Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 9 (2010) / Chapter Skim
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6 Xylenes
6 Xylenes
Pages 293-380
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From page 293... ...
Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels.
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Only mild eye irritation was noted during a 30-min exposure to mixed xylenes at 400 ppm (Hastings et al.
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1981) ; a 15-min exposure to mixed xylenes at 230 ppm resulting in mild eye irritation and dizziness with no loss of coordination in one individual (Carpenter et al.
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No significant differences in the potency of the isomers after oral or inhalation exposure were identified, metabolism of each isomer proceeds via the same pathways, and PBPK model predictions indicate that the internal dose (CV) after exposure does not vary significantly among the individual isomers.
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ppm ppm mixed xylenes at (11,000 (5,600 (4,000 (2,200 (1,700 1,300 ppm exhibited mg/m3)
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1996 Molecular weight 106.17 Budavari et al. 1996 Physical state Liquid Budavari et al.
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Within 24 h of admission, 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)
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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%)
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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)
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(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 statistically significant)
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On the day of the exposure, the performance tests were administered 1 h before exposure, at the commencement of exposure, and 3 h into the exposure; only the results with xylene are reported here. Xylene exposure for 3 h resulted in significant reductions in performance of the simple reaction time test (prolongation of simple reaction time; p < 0.001)
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Of these notations, one individual in the 7.5-h exposure group wearing contact lenses noted eye irritation almost every day, while another subject complained twice at 100 ppm and three times at 150 ppm. No irritation was noted by males during any 3-h exposure, but one subject complained of eye irritation during a 1-h exposure to 150 ppm.
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The results from the study demonstrated that xylene exposure at rest did not result in any consistent effects on VEPs, while xylene expo
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No definitive conclusions on the effects of mxylene exposure on reaction times could be drawn because reaction times did not consistently change with the intensity of exposure. In the afternoon, longer simple reaction times were noted after exposure to peaks of m-xylene at rest, while prolonged audiomotor choice reaction times were prolonged after exposure to peaks of m-xylene while exercising.
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(1985b) found that body sway was negatively correlated with xylene concentration; that is, xylene exposure improved (decreased)
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Xylene exposure did not affect nystagmus, Santa Ana manual dexterity test, or critical flicker fusion (Riihimaki and Savolainen 1980)
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Death occurred due to pulmonary failure after inhalation of mixed xylenes at about 10,000 ppm.
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; dizziness (4/6, with one having loss of balance) , eye/nose/throat irritation 0, 100, 200, 400 30 min Mixed Eye irritation reported, but incidence not statistically significant: Hastings et al.
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1983 200 5.5 h m- No effect on body sway, reaction times, active or quiet sleep; only Laine et al. 1993 effect was sleep movements slightly decreased during night after exposure 100 or 150 7.5 h p- Mild eye irritation, primarily in person wearing contacts Hake et al.
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approximately 5 weeks of age were exposed for 4 h to air containing measured concentrations of mixed xylenes at 580, 1,300, 2,800, 6,000, or 9,000 ppm (p-xylene, 7.84%; m-xylene, 65.01%; o-xylene, 7.63%; ethylbenzene, 19.27%) (Carpenter et al.
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TABLE 6-5 Mortality of Male Rats Exposed to Xylene Vapor for 4 Hours Concentration (ppm) Mortality Other Effects 580 0/10 None observed 1,300 0/10 Poor coordination (slight coordination loss)
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The rat that survived was said to have poor coordination, but the duration of that condition was not stated. No mortality was observed in rats exposed to mixed xylenes at 11,000 ppm for 15, 30, or 60 min.
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TABLE 6-7 Mortality of Rats Exposed to Xylene Vapor Isomer Concentration (ppm) Length of Exposure (h)
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. Individual exposure concentrations and mortalities were not provided in the study; it was stated that mice exposed to o-xylene had incidences of delayed mortality between 5 and 10 days postexposure.
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Dogs Lacrimation developed in male beagles (number of animals not provided) exposed to mixed xylenes at 1,200 ppm for 4 h, while a 4-h exposure to mixed xylenes at 530 ppm had no observable effects (xylene composed of p-xylene, 7.84%; m-xylene, 65.01%; o-xylene, 7.63%; ethylbenzene, 19.27%)
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rats. The mixed xylenes comprised m-, p-, and o-xylene with ethylbenzene present as a contaminant; the percent composition was not provided.
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The mixed xylenes comprised m-, p-, and o-xylene with ethylbenzene present as a contaminant; the percent composition was not provided. Xylene exposure and behavioral testing were carried out in a dynamic exposure behavioral chamber.
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(1990) exposed groups of 10 male Wistar rats for 6 h to o-, m-, or p-xylene at approximately 3,000 ppm to determine any potential differences in the toxicity of the individual isomers as measured by a rotarod test.
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Xylene concentrations were measured in the exposure chamber in 30-min increments by gas chromatography. Exact exposure concentrations were not provided, but graphic representation of data showed m-xylene exposure concentrations of about 500, 1,000, 1,500, 2,000, or 3,000 ppm.
