17
Toluene

Hector D. García, Ph.D.

Toxicology Group

Habitability and Environmental Factors Division

Johnson Space Center

National Aeronautics and Space Administration

Houston, Texas


Toluene is a clear, colorless, noncorrosive, flammable liquid with a sweet, pungent, “aromatic” odor. Values reported for the odor threshold range from 0.2 to 16 parts per million (ppm) (Sandmeyer 1981). One ppm of toluene = 3.77 milligrams per cubic meter (mg/m3).

Spacecraft maximum allowable concentrations (SMACs) for toluene were published in Volume 2 of this series, Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, for exposure durations of 1 h, 24 h, 7 d, 30 d, and 180 d (Garcia 1996). In anticipation of longer exploration missions, this document establishes a SMAC for toluene for an extended exposure of 1,000 d and revises the values for some shorter exposures based on data published since 1996.

OCCURRENCE AND USE

Toluene has been measured in urban air at 0.01 to 0.05 ppm, probably from production facilities, automobile and coke oven emissions, gasoline evaporation, and cigarette smoke; it can occur in human respiratory air in smokers and nonsmokers (Sandmeyer 1981). It is used extensively as a component of gasoline; as a solvent in the chemical, rubber, paint, and drug industries; as a thinner for inks, perfumes, and dyes; and as a nonclinical thermometer liquid and suspension solution for navigation instruments (Sandmeyer 1981). Intentional inhalation of toluene vapors from glue has been an abuse problem among youth during the last few decades because of toluene’s effects on the central nervous system. Measurements of toluene in spacecraft air have indicated trace (<0.05 mg/m3 or <0.013 ppm) concentrations for almost all missions, but, on rare occasions, individual measurements have found up to 64 ppm of toluene in one International Space Station module (after a malfunction of the Elektron oxygen generation system), whereas other modules registered only trace amounts.



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17 Toluene Hector D. García, Ph.D. Toxicology Group Habitability and Environmental Factors Division Johnson Space Center National Aeronautics and Space Administration Houston, Texas Toluene is a clear, colorless, noncorrosive, flammable liquid with a sweet, pungent, “aromatic” odor. Values reported for the odor threshold range from 0.2 to 16 parts per million (ppm) (Sandmeyer 1981). One ppm of toluene = 3.77 milligrams per cubic meter (mg/m3). Spacecraft maximum allowable concentrations (SMACs) for toluene were published in Volume 2 of this series, Spacecraft Maximum Allowable Concen- trations for Selected Airborne Contaminants, for exposure durations of 1 h, 24 h, 7 d, 30 d, and 180 d (Garcia 1996). In anticipation of longer exploration mis- sions, this document establishes a SMAC for toluene for an extended exposure of 1,000 d and revises the values for some shorter exposures based on data pub- lished since 1996. OCCURRENCE AND USE Toluene has been measured in urban air at 0.01 to 0.05 ppm, probably from production facilities, automobile and coke oven emissions, gasoline evapo- ration, and cigarette smoke; it can occur in human respiratory air in smokers and nonsmokers (Sandmeyer 1981). It is used extensively as a component of gaso- line; as a solvent in the chemical, rubber, paint, and drug industries; as a thinner for inks, perfumes, and dyes; and as a nonclinical thermometer liquid and sus- pension solution for navigation instruments (Sandmeyer 1981). Intentional inha- lation of toluene vapors from glue has been an abuse problem among youth dur- ing the last few decades because of toluene’s effects on the central nervous system. Measurements of toluene in spacecraft air have indicated trace (<0.05 mg/m3 or <0.013 ppm) concentrations for almost all missions, but, on rare occa- sions, individual measurements have found up to 64 ppm of toluene in one In- ternational Space Station module (after a malfunction of the Elektron oxygen generation system), whereas other modules registered only trace amounts. 329

