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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 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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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 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 intoxication 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. In setting ACs for 1- and 24-h exposures, mild effects such as headaches, irritation, and not-quite-significant decrements in psychometric tests would be acceptable for short-term contingency exposures, but dizziness would not be acceptable, 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. 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 exposure 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. Some irritation is acceptable for short-term SMACs; therefore, the irritancy ACs for 1 and 24 h were set equal to the 100-ppm lowest-observed-adverse-effect level (LOAEL).
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 TABLE 17-1 Spacecraft Maximum Allowable Concentrations for Toluene (Garcia 1996) SMAC Duration ppm mg/m3 Target Toxicity 1 h 16 60 Neurotoxicity 24 h 16 60 Neurotoxicity 7 d 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 adjustments when the data permit. RECENT AND ADDITIONAL DATA ON TOLUENE TOXICITY Overview Numerous articles have been published since 1996 describing toluene toxicity 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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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 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 neurochemical 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 ethanol). 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 toluene 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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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 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 concentration 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 physiologically based pharmacokinetic model, for rats and humans, measuring behavioral effects as the response (Benignus et al. 1998). The mechanism of the toluene-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 additive effects if toluene exposure occurs after noise exposures or synergistic effects 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 acidosis 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 organic 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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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 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) studied rotogravure workers and reported a LOAEL of >100 ppm for >12-y exposures 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 toluene 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 exposed for 3 h to 50 ppm of toluene. No abnormalities were observed in the pulsatile secretion profiles of LH or follicle-stimulating hormone (FSH), but mean concentrations of LH in men were significantly decreased during exposure without any effect on testosterone concentrations. In women, the LH pulse frequency showed a trend toward decreasing concentrations during exposures.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 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 concentrations of prolactin were related to blood toluene concentrations. In 8 printers, 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, although some are subtle, can have profound adverse effects that develop gradually over several months. When circulating testosterone concentrations in mammalian 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) production. 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, results in loss of estrous cycling, premature menopause, weight gain and fluid retention, and neurobehavioral changes such as mood swings (including increased irritability), headaches, loss of concentration, and depression. In men, this profile (high FSH, low testosterone), over time, results in reduced 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, decision making). Because of the effects of long-term exposure to toluene on FSH and testosterone (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 methodology. 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 significant 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 intensity was slight to moderate.” Table 17-3 lists selected data published since 1996
