers at about 100 ppm for 6.5 h failed to show significant changes in β-microglobulin or albumin compared with air-exposed controls (Nielsen et al. 1985).

Occupational studies suggest that chronic toluene exposure may be associated with hearing loss (reviewed in ATSDR 2000; Morata et al. 1997; Chang et al. 2006) but these studies do not always account for noise-induced hearing damage. In a study (Chang et al. 2006) of adhesive plants where “noise only” reference occupational populations were also examined, the “noise + toluene” population exhibited hearing losses of a type and magnitude similar to those in the “noise only” group (both groups had been employed for more than 20 years), but the prevalence of hearing loss was significantly greater (p < 0.001) in the “noise + toluene” group even at the lowest occupational toluene exposure concentration of 33 ppm. In studies of 333 rotogravure-printing workers (Schaper et al. 2003) and 192 rotary-printing plant workers (Seeber et al. 2005), exposure at less than 50 ppm could not be related to ototoxicity.

In animal models, toluene is associated with damage to outer-ear hair cells in rats exposed at 1,400 ppm 14 h/day for 8 days (Johnson and Canlon 1994). Guinea pigs have not been shown to exhibit solvent-induced hearing loss (Campo et al. 1993); this may be due to significant and large differences in toluene uptake and metabolism between the rat and guinea pig (lower in the guinea pig). The result is lower toluene body burdens for the guinea pig (Campo et al. 2006), which are surmised to induce few or no ototoxic effects.

One evaluation of color-vision impairment in toluene-exposed workers (Zavalic et al. 1998) determined that alcohol use and age were confounding factors. Potential mechanisms of toluene-related effects on hearing and color vision are further discussed under “Toxicokinetics and Mechanistic Considerations.”

Effects in Animals

Acute Toxicity

Lethality and sublethality data on the rat (Pryor et al. 1978; Cameron et al. 1938; Hinman 1987; Kojima and Kobayashi 1973; Smyth et al. 1969; Wada et al. 1989; Mullin and Krivanek 1982; and Lammers et al. 2005b), the mouse (Moser and Balster 1985; Bruckner and Peterson 1981a,b; Bushnell et al. 1985; Bonnet et al. 1979; and Svirbely et al. 1943), and the dog (Ikeda et al. 1990) are available. On the basis of LC50 values, the mouse is slightly more sensitive to the effects of toluene than the rat. For the mouse, LC50 values ranged from 38,465 ppm for 10 min to 5,320 ppm for 7 h. Highest nonlethal exposures were 12,000 ppm for 20 min for the mouse (Bruckner and Peterson 1981a) and 5,000 and 6,250 ppm for 2 h for the rat (Kojima and Kobayashi 1973; Mullin and Krivanek 1982).

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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Because few human experimental data on neurotoxicity at concentrations below those causing frank narcosis are available, the extensive animal database characterizing neurobehavioral effects has been examined for application to the current analysis. The experimental-animal dataset is large (especially on the laboratory rat) and this necessitates presentation of selected studies representative of the body of available data (see Table 11-4).

Toluene, like many other CNS depressants and anesthetics, generates an initial excitatory stage followed by narcosis. Except for increased activity, experimental toluene concentrations below 1,000 ppm have little or no effect on gross manifestations of animal behavior (NRC 1981) (see Table 11-4). At 2,000 ppm, motor activity and the rate of response in neurobehavioral tests are increased. Higher concentrations suppress activity. In neurotoxicity tests, CNS depression increases motor activity and response rates (excitation) at low concentrations and decreases activity and responses at higher concentrations (Moser and Balster 1981, 1985; Wood et al. 1984). Increases in activity with no or minor decrements in accuracy on tasks occurred in rats and mice at 1,000-2,000 ppm (Mullin and Krivanek 1982; Kishi et al. 1988; Wood and Cox 1995). Mice exposed at about 2,000 ppm for short periods began to fail equilibrium tests in some studies (Moser and Balster 1985; Tegeris and Balster 1994) but exhibited increased activity in others (Kishi et al. 1988; Wada 1997). Mice exposed at 5,200 ppm became immobile in 45 min and lost consciousness in 1.5 h (Bruckner and Peterson 1981a). Those neurologic deficits are similar to ones observed in humans. The onset of neurobehavioral deficits is not readily observable in rodents, so extrapolation to humans is difficult. Furthermore, the increase in activity exhibited by rodents exposed to toluene at low concentrations is not readily observed in humans.

In general, acute exposures to toluene at high concentrations have produced conflicting data in animal studies, some reporting significant neurobehavioral effects and others no significant effects. None of the animal studies reproduced effects observed in humans exposed to toluene at high concentrations for extended periods (Schaumburg 2000). Furthermore, toluene at concentrations that produced unconsciousness in experimental animals has failed to produce residual organ damage (Svirbely et al. 1943; Bruckner and Peterson 1981b; NTP 1990).

Repeated Exposure and Subchronic Toxicity

Taylor and Evans (1985) subjected adult female cynomolgus macaques to 50-min, head-only exposures to toluene at 0, 100, 200, 500, 1,000, 2,000, 3,000, or 4,500 ppm and simultaneously tested for delayed matching-to-sample behavior as a measure of cognitive function. Monkeys were exposed singly at each concentration, and each monkey was tested twice at each concentration. The procedure took 6 weeks. Previously, two of the monkeys were exposed at

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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TABLE 11-4 Neurobehavioral Effects of Acute Toluene Inhalation Exposure in Rats

Concentration (ppm)

Duration

Effects

Reference

150

0.5, 1 h

Stimulatory effect, multiple schedule performance

Geller et al. 1979

150

2, 4 h

Reduced performance

0, 1,200, 1,600, 2,000, 2,400

70 min

Signal-detection task; concentration-related reduced attention and increased response time; no effect on false hits; rats sleepy but arousable at 2,400 ppm

Oshiro and Bushnell 2004

178, 300, 560

2 h

Increased activity (for reward)

