12
Xylene

This chapter summarizes the relevant epidemiologic and toxicologic studies of xylene. Xylene is usually found as a mixture of three isomers: m-xylene, o-xylene, and p-xylene, with the m- isomer predominating. In this profile, the term xylene refers to the mixture of isomers unless otherwise stated. Small amounts of benzene and ethyl benzene may be present in technical formulations of xylene, but these chemicals are not considered in this document.

Selected chemical and physical properties, toxicokinetic and mechanistic data, and inhalation exposure levels from the National Research Council (NRC) and other agencies are presented. The committee considered all that information in its evaluation of the Navy’s current and proposed 1-h, 24-h, and 90-day exposure guidance levels for xylene. The committee’s recommendations for xylene exposure guidance levels are provided at the conclusion of this chapter with a discussion of the adequacy of the data for defining them and research needed to fill the remaining data gaps.

PHYSICAL AND CHEMICAL PROPERTIES

Xylene is a colorless, combustible, sweet-smelling liquid (NRC 1984). The odor threshold for xylene has been reported to range from 0.09 to 0.4 ppm. Selected physical and chemical properties are listed in Table 12-1.

OCCURRENCE AND USE

Xylene is a component of gasoline, a raw material in the production of many industrial chemicals, and a solvent (Cannella 1998). Xylene has been measured in outdoor and indoor air. The Agency for Toxic Substances and Disease Registry (ATSDR 2005) reported concentrations of 1-30 ppb in outdoor



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12 Xylene This chapter summarizes the relevant epidemiologic and toxicologic stud- ies of xylene. Xylene is usually found as a mixture of three isomers: m-xylene, o-xylene, and p-xylene, with the m- isomer predominating. In this profile, the term xylene refers to the mixture of isomers unless otherwise stated. Small amounts of benzene and ethyl benzene may be present in technical formulations of xylene, but these chemicals are not considered in this document. Selected chemical and physical properties, toxicokinetic and mechanistic data, and inhalation exposure levels from the National Research Council (NRC) and other agencies are presented. The committee considered all that information in its evaluation of the Navy’s current and proposed 1-h, 24-h, and 90-day expo- sure guidance levels for xylene. The committee’s recommendations for xylene exposure guidance levels are provided at the conclusion of this chapter with a discussion of the adequacy of the data for defining them and research needed to fill the remaining data gaps. PHYSICAL AND CHEMICAL PROPERTIES Xylene is a colorless, combustible, sweet-smelling liquid (NRC 1984). The odor threshold for xylene has been reported to range from 0.09 to 0.4 ppm. Selected physical and chemical properties are listed in Table 12-1. OCCURRENCE AND USE Xylene is a component of gasoline, a raw material in the production of many industrial chemicals, and a solvent (Cannella 1998). Xylene has been measured in outdoor and indoor air. The Agency for Toxic Substances and Disease Registry (ATSDR 2005) reported concentrations of 1-30 ppb in outdoor 276

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277 Xylene TABLE 12-1 Physical and Chemical Data on Xylene Synonyms and trade Dimethylbenzene (1,2-, 1,3-, or 1,4-); xylol; m-xylene (m- names isomer); o-xylene (o- isomer); p-xylene (p- isomer); methyl toluene CAS registry number 1330-20-7 108-38-3 (m- isomer) 95-47-6 (o- isomer) 106-42-3 (p- isomer) Molecular formula C8H10 Molecular weight 106.16 Boiling point 137-140ºC Melting point No data on mixture −47.4ºC (m- isomer) −25ºC (o- isomer) 13-14ºC (p- isomer) Flash point 29 ºC Explosive limits NA Specific gravity 0.864 at 20ºC/4ºC Vapor pressure 6.72 mm Hg at 21ºC Solubility Practically insoluble in water; miscible with absolute alcohol, ether, many other organic liquids 1 ppm = 4.34 mg/m3; 1 mg/m3 = 0.23 ppm Conversion factors Abbreviations: NA, not available or not applicable. Sources: Vapor pressure from ATSDR 1995; specific gravity from HSDB 2005; all other data from Budavari et al. 1989. air and 1-10 ppb in indoor air. Major sources of xylene in outdoor air are emis- sions from vehicles, chemical plants, and paints. Sources in indoor air are ciga- rette smoke and consumer products. Xylene has been detected in some foods. Sources of xylene in a submarine are paints and coatings (Crawl 2003). Holdren et al. (1995) reported the results of air sampling at three locations con- ducted over 6 h during the missions of two submarines. Data were provided on p-xylene and o-xylene. Sampling indicated concentrations of p-xylene of 15.6- 20.2 ppb in one submarine, depending on the collection method and location, and concentrations of 7.5-12 ppb in the other submarine, depending on the col- lection method and location. Concentrations of o-xylene ranged from 28.5 to 38.6 ppb, depending on the collection method and location on one submarine, and from 6.3 to 16 ppb on the other submarine, depending on the collection method and location. Raymer et al. (1994) reported the results of a similar sam- pling exercise (two submarines, three locations, and sampling duration of 6 h).