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330 SMACs for Selected Airborne Contaminants SUMMARY OF ORIGINAL APPROACH The toluene SMACs for exposure durations of 1 h to 180 d (Table 17-1) were set in 1996 based on the lack of neurotoxicity (eight tests measuring 20 parameters) and the lack of irritation of the eyes and nose reported in 16 subjects exposed for 6 h to toluene vapors at 40 . During the same experiment, exposures of 100 ppm resulted in reports of headache, dizziness, and a feeling of intoxica- tion significantly more often than when exposed to clean air (Andersen et al. 1983). Acceptable concentrations (ACs) for neurotoxicity (headache, dizziness, and a feeling of inebriation) were calculated as follows: The ACs for 7, 30, and 180 d were based on the 40-ppm no-observed- adverse-effect level (NOAEL), using the factor (√n)/10 to adjust for the small number (n) of subjects. 16 7-, 30-, and 180-d AC (neurotoxicity) = 40 (NOAEL) × 10 (small n factor) = 16 ppm In setting ACs for 1- and 24-h exposures, mild effects such as headaches, irrita- tion, and not-quite-significant decrements in psychometric tests would be ac- ceptable for short-term contingency exposures, but dizziness would not be ac- ceptable, even for brief exposures during contingency operations. Thus, the ACs for 1 and 24 h were also based on the 40-ppm NOAEL, adjusting for the number of subjects. 16 1- and 24-h AC (neurotoxicity) = 40 (NOAEL) × 10 (small n factor) = 16 ppm A NOAEL of 40 ppm of toluene vapor was reported for irritation of the eyes and nose during a 6-h exposure was reported in the same study in 16 young male volunteers. Because irritation depends on concentration but not on expo- sure duration, the ACs for all exposure durations from 7 to 180 d were based on the 40-ppm NOAEL, adjusting for the small number of subjects by a factor equal to 1/10th the square root of the number of subjects tested. 16 7-, 30-, and 180-d AC (irritation) = 40 (NOAEL) × 10 (small n factor) = 16 ppm Some irritation is acceptable for short-term SMACs; therefore, the irri- tancy ACs for 1 and 24 h were set equal to the 100-ppm lowest-observed- adverse-effect level (LOAEL). 1- and 24-h AC (irritation) = 100 ppm (LOAEL)

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331 Toluene TABLE 17-1 Spacecraft Maximum Allowable Concentrations for Toluene (Garcia 1996) mg/m3 SMAC Duration ppm Target Toxicity 1h 16 60 Neurotoxicity 24 h 16 60 Neurotoxicity 7d 16 60 Neurotoxicity, irritation 30 d 16 60 Neurotoxicity, irritation 180 d 16 60 Neurotoxicity, irritation Source: Garcia 1996. Because the 1- and 24-h ACs for neurotoxicity are lower than the 1- and 24-h ACs for irritation, the ACs for neurotoxicity were used to set the 1- and 24-h SMACs. CHANGES IN FUNDAMENTAL APPROACHES RECOMMENDED BY THE NATIONAL RESEARCH COUNCIL The original SMACs for toluene, set in 1996, were calculated by using a NOAEL as the point of departure to which a “small n” factor was applied. More recently, instead of a NOAEL, the National Research Council has recommended using a benchmark dose analysis (preferred) for estimating an AC and ten Berge’s generalization (CN × T = K) of Haber’s rule for exposure duration ad- justments when the data permit. RECENT AND ADDITIONAL DATA ON TOLUENE TOXICITY Overview Numerous articles have been published since 1996 describing toluene tox- icity in humans and animals. Various end points have been studied including transient renal tubular acidosis (at high doses) (Tang et al. 2005), effects on color vision in workers (Zavalic et al. 1998a,b,c; Cavalleri et al. 2000; Gobba 2000; Gobba and Cavalleri 2003), ototoxicity in workers (Vrca et al. 1996, 1997; Morata et al. 1997; Schaper et al. 2003) and in chinchillas (Davis et al. 2002), effects of chronic exposures on monoamine biosynthesis in rat brains (Berenguer et al. 2003; Soulage et al. 2004), behavioral hypersensitivity in rats and humans (Benignus et al. 1998; Lees-Haley 2000; Lopez-Rubalcava et al 2000; Wiaderna and Thomas 2002; Berenguer et al. 2003; Paez-Martinez et al. 2003; Berenguer et al. 2004), reproductive effects in men and women (Luderer et al. 1999; Yilmaz et al. 2001; Nakai et al. 2003; Hooiveld et al. 2006), effects on anxiety and nociception in mice (Lopez-Rubalcava et al 2000; Cruz et al. 2001; Paez-Martinez et al. 2003), genotoxicity in workers (Nakai et al. 2003),

