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



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11 Toluene This chapter summarizes relevant epidemiologic and toxicologic studies of toluene. Selected chemical and physical properties, toxicokinetic and mechanis- tic 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 chap- ter 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 com- ponent for automotive fuels, as a chemical intermediate, and as a solvent primar- ily 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 230

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231 Toluene 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 110.6EC Melting point −95°C Flash point 4.4°C (closed cup) Explosive limits NA Specific gravity 0.866 at 20°C/4EC 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 1 ppm = 3.77 mg/m3; 1 mg/m3 = 0.27 ppm Conversion factors 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 in- door air concentrations include emissions from household products and cigarette smoke. The toluene emission factor for cigarettes was reported as 80 µg/ciga- rette (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 simi- lar sampling exercise (two submarines, three locations, and sampling duration of 6 h) was reported by Holdren et al. (1995). Toluene concentrations in one sub- marine 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.

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232 Exposure Guidance Levels for Selected Submarine Contaminants 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 in- tentional inhalation include renal toxicity, cardiac arrhythmias, blood dyscrasias, hepatomegaly, and developmental toxicity (ACGIH 1998, 2001, 2007). Suffi- ciently high concentrations of toluene vapor can produce euphoria; with increas- ing concentration, stupor, unconsciousness, or coma can occur with little ac- companying 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 mod- ern submarine. For a review of the effects of exposure to toluene under condi- tions 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 deriva- tion 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 con- tent. 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 tolu- ene 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 docu- mented 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 concentra- tions reach a steady state rapidly. As a consequence, effects observed during the

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233 Toluene 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 con- trolled 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 stud- ies specifically designed to evaluate toluene carcinogenicity have found no asso- ciation between cumulative toluene dose (as ppm-years) and standardized mor- tality 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 re- sulted in intoxication, manifested as narcotic effects (muscular weakness, inco- ordination, and mental confusion). Early reports suggesting bone marrow toxic- ity 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 re- ported 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. Physi- cal 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

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234 Exposure Guidance Levels for Selected Submarine Contaminants 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 au- thors attributed to a high plasma concentration of toluene metabolites (benzoic or hippuric acid) or distal tubular acidosis. Both patients recovered without per- manent sequelae. Longley et al. (1967) reported two cases of accidental occupational expo- sure to toluene at high concentrations. In one case, workers spraying an antirust paint in an enclosed space (ballast tank) aboard a commercial ship were over- come 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 be- havior. All affected workers recovered fully within 30 min after breathing oxy- gen. No estimate of toluene exposure concentrations was reported. In the second case, the hold of a merchant ship was mistakenly sprayed with an undiluted in- secticide mixture containing malathion (20%), piperonyl butoxide (8%), pyre- thrum (1.5%), and toluene (to 100%) (Longley et al. 1967). Effects exhibited by workers and rescuers could not be attributed to toluene exposure alone. Every- one involved recovered without persistent effects after leaving the vessel. Experimental Studies Numerous studies have been conducted with healthy human subjects ex- posed 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 spec- trum 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 concen- tration 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.

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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 6h 16 men, 21-32 years old Andersen et al. Slight irritation of eyes and nose at 100 ppm; no effect on mood, fatigue, or 1983 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 40 4 h (each of 2 12 men, 20-50 years old Lammers et al. sessions separated No effects on measures of motor performance, attention, perceptual coding and 2004, 2005a by 1 week) memory, or mood and affect; positive correlation between results of finger-tapping 3, 30-min peaks Over 4 h test with alternate hands and blood toluene concentrations at end of 4 h to 110 (1 session) 3h 10 men, 20 women, 19-45 years old Luderer et al. 50a No subjective symptoms; no abnormal episodic LH secretion profile in females or 1999 males; “subtle effects” on LH secretion in males and females in luteal phase (clinical significance unclear) 50 4.5 h 20 nonsmoking men, 30.5 ± 5.2 years old Muttray et al. Sleepiness measured after exposure with Pupillographic Sleeping Test and 2005 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 8 men, 22-50 years old Cherry et al. 1983 80 4h No impairment in neurobehavioral tasks (Continued) 235

