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6 Xylenes1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals. AEGLs rep- resent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs have been defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million [ppm] or milligrams per cubic meter [mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory 1 This document was prepared by the AEGL Development Team composed of Clau- dia Troxel (Oak Ridge National Laboratory) and Chemical Manager Loren Koller (Na- tional Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances). The NAC reviewed and revised the document and AEGLs as deemed neces- sary. Both the document and the AEGL values were then reviewed by the National Re- search Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC com- mittee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guideline reports (NRC 1993, 2001). 293

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294 Acute Exposure Guideline Levels effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects, or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure levels that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsensory effects. With increasing airborne concentrations above each AEGL, there is a progres- sive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGLs represent threshold levels for the general public, including susceptible subpopulations, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic responses, could experience the effects described at concentrations below the corresponding AEGL. SUMMARY Xylene is found in a number of consumer products, including solvents, paints and coatings, and as a blend in gasoline. Mixed xylenes are composed of three isomers: m-xylene, o-xylene, and p-xylene, with the m-isomer predominat- ing. Ethylbenzene is also present in the technical product formulation. Absorbed xylene is rapidly metabolized and is excreted almost exclusively in the urine as methylhippuric acid isomers in humans and as methylhippuric acid isomers and toluic acid glucuronides in animals. Xylene causes mucus irritation and affects the central nervous system (CNS) in humans and animals after acute inhalation exposure. Hepatic effects have been noted in humans after acute inhalation ex- posure to high concentrations and in rats after subchronic oral or inhalation ex- posure. No consistent developmental or reproductive effects were observed in the studies found in the available literature. Commercial xylene and all three isomers have generally tested negative for genotoxicity. Xylenes are currently not classifiable as to carcinogenicity by the International Agency for Research on Cancer (IARC) or the Environmental Protection Agency (EPA). The AEGL-1 is based on the no-effect level for notable discomfort in hu- man subjects. Only mild eye irritation was noted during a 30-min exposure to mixed xylenes at 400 ppm (Hastings et al. 1984). An interspecies uncertainty factor was not applied because the key study used human data. An intraspecies uncertainty factor of 3 was applied because slight eye irritation is caused by a

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295 Xylenes direct effect of the chemical and the response is not expected to vary greatly among individuals. Because irritation is considered a threshold effect, which should not vary over time, the AEGL-1 value was not scaled across time, but rather the same value is applied at all times. The resulting value of 130 ppm is supported by several other studies, including a 150-ppm p-xylene exposure re- sulting in eye irritation in a contact lens wearer (Hake et al. 1981); a 15-min exposure to mixed xylenes at 230 ppm resulting in mild eye irritation and dizzi- ness with no loss of coordination in one individual (Carpenter et al. 1975b); and a 3-h exposure to m- or p-xylene at 200 ppm (Ogata et al. 1970), a 4-h exposure to m-xylene at 200 ppm (Savolainen et al. 1981), and a 5.5-h exposure to m-xylene at 200 ppm (Laine et al. 1993), all representing no-effect levels for notable discomfort. The AEGL-2 is based on the no-effect level for impaired ability to escape. During a 4-h exposure to mixed xylenes at 1,300 ppm, rats developed poor co- ordination (slight coordination loss) after 2 h of exposure, returning to normal coordination postexposure (Carpenter et al. 1975b). The point of departure of 1,300 ppm for 2 h therefore represents the threshold for reversible equilibrium disturbances and the no-effect level for impaired ability to escape. This concen- tration and end point are consistent with the preponderance of available data for 4-h exposures in rats: the median effective concentration (EC50) for decreased rotarod performance was 1,982 ppm (Korsak et al. 1993); the minimum narcotic concentration for m-, o-, and p-xylene ranged from 1,940 to 2,180 ppm (Molnár et al. 1986); and exposure to p-xylene at 1,600 ppm resulted in hyperactivity, fine tremor, and unsteadiness (Bushnell 1989) and caused changes in the flash evoked potential suggestive of increased arousal (Dyer et al. 1988). It is as- sumed that the CNS response observed after xylene exposure is directly related to the concentration of parent material reaching the brain, and that venous blood concentrations (CV) correlate with brain concentrations. Therefore, the CV of xylene after a 2-h exposure to xylene at 1,300 ppm is expected to provide an internal dose measurement correlating with the clinical sign of poor coordina- tion. With a physiologically based pharmacokinetic (PBPK) model (see Appen- dix C), the internal dose (CV) producing impaired coordination in rats was de- termined. Then, the human PBPK model was run for each defined AEGL time period to determine the equivalent exposure concentration producing the target CV. The AEGL-3 derivation is based on reversible prostration in rats and a no- observed-effect level (NOEL) for death in rats exposed to 2,800 ppm for 4 h (Carpenter et al. 1975b). Although coordination initially remained poor, it re- turned to normal the next day. This concentration represents a threshold for marked CNS depression, which could lead to death. As for the AEGL-2, it is assumed that the CNS effects observed after xylene exposure are directly related to the concentration of parent material reaching the brain. Therefore, PBPK modeling (see Appendix C) was again used to calculate the internal dose (CV) correlating with an exposure of rats to 2,800 ppm for 4 h that produced prostra-