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 TABLE 17-3 Toxicity Summary Concentration/Dose and Chemical Form, Route Exposure Duration Species and Strain Reported Adverse Effects Reference Acute and short–term exposures (<10 d) 50 ppm, inhalation (only dose tested) 3 h Humans, Male Significantly decreased pulsatile secretion of LH into blood during exposure. No change in testosterone concentration in blood. Luderer et al. 1999 50 ppm, inhalation (only dose tested) 3 h Humans, female Trend toward decreased pulsatile secretion of LH into blood during exposure. No other effects were significant. Luderer et al. 1999 50 ppm, inhalation (only dose tested) 3 h Men and women No abnormal episodic LH or FSH secretion profiles; however, subtle effects on LH secretion seen in men and in women in the luteal phase. Luderer et al. 1999 500-8,000 ppm, inhalation 30 min Mice Increased nociception using the hot plate test. Cruz et al. 2001 1,000-4,000 ppm, inhalation 30 min Mice Increased nociception and anxiety (conditioned defensive burying test) and impaired learning. Paez-Martinez et al. 2003 1,000-4,000 ppm, inhalation 30 min Mice Increased nociception and anxiety (conditioned defensive burying test) and impaired learning. Lopez-Rubalcava et al. 2000 Subchronic exposures (10-90 d) 50 mg/kg/d, subcutaneous injection 10 d Rats, male 8-oxo-7,8-dihydro-2'-deoxyguanosine formation in testes, the biological marker for oxidative DNA damage, was increased by toluene. Nakai et al. 2003 100 and 250 ppm, inhalation 6 h/d, 5d/wk 4 wk Rats Long-term behavioral changes linked to reduced functional tonus of the dopaminergic system. Wiaderna and Tomas 2002 300 ppm, inhalation 8 wk Mice Reduced bone mineral density in femoral neck. Atay et al. 2005
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 2,000 ppm, inhalation 8 or 12 h/d 10 d Chinchillas Nochange in auditory brainstem response. Davis et al. 2002 3,000 ppm 15 d Rats, male Significantly suppressed serum LH. Yilmaz et al. 2001 Chronic exposures (>90 d) <20 ppm, TWA, inhalation <13 y (rotogravure) Workers n = 30 NOAEL for neurologic and neuropsychological effects. Eller et al. 1999 35 ppm, average, inhalation Occupational Workers n = 41 NOAEL for impaired color vision Zavalic et al. 1998a,c 40 ppm, inhalation 104 h/wk, 16 wk Rats Significant and gender-dependent alteration in both catecholamine and 5-hydroxytryptamine biosynthesis rate in brainstem catecholaminergic cell groups and hypothalamus. Soulage et al. 2004 40 ppm, inhalation 104 h/wk, 16 wk Rats Alterations in dopamine and serotonin turnover in rat brain, decreased rearing activity, sensitization to toluene-induced narcosis. Berenguer et al. 2003 40 ppm, inhalation 104 h/wk, 16 wk Rats Decreased rearing activity, sensitization to toluene-induced narcosis. NOAEL for ototoxicity. Berenguer et al. 2004 40-60 ppm, measured by blood toluene concentration and urine metabolite concentrations 20.3 y, average Workers n = 49 Increased amplitude and longer latency in N75, P100, and N145 waves of pattern reversal visual evoked potentials. Vrca et al. 1995 40-60 ppm, measured by blood toluene concentration and urine metabolite concentrations 20.3 y, average Workers n = 49 Decreased amplitude, longer P1 latency and interpeak latencies (P3-P5)in auditory evoked potentials. Vrca et al. 1996
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 Concentration/Dose and Chemical Form, Route Exposure Duration Species and Strain Reported Adverse Effects Reference 40-60 ppm, measured by blood toluene concentration and urine metabolite concentrations 20.3 y, average Workers n = 49 Effects on auditory and visual evoked potentials were correlated with duration of exposure. Vrca et al. 1997 45 ± 17 ppm (mean ± SD), Inhalation Occupational ≥5 y Workers n = 333 No ototoxicity (by pure tone audiometry). Schaper et al. 2003 45 ppm, lifetime weighted average exposure Occupational 21 y Workers n = 192 No significant effects on attention, memory, or psychomotor functions by repeated measures analysis over four examinations in 5 y. Seeber et al. 2004 46 ppm, geometric mean, predominantly toluene Occupational Human n = 174 No color vision deficits. Nakatsuka et al. 1992 66-250 ppm Occupational Workers n = 32 Significantly impaired color vision. Zavalic et al. 1998a 75-600 ppm Occupational (rotogravure) 1-25 y Workers n = 39 Ototoxicity. Morata et al. 1993 0.037-243 ppm Occupational (rotogravure) 1-25 y Workers n = 124 Ototoxicity. Morata et al. 1997 88 ppm, TWA, blood toluene = 1.25 mg/L Occupational Workers n = 30 Altered manual dexterity (grooved peg board), visual scanning (trail making, visual reproduction, Benton visual retention, and digit symbol), and verbal memory (digit span) but no clinical signs or symptoms. Foo et al. 1990