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(1975a,b) exposed Swiss-Webster male mice to air containing measured concentrations of mixed xylenes (p-xylene, 7.84%; m-xylene, 65.01%; o-xylene, 7.63%; ethylbenzene, 19.27%)
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Because the purpose of the study was to qualitatively compare six alkylbenzenes, no attempt was made to determine minimally effective concentrations. The effects of the individual xylene isomers and a commercial xylene mixture on operant responding and motor performance were assessed in CD-1 male albino mice (Moser et al.
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To assess potential developmental toxicity, one-half of the Group I F0 females (20 females; control group) and Group IV F0 females (12 females; mixed xylenes at 500 ppm by inhalation for 6 h/day, 5 days/week, for 131 days before to mating and during GD 1 to 20)
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The only effect noted in fetuses from xylene-treated dams was an increased incidence of delayed ossification of the os maxcillare in the skull, with 18/26 exposed litters affected versus 2/22 control litters. In the postnatal study, statistically decreased rotarod performance was observed in female pups on postnatal days 22 and 23
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study is limited in that only one exposure concentration was tested and only a limited battery of behavioral tests was used.
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In a National Toxicology Program (NTP 1986) chronic toxicity and carcinogenesis bioassay, groups of 50 male and 50 female F344 rats and 50 male and 50 female B6C3F1 mice were administered mixed xylenes (60% m-xylene, 13.6% p-xylene, 17.0% ethylbenzene, and 9.1% o-xylene)
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Commercial xylene and the three individual isomers failed to demonstrate any evidence of genotoxicity. Xylenes are currently not classified as to carcinogenicity by IARC (1999)
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1975b 1,300 4 Mixed Poor coordination after 2 h, recovered postexposure 2,800 4 Mixed Irritation; rats prostrate within 2.5-3 h into exposure; recovered within 1 h, but poor coordination until following day. 1,600 4 p- Changes in flash evoked potential suggest Dyer et al.
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1985 EC50 for inverted screen test 3,640 0.5 (static) o 2,676 0.5 (static)
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found evidence that of the three xylene isomers, m-xylene is preferentially metabolized to methylhippuric acid in the presence of the other two isomers, regardless of the isomer composition. The relevance of this finding in assessing the toxicity of the individual isomers is not known at this time.
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Metabolism of xylenes in common laboratory animals also proceeds via hepatic side-chain dehydroxylation by mixed function oxidases to toluic acids. Further metabolism depends on species and isomer composition, with fluctuations occurring primarily in the ratio of urinary methylhippuric acid and toluic acid glucuronides (Bray et al.
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In general, a linear correlation has been found between the intensity of xylene exposure and the amount of methylhippuric acid isomers excreted in the urine (Lundberg and Sollenberg 1986; Imbriani et al. 1987; Kawai et al.
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. Xylene exposure reduced transport of cellular materials to axons and nerve ending regions in rats (Padilla and Lyerly 1989)
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. PBPK modeling allows a comparison of the internal dose in both species receiving identical external exposures.
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The human PBPK model of xylene was then run for each defined AEGL time period to determine the equivalent atmospheric exposure concentration producing the target CV.
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producing the toxicity end point of concern in rats was determined. The human PBPK model of xylene was then run for each defined AEGL time period to determine the equivalent atmospheric exposure concentration producing the target CV.
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Exposure to mixed xylenes at 110 ppm for 15 min resulted in intermittent, mild throat irritation in 1/6 individuals, while exposure to 230 ppm for 15 min resulted in eye irritation and mild dizziness in 1/7 individuals (Carpenter et al.
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1981) ; the 15-min exposure to mixed xylenes at 230 ppm resulting in mild eye irritation and dizziness in one individual; and the 3-h exposure to m- or p-xylene at 200 ppm (Ogata et al.
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. Then, the human PBPK model was run for each defined AEGL time period to determine the equivalent exposure concentration producing the target CV.
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7.2. Animal Data Relevant to AEGL-3 Two cats exposed to mixed xylenes at 9,500 ppm exhibited signs of CNS depression followed by death 2 h into the exposure (Carpenter et al.
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correlating with an exposure of rats to 2,800 ppm for 4 h, which produced prostration. The human PBPK model was then run for each defined AEGL time period to determine the equivalent exposure concentration producing the target CV.
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SUMMARY OF PROPOSED AEGLs 8.1. AEGL Values and Toxicity End Points The AEGL values for xylenes summarized in Table 6-15 apply to each of the individual xylene isomers or a mixture of xylene isomers.
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. Animal data on nonlethal effects were available for dogs, cats, rats, and mice, although most of the data documenting CNS effects after acute exposure were
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The 1-h SMAC is a concentration of airborne substance that will not compromise the performance of specific tasks by astronauts during emergency conditions or cause serious or permanent toxic effects. Such exposure may cause reversible effects, such as skin or eye irritation, but they are not expected to impair judgment or interfere with proper responses to emergencies.
