19
Xylenes

Raghupathy Ramanathan, Ph.D.

Toxicology Group

Habitability and Environmental Factors Division

Johnson Space Center

National Aeronautics and Space Administration

Houston, Texas

BACKGROUND

Xylene, also known as dimethylbenzene (formula: C6H4 (CH3)2) exists as three isomers—ortho-(1,2-dimethylbenzene), meta-(1,3-dimethylbenzene), and para-(1,4-dimethylbenzene)—whose structures are shown below. Commercial xylenes (also called mixed xylenes) are a mixture of the three forms with meta- (abbreviated “m-”) being the major component and ortho- (abbreviated “o-”) and para- (abbreviated “p-”) present in minor amounts; usually, the proportions are 40% m-isomer and 20% each of the p- and o-isomers. Technical-grade xylenes also contain ethylbenzene. In general, they have similar physical, chemical, and toxicologic properties. Although the odor threshold is listed as 1 part per million (ppm) in air, it seems to vary among the isomers, being 3.7, 0.17, and 0.47 ppm for m-, o-, and p-xylene, respectively (ATSDR 2007). The vapor pressures for the three are comparable (8.29, 6.61, and 8.84 mm Hg for m-, o-, and p-xylenes, respectively (ATSDR 2007).

Conversion factors at 25°C and 1 standard unit of atmospheric pressure (atm) are as follows: 1 ppm = 4.34 milligrams per cubic meter (mg/m3) and 1 mg/m3 = 0.23 ppm. Partition coefficients for m-xylene are as follows: blood:air = 46 for male Wistar rats and 26.4 for humans (Gargas et al. 1989, Tardif et al. 1997).



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19 Xylenes Raghupathy Ramanathan, Ph.D. Toxicology Group Habitability and Environmental Factors Division Johnson Space Center National Aeronautics and Space Administration Houston, Texas BACKGROUND Xylene, also known as dimethylbenzene (formula: C6H4 (CH3)2) exists as three isomers—ortho-(1,2-dimethylbenzene), meta-(1,3-dimethylbenzene), and para-(1,4-dimethylbenzene)—whose structures are shown below. Commer- cial xylenes (also called mixed xylenes) are a mixture of the three forms with meta- (abbreviated “m-”) being the major component and ortho- (abbreviated “o-”) and para- (abbreviated “p-”) present in minor amounts; usually, the pro- portions are 40% m-isomer and 20% each of the p- and o-isomers. Technical- grade xylenes also contain ethylbenzene. In general, they have similar physical, chemical, and toxicologic properties. Although the odor threshold is listed as 1 part per million (ppm) in air, it seems to vary among the isomers, being 3.7, 0.17, and 0.47 ppm for m-, o-, and p-xylene, respectively (ATSDR 2007). The vapor pressures for the three are comparable (8.29, 6.61, and 8.84 mm Hg for m- , o-, and p-xylenes, respectively (ATSDR 2007). CH 3 CH 3 CH 3 CH 3 H 3 C H3C m-xylene p-xylene o-xylene Conversion factors at 25°C and 1 standard unit of atmospheric pressure (atm) are as follows: 1 ppm = 4.34 milligrams per cubic meter (mg/m3) and 1 mg/m3 = 0.23 ppm. Partition coefficients for m-xylene are as follows: blood:air = 46 for male Wistar rats and 26.4 for humans (Gargas et al. 1989, Tardif et al. 1997). 356

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357 Xylenes OBJECTIVE With NASA’s current focus on exploration missions beyond low Earth or- bit to the Moon and Mars, there is a need to derive an acceptable concentration (AC) of xylene in spacecraft atmospheres for 1,000 d, which has not previously been derived. Typical spacecraft concentrations have been 0.48 ppm, and it is not known what the concentrations will be for the newer spacecraft being de- signed for Mars and Moon missions (NASA, personal communication, May 19, 2008). Spacecraft maximum allowable concentrations (SMACs) for xylene were originally developed and published in Volume 3 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). This docu- ment reviews all available subchronic and chronic duration xylene exposure studies and derives exposure limits acceptable for exposures up to 1,000-d (1,000-d AC). At the same time, NASA will evaluate the need to update the pre- viously published SMACs for up to 180 d based on toxicologic studies pub- lished since the last evaluation. NASA will also consider whether the previously used data are suitable for processing by current risk assessment methodologies (such as benchmark dose computations) recommended by the National Research Council (NRC) Committee on Spacecraft Exposure Guidelines. PHARMACOKINETICS AND METABOLISM A detailed summary of the pharmacokinetics and metabolism of xylene was presented in the 1996 SMAC document (Garcia 1996). A brief summary is presented here. It has been reported that humans absorb about 60% of the xylene from inhalation exposures over concentrations ranging from 46 to 200 ppm, and the percent retained is independent of the duration of exposure time from 15 min to 8 h in a single day, or after 5 d of 6-h/d exposure. The percent retention varies only slightly among individuals and among the three isomers of xylene (Sedivec and Flek 1976, Riihimäki et al. 1979). Postexposure, 4% to 6% of the amount retained is expired as unchanged xylene. In humans exposed to 100 ppm, the half-lives for elimination of xylene were 0.8 h for the initial phase, 7.7 h for the intermediate phase, and 17.7 h for the slowest phase (Sedivec and Flek 1976). Monitoring of urine from humans exposed to xylene both experimentally and in the workplace indicates that almost all the absorbed xylene undergoes oxidation of the methyl group by the microsomal mixed function oxidases to yield methylhippuric acid (MHA), which is excreted in the urine (Ogata et al. 1970, Sedivec and Flek 1976, Senczuk and Orlowski 1978, Ogata and Fujii 1979, Riihimäki et al. 1979). Metabolism of xylene does not appear to saturate even at 200 ppm of exposure (Riihimäki et al. 1979). Urinary excretion of MHA correlates well with xylene uptake, so that one can use it to estimate exposure. Physiologically based pharmacokinetic (PBPK) models indicate that the elimi- nation of MHA is linear up to an exposure concentration of 500 ppm (Kaneko et

