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HEMIMELLITENE (1,2,3-TRIMETHYLBENZENE) IN THE LIVER, LUNG, KIDNEY, AND BLOOD, AND DIMETHYLBENZOIC ACID ISOMERS IN THE LIVER, LUNG, KIDNEY AND URINE OF RATS AFTER SINGLE AND REPEATED INHALATION EXPOSURE TO HEMIMELLITENE.

INTRODUCTION

The volatile organic compounds (VOC) including a very wide use of numerous petroleum products are hazardous to the human health. Trimethylbenzenes (TMBs) belong to a wide category of VOC compounds that are contained in many petroleum products. Hemimellitene (1,2,3-TMB), in addition to pseudocumene (1,2,4-TMB) and mesitylene (1,3,5-TMB), is one of TMB isomers. The continuing growth of petroleum products manufacture is directly responsible for an extensive exposure of people involved in their manufacturing and processing in various sectors [1-3]. Many countries have issued regulations governing hygienic standard values for TMB isomers in workplace atmospheres ranging ca. 20-25 ppm [4,5]. However, based on the effects observed in the respiratory and central nervous systems in animals, the threshold limit values of at least 10 ppm should be considered in the occupational exposure to TMB isomers [6].

Hemimellitene, together with some VOCs in the indoor air pollutants, have been reported to induce irritation syndrome, deteriorated performance, and cardiovascular and pulmonary effects [7]. Hemimellitene and organic compounds in urban areas are released into the atmosphere from vaporization of gasoline and diesel fuel and in vehicle exhaust [8-10]. The children living in an ecologically poor area showed sensitization to benzene derivatives, such as TMB, and a high incidence of allergic diseases [11]. Based on a comprehensive review on TMB, the reference concentration (RfC) was calculated and the value of 0.6 ppm was adopted [12].

TMB isomers were similar in their physical properties, such as the boiling point, density, flash point and refraction index [13]. Blood/air, water/air and oil/air partition coefficients for the 3 isomers of TMB were determined in vitro. It is worth noting that all those values increase in the order: 1,3,5-TMB < 1,2,4-TMB < 1,2,3-TMB [14].

Some experimental studies on cell cultures and experimental animals revealed significant differences in the toxicity of the TMB isomers. In the Ames test, only the hemimellitene was found to produce mutagenic effects in Salmonella Typhimurium cells [15]. Neurotoxic effects of TMB isomers in male rats were investigated in conditions of acute and subchronic inhalation exposure. Neurotoxic effect of hemimellitene was more pronounced than that of pseudocumene and mesitylene [16].

The toxicokinetic data of experimental human exposure to TMB isomers has made it possible to estimate the proposed value of biological exposure limit (BEL). The values of BEL for urinary metabolites of hemimelitene and mesitylene were low in comparison to pseudocumene [17]. The Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area recommends--in terms of the biological tolerance value--determination of dimethylbenzoic acids (sum of all isomers after hydrolysis) in urine of people exposed to TMB isomers [18].

The aim of the study has been to explore the distribution of hemimellitene and dimethylbenzoic acids (DMBA) isomers in tissues as well as the kinetics of hemimellitene excretion with blood and DMBA isomers excretion with urine in rats after single and repeated inhalation exposures to hemimellitene at concentrations of 25 ppm, 100 ppm, and 250 ppm. The study sums up our earlier investigations exploring the toxicokinetics of mesitylene and pseudocumene in rats after single and repeated inhalation exposure to TMB isomer vapors [19-22].

MATERIAL AND METHODS

Chemicals

Hemimellitene (No. CAS: 526-73-8) was supplied by Aldrich (Cat. No. T7,320-2), its purity was [greater than or equal to] 90%. The conversion factors for hemimellitene: 1 ppm ~ 4.92 mg/[m.sup.3], 1 mg/[m.sup.3] ~ 0.20 ppm.

Animals and inhalation exposure monitoring

Male Wistar rats IMP:WIST (5 animals in each group), body weight of 200-360 g (2-3 months old) were exposed to hemimellitene vapors at the nominal concentration of 0 ppm, 25 ppm, 100 ppm, or 250 ppm in the dynamic inhalation chambers (volume of 0.25 [m.sup.3]) for 6 h or 4 weeks (6h/day, 5 days/week). In the inhalation chambers, the animals were placed in stainless-steel wire mesh cages [22]. The animals were given standard laboratory diet and water ad libitum, except for the exposure to hemimellitene vapors in the dynamic inhalation chambers. Body weight of the rats was measured once a week.

The Local Ethics Committee for Experiments on Animals approved the study protocol (Opinion No. L/BD/269). Hemimellitene vapors were generated by heating liquid solvents in a washer. The desired concentrations of vapors were obtained by diluting them with the air. Concentrations of solvent vapors in the exposure chamber were measured every 30 min by gas chromatography (Hewlett-Packard 5890) with a flame ionization detector (FID) using a capillary column (HP-1; 30 m x 0.53 mm x 2.65 [micro]m film thickness). The operating conditions were: carrier gas--helium, constant flow mode, column flow 10 [cm.sup.3]/min; makeup gas (helium) 20 [cm.sup.3]/min; air 300 [cm.sup.3]/min; oven 150[degrees]C; inlet split 200[degrees]C, detector 200[degrees]C. Vapor samples (0.5 d[m.sup.3]) were absorbed on a solid sorbent tube (charcoal activated for gas chromatography, MERCK, 20-36 mesh, 1st layer, 100 mg and 2nd layer, 50 mg) and desorbed with carbon disulfide (0.5 [cm.sup.3], 15 min).

Biological material collection and analysis for hemimellitene

Samples of the liver, lung and kidney (5 animals in each group) were collected from hemimellitene-exposed rats immediately after termination of exposure and decapitation. Samples were stored in glass vessels at -80[degrees]C. The tissues were homogenized before the determination of hemimellitene. In about 100 mg of organ homogenate, hemimellitene was quantitatively assessed. Venous blood samples drawn from the tail vein (5 animals in each group) were collected 3 min, 15 min, 30 min, and 45 min and 1 h, 2 h, 3 h, 4 h, 5 h, and 6 h after termination of exposure to hemimellitene vapors into 100 [micro]l heparinized glass capillary tubes. The collected samples were stored at +5[degrees]C until the determinations. Blood and tissue hemimellitene concentrations were estimated by gas chromatography combined with the headspace technique, using p-xylene as an internal standard [23]. Gas chromatography (Hewlett-Packard 5890 Series II) was equipped with FID. The working temperature of the capillary column (HP-1; 30 m x 0.53 mm x 2.65 [micro]m film thickness) was 100[degrees]C. The operating conditions were: carrier gas--helium, constant flow mode, column flow 10 ml/min; make-up gas (helium) 20 ml/min; air 300 ml/min; inlet split 180[degrees]C, detector 200[degrees]C. The limit of detection of hemimellitene was 0.05 [micro]g/g of wet tissue and was the same as for blood analysis.

Biological material collection and analysis for DMBA isomers

Samples of the liver, lung and kidney (5 animals in each group) were collected from hemimellitene-exposed rats immediately after termination of exposure and decapitation. Samples were stored in glass vessels at -80[degrees]C. The tissues were homogenized before the determination of hemimellitene metabolite. Urine samples (5 animals in each group) were collected 18 h after termination of exposure in metabolic cages (TECNIPLAST). Urine samples were stored in glass vessels at -20[degrees]C.

Two metabolites of hemimellitene were measured in urine and tissue samples: 2,6-dimethylbenzoic acid (2,6-DMBA) and 2,3-dimethylbenzoic acid (2,3-DMBA). The metabolites were measured by means of gas chromatography equipped with FID (Hewlett-Packard 5890 Plus, Chem Station Rev A. 08.03), using 2-naphthol (Fluka) as internal standard, 2,3-DMBA (Fluka) and 2,6-DMBA (Fluka) as standards [17].