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g TLV-STEL (Threshold Limit Value–short-term exposure limit, American Conference of Governmental Industrial Hygienists )
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1989. Behavioral effects of acute p-xylene inhalation in rats: Autoshaping, motor activity, and reversal learning.
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1993. Brain aminopep tidase activity after subacute xylene exposure.
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PB82-152844. Prepared for Na tional Institute for Occupational Safety and Health, Cincinnati, OH, by the Medical College of Wisconsin, Milwaukee, WI.
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1993. Excretion of methlyhippuric acids in urine of workers ex posed to a xylene mixture: Comparison among three xylene isomers and toluene.
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1986. Correlation of xylene exposure and methyl hippu ric acid excretion in urine among paint industry workers.
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1999. Possible preferential metabolism of xylene iso mers following occupational exposure to mixed xylenes.
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2002. Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol.
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1980. Effects of short term m-xylene exposure and physical exercise on the central nervous system.
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1990. The effect of xylene exposure on the liver.
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1983. Induction of morphologically abnormal sperm in rats exposed to o-xylene.
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Uncertainty factors: 1 for interspecies variability 3 for intraspecies variability Modifying factor: Not applicable 10-min, 30-min, 1-h, 4-h, 8-h AEGL-1: Concentration producing effect was applied to all times: 400 ppm/3 = 130 ppm Derivation of AEGL-2 Values Key study: Carpenter et al. 1975b Toxicity end point: Rats exposed 2 h into a 4-h exposure to 1,300 ppm exhibited poor coordination Scaling: It is assumed that the CNS effects observed after xylene exposure are directly related to parent material reaching the brain.
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1975b Toxicity end point: Reversible prostration and a no-effect level for mortality in rats exposed to 2,800 ppm for 4 h Scaling: It is assumed that the CNS effects observed after xylene exposure are directly related to parent material reaching the brain. Therefore, PBPK modeling (see Appendix C)
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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)
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Test Species/Strain/Number: Volunteer human male Exposure Route/Concentration s/Durations: Subjects were exposed by inhalation via an olfactometer delivery hood to mixed xylenes at 0, 100, 200, or 400 ppm for 30 min Effects: Mild eye irritation reported by 56%, 60%, 70%, and 90% of subjects exposed to mixed xylenes at 0, 100, 200, and 400 ppm, respectively; no effects observed on behavioral test results End Point/Concentration/Rationale: Mild eye irritation was noted by 90% of the subjects exposed to 400 ppm Uncertainty Factors/Rationale: Total uncertainty factor: 3 Interspecies: 1 for human data used Intraspecies: 3 because slight eye irritation is caused by a direct effect of the chemical and the response is not expected to vary greatly among individuals. Modifying Factor: Not applied Animal to Human Dosimetric Adjustment: Not applied, human data used Time-Scaling: Irritation is considered a threshold effect and should not vary over time.
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It is assumed that the CNS effects observed after xylene exposure are directly related to parent material reaching the brain and that CV values correlate with brain concentrations. Therefore, the CV of xylene after a 2-h exposure to xylene at 1,300 ppm would be expected to provide an internal dose measurement correlating with the clinical sign of poor coordination.
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. Modifying Factor: Not applied Animal to Human Dosimetric Adjustment: Not applied Time Scaling: PBPK modeling predicted human exposure concentrations correlating with a target CV at each defined AEGL time period.
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From page 363... ...
. Modifying Factor: Not applied Animal to Human Dosimetric Adjustment: Not applied Time Scaling: PBPK modeling predicted human exposure concentrations correlating with a target CV at each defined AEGL time period.
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Then the human model was run for each time period to determine the equivalent exposure concentration producing the same CV. The application of PBPK modeling to the derivation of the xylene AEGL values was based on guidance in the PBPK modeling White Paper (Dennison et al.
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Vmax was scaled to the body weight by using VmaxC × BW0.75. The following data were used to develop the rat PBPK model: Gas-uptake data from rats exposed at 500, 1,000, 2,000, or 4,000 ppm (Tardif et al.
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is based on an exposure concentration (2,800 ppm) that lies within the range of concentrations used in the gas uptake study.
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0.25 0.32 Fraction to slowly perfused (QSC) 0.15 0.21 Partition coefficients Blood-air (PB)
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41.9 41.9a Rapidly perfused-air (PR)
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(1993) gas uptake data (500, 1,000, 2,000, and 4,000 ppm)
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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.
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(1993) gas uptake data (500, 1,000, 2,000, and 4,000 ppm)
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(1993) gas uptake data.
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. Several human blood-air partition coefficients (PB)
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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.
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. The AEGL-2 and -3 values are based on a study in rats exposed to mixed xylenes for 4 h (Carpenter et al.
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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.
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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 performance tests and noted only mild eye irritation (Hake et al.
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QS = QC – QF – QL – QR Blood flow to non-fat tissue (L/h) QR = QRC QC Blood flow to rapidly perfused (L/h)
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2009. PBPK Modeling White Paper: Ad dressing the Use of PBPK Models to Support Derivation of Acute Exposure Guideline Levels.
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1989. Changes induced by short-term xylene exposure in human evoked potentials.
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