Wood and Cox 1995

1,000, 1,780

2 h

Increased activity, then return to control rate

3,000

2 h

Increased activity, then decrease below control rate

800

4 h

Threshold, decreased unconditioned reflexa

Mullin and Krivanek 1982

1,340

1 h

EC50, most sensitive unconditioned reflexa

3,200

2 h

Decreased conditioned-avoidance response

125, 250, 500

4 h

Decreased conditioned-avoidance responses

Kishi et al. 1988

1,000, 2,000

4, 2 h

Increased incorrect responses and reaction time

4,000

4 h

Excitation, increased response rate, ataxia

1,000, 1,500, 2,000

1 h

Initial decrease in detection of auditory signals at all concentrations followed by return to control levels

Bushnell et al. 1994

1,000

4 h

Little effect on avoidance responses

Shigeta et al. 1978

3,000

4 h

Changes in response pattern

1,000, 1,780, 3,000

2 h

1,780 and 3,000 ppm: increased concentration-dependent rates of response to food reward in spite of electric-shock punishment

Wood et al. 1984

3,000

4 h

Ataxia

 

1,000

4 h

No change in behavior (number of rearings)

Takeuchi and Hisanaga 1977

2,000

4 h

Increased rearings and seizures

4,000

4 h

Excitation followed by narcosis

2,000

4 h

Increased number of lever presses to avoid shock, no change in avoidance behavior

Harabuchi et al. 1993

4,000

4 h

Increased number of lever presses to avoid shock, decrease in avoidance response

1,700

4 h

No decrease in activity after exposure

Miyagawa et al. 1986

3,400

4 h

Activity decreased by 31% followed by recovery

5,100

4 h

Inactivity followed by partial recovery

2,000

4 h

Increased locomotor activity

Wada et al. 1989

4,000

4 h

Decreased conditioned-avoidance responses

6,000, 8,000

4 h

Decreased conditioned-avoidance responses, ataxia, narcosis

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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Concentration (ppm)

Duration

Effects

Reference

1,333, 2,667

7.5 h

Effects on visual discrimination, increased motor activity, return to baseline on following day

van Asperen et al. 2003

8,000

Peak

2,500

1 h

No effect on motor activity during exposure

Hinman 1987

5,000

1 h

Increased locomotor activity

10,000

1 h

Increased activity followed by slight decrease

15,000

1 h

Increased activity followed by cessation

aUnconditioned reflex tests evaluated locomotor activity, coordination, corneal reflex, and righting reflex; EC50 determined for test failure (Mullin and Krivanek 1982).

Abbreviations: EC50, statistical determination of the effect concentration in 50% of the sample population.

100 ppm and one monkey at 1,000 ppm 6 h/day, 5 days/week for 90 days. Toluene concentration was monitored continuously. Responses at 100 and 200 ppm were similar to those during the control sessions. Responses at 500 and 1,000 ppm were nonsignificantly lower than control responses. Cognitive function was impaired at 2,000 ppm as indicated by an increase in response time and a decrease in matching accuracy. Response time at 4,500 ppm increased by 0.26 sec over the control response time, and monkeys failed to respond during the second half of the session. Most monkeys remained awake at 4,500 ppm but failed to respond. The effect was characterized by the study authors as an attentional deficit with no specific memory effect.

In some cases, behavioral measurements (particularly of olfactory sensitivity to toluene) can be demonstrated as positively associated with histopathologic changes, such as altered cell density and epithelial thickness in olfactory neuroepithelium (Jacquot et al. 2006). Jacquot et al. (2006) compared T-maze sensitivity to toluene odor with nasal-cavity neuroepithelial changes in naive female OF-1 mice during each week of repeated exposure to toluene at 1,000 ppm 5 h/day, 5 days/week for 4 weeks.

Atay et al. (2005) exposed 4-week-old Swiss albino BALB/c mice repeatedly to toluene at 300 ppm 6 h/day for 8 weeks to evaluate potential changes in bone mineralization. Dual x-ray absorptiometry of the right femoral neck allowed accurate measurement of bone mineral density (BMD) and bone mineral content (BMC). In the toluene-exposure group, statistically significant (p < 0.05) decrements in both BMD and BMC were observed in comparison with the controls. Atay and co-workers are uncertain about the mechanisms whereby toluene-vapor exposure alters bone metabolism.

Jenkins et al. (1970) exposed Sprague-Dawley rats to inhaled toluene repeatedly or continuously to evaluate long-term effects on mortality, body weight, and hematology. A group of 15 male and female rats was exposed to toluene at 1,085 ppm 8 h/day, 5 days/week for 6 weeks and a group of 13 male and female rats continuously exposed at 107 ppm for 90 days. The control group

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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was composed of 14 rats. No rats died during the repeated exposure. Two rats died during the continuous exposure (one on day 28 and the second on day 56). Rats in both treatment groups gained more weight than the control group; however, starting weights were not balanced: both treated groups weighed more than the control group. There were no apparent effects on hemoglobin, hematocrit, or leukocyte count.

The NTP (1990) reported subchronic inhalation-exposure studies of groups of 10 male and 10 female F344/N rats and 10 male and 10 female B6C3F1 mice exposed to toluene vapor at 0, 100, 625, 1,250, 2,500, or 3,000 ppm (rats) or 0, 312, 625, 1,250, 2,500 or 3,000 ppm (mice) 6.5 h/day, 5 days/week for 15 weeks (rats) or 14 weeks (mice).

In the rats, eight of the 10 males exposed at 3,000 ppm died during week 2; there were no other deaths in any other exposure group among the males and no deaths at any concentration among the females throughout the study. Final body weights were lower, and ataxia was noted in the 2,500- and 3,000-ppm groups. Dyspnea as a clinical sign was observed in all exposed groups “except males exposed at 3000 ppm and females exposed at 1250 ppm” (NTP 1990, p. 34). Relative weights of multiple organs in males and females were increased at 2,500 and 3,000 ppm, as were the kidney and liver weights in males at 1,250 ppm. The NTP (1990) authors did not consider any observed differences in hematologic measures or serum chemistry to be biologically significant. There were no treatment-related effects on sperm count or the estrous cycle.