Tissues (0.25-2 g) or urine samples (2 ml) were hydrolyzed (2 ml 11 mol NaOH, 2 h at 95[degrees]C). After cooling, 5 ml of 6 N [H.sub.2]S[O.sub.4] with 0.5 g NaCl was added and then extracted (10 ml diethyl ether, 10 min).

The ether layer of 5 ml was collected after evaporation of diethyl ether, the residue was silylated for 30 min (70[degrees]C) with 0.5 ml N,O-bis(trimethylsilyl)trifluoroacetamine (BSTFA) (Fluka). Samples were separated, using a HP-PONA methyl siloxane capillary column (50 m x 0.2 mm x 0.5 [micro]m film thickness); the programmed temperature: initial oven, 40[degrees]C/0.5 min; rate A: 5[degrees]C/min to 100[degrees]C, held 1 min; rate B: 3[degrees]C/min to 150[degrees]C, held 10 min; rate C: 3[degrees]C/min to 160[degrees]C, held 30 min; rate D: 20[degrees]C/min to 240[degrees]C, held 30 min. Split injection with a split ratio of 10:1 and helium at the constant flow of 0.6 ml/min was used as carrier gas. The limit of detection for all metabolites was 0.25 [micro]g/g of wet tissue and was the same as for urine analysis.

Statistical analysis

A 2-way analysis of variance with simple effects to evaluate 2x3 factorial experiment having 5 observations per cell and log-linear models was used to describe association patterns among categorical variables (6-h and 4-week) and concentrations (25 ppm, 100 ppm, and 250 ppm) [24,25]. When interaction was significant, Student's t-test was performed [26]. A value of p < 0.05 was considered to indicate statistical significance. The kinetic analysis of hemimellitene in blood was calculated on an open 2-compartment model, using SigmaPlot 4.0 (Jandel Corporation) for Windows.

RESULTS

All the rats survived inhalation exposure to hemimellitene. The Table 1 gives nominal and actual hemimellitene concentrations in toxicological chambers and the mean values of body mass of the rats, from which biological material was collected for further analysis. The chamber relative temperature and humidity were maintained at 20-23[degrees]C and 30-45%, respectively.

Masses of tissues collected from animals after termination of exposure to hemimellitene are given in the Table 2.

Compared with controls, no statistically significant changes were found either in tissue masses or in body mass of exposed animals during a 4-week exposure (Figure 1).

Hemimellitene was not found in tissues or blood of the control rats. Hemimellitene concentrations in the liver, lung, kidney, and venous blood collected immediately after termination of exposure are shown in the Table 3 and 4.

Hemimellitene concentrations in the biological material were dependent on the magnitude of exposure to hemimellitene vapors. After single and repeated exposures to similar concentrations of hemimellitene vapors, their highest levels were found in kidneys of the exposed rats. The mean hemimellitene partition coefficients of kidney/liver after a 6-h exposure were similar, 1.7, 1.9 and 1.5 for 25 ppm, 100 ppm and 250 ppm, respectively. The mean hemimellitene partition coefficients of kidney/lung, and kidney/blood after a 6-h exposure were decreased with increasing exposure, and were: 4.5 and 3.7 for 25 ppm; 3.0 and 2.0 for 100 ppm; and, 1.7 and 2.9 for 250 ppm. After 4 weeks of exposure, partition coefficients of kidney/liver, kidney/lung, and kidney/blood were evidently lower with increasing exposure, 3.9, 5.5, 7.8 for 25 ppm; 3.8, 4.6, 3.2 for 100 ppm; and 2.7, 1.7, 4.4 for 250 ppm, respectively.

After repeated exposure at 25 ppm and 250 ppm in blood and at 100 ppm and 250 ppm in liver, significantly lower concentrations of hemimellitene were found as compared to those observed after single inhalation exposure. After repeated exposure at 25 ppm in lung and kidneys, significantly higher levels of hemimellitene were found as compared to those after single inhalation exposure.

Hemimellitene concentrations in blood collected from the tail vein after termination of single and repeated inhalation exposure to hemimellitene vapors are given in the Tables 5 and 6.

During the 1st hour after exposure termination, hemimellitene was rapidly eliminated from blood of the rats exposed to its different concentrations. The elimination was calculated using a 2-compartment model. The kinetic equations are presented in the Tables 7 and 8.

Phase I and II half-lives of hemimellitene in blood were dependent on the magnitude and duration of exposure to hemimellitene. The half-lives evidently increased with increasing magnitude of exposure to hemimellitene after both 6-h and 4-week exposures. The trend of its elimination rate at the same magnitude of exposure and its different duration was similar (Figure 2).

The DMBA isomers were not observed in tissues or urine of control animals. The 2,6-DMBA was not observed in the liver, lung or kidney of rats after termination of exposure to hemimellitene. Concentrations of 2,3-DMBA in the liver, lung, and kidney after termination of exposure to hemimellitene are summarized in the Table 9 and 10. After single and repeated exposure to hemimellitene at 25 ppm and 100 ppm, the 2,3-DMBA was not observed in the lung of rats. The 2,3-DMBA concentrations in the liver and kidney were similar, and its concentrations increased with increasing magnitude of the exposure of the rats. As compared to single exposures at 100 ppm and 250 ppm, 2,3-DMBA concentrations were significantly lower in the liver and kidney of rats after repeated exposure to hemimellitene. However, after 6-h and 4-week exposures to hemimellitene at 25 ppm, 100 ppm and 250 ppm, average partition coefficients of 2,3-DMBA in kidney/liver were similar (after a 6-h exposure 0.72, 1.11 and 1.04; after 4-week exposure 0.80, 0.81 and 1.03, respectively).

Concentrations of 2,3-DMBA and 2,6-DMBA in the urine after termination of exposure to hemimellitene are given in the Table 11 and 12.

Urine concentration of DMBA isomers increased with increasing magnitude of the exposure of the rats. As compared to single exposures at 100 ppm for 2,6-DMBA and 50 ppm and 100 ppm for 2,3-DMBA, the concentrations were significantly high in the urine of rats after repeated exposure to hemimellitene.

DISCUSSION

The use of biomarkers in toxicology is becoming increasingly important [27]. Quantitative analysis of volatile neurotoxic chemicals in blood is a good marker of their effective doses. Blood concentrations of the solvents were found to be dose-related in the experimental animals after single administration of the TMB isomers [28]. The current study and our earlier investigations on the assessment of pseudocumene and mesitylene concentrations in rat blood and tissues that were performed in similar conditions point to distinct differences of TMB isomer levels in the case of single and repeated inhalation exposures [20,22].

The Table 13 presents trends of pseudocumene, mesitylene and hemimellitene concentration variations in selected tissues, including blood of animals exposed to single, as relative to repeated exposure to TMB isomers.

When analyzing single vs. repeated exposure to one of the studied 3 TMB isomers, the concentration of hemimellitene in blood and liver after repeated exposure was significantly lower as compared to single exposure practically for all 3 exposure levels. A similar, although less intensive pattern of changes was observed after exposure to mesitylene. The patterns of changes of pseudocumene, concentrations in the solid tissues and blood were ambivalent or varied at similar levels that depended on the exposure magnitude instead of inhalation exposure time.

If it is assumed that the neurotoxic effect after 4-week exposure depends on the level of TMB isomers in blood, then the most potent isomer is pseudocumene, the blood level of which was dependent on exposure magnitude and practically independent of exposure time.

The Table 14 sums up toxicokinetic characteristics of TMB isomers.