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296 Acute Exposure Guideline Levels tion. The human PBPK model was then run for each defined AEGL time period to determine the equivalent exposure concentration producing the target CV. A total uncertainty factor of 3 was applied to the AEGL-2 and -3 dose metrics. An intraspecies uncertainty factor of 3 was applied for the pharmacoki- netic and pharmacodynamic uncertainty because the minimum alveolar concen- tration (MAC) for volatile anesthetics should not vary by more than 2- to 3-fold among humans (NRC 2002). An interspecies uncertainty factor of 3 would usu- ally be applied. PBPK modeling reduced the toxicokinetic component of the uncertainty factor to 1, but the pharmacodynamic component would normally be retained and assigned a 3 (although it appears that similar CNS effects occur in humans and animals, it is not known if they occur at the same tissue dose). A total uncertainty factor of 10, however, drives the 8-h AEGL-2 value to 180 ppm and the 4-h AEGL-3 value to 447 ppm. These amounts are exposure concentra- tions that humans are known to tolerate with minimal or no adverse effects. With regard to the AEGL-2, humans exposed to p-xylene at 150 ppm for 7.5 h exhibited no effects on performance tests and noted only mild eye irritation (Hake et al. 1981). With regard to the AEGL-3, numerous human studies inves- tigated the effects of exposure to m-xylene at 130 to 200 ppm for 4 to 6 h, with 20-min peaks of 400 ppm with or without exercise, and found no effect or re- ported minimal CNS effects (Savolainen and Linnavuo 1979; Savolainen et al. 1984, 1985a,b; Seppalainen et al. 1989, 1991; Laine et al. 1993). Therefore, the interspecies uncertainty factor is reduced to 1, and a total uncertainty factor of 3 is applied to the AEGL-2 and AEGL-3 values (NRC 2002). The proposed xylene AEGL values apply to all three xylene isomers or a mixture of xylene isomers. No significant differences in the potency of the iso- mers after oral or inhalation exposure were identified, metabolism of each iso- mer proceeds via the same pathways, and PBPK model predictions indicate that the internal dose (CV) after exposure does not vary significantly among the in- dividual isomers. The AEGL values are listed in Table 6-1. AEGL-2 and AEGL-3 values are greater than 10% of the lower explosive limit. 1. INTRODUCTION Commercial or mixed xylene is composed of three isomers: meta-xylene (m-xylene), ortho-xylene (o-xylene), and para-xylene (p-xylene), of which the m-isomer usually predominates (40% to 70% of the mixture) (Fishbein 1988; ATSDR 2007). The exact composition of the isomers depends on the xylene formulation. Ethylbenzene is often present in mixed xylenes; in fact, the techni- cal product contains approximately 40% m-xylene and approximately 20% each o- and p-xylene and ethylbenzene (Fishbein 1988). Other minor contaminants of xylene include toluene and C9 aromatic fractions. Mixed xylenes are used in production of the individual isomers or ethylbenzene, as a solvent, in paints and coatings, and as a blend in gasoline (Fishbein 1988; ATSDR 2007). The annual

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297 Xylenes production capacity of mixed xylenes has been estimated at 13.1 billion pounds, with 1990 and 1991 production estimates of about 6 billion pounds (ATSDR 2007). The individual isomers are used primarily as chemical intermediates (OECD 2003). Almost all o-xylene produced in the United States is consumed in the manufacture of phthalic anhydride. Other minor uses include the use of o- xylene as a feedstock in the production of bactericides, soybean herbicides, and dyes. Most m-xylene is used as a chemical intermediate in the production of isophthalic acid. Small amounts of m-xylene are also consumed in the produc- tion of m-tolic acid, isophthalonitrile, and other compounds. Almost all U.S. production of p-xylene is consumed in the manufacture of dimethyl terephtha- late and terephthalic acid, which are used in the production of polyester fiber and plastics. The physical and chemical properties of xylenes are presented in Table 6- 2. The odor of xylenes is described as an aromatic hydrocarbon odor. The odor threshold ranges between 0.8 and 40 ppm, and the irritating concentration is 100 ppm (Ruth 1986). TABLE 6-1 Summary of Proposed AEGL Values for Xylenes End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 130 130 130 130 130 Eye irritation in (Nondisabling) ppm ppm ppm ppm ppm human volunteers (560 (560 (560 (560 (560 exposed to mixed mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) xylenes at 400 ppm for 30 min (Hastings et al. 1984) AEGL-2 2,500 1,300 920 500 400 Rats exposed to ppma ppma ppma (Disabling) ppm ppm mixed xylenes at (11,000 (5,600 (4,000 (2,200 (1,700 1,300 ppm exhibited mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) poor coordination 2 h into a 4-h exposure (Carpenter et al. 1975b) —b AEGL-3 3,600 2,500 1,300 1,000 Rats exposed to ppma ppma ppma ppma (Lethal) mixed xylenes at (16,000 (11,000 (5,600 (4,300 2,800 ppm for 4 h mg/m3) mg/m3) mg/m3) mg/m3) exhibited prostration followed by a full recovery (Carpenter et al. 1975b) a Concentrations are at or higher than 1/10th of the lower explosive limit (LEL) for all forms of xylene (o-xylene LEL, 9,000 ppm; m- and p-xylene LEL, 11,000 ppm). There- fore, safety considerations against the hazard of explosion must be taken into account. b 10-min AEGL-3 = 7,200 ppm is ≥50% of LEL. Therefore, extreme safety considerations against the hazards of explosions must be taken into account.