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358 SMACs for Selected Airborne Contaminants al. 1991). In humans, there appear to be some small gender differences for ex- cretion of MHA, with men excreting more than women do (Ernstgard et al. 2002, 2003). SUMMARY OF ORIGINAL APPROACH The xylene SMACs for exposures of 1 h to 180 d were primarily based on neurotoxicity end points such as headache, dizziness, and central nervous system (CNS) depression; subjective measures of irritation of the nose and eyes; and throat discomfort. Several controlled human exposure studies and several animal studies were reviewed (Garcia 1996). The 1- and 24-h ACs were derived for various end points based on reports on acute effects, which included both human and animal data. Lethality in rats and humans (Morley et al. 1970, Carpenter et al. 1975), mild throat irritation and eye irritation in humans (Carpenter et al. 1975), narcosis in rats (Molnar et al. 1986), and cardiac depression in dogs (Kobayashi et al. 1989) were used as end points. Both the 1- and 24-h SMACs of 100 ppm were driven by mild throat irritation in humans and narcosis in rats. Garcia (1996) calculated 1- and 24-h ACs based on mild throat irritation and discomfort reported by Carpenter et al. (1975) for one of seven human vol- unteers during the first minute of inhalation to 230 ppm and again during the seventh minute of a 15-min inhalation to 230 ppm m-xylene. The degree of irri- tation reported was minor. Such mild irritation would be acceptable for a brief contingency exposure; thus, in calculating the ACs for 1- and 24-h exposures, the 106-ppm value was considered a no-observed-adverse-effect level (NOAEL) and was not adjusted for exposure duration. The value was rounded to 100 ppm. As the NOAEL for throat irritation is much lower than that for eye irritation, eye irritation did not drive the SMAC for 1- and 24-h exposure durations. Similarly, as the NOAEL for throat irritation is much lower, the end point of dizziness did not drive the SMAC for these durations. Garcia (1996) also derived 1- and 24-h ACs from the results of a rat study by Molnar et al. (1986) in which narcosis of rats was noted when they were ex- posed for 4 h at 2,100 ppm but not at 1,000 ppm. Using 1,000 ppm as a NOAEL, Garcia (1996) derived 1- and 24-h ACs for narcosis of 100 ppm after applying a species factor of 10. ACs and SMACs for 7, 30, and 180 d (Garcia 1996) were calculated on the basis of eye irritation and mild throat irritation in humans (Carpenter et al. 1975); narcosis in rats (Molnár et al. 1986); reduced cardiac output in dogs (Ko- bayashi et al. 1989); absence of abnormal serum clinical chemistry, hematology, and urine chemistry in rats and dogs; and electrocardiogram in rats and dogs (Carpenter et al. 1975). For calculating the SMACs for these short and long du- rations (7-, 30-, and 180-d), 106 ppm from the human study was considered a lowest-observed-adverse-effect level (LOAEL). Because prolonged irritation of eyes and throat would not be acceptable, the LOAEL was divided by 2 to obtain

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359 Xylenes the NOAEL. Garcia (1996) derived the same SMAC of 50 ppm (217 mg/m3) for 7-, 30-, and 180-d durations, driven by the lowest of ACs for mild throat irrita- tion reported by humans in the Carpenter et al. (1975) study. Garcia (1996) also evaluated an animal experiment by Carpenter et al. (1975) in which a subchronic intermittent inhalation exposure study of dogs and rats (180, 460, or 810 ppm of commercial mixed xylenes for 6 h/d and 5 d/wk for 13 wk) resulted in no changes from controls in blood and urine chemistry, hematology, and histopathology of several tissues. As the NOAEL of 810 ppm for rats and dogs for systemic effects is much higher (even after considering the species factor) than that for throat irritation, the end points for systemic effects in rodents and dogs did not drive the AC for 30 and 180 d. CARCINOGENIC RISK ASSESSMENT Xylenes are not classifiable as to their carcinogenicity to humans (Group 3) (IARC 1999, p. 1189). The U.S. Environmental Protection Agency (EPA) categorized xylene as D, meaning there is no evidence of carcinogenicity in hu- man or animal studies. In vivo genotoxicity of xylenes in humans occupationally exposed or experimentally exposed for short durations, or in rats or mice intrap- eritoneally injected with xylene, were all found to be negative. Thus, Garcia (1996) calculated no carcinogenic risk factor for xylene. A summary of SMACs for xylene presented by Garcia (1996) is shown in Table 19-1. STUDIES NOT COVERED IN THE 1996 SMAC DOCUMENT FOR XYLENE Acute Exposure Studies Sixteen men were studied in an exposure chamber to assess the effect of 4 h of exposure to 70 ppm of p-xylene and a control condition. Subjects performed computer-administered tests of simple reaction time, short-term memory, and choice reaction time immediately after entering the chamber and after 2 and 4 h of exposure. Xylene exposure did not affect their performance on these tests (Olson et al. 1985). In a similar study, Dudek et al. (1990) assessed CNS functions in 10 male volunteers aged 22 to 35 y by means of a battery of nine psychological tests, during an experimental exposure to 100 ppm of pure xylene (purity not speci- fied) for 4 h compared with clean air. Each individual served as his or her own control and the treatments were randomized. This produced a statistically sig- nificant effect at P ≤ 0.01 on two of the nine tests—namely, simple reaction time (SRT) (prolongation of simple reaction time test) and choice reaction time (ChRT) (22% and 13% longer, respectively, than controls). No adverse re- sponses to the other tests were observed. The only concentration used (100 ppm)