After comparing the toxicokinetic parameters of TMB isomers, it is evident that there are no differences in the area under the curve (AUC) and half-life values calculated from the kinetic equations after 6-h and 4-week exposures to TMB isomers at 25 ppm and 100 ppm. The AUC evidently decreased after 4-week exposure as compared to 6-h exposure to TMB isomers at 250 ppm. The trend of elimination of TMB isomers from blood of rats exposed to TMB isomers at 250 ppm is specific for each solvent. After 4-week exposure, as compared to 6-h exposure, the value of half-life calculated for mesitylene phase II was similar, while for pseutocumene and hemimellitene, it was lower and higher, respectively.

The reduction of mesitylene and hemimellitene concentrations in the blood in the case of repeated exposure as compared to single-exposed animals is likely to result in a weaker neurotoxic activity of those compounds in the case of repeated exposure as compared to single exposures. The more so that in many studies involving repeated inhalation exposure to TMB isomers, the behavioral changes of experimental animals pointed to the non-linear character of the concentration/effect relationships for those compounds [29-30]. For acute inhalation exposure to TMB isomers, the neurotoxic effects in rats were concentration-dependent for pesudocumene, hemimellitene and mesitylene [16].

Low concentrations of TMB isomers were observed to induce the behavioral changes. The authors suggest that prolonged exposures for low TMB isomer concentrations are likely to produce significant changes in the function of the rats' central nervous system [31].

In our earlier studies, we had detected significant changes in the results of neurobehavioral tests, during which rats exposed by inhalation to pseudocumene or hemimellitene were given amphetamine, which is a strong psychostymulant. For each of the 2 solvents, the concentration-effect relationship was nonlinear. Out of the 3 concentrations used: 25 ppm, 100 ppm and 250 ppm, the concentration of 100 ppm appeared to be the most effective. The alterations induced by exposure to 100 ppm hemimellitene or pseudocumene go in opposite directions: exposure to hemimellitene results in increased, and exposure to pseudocumene in decreased behavioral sensitivity to amphetamine and susceptibility to sensitization by a repeated amphetamine treatment [32]. A reduction of hemimellitene and pseudocumene concentration observed after repeated exposure in the blood of rats exposed to high concentrations of the solvents could be responsible for no dose/response relationship in the behavioral tests of the animals.

Differences in the absorption and specific metabolic activity of TMB isomers in rats affected formation of the metabolites in the biological material and the removal of the metabolites with urine. The Table 15 shows trends in TMB metabolite changes in the biological material after 4-week exposure as compared to 6-h inhalation exposure to the tested TMB isomer. Lower concentrations of pseudocumene metabolites in urine found in our study 4 weeks after exposure termination as compared with those after a single exposure may evidence the saturation of pseudocumene metabolic transformation in tissues. Some findings on the increased activity of microsomal monooxygenases in rat tissues after chronic (4-month) exposure to pseudocumene at the concentration of 10 mg/[m.sup.3] (c.a. 2 ppm) have been reported [33]. After repeated exposure to pseudocumene at 100 ppm and 250 ppm, concentrations of all the 3 DMBA isomers in the rat kidneys were higher than after a single exposure, which indicates a possible stimulation of pseudocumene metabolism.

Repeated inhalation exposure to mesitylene and hemimellitene vapors usually in the majority of experimental animals generated higher metabolite concentrations in the rat tissue and increased excretion of those metabolites with urine as compared to a single exposure due to induction of mesitylene and hemimellitene metabolizing enzymes. A number of authors have observed the increased cytochrome P-450 concentration and induced specific enzymes associated with xenobiotic metabolism not only in the liver but also in the kidney and lung after repeated administration of mesitylene to rats by gastric tube [34,35]. Nevertheless, at elevated hemimellitene concentration following repeated exposure as compared to single exposure, lower concentrations of its metabolite were detected in the tissues, indicating possible saturation of the metabolic processes occurring in the studied rat tissues.

By analogy to the differences observed in rats, humans are also likely to show significant differences in the absorption, metabolism and removal of TMB isomers under circumstances of repeated inhalation exposure to those compounds. Elevated metabolic hemimellitene and mesitylene efficiency may lead to the erroneous assessment of biomonitoring results.

The American Conference of Governmental Industrial Hygienists (ACGIH) and Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) publish values of admissible concentrations of various chemical compounds in the biological material [4,18]. Out of those 2 organizations, the DFG has decided to express biological tolerance values of TMB isomers exposures in terms of determined dimethylbenzoic acid concentrations (sum of all isomers after hydrolysis) in urea [18].

Human studies show that the urinary excretion of dimethylhippuric acid isomers and dimethylbenzoic acid isomers in humans after short-term-exposure is a good indicator of TMB exposure [17,36]. The simulation model of accretion and excretion of dimethylbenzoic acids in human urine during a working week points to increased removal of 2,6-DMBA, one of 2 hemimellitene metabolites [17]. Our animal studies have confirmed increased removal of 2,6- and 2,3-DMBA with urine of rats repeatedly exposed to hemimellitene. To determine the biological tolerance values for TMB, an individual approach, i.e., considering each TMB isomer separately, seems preferable.

CONCLUSIONS

In conclusion, the studies have revealed that in rats after inhalation exposure to hemimellitene, the detected significantly lower hemimellitene concentrations in the blood and solid tissues of the repeatedly exposed animals may point to a reduced hemimellitene retention in the lungs of the rats. Hemimellitene elimination from the blood of rats after single and repeated inhalation exposure depended on the exposure magnitude and not on exposure time. For the 2 hemimellitene metabolites determined in rat urine, the main trend of their metabolism in the animal tissues involved formation of 2,3-DMBA. The significantly higher urinary 2,3-DMBA concentration after repeated inhalation exposure to hemimellitene as compared to the single exposure points to the induction of enzymatic processes in the rats exposed by inhalation to hemimellitene.

The results of the study indicate that metabolic transformations of TMB isomers in rats, leading to the production of DMBA isomers, are specific and their intensity differs depending on the organ (liver, lung, or kidney). The analysis of the concentration of TMB isomer metabolites in urine of animals indicates that the use of the value of biological exposure limit specified in terms of the total for all isomers may result in over- or underestimation of the risk of exposure to TMB isomers under circumstances of repeated inhalation exposure to those chemical compounds.

http://dx.doi.org/10.13075/ijomeh.1896.00599

ACKNOWLEDGMENTS

The authors are grateful to Krzysztof Mader for his excellent technical assistance.

REFERENCES

[1.] Ritchie G, Still K, Rossi J 3rd, Bekkedal M, Bobb A, Arfsten D. Biological and health effects of exposure to kerosene-based jet fuels and performance additives. J Toxicol Environ Health B Crit Rev. 2003;6:357-451, http://dx.doi. org/10.1080/10937400306473.

[2.] Takamiya M, Niitsu H, Saigusa K, Kanetake J, Aoki Y. A case of acute gasoline intoxication at the scene of washing a petrol tank. Leg Med. 2003;5:165-9, http://dx.doi.org/10.1016/ S1344-6223(03)00051-8.

[3.] Wesolowski W, Gromiec JP. Occupational exposure in Polish paint and lacquer industry. Int J Occup Med Environ Health. 1997;10:79-88.

[4.] American Conference of Governmental Industrial Hygienists. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati (OH): ACGIH; 2013. p. 59.

[5.] Czerczak S, Kupczewska M. Assignment of skin notation for maximum allowable concentration (MAC) list in Poland. Appl Occup Environ Hyg. 2002;17:187-99, http://dx.doi. org/10.1080/104732202753438270.

[6.] Korsak Z, Rydzynski K, Jajte J. Respiratory irritative effects of trimethylbenzenes: An experimental animal study. Int J Occup Med Environ Health. 1997;10:303-11.