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332 SMACs for Selected Airborne Contaminants and bone mass toxicity in toluene abusers (Atay et al. 2005). Effects at doses at or below the current threshold limit value of 50 ppm (ACGIH 1999) include impaired color vision and effects on auditory and visual evoked potentials in workers, subtle changes in serum concentrations of luteinizing hormone (LH) in humans, behavioral changes in rats, and changes in the rate of synthesis of neu- rochemical transmitters in discrete areas of the rat brain. Ototoxicity In two studies, ototoxicity, based on pure-tone audiometry and immittance audiometry, was reported in cohorts of Brazilian rotogravure workers exposed for 1 to 25 y to a mixture of organic solvents (toluene, ethyl acetate, and etha- nol). The concentration of toluene vapor in this mixture ranged from 75 to 600 ppm in one study (Morata et al. 1993) and from 0.037 to 243 ppm in another study (Morata et al. 1997). Epidemiologic studies in Croatian printing press workers exposed for an average of 20.3 y to toluene vapors at concentrations estimated from 40 to 60 ppm (based on concentrations of toluene in blood and metabolites in urine) showed changes in auditory evoked potentials including decreased amplitudes, longer P1 latency and interpeak latencies (Vrca et al. 1996), which correlated with the duration of exposure (Vrca et al. 1997). An earlier study had shown altered auditory evoked potentials but no clinical effects in rotogravure workers exposed to toluene at unstated concentrations (Abbate et al. 1993). Pure tone audiometry measurements of ototoxicity, however, failed to show ototoxicity in workers exposed for >5 y to toluene vapors at concentrations of 45 ± 17 ppm (Schaper et al. 2003). Pryor et al. (1984) conducted seven experiments with young male Fischer rats to examine concentration and exposure parameters necessary and sufficient to cause toluene-induced ototoxicity. They found a complicated pattern for the dependence of ototoxicity on exposure concentration and duration (Pryor et al. 1984). Hearing loss, measured by behavioral and electrophysiologic methods, was repeatedly observed after as few as 2 wk of exposure to 1,000 ppm of tolu- ene for 14 h/d, but lower concentrations (400 and 700 ppm) had no effect even after 16 wk of exposure. Three-day exposures to 1,500 ppm of toluene for 14 h/d or to 2,000 ppm for 8 h/d were ototoxic, whereas single exposures to 4,000 ppm for 4 h or to 2,000 ppm for 8 h were without effect. Intermittent exposure to 3,000 ppm for 30 min every hour for 8 h/d caused hearing loss within 2 wk, but a similar exposure schedule for 4 h/d had no effect even after 9 wk. The results from the Pryor et al. study are summarized and the calculated total doses, in ppm-h, to which the rats were exposed are shown in Table 17-2. Based on Table 17-2 and the discussion of results from Pryor et al. (1984), the lack of an apparent dose-response relationship may be explained by results obtained in studies by the U.S. Environmental Protection Agency that showed

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333 Toluene TABLE 17-2 Summary of Dose-Response Data for Ototoxicity Exposure, Duration ppm-H Ototoxic 3,000 ppm, 30 min/h × 8 h/d × 2 wk 168,000 2,000 ppm, 8 h/d × 3 d 48,000 1,500 ppm, 14 h/d × 3 d 63,000 1,000 ppm, 14 h/d × 2 wk 196,000 Nonototoxic 3,000 ppm, 4 h/d × 9 wk 756,000 2,000 ppm × 8 h, once 16,000 4,000 ppm × 4 h, once 16,000 700 ppm, 14 h/d × 16 wk 1,097,600 Source: Pryor et al. 1984. Reprinted with permission; copyright 1984, Neurobehavioral Toxicology and Teratology. that, although a poor dose-response was observed when the exposure concentra- tion of toluene in air was used as the dose metric, good correlation was obtained using the concentration of toluene in arterial blood, as calculated with a physio- logically based pharmacokinetic model, for rats and humans, measuring behav- ioral effects as the response (Benignus et al. 1998). The mechanism of the tolu- ene-induced hearing loss involves permanent loss of outer hair cells in the cochlea, beginning with those involved in hearing high frequencies (Pryor and Rebert 1984; Sullivan et al. 1989). Exposure to noise at levels > 85 decibels can also induce hearing loss, and exposure to both toluene and noise can induce ad- ditive effects if toluene exposure occurs after noise exposures or synergistic ef- fects if toluene exposure precedes noise exposures (Johnson 1993; Morata et al. 1993, 1997; Sliwinska-Kowalska et al. 2004). Renal Tubular Acidosis Although there have been several clinical case reports of renal tubular aci- dosis after exposures to abuse concentrations of toluene (Patel and Benjamin 1986; Batlle et al 1988; Tang et al. 2005), a controlled clinical trial involving 86 subjects exposed to 100 ppm of toluene for 6.5 h found no renal toxicity and concluded that no causal relationship exists between moderate exposure to or- ganic solvents and renal injury (Nielsen et al. 1985). Visual Effects Toluene exposure has been shown to decrease the ability of subjects to discriminate among shades of colors (Nakatsuka et al. 1992; Vrca et al. 1995,