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360 SMACs for Selected Airborne Contaminants TABLE 19-1 A Summary of SMACs for Xylene mg/m3 Duration ppm Adverse End Point Principal Study 1h 100 435 Throat irritation, narcosis Carpenter et al. 1975, Molnar et al. 1986 24 h 100 435 Throat irritation, narcosis Carpenter et al. 1975 7d 50 217 Throat irritation Carpenter et al. 1975 30 d 50 217 Throat irritation Carpenter et al. 1975 180 d 50 217 Throat irritation Carpenter et al. 1975 Source: Garcia 1996. seems to be the LOAEL (compared with no effect seen at 70 ppm in the Olson et al. study [1985]) for neurologic effects and should be considered for 1- and 24-h AC derivations. Thus, a NOAEL of 70 ppm based on the Olson study and a LOAEL of 100 ppm based on the Dudek study could be identified. Ernstgard et al. (2002) conducted an acute exposure study in which 56 healthy volunteers (28 of each sex) were exposed to 50 ppm of m-xylene for 2 h at rest. This study involved measuring the adverse effects by both subjective assessment and objective measurements. The subjects rated symptoms (per- ceived level of discomfort) for 10 questions on a visual analog scale (VAS) be- fore exposure, during exposure (at 3, 60, and 118 min), and after exposure (20 min and about 4 h after exposure). The VAS results were rated on a scale of 0 to 100 mm where the level of perceived discomfort was rated as follows: 0 mm (none at all) to 6 mm (hardly at all) to 26 mm (somewhat) to 48 mm (rather) to 71 mm (quite) to 90 mm (very) to 100 mm (unbearable). Increased symptom ratings were rated by both sexes for nearly all 10 questions during exposure to m-xylene; most increases were statistically significant for at least one time point (at either 60 or 118 min during the exposure). The rating of “discomfort in the throat or airways” was higher in women. Solvent smell was rated as “rather” by both sexes. Discomfort to the eye, nose, and throat were only just above “hardly at all.” Although “fatigue” was rated close to “somewhat,” it did not differ from the rating of unexposed controls. Nausea, giddiness, and a feeling of intoxication were below 6 mm in the VAS scale. Although these VAS scores for “discomfort in the throat or airways” were statistically significantly different from those of control subjects exposed to clean air, the absolute numbers indicated only mini- mal discomfort from xylene exposure. On the basis of these ratings and overall significance and importance, 50 ppm is considered as a minimal LOAEL. Pulmonary function, nasal swelling, inflammatory markers in nasal lav- age, and color vision (color confusion index) were measured before and 0 and 3 h after the exposure. No significant effect on pulmonary function was seen in men after either exposure or 3 h after exposure or in women immediately after exposure. Women had small but significant decreases in forced vital capacity 3 h after exposure to m-xylene. An evaluation of the data expressed as percent change indicates that 3 h after exposure the change was less than 4% (Ernstgard

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361 Xylenes et al. 2002). Thus, these changes are considered unremarkable, as they are not expected to pose any concern. No significant effects were noted in nasal swelling, in inflammatory mark- ers in the nasal lavage, or in blinking frequency (Ernstgard et al. 2002). Short-Term and Subchronic Duration Studies Riihimäki and Savolainen (1980) reported changes in body balance (func- tion of the vestibular system), and psychomotor function (choice reaction time and simple reaction time) in male volunteers exposed to m-xylene at 100 to 400 ppm over 5 consecutive days, 6 h/d with a break for 1 h at noon, then for 1 to 3 d after a weekend. Because the exposure regimens (constant exposure levels and fluctuating exposure levels) were very complex, the data could not be inter- preted properly to find out the NOAEL or LOAEL and the dose-effect response pattern. Hake et al. (1981), in a controlled human exposure study, evaluated the ef- fect on men (one to four subjects) of exposure to p-xylene for 7.5, 3, or 1 h/d, 5 d/wk, for 4 wk. The exposure concentration was 100 ppm during the first week, then 20, 150, and 100 ppm in the following weeks. Groups of women (two or three per group) were exposed to p-xylene for 7.5, 3, or 1 h/d for 5 d. Data on subjective responses and objective responses such as neurologic tests, cognitive tests, and cardiopulmonary function tests were gathered. Except for irritating effects reported at 100 ppm, no serious effects were noted. The sample size was too small to draw any meaningful conclusions. In a 4-wk inhalation exposure study, rats (10 or 11 per group) were ex- posed repeatedly to 100 ppm of m-xylene for 6 h/d, 5 d/wk (Gralewicz and Wiaderna 2001). Starting 2 wk postexposure, the behavior of the rats was as- sessed by radial maze performance, spontaneous activity in an open field, and learning and retention of passive and active (two-way) avoidance responses. There was no significant change in radial maze performance. Treated groups showed significantly higher spontaneous locomotor activity in the open field and impaired passive avoidance learning. As the only concentration used (100 ppm) resulted in adverse effects, this concentration would be considered a LOAEL for 4 wk of discontinuous exposure. Because the measurements were made 2 wk after exposure ceased, when all xylene should have been eliminated from the system, it appears that xylene exposure resulted in some potentially persistent neurologic effects on sensorimotor functions. In subchronic inhalation experiments, male Wistar rats (12 per group) were exposed to m-xylene for 6 h/d, 5 d/wk at 1,000 ppm for 3 mo or at 100 ppm for 6 mo. Disturbances in the Rotarod performance test and a decrease in spontaneous motor activity that were observed were significantly different from those in controls (Korsak et al. 1992) for both exposure groups. The authors conducted another animal study using one lower dose (Korsak et al. 1994) in which male Wistar rats (12 per dose group) were exposed to 50 and 100 ppm of