[7.] Wolkoff P. Indoor air pollutants in office environments: Assessment of comfort, health, and performance. Int J Hyg Environ Health. 2013;216:371-94, http://dx.doi.org/10.1016/ j.ijheh.2012.08.001.

[8.] Jia LW, Shen MQ, Wang J, Lin MQ. Influence of ethanol-gasoline blended fuel on emission characteristics from a four-stroke motorcycle engine. J Hazard Mater. 2005;123:29-34, http://dx.doi.org/10.1016/j.jhazmat.2005.03.046.

[9.] Nishino N, Arey J, Atkinson R. Formation yields of glyoxal and methylglyoxal from the gas-phase OH radical-initiated reactions of toluene, xylenes, and trimethylbenzenes as a function of N[O.sub.2] concentration. J Phys Chem A. 2010;114:10140-7, http://dx.doi.org/10.1021/jp105112h.

[10.] Rahman MM, Kim KH. Exposure to hazardous volatile pollutants back diffusing from automobile exhaust systems. J Hazard Mater. 2012;241-2:267-78, http://dx.doi. org/10.1016/j.jhazmat.2012.09.042.

[11.] Petrov EJ, Pereslegina IA, Mineev BA, Maianskaia IV [The effect of benzene derivatives on the body sensitization of children] Gig Sanit. 1999;5:42-4. Russian.

[12.] Firth MJ. Derivation of a chronic reference dose and reference concentration for trimethylbenzenes and C9 aromatic hydrocarbon solvents. Regul Toxicol Pharmacol. 2008;52:248-56, http://dx.doi.org/10.1016/j.yrtph.2008.08.017.

[13.] Laham S. Mesitylene. Pseudocumene. Hemimellitene. In: Snyder R., editor. Ethel Browning's toxicity and metabolism of industrial solvents. Amsterdam: Elsevier; 1987. p. 121-42.

[14.] Jarnberg J, Johanson G. Liquid/air partition coefficients of the trimethylbenzenes. Toxicol Ind Health. 1995;11:81-8, http://dx.doi.org/10.1177/074823379501100107.

[15.] Janik-Spiechowicz E, Wyszynska K, Dziubaltowska E. Genotoxicity evaluation of trimethylbenzenes. Mutat Res. 1998;412:299-305, http://dx.doi.org/10.1016/S1383-5718 (97)00202-7.

[16.] Korsak Z, Rydzynski K. Neurotoxic effects of acute and subchronic inhalation exposure to trimethylbenzene isomers (pseudocumene, mesitylene, hemimellitene) in rats. Int J Occup Med Environ Health. 1996;9:341-9.

[17.] Kostrzewski P, Wiaderna-Brycht A, Czerski B. Biological monitoring of experimental human exposure to trimethylbenzene. Sci Total Environ. 1997;199:73-81, http://dx.doi. org/10.1016/S0048-9697(97)05504-6.

[18.] Deutshe Forschungsgemeinschaft. List of MAK and BAT Values 2012. Weinheim: WILEY-VCH Verlag GmbH&Co; 2012. p. 223.

[19.] Swiercz R, Rydzynski K, W[micro]sowicz W, Majcherek W, Wesolowski W. Toxicokinetics and metabolism of pseudocumene (1,2,4-trimethylbenzene) after inhalation exposure in rats. Int J Occup Med Environ Health. 2002;15:37-42.

[20.] Swiercz R, Wiaderna D, W[micro]sowicz W, Rydzynski K. Pseudocumene in brain, liver, lung and blood of rats after single and repeated inhalation exposure. Int J Occup Med Environ Health. 2003;16:61-6.

[21.] Swiercz R, W[micro]sowicz W, Majcherek W. Dimethylbenzoic acid isomers in lung, kidney, liver and urine of rats after single and repeated inhalation exposure to pseudocumene. Pol J Environ Stud. 2005;14:527-34.

[22.] Swiercz R, W[micro]sowicz W, Majcherek W. Mesitylene (1,3,5-trimethylbenzene) in the liver, lung, kidney, and blood and 3,5-dimethylbenzoic acid in the liver, lung, kidney and urine of rats after single and repeated inhalation exposure to mesitylene. Pol J Environ Stud. 2006;15:485-92.

[23.] Radzikowska-Kintzi H, Jakubowski M. Internal standardization in the Head Space analysis of organic solvent in blood. Int Arch Occup Environ Health. 1981;49:115-21, http://dx. doi.org/10.1007/BF00377664.

[24.] Agresti A. Categorical Data Analysis. New York: Wiley; 1990.

[25.] Winer BJ, Brown DR, Michels KM. Statistical Principles in Experimental Design. 3rd ed. New York: McGraw-Hill Book Company; 1991.

[26.] Snedecor GW, Cochran WG. Statistical Methods. 6th ed. Ames (IA): Iowa State University; 1967.

[27.] Timbrell JA. Biomarkers in toxicology. Toxicology. 1998;129:1-12, http://dx.doi.org/10.1016/S0300-483X(98) 00058-4.

[28.] Tomas T, Swiercz R, Wiaderka D, Gralewicz S. Effects of acute exposure to aromatic hydrocarbons C 9 on locomotor activity in rats. Trimethylbenzene isomers. Int J Occup Med Environ Health. 1999;12:331-43.

[29.] Gralewicz S, Wiaderka D, Tomas T, Rydzynski K. Behavioral changes following 4-week inhalation exposure to pseudocumene (1,2,4-trimethylbenzene) in the rat. Neurotoxicol Teratol. 1997;19:327-33, http://dx.doi.org/10.1016/S0892-0362 (97)00001-9.

[30.] Wiaderna D, Gralewicz S, Tomas T. Behavioural changes following a four-week inhalation exposure to hemimellitene (1,2,3-trimethylbenzene) in rats. Int J Occup Med Environ Health. 1998;11:319-34.

[31.] Wiaderna D, Gralewicz S, Tomas T. Assessment of long-term neurotoxic effects of exposure to mesitylene (1,3,5-trimethylbenzene) based on the analysis of selected behavioral responses. Int J Occup Med Environ Health. 2002;15:385-92.

[32.] Lutz P, Gralewicz S, Wiaderka D, Swiercz R, Grzelinska Z, Majcherek W. Contrasting effects of 4-week inhalation exposure to pseudocumene or hemimellitene on sensitivity to amphetamine and propensity to amphetamine sensitization in the rat. Int J Occup Med Environ Health. 2010;23:85-94, http://dx.doi.org/10.2478/v10001-010-0005-8.

[33.] Shakirov DF. [Microsomal monooxygenases upon inhalation exposure to pseudocumene and durene]. Gig Sanit. 2001;4:53-6. Russian.

[34.] Pyykko K. Effects of methylbenzenes on microsomal enzymes in rat liver, kidney and lung. Biochim Biophys Acta. 1980;633:1-9, http://dx.doi.org/10.1016/0304-4165(80)90032-X.

[35.] Zajworoniuk H, Rzeczycki W. Effect of mesitylene on ethanol metabolism in rat liver microsomes. Acta Biochim Pol. 1992;39:335-43.

[36.] Jarnberg J, Stahlbon B, Johanson G, Lof A. Urinary excretion of dimethylhippuric acids in humans after exposure to trimethylbenzenes. Int Arch Occup Environ Health. 1997;69:491-7, http://dx.doi.org/10.1007/s00420 0050179.

This work is available in Open Access model and licensed under a Creative Commons Attribution-NonCommercial 3.0 Poland License--http://creativecommons.org/ licenses/by-nc/3.0/pl/deed.en.