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298 Acute Exposure Guideline Levels TABLE 6-2 Physical and Chemical Data for Xylenes Parameter Value Reference Synonyms Dimethylbenzene (1,2-; 1,3-; or 1,4-); ACGIH 1991; xylol, m-xylene (m-isomer); o-xylene Budavari et al. 1996 (o-isomer); p-xylene (p-isomer); methyltoluene CAS registry no. 1330-20-7 108-38-3 (m-isomer) 95-47-6 (o-isomer) 106-42-3 (p-isomer) Chemical formula C8H10 Budavari et al. 1996 Molecular weight 106.17 Budavari et al. 1996 Physical state Liquid Budavari et al. 1996 Color Colorless Budavari et al. 1996 Melting point No data for mixture Budavari et al. 1996 −47.4C (m-isomer) −25C (o-isomer) 13-14C (p-isomer) 137-140C Boiling point Budavari et al. 1996 Solubility Practically insoluble in water; ATSDR 2007 106 mg/L at 25C Vapor pressure 6.72 mmHg ATSDR 2007 at 21C 0.864 g/cm3 Density ATSDR 2007 Log KOW 3.12-3.20 ATSDR 2007 3 Conversion 1 ppm = 4.34 mg/m NRC 1984 1 mg/m3 = 0.23 ppm factors in air 2. HUMAN TOXICITY DATA 2.1. Acute Lethality Three men were employed to paint a double-bottomed tank in the engine room of a ship (Morley et al. 1970). Solvent composed 34% of the total weight of the paint, with xylene composing in excess of 90% of the solvents, and only a trace amount of toluene was present. The men started work at 10:30 am, and after being reported missing later that evening were found unconscious at 5:00 am the next day. The first patient was dead upon admission to the hospital. Au- topsy revealed severe pulmonary congestion with focal alveolar hemorrhage and acute pulmonary edema, hepatic congestion with swelling and vacuolization of many cells in the centrilobular areas, and microscopic petechial hemorrhages in

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299 Xylenes both the gray and white matter of the brain. In addition, evidence of axonal neu- ronal damage was indicated by swelling and loss of Nissl substance. The second patient was admitted to the hospital unconscious, exhibiting only a slight re- sponse to painful stimuli. He was also hypothermic, had a flushed face, and had peripheral cyanosis. Medium-grade moist sounds were present in his lungs, and a chest x-ray revealed patchy diffuse opacity in both lungs. Five hours after treatment with tracheal aspiration and oxygen, the patient regained conscious- ness, but was amnesic for 2 to 3 days. Evidence of renal damage was indicated by an increase in blood urea of 59 mg/100 milliliters (mL) to 204 mg/100 mL 3 days after admission. Endogenous creatinine clearance was also reduced at this time. Slight hepatic impairment was indicated by a rise in serum transaminase activity to 100 international units (IU) over 48 h, followed by a return to normal levels. Patient 3 recovered consciousness after admission and was confused and amnesic, had slurred speech, and was ataxic upon walking. Within 24 h of ad- mission, he was fully conscious and alert, and the ataxia disappeared over 48 h. There was no evidence of renal impairment, and slight hepatic impairment was indicated by a slight rise in serum transaminase activity (52 IU) over 48 h, fol- lowed by a return to normal levels. The circumstances of the accident were re-created by the study authors. On the basis of the quantity of paint applied, the volume of the space, and the assumption of still air conditions (based on the limited ventilation present), the probable xylene concentration was estimated to have been 10,000 ppm. Al- though two cans of cleaning fluid composed primarily of toluene were also found at the scene, neither of the survivors remembered using the cleaning fluid. Therefore, it was assumed by the study authors that exposure was mainly to xy- lene. 2.2. Nonlethal Toxicity 2.2.1. Case Reports Two case reports of seizures after exposure to xylene-based products have been reported in the literature. Goldie (1960) reported a case in which eight painters were exposed to paint containing 80% xylene and 20% methylgly- colacetate. When they were painting the inside of a gun tower, adequate ventila- tion was not present because the ventilation system created too great a draft for painting. The workers complained of headache, vertigo, gastric discomfort, dry- ness of the throat, and slight drunkenness after 30 min of exposure; therefore, the painters worked in the unventilated area for 30 min at a time followed by 10- min breaks to breathe fresh air. After working for about 2 months, an 18-year- old male exhibited behavior indicative of a convulsive seizure one day after leaving work. Signs included weakness, dizziness, inability to speak, uncon- sciousness, eyes and head rotated to one side, chewing but no foaming, and short, sharp interrupted jerks of the upper and lower limbs. The patient recov-

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300 Acute Exposure Guideline Levels ered consciousness 20 min later. Although the patient experienced another shorter seizure after admission to the hospital, hospital tests were unable to con- firm the diagnosis. In another case, Arthur and Curnock (1982) reported that an adolescent male developed major and minor seizures after using a xylene-based glue used for building model airplanes. Neither case report provides an exposure concentration, and exposures were not limited to xylene. Klaucke et al. (1982) reported that during work one day, 15 male and fe- male employees of a small community hospital reported at least two of the fol- lowing symptoms lasting from 2 to 48 h: headache, nausea, vomiting, dizziness or vertigo, eye irritation, and nose or throat irritation. The frequency of the symptoms was as follows: headache, 12/15; nausea, 10/15; eye irritation, 8/15; nose or throat irritation, 7/15; dizziness or vertigo, 7/15; and vomiting, 6/15. Fourteen of the 15 employees noted an unusual odor 15 to 30 min before the onset of symptoms. After investigation, it was determined that the “illness” was caused when 1 L of liquid xylene was poured down a drain in a pathology labo- ratory, and the vapors were then drawn into the room, which contained a ventila- tion fan that distributed the vapors throughout the affected area of the hospital. It was estimated that workers were exposed to levels as high as 700 ppm. 2.2.2. Controlled Exposures Twenty-three male volunteers (mean age 23 years) were divided in groups of four or five and exposed to air containing measured concentrations of m- xylene, p-xylene, or toluene at 100 or 200 ppm for 3 h or for 7 h with a 1-h lunch break (Ogata et al. 1970). Vapor concentrations were analyzed every half- hour by gas chromatography. Systolic and diastolic blood pressure, pulse rate, flicker value, and reaction time were assessed in all volunteers at the beginning and end of exposures. Exposure to m- or p-xylene did not significantly influence any of these parameters. Six or seven7 volunteers (21 to 60 years of age; sex not provided) were exposed to air containing measured concentrations of mixed xylenes (p-xylene, 7.84%; m-xylene, 65.01%; o-xylene, 7.63%; ethylbenzene, 19.27%) for 15 min in the following order: 230, 110, 460, or 690 ppm, with exposures limited to one per day (Carpenter et al. 1975a,b). Volunteers provided written responses at 1- min intervals throughout the 15-min exposure. Xylene concentration was ana- lyzed by gas chromatography. Results of the exposure are summarized in Table 6-3. Complaints at 110 ppm were limited to mild throat discomfort in one volun- teer during the first and seventh minute of exposure; this individual did not ex- perience discomfort during exposure to 230 ppm. Exposure to 230 ppm resulted in one volunteer complaining of eye irritation during the 4th, 5th, and 15th min- ute of exposure; another noting sleepiness at the 13th minute followed by eye wetness (but no tears formed) at the 14th and 15th minute of exposure; one vol- unteer reporting possible mild nasal irritation; and another volunteer reporting