In the mice, death occurred swiftly at 3,000 ppm in both sexes, and all females at this concentration were dead by week 2. Deaths also occurred among females exposed at 625 ppm or higher in a roughly dose-dependent manner. Final body weights were lower in all exposed groups. Dyspnea occurred only at 2,500 and 3,000 ppm. Relative organ weights were greater in populations exposed at 625 ppm or higher. The NTP (1990) authors did not consider any observed differences in hematologic measures or serum chemistry to be biologically significant. There were no treatment-related effects on sperm count or the estrous cycle.

Chronic Toxicity

Gibson and Hardisty (1983) evaluated the chronic toxicity and carcinogenicity of inhaled toluene in male and female F344 rats exposed at 0, 30, 100, or 300 ppm 6 h/day, 5 days/week for up to 2 years. Groups of 120 animals of each sex were exposed with interim sacrifices at 6, 12, and 18 months. Each animal was examined for clinical changes, and selected animals were examined further for ophthalmologic, hematologic, urinary, or clinical blood chemistry effects. Although female rats exposed at 100 and 300 ppm exhibited slightly (but significantly) reduced hematocrit and the females exposed at 300 ppm exhibited slightly (but significantly) increased mean corpuscular hemoglobin concentration, the authors did not appear to consider these findings as biologically

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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significant. They concluded that there were no treatment-related effects on hematology or clinical chemistry measures and that no tissue or organ lesions were attributable to toluene treatment. The observed low incidence of “proliferative, degenerative and inflammatory” lesions was similar in the control and toluene-exposed groups and was not considered attributable to treatment; the authors observed that such lesions were similar to those expected spontaneously. Thus, there were no increases in the incidences of neoplasms in treated rats compared with air controls.

IARC (1989) considered that the Gibson and Hardisty (1983) exposure regimen evaluated toluene at concentrations that may have been too low. As a consequence, the NTP (1990) conducted a second series of oncogenic bioassays in rats and mice exposed at higher concentrations. Groups of 60 male and 60 female F344/N rats and 60 male and 60 female B6C3F1 mice were exposed to toluene at 0, 600, or 1,200 ppm (rats) or 0, 120, 600, or 1,200 ppm (mice) 6.5 h/day, 5 days/week for up to 2 years. The results revealed no evidence of carcinogenicity compared with concurrent controls. Mild degeneration of the nasal-cavity olfactory and respiratory epithelium was observed at 600 and 1,200 ppm, and inflammation and metaplasia of nasal mucosa was observed in exposed female rats. The NTP authors noted that the spectrum of lesions was “not unusual” during inhalation studies of organic solvents and was representative of a generic solvent effect rather than a toluene-specific effect (NTP 1990, p. 43). The NOAELs for carcinogenicity and survival were both 1,200 ppm in rats and mice.

Reproductive Toxicity in Males

Although toluene is reported to produce teratogenic effects in the infants of women who have abused it (Schaumburg 2000), male-mediated effects on reproduction have not been convincingly demonstrated. Most human studies characterizing potential reproductive effects are occupational studies in which mixed exposures cannot be eliminated or studies of persons known or suspected to have abused solvents. Such studies provide little quantitative information regarding dose response and will not be considered further in the present analysis.

In a study of 1,077 male rotogravure workers compared with a referent group of 109 male workers in the paper industry, Gericke et al. (2001) found no effect of chronic (at least 20 years) toluene exposure on follicle-stimulating hormone (FSH), luteinizing hormone (LH), or testosterone concentration; workplace toluene exposure concentrations monitored in 1993-1995 were 50-100 ppm (TWA) for a portion (24%) of the study participants; the remainder were exposed at lower concentrations (Neubert et al. 2001b). Gericke et al. (2001) and Neubert et al. (2001b) both acknowledge that the estimation of chronic individual exposures for past decades is undefined and variable. Luderer et al. (1999) examined the reproductive endocrine effects of acute exposure on 10 males and 20 females by mouthpiece exposure at 50 ppm for 3 h; no alterations in serum gonadotrophins, including LH and FSH, resulted; however, subtle ef-

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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fects on LH secretion were observed in male participants and in luteal-phase females. The clinical relevance of the findings is not clear. Luderer et al. (1999) observed no change in male blood testosterone concentration in the exposure regimen described.

More complete data are available on laboratory animals. Male F344/N rats and B6C3F1 mice evaluated during the toluene-inhalation studies of the NTP (1990) exhibited no compound-related effects on sperm count or motility when exposed at up to 3,000 ppm for 14 weeks or up to 1,200 ppm for 2 years. There were no histopathologic lesions observed in the epididymes, prostate, or testes of male mice or rats. The relative weights of the right testis of male rats exposed at 2,500 ppm or higher for 15 weeks were increased 15-24% compared with the control; although the changes were statistically significant, the NTP did not consider the difference to be biologically meaningful.

Male Sprague-Dawley rats exposed at 600 ppm 6 h/day for 90 days exhibited a slight decrease (13%) in sperm count; when exposed at 2,000 ppm under the same protocol, the sperm count decreased significantly by 26% and the weight of the epididymes decreased by 15% (Ono et al. 1996); the changes had no effect on mating performance or fertility as characterized by fertility and copulation indexes.