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362 SMACs for Selected Airborne Contaminants m-xylene, 6 h/d, 5 d/wk for 3 mo. The Rotarod performance test (motor coordi- nation) was done before the exposure, and in each month during the 3 mo of inhalation exposure. Clinical chemistry values were unremarkable. In this study, the NOAEL for decrease in Rotarod performance (motor coordination and bal- ance) was identified as 50 ppm for 3 mo. Gralewicz et al. (1995) investigated the effects of a 3-mo (6 h/d, 5 d/wk) inhalation exposure of 8-mo-old male Wistar rats to m-xylene, at concentrations of 100 and 1,000 ppm, on changes in electroencephalogram (EEG) recordings and on spatial learning in an eight-arm radial maze. EEG recordings were per- formed before the exposure; on days 28, 56, and 84 of exposure; and again on days 14, 28, 42, and 84 after the exposure. According to the authors, exposure to m-xylene did not appear to influence the level of arousal as shown in the EEG, although retarded development of spontaneous neocortical spike and wave dis- charge activity was seen. The authors stated that large interindividual variations could not explain these results. The testing in the maze (one trial daily for 5 d) performed 2 mo after the exposure indicated that rats exposed to m-xylene at 1,000 ppm developed a learning deficit, as reflected by the number of omission errors and response speed even after training in successive trials, compared with the performance of control rats. The maze behavior of the 100-ppm group was similar to that of the 1,000- ppm group, but it was less pronounced. Thus, 100 ppm was identified as a 3-mo LOAEL for neurotoxicity (neurobehavioral) in this study. Another important adverse effect of xylene exposure is ototoxicity—loss of hearing—and this has been the subject of many studies on exposures to or- ganic solvents. Gagnaire et al. (2001) exposed 13-wk-old male Sprague-Dawley rats to o-, m-, and p-xylene at 450, 900, and 1,800 ppm, 6 h/d, 6 d/wk for 13 wk. Brainstem auditory evoked response, electrophysiologic auditory thresholds, and histologic analysis of the organ of Corti were used to assess the ototoxicity of individual isomers of xylene. Increased auditory thresholds were found at the end of the exposure period (13 wk) in rats exposed to 1,800 ppm. This did not reverse even by 8 wk after exposure. In addition, morphologic investigations conducted 8 wk postexposure revealed moderate to severe losses of outer hair cells of the organ of Corti in animals exposed to 900 and 1,800 ppm of p-xylene. However, the m- and the o-isomers did not exhibit any ototoxicity (no changes in audiometric thresholds or loss of either inner or outer hair cells). A recent study (Maguin et al. 2006) confirmed that only p-xylene was ototoxic and all of the xylene isomers were cochleotoxic when rats were exposed to 1,800 ppm for 6 h/d, 5 d/wk. According to the authors, 450 ppm is the NOAEL for ototoxicity for p-xylene. Moser et al. (1985) reported that, even though xylene produced pronounced neurobehavioral effects (based on operant performance and inverted screen test) after acute exposures over the concentration ranges of 500 to 7,000 ppm in mice, only slight potency differences among the isomers existed for neu- robehavioral effects. Taking into consideration the ototoxic effects of xylene in all of these studies (Pryor et al. 1987, Crofton et al. 1994, Nylen and Hagman 1994, Gagnaire et al. 2001), ototoxicity should be considered an important ad-

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363 Xylenes verse effect of exposure to xylene and may be useful for AC derivation. How- ever, it is clear that there is a remarkable difference in ototoxic potential among the isomers. In a recent study, two types of mixed xylene with known proportions of each of the xylene isomers with ethylbenzene were tested for ototoxicity (Gag- naire et al. 2007). The first mixture contained 20% o-, 20% p-, and 40% m- xylenes and 20% ethylbenzene; and the second synthetic mixture contained 30% o-, 10% p-, and 50% m-xylene with 10% ethylbenzene. Male Sprague-Dawley rats (n = 16) were exposed to 250, 500, 1,000, and 2,000 ppm of each of these mixtures for 6 h/d, 6 d/wk for 13 wk. The brain auditory responses (changes in the thresholds) to different frequencies and a morphologic study of the organ of Corti confirmed that exposure to synthetic xylene mixtures resulted in ototoxic- ity. The confounding effects of ethylbenzene as a more potent ototoxicant than the xylenes make it difficult to interpret the data with respect to the xylenes. The Gagnaire et al. (2001) study would be more useful for deriving ACs. Pryor et al. (1987) investigated male weanling F344 rats (3 wk old) ex- posed to mixed xylene (10% of ortho, 80% of meta, and 10% of para-xylene) at 800, 1,000, and 1,200 ppm daily for 14 h/d, 7 d/wk for 6 wk. They reported sub- stantial loss of auditory sensitivity (20 to 25 decibels at 12.5 kHz) assessed by behavioral (conditioned avoidance) and electrophysiologic (brainstem auditory evoked response) methods. As rats used in this study were too young, this study will not be useful for deriving ACs. In another study (Nylen and Hagman 1994), 8-wk-old male albino Spra- gue-Dawley rats (n = 23) were exposed to mixed xylene (1.5% o-xylene, 65% m-xylene, 32% p-xylene, and 2.5% ethylbenzene) at 1,000 ppm, 18 h/d, 7 d/wk for 61 d (Nylen and Hagman 1994). Neurophysiologic (electrophysiologic) re- cordings to assess latencies of the flash-evoked potentials and nerve and muscle action potentials were made 2 d, 4 mo, and 10 mo after the end of exposure. The authors characterized the loss of auditory sensitivity in low to middle frequen- cies in response to a click stimulus, observed 2 d after the exposure ended, as only minor; 4 and 10 mo after exposure, the results were comparable to those for controls (Nylen and Hagman 1994). Though only one concentration (1,000 ppm) was used, this study used the most continuous hours of exposure of any of the subchronic studies reviewed. However, Crofton et al. (1994) reported that, in adult male Long-Evans rats exposed to mixed xylenes at 1,800 ppm, 6 h/d for 5 d, the reflex modification audiometry data collected 5 to 8 wk postexposure in- dicated a hearing loss in the middle-frequency ranges (8 and 16 kHz). Reflex modification audiometry data at lower- and higher-frequency ranges were com- parable to those for controls. Chronic Duration Study Uchida et al. (1993) carried out a cross-sectional evaluation of Chinese factory workers who were exposed to vapors that were predominantly xylene