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278 Exposure Guidance Levels for Selected Submarine Contaminants Reported concentrations of a “xylene isomer” were 4.6 and 12 ppb in the fan rooms, 6.9 and 16 ppb in the galleys, and 6.9 and 23 ppb in the engine rooms. Data were also provided on a “xylene isomer + C10H22 isomer,” but the propor- tions of the two components in the mixture were not stated. The committee notes that the results presented by Raymer et al. (1994) and Holdren et al. (1995) rep- resent one-time sampling events on four submarines. Whether the reported con- centrations are representative of the submarine fleet is not known, particularly inasmuch as few details were provided about the conditions on the submarines when the samples were taken. SUMMARY OF TOXICITY Inhaled xylene is rapidly absorbed and metabolized. It is excreted almost exclusively in the urine of humans as methylhippuric acid isomers but in the urine of animals as methylhippuric acid isomers and toluic acid glucuronides. Elimination is biphasic; the elimination half-life for the first phase is about 1 h, and that for the second is about 20 h. Xylene is an irritant of eyes and mucous membranes at sufficiently high concentrations and predominantly a central nervous system (CNS) depressant. No substantive differences in potency among the isomers have been identified after inhalation exposure. Acute and longer-term exposures to xylene result in irritation of the eyes, nose, and throat. Early symptoms of CNS disturbances are headache, nausea, fatigue, irritability, dizziness, vertigo, impaired concentration, and confusion. Reproductive or developmental toxicity has not been observed in males exposed to xylene. Xylene is neither genotoxic nor classified as a human carcinogen by the International Agency for Research on Cancer (IARC) or the U.S. Environmental Protection Agency (EPA). Effects in Humans The clinical toxicology of xylene exposure has been summarized (see ACGIH 2001; ATSDR 1995; EPA 2003, 2005), and only data relevant to deri- vation of submarine EEGL and CEGL values are discussed below. Accidental Exposures Of three men exposed to xylene at an estimated concentration of 10,000 ppm for at least 15 h, one died, and the other two were admitted to a hospital unconscious (Morley et al. 1970). The three men had been employed to paint a double-bottom tank in the engine room of a ship with a paint containing 34% solvent (by weight), of which 90% was xylene and only a trace was toluene. The men started work at 10:30 a.m. and were found unconscious at 5 a.m. the next day. The deceased exhibited pulmonary congestion. One of the patients recov- ered consciousness after admission and was confused and amnesic, had slurred

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279 Xylene speech, and was ataxic on walking. Within 24 h after admission, he was fully conscious and alert; by 48 h, the ataxia had disappeared. A slight nonsignificant increase in serum transaminase occurred over 48 h before returning to normal. On admission, the other patient was unconscious and hypothermic and exhibited medium-grade moist rales in the lungs. He regained consciousness after 5 h of treatment with tracheal aspiration and oxygen but remained amnesic for 2-3 days. Renal damage was evident in an increase in blood urea from 59 mg/100 mL to 204 mg/100 mL measured 3 days after admission. Slight hepatic impair- ment was observed with a rise in serum transaminase to 100 IU over 48 h and thereafter a return to normal. A variety of signs and symptoms have been identified in case reports of humans exposed to xylene as a paint component or laboratory solvent, including eye irritation, irritation of the nose and throat, headache, dizziness, vertigo, nau- sea, vomiting, and signs similar to those of slight drunkenness (Goldie 1960; Klaucke et al. 1982). In one report, workers noticed an unusual odor 15-30 min before onset of symptoms; exposure concentrations (of unknown duration) were estimated to be as high as 700 ppm (Klaucke et al. 1982). Experimental Studies Groups of six or seven volunteers were exposed for 15 min once a day to air containing mixed xylenes at 110, 230, 460, or 690 ppm (Carpenter et al. 1975a,b). Volunteers recorded responses at 1-min intervals throughout the expo- sure. At 110 ppm, one of six subjects experienced throat discomfort; at 230 ppm, one of seven subjects reported eye irritation, tears, and dizziness or light- headedness. None of those exposed at 110 or 230 ppm complained of throat irritation. At 460 ppm, four of six subjects reported mild eye irritation, and one of the four left the chamber; a fifth reported mild dizziness; and the sixth re- corded mild nose and throat irritation. Exposure at 690 ppm resulted in dizziness or light-headedness in four of six subjects (mild in three, and a slight loss of balance in the fourth). The authors concluded that xylene at 100 ppm would not be objectionable to most people; the volunteers did not believe that xylene at 690 ppm could be tolerated over an 8-h workday. Male college volunteers were exposed to mixed xylenes at 0, 100, 200, or 400 ppm for 30 min (Hastings et al. 1986). The effects of exposure to xylene were mild. Eye irritation was reported by 56%, 60%, 70%, and 90% of the sub- jects at 0, 100, 200, and 400 ppm, respectively. No definitive increase was noted in the exposed groups compared with the control group in nose or throat irrita- tion, eye blinks per minute, respiration rate, or performance of behavior tasks. Groups of five healthy volunteers were exposed to xylene at 0, 100, or 300 ppm for 70 min on one of 3 days (Gamberale et al. 1978). In a second experi- ment, eight of the volunteers who participated in the first study were exposed to xylene at 300 ppm for 70 min; they exercised (at 100 W) on a bicycle for the first 30 min of exposure. Although a slight increase in frequency of headache,