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334 SMACs for Selected Airborne Contaminants 1997; Zavalic et al. 1998a,b,c; Cavalleri et al. 2000; Gobba 2000; Gobba and Cavalleri 2003). Workers occupationally exposed to toluene at concentrations of 11.3 to 49.3 ppm (median 35 ppm) showed no effect on color discrimination, whereas workers exposed to concentrations of 66.0 to 250 ppm (median 156 ppm) had significantly higher color confusion index scores and alcohol intake- adjusted color confusion index scores—that is, decreased ability to discriminate shades of color (Zavalic et al. 1998a). Neurochemical and Behavioral Effects Numerous studies have confirmed the toxicity of toluene to the nervous system as measured by either changes in behavior (rearing frequency, avoidance of noxious stimuli in rodents; choice reaction time, mood in humans) or changes in neurochemistry (Weiss et al. 1979; Kostas and Hotchin 1981; Dyer et al. 1984; Juntunen et al. 1985; Taylor and Evans 1985; Alho et al. 1986; Kishi et al. 1988; Mattsson et al. 1989; Foo et al. 1990; Abbate et al. 1993; Murata et al. 1993; Boey et al. 1997; Benignus et al. 1998; Eller et al. 1999; Lopez-Rubalcava et al. 2000; Cruz et al. 2001; Berenguer et al. 2003, 2004; Paez-Martinez et al. 2003; Soulage et al. 2004; Wiaderna and Tomas 2002). Eller et al. (1999) stud- ied rotogravure workers and reported a LOAEL of >100 ppm for >12-y expo- sures and a NOAEL of <20 ppm for <13-y exposures for deficits in cognitive functions (learning, memory, attention, concentration, eye-hand coordination) and neurologic effects (tremor and sway). Vrca et al. (1995, 1996, 1997) found changes in both auditory and visual evoked potentials in workers occupationally exposed to ≥40 ppm of toluene for an average of 21.4 y. Similarly, rats exposed to 40 ppm toluene for 16 wk showed significant changes in the biosynthesis rates of catecholamine and 5-hydroxytryptamine in specific regions of the brain (Soulage et al. 2004). The dose-response relationship for toluene exposures is inconsistent and difficult to interpret when dosimetry is measured by exposure concentration and duration, but it correlates well with the concentration of tolu- ene in arterial blood estimated by the physiologically based pharmacokinetic method in both rats and humans (Benignus et al. 1998). Effects on Reproductive Hormones Luderer et al. (1999) reported subtle effects on the secretion of LH in both male and female (during the luteal phase of the menstrual cycle) volunteers ex- posed for 3 h to 50 ppm of toluene. No abnormalities were observed in the pul- satile secretion profiles of LH or follicle-stimulating hormone (FSH), but mean concentrations of LH in men were significantly decreased during exposure with- out any effect on testosterone concentrations. In women, the LH pulse frequency showed a trend toward decreasing concentrations during exposures.