Immunotoxicity

Numerous investigators have noted that results of many early toluene studies (for example, those conducted before about 1985) have been confounded by the presence of benzene (a bone-marrow suppressant) as a contaminant (NTP 1990; NRC 1987; EPA 1985, 1987, as cited in ATSDR 2000). In those earlier times, solvent-extraction procedures were such that industrial toluene often contained some benzene (percentage not reported). Most later studies performed in North America and Europe include purity characterization as part of the experimental protocol. Burns-Naas et al. (2001) note that toluene possesses some immunomodulating activity but that “when compared to benzene” toluene has “little to no effect on immunocompetence.” Because of assumed competition for metabolic enzymes, Burns-Naas et al. (2001) point out that toluene exposure can attenuate benzene immunotoxicity. The following immunotoxicity analysis is drawn from summaries prepared by the NTP (1990), ATSDR (2000), and Gibson and Hardisty (1983).

During the 14-week and 15-week inhalation studies of the NTP (1990), male and female F344/N rats and B6C3F1 mice (exposed to toluene at 0, 100, 625, 1,250, 2,500, or 3,000 ppm 6.5 h/day, 5 days/week) exhibited no “biologically meaningful” differences in multiple hematologic measures, including counts of leukocytes, lymphocytes, reticulocytes, and eosinophils. The NTP (1990) authors observed an insignificant decrease in leukocyte count in female rats exposed at 1,250 ppm or higher. An additional NTP study for 15 months (rats exposed at 0, 600, or 1,200 ppm and mice exposed at 0, 120, 600 or 1,200

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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ppm) led the NTP (1990) to conclude that there were no compound-related effects on any of the hematologic measures. There were no histologic changes in the rat or mouse spleen or thymus at any exposure concentration during the 14-week and 15-week studies nor in the thymus of rats and mice exposed at concentrations at up to 1,200 ppm for 24 months (NTP 1990). The incidence of spleen pigmentation in male mice increased at 120 ppm or higher in the 24-month study; the biologic significance of the observation is not known and was not linked to any immunologic end point by the NTP (1990); it is mentioned here for completeness.

The long-term CIIT studies of male and female F344 rats exposed to toluene at 0, 30, 100, or 300 ppm for up to 24 months also examined multiple hematologic measures, including total and differential leukocyte counts. At study termination, leukocyte values were not different from those of the controls.

Variable response of toluene-exposed CD-1 mice to Streptococcus zooepidemicus challenge has been documented (Aranyi et al. 1985, as cited in ATSDR 2000). A single 3-h exposure to toluene at 2.5-500 ppm was associated with significant increases in susceptibility to S. zooepidemicus infection, as was serial exposure to toluene at over 100 ppm 3 h/day for 4 weeks. “Pulmonary bactericidal activity” was decreased after toluene exposure at 2.5 ppm and 100-500 ppm but not 5-50 ppm.

Genotoxicity

Toluene has undergone extensive in vitro and in vivo genotoxicity characterization; the large body of evidence indicates that toluene exhibits no genotoxic activity (NTP 1990). The few positive studies (rat in vivo studies by Dobrokhotov 1972; Liapkalo 1973; Sina et al. 1983; Dobrokhotov and Enikeev 1977, all as cited in NTP 1990 and EPA 2007a) have confounding factors—such as protocol artifacts, test-article purity, and presence of other solvents—that limit study reliability and relevance (NTP 1990). Summarized below are selected studies previously reviewed in CIR (1987, as cited in EPA 2007a), NTP (1990), ATSDR (2000), and EPA (2007a,b).

Negative cellular assays reviewed include reverse mutation or growth inhibition due to DNA damage in Salmonella typhimurium (with and without activation), mitotic gene conversion and mitotic crossover in Saccharomyces cerevisiae, chromosomal aberrations in bone marrow cells of laboratory rodents, and chromosomal aberrations or sister-chromatid exchange (SCE) in cultured human lymphocytes (EPA 2007a and NTP 1990). Reviewed studies in mouse lymphoma L5178Y cells, Chinese hamster ovary cells, Bacillus subtilis and Escherichia coli were all negative for genotoxicity (EPA 2007a).

Mouse in vivo studies of toluene have been negative for micronucleus induction, sperm-head abnormalities, dominant lethal mutations, SCE, and chromosomal aberrations (reviewed in EPA 2007a).

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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Carcinogenicity

IARC has published evaluations of toluene twice, most recently in 1999 (IARC 1989, 1999). In both cases, IARC has classified toluene as a group 3 compound (“not classifiable as to its carcinogenicity to humans”) on the basis of “inadequate evidence” in humans and experimental animals. Human evidence evaluated by IARC (1999) included results of eight studies: three cohort studies of Swedish rotogravure printing workers by Svensson et al. (1990), U.S. aircraft maintenance workers in Utah by Blair et al. (1998), and U.S. shoe-manufacturing workers in Ohio by Walker et al. (1993); three nested case-control studies of Texas petrochemical plant workers by Austin and Schnatter (1983), U.S. rubber workers by Wilcosky et al. (1984), and U.S. nuclear facility workers by Carpenter et al. (1988); and two case-control community studies of brain cancer in the male workers of Lund, Sweden by Olsson and Brandt (1980) and multiple cancers in male residents of Montreal, Canada by Grin et al. (1998). IARC (1999) considers the findings of those epidemiologic studies to be only weakly consistent and compromised by multiple workplace exposures and the small numbers sampled. IARC notes further that cancers observed at most anatomic sites were not significantly associated with toluene exposures in any human studies examined.

Experimental laboratory animal evidence includes the inhalation-exposure studies of F344 rats by Gibson and Hardisty (1983; the CIIT study previously discussed) and F344 rats and B6C3F1 mice by NTP (1990). Under conditions of the 2-year inhalation-exposure protocol (for example, 6.5 h/day, 5 days/week for 52 weeks), the NTP (1990) states that there was “no evidence of carcinogenic activity” in male or female F344/N rats exposed to toluene at 600 or 1,200 ppm or in male or female B6C3F1 mice at 120, 600, or 1,200 ppm.