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TABLE 11-2 Continued 236 Concentration (ppm) Exposure Duration Subjects and Effects Reference 80 4h 16 men, 23-38 years old Olson et al. 1985 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 80 4.5 h 12 men, 22-44 years old Iregren et al. 1986 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) 100 3.5 h 18 Winneke 1982 No behavioral deficits in psychomotor tests 100 4h 30 men and women Dick et al. 1984 No serious impairment in series of neurobehavioral tests (choice response time and pattern recognition); significant impairment in one measure of visual-vigilance test 100 6h 6 men and women, 27-38 years old Rahill et al. 1996 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) 100 6.5 h 43 male printers and 43 male nonprinter referents, 29-50 years old; 4 groups Baelum et al. 1985 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

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100 1, 3, 7.5 h, over 10 men and 9 women Stewart et al. 1975 several days 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 100 7h 32 men and 39 women, 31-50 years old Baelum et al. 1990 100 (TWA; varied with (3 15-min exercise Sensory irritation of nose and lower airways, but not eyes, in toluene-exposed 15-min peaks to 300 periods with load of groups; slight decrease on 1 of 4 psychomotor performance tests; no differences in ppm every 30 min) 50-100 W; both symptoms or performances between groups exposed to constant and varied toluene exposures) concentrations 75 7 h over 3 days 42 male and female students, 18-35 years old Echeverria et al. 150 7 h over 3 days Mean 7% decrement on several neurobehavioral tests at 150 ppm; slight increases 1989, 1991 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 30, 60 min 11 men, 18-29 years old; 4 women, 27-46 years old Astrand et al. 100a, 200a No difference in heart rate, pulmonary ventilation, oxygen consumption, or blood 1972 lactate either at rest or during a work load of 50 W (Continued) 237

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TABLE 11-2 Continued 238 Concentration (ppm) Exposure Duration Subjects and Effects Reference 100, 200 3, 7 h with 1-h break 23 naive men, average 23 years old Ogata et al. 1970 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 100a Successive 20-min 12 men, 20-35 years old Gamberale and 300a exposure periods At 100 ppm, no effect on reaction time or perceptual speed; at 300 ppm, increase in Hultengren 1972 500a (one 5-min break); simple reaction time; at 500 ppm, increase in complex reaction time; at 700 ppm, 700a total 85 min 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 200, 400, 600, 800 7-8 h 2 subjects Carpenter et al. Transitory mild throat and eye irritation and slight exhilaration at 200 ppm; metallic 1944 taste, transitory headache, lassitude, inebriation, and slight nausea at 800 ppm; threshold for “steadiness” task, 800 ppm 220b 15 min 6 subjects Carpenter et al. 427b At 220 ppm, all subjects willing to work for 8 h, negligible sensory symptoms; at 1976 427 ppm, 3 of 6 subjects willing to work for 8 h; 2 subjects reported slight “lightheadedness”; 1 reported “stuffy, drowsy feeling” 200 6h 5 men, resting Suzuki 1973 Increase in pulse rate; no changes in respiration rate, galvanic skin reflex, or EEG. 240 Three 30-min 11 men, 20-21 years old Horvath et al. sessions Impaired vigilance in third session; decreased fatigue during second session 1981 a Subjects exposed via mouthpiece. b Measured 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.

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239 Toluene Although slight irritation involving the eyes and nose in humans was re- ported 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 asso- ciated with a 50% depression in respiratory rate) of 5,300 ppm in male Swiss- Webster mice (Nielsen and Alarie 1982). Complaints increased among the con- trols, 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 re- ported 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 (Gam- berale 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 kid- ney 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 dis- comfort 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 expo- sures 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 moni- tored (Muttray et al. 2005). Compared with the results of air-only exposure, pa- rametric 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 dura- tions during the workday (Deschamps et al. 2001). The 20-min NOAEL expo- sure 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 Carpen- ter et al. (1944), but the studies suffered from inferior analytic techniques and

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240 Exposure Guidance Levels for Selected Submarine Contaminants potential benzene contamination of the test article. The clinical study of Gam- berale 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 es- cape (von Oettingen et al. 1942a,b; Carpenter et al. 1944). Occupational and Epidemiologic Studies Occupational studies have focused primarily on CNS impairment. Al- though exposure concentrations and durations are usually not well characterized, the studies provide information about the more common toxic effects. Interpre- tation 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; work- ers exposed at 200-500 ppm complained of more pronounced headache, lassi- tude, 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 com- plaints 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 pres- ence 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 sol- vents 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,

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