Toluene blood levels

Frantik, E. Benes, V. (1984) Central nervous effect and blood level regressions on exposure time paralleled in solvents (toluene, carbon tetrachloride and chloroform). Act. nerv. super. (Praha), 26, 131-133... 

The liver, gastric wall, and lungs had the highest gasoline concentrations at 663, 324, and 457 ppm, respectively. The brain, bile, and kidney contained 44.2, 59, and 51.5 ppm, respectively, while the concentrations in the blood from the brain, lungs, and heart were 29.4, 132, and 51.5 ppm, respectively. Autopsies of humans who were apparently exposed to gasoline indicated elevated blood levels of hydrocarbons such as benzene, toluene, pentane, and hexane (Brugnone et al. 

The hydrocarbon components of gasoline such as benzene, toluene, pentane, and hexane have been measured in the blood of gasoline-exposed humans (Brugnone et al. 1986 Kimura et al. 1988 Matsubara et al. 1988). Also, benzene, toluene, and xylenes were detected in the blood samples collected from Wistar rats immediately after exposure to 5,000 ppm gasoline vapor for 30 minutes (Kimura et al. 1988). Increased hydrocarbon blood levels are not specific for gasoline exposure and are not commonly used as biomarkers of exposure. 

The types of medical data that help accident investigations include (1) type and level of toxic or abusive substances in the blood, (2) location and magnitude of injuries, (3) type of poisoning (carbon monoxide, toluene, etc.), (4) signs of suffocation, (5) signs of heat exposure or heat exhaustion, and (6) signs of eye irritation. 

Cresols are formed from the commonly found amino acid tyrosine, and occur naturally in human and animal tissues, fluids, and urine. Cresols are also formed as minor metabolites of toluene, and an increased presence of cresol in the body could be due to exposure to this substance. Therefore, even the cresols themselves cannot be considered to be biomarkers of cresol exposure unless very high levels are found. There is some evidence that methemoglobinemia, reduced glutathione levels in red blood cells, and Heinz body formation are associated with oral exposure to cresols in humans (Chan et al. 1971 Cote et al. 1984), but these effects are too general and occur at too high doses to be useful as biomarkers of exposure to cresols. 

Biomarkers of Exposure and Effect. No biomarkers of exposure to cresols have been identified. In fact, even the cresols themselves cannot be considered specific biomarkers for cresol exposure because they are also formed as breakdown products of toluene and tyrosine. However, if toluene exposure could be ruled out, then a high level of cresols or metabolites in the blood or urine would strongly suggest cresol exposure. Distinguishing biomarkers of exposure to cresols would enable early detection of cresol exposure and provide the opportunity for early treatment. One possibility that can be further investigated is Heinz body formation in the blood of exposed humans (Chan et al. 1971 Cote et al. 1984). 

Measured airborne and blood concentrations of ethylbenzene in several occupational settings are presented in Tables 3 and 4, respectively. Most occupational exposures to ethylbenzene result from use of products containing technical grades of mixed xylenes. No ethylbenzene was found from off-gassing of cured paint in a hyperbaric pressure chamber under normal atmospheric pressure, but under higher pressures, levels of 0.4-4.5 ppm [1.7-19.5 mg/m ] were measured (Lillo et al., 1990). Silk screen operations were found to entail exposure levels of less than 4 mg/m (Verhoeff et al., 1988). Ethylbenzene may also be present in low-grade toluene preparations (Inoue et al, 1995). 

During inhalation exposure of human volunteers to low levels of toluene (200-300 mg/mty, approximately 50% of the inhaled toluene was absorbed (Lbf et al., 1993). Such studies at low toluene exposure are complicated by the presence of toluene from other sources, in blood or in urine (Pierce et al., 1996). If the deuterated [ Hgjtoluene is used for exposure, this problem is avoided [but an isotope effect may reduce the rate of the metabolism of deuterated toluene compared to normal toluene, possibly by 30-50%]. When toluene is administered orally, it is virtually completely absorbed from the gastrointestinal tract (Baelum et al., 1993). 