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280 Exposure Guidance Levels for Selected Submarine Contaminants sickness, and intoxication was noted, the numbers of subjects with these com- plaints were not indicated. The authors stated that most volunteers reported no or negligible subjective symptoms and that xylene exposure at rest did not sig- nificantly affect the results of performance tests of subjects exposed at 100 or 300 ppm. Xylene exposure combined with 100-W exercise, however, impaired performance on all tests. Healthy male volunteers were exposed in random sequence to air contain- ing toluene at 100 ppm, xylene at 100 ppm, or a mixture of toluene at 50 ppm and xylene at 50 ppm, or to control air for 4-h sessions; exposure sessions were separated by 7-day intervals (Dudek et al. 1990). A battery of nine psychologic tests was administered 1 h before exposure, at the beginning of exposure, and 3 h into exposure. The 3-h xylene exposure significantly increased simple reaction time and choice reaction time; no significant effects were observed in the other seven tests. Male student volunteers were divided into three groups and exposed to m- xylene at a fixed concentration of 200 ppm, m-xylene at a basal concentration of 135 ppm with 20-min peak concentrations of 400 ppm at the beginning of morn- ing and afternoon sessions, or control air (Seppalainen et al. 1989; Seppalainen et al. 1991; Laine et al. 1993). Exposures were for 3 h in the morning and 40 min in the afternoon with a 40-min break between morning and afternoon expo- sures. The subjects were exposed either at rest or with 10 min of exercise (at 100 W) at the beginning of each exposure session; exposure occurred on 6 separate days with a minimum of 5 days between exposures. Xylene exposure at rest did not result in any consistent effects on visual evoked potentials (VEPs), but expo- sure with exercise resulted in a minor statistically significant decrease in VEPs in two subjects given xylene at fluctuating concentrations of 400 ppm (the sec- ond condition described above). No exposure-related changes were noted in brainstem auditory evoked potentials, but the peak exposure concentration (400 ppm) resulted in decreased body sway in both sedentary and exercising subjects. Six of 17 healthy male volunteers were exposed to m-xylene at 100 ppm for 3 h in the morning with hourly peaks of 200 ppm and for 3 h in the afternoon at 200 ppm with hourly peaks of 400 ppm (Savolainen and Linnavuo 1979). A 1-h break separated the exposure sessions. Body balance was not affected by the morning exposure, but impairment of body balance was noted in subjects during the afternoon session. However, tolerance of xylene has been observed with continuing exposure (Riihimaki and Savolainen 1980; Savolainen and Rii- hamaki 1981). Using a similar experimental design, Savolainen and co-workers (1984, 1985a, 1985b) exposed nine male volunteers to m-xylene at a fixed concentra- tion of 200 ppm m-xylene or a basal concentration of 135 ppm with 20-min peak concentrations of 400 ppm at the beginning of the morning and afternoon ses- sions. The subjects were exposed when sedentary or with 10 min of exercise (at 100 W) at the beginning of each exposure session. Exposures occurred at 6-day intervals during 6 successive weeks; end points monitored were body sway along the anteroposterior and lateral axis, simple and choice reaction times, and

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281 Xylene auditory and visual stimuli. The anteroposterior axis was impaired at peak expo- sure with opposite results when body sway was measured along the lateral axis. No consistent significant effects were noted on reaction times, and effects were observed only at peak exposure (400 ppm). Six male volunteers were exposed to m-xylene at 100 or 200 ppm 6 h/day, 3 days/week for 2 weeks (Savolainen et. al. 1979, 1980; Riihimaki and Savolainen 1980). In one experiment, a peak concentration of 400 ppm was used. Significant increases in reaction time and some impairment of equilibrium were observed during the first week of exposure at 100 ppm. Those transient effects reappeared during the second week at higher concentrations. There were no changes in dexterity or visual functions. In four male volunteers exposed to p-xylene at 70 ppm for 4 h, there was no effect on choice reaction time, simple reaction time, or short-term memory performance measured during exposure at 1, 2, and 4 h (Olson et al. 1985). In addition, no changes from baseline were noted in measured heart rate or subjec- tive symptoms as reported on a questionnaire administered at exposure termina- tion. Twenty-three male volunteers, divided into four or five per group, were exposed to m-xylene, p-xylene, or toluene at 100 or 200 ppm for 3 or 7 h with a 1-h break at some point after the beginning of exposure (Ogata et al. 1970). Xy- lene exposures did not significantly affect blood pressure, pulse rate, flicker value, or reaction time as measured at the beginning and end of exposure. Nine male students were exposed to m-xylene at 200 ppm 4 h/day once a week for 6 consecutive weeks with a 6-day interval between successive expo- sures (Savolainen et al. 1981; Seppalainen et al. 1983). Xylene exposure did not result in any marked adverse effects, but a slight improvement was observed in performance as measured by a decrease in body sway, a shortened reaction time, and an increase in the critical flicker fusion thresholds. No significant effects in pattern VEP were observed. Twelve healthy male volunteers (four groups of three) were exposed at rest to xylene at 200 ppm for 5.5 h on 2 days separated by a week (Laine et al. 1993). There were no effects on body sway or reaction times or on auditory, visual, and associative signals. Nine males and seven females were divided into three “daily groups” and exposed at rest to p-xylene vapors for 1, 3, or 7.5 h daily (Hake et al. 1981). All subjects were exposed to xylene at 100 ppm on 5 consecutive days in the first week. The males were exposed at 20 ppm in the second week, at 150 ppm in the third week, and at fluctuating concentrations of 50-150 ppm (time-weighted average [TWA], 100 ppm) during the fourth week (5 days/week). Toxicity was evaluated with neurologic, cardiopulmonary-function, cognitive, and subjective tests. In males, eye irritation was noted during the weeklong exposures seven times at 100 ppm, eight times at 150 ppm, and three times during the 4 control days. One subject wearing contact lenses in the 7.5-h exposure noted eye irrita- tion almost every day; another complained twice at 100 ppm and three times at 150 ppm. No irritation was noted by the males during any 3-h exposure, al-