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 >100 ppm, TWA >12 y (rotogravure) Workers n = 49 Impaired neuropsychological function (visuospatial function, number learning, and word recognition). Eller et al. 1999 120 ppm Occupational Workers n = 45 Significantly impaired color vision persists >64 h. Zavalic et al. 1998b 156 ppm, average, inhalation Occupational Workers n = 32 Significantly impaired color vision. Zavalic et al. 1998c 1,000 ppm 5 h/d, 5d/wk Mice Impaired behavior in T-maze test and decreased cell density and thickness of nasal epithelium. Jacquot et al. 2006 Inhalation dose estimated by measuring urinary toluene Occupational (rubber) Humans n = 33 Subclinical reduction in color vision. Cavalleri et al. 2000 36 ppm, median 8-111 ppm, range Occupational (rotogravure) Humans n = 20 Decreased LH, FSH, and testosterone in plasma. Svensson et al. 1992 Inhalation dose not stated Occupational (rotogravure) Humans n = 40 Altered auditory evoked potentials but no clinical effects. Abbate et al. 1993 Inhalation dose not stated Occupational (offset printing) Humans n = 26 Slightly increased cytogenetic damage in lymphocytes. Aksoy et al. 2006 Inhalation dose not stated. mean blood toluene = 1.25 µg/mL standard deviation = 0.37 µg/mL Occupational Humans n = 29 Impaired short-term memory, sustained attention and concentration, visual scanning, perceptual motor speed, and finger dexterity. Boey et al. 1997 Dose not stated for various paint solvents Occupational (painting) Workers n = 398 Increased risk of congenital malformations. Hooiveld et al. 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.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 and some earlier supporting data. Table 17-4 lists standards other organizations have published for toluene vapors. Table 17-5 lists updated SMACs as determined 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: auditory 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 REL TWA, 10 h 100 ppm (377 mg/m3) STEL, 15 min 150 ppm (566 mg/m3) OSHA, NIOSH 2005 PEL TWA, 8 h 200 ppm (754 mg/m3) PEL TWA, ceiling 300 ppm (1,130 mg/m3) PEL TWA, 10 min max peak 500 ppm (1,880 mg/m3) ACGIH, ACGIH 2008 TLV TWA, skin 20 ppm (75 mg/m3) 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 Duration ppm mg/m3 Target Toxicity 1 h 16 60 Neurotoxicity (dizziness) 24 h 16 60 Neurotoxicity (dizziness) 7 d 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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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 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 45ppm 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 factor of 10 to estimate a NOAEL. Because the LOAEL is from multiyear (occupational) exposures, the calculated AC will be applicable to 1,000-d exposures. Because no published studies were found that examined auditory and visual effects in humans after short-term exposures to toluene vapors (which might have provided data to support the calculation of higher ACs for short-term exposures), the AC calculated for 1,000-d exposures will be used for all exposure durations ≥7 d. 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 workers exposed for years, will be conservatively applied for exposure durations as short as 7 d. Although no data are available for neurologic and neuropsychological 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,
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 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 reproductive 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 estimated by reducing the LOAEL 10-fold: No factors are needed to adjust for species, exposure duration, or spaceflight 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 using 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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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5 TABLE 17-6 Acceptable Concentrations for Toluene Effect Exposure Data Species and Reference Uncertainty Factors Acceptable Concentration, ppm NOAEL Species Time Space Flight 1 h 24 h 7 d 30 d 180 d 1,000 d Auditory and visual evoked potentials 40-60 ppm, 20.3 y, occupational Human (Vrca et al. 1995, 1996, 1997) 10 1 1 1 — — 4 4 4 4 NOAEL: neurologic and neuropsychological effects <20 ppm, occupational Human, n = 30 (Eller et al. 1999) 1 1 1 1 20 20 — — — — NOAEL: neurologic and neuropsychological effects <20 ppm, occupational Human, n = 30 (Eller et al. 1999) 1 1 1 — — 10 10 10 10 Decreased LH, FSH, testosterone, prolactin 50 ppm, 3 h Human (Luderer et al. 1999) 10 1 1 1 — — — — 4 4 36 ppm, occupational Human n = 20 (Svensson et al. 1992) Neurotoxicity, irritation 40 ppm, 6 h NOAEL Human, n = 16 (Andersen et al. 1983) 1 1 1 16 16 16 16 16 — SMACs 16 16 4 4 4 4 Abbreviation: —, not calculated.
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