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301 Xylenes TABLE 6-3 Xylene Irritation Thresholds (Subjects Exposed for 15 Min) Concentrations (ppm) Condition of Subjects 110 230 460 690 Volunteers 6 7 6 6 Throat irritation 1 0 1 2 Eye irritation 0 1 4 4 Tears 0 1 1 2 Dizziness and light-headedness 0 1 1 4 Source: Carpenter et al. 1975b. Reprinted with permission; copyright 1975, Toxicology and Applied Pharmacology. intermittent dizziness and light-headedness (with no loss of coordination) during the last 2 min of exposure. At 460 ppm, four volunteers reported intermittent or continuous mild eye irritation, with one additionally reporting eye wetness when leaving the chamber; one volunteer noted mild dizziness at the sixth minute of exposure that persisted throughout the 15-min exposure (the same individual who noted dizziness at 230 ppm); and one volunteer reported possible mild nasal and throat irritation (the same individual who reported nasal irritation at 230 ppm). Exposure to 690 ppm resulted in dizziness and light-headedness in four volunteers. Three of the volunteers reported the dizziness to be mild and not associated with a loss of balance, while the other volunteer reported a slight loss of balance. Eye, nose, and throat irritation was noted during exposure but ceased within 10 min postexposure. Carpenter and associates (1975b) concluded that exposure to xylene at 100 ppm would not be objectionable to most people, while none of the volunteers thought that 690 ppm could be tolerated over an 8-h work day. Volunteer male college students 18 to 30 years old were exposed to air containing mixed xylenes at 0, 100, 200, or 400 ppm (0, 0.43, 0.86, and 1.72 mg/L) for 30 min (p-xylene, 7.84%; m-xylene, 65.01%; o-xylene, 7.63%; ethyl- benzene, 19.27%) (Hastings et al. 1984). The students were exposed using an olfactometer delivery hood made of transparent Lucite, which allowed adequate air flow. Solvent or distilled water (for control exposures) was delivered with a motorized syringe, and heating tapes vaporized the solvent or water before in- troduction into the hood. Samples of air taken from the breathing zone in the hood were analyzed by gas chromatography for the actual exposure concentra- tions and were acceptable. A contact electrode was taped near the skin of the outer canthus of one eye on each subject to measure eye blinks, and an indiffer- ent electrode was clipped to the ipsilateral ear. Respiratory measurements were recorded with the aid of a thermistor placed near one naris. Behavioral tests, two measuring psychomotor performance (consisting of the Michigan Eye-Hand Coordination Test and a visuomotor-skill TV game) and one measuring cogni- tive performance (choice reaction time), were administered before, during, and

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302 Acute Exposure Guideline Levels after exposure (10 min after placement in the hood when exposed to control air, during the last 5 min of the 30-min exposure to xylene, and 10 min after the sub- jects were again exposed to control air for 10 min). The reader is referred to the study for additional details about the behavioral testing. The subjects were asked every 5 min during the experiment if they detected any odor or experienced eye, nose, or throat irritation. The only clear concentration-related effect of exposure in the Hastings et al. (1984) study was mild eye irritation reported by 56%, 60%, 70%, and 90% of the subjects in the 0-, 100-, 200-, and 400-ppm groups, respectively (not statisti- cally significant). No concentration-related increase in the percentage of ex- posed subjects experiencing nose or throat irritation was observed and the num- ber of eye blinks per minute and respiration rate (breaths per minute) were not statistically increased in any of the exposure groups compared with the controls, confirming that the reported irritation was mild. No statistically significant dif- ferences in the performance of the behavioral tasks by the exposed subjects were observed compared with controls. Gamberale et al. (1978) conducted two series of experiments assessing the effects of xylene exposure in healthy male volunteers age 21 to 33 years. In the first investigation, groups of five males were exposed to xylene at 0, 100, or 300 ppm for 70 min on day 1, 2, or 3, with the sequence of the exposure balanced among the three groups (on day 1, groups 1, 2, and 3 were exposed to 0, 300, and 100 ppm, respectively). In the second investigation, a group of eight volun- teers (who had also participated in the first series) were exposed to xylene at 300 ppm for 70 min; they exercised four times per day on a bicycle equipped with an ergometer at 100 watts [W]) for the first 30 min of exposure and sat in a chair the remaining 40 min of exposure. In both experiments, a breathing valve with low resistance was used to supply the air or xylene, and menthol crystals were placed in the tube of the mouthpiece to mask the odor of solvent. A total hydro- carbon analyzer was used to continuously measure the inspired xylene concen- tration during exposure, and a gas chromatographic technique was used to measure the alveolar air concentration of xylene (further details were not pro- vided). Heart rate was checked regularly. Five performance tests were adminis- tered to volunteers during the exposures: one administered at the beginning of the exposure period and all five during the last 35 min of exposure. The per- formance tests included critical flicker fusion, reaction time addition, simple reaction time, short-term memory, and choice reaction time. All the tests utilized visual stimulation with electronic recording of responses. After each exposure trial, subjects were asked to fill out a questionnaire addressing subjective symp- toms experienced during exposures. The concentration of xylene in the alveolar air at 30 and 70 min of expo- sure corresponded to the nominal concentration: the alveolar air concentration in the 300-ppm group was three times that of the 100-ppm group (Gamberale et al. 1978). After subjects exercised during exposure to 300 ppm, the alveolar xylene concentration increased 3.7- and 2.2-fold at 30 and 70 min, respectively, com- pared with exposure to 300 ppm at rest. No exposure-related changes in heart