RADOSLAW SWIERCZ, WANDA MAJCHEREK, and WOJCIECH WASOWICZ

Nofer Institute of Occupational Medicine, Lodz, Poland

Department of Toxicology and Carcinogenesis

This research was supported under the statutory activities of the Nofer Institute of Occupational Medicine IMP grant 1.11. "Toxicokinetics and metabolism of hemimellitene after inhalation exposure in rats". Project manager: Radoslaw Swiercz, Ph.D.

Received: February 3, 2015. Accepted: March 26, 2015.

Corresponding author: R. Swiercz, Nofer Institute of Occupational Medicine, Department of Toxicology and Carcinogenesis, sw. Teresy 8, 91-348 Lodz, Poland (e-mail: radek@imp.lodz.pl).

Caption: Fig. 1. Mean body weights of rats exposed to hemimellitene at 0 ppm (N = 5), 25 ppm (N = 5), 100 ppm (N = 5) and 250 ppm (N = 5) for 4 weeks

Caption: Fig. 2. Kinetics of hemimellitene elimination from venous blood of rats after termination of 6-h and 4-week exposures to hemimellitene vapors at nominal concentration of: a) 25 ppm (N = 5), b) 100 ppm (N = 5) and c) 250 ppm (N = 5)
Table 1. Air concentrations of hemimellitene in inhalation
chambers and body mass of rats

                            Hemimellitene       Hemimellitene
                               target           concentration
  Biological material       concentration      in inhaled air
                           in inhaled air          [ppm]
                                [ppm]          (M [+ or -] SD)

Liver, lung and
kidney homogenates
  after 6-h                    control                0
  exposure                       25             25 [+ or -] 5
                                 100           105 [+ or -] 10
                                 250           242 [+ or -] 10
  after 4-week                 control                0
  exposure                       25             25 [+ or -] 2
                                 100            97 [+ or -] 7
                                 250           246 [+ or -] 16
Blood
  after 6-h exposure           control                0
                                 25             28 [+ or -] 2
                                 100           110 [+ or -] 9
                                 250           234 [+ or -] 26
  after 4-week                 control                0
  exposure                       25             24 [+ or -] 3
                                 100           104 [+ or -] 6
                                 250           243 [+ or -] 13
Urine
  after 6-h exposure           control                0
                                 25             21 [+ or -] 1
                                 100            99 [+ or -] 3
                                 250           225 [+ or -] 13
  after 4-week                 control                0
  exposure                       25             25 [+ or -] 2
                                 100            97 [+ or -] 7
                                 250           246 [+ or -] 16

                            Hemimellitene
                               target
  Biological material       concentration     Animals
                           in inhaled air     treated
                                [ppm]            [n]

Liver, lung and
kidney homogenates
  after 6-h                    control            5
  exposure                       25               5
                                 100              5
                                 250              5
  after 4-week                 control            5
  exposure                       25               5
                                 100              5
                                 250              5
Blood
  after 6-h exposure           control            5
                                 25               5
                                 100              5
                                 250              5
  after 4-week                 control            5
  exposure                       25               5
                                 100              5
                                 250              5
Urine
  after 6-h exposure           control            5
                                 25               5
                                 100              5
                                 250              5
  after 4-week                 control            5
  exposure                       25               5
                                 100              5
                                 250              5

                            Hemimellitene
                               target
  Biological material       concentration        Body weight
                           in inhaled air            [g]
                                [ppm]          (M [+ or -] SD)

Liver, lung and
kidney homogenates
  after 6-h                    control         226 [+ or -] 4
  exposure                       25            207 [+ or -] 5
                                 100           215 [+ or -] 20
                                 250           205 [+ or -] 5
  after 4-week                 control         309 [+ or -] 26
  exposure                       25            280 [+ or -] 17
                                 100           323 [+ or -] 28
                                 250           310 [+ or -] 13
Blood
  after 6-h exposure           control         210 [+ or -] 7
                                 25            223 [+ or -] 10
                                 100           214 [+ or -] 11
                                 250           208 [+ or -] 5
  after 4-week                 control         311 [+ or -] 10
  exposure                       25            333 [+ or -] 23
                                 100           321 [+ or -] 22
                                 250          292  [+ or -] 20
Urine
  after 6-h exposure           control        250  [+ or -] 9
                                 25            243 [+ or -] 10
                                 100           251 [+ or -] 15
                                 250           238 [+ or -] 14
  after 4-week                 control         310 [+ or -] 10
  exposure                       25            305 [+ or -] 15
                                 100           317 [+ or -] 22
                                 250           284 [+ or -] 23

M--mean; SD--standard deviation.

Table 2. Absolute and relative weight of liver, lung and kidney
of rats after exposure to hemimellitene

                            Absolute organ weight
 Hemimellitene                       [g]
     target                    (M [+ or -] SD)
 concentration
 in inhaled air
     [ppm]                 liver                   lung

6-h exposure
  control           9.48 [+ or -] 0.63      1.31 [+ or -] 0.13
  25                9.25 [+ or -] 0.46      1.17 [+ or -] 0.30
  100               9.09 [+ or -] 1.06      1.34 [+ or -] 0.29
  250               9.37 [+ or -] 0.61      1.21 [+ or -] 0.20
4-week exposure
  control           12.63 [+ or -] 1.02     1.47 [+ or -] 0.24
  25                11.61 [+ or -] 1.62     1.63 [+ or -] 0.32
  100               13.37 [+ or -] 2.37     1.54 [+ or -] 0.33
  250               13.15 [+ or -] 1.12     1.43 [+ or -] 0.33

                    Absolute organ weight
 Hemimellitene               [g]
     target            (M [+ or -] SD)
 concentration
 in inhaled air
     [ppm]                  kidney

6-h exposure
  control             1.83 [+ or -] 0.19
  25                  1.93 [+ or -] 0.15
  100                 1.82 [+ or -] 0.11
  250                 1.87 [+ or -] 0.16
4-week exposure
  control             2.28 [+ or -] 0.19
  25                  2.07 [+ or -] 0.08
  100                 2.51 [+ or -] 0.32
  250                 2.49 [+ or -] 0.17

                               Relative organ weight
 Hemimellitene                    [g/100 g b.w.]
     target                      (M [+ or -] SD)
 concentration
 in inhaled air
     [ppm]                  liver                     lung

6-h exposure
  control             4.50 [+ or -] 0.41       0.62 [+ or -] 0.08
  25                  4.47 [+ or -] 0.26       0.57 [+ or -] 0.14
  100                 4.27 [+ or -] 0.72       0.63 [+ or -] 0.17
  250                 4.57 [+ or -] 0.35       0.59 [+ or -] 0.09
4-week exposure
  control             4.09 [+ or -] 0.27       0.47 [+ or -] 0.06
  25                  4.14 [+ or -] 0.50       0.58 [+ or -] 0.10
  100                 4.11 [+ or -] 0.42       0.48 [+ or -] 0.09
  250                 4.24 [+ or -] 0.31       0.46 [+ or -] 0.09

 Hemimellitene       Relative organ weight
     target            [g/100 g b.w.]
 concentration         (M [+ or -] SD)
 in inhaled air
     [ppm]                kidney

6-h exposure
  control           0.87 [+ or -] 0.10
  25                0.93 [+ or -] 0.07
  100               0.85 [+ or -] 0.04
  250               0.91 [+ or -] 0.08
4-week exposure
  control           0.74 [+ or -] 0.08
  25                0.74 [+ or -] 0.01
  100               0.77 [+ or -] 0.04
  250               0.80 [+ or -] 0.05

Abbreviations as in Table 1.