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364 SMACs for Selected Airborne Contaminants (70% of the total exposures) for about 7 y; 175 xylene-exposed workers (107 men and 68 women) were selected. Monitoring by personal diffusive sampling showed that the concentration of xylene vapor was 14 ppm (as a geometric mean) and 21 ppm (as an arithmetic mean). m-Xylene was about 50% of these mixed isomers. Urinary MHA was used to verify the exposure estimate. The authors noted that the subjects were also coexposed to toluene and ethylbenzene at 1 and 3 ppm, respectively. As controls, 241 nonexposed workers (116 men and 125 women) were included. There was an increased prevalence of subjec- tive symptoms (as reported in a questionnaire and self-reported) in the exposed workers; these symptoms were apparently related to CNS effects (dizziness, forgetfulness, anxiety) and to local effects on the eyes, nose, and throat (irrita- tion). Because the intensity of exposure was rather low, a dose-response rela- tionship between level of exposure and severity of reported symptoms was per- haps not evident. Hematology and serum biochemistry with respect to liver and kidney function were generally unaffected (Uchida et al. 1993). On the basis of these observations (mild subjective symptoms in a small number of cases), 14 ppm could be considered as a LOAEL. Reproductive Toxicity Biodynamics (Bio/dynamics 1983) conducted a study in which male and female Sprague-Dawley rats were exposed by inhalation to a mixture of xylenes at concentrations of 0, 60, 250, or 500 ppm, 6 h/d for 131 d before mating and during a 20-d mating period. The mated females were also exposed during ges- tation from gestation days 1 to 20 and during days 5 to 20 of lactation. Addition- ally, exposed males from the highest-dose group were mated with unexposed females and vice versa. No mortalities occurred and there were no treatment- related effects on mating, fertility, pregnancy indices, mean duration of gesta- tion, mean litter size, or mean pup weight. No effect on reproductive organs or sperm count of the male rats was observed. In another long-term exposure study by Nylen et al. (1989), in which male Sprague-Dawley rats were exposed by inhalation to mixed xylenes at 1,000 ppm for 61 d, 18 h/d, 7 d/wk, no alterations in testes, accessory glands, or circulating male hormone levels were noted. All rats exposed to xylene were fertile. Saillenfait et al. (2003) evaluated the developmental toxicities of o-, m-, and p-xylene and technical xylene in Sprague-Dawley rats after inhalation expo- sures. Animals were exposed at 100, 500, 1,000, or 2,000 ppm for 6 h/d, during days 6 to 20 of gestation. All the agents tested caused maternal toxicity, ex- pressed as a reduction in maternal body weight gain, at 1,000 and 2,000 ppm. Even at the highest dose tested, no evidence of teratogenic effects was found. Fetal toxicity as evidenced by decreases in fetal body weight occurred only in groups exposed to 1,000 ppm or greater in the case of m-xylene and p-xylene.

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365 Xylenes This effect was seen at 500 ppm and was higher in the case of groups exposed to o-xylene and mixed (technical) xylene; however, the fetal body weight reduc- tions were only 5% and 4%, respectively, in the case of these two xylenes (Sail- lenfait et al. 2003). Several studies reported reproductive and developmental effects of short- term xylene exposures (e.g., see Ungvary and Tatrai 1985, Rosen et al. 1986, Hass et al. 1997). Results of these studies were either negative or indicated that reproductive and developmental toxicity effects can be noted only at high con- centrations. Thus, these studies were not used to derive ACs. Immunologic Effects Studies of immune system effects in human subjects occupationally ex- posed to xylene had serious uncertainty with respect to specific association of xylene exposure and changes, because subjects had extensive coexposure to other solvents. Carpenter et al. (1975) reported no immune system effects in dogs and rats exposed to mixed xylenes for 13 wk at 810 ppm. No specific immunologic ad- verse end points were measured except for spleen weight, which was unaffected. A study not included in the 1996 SMAC document for xylene was that of Sel- grade et al. (1993). They exposed mice to p-xylene at 600 or 1,200 ppm, 6 h/d for 4 d, and infected them with a sublethal dose of murine cytomegalovirus (MCMV) after the first exposure to xylene. A death rate of 34% occurred in MCMV-challenged mice exposed to xylene at 1,200 ppm. However, no deaths occurred in other groups, including mice exposed to p-xylene at 600 ppm and infected with MCMV. In the group that showed high mortality, spleen natural killer cell activity was unaltered, and so were the virus titers in the liver. Be- cause serum hepatotoxic marker enzymes, which indicate liver damage, in- creased only in mice exposed to xylene at 1,200 ppm and infected with MCMV, the authors stated that enhanced mortality was caused not by immune suppres- sion but by enhanced liver damage. The mechanism was not understood. The toxicity literature on xylene exposure discussed in this document is summarized in Table 19-2. RATIONALE FOR THE 1,000-d AC ACs were determined according to the Subcommittee on Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants (NRC 1992). The resulting ACs for the various end points were compared and the lowest AC at each exposure duration was selected as the SMAC. NASA also reviewed the recommended or permissible exposure levels set by other regulatory and nonregulatory organizations shown in Tables 19-3 and 19-4.

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TABLE 19-2 Toxicity Summary of Studies Included in This Document 366 Concentration, ppm Exposure Duration Species Adverse End Points Reference 0, 100, 300 mixed xylenes 70 min humans No effect on performance or subjective symptoms; Gamberale et al. (w/o decreased performance and decreased short-term 1978 exercise); 300 memory with exercise. (w/exercise) 50 m-xylene at 2h humans, male Affirmative answers to many subjective symptoms, Ernstgard et al. rest and female sensory irritations; increased color confusion index at 0 2002 volunteers, 28 and 3 h postexposure; significant decreases in per sex pulmonary function 3 h after exposure. 100 pure xylene 4h humans, male Significant adverse effect on choice reaction time and Dudek et al. 1990 (purity not volunteers, n simple reaction time (psychomotor efficiency). specified) = 10 70 p-xylene 4h humans, male, Computerized tests for simple reaction time, short-term Olson et al. 1985 n = 16 memory, and choice reaction time immediately measured at 0, 2, and 4 h of exposure indicated that performance on the tests was unaffected by exposure. 600; 1,200 p-xylene, 6 h/d, 4 d Mice 34 percent death occurred in MCMV-challenged mice Selgrade et al. 199 infected with a exposed to xylene at 1,200 ppm; no deaths in mice sublethal dose exposed to p-xylene at 600 ppm and infected with of MCMV MCMV; liver damage in 1,200-ppm group infected with after the first MCMV. In the 1,200-ppm group challenged with the exposure to virus, among those that died, spleen natural killer cell xylene activity was unaltered and liver virus titers were also unaffected. Mortality was not caused by immune suppression. 100, 500, o-, m-, and p- 6 h/d, during Sprague- Maternal toxicity (reduction in maternal body weight Saillenfait et al. 1,000, 2,000 xylene and days 6 to 20 of Dawley rats gain), at 1,000 and 2,000 ppm; no teratogenic effects 2003 mixed xylene gestation found; fetal toxicity (decreases in fetal body weight) seen in 1,000- and 2,000 ppm m-xylene and p-xylene