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335 Toluene Svensson et al. (Svensson et al. 1992) reported decreased concentrations of FSH (3.2 versus 4.9 international units per liter [IU/L]) and LH (6.4 versus 7.2 IU/L) in plasma and decreased (7.8 versus 86.8 pmol/L) free testosterone in the serum of 20 rotogravure printers exposed to 8 to 111 ppm (median = 36 ppm) of toluene compared with 44 unexposed referents. Reduced plasma con- centrations of prolactin were related to blood toluene concentrations. In 8 print- ers, concentrations of LH and FSH increased during a 4-wk vacation, indicating that the effect was reversible. Such effects on the plasma concentrations of reproductive hormones, al- though some are subtle, can have profound adverse effects that develop gradu- ally over several months. When circulating testosterone concentrations in mam- malian males and 17β-estradiol concentrations in mammalian females fall, the hypothalamic-pituitary-gonadal axis feedback loop responds by releasing FSH from the pituitary into the circulation, which acts on the hormone-producing cells of the testis (or ovary) to stimulate testosterone (or 17β-estradiol) produc- tion. When the gonads do not respond by producing steroid sex hormone, the pituitary continues to release FSH in response to continuing low concentrations of testosterone (or 17β-estradiol). In women, this profile (high FSH, low 17β- estradiol) is considered indicative of incipient menopause, and, over time, re- sults in loss of estrous cycling, premature menopause, weight gain and fluid retention, and neurobehavioral changes such as mood swings (including in- creased irritability), headaches, loss of concentration, and depression. In men, this profile (high FSH, low testosterone), over time, results in re- duced upper body strength, reduced size and weight of the testes, reduced male- pattern hair loss, reduced sexual arousal and function, reduced aggressive and assertive behavior, and reduced executive functions (command and control, de- cision making). Because of the effects of long-term exposure to toluene on FSH and tes- tosterone (and presumably 17β-estradiol) serum concentrations in mammalian animal models and the potential (but highly likely) long-term consequences of such changes in the crew, the data for these end points are used to set 180- and 1,000-d ACs. NEW RISK ASSESSMENT APPROACHES Neither the data available when the original SMACs were set in 1996 nor the data available since then are amenable to analysis by benchmark dose meth- odology. The published data on which the original SMACs were based did not include the raw data for individual subjects and included only one dose (100 ppm) at which significant effects were reported. For the only statistically signifi- cant effects reported (headache, dizziness, and feeling of intoxication at 100 ppm but not at 40 or 10 ppm), the only description in the published report was: “This phenomenon was experienced by about half of the subjects, and the inten- sity was slight to moderate.” Table 17-3 lists selected data published since 1996

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TABLE 17-3 Toxicity Summary 336 Concentration/Dose and Exposure Species and Chemical Form, Route Duration Strain Reported Adverse Effects Reference Acute and short–term exposures (<10 d) 50 ppm, inhalation 3h Humans, Male Luderer et al. Significantly decreased pulsatile secretion of LH into (only dose tested) 1999 blood during exposure. No change in testosterone concentration in blood. 50 ppm, inhalation 3h Humans, Luderer et al. Trend toward decreased pulsatile secretion of LH into (only dose tested) female 1999 blood during exposure. No other effects were significant. 50 ppm, inhalation 3h Men and Luderer et al. No abnormal episodic LH or FSH secretion profiles; (only dose tested) women 1999 however, subtle effects on LH secretion seen in men and in women in the luteal phase. 500-8,000 ppm, inhalation 30 min Mice Cruz et al. 2001 Increased nociception using the hot plate test. 1,000-4,000 ppm, inhalation 30 min Mice Paez-Martinez et Increased nociception and anxiety (conditioned defensive al. 2003 burying test) and impaired learning. 1,000-4,000 ppm, inhalation 30 min Mice Lopez-Rubalcava Increased nociception and anxiety (conditioned defensive et al. 2000 burying test) and impaired learning. Subchronic exposures (10-90 d) 50 mg/kg/d, subcutaneous 10 d Rats, male Nakai et al. 2003 8-oxo-7,8-dihydro-2'-deoxyguanosine formation in injection testes, the biological marker for oxidative DNA damage, was increased by toluene. 100 and 250 ppm, inhalation 6 h/d, 5 d/wk 4 Rats Wiaderna and Long-term behavioral changes linked to reduced wk Tomas 2002 functional tonus of the dopaminergic system. 300 ppm, inhalation 8 wk Mice Atay et al. 2005 Reduced bone mineral density in femoral neck.