The acute interaction with ethanol was studied by oral administration of toluene as a 2 mg/min infusion for 3 h through a feeding tube into the stomach (Baelum et al., 1993). The infusion was chosen such that the exposure level was similar to inhalation of approximately 200 mg/m3 in combination with light exercise (50 W). Toluene was measured in exhaled air to monitor the toluene concentration in alveolar arterial blood. When ethanol was co-administered orally at a dose of 0.32 g/kg bw, a pronounced increase in the alveolar toluene concentration occurred, from 0.07 (range, 0.00-0.12) without ethanol to 74 (range, 60-93) mg/ni with ethanol. The rate of urinary excretion of the hippurate was reduced by ethanol, but otherwise little affected. Excretion of ortAo-cresol... 

Sullivan and Conolly (1988) compared toluene levels in the blood of Sprague-Dawley rats after inhalation w ith those seen after subcutaneous or oral administration. They concluded that, at low- exposure levels, subcutaneously administered toluene better mimics steady-state levels observed after inhalation exposure, while at high exposures, oral dosage gives satisfactory results. However, orally administered toluene was more rapidly eliminated, presumably because of first-pass oral metabolism. 

Tardif et al. (1992, 1993 a, 1997) have developed a physiologically based toxicokinetic model for toluene in rats (and humans—see Section 4.1.1). They determined the conditions under which interaction between toluene and xylene(s) occurred during inhalation exposure, leading to increased blood concentrations of these solvents, and decreased levels of the hippurates in urine. Similar metabolic interactions have been observed for toluene and benzene in rats (Purcell et al., 1990) toluene inhibited benzene metabolism more effectively than the reverse. Tardif et al. (1997) also studied the exposure of rats (and humans) to mixtures of toluene, we/a-xylene and ethylbenzene, using their physiologically based pharmacokinetic model the mutual inhibition constants for their metabolism were used for simulation of the human situation. 

Richer, C.-L., Chakrabarti, S., Senecal-Quevillon, M., Duhr, M.A., Zhang, X.X. Tardif, R. (1993) Cytogenetic effects of low-level exposure to toluene, xylene, and their mixture on human blood lymphocytes. Int. Arch, occup. environ. Health, 64, 581-585... 

Sullivan, M.J. Conolly, R.B. (1988) Comparison of blood toluene levels after inhalation and oral administration. Environ. Res., 45, 64-70... 

Figure 2.7 Representation of the PBTK model developed for a mixture of 5 VOCs (m-xylene, toluene, ethylbenzene, benzene, and dichloromethane). All binary interactions that occur at the level of the rate of metabolism (RAM) are taken into account between the mixture constituents as shown by the dotted arrows. Because all chemicals interact by competitive inhibition, the Km of all mixture constituents is modulated by the presence of other chemicals as can be seen in the RAM equations. Cvl refers to venous blood concentrations. Vmax and Km refer to the maximal rate of metabolism and Michaelis affinity constant, respectively. Kuj is the constant describing competitive inhibition of the metabolism of chemical i by chemical j. (Figure adapted from Krishnan et al. [2002]).

Changes in urinary phenol levels (pre- and post-shift sample results) were observed in examinations carried out on 33 female workers (23-54 years old) employed at a shoe factory for 5-30 years (Karacic et al. 1987). Their exposure was to solvents, glues, and paints known to contain benzene. Workers were known to be coexposed to toluene, which was listed as an ingredient of several of the glues. Urine samples were collected on Monday mornings before work (M,) and on Wednesdays before work (W,) and after work (Wn). Additionally, venous blood was taken on Wn only. All samples were coupled with controls from 29 females (19-58 years old) who were not occupationally exposed to solvents. Results indicated there was no difference in the urinary phenol concentrations measured on M, and W, but Wn was about 2 times that of W,. Both benzene and toluene were found in the blood samples of exposed workers but were not detected in control blood samples. The difference in pre- and post-shift phenol... 

CUT conducted a 2 year inhalation toxicology study in Fischer 344 rats exposed to atmospheric toluene. The concentrations used were 30, 100, or 300 ppm (113, 377, or 1130mgm ) for 6 h per day, 5 days per week. The only finding was a dose-related reduction in hematocrit values (number of red blood cells) in female rats exposed to 100 and 300 ppm toluene. This is not considered a significant toxic effect. Therefore, a no-observed-adverse-effect level... 

---