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376 SMACs for Selected Airborne Contaminants 7-d AC (neurotoxicity) = 50 ppm (NOAEL) × 1/3 (species factor) = 16.70 ppm, rounded to 17 ppm Thus, the 7-d AC for neurotoxicity is 17 ppm. Revised Derivation of 30-d AC No controlled human-exposure study could be found that was conducted for a longer time and was suitable for calculating the 30- and 180-d ACs. Thus, animal studies carried out for 3 mo were chosen. First, data from the Korsak et al. (1992, 1994) studies, described above, were considered. Male Wistar rats (12 per dose group) were exposed to m- xylene at 50 and 100 ppm, 6 h/d, 5 d/wk for 3 mo (Korsak et al. 1994) and 100 ppm for 6 mo (Korsak et al. 1992). The disturbances in the Rotarod performance test and the decrease in spontaneous motor activity observed in the group ex- posed to 100 ppm (Korsak et al. 1992) were not seen in rats exposed to 50 ppm for 3 mo. Even though the measurements were taken at 1, 2, and 3 mo, the per- cent of failure in the Rotarod test did not increase with the length of exposure, which appears to indicate that it is the concentration that matters. Thus, for the 30-d AC derivation, the concentration is not adjusted for discontinuous-to- continuous exposures or for the duration of exposure for this end point. Thus, a 3-mo NOAEL of 50 ppm for motor coordination disturbance was chosen for AC calculations. A species factor of 3 was used. The 30-d AC can be calculated as follows: 30-d AC (motor coordination disturbance) = 50 pm (NOAEL) × 1/3 (species factor) = 16.67, rounded to 17 ppm Thus, the 30-d AC for motor coordination disturbance is 17 ppm. Another study considered for deriving the AC for 30 d is a 13-wk study in which ototoxicity was observed (Gagnaire et al. 2001). Male Sprague-Dawley rats (13 wk old) were exposed to o-, m-, and p-xylene separately at 450, 900, and 1,800 ppm, 6 h/d, 6 d/wk for 13 wk. Electrophysiologic measurements for brainstem auditory evoked response recordings at threshold frequencies of 2, 4, 8, and 16 kHz revealed increased auditory thresholds (indicating loss of hearing) in rats exposed to 1,800 ppm. In addition, morphologic investigations conducted 8 wk postexposure revealed moderate to severe losses of outer hair cells of the organ of Corti in animals exposed to 900 and 1,800 ppm of p-xylene. It is im- portant to note that the m- and the o-isomers of xylene did not exhibit ototoxic- ity. For p-xylene, 450 ppm could be identified as a NOAEL for ototoxicity. Though three concentrations were used, the data were presented as graphs and electron micrographs; hence, BMD methodology could not be used. The NRC committee suggested that NASA look at the possibility of digitizing the

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377 Xylenes graphic data to obtain numerical data that could be used with the BMD method. In the present case, the only study with various concentrations is the ototoxicity study by Gagnaire et al. (2001) in which 450, 900, and 1,800 ppm were used as exposure concentrations. According to the literature, p-xylene is the only oto- toxic agent and not the m- and o-isomers. Even in the case of p-xylene, only one concentration produced a change. If there are four groups including untreated controls and only the fourth concentration gives a change, obtaining a reliable BMD response curve that can be used to obtain a point-of-departure dose is not very accurate. Hence, NASA decided not to extract data by digitizing the charts created by the investigators. A review of data on ototoxicity by xylene clearly indicated that it is not only concentration dependent but also duration dependent. Therefore, it was decided to adjust the concentration for discontinuous-to-continuous exposure. The use of this adjustment factor is considered for this end point in contrast to the neurotoxicity end point because the published data indicate that the mecha- nism of ototoxicity is different from the neurotoxicity mechanism (e.g., mor- phologic organ changes reported). As a 13-wk exposure study is used, it will be protective of a 30-d AC and no time factor is needed. A species factor of 3 is used as in other cases. The 30-d AC for ototoxicity can be calculated as follows after adjusting for intermittent exposure to continuous exposure: NOAEL (adjusted) = 450 ppm (NOAEL) × [6 h/24 h × 6 d/7 d] (discontin. to contin.) = 96.4 ppm 30-d AC (ototoxicity) = 96.4 (NOAEL adjusted) × 1/3 (species factor) = 32.13 ppm, rounded to 32 ppm Thus, the 30-d AC for ototoxicity is 32 ppm. Another study considered for 30- and 180-d ACs was a rat ototoxicity study by Nylen and Hagman (1994). They exposed male Sprague-Dawley rats to 1,000 ppm of mixed xylenes (consisting of 1.5% o-xylene, 65% m-xylene, 32% p-xylene, and 2.5% ethylbenzene) for 18 h/d, 7 d/wk for 61 d. Two days postex- posure, the loss of auditory sensitivity in response to a click stimulus and laten- cies and amplitudes in auditory brain stem response of treated animals were no different from those of controls. However, when loss of auditory sensitivity was filtered by frequency, at 12 kHz, treated animals had a significant loss compared with controls. Even this minor change might have been caused by the small amounts of ethylbenzene in the sample. The flash-evoked potential of nerve or muscle was unaltered. Thus, 1,000 ppm was considered a LOAEL. At 4 and 10 mo postexposure, the flash-evoked potentials were no different from controls. The study design involved much longer daily and weekly exposure duration protocols than many other studies in the literature, and it was decided to use the study even though only one dose was used. In this study, the authors did not evaluate morphologic changes in the organ of Corti.