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282 Exposure Guidance Levels for Selected Submarine Contaminants though one complained of eye irritation during the 1-h exposure to 150 ppm. The exposures did not result in any significant neurologic, cardiopulmonary, or cognitive abnormalities in the males or females. Irritation reported by the female volunteers was confined to the nose and throat. It is known that xylene vapor may be absorbed through the skin (Kezic et al. 2000, as cited in Kezic et al. 2004). Recent experimental determinations of percutaneous absorption in male human volunteers (21-53 years old) after a maximal exposure duration of 180 min (range, 20-160 min) have been incorpo- rated into an estimate of the dermal contribution during whole-body xylene ex- posure (Kezic et al. 2004). If it is assumed that the exposed area of skin of a clothed person is 1.24 m2, 58% of total adult body surface (Loizou et al. 1999, as cited in Kezic et al. 2004), the dermal contribution during an assumed 3-h whole-body exposure would be 0.2% (Kezic et al. 2004). That contribution to whole-body absorption is negligible. Therefore, the present analysis focuses on vapor inhalation as the primary exposure route of concern. Occupational and Epidemiologic Studies The most frequent symptoms reported in workers exposed to xylene are headache, fatigue, lassitude, irritability, nausea, anorexia, and flatulence (Ger- arde 1960). Workers exposed to commercial grade xylene vapors at over 200 ppm have complained of nausea, vomiting, heartburn, and loss of appetite (Browning 1965). Uchida et al. (1993) reported a significant increase in the prevalence of eye, nose, and throat irritation, anxiety, forgetfulness, inability to concentrate, and dizziness in workers chronically exposed to mixed xylene va- pors. The exposure intensity was broken into 1-20 ppm and greater than 21 ppm, with a geometric mean concentration of 14 ppm and an average exposure of 7 years. The symptoms were reported in a questionnaire survey of 175 workers whose exposure to xylene was at an average of 21 ppm. No abnormalities were seen in physical examination, clinical chemistry, or hematology. It is unclear whether the worker complaints reported resulted from short-term exposure at peak concentrations of xylene. Furthermore, no day-to-day or week-to-week data analysis or acute exposure excursions were presented (workers were stated to have been exposed to xylene at up to 175 ppm). Separate groups were not adequately described in the study, nor was there a concentration-dependent in- crease in symptoms (Table 12-2). Effects in Animals Several reviews of the animal-toxicity data on xylene are available (see ATSDR 1995; EPA 2003, 2005). Because primarily human data were used to derive the EEGL and CEGL values here, the relevant supporting animal data are only briefly discussed below.

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TABLE 12-2 Effects of Xylene in Controlled Human Studies Concentration (ppm) Time Isomer Subjects and Effects Reference 110, 230, 460, 690 15 min daily Mixed Healthy subjects (groups of 6 or 7) Carpenter et al. At 110 ppm, 1 of 6 had throat discomfort; at 230 ppm, 1 of 7 had eye irritation, 1975b tears, dizziness or light-headedness; at 460 ppm, 4 of 6 had mild eye irritation, 1 of 6 had mild dizziness, 1 of 6 had mild nose and throat irritation; at 690 ppm, 4 of 6 had dizziness or light-headedness 0, 100, 200, 400 30 min Mixed Healthy male students (50) Hastings et al. Eye irritation reported by 56% of controls, 60% of subjects exposed at 100 ppm, 1986 70% of subjects at 200 ppm, and 90% of subjects at 400 ppm; no definitive in- crease noted between exposed and control groups in nose or throat irritation, eye blinks per minute, respiration rate, or performance of behavioral tasks 0, 100, 300 70 min NA Healthy subjects (groups of 5) Gamberale et al. No reported effect on 5 performance tests. 1978 300 with exercise 70 min Healthy subjects (8 subjects from first study) Exposure combined with 100-W exercise impaired performance on all tests 100 3h NA Healthy males (10) Dudek et al. 1990 Decreased performance in simple and choice reaction times; no significant effects on other 7 psychologic tests 135-400 3 h in morning, m- Healthy males (9) Seppalainen et al. 40 min in after- No consistent effects on VEPs while at rest; exposure with exercise resulted in 1989 noon minor statistically significant decrease in VEP values in two subjects given fluctu- ating concentrations of 400 ppm; no exposure-related changes noted in brainstem auditory evoked potentials, but peak exposure concentration (400 ppm) resulted in decreased body sway in both sedentary and exercising subjects (Continued) 283

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TABLE 12-2 Continued 284 Concentration (ppm) Time Isomer Subjects and Effects Reference 200-400 4h m- Healthy subjects (9) Seppalainen et al. Effects of short-term exposure were minor, and no deleterious effects noted 1991 200 5.5 h m- Healthy males (12) Laine et al. 1993 No effect on body sway or reaction times, or auditory, visual, and associative Signals 100-400 3 h in morning, m- Healthy males (6 of 17 volunteers) Savolainen and 3 h in evening Body balance not affected by exposure in morning but affected by afternoon Linnavuo 1979 Exposure 100-400 3 h in morning, m- Healthy males (6 of 17) Riihimaki and 3 h in evening Tolerance of xylene for effects of body sway and balance was observed with Savolainen 1980; continuing exposure Savolainen and Riihamaki 1981 135-400 4h m- Healthy males (9) Savolainen et al. Anteroposterior axis impaired at peak exposure with opposite results when body 1984, 1985a, sway was measured along lateral axis; no consistent significant effects noted on 1985b reaction time, and effects observed only at 400 ppm p- Healthy males (4) Olson et al. 1985 70 4h No effect on choice reaction time, simple reaction time, short-term memory, heart rate, or subjective symptoms 100, 200 3 or 7 h with m-, p- Healthy males (23), 4 or 5 per group Ogata et al. 1970 1-h break m- or p-xylene exposure had no effect on blood pressure, pulse rate, flicker value, or reaction time

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200 4 h/day for 6 m- Healthy males (9) Savolainen et al. weeks No marked adverse effects but slight improvement in performance as measured 1981; Sep- by decrease in body sway, shortened reaction time, and increase in critical palainen et al. flicker fusion thresholds; no significant effects on pattern VEP 1983 20, 100, 150 1, 3, or 7.5 h p- Healthy males (9) and females (7) Hake et al. 1981 daily In males, eye irritation noted 7 times at 100 ppm, 8 times at 150 ppm, and 3 times on control days; no irritation noted by males during any 3-h exposure, although one complained of eye irritation during 1-h exposure at 150 ppm; no significant neurologic, cardiopulmonary, or cognitive abnormalities in males or females; irri- tation in female subjects confined to nose and throat Abbreviations: NA, not available; VEP, visual evoked potentials. 285