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303 Xylenes rate were observed. Although a slight increase in the frequency of headache and feeling of “sickness” were noted, the number of subjects with these complaints was not provided. However, the authors stated that most subjects reported no or negligible symptoms. Xylene exposure at rest did not significantly affect the results of the performance tests of subjects exposed to xylene at 100 or 300 ppm. When xylene exposure was combined with 100 W of work, impaired perform- ance was observed on all tests, significantly so (p < 0.05) in the reaction time addition test and the short-term memory test (further details not provided). Exposure of groups of four male volunteers to p-xylene at 70 ppm, toluene at 80 ppm, or a combination of toluene at 50 ppm and p-xylene at 20 ppm for 4 h did not affect the results of choice reaction time, simple reaction time, or short-term memory performance tests as assessed by microcomputers immedi- ately upon entry into the exposure chamber, after 2 h of exposure, or after 4 h of exposure compared with control air exposure (Olson et al. 1985). Solvent expo- sure did not affect heart rate or the reporting of subjective symptoms recorded by questionnaire at the end of the exposures. Groups of two healthy male volunteers aged 22 to 35 years were exposed in random sequence to air containing toluene at 100 ppm, xylene at 100 ppm, a mixture of toluene at 50 ppm and xylene at 50 ppm, or control air for 4-h ses- sions, with each exposure session separated by 7-day intervals (Dudek et al. 1990). No information about the purity or composition of xylene was provided. Exposures occurred in a chamber, with the test solvent concentrations controlled by monitoring with gas chromatography and infrared spectrophotometry. Terpon vapors were used to mask the odor of the test solvents. A battery of nine psycho- logical tests was used to evaluate the effects of the solvents on the subjects dur- ing exposure. The tests evaluated memory (Sperling’s test), interference of cog- nitive processes (Stroop’s test), cognitive processes (Sternberg’s test), motor- visual coordination (Flanagan’s test), speed and precision of hand movements (aiming), psychomotor efficiency (simple reaction time, choice reaction time, and Santa Ana), and mood (profile of mood state). The volunteers completed a training session on these performance tests 1 week before the exposure. On the day of the exposure, the performance tests were administered 1 h before expo- sure, at the commencement of exposure, and 3 h into the exposure; only the re- sults with xylene are reported here. Xylene exposure for 3 h resulted in signifi- cant reductions in performance of the simple reaction time test (prolongation of simple reaction time; p < 0.001) and the choice reaction time test (p < 0.001). No statistically significant effects were observed in any of the other psychologi- cal tests. An average of 10 subjects (mix of males and females) were exposed to xy- lene in a 1,200-cubic-foot gas chamber for 3 to 5 min, and the level of irritation experienced by the subjects was recorded upon exit from the chamber (Nelson et al. 1943). Further experimental details were not provided. The study authors reported that exposure to xylene at 200 ppm resulted in eye, nose, and throat irritation in most subjects and it was classified as objectionable.

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370 Acute Exposure Guideline Levels Using the Haddad et al. (1999) model, the starting concentrations were op- timized to reflect the measured concentrations of the first data points. At the high concentrations of interest for xylene, enzymatic saturation of the primary metabolic pathway may have occurred. Therefore, a second pathway of metabo- lism (lumped metabolism by all the CYPs other than CYP2E1) was added to account for high-capacity low-affinity pathways of metabolism, which would occur at the much higher exposure concentrations (Clewell et al. 2001). The metabolism by the second series of CYPs is given as Rate of metabolism (RAM) = KF × CVL, where CVL = concentration of xylenes in the venous blood leaving the liver and KF = 0.1/BW0.3. The second pathway of metabolism was added and KF (first-order rate constant for high-capacity low-affinity enzymes) was determined. Figure 6C-3 shows the results of optimizing the starting concentrations and adding the sec- ond pathway of metabolism. Adding the second metabolic pathway resulted in a very close correspondence between the model and the data. After optimizing the Haddad model with the Tardif et al. (1993) data, the model was run again with the same parameters against the Haddad data (Figure 6C-4). A good fit is obtained overall, although the 200-ppm experimental data are slightly underpredicted. However, the concern is primarily with estimating CV in rats at very high concentrations (1,000 to 3,000 ppm). Figure 6C-4 shows what the model does without the second metabolic pathway (perfect fit) and with it. There is no real difference at 50 or 100 ppm, but the second line from the top is the new model at 200 ppm. Application of the Model to Humans The optimized rat model can now be used to develop a xylene PBPK model for humans. The model was visually reoptimized for m- and p-xylene with the available human data. Multiple papers were available in which human m-xylene CV values were measured during exposure to m-xylene at 200 ppm (Savolainen et al. 1981, 1984, 1985; Seppalainen et al. 1989, 1991; Laine et al. 1993) (see Table 6C-1). Postexposure human CV were also reported by Hake et al. (1981) after exposure to p-xylene at 20, 100, or 150 ppm for 1, 3, or 7 h and by Tardif et al. (1997) after exposure to m-xylene at 33 ppm for 7 h.