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378 SMACs for Selected Airborne Contaminants With a LOAEL of 1,000 ppm for decreased auditory sensitivity, a 30-d AC can be calculated. The concentration is adjusted for discontinuous exposure. No time extrapolation is required to derive a 30-d AC, as the data used are from a 61-d exposure study. A factor of 3 is used for species extrapolation. LOAEL (adjusted) = 1,000 ppm (LOAEL) × [18 h/24 h] (discontin. to contin.) = 750 ppm 30-d AC (ototoxicity) = 750 ppm (LOAEL adjusted) × 1/10 (LOAEL to NOAEL) × 1/3 (species factor) = 25 ppm Thus, the 30-d AC for ototoxicity is = 25 ppm. Another study considered for deriving the 30- and 180-d ACs was that of Gralewicz et al.(1995), in which exposure of rats to m-xylene at concentrations of 100 and 1,000 ppm for 3 mo, 6 h/d, 5 d/wk resulted in a deficit in spatial learning in an eight-arm radial maze in rats exposed to 1,000 ppm. The radial maze test was run 2 mo after the exposure ended. In rats exposed to m-xylene at 100 ppm, the effects on maze behavior were similar to those in the 1,000-ppm treated group, but they were less pronounced. Of the five trials during the test- ing, only the last two trials showed differences from the controls, and the results are somewhat difficult to interpret. As a NOAEL was not seen in this study, nor was a clear concentration-dependent response, it is difficult to use a proper fac- tor for LOAEL to NOAEL. Thus, this study was not considered for AC deriva- tion for 30 or 180 d. Revised Derivation of 180-d AC No suitable human exposure study was found. Three rodent studies with two different end points—neurotoxicity and ototoxicity—were used to derive the 180-d AC (Korsak et al. 1992, Nylen and Hagman 1994, Gagnaire et al. 2001). First, the rodent study by Korsak et al. (1992) described earlier was con- sidered. The authors had used m-xylene exposure concentrations of 1,000 ppm for 3 mo and 100 ppm for 6 mo. Rotarod performance was measured after 1, 2, and 3 mo of exposure (1,000- and 100-ppm groups) and at 6 mo (100-ppm group). At the end of 6 mo, the rats exposed to 100 ppm showed decreased per- formance in the Rotarod test. A LOAEL of 100 ppm for 6 mo was identified. The effect appeared to be more concentration dependent than duration depend- ent, and thus no factor was used for discontinuous-to-continuous exposure. The use of a factor of only 3 for LOAEL to NOAEL was used based on the observa- tion of a 3-mo NOAEL of 50 ppm (Korsak et al. 1994). If one were to use the same data for 180 d, a factor of 2 (Haber’s rule) would have been applied on 50 ppm to give a NOAEL of 25 ppm for 180 d. A species factor of 3 has also been used. .

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379 Xylenes Thus, with a LOAEL of 100 ppm for changes in Rotarod performance, the 180-d AC is derived as follows using factors of 3 for LOAEL to NOAEL and 3 for species extrapolation. 180-d AC (neurotoxicity) = 100 pm (LOAEL) × 1/3 (LOAEL to NOAEL) × 1/3 (species factor) = 11.11 ppm, rounded to 11 ppm Thus, the 180-d AC for neurotoxicity is 11ppm. A second study was also used to derive a 180-d AC using ototoxicity as the end point. This AC was based on the results from Gagnaire et al. (2001), as described earlier in this chapter. A NOAEL of 450 ppm of p-xylene for ototoxic- ity was identified in this study. For derivation of the 180-d AC, in addition to the adjustment for discontinuous-to-continuous exposure, a species factor of 3 and a time extrapolation factor of 91 d/180 d following Haber’s rule were used. The 180-d AC for ototoxicity can be calculated as follows: NOAEL (adjusted) = 450 ppm (NOAEL) × [6 h/24 h × 6 d/7 d] (discontin. to contin.) = 96.4 ppm 180-d AC (ototoxicity) = 96.4 ppm (NOAEL adjusted) × 1/3 (species factor) × (91 d/180 d) (time extrapolation) = 16.2, rounded to 16 ppm Thus, the 180-d AC for ototoxicity is 16 ppm. The third study considered for the 180-d AC was that of Nylen and Hag- man (1994), described above, in which 1,000 ppm could be identified as a LOAEL for loss of auditory sensitivity at a frequency of 12 kHz. Rats were ex- posed to mixed xylenes at 1,000 ppm for 18 h/d, 7 d/wk for 61 d. After adjusting the LOAEL for discontinuous to continuous exposure (18 h/24 h), and after ap- plying factors of 10 for LOAEL-to-NOAEL, 3 for interspecies extrapolation, and a time extrapolation factor of 61 d/180 d following Haber’s rule, the 180-d AC for ototoxicity is derived as follows: LOAEL (adjusted) = 1,000 ppm (LOAEL) × 18 h/24 h (discontin. to contin.) = 750 ppm 180-d AC (ototoxicity) = 750 ppm (LOAEL adjusted) × 1/10 (LOAEL to NOAEL) × 61 d/180 d (time extrapolation) × 1/3 (species factor) = 8.47 ppm, rounded to 8.5 ppm Thus, the 180-d AC for ototoxicity is 8.5 ppm.