The most recent EPA assessment of toluene carcinogenicity for lifetime exposure characterizes toluene as a class D compound, “not classified” as to carcinogenicity (revision of February 1994; IRIS accessed December 2004). The basis of that determination is the stated lack of human data and “inadequate animal data” and the observation that toluene was not genotoxic in the majority of assays available for examination. Laboratory animal evidence presented to support the EPA classification included the CIIT chronic vapor-inhalation study of F344 rats (CIIT 1980) and dermal-application studies of mice: chronic exposure of three times a week (Poel 1963), two times a week for 50 weeks followed by observation for 1 year after exposure termination (Coombs et al. 1973), two times a week for 56 weeks (Doak et al. 1976), and two times a week for 72 weeks (Lijinsky and Garcia 1972), all as cited by EPA (2007b). Cellular-assay data evaluated included much of what is summarized in the genotoxicity analysis above. The EPA assessment also considered in vivo evaluations of potential chromosomal aberration in the lymphocytes of workers exposed to toluene (only) (Maki-Paakkanen et al. 1980; Forni et al. 1971, as cited in EPA 2007b).

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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TOXICOKINETIC AND MECHANISTIC CONSIDERATIONS

An extensive database evaluating the uptake, metabolism, distribution, and toxic mechanisms of toluene is available and has been reviewed by the NTP (1990), IARC (1989, 1999), NRC (1987), Garcia (1996), and EPA (2007a).

Toxicokinetics

Toluene is a CNS depressant and is readily absorbed by the blood after pulmonary exposure. Although inhalation is the principal route of exposure, absorption can also take place through the skin or alimentary tract; dermal absorption approximates 1% of that from respiratory absorption (Kezic et al. 2000, as cited in EPA 2007a). Pulmonary retention of toluene was 50% in healthy male subjects as measured by inspired and expired air concentrations when it was inhaled at 50 ppm at a 50-W workload or at 80 ppm in sedentary conditions (Lof et al. 1990, 1993, as cited in EPA 2007a). Because of the dependence of toluene uptake on respiratory rate, uptake is greater during exercise than at rest (Astrand et al. 1972; Veulemans and Masschelein 1978; Carlsson and Lindqvist 1977; Carlsson 1982, all as cited in EPA 2007a); however, once steady state is achieved, blood concentrations are relatively independent of respiratory rate. Toluene can be detected in human blood within 10-15 sec of an exposure; at air concentrations as low as 100 or 200 ppm, toluene reaches 60% of maximal arterial concentrations within 10-15 min (Astrand et al. 1972; Benignus 1981, all as cited in EPA 2007a). When monitored subjects were sedentary and exposed at 80 ppm for 4 h, 90% of the final 4-h blood concentration of toluene was attained after 2 h (Hjelm et al. 1988; Lof et al. 1990, 1993, all as cited in EPA 2007a); when subjects were exercising, a steady state was achieved more rapidly. After a 90-min exposure of seven human subjects to toluene at 50 ppm, Benoit et al. (1985, as cited in EPA 2007a) reported that retention was 83% at steady state as measured by elimination in exhaled air.

Toluene is highly lipophilic, so its distribution to body tissues and organs depends on the lipid content of the tissue, blood flow to the tissue, metabolic rate, and exposure duration. After absorption, toluene is rapidly distributed to highly vascularized tissues, such as the liver, kidney, and brain; accumulation in the brain is rapid because of that organ’s high lipid content (Bruckner and Warren 2001). Toluene is eventually taken up and stored in adipose tissues; consequently, obese people tend to accumulate more toluene than do people with low body fat (Carlsson and Lindqvist 1977, as cited in EPA 2007a). Male Sprague-Dawley rats that inhaled 14C-labeled toluene at 550 ppm for 1 h exhibited a higher concentration of labeled material in adipose tissue than in any other tissue examined: adipose tissue, 87 µg/g; adrenal, 56 µg/g; kidney, 55 µg/g; liver, 21 µg/g; and brain, 15 µg/g (Carlsson and Lindqvist 1977). Other metabolic studies of 14C-labeled toluene in rats indicate that initial 14C activity in the brain was highest in the lipid-rich medulla and pons, followed by the midbrain (10-min

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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exposure at an unstated toluene vapor concentration; Gospe and Calaban 1988, as cited in ATSDR 2000).

Lof et al. (1993) found that toluene elimination from the blood of nine human volunteers after exposure to toluene at 53 ppm for 2 h was triphasic, with three half-lives of 3, 40, and 738 min. Presumably, the longer half-life represents the mobilization of toluene from adipose tissue given its high lipophilicity. Brugnone (1985) reported half-lives of 31.8 and 29 min in vessel-rich tissue and muscle, respectively, and 36 and 2.7 h in fat and vessel-poor tissues. After the first 20-30 min of inhalation exposure, the ratio of toluene concentration in the blood and brain is constant until exposure termination (Benignus et al. 1984).

Absorbed toluene is rapidly and extensively metabolized, primarily in the liver (Low et al. 1988; ATSDR 2000). Metabolism to benzoic acid and later conjugation to form hippuric acid is the primary pathway of toluene detoxification and elimination. In humans, oxidation of the methyl group by the hepatic cytochrome isozyme CYP2E1 in humans yields benzyl alcohol (Liira et al. 1991; Nakajima et al. 1997), which is rapidly oxidized by alcohol dehydrogenase to benzaldehyde. Benzaldehyde is converted to benzoic acid by aldehyde dehydrogenases. About 75-80% of the absorbed dose of toluene is ultimately metabolized to benzoic acid. Benzoic acid is primarily conjugated with glycine and excreted in the urine as hippuric acid; smaller amounts of benzoic acid are excreted as the sulfate or glucuronide conjugate. Toluene can also be hydroxylated to form o-, m-, or p-cresols, which are conjugated with sulfate or glucuronide and are also excreted in the urine. The cresols are considered minor urinary metabolites. The remainder of the absorbed dose of toluene (about 18%) is eliminated via the lungs as unchanged toluene. Studies with rat liver microsomes indicate that metabolic pathways are the same in humans and rats. Because of population variability in the time course and yields of metabolic reactions, monitoring of the urinary metabolites hippuric acid and cresols are best considered qualitative, rather than quantitative, markers of toluene exposure (Andersen et al. 1983; Baelum et al. 1987; Hasegawa et al. 1983).