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286 Exposure Guidance Levels for Selected Submarine Contaminants Acute Toxicity The 4-h LC50s of xylene range from 3,907 to 11,000 ppm in rats and mice (EPA 2005). In rats exposed to mixed xylene for 4 h, no adverse effects were noted at 580 ppm, and the poor coordination noted after a 2-h exposure at 1,300 ppm was reversible after exposure termination (Carpenter et al. 1975b). Expo- sure at 1,600 ppm for 4 h resulted in hyperactivity, fine tremors, and unsteadi- ness (Bushnell 1989). Female rats exposed to p-xylene at 1,000, 1,500, or 2,000 ppm for 4 h developed increased serum enzyme activities indicative of acute hepatic damage (Patel et al. 1979). A minimal narcotic concentration of m- xylene in the rat was 2,100 ppm for 4 h of exposure (Molnár et al. 1986). Repeated Exposure and Subchronic Toxicity Rats, guinea pigs, monkeys, and dogs that were exposed to o-xylene at 78 ppm for 90 days or at 780 ppm for 6 weeks had no significant changes in body weight or hematology (Jenkins et al. 1970). In a study in which rats and dogs inhaled mixed xylene at 180, 460, or 810 ppm for 13 weeks, there were no de- tectable changes in body weight, hematology, blood chemistry, urinalysis, organ weights, or histopathology at any of the concentrations tested (Carpenter et al. 1975a,b). In another study, however, when rats were exposed to mixed xylenes at 690 ppm 8 h/day, 6 days/week for 110-130 days and rabbits were exposed at 1,200 ppm 8 h/day, 6 days/week for 40-50 days, some of the animals showed signs of hind limb paralysis and weight loss (Fabre et al. 1960). Chronic Toxicity Rats exposed to o-xylene at 1,090 ppm 8 h/day, 7 days/week for 6-12 months had decreased body weight, increased absolute and relative liver weight, and induction of enzymes of the hepatic mixed-function oxidase system (Tátrai et al. 1981). In another study, rats were exposed to mixed xylenes at 0, 140, 350, or 920 ppm 8 h/day, 7 days/week for 6 weeks and then 5 days/week for 6 months (Ungváry 1990). The author did not consider exposure to those concen- trations to have produced any significant adverse effects. Rats that inhaled m- xylene at 100 ppm for 6 months or at 1,000 ppm for 3 months were evaluated with a rotarod test to measure motor coordination (Korsak et al. 1992). Rats ex- posed at 1,000 ppm had about 60% failures in the test compared with 35% in the 100-ppm rats and none in the controls. Furthermore, exposure at 100 ppm re- sulted in nearly a 50% reduction in spontaneous motor activity. In another study by Korsak et al. (1994), m-xylene at 50 ppm 6 h/day, 5 days/week for 3 months was considered a no-observed-adverse-effect level (NOAEL) for the rotarod test.

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287 Xylene Reproductive Toxicity in Males The male reproductive system appears not to be a primary target of xylene toxicity. For example, no effects were observed in the testes, accessory glands, or circulating male hormone concentrations in male Sprague-Dawley rats ex- posed to mixed xylene at a high dose (1,000 ppm) for 61 days (Nylen et al. 1989). And no animal studies have shown any evidence of developmental toxic- ity when males were exposed to xylene (reviewed in EPA 2005). The human workplace data regarding the reproductive and developmental effects of xylene are complicated by concurrent exposures to other solvents, small numbers of subjects tested, and absence of quantified exposure concentra- tions (summarized in ATSDR 1995). Immunotoxicity Workers exposed to xylene have manifested decreased lymphocytes and serum complement (Moszczynsky and Lisiewicz 1983, 1984). However, the workers were exposed concurrently to other chemicals, most notably to the trace quantities of benzene often present in technical-grade xylene. Genotoxicity Mixed xylene and the individual isomers have been tested for genotoxicity in a variety of in vitro and in vivo assays (reviewed in ATSDR 1995). Results of the various assays indicate that in vitro or in vivo exposure to mixed xylene and xylene isomers is not genotoxic or clastogenic. Furthermore, all studies evalu- ated by the GENETOX panel were negative except for one on which no conclu- sion was drawn (GENETOX 1992). Xylene was not mutagenic in bacterial test systems or cultured lymphoma cells and has not induced chromosomal aberra- tions or sister-chromatid exchanges in Chinese hamster ovary cells or cultured human lymphocytes (EPA 2005). Xylene has not induced chromosomal aberra- tions in rat bone marrow or in micronuclei in mouse bone marrow or caused sperm-head abnormalities (reviewed in EPA 2005). Carcinogenicity Animal studies have not assessed carcinogenicity of inhalation exposure to xylene; rather, xylene has been administered orally (Maltoni et al. 1985; NTP 1986) or dermally in an initiation-promotion study (Pound 1970). The National Toxicology Program (NTP 1986) found no significant dose-related neoplastic effects in male or female F344/N rats or B6C3F1 mice exposed at up to 500 mg/kg per day (rats) or 1,000 mg/kg per day (mice) 5 days/week for 103 weeks. Although xylene is not classified as a human carcinogen, some human oc- cupational studies have suggested that it is associated with an increased risk of