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380 SMACs for Selected Airborne Contaminants Derivation of 1,000-d ACs A human subject study was first considered for deriving a 1,000-d AC. In this human cross-sectional study conducted in a Chinese production factory by Uchida et al. (1993) workers were exposed to a mixture of solvent vapors, mostly xylene, with some level of exposure to toluene and ethylbenzene. The study included 107 men and 68 women exposed to xylene and 200 unexposed control subjects (116 men and 125 women). The time-weighted average for 7 y for xylene exposure was 21 ppm (arithmetic mean) with a calculated geometric mean of 14 ppm. The data were collected from a self-reported questionnaire for various symptoms of irritations of the eye and nose, dizziness, and other symp- toms that represent neurotoxicity. However, there are limitations in using this study for deriving a 1,000-d AC. First, data were collected from subjects only once. Even though exposure was measured before data of the symptom assessment were collected, the data may not truly represent a correlation between exposure and response; exposure to a higher concentration on several occasions before the test was administered is possible. In addition, the study involves exposures to 30% of mixed vapors (exposure to toluene and ethylbenzene) and not just xylene isomers. The end points were also subjective. No objective neurologic tests were conducted. Many rodent studies have documented neurologic and ototoxic effects of xylenes, although the duration of each of them was less than subchronic (Korsak et al. 1992, 1994; Gralewicz et al. 1995; Gagnaire et al. 2001). Because these effects have been well documented in several studies, and in the absence of ro- bust chronic exposure data in humans or in rodents, it was decided to use a time extrapolation factor from subchronic studies to chronic studies. Thus, a 1,000-d AC was derived with the ototoxicity results of Nylen and Hagman (1994) with supporting observations from Gagnaire et al. (2001) and applying a time extrapolation factor. A 180-d AC for ototoxicity was derived earlier as 8.5 ppm (based on Nylen and Hagman 1994). A time factor of 1,000 d/180 d is applied to the 180-d AC to reduce the dose for 1,000 d. Thus, the 1,000-d AC is calculated as follows: 1,000-d AC (ototoxicity) = 8.5 ppm (180-d AC, ototoxicity) × 180 d/1,000 d (time extrapolation) = 1.53 ppm, rounded to 1.5 ppm Spaceflight Effects The national standard for exposure to noise in the occupational environ- ment is an 8-h equivalent continuous A-weighted sound pressure level of 85 decibels (dB)A. For peak noise, the national standard is a C-weighted peak sound pressure level of 140 dBC. From the National Institute for Occupational Safety and Health criteria document for noise (NIOSH 1998), one can find that

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381 Xylenes an exposure level of 80 dBA may be acceptable for as long as 25 h and 24 min. The flight rules established by NASA for the International Space Station (ISS) and the Shuttle established that a noise level of 65 dBA on ISS could be toler- ated for 24 h. The ISS acoustics office provides support for acoustic measure- ment devices, on-orbit testing, and real-time remedial actions to protect crew- member’s hearing. There is an extensive literature aimed at establishing whether exposure to neurotoxic solvents causes ototoxicity in humans and whether there is any sig- nificant level of interaction between exposure to neurotoxic solvents and noise levels, for example additive or synergistic effects on ototoxicity. In an industrial setting, coexposure to various solvents limits any interpretations or conclusions. An evaluation of the ACs derived for xylene for various durations, espe- cially the 30-d AC (32 and 25 ppm form two different studies) and the 180-d AC (16 and 8.5 ppm) do not drive the SMAC for the respective durations, especially for 30 d, even if one were to apply a customary default factor of 3. In addition, based on consistent data that only p-xylene appears to be ototoxic, and not m- and o-xylene, and the fact that the ACs were derived based on the assumption that all the xylene vapors are p-xylene indicates that the ACs for ototoxicity end points are conservative. Therefore, consideration of any interaction of noise with xylene induced ototoxicity is not necessary. A summary of revised SMACs for various durations and effects are shown in Table 19-5. Updated ACs, new ACs, and final SMACs for 1 h to 1,000 d are listed in Table 19-6. RESEARCH NEEDS Data that establish a relationship between a target tissue concentration (dose), instead of an exposure concentration, and two critical adverse end points of xylene toxicity—namely, the neurobehavioral effects and ototoxic effects in humans are needed. Although PBPK modeling studies based on the pharma- cokinetics of xylene in rats and humans have been published, pharmacody- namic-based models are needed. Savolainen et al. (1985) reported a correlation between venous blood xylene concentrations and changes in both average and maximal body sway along the sagittal axis and along the lateral axis (an indica- tion of vestibular system balance) in nine human volunteers exposed to constant or fluctuating concentrations of m-xylene. The literature indicates that this re- sponse seems to be biphasic, making it difficult for dosemetric analysis. Hence, data are needed for neurobehavioral end points (such as ChRT and SRT that can be assessed by a computerized test battery), so that a physiologically based pharmacodynamic model can be developed to predict reasonable exposure con- centrations for various durations of expected exposures using blood levels as surrogates for target (brain) dose. Research is also needed to understand certain persistent neurobehavioral effects seen in many studies several weeks after ex-

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382 SMACs for Selected Airborne Contaminants TABLE 19-6 A Summary of Updated and New ACs and SMACs for Various Durations Acceptable Concentrations, ppm Adverse End Point and Principal Study 1h 24 h 7d 30 d 180 d 1,000 d Reported symptoms of irritation of eye, 50 17 — — — — nose, and throat and headache (Ernstgard et al. 2002). Neurologic function: decreased SRT, 70 — — — — — ChRT, and short-term memory (Olson et al. 1985). Neurotoxicity: Decreased neuromotor — — 17 — — — function (Korsak et al. 1994). Neurotoxicity: Decreased neuromotor — — — 17 — — function (Korsak et al. 1994). Ototoxicity: Decreased auditory — — — 32 — — threshold and loss of hair cells of organ of Corti (Gagnaire et al. 2001). Ototoxicity: Loss of auditory — — — 25 — — sensitivity/response (ototoxicity) (Nylen and Hagman 1994). Neuromotor function (Korsak et al. — — — — 11 — 1994). Ototoxicity (Gagnaire et al. 2001). — — — — 16 — Loss of auditory sensitivity/response — — — — 8.5 — (ototoxicity) (Nylen and Hagman 1994). Loss of auditory sensitivity/response — — — — — 1.5 (ototoxicity) (Nylen and Hagman 1994). SMAC,a ppm 50 17 17 17 8.5 1.5 a SMAC is the lowest of the ACs for that particular duration. Abbreviation: —, not derived for the endpoint for this duration. posure ceased when xylene is undetectable in the blood, even though these ef- fects are generally believed to depend on circulating blood concentrations of the parent compound. This is important in reducing uncertainties in AC derivations. REFERENCES Abdel-Rahman, M.S., and A.M. Kadry. 1995. Studies on the use of uncertainty factors in deriving RfDs. Hum. Ecol. Risk Assess. 1(5):614-624. ACGIH (American Conference of Governmental Industrial Hygienists). 1997. Threshold Limit Values for Chemical Substances and Physical Agents. Biological Exposure Indices. ACGIH, Cincinnati, OH ATSDR (Agency for Toxic Substances and Disease Registry). 2007. Toxicological Pro- file for Xylene. U.S. Department of Health and Human Services, Public Health

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