Toluene concentrations in blood and tissues are proportional to alveolar air concentrations. Numerous investigators have reported on exposure and alveolar toluene concentrations in relation to tissue concentrations during controlled exposures of human subjects (Astrand et al. 1972; Gamberale and Hultengren 1972; Veulemans and Masschelein 1978; Carlsson 1982; Hjelm et al. 1988; Tardif et al. 1991) and animal models (Benignus 1981; Benignus et al. 1984; Bruckner and Peterson 1981a; Tardif et al. 1992; van Asperen et al. 2003). Several studies measured toluene concentrations in the rodent brain. With the exception of concentrations greater than 5,200 ppm in a mouse study (Bruckner and Peterson 1981a), all the studies demonstrated a linear relationship between blood concentration and concentrations in atmospheric and alveolar air. Where several studies involving the same species can be compared, there is relatively good agreement among peak blood concentrations. In general and for similar air concentrations, peak blood concentrations are inversely related to body size.

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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Empirical data on humans and rodents indicate that venous blood concentrations rapidly increase to a plateau during the first 15 min of vapor exposure, which is followed by minimal increases in blood concentration with continuing exposure (Tardif et al. 1993, 1995). Available human and animal data demonstrate that increasing toluene exposure concentration positively correlates with increase in venous blood concentration. The data indicate that concentration, not duration, is a prime determinant of toluene-induced CNS toxicity. Evidence indicates that toluene irritation of mucous membranes depends on toluene concentration rather than exposure duration. It would thus be inappropriate to apply a time-scale adjustment to exposure guidelines on the basis of narcosis or sensory irritation.

Mechanisms of Toxicity

Toluene is considered primarily a CNS depressant, although it can also cause ocular irritation at high concentrations. CNS depression and narcosis are thought to involve reversible interaction of toluene (not its metabolites) and lipid or protein components of nervous system membranes. Bruckner and Warren (2001) summarized several theories on mechanisms of action: a change in membrane fluidity that alters intercellular communication and normal ion movements, interaction with hydrophobic regions of proteins that alters membrane-bound enzyme activity or receptor specificity, enhancement of the neurotransmitter gamma-aminobutyric acid (GABA) receptor function, and activation of the dopaminergic system. For repeated exposure, two toxic mechanisms have been proposed for CNS effects (ATSDR 2000): interaction of toluene with membrane proteins or phospholipids in brain cells may change activities of enzymes involved in synthesis or degradation of neurotransmitters, and toluene may change neurotransmitter binding to membrane receptors. Toluene is highly lipophilic and, as a nonpolar planar molecule, behaves as an anesthetic and dissolves in the interior lipid matrix of a membrane. Increasing toluene concentrations are thought to produce membrane expansion and changes in membrane structure and fluidity. After acute exposure, toluene diffuses out of the membrane, original integrity is regained, and functional characteristics can be restored (ATSDR 2000).

The molecular mechanisms of action for hearing loss and potential color-vision impairment are poorly understood (ATSDR 2000). Toluene exposure may lead to a loss of outer hair cells in the ear; there may also be neural-cell membrane effects. Color-vision impairment may involve toluene interference with dopaminergic mechanisms of retinal cells or demyelinization of optic nerve fibers (see Zavalic et al. 1998; Gericke et al. 2001).

At the exposure concentrations found in cases of life-threatening toluene abuse, distal renal tubular acidosis has been reported and manifested by generalized muscle weakness, neuropsychiatric derangements, and other effects (Streicher et al. 1981; Batlle et al. 1988; Marjot and McLeod 1989). The disorder re-

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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sults from the inability of the distal tubule of the nephron to secrete hydrogen ions through the active transport pathway of the kidney tubule, which leads to metabolic acidosis and production of alkaline urine. The high anion gap of the blood may be due to accumulation of the acidic toluene metabolites benzoic acid and hippuric acid.

INHALATION EXPOSURE LEVELS FROM THE NATIONAL RESEARCH COUNCIL AND OTHER ORGANIZATIONS

A number of organizations have established or proposed inhalation exposure levels or guidelines for toluene. Selected values are summarized in Table 11-5.

COMMITTEE RECOMMENDATIONS

The committee’s recommendations for EEGL and CEGL values for toluene are summarized in Table 11-6. The current and proposed U.S. Navy values are provided for comparison.

The literature contains an abundance of human-exposure data derived from multiple clinical, monitoring, and metabolic studies carried out at toluene concentrations less than 1,000 ppm for various exposure durations and thus suitable for direct estimation of exposure guidelines. Several hundred adults were subjects of the clinical studies summarized in Table 11-2, and several thousand workers were monitored in the occupational studies summarized in Table 11-3; it is rare to have access to such a robust human dataset for analysis. Some studies (von Oettingen et al. 1942a,b; Wilson 1943; Greenberg et al. 1942; Carpenter et al. 1944) were not used in the following assessment, because of the strong likelihood that the toluene test article was contaminated with other solvents (not unusual before 1960), the potential for exposure to multiple solvents in the workplace, and acknowledgment of the poor analytic detection capability for vapor exposures during the 1940s. The dataset that was considered includes human populations made up of healthy people representing a broad spectrum of activities (and thus uptake rates), ranging from sedentary to working and exercise conditions; individual differences in metabolic rates are also present (Gamberale and Hultengren 1972; Veulemans and Masschelein 1978; Brugnone et al. 1986; Hjelm et al. 1988). Although slight respiratory irritation was reported in several studies at 100 and 200 ppm, that toluene is not considered to be a respiratory irritant is supported by the high RD50 value, 5,300 ppm (Nielsen and Alarie 1982).