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2,000 ppm, inhalation 8 or 12 h/d 10 Chinchillas Davis et al. 2002 No change in auditory brainstem response. d 3,000 ppm 15 d Rats, male Yilmaz et al. Significantly suppressed serum LH. 2001 Chronic exposures (>90 d) <20 ppm, TWA, inhalation <13 y Workers Eller et al. 1999 NOAEL for neurologic and neuropsychological effects. (rotogravure) n = 30 35 ppm, average, inhalation Occupational Workers Zavalic et al. NOAEL for impaired color vision n = 41 1998a,c 40 ppm, inhalation 104 h/wk, Rats Soulage et al. Significant and gender-dependent alteration in both 16 wk 2004 catecholamine and 5-hydroxytryptamine biosynthesis rate in brainstem catecholaminergic cell groups and hypothalamus. 40 ppm, inhalation 104 h/wk, Rats Berenguer et al. Alterations in dopamine and serotonin turnover in rat 16 wk 2003 brain, decreased rearing activity, sensitization to toluene- induced narcosis. 40 ppm, inhalation 104 h/wk, Rats Berenguer et al. Decreased rearing activity, sensitization to toluene- 16 wk 2004 induced narcosis. NOAEL for ototoxicity. 40-60 ppm, measured by blood 20.3 y, average Workers Vrca et al. 1995 Increased amplitude and longer latency in N75, P100, toluene concentration and urine n = 49 and N145 waves of pattern reversal visual evoked metabolite concentrations potentials. 40-60 ppm, measured by blood 20.3 y, average Workers Vrca et al. 1996 Decreased amplitude, longer P1 latency and interpeak toluene concentration and urine n = 49 latencies (P3-P5) in auditory evoked potentials. metabolite concentrations (Continued) 337

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TABLE 17-3 Continued 338 Concentration/Dose and Exposure Species and Chemical Form, Route Duration Strain Reported Adverse Effects Reference 40-60 ppm, measured by blood 20.3 y, average Workers Vrca et al. 1997 Effects on auditory and visual evoked potentials were toluene concentration and urine n = 49 correlated with duration of exposure. metabolite concentrations 45 ± 17 ppm (mean ± SD), Occupational Workers Schaper et al. No ototoxicity (by pure tone audiometry). Inhalation ≥5 y n = 333 2003 45 ppm, lifetime weighted Occupational Workers Seeber et al. 2004 No significant effects on attention, memory, or average exposure 21 y n = 192 psychomotor functions by repeated measures analysis over four examinations in 5 y. 46 ppm, geometric mean, Occupational Human Nakatsuka et al. No color vision deficits. predominantly toluene n = 174 1992 66-250 ppm Occupational Workers Zavalic et al. Significantly impaired color vision. n = 32 1998a 75-600 ppm Occupational Workers Morata et al. Ototoxicity. (rotogravure) n = 39 1993 1-25 y 0.037-243 ppm Occupational Workers Morata et al. Ototoxicity. (rotogravure) n = 124 1997 1-25 y 88 ppm, TWA, blood toluene = Occupational Workers Foo et al. 1990 Altered manual dexterity (grooved peg board), visual 1.25 mg/L n = 30 scanning (trail making, visual reproduction, Benton visual retention, and digit symbol), and verbal memory (digit span) but no clinical signs or symptoms.