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1 e+ 4 1000 100 10 1 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 TIME gh, #Tardif1993GUH2ndhigh, #Tardif1993GU3rd FIGURE 6C-3 The Haddad et al. (1999) model with the Tardif et al. (1993) gas uptake data (500, 1,000, 2,000, and 4,000 ppm), optimized for the starting concentration and inclusion of a second metabolism pathway. 371

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10 372 1 Cv (mg/L) 0.1 Blue line 0.01 0 1 2 3 4 5 6 7 8 9 cv, #Xylenedata50, #Xylenedata100, #Xylenedata2 TIM E FIGURE 6C-4 Haddad et al. (1999) model after being optimized for the Tardif et al. (1993) gas uptake data.

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373 Xylenes Human anatomic parameters were generally taken from Astrand (1983) (see Table 6C-2). Kinetics were scaled from the rat model except for VmaxC, which was reoptimized and reduced to 5.5. Without the adjustment, the model tended to underpredict most of the data. Values for QCC or QPC were not opti- mized because these values came from part of a physiologic parameter set (As- trand 1983). Several human blood-air partition coefficients (PB) for the xylene isomers were reported in the literature and are presented in Table 6C-2. The av- erage PB for the respective xylene isomer was used for modeling data. Figures 6C-5 to 6C-8 show the reoptimized human model predictions for CV for m- or p-xylene compared with the measured human CV values. 7 6 5 Cv (mg/L) 4 3 2 1 0 0 1 2 3 4 5 6 7 8 9 Time (hr) F IGURE 6C-5 Model predictions of CV (line; using human input parameters with PB of 30.3) compared with the actual measured human CV values during exposure to m-xylene at 200 ppm (open circles; combined data summarized in Table 6C-1). 0.45 0.4 0.35 0.3 Cv (mg/L) 0.25 0.2 0.15 0.1 0.05 0 0 1 2 3 4 5 6 7 8 9 Time (hr) FIGURE 6C-6 Mmodel predictions of CV (line; using human input parameters with PB of 30.3) compared with the actual measured human CV values (open circles) during and after exposure to m-xylene at 33 ppm for 7 h (Tardif et al. 1997).

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374 Acute Exposure Guideline Levels 4.5 4 3.5 3 Cv (mg/L) 2.5 2 1.5 1 0.5 0 0 1 2 3 4 5 6 7 8 9 Time (hr) FIGURE 6C-7 Model predictions of CV (line; using male human input parameters with PB of 40.4) compared with the actual measured male human CV values (open circles) after exposure to p-xylene at 150 ppm for 1, 3, or 7.5 h (Hake et al. 1981). 2.5 2 Cv (mg/L) 1.5 1 0.5 0 0 1 2 3 4 5 6 7 8 9 Time (hr) FIGURE 6C-8 Model predictions of CV (lines; using human female input parameters with PB of 40.4) compared with the actual measured human female CV values (open circles) after exposure to p-xylene at 100 ppm for 1, 3, or 7.5 h (Hake et al. 1981). Comparison of Pharmacokinetics in Rats and Humans Because the AEGL-2 and AEGL-3 key studies are based on rat data, ex- trapolation to humans is required. PBPK modeling allows a comparison of the internal dose that is received in both species receiving identical external expo- sures. As shown in Figure 6C-9, rats achieve higher blood m-xylene concentra- tions than humans. This is primarily due to a higher PB in rats (46) compared with humans (26 to 32 in humans). Figure 6C-9 plots CV for rats and humans using the validated models presented earlier at 200, 1,000, and 5,000 ppm.

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375 Xylenes 1000 5000 ppm 100 Log Cv (mg/L) 1000 ppm rat 10 200 ppm human 1 0.1 0 1 2 3 4 5 6 7 8 Time (hr) FIGURE 6C-9 Model predictions for CV in rats (top line of each pair of lines) and hu- mans (bottom line of each pair of lines). Open circles are the actual measured human CV values for exposure to xylene at 200 ppm. The y axis in Figure 6C-9 is on a logarithmic scale. By 8 h, steady state is still slowly increasing. Application of Modeling to Derive AEGL Values Because xylene can exist as a mixture or as any of three individual iso- mers, the question arises as to whether there are any differences in toxicity among the individual isomers and the mixture. No significant differences in the potency of the isomers after oral or inhalation exposure were identified and me- tabolism of each isomer proceeds via the same pathway. PBPK model predic- tions indicate that the internal dose (CV) after exposure does not vary signifi- cantly among the individual isomers (see Figure 6C-10). The AEGL-2 and -3 values are based on a study in rats exposed to mixed xylenes for 4 h (Carpenter et al. 1975). The composition of the mixed xylenes used was provided as follows: Component Volume Percent Nonaromatics 0.07 Toluene 0.14 Ethylbenzene 19.27 p-Xylene 7.84 m-Xylene 65.01 o-Xylene 7.63 C9 + aromatics 0.04 Total 100.00