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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TABLE 11-5 Selected Inhalation Exposure Levels for Toluene from the NRC and Other Agenciesa

Organization

Type of Level

Exposure Level (ppm)

Reference

Occupational

 

 

 

ACGIH

TLV-TWA

20

ACGIH 2007

NIOSH

REL-TWA

100

NIOSH 2005

REL-STEL

150

OSHA

PEL-TWA

200

29 CFR 1910.1000

PEL-CC

300

PEL-MP

500

Spacecraft

 

 

 

NASA

SMAC

 

Garcia 1996

1-h

16

24-h

16

30-day

16

180-day

16

Submarine

 

 

 

NRC

EEGL

 

NRC 1987

 

1-h

200

24-h

100

CEGL

 

90-day

20

General Public

 

 

 

ATSDR

Acute MRL

1.0

ATSDR 2000

Chronic MRL

0.08

NAC/NRC

AEGL-1 (1-h)

200

EPA 2007c (Interim)

AEGL-2 (1-h)

1,200

AEGL-1 (8-h)

200

AEGL-2 (8-h)

650

aThe comparability of EEGLs and CEGLs with occupational-exposure and public-health standards or guidance levels is discussed in Chapter 1 (“Comparison with Other Regulatory Standards or Guidance Levels”).

Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; AEGL, acute exposure guideline level; ATSDR, Agency for Toxic Substances and Disease Registry; CC, ceiling concentration; CEGL, continuous exposure guidance level; EEGL, emergency exposure guidance level; MP, maximum peak; MRL, minimal risk level; 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; REL, recommended exposure limit; SMAC, spacecraft maximum allowable concentration; STEL, short-term exposure limit; TLV, Threshold Limit Value; TWA, time-weighted average.

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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TABLE 11-6 Emergency and Continuous Exposure Guidance Levels for Toluene

Exposure Level

U.S. Navy Values (ppm)

Committee Recommended Values (ppm)

Current

Proposed

EEGL

 

 

 

1-h

200

150

200

24-h

100

50

100

CEGL

 

 

 

90-day

20

16

20

Abbreviations: CEGL, continuous exposure guidance levels; EEGL, emergency exposure guidance level.

1-Hour EEGL

On the basis of the human data summarized in Tables 11-2 and 11-3, the highest concentrations that resulted in minimal effects after exposure for about 1 h were 200 ppm for 60 min (Astrand et al. 1972) and the serial concentrations (in successive 20-min periods) of 100-700 ppm over 85 min in Gamberale and Hultengren (1972). The exercise regimen incorporated into the study of Astrand et al. (1972) took into account the physical stress that may occur during an emergency situation onboard a submarine.

The Astrand et al. (1972) study of 15 subjects (11 men and four women) noted no treatment-related effects on heart rate, pulmonary ventilation, oxygen consumption, or blood lactate; subjective symptoms were not reported. Subjects were exposed via mouthpiece and exercised during exposure periods on a bicycle ergometer at intensities of 50 W or 75 W.

The neurobehavioral effects observed by Gamberale and Hultengren (1972) in 12 male subjects were subtle and reversible. The gradual changes observed were from no effect on reaction time or perceptual speed after a 20-min exposure at 100 ppm to an increase in simple reaction time after 20 min at 100 ppm and 20 min at 300 ppm (an average of 200 ppm for 40 min) to an eventual decrease in perceptual speed after successive 20-min exposures at 100, 300, 500, and 700 ppm (with one 5-min break presumably at 0 ppm). The latter serial-exposure regimen is equivalent to an average concentration of 376 ppm over 85 min. The degree of effect observed in Gamberale and Hultengren (1972) is minimal and reversible and should not interfere with performance of critical tasks during an emergency onboard.

Empirical data and pharmacokinetic modeling in humans and rodents indicate that rapid increases in blood concentration during the first 15-20 min of exposure are followed by minimal increases with continuing exposure (Gamberale and Hultengren 1972; Tardif et al. 1993; 1995). Toluene reaches an asymptote in the blood within 20-30 min (Gamberale and Hultengren 1972; Carlsson 1982), and a steady state between blood and brain would be attained in a similar

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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period (Benignus et al. 1984). With exercise during exposure, the steady-state concentration could be attained more quickly. Thus, effects are not expected to become more severe in the period from attainment of steady state to the termination of exposure at 1 h.

The preponderance of data from clinical studies indicates that even a multiple-hour exposure to toluene at about 200 ppm would result in few substantial effects of concern for emergency exposure (for example, see Ogata et al. 1970; Suzuki 1973). The TWA of 376 ppm for the 85-min serial-exposure study of Gamberale and Hultengren (1972) indicates that a 1-h EEGL of 200 ppm would be protective. The weight of evidence from the extensive clinical dataset and the clinical studies of Astrand et al. (1972) and Gamberale and Hultengren (1972) have been used to derive the 1-h EEGL of 200 ppm. The use of human-subjects data obviates the application of an interspecies uncertainty factor. Furthermore, at such low and nonnarcotic concentrations, there is little justification for application of an intraspecies uncertainty factor.

24-Hour EEGL

The clinical human-exposure studies of Andersen et al. (1983), Baelum et al. (1985, 1990), Nielsen et al. (1985), Ogata et al. (1970), and Stewart et al. (1975) were evaluated to determine the 24-h EEGL (see Table 11-2). With the exception of Stewart et al. (1975) who used serial exposures at 100 ppm for a maximum of 7.5 h over multiple days, all the studies were of single exposures at 100 ppm for multiple hours (range, 3-7 h). That exposure duration is sufficient to allow blood concentrations of toluene to maximize and attain a steady state between blood and brain concentrations.