Table 3. Concentration of hemimellitene in liver, lung, kidney
homogenates and venous blood of rats after exposure to
hemimellitene

                            Hemimellitene concentration
 Hemimellitene                     (M [+ or -] SD)
     target
  concentration              liver                      lung
 in inhaled air       [[micro]g/g tissue]        [[micro]g/g tissue]

6-h exposure
  25 ppm            1.66 [+ or -] 0.48         0.62 [+ or -] 0.08
  100 ppm           4.20 [+ or -] 0.85         2.57 [+ or -] 0.40
  250 ppm          20.75 [+ or -] 3.30        18.73 [+ or -] 2.81
4-week exposure
  25 ppm            1.18 [+ or -] 0.28         0.83 [+ or -] 0.11 **
  100 ppm           2.68 [+ or -] 0.76 *       2.17 [+ or -] 0.24
  250 ppm          11.30 [+ or -] 3.42 **     17.28 [+ or -] 6.02

                    Hemimellitene concentration
 Hemimellitene           (M [+ or -] SD)
     target
  concentration              kidney
 in inhaled air       [[micro]g/g tissue]

6-h exposure
  25 ppm             2.81 [+ or -] 0.40
  100 ppm            7.78 [+ or -] 3.17
  250 ppm           31.16 [+ or -] 3.84
4-week exposure
  25 ppm             4.55 [+ or -] 0.32 ***
  100 ppm           10.07 [+ or -] 0.67
  250 ppm           29.99 [+ or -] 8.00

                   Hemimellitene concentration
 Hemimellitene         (M [+ or -] SD)
     target
  concentration              blood
 in inhaled air          [[micro]g/ml]

6-h exposure
  25 ppm            0.76 [+ or -] 0.09
  100 ppm           3.82 [+ or -] 0.94
  250 ppm          10.73 [+ or -] 1.30
4-week exposure
  25 ppm            0.58 [+ or -] 0.08 **
  100 ppm           3.14 [+ or -] 0.61
  250 ppm           6.87 [+ or -] 1.05 ***

Abbreviations as in Table 1.

* p < 0.05; ** p < 0.01; *** p < 0.001--significantly
different from the single exposure (Student's t-test).

Table 4. Statistics of hemimellitene concentration in liver,
lung, kidney homogenates and venous blood of rats after exposure to
hemimellitene

                                                p
       Statistics
                             liver       lung      kidney     blood
Main effects
  exposure                  < 0.001    n.s.       n.s.       < 0.001
  concentration             < 0.001    < 0.001    < 0.001    < 0.001
Interaction effect
  exposure by               < 0.001    n.s.       n.s.       < 0.001
  concentration
Simple effects
  concentration within      < 0.001    < 0.001    < 0.001    < 0.001
  6-h exposure
  concentration within      n.s.       < 0.001    < 0.010    < 0.050
  4-week exposure
Exposure within
concentration
  25 ppm                    n.s.       n.s.       n.s.       n.s.
  100 ppm                   n.s.       n.s.       n.s.       n.s.
  250 ppm                   < 0.050    n.s.       n.s.       n.s.

n.s.--not statistically significant (p > 0.05).

Table 5. Venous blood hemimellitene concentrations after
a 6-h inhalation exposure to hemimellitene

                   Hemimellitene concentration
                          [[micro]g/ml]
                          (M [+ or -] SD)
   Time
[h (min)]      25 ppm exposure        100 ppm exposure

0 (3)         0.76 [+ or -] 0.09     3.82 [+ or -] 0.94
0 (15)        0.75 [+ or -] 0.08     3.21 [+ or -] 0.91
0 (30)        0.67 [+ or -] 0.14     2.83 [+ or -] 0.35
0 (45)        0.52 [+ or -] 0.14     2.76 [+ or -] 0.47
1 (0)         0.50 [+ or -] 0.03     2.29 [+ or -] 0.34
2 (0)         0.45 [+ or -] 0.15     1.63 [+ or -] 0.16
3 (0)         0.26 [+ or -] 0.06     1.32 [+ or -] 0.23
4 (0)         0.18 [+ or -] 0.08     0.87 [+ or -] 0.03
5 (0)         0.12 [+ or -] 0.10     0.55 [+ or -] 0.10
6 (0)         0.07 [+ or -] 0.05     0.48 [+ or -] 0.14

             Hemimellitene concentration
                  [[micro]g/ml]
                 (M [+ or -] SD)
   Time
[h (min)]       250 ppm exposure

0 (3)         10.73 [+ or -] 1.30
0 (15)         9.56 [+ or -] 1.40
0 (30)         7.09 [+ or -] 1.70
0 (45)         6.73 [+ or -] 1.16
1 (0)          7.71 [+ or -] 0.58
2 (0)          5.10 [+ or -] 0.62
3 (0)          3.50 [+ or -] 0.71
4 (0)          3.13 [+ or -] 0.45
5 (0)          1.51 [+ or -] 0.39
6 (0)          1.25 [+ or -] 0.30

Abbreviations as in Table 1.

Table 6. Venous blood hemimellitene concentrations after a
4-week inhalation exposure to hemimellitene

                    Hemimellitene concentration
                           [[micro]g/ml]
                          (M [+ or -] SD)

   Time
 [h (min)]      25 ppm exposure        100 ppm exposure

0 (3)          0.58 [+ or -] 0.09     3.14 [+ or -] 0.70
0 (15)         0.40 [+ or -] 0.07     2.77 [+ or -] 0.50
0 (30)         0.42 [+ or -] 0.10     2.03 [+ or -] 0.15
0 (45)         0.43 [+ or -] 0.10     1.78 [+ or -] 0.18
1 (0)          0.43 [+ or -] 0.13     1.80 [+ or -] 0.24
2 (0)          0.30 [+ or -] 0.06     1.38 [+ or -] 0.30
3 (0)          0.30 [+ or -] 0.03     1.03 [+ or -] 0.15
4 (0)          0.25 [+ or -] 0.03     0.85 [+ or -] 0.10
5 (0)          0.19 [+ or -] 0.06     0.82 [+ or -] 0.16
6 (0)          0.18 [+ or -] 0.07     0.75 [+ or -] 0.21

               Hemimellitene concentration
                      [[micro]g/ml]
                      (M [+ or -] SD)

   Time
 [h (min)]           250 ppm exposure

0 (3)               6.87 [+ or -] 1.05
0 (15)              6.04 [+ or -] 0.80
0 (30)              4.56 [+ or -] 0.73
0 (45)              4.02 [+ or -] 0.91
1 (0)               3.45 [+ or -] 0.74
2 (0)               3.04 [+ or -] 0.32
3 (0)               2.43 [+ or -] 0.37
4 (0)               2.04 [+ or -] 0.67
5 (0)               1.66 [+ or -] 0.36
6 (0)               1.56 [+ or -] 0.37

Abbreviations as in Table 1.

Table 7. Toxicokinetics of hemimellitene elimination from blood
after a 6-h inhalation exposure to hemimellitene

Exposure
  [ppm]                   Elimination (E) equation

25              E = 0.60[e.sup.-3.04t] + 0.52[e.sup.-0.23t]
100             E = 3.05[e.sup.-2.23t] + 2.00[e.sup.-0.19t]
250             E = 9.00[e.sup.-1.28t] + 4.00[e.sup.-0.13t]

                                       Half-life
                 [AUC.sub.0
Exposure      [right arrow]6h]    phase I    phase II
  [ppm]          [mg x h/l]        [min]     [h (min)]

25                  1.89             14        3 (4)
100                 8.53             19        3 (42)
250                23.70             32        5 (20)

AUC--area under curve.

Table 8. Toxicokinetics of hemimellitene elimination from
venous blood after a 4-week inhalation exposure to hemimellitene

Exposure
  [ppm]                  Elimination (E) equation

25             E = 0.58[e.sup.-23.35t] + 0.40[e.sup.-0.12t]
100             E = 2.70[e.sup.-5.09t] + 1.80[e.sup.-0.15t]
250             E = 7.00[e.sup.-3.24t] + 3.00[e.sup.-0.09t]

                                       Half-life
                [AUC.sub.0
Exposure     [right arrow]6h]    phase I     phase II
  [ppm]         [mg x h/l]         [min]     [h (min)]

25                 1.75              2         5 (52)
100                7.66              8         4 (34)
250               16.09             13         7 (58)

AUC--area under curve.