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>100 ppm, TWA >12 y Workers Eller et al. 1999 Impaired neuropsychological function (visuospatial (rotogravure) n = 49 function, number learning, and word recognition). 120 ppm Occupational Workers Zavalic et al. Significantly impaired color vision persists >64 h. n = 45 1998b 156 ppm, average, inhalation Occupational Workers Zavalic et al. Significantly impaired color vision. n = 32 1998c 1,000 ppm 5 h/d, 5 d/wk Mice Jacquot et al. Impaired behavior in T-maze test and decreased cell 2006 density and thickness of nasal epithelium. Inhalation dose estimated by Occupational Humans Cavalleri et al. Subclinical reduction in color vision. measuring urinary toluene (rubber) n = 33 2000 36 ppm, median 8-111 ppm, Occupational Humans Svensson et al. Decreased LH, FSH, and testosterone in plasma. range (rotogravure) n = 20 1992 Inhalation dose not stated Occupational Humans Abbate et al. Altered auditory evoked potentials but no clinical effects. (rotogravure) n = 40 1993 Inhalation dose not stated Occupational Humans Aksoy et al. 2006 Slightly increased cytogenetic damage in lymphocytes. (offset n = 26 printing) Inhalation dose not stated. Occupational Humans Boey et al. 1997 Impaired short-term memory, sustained attention and mean blood toluene = 1.25 n = 29 concentration, visual scanning, perceptual motor speed, µg/mL and finger dexterity. standard deviation = 0.37 µg/mL Dose not stated for various paint Occupational Workers Hooiveld et al. Increased risk of congenital malformations. solvents (painting) n = 398 2006 Abbreviations: mg/kg/d, milligrams per kilogram of body weight per day; TWA, time-weighted average; SD, standard deviation; µg/mL, micrograms per milliliter. 339

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340 SMACs for Selected Airborne Contaminants and some earlier supporting data. Table 17-4 lists standards other organizations have published for toluene vapors. Table 17-5 lists updated SMACs as deter- mined in this document. Table 17-6 lists the ACs calculated in the Rationale section for each end point and exposure duration. RATIONALE ACs were determined following the guidelines of the National Research Council (NRC 1992). ACs are calculated for the following effects of toluene, which have been reported for exposure concentrations below the current regulatory levels: audi- tory and visual toxicity, neurotoxicity, and decreased blood concentrations of reproductive hormones. TABLE 17-4 Air Standards for Toluene Vapors Set by Other Organizations Organization, Standard Amount Reference NIOSH, NIOSH 2005 IDLH 500 ppm 100 ppm (377 mg/m3) REL TWA, 10 h 150 ppm (566 mg/m3) STEL, 15 min OSHA, NIOSH 2005 200 ppm (754 mg/m3) PEL TWA, 8 h 300 ppm (1,130 mg/m3) PEL TWA, ceiling 500 ppm (1,880 mg/m3) PEL TWA, 10 min max peak ACGIH, ACGIH 2008 20 ppm (75 mg/m3) TLV TWA, skin TLV STEL None set Abbreviations: NIOSH, National Institute for Occupational Safety and Health; IDLH, immediately dangerous to life and health; REL, recommended exposure limits; TWA, time-weighted average; STEL, short-term exposure limit; OSHA, Occupational Safety and Health Administration; PEL, permissible exposure limit; ACGIH, American Conference of Governmental Industrial Hygienists; TLV, threshold limit value; STEL, short-term exposure limit. TABLE 17-5 2008 Spacecraft Maximum Allowable Concentration for Toluene Vapors mg/m3 Duration ppm Target Toxicity 1h 16 60 Neurotoxicity (dizziness) 24 h 16 60 Neurotoxicity (dizziness) 7d 4 15 Auditory and visual toxicity 30 d 4 15 Auditory and visual toxicity 180 d 4 15 Auditory, visual, and hormonal effects 1,000 d 4 15 Auditory, visual, and hormonal effects