The Baelum et al. (1990) study included exercise at a load of 50-100 W and two exposure regimens: one with a constant 100-ppm exposure for 7 h and one with exposure at a 100-ppm TWA with 15-min peaks to 300 ppm every 30 min for 7 h. Effects noted were minor and included sensory irritation of nose and lower airways but not eyes, increase in dizziness and feeling of intoxication, and a slight decrement in one of four psychomotor performance tests. No differences were observed in symptoms or performance between groups exposed to toluene at constant and varying concentrations. The study design was an improvement over that of Baelum et al. (1985) and Nielsen et al. (1985), which tested groups of previously (occupationally) exposed rotogravure printers. After exposure of naive male students at 100 ppm, Ogata et al. (1970) observed no change from control in pulse rate, diastolic or systolic blood pressure, flicker value, or reaction time. After 6 h at 100 ppm, Andersen et al. (1983) reported slight irritation of the eyes and nose and some increase in occurrence of headache, dizziness, and “feelings of intoxication” but no effect on sleepiness, fatigue, lung function, nasal mucus flow, or performance on eight psychomotor tests. By the end of each exposure duration, subjects reported air-quality deterioration and odor in most of the studies.

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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The effects are minimal and reversible and should not interfere with performance of critical tasks during an emergency onboard. Furthermore, effects do not appear to increase in severity significantly with repeated equivalent doses of similar duration (Stewart et al. 1975).

A time-scaling adjustment is not applied in this case, for several reasons: a steady state in the blood is achieved, no greater effects were observed after repeated exposure, CNS and irritation effects of toluene are known to be concentration-dependent rather than time-dependent, and adaptation and acclimatization are associated with the irritation caused by toluene. The preponderance of clinical human data on minimal effects at 100 ppm after exposure for multiple hours and repeated exposure supports the selection of 100 ppm as the 24-h EEGL. The use of human-subjects data obviates the application of an interspecies uncertainty factor. Again, at such low and nonnarcotic concentrations, there is little justification for application of an intraspecies uncertainty factor.

90-Day CEGL

Estimation of a 90-day CEGL is on the basis of long-term occupational and epidemiologic evidence (see Table 11-3). The most completely characterized occupational assessments are of German rotogravure-factory workers, as documented in Gericke et al. (2001), Neubert et al. (2001a,b), and Seeber et al. (2005). About 1,500 volunteers in 12 factories were evaluated by Gericke et al. (2001) and Neubert et al. (2001a,b), and 192 workers in an unreported number of rotary-printing facilities were evaluated by Seeber et al. (2005). Although the investigators acknowledge the inability to determine toluene exposures over several decades, maximally exposed people are known to be printers and their helpers. Study participants in that occupational category had been employed for at least 240 months. The purity of toluene used was high (over 99.98%), and the authors state that benzene contamination has not been a problem since 1960 (Neubert et al. 2001a). Since 1993, the maximal allowable workplace concentration of toluene permitted by the Federal Republic of Germany has been 50 ppm (Gericke et al. 2001). The Neubert et al. (2001a,b) studies measured ambient air concentrations (the TWA for 6-h shift) of 50-100 ppm in the workplaces of the majority of printers. Nevertheless, neither those air concentrations nor blood toluene concentrations of 850-1,700 µg/L in the highest toluene-exposure group was “convincingly associated” with subjective complaints or alteration from the referent group on standard tests of psychophysiologic and psychomotor functions; all scores of the toluene-exposure group were within the referent ranges (Neubert et al. 2001a,b). The standard tests administered evaluate short-term and visual memory, vigilance, CNS-depressant effects, and dimensions of neuroticism. Some printers are exposed at concentrations greater than 100 ppm, but Neubert et al. (2001a,b) consider the dataset on that group to be too small “for reaching conclusions.”

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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If straight-line extrapolation is assumed for the psychophysiologic and psychomotor functions tested, a concentration of 50-100 ppm over a 6-h shift is about equivalent to continuous exposure at 12.5-25 ppm for 24 h during the multiple years described in the occupational studies of Neubert et al. (2001a,b). Workers exposed at 26 ± 19 ppm for multiple years exhibited no change from controls in several sensory and cognitive functions and psychomotor measures (Seeber et al. 2005).

Given that the rotogravure workers evaluated by Neubert et al. (2001a,b), Gericke et al. (2001), and Seeber et al. (2005) have been exposed to toluene at concentrations greater than 25 ppm for multiple years and exhibit no adverse effects in standard and well-conducted tests of cognition, vigilance, and CNS effects; the weight of evidence from other occupational studies; and the toxicokinetics of toluene, the committee recommends a 90-day CEGL of 20 ppm, the same value as recommended by NRC (1987). The committee notes that there is little justification for an intraspecies uncertainty factor because the CEGL is based on studies that evaluate large populations and thus incorporate variability and susceptibility that might be observed in the submariner population.

DATA ADEQUACY AND RESEARCH NEEDS

Because toluene is a common solvent, its effects on humans have been extensively studied. Numerous controlled human-exposure studies assess end points meeting the EEGL definition. Animal neurotoxicity studies are extensive, and supporting animal data were in reasonable agreement with values based on human studies. Toluene is fatal to humans only after exposure to extremely high concentrations (greater than 10,000 ppm), and deaths most often occur in cases of solvent abuse.

The anesthetic effects and metabolism of toluene are well documented and characterized. Although specific sensitive populations are not identified, the mechanism of action of CNS depression is the same in all mammalian species, and the concentration at which this effect occurs after toluene inhalation does not differ greatly among individual humans.

Although empirical data on toluene toxicity in humans and animals are abundant, few experimental dose-response data on human serial exposures are available. This is especially true for long-term human exposures encompassing multiple days or weeks. Several well-conducted chamber studies have involved human volunteers, but exposure concentrations were limited to concentrations that produce little if any impairment or anesthesia in humans and to exposure durations of less than 12 h. On the basis of existing human studies that describe effects over time and the fact that blood and brain concentrations reach a steady state rapidly, effects observed during the first hours of an exposure are relevant for exposures up to 24 h. Nevertheless, better characterization could be obtained from studies of a larger range of nonanesthetic concentrations for longer continuous exposure durations.

Suggested Citation:"11 Toluene." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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