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288 Exposure Guidance Levels for Selected Submarine Contaminants cancer (EPA 2005). However, the studies are weakened by small sample sizes, lack of quantified exposure concentrations, or concurrent exposures to other solvents. In addition, there are inconsistencies in cancer expression between studies. Animal carcinogenicity studies have been limited to equivocal oral ex- posure (Maltoni et al. 1985; NTP 1986) and a dermal initiation-promotion study (Pound 1970). IARC (1999) has concluded that there is inadequate evidence of the carcinogenicity of xylene and therefore states that xylene is not classifiable as to its carcinogenicity in humans (IARC 1999). EPA (2003) considers the data inadequate for an assessment of the carcinogenic potential of xylene. TOXICOKINETIC AND MECHANISTIC CONSIDERATIONS Inhaled xylene is rapidly absorbed from the lungs into the blood and is distributed to the kidneys, brain, subcutaneous body fat, bone marrow, spinal cord and spinal nerves, liver, and nasal mucosa. It is rapidly eliminated from those tissues with the exception of fat (Bergman 1983; Carlsson 1981; Kumara- thasan et al. 1997). Circulating xylene is associated primarily with serum pro- teins in human blood (Riihimaki et al. 1979). The primary metabolic pathway in humans is side-chain dehydroxylation by hepatic mixed-function oxidases to toluic acids, which are then conjugated with glycine to form methlyhippuric acid isomers that are excreted in the urine (Ogata et al. 1980; Tardif et al. 1989). In animals, xylene is excreted in the urine as methylhippuric acid isomers and toluic acid glucuronides (Ogata et al. 1980). It has been estimated that excretion of xylene in air and urine has an initial half-life of 1 h followed by a slow phase with an estimated 20-h half-life (Riihimaki et al. 1979; Riihimaki and Savolainen 1980). Xylene is an irritant of eyes and mucous membranes. Regarding systemic effects, the most prominent and consistent in humans and animals is CNS dis- turbances. CNS toxicity resulting from exposure to xylene at high concentra- tions has been attributed to its liposolubility (Desi et al. 1967; Gerarde 1959; Savolainen and Pfaffli 1980; Tahti 1992). Although the mechanism of action remains unknown, it has been suggested that xylene acts like other general anes- thetic agents by disturbing the action of proteins essential for normal neuronal function (ATSDR 1995). Others have suggested that metabolic intermediates may be responsible for the toxic effects of xylene (Savolainen and Pfaffli 1980). INHALATION EXPOSURE LEVELS FROM THE NATIONAL RESEARCH COUNCIL AND OTHER ORGANIZATIONS A number of organizations have established or proposed inhalation expo- sure levels or guidelines for xylene. Selected values are summarized in Table 12-3.

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289 Xylene TABLE 12-3 Selected Inhalation Exposure Levels for Xylene from the NRC and Other Agenciesa Organization Type of Level Exposure Level (ppm) Reference Occupational ACGIH TLV-TWA 100 ACGIH 2001 TLV-STEL 150 NIOSH REL-TWA 100 NIOSH 2005 REL-STEL 150 OSHA PEL-TWA 100 29 CFR 1910.1000 Spacecraft NASA SMAC Garcia 1996 1-h 100 24-h 100 30-day 50 180-day 50 Submarine NRC EEGL NRC 1984 1-h 200 24-h 100 CEGL 90-day 50 General Public ATSDR Acute MRL 2.0 ATSDR 2005 Intermediate 0.6 MRL Chronic MRL 0.05 NAC/NRC AEGL-1 (1-h) 130 EPA 2005 AEGL-2 (1-h) 920 AEGL-1 (8-h) 130 AEGL-2 (8-h) 400 a The comparability of EEGLs and CEGLs with occupational-exposure and public-health standards or guidance levels is discussed in Chapter 1 (“Comparison with Other Regulatory Standards or Guidance Levels”). Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; AEGL, acute exposure guideline level; ATSDR, Agency for Toxic Substances and Disease Registry; CEGL, continuous exposure guidance level; EEGL, emergency exposure guidance level; MRL, minimal risk level; NAC, National Advisory Committee; NASA, National Aeronautics and Space Administration; NIOSH, National Institute for Occupational Safety and Health; NRC, National Research Council; OSHA, Occupational Safety and Health Administration; PEL, permissible exposure limit; REL, recommended exposure limit; SMAC, spacecraft maximum allowable concentration; STEL, short-term exposure limit; TLV, Threshold Limit Value; TWA, time-weighted average.

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290 Exposure Guidance Levels for Selected Submarine Contaminants COMMITTEE RECOMMENDATIONS The committee’s recommendations for EEGL and CEGL values for xy- lene are summarized in Table 12-4. The current and proposed U.S. Navy values are provided for comparison. 1-Hour EEGL Xylene vapor at low concentrations is an irritant of eyes and mucous membranes, and at higher concentrations it results in signs of CNS depression. For CNS effects, several acute studies in volunteers reported that exposures to xylene at 70-400 ppm for up to 4 h either failed to affect performance of sub- jects on neurobehavioral tests (Olson et al. 1985; Gamberale et al. 1978; Hast- ings et al. 1986; Seppalainen et al. 1989; Seppalainen et al. 1991) or actually improved performance (Laine et al. 1993; Savolainen et al. 1984, 1985b). But, other studies reported a correlation between acute exposure to m-xylene at 100- 400 ppm for up to 4 h and impaired performance (Savolainen et al. 1979, 1980, 1984, 1985a; Savolainen and Linnavuo 1979; Savolainen and Riihimaki 1981; Dudek et al. 1990; Gamberale et al. 1978; Seppalainen et al. 1983, 1989, 1991). In six volunteers exposed to m-xylene at 100 or 200 ppm 6 h/day, 3 days/week for 2 weeks, significant increases in reaction time and some impairment of equi- librium were observed, but the effects were transient, and no changes were noted in manual dexterity or visual function (Savolainen et al. 1979, 1980; Riihimaki and Savolainen 1980). Dizziness occurred in one of six subjects exposed to xy- lene at 460 ppm for 15 min (Carpenter et al. 1975a), and there was no impair- ment in performance tests in 15 men exposed at 299 ppm for 70 min (Gamberale et al. 1978) or among 10 men who inhaled xylene at 369 ppm for 30 min (Hast- ings et al. 1986). Nevertheless, xylene exposure at 100 ppm for 3 h resulted in reduced performance in two (simple reaction and choice reaction times) of nine psychologic tests (Dudek et al. 1990). Results on those two, however, were not affected in other studies conducted at equivalent or higher concentrations of TABLE 12-4 Emergency and Continuous Exposure Guidance Levels for Xylene U.S. Navy Values, ppm Exposure Level Committee Recommended Values, ppm Current Proposed EEGL 1-h 200 100 200 24-h 100 100 100 CEGL 90-day 50 50 50 Abbreviations: CEGL, continuous exposure guidance levels; EEGL, emergency exposure guidance level.