Table 9. Concentration of 2,3-dimethylbenzoic acid (2,3-DMBA)
in liver, lung and kidney of rats after exposure to hemimellitene

 Hemimellitene               2,3-DMBA concentration
     target                   [[micro]g/g tissue]
 concentration                  (M [+ or -] SD)
 in inhaled air

                            liver                     lung

6-h exposure
  25 ppm             7.68 [+ or -] 1.64               n.d.
  100 ppm           21.19 [+ or -] 0.59               n.d.
  250 ppm           27.66 [+ or -] 3.62        3.23 [+ or -] 0.56
4-week exposure
  25 ppm             8.54 [+ or -] 1.17               n.d.
  100 ppm           13.78 [+ or -] 2.84 **            n.d.
  250 ppm           17.93 [+ or -] 4.33 **     2.82 [+ or -] 0.44

 Hemimellitene      2,3-DMBA concentration
     target           [[micro]g/g tissue]
 concentration          (M [+ or -] SD)
 in inhaled air

                             kidney

6-h exposure
  25 ppm               5.52 [+ or -] 0.77
  100 ppm             23.59 [+ or -] 3.33
  250 ppm             28.69 [+ or -] 6.55
4-week exposure
  25 ppm               6.84 [+ or -] 0.76
  100 ppm             11.19 [+ or -] 1.58 ***
  250 ppm             18.53 [+ or -] 2.31 *

n.d.--not detected. Other abbreviations as in Table 1 and 3.

Table 10. Statistics of 2,3-dimethylbenzoic acid (2,3-DMBA)
concentration in liver, lung and kidney of rats after exposure to
hemimellitene

                                                p

Statistics                         liver      lung   kidney

Main effects
  exposure                         < 0.001           < 0.001
  concentration                    < 0.001           < 0.001
Interaction effect
  exposure by concentration        < 0.001           < 0.001
Simple effects
  concentration within 6-h         < 0.001           < 0.001
  exposure
  concentration within 4-week      n.s.              n.s.
  exposure
Exposure within concentration
  25 ppm                           n.s.              n.s.
  100 ppm                          n.s.              < 0.050
  250 ppm                          < 0.050           n.s.

n.s.--not statistically significant (p > 0.05).

Table 11. Urinary excretion of dimethylbenzoic acid (DMBA)
isomers after exposure to hemimellitene

                                       Urine
  Hemimellitene                      [mg/18 h]
     target                       (M [+ or -] SD)
  concentration
 in inhaled air            2,6-DMBA              2,3-DMBA

6-h exposure
  25 ppm                     n.d.            0.07 [+ or -] 0.01
  100 ppm             0.17 [+ or -] 0.03     0.58 [+ or -] 0.06
  250 ppm             0.59 [+ or -] 0.26     2.19 [+ or -] 0.66
4-week exposure
  25 ppm                     n.d.            0.11 [+ or -] 0.005 ***
  100 ppm             0.39 [+ or -] 0.13 *   1.60 [+ or -] 0.40 **
  250 ppm             0.58 [+ or -] 0.14     2.79 [+ or -] 0.76

Other abbreviations as in Table 1 and 3.

Table 12. Statistics of urinary excretion of dimethylbenzoic
acid (DMBA) isomers after exposure to hemimellitene

                                             p

Statistics                          2,6-DMBA    2,3-DMBA

Main effects
  exposure                          n.s.        < 0.005
  concentration                     < 0.001     < 0.001
Interaction effect
  exposure by concentration         n.s.        n.s.
Simple effects
  concentration within              < 0.050     < 0.050
  6-h exposure
  concentration within              n.s.        < 0.001
  4-week exposure
Exposure within concentration
  25 ppm                                        n.s.
  100 ppm                           n.s.        n.s.
  250 ppm                           n.s.        n.s.

n.s.--not statistically significant (p > 0.05).

Table 13. Changes of trimethylbenzene (TMB) isomers in tissues
and blood of rats after 6-h vs. 4-week exposure to isomers of TMB

                     Changes of TMB isomers
                        concentration
                              [%]

                         25 ppm exposure

    TMB isomer                  lung

Pseudocumene (a)     9 [up arrow]
Mesitylene (b)       35 [up arrow]
Hemimellitene        34 [up arrow][up arrow]

                     Changes of TMB isomers
                        concentration
                              [%]

                          25 ppm exposure

    TMB isomer                   blood

Pseudocumene (a)     6 [up arrow]
Mesitylene (b)       0
Hemimellitene        24 [down arrow][down arrow]

                           Changes of TMB isomers
                               concentration
                                    [%]

                     25 ppm exposure     100 ppm exposure

    TMB isomer             liver                lung

Pseudocumene (a)     2 [up arrow]        10 [down arrow]
Mesitylene (b)       27 [down arrow]     31 [down arrow]
Hemimellitene        29 [down arrow]     29 [up arrow]

                     Changes of TMB isomers
                        concentration
                              [%]

                        100 ppm exposure

    TMB isomer               blood

Pseudocumene (a)     24 [up arrow]
Mesitylene (b)       25 [down arrow]
Hemimellitene        18 [down arrow]

                        Changes of TMB isomers
                            concentration
                                 [%]

                          100 ppm exposure

    TMB isomer                   liver

Pseudocumene (a)     58 [down arrow][down arrow]
Mesitylene (b)       3 [down arrow]
Hemimellitene        36 [down arrow][down arrow]

                   Changes of TMB isomers
                       concentration
                            [%]

                     250 ppm exposure

    TMB isomer              lung

Pseudocumene (a)     19 [up arrow]
Mesitylene (b)       35 [down arrow]
Hemimellitene        4 [down arrow]

                      Changes of TMB isomers
                          concentration
                               [%]

                         250 ppm exposure

    TMB isomer                   blood

Pseudocumene (a)     3 [down arrow]
Mesitylene (b)       43 [down arrow][down arrow]
Hemimellitene        36 [down arrow][down arrow]

                       Changes of TMB isomers
                           concentration
                                [%]

                         250 ppm exposure

    TMB isomer                  liver

Pseudocumene (a)     20 [down arrow]
Mesitylene (b)       24 [down arrow]
Hemimellitene        46 [down arrow][down arrow]

[up arrow]--insignificant increase; [up arrow][up arrow]
--significant increase; [down arrow][down arrow]--
insignificant decrease; 11--significant decrease.

(a) Swiercz et al., 2003 [20]; (b) Swiercz et al., 2006 [22].