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376 Acute Exposure Guideline Levels Xylene isomers 1000 Venous blood, mg/L 800 o-xylene 600 m-xylene 400 p-xylene 200 0 0 5000 10000 15000 20000 25000 Concentration, ppm FIGURE 6C-10 The model predictions for CV in humans after exposure to the individ- ual isomers (model parameters remain the same with the exception of PB values specific to the individual isomers; symbol for m-xylene is superimposed on symbol for o-xylene). The amount of ethylbenzene is a typical amount seen in a xylene mixture. For the purpose of the modeling, it is known that ethylbenzene has the same spectrum of neurotoxic effects as xylenes, so assuming the exposure is to xy- lenes alone is reasonable. When considering only the amount of xylene isomers in the mixture and normalizing them to a total of 100%, 80% is the m-xylene isomer, while 10% is the o-xylene isomer and 10% is the p-xylene isomer. Therefore, the PB for m-xylene is used in the model. The AEGL-2 derivation is based on poor coordination exhibited in rats 2 h into a 4-h exposure to mixed xylenes at 1,300 ppm (Carpenter et al. 1975). The rat PBPK model predicts that an exposure to xylenes at 1,300 ppm for 2 h would result in a CV of 48.9 mg/L. It is assumed that this internal dose of 48.9 mg/L is the dose resulting in the clinical sign of poor coordination. Therefore, it is as- sumed that the same internal dose of 48.9 mg/L would also result in adverse effects in humans. Using the human PBPK model, the model was run for each defined AEGL time point to determine the equivalent exposure concentration producing the same CV. The AEGL-3 derivation is based on reversible prostration and a NOEL for death in rats exposed to 2,800 ppm for 4 h (Carpenter et al. 1975). The rat PBPK model predicts that an exposure to xylenes at 2,800 ppm for 4 h would result in a CV of 143.8 mg/L. Therefore, it is assumed that the same internal dose of 143.8 mg/L would also result in adverse effects in humans. Using the human PBPK model, the model was run for each defined AEGL time point to determine the equivalent exposure concentration producing the same CV.

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377 Xylenes Recommended AEGL Values A total uncertainty factor of 3 was applied to the AEGL-2 and -3 dose metrics. An intraspecies uncertainty factor of 3 was applied for the pharmacoki- netic and pharmacodynamic uncertainty because the MAC for volatile anesthet- ics should not vary by more than 2- to 3-fold among humans (NRC 2002). An interspecies uncertainty factor of 3 would usually be applied. PBPK modeling reduced the toxicokinetic component of the uncertainty factor to 1, but the pharmacodynamic component would normally be retained and assigned a 3 (although it appears that similar CNS effects occur in humans and animals, it is not known if they occur at the same tissue dose). A total uncertainty factor of 10, however, drives the 8-h AEGL-2 value to 180 ppm and the 4-h AEGL-3 value to 447 ppm. These are exposure concentrations that humans are known to tolerate with minimal or no adverse effects. With regard to the AEGL-2, humans exposed to p-xylene at 150 ppm for 7.5 h did not exhibit any effects on perform- ance tests and noted only mild eye irritation (Hake et al. 1981). With regard to the AEGL-3, numerous human studies investigated the effects of exposure to m- xylene at 130 to 200 ppm for 4 to 6 h, with 20-min peaks of 400 ppm with or without exercise (Savolainen and Linnavuo 1979; Savolainen et al. 1984, 1985; Seppalainen et al. 1989, 1991; Laine et al. 1993) and found no effect or minimal CNS effects. Therefore, the interspecies uncertainty factor is reduced to 1, and a total uncertainty factor of 3 is applied to the AEGL-2 and AEGL-3 values (NRC 2002). GLOSSARY OF PBPK MODEL TERMS Most used in the presentation: CV venous blood concentration PB Blood-air partition coefficient Physiologic Parameters BW Body weight (kg) QPC Alveolar ventilation rate (L/h/kg) QCC Cardiac output (L/h/kg) VFC Fraction fat tissue (kg/(kg/BW)) VLC Fraction liver tissue (kg/(kg/BW)) VRC Fraction rapidly perfused (kg/(kg/BW)) QFC Fractional blood flow to fat ((L/h)/QC) QLC Fractional blood flow to liver ((L/h)/QC) QRC Fractional blood flow to rapidly perfused ((L/h)/QC) SF Scaling coefficient

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378 Acute Exposure Guideline Levels Chemical-Specific Parameters PLA = Liver-air partition coefficient PFA = Fat-air partition coefficient PSA = Slowly perfused air partition coefficient PRA = Rapidly perfused air partition coefficient PB = Blood-air partition coefficient PL = PLA/PB Liver-blood partition coefficient PF = PFA/PB Fat-blood partition coefficient PS = PSA/PB Slowly perfused blood partition coefficient PR = PRA/PB Rapidly perfused blood partition coefficient MW = Molecular weight (g/mol) VmaxC = Maximum velocity of metabolism (mg/h/kg) Km = Michaelis-Menten (mg/L) KFC = 0.1 CONC = Inhaled concentration (ppm) Calculated Parameters QC = QCC  BWSF Cardiac output QP = QPC  BWSF Alveolar ventilation VS = VSC  BW Volume slowly perfused tissue (L) VF = VFC  BW Volume fat tissue (L) VL = VLC  BW Volume liver (L) VR= VRC  BW Volume rapidly perfused (L) QF = QFC  QC Blood flow to fat (L/h) QL = QLC  QC Blood flow to liver (L/h) QS = QC – QF – QL – QR Blood flow to non-fat tissue (L/h) QR = QRC  QC Blood flow to rapidly perfused (L/h) CIX = CONC  MW/24,450 Exposure concentration (mg/L) Vmax = VmaxC  BWSF KF = KFC/BW0.3 First-order rate constant for high-capacity low-affinity enzymes REFERENCES Astrand, I. 1983. Effect of physical exercise on uptake, distribution and elimination of vapors in man. Pp. 107-130 in Modeling of Inhalation Exposures to Vapors: Up- take, Distribution, and Elimination, V. Fiserova-Bergerova, ed. Boca Raton, FL: CRC Press. Carpenter, C.P., E.R. Kinkead, D.L. Geary Jr., L.J. Sullivan, and J.M. King. 1975. Petro- leum hydrocarbon toxicity studies. V. Animal and human response to vapors of mixed xylene. Toxicol. Appl. Pharmacol. 33(3):543-558.