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291 Xylene xylene and durations of exposure (Hastings et al. 1986; Olson et al. 1985; Laine et al. 1993; Savolainen et al. 1985b). Thus, although five of the 24 neurologic performance and cognitive tests performed by various investigators showed ef- fects, overall the results were inconsistent. The 1-h EEGL is based on notable discomfort in humans in the form of eye irritation. Eye irritation was reported in four of six subjects exposed to mixed xylene at 460 ppm for 15 min and in one of seven at 230 ppm; no eye irritation was noted at 110 ppm (Carpenter et al. 1975b). Slight eye irritation was noted in humans exposed to mixed xylene at 100, 200, or 400 ppm for 30 min (Hastings et al. 1986). Irritation was noted in 56% of the controls, 60% of those exposed at 100 ppm, 70% at 200 ppm, and 90% at 400 ppm. Males ex- posed to p-xylene at 100 or 150 ppm 7.5 h/day for 5 consecutive days reported eye irritation seven times and eight times during 5 days of exposure, respec- tively (Hake et al. 1981). One volunteer wearing contact lenses reported eye irritation almost every day. No irritation was reported during any 3-h exposure, although one subject complained of eye irritation during a 1-h exposure to p- xylene at 150 ppm. On the basis of those data and a weight-of-evidence ap- proach, a 1-h EEGL of 200 ppm was selected. That exposure concentration re- sulted in minimal or no eye irritation in 1-h exposures in numerous controlled studies that evaluated xylene-induced eye and throat irritation. Thus, the com- mittee concluded that there was little justification for an intraspecies uncertainty factor. 24- Hour EEGL Xylene-induced ocular irritation depends heavily on concentration and much less on exposure duration. Humans exposed to p-xylene at 20, 100, or 150 ppm 7.5 h/day for 5 weeks reported eye irritation seven times during exposure at 100 ppm, eight times at 150 ppm, and three times during the 4 control days be- tween exposures (Hake et al. 1981). The irritation was minimal and intermittent, and there were no significant neurologic, cardiopulmonary, or cognitive abnor- malities. Therefore, a 24-h EEGL of 100 ppm was selected. The committee con- cludes that the very mild and transient irritation observed in experimental sub- jects in successive exposures at that concentration would not impair crew performance, cause irreversible harm, or have any delayed health effects. The human data, collectively, support a 24-h EEGL of 100 ppm. Because minimal or intermittent irritation in humans was the end point for the 24-h EEGL and no other effects were noted, an intraspecies uncertainty factor was not justified. 90-Day CEGL A 90-day CEGL of 50 ppm for xylene is supported by human data. Acute and short-term repeated human exposure to xylene has not reported ocular or respiratory tract irritation at concentrations less than 50 ppm. Furthermore, sev-

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292 Exposure Guidance Levels for Selected Submarine Contaminants eral studies evaluating more than 2 dozen neurologic performance and cognitive tests have shown no adverse effects of exposure at below 50 ppm (see Table 12- 2). Only five of the more than 24 tests have shown effects, and all of those were highly inconsistent. Chronic human data are limited to a study by Uchida et al. (1993) that identified a “concentration-related” increase in eye irritation, sore throat, and a “floating sensation” during the workshift. As discussed above, it is unclear whether the worker complaints resulted from short-term exposure at peak concentrations of xylene. Furthermore, no day-to-day or week-to-week data analysis or acute exposure excursions were presented (workers were stated to have been exposed to xylene at up to 175 ppm). Separate groups were not adequately described in the study, nor was there a concentration-dependent in- crease in symptoms. Thus, the data as presented by Uchida and co-workers are inadequate to derive air exposure guidance levels for xylene. Animal studies support a 90-day CEGL of 50 ppm. Using three 90-day exposure studies that included three animal species, the committee calculated 90-day CEGL values of 47 ppm, 48 ppm, and 260 ppm (Ungvary 1990; Carpenter et al. 1975b; Jenkins et al. 1970). Those values were calculated by identifying the NOAEL in each study and applying an interspecies uncertainty factor of 3 on the basis of a range of a factor of 2-3 in the minimal alveolar concentration of volatile anesthetics in humans (EPA 2005). The committee found that continuous exposure to xylene at 50 ppm for 90 days would result in minimal eye or throat irritation, if any, and that there is no evidence of systemic effects in humans exposed at that concen- tration. Therefore, the committee saw little justification for the addition of an intraspecies uncertainty factor and concluded that a 90-day CEGL of 50 ppm would not degrade crew performance or produce immediate or delayed adverse health effects. DATA ADEQUACY AND RESEARCH NEEDS The human data for determining 1- and 24-h EEGLs are fairly robust, al- though many of the studies did not specifically report sensory irritation as an end point or as a symptom. A study designed to determine the presence and de- gree of eye and throat irritation for exposure of 1 and 24 h would improve the level of confidence in the EEGL and CEGL values. Epidemiologic investiga- tions of workers exposed to xylene or longer-term controlled exposure studies of xylene at 25-75 ppm would benefit derivation of the 90-day CEGL. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 2001. Xylene. Documentation of the Threshold Limit Values and Biological Exposure Indices, 7th Ed. American Conference of Governmental Industrial Hygienists, Cincinnati, OH.