Table 14. Toxicokinetics of trimethylbenzene (TMB) isomers
elimination from venous blood after 6-h or 4-week exposure
to isomers of TMB

                             Toxicokinetics of TMB isomers

                           25 ppm exposure   100 ppm exposure
       TMB isomer
                            6-h     4-week    6-h     4-week
Pseudocumene (a)
  [AUC.sub.0[right          1.25     0.92     7.02     8.14
  arrow]6h] [mg x h/l]
  half-life [h (min)]
    phase I                0 (10)   0 (9)    0 (28)   0 (32)
    phase II               3 (51)   2 (53)   5 (20)   5 (47)
Mesityleneb
  [AUC.sub.0[right          0.33     0.40     5.72     4.84
  arrow]6h] [mg x h/l]
  half-life [h (min)]
    phase I                0 (12)   0 (23)   0 (11)   0 (8)
    phase II               2 (40)   2 (23)   3 (9)    4 (37)
Hemimellitene
  [AUC.sub.0[right
  arrow]6h] [mg x h/l]      1.89     1.75     8.53     7.66
  half-life [h (min)]
    phase I                0 (14)   0 (2)    0 (19)   0 (8)
    phase II               3 (4)    5 (52)   3 (42)   4 (34)

                           Toxicokinetics of
                              TMB isomers

                           250 ppm exposure
       TMB isomer
                             6-h      4-week
Pseudocumene (a)
  [AUC.sub.0[right          53.74     23.33
  arrow]6h] [mg x h/l]
  half-life [h (min)]
    phase I                 0 (57)    1 (8)
    phase II               17 (20)    9 (54)
Mesityleneb
  [AUC.sub.0[right          32.46     15.67
  arrow]6h] [mg x h/l]
  half-life [h (min)]
    phase I                 0 (16)    0 (10)
    phase II                4 (5)     4 (37)
Hemimellitene
  [AUC.sub.0[right
  arrow]6h] [mg x h/l]      23.70     16.09
  half-life [h (min)]
    phase I                 0 (32)    0 (13)
    phase II                5 (20)    7 (58)

AUC--area under curve.

(a) Swiercz et al., 2002, 2003 [19,20]; (b) Swiercz et
al., 2006 [22].

Table 15. Changes of dimethylbenzoic acid (DMBA) isomers in
tissues and urine of rats after 6-h vs. 4-week exposure to isomers
of trimethylbenzene (TMB)

                          TMB concentration
                           in inhaled air

DMBA-isomer             25 ppm exposure

                            lung

Pseudocumene (a) [%]
  2,5-DMBA               n.d.
  2,4-DMBA               21 [down arrow]
  3,4-DMBA               42 [down arrow]
Mesitylene (b) [%]
  3,5-DMBA               29 [up arrow]
Hemimellitene [%]
  2,6-DMBA               n.d.
  2,3-DMBA               n.d.

                          TMB concentration
                           in inhaled air

DMBA-isomer                25 ppm exposure

                                  liver

Pseudocumene (a) [%]
  2,5-DMBA               n.d.
  2,4-DMBA               15 [down arrow]
  3,4-DMBA               47 [down arrow][down arrow]
Mesitylene (b) [%]
  3,5-DMBA               48 [down arrow][down arrow]
Hemimellitene [%]
  2,6-DMBA               n.d.
  2,3-DMBA               11 [up arrow]

                          TMB concentration
                           in inhaled air

DMBA-isomer                 25 ppm exposure

                               kidney

Pseudocumene (a) [%]
  2,5-DMBA               49 [down arrow][down arrow]
  2,4-DMBA               61 [down arrow][down arrow]
  3,4-DMBA               44 [down arrow][down arrow]
Mesitylene (b) [%]
  3,5-DMBA               26 [up arrow]
Hemimellitene [%]
  2,6-DMBA               n.d.
  2,3-DMBA               24 [up arrow]

                         TMB concentration
                           in inhaled air

DMBA-isomer              25 ppm exposure

                                urine

Pseudocumene (a) [%]
  2,5-DMBA               62 [down arrow][down arrow]
  2,4-DMBA               6 [down arrow]
  3,4-DMBA               34 [down arrow]
Mesitylene (b) [%]
  3,5-DMBA               60 [up arrow][up arrow]
Hemimellitene [%]
  2,6-DMBA               n.d.
  2,3-DMBA               57 [up arrow][up arrow]

                        TMB concentration
                          in inhaled air

DMBA-isomer             100 ppm exposure

                             lung

Pseudocumene (a) [%]
  2,5-DMBA               37 [down arrow]
  2,4-DMBA               26 [down arrow]
  3,4-DMBA               39 [down arrow][down arrow]
Mesitylene (b) [%]
  3,5-DMBA               62 [up arrow][up arrow]
Hemimellitene [%]
  2,6-DMBA               n.d.
  2,3-DMBA               n.d.

                       TMB concentration
                         in inhaled air

DMBA-isomer            100 ppm exposure

                            liver

Pseudocumene (a) [%]
  2,5-DMBA               34 [down arrow]
  2,4-DMBA               10 [down arrow]
  3,4-DMBA               43 [down arrow][down arrow]
Mesitylene (b) [%]
  3,5-DMBA               17 [down arrow][down arrow]
Hemimellitene [%]
  2,6-DMBA               n.d.
  2,3-DMBA               35 [down arrow][down arrow]

                           TMB concentration
                            in inhaled air

DMBA-isomer               100 ppm exposure

                               kidney

Pseudocumene (a) [%]
  2,5-DMBA               34 [up arrow]
  2,4-DMBA               19 [up arrow]
  3,4-DMBA               151 [up arrow]
Mesitylene (b) [%]
  3,5-DMBA               15 [up arrow]
Hemimellitene [%]
  2,6-DMBA               n.d.
  2,3-DMBA               53 [down arrow][down arrow]

                         TMB concentration
                           in inhaled air

DMBA-isomer               100 ppm exposure

                               urine

Pseudocumene (a) [%]
  2,5-DMBA               46 [down arrow][down arrow]
  2,4-DMBA               33 [down arrow][down arrow]
  3,4-DMBA               33 [down arrow][down arrow]
Mesitylene (b) [%]
  3,5-DMBA               19 [up arrow]
Hemimellitene [%]
  2,6-DMBA               129 [up arrow][up arrow]
  2,3-DMBA               176 [up arrow][up arrow]

                         TMB concentration
                          in inhaled air

DMBA-isomer              250 ppm exposure

                             lung

Pseudocumene (a) [%]
  2,5-DMBA               20 [down arrow]
  2,4-DMBA               22 [down arrow]
  3,4-DMBA               25 [down arrow]
Mesitylene (b) [%]
  3,5-DMBA               48 [up arrow][up arrow]
Hemimellitene [%]
  2,6-DMBA               n.d.
  2,3-DMBA               13 [down arrow]

                         TMB concentration
                           in inhaled air

DMBA-isomer              250 ppm exposure

                              liver

Pseudocumene (a) [%]
  2,5-DMBA               17 [down arrow]
  2,4-DMBA               13 [down arrow]
  3,4-DMBA               43 [down arrow][down arrow]
Mesitylene (b) [%]
  3,5-DMBA               44 [up arrow][up arrow]
Hemimellitene [%]
  2,6-DMBA               n.d.
  2,3-DMBA               35 [down arrow][down arrow]

                          TMB concentration
                            in inhaled air

DMBA-isomer               250 ppm exposure

                            kidney

Pseudocumene (a) [%]
  2,5-DMBA               50 [up arrow]
  2,4-DMBA               39 [up arrow]
  3,4-DMBA               148 [up arrow]
Mesitylene (b) [%]
  3,5-DMBA               35 [up arrow]
Hemimellitene [%]
  2,6-DMBA               n.d.
  2,3-DMBA               35 [down arrow][down arrow]

                          TMB concentration
                            in inhaled air

DMBA-isomer              250 ppm exposure

                            urine

Pseudocumene (a) [%]
  2,5-DMBA               10 [up arrow]
  2,4-DMBA               13 [down arrow]
  3,4-DMBA               20 [up arrow]
Mesitylene (b) [%]
  3,5-DMBA               8 [up arrow]
Hemimellitene [%]
  2,6-DMBA               2 [down arrow]
  2,3-DMBA               27 [up arrow]

Abbreviations as in Table 9 and 10.

(a) Swiercz et al., 2005 [21]; (b) Swiercz et al.,
2006 [22].
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Title Annotation:ORIGINAL PAPER
Author:Swiercz, Radoslaw; Majcherek, Wanda; Wasowicz, Wojciech
Publication:International Journal of Occupational Medicine and Environmental Health
Date:Jan 1, 2016
Words:8437
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