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379 Xylenes Clewell, H.J., P.R. Gentry, J.M. Gearhart, B.C. Allen, and M.E. Andersen. 2001. Com- parison of cancer risk estimates for vinyl chloride using animal and human data with a PBPK model. Sci. Total Environ. 274(1-3):37-66. Dennison, J.E., C.M. Troxel, and R. Benson. 2009. PBPK Modeling White Paper: Ad- dressing the Use of PBPK Models to Support Derivation of Acute Exposure Guideline Levels. AEGL National Advisory Committee. September 1, 2009. Digimatic. 2004. Digimatic, Version 2. FEBSoftware, Chesterfield, VA. Gargas, M.L., R.J. Burgess, D.E. Voisard, G.H. Cason, and M.E. Anderson. 1989. Parti- tion coefficients of low-molecular-weight volatile chemicals in various liquids and tissues. Toxicol. Appl. Pharmacol. 98(1):87-99. Haddad, S., R. Tardif, G. Charest-Tardif, and K. Krishnan. 1999. Physiological modeling of the toxicokinetic interactions in a quaternary mixture of aromatic hydrocarbons. Toxicol. Appl. Pharmacol. 161(3):249-257. Hake, C.L., R.D. Stewart, A. Wu, S.A. Graff, H.V. Forster, W.H. Keeler, A.J. Lebrun, P.E. Newton, and R.J. Soto. 1981. p-Xylene: Development of a Biological Stan- dard for the Industrial Worker by Breath Analysis. PB82-152844. Prepared for Na- tional Institute for Occupational Safety and Health, Cincinnati, OH, by the Medical College of Wisconsin, Milwaukee, WI. Kaneko, T., K. Endoh, and A. Sato. 1991a. Biological monitoring of exposure to organic solvent vapors. I. Simulation studies using a physiological pharmacokinetic model for m-xylene. Yamanashi Med. J. 6:127-135. Kaneko, T., K. Endoh, and A. Sato. 1991b. Biological monitoring of exposure to organic solvent vapors. II. Simulation studies using a physiological pharmacokinetic model for m-xylene. Yamanashi Med. J. 6:137-149. Kaneko, T., J. Horiuchi, and A. Sato. 2000. Development of a physiologically based pharmacokinetic model of organic solvent in rats. Pharmacol. Res. 42(5):465-470. Laine, A., K. Savolainen, V. Riihimaki, E. Matikainen, T. Salmi, and J. Juntunen. 1993. Acute effects of m-xylene inhalation on body sway, reaction times, and sleep in man. Int. Arch. Occup. Environ. Health 65(3):179-188. Macey, R.I., and G.F. Oster. 2002. Berkeley Madonna. University of California, Berkley, CA [online]. Available: http://www.berkeleymadonna.com/ [accessed June 11, 2010] NRC (National Research Council). 2002. Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 2. Washington, DC: The National Academies Press. Pierce, C.H., R.L. Dills, G.W. Silvey, and D.A. Kalman. 1996. Partition coefficients be- tween blood or adipose tissue and air for aromatic solvents. Scan. J. Work Envi- ron. Health 22(2):112-118. Ramsey, J.C., and M.E. Andersen. 1984. A physiologically-based description of the inha- lation pharmacokinetics of styrene in rats and humans. Toxicol. Appl. Pharmacol. 73(1):159-175. Sato, A., and T. Nakajima. 1979. Partition coefficients of some aromatic hydrocarbons and ketones in water, blood and oil. Br. J. Ind. Med. 36(3):231-234. 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, K., V. Riihimaki, 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. Riihimaki, and A. Laine. 1984. Immediate effects of m- xylene on the human central nervous system. Arch. Toxicol. (Suppl. 7):412-417.

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380 Acute Exposure Guideline Levels Savolainen, K., V. Riihimaki, O. Muona, J. Kekoni, R. Luukkonen, and A. Laine. 1985. Conversely exposure-related effects between atmospheric m-xylene concentrations and human body sense of balance. Acta Pharmacol. Toxicol. 57(2):67-71. Seppalainen, A.M., Laine, A., Salmi, T., Riihimaki, V., and Verkkala, E. 1989. Changes induced by short-term xylene exposure in human evoked potentials. Int. Arch. Oc- cup. Environ. Health. 61: 443-449. Seppalainen, A.M., A. Laine, T. Salmi, E. Verkkala, V. Riihimaki, and R. Luukkonen. 1991. Electroencephalographic findings during experimental human exposure to m-xylene. Arch. Environ. Health 46(1):16-24. Tardif, R., S. Lapare, K. Krishnan, and J. Brodeur. 1993. Physiologically based modeling of the toxicokinetic interaction between toluene and m-xylene in the rat. Toxicol. Appl. Pharmacol. 120(2):266-273. Tardif, R., G. Charest-Tardif, J. Brodeur, and K. Krishnan. 1997. Physiologically based pharmacokinetic modeling of a ternary mixture of alkyl benzenes in rats and hu- mans. Toxicol. Appl. Pharmacol. 144(1):120-134.