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296 Exposure Guidance Levels for Selected Submarine Contaminants Olson, B.A., F. Gamberale, and A. Iregren. 1985. Coexposure to toluene and p-xylene in man: Central nervous functions. Br. J. Ind. Med. 42(2):117-122. Patel, J.M., C. Harper, B.N. Gupta, and R.T. Drew. 1979. Changes in serum enzymes after inhalation exposure of p-xylene. Bull. Environ. Contam. Toxicol. 21(1-2):17- 24. Pound, A.W. 1970. Induced cell proliferation and the initiation of skin tumor formation in mice by ultraviolet light. Pathology 2(4):269-275. Raymer, J.H., E.D. Pellizzari, R.D. Voyksner, G.R. Velez, and N. Castillo. 1994. Qualita- tive Analysis of Air Samples from Submarines. Project RTI/5937/00-01F. Pre- pared for Geo-Centers, Inc., Newton Upper Falls, MA, by Research Triangle Insti- tute, Research Park, NC. December 22, 1994. Riihimäki, V., and K. Savolainen. 1980. Human exposure to m-xylene: Kinetics and acute effects on the central nervous system. Ann. Occup. Hyg. 23(4):411-422. Riihimäki, V., P. Pfäffli, K. Savolainen, and K. Pekari. 1979. Kinetics of m-xylene in man: General features of absorption, distribution, biotransformation and excretion in repetitive inhalation exposure. Scand. J. Work Environ. Health 5(3):217-231. Savolainen, K., and M. Linnavuo. 1979. Effects of m-xylene on human equilibrium measured with a quantitative method. Acta Pharmacol. Toxicol. 44(4):315-318. Savolainen, H., and P. Pfaffli. 1980. Dose-dependent neurochemical changes during short-term inhalation exposures to m-xylene. Arch. Toxicol. 45(2):117-122. Savolainen, K., and V. Riihimäki. 1981. An early sign of xylene effect on human equilib- rium. Acta Pharmacol. Toxicol. 48(3):279-283. Savolainen, K., V. Riihimäki, and M. Linnoila. 1979. Effects of short-term xylene expo- sure on psychophysiological functions in man. Int. Arch. Occup. Environ. Health 44(4):201-212. Savolainen, K., V. Riihimäki, A.M. Seppäläinen, and M. Linnoila. 1980. Effects of short- term m-xylene exposure and physical exercise on the central nervous system. Int. Arch. Occup. Environ. Health 45(2):105-121. Savolainen, K., V. Riihimäki, A. Laine, and J. Kekoni. 1981. Short-term exposure of human subjects to m-xylene and 1,1,1-trichloroethane. Int. Arch. Occup. Environ. Health 49(1):89-98. Savolainen, K., J. Kekoni, V. Riihimäki, and A. Laine. 1984. Immediate effects of m- xylene on the human central nervous system. Arch. Toxicol. 7(Suppl.):412-417. Savolainen, K., V. Riihimäki, R. Luukkonen, and O. Muona. 1985a. Changes in the sense of balance correlate with concentrations of m-xylene in venous blood. Br. J. Ind. Med. 42(11):765-769. Savolainen, K., V. Riihimäki, O. Muona, J. Kekoni, R. Luukkonen, and A. Laine. 1985b. Conversely exposure-related effects between atmospheric m-xylene concentrations and human body sense of balance. Acta Pharmacol. Toxicol. 57(2):67-71. Seppäläinen, A.M., T. Salmi, K. Savolainen, and V. Riihimäki. 1983. Visual evoked potentials in short-term exposure of human subjects to m-xylene and1,1,1- trichloroethane. Pp. 349-352 in Application of Behavioral Pharmacology in Toxi- cology, G. Zbinden, ed. New York: Raven Press. Seppäläinen, A.M., A. Laine, T. Salmi, V. Riihimäki, and E. Verkkala. 1989. Changes induced by short-term xylene exposure in human evoked potentials. Int. Arch. Oc- cup. Environ. Health 61(7):443-449. Seppäläinen, A.M., A. Laine, T. Salmi, E. Verkkala, V. Riihimäki, and R. Luukkonen. 1991. Electroencephalographic findings during experimental human exposure to m-xylene. Arch. Environ. Health 46(1):16-24.

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297 Xylene Tähti, H. 1992. The neurotoxicity of organic solvents, studied with in vitro models. ALTA 20(2):290-296. Tardif, R., J. Brodeur, and G.L. Plaa. 1989. Simultaneous high-performance liquid chro- matographic analysis of hippuric acide and ortho-, meta-, and para-methylhippuric acids in urine. J. Anal. Toxicol. 13(6):313-316. Tátrai, E., G. Ungváry, I.R. Cseh, S. Mányai, S. Szeberényi, J. Molnár, and V. Morvai. 1981. The effect of long-term inhalation of o-xylene on the liver. Pp. 293-300 in Industrial and Environmental Xenobiotics: Metabolism and Pharmacokinetics of Organic Chemicals and Metals: Proceedings of International Conference, May 27- 30, 1980, Prague, Czechoslovakia, I. Gut, M. Cikrt, and G.L. Plaa, eds. New York: Springer. Uchida, Y., H. Nakatsuka, H. Ukai, T. Watanabe, Y.T. Liu, M.Y. Huang, Y.L. Wand, F.Z. Zhu, H. Yin, and M. Ikeda. 1993. Symptoms and signs in workers exposed predominantly to xylene. Int. Arch. Occup. Environ. Health. 64(8):597-605. Ungváry, G. 1990. The effect of xylene exposure on the liver. Acta Morphol. Hung. 38(3- 4):245-258.