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341 Toluene Auditory and Visual Effects Vrca et al. (1995, 1996, 1997) found changes in both auditory and visual evoked potentials in workers occupationally exposed to toluene concentrations of 40 to 60 ppm for an average of 20.3 y. Schaper et al. (2003) reported a 45- ppm NOAEL for ototoxicity in workers exposed for 5 y. Zavalic et al. (1998a,c) found NOAELs for impaired color vision at an average toluene concentration of 35 ppm in workers. Assuming that 40 ppm is a LOAEL for auditory and visual effects, an AC can be calculated by dividing the LOAEL by a default safety fac- tor of 10 to estimate a NOAEL. Because the LOAEL is from multiyear (occupa- tional) exposures, the calculated AC will be applicable to 1,000-d exposures. Because no published studies were found that examined auditory and visual ef- fects in humans after short-term exposures to toluene vapors (which might have provided data to support the calculation of higher ACs for short-term expo- sures), the AC calculated for 1,000-d exposures will be used for all exposure durations ≥7 d. 7-, 30-, 180-, 1,000-d AC (auditory, visual effects) = 40 ppm (LOAEL) ÷ 10 (LOAEL to NOAEL) = 4 ppm No factors are needed to adjust for species or spaceflight effects. Neurotoxicity Seeber et al. (2004) report a NOAEL in workers for effects on attention, memory, and psychomotor functions at an average exposure concentration of 45 ppm for 21 y. The weight of evidence from the studies listed in Table 17-3 supports treating a concentration of 20 ppm (Eller et al. 1999) as a human NOAEL for neurotoxicity. Because this study included only 30 workers exposed at <20 ppm, the NOAEL is multiplied by a factor of (√30)/10 to adjust for the small sample size in calculating an AC. The resulting AC, based on effects measured in work- ers exposed for years, will be conservatively applied for exposure durations as short as 7 d. Although no data are available for neurologic and neuropsychologi- cal effects during or after short-term exposures (1 to 24 h), the severity of the effects reported for long-term exposures is mild enough to be acceptable in a short-term emergency situation. Thus, 1- and 24-h AC (neurotoxicity) = 20 ppm 7-, 30-, 180-, and 1,000-d AC (neurotoxicity) = 20 ppm (NOAEL) × √30/10 (small n factor) = 10 ppm

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342 SMACs for Selected Airborne Contaminants Reproductive Hormone Effects Decreased circulating concentrations of LH and FSH were reported both for short (3 h) exposures to 50 ppm of toluene and for chronic (occupational) exposures to a median of 36 ppm of toluene and decreased testosterone and prolactin were reported for the occupational exposures. Because the reproduc- tive effects of altered serum hormone concentrations develop gradually over several months and are reversible upon cessation of exposure to toluene, ACs for reproductive effects will be calculated only for exposure durations of 180 and 1,000 d. Normal monthly cycling of serum hormones in women is known to affect mood and behavior, but NASA does not consider it necessary to protect the crew against such normal behavioral effects. Thus, with 36 ppm used as a LOAEL, a NOAEL for long-term reproductive hormone effects can be esti- mated by reducing the LOAEL 10-fold: 180- and 1,000-d AC (reproductive hormone effects) = 36 ppm (LOAEL) ÷ 10 (LOAEL to NOAEL) = 3.6 ppm, rounded to 4 ppm No factors are needed to adjust for species, exposure duration, or space- flight effects. Neurochemical Effects Rats exposed to 40 ppm of toluene for 16 wk showed significant changes (both increases and decreases) in the biosynthesis rates of catecholamine and 5- hydroxytryptamine in specific regions of the brain (Soulage et al. 2004). These changes could not be correlated with any signs, symptoms, or clinical effects. Thus, although these changes may have some functional effects, the clinical magnitude, relevance, and adverse nature of such putative functional effects cannot be determined from the available data. Therefore, no AC will be set us- ing the results of the study of Soulage et al. Spaceflight Effects None of the reported adverse effects of toluene exposures is known to be affected by spaceflight.

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TABLE 17-6 Acceptable Concentrations for Toluene Uncertainty Factors Acceptable Concentration, ppm Species and Space Effect Exposure Data Reference NOAEL Species Time Flight 1h 24 h 7d 30 d 180 d 1,000 d Auditory and 40-60 ppm, 20.3 Human (Vrca et al. 10 1 1 1 — — 4 4 4 4 visual evoked y, occupational 1995, 1996, 1997) potentials 1 1 1 1 20 20 — — — — NOAEL: <20 ppm, Human, n = 30 neurologic and occupational (Eller et al. 1999) neuropsychological effects NOAEL: <20 ppm, Human, n = 30 1 1 1 — — 10 10 10 10 30 neurologic and occupational (Eller et al. 1999) 10 neuropsychological effects Human (Luderer et 10 1 1 1 — — — — 4 4 Decreased LH, 50 ppm, 3 h al. 1999) FSH, testosterone, Human n = 20 prolactin 36 ppm, occupational (Svensson et al. 1992) Neurotoxicity, 40 ppm, 6 h Human, n = 16 1 1 1 16 16 16 16 16 — 16 irritation NOAEL (Andersen et al. 10 1983) SMACs 16 16 4 4 4 4 Abbreviation: —, not calculated. 343

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