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1.  Effects of ethanol and phenobarbital treatments on the pharmacokinetics of toluene in rats. 
Rats were exposed to toluene at a wide range of concentrations from 50 to 4000 ppm for six hours, and the effects of ethanol and phenobarbital (PB) treatments on the pharmacokinetics of toluene metabolism were investigated. Ethanol treatment influenced toluene metabolism mainly at low exposure concentrations. Thus ethanol accelerated the clearance of toluene from blood only when the blood concentration of toluene was not high (less than 360 microM), and ethanol increased hippuric acid (HA) excretion in urine more significantly at low (less than 250 ppm) than at high atmospheric toluene concentrations. Ethanol also expressed a similar effect on p-cresol excretion as on HA, but had little effect on o-cresol. Phenobarbital treatment promoted the urinary excretion of all of the metabolites of toluene, especially after exposure to high toluene concentration. As well as HA, benzoylglucuronide (BG) and free benzoic acid were found in urine. These are the products of the side chain metabolism of toluene. Amounts of BG could be detected when the urinary excretion of free benzoic acid exceeded 5 mumol/kg/6 h, indicating that a great deal of benzoic acid is required for the formation of BG. The Michaelis constant (Km) and the maximum rate of metabolic excretion in urine during six hours exposure (Vmax) of isozymes involved in the excretion of toluene metabolites were calculated, and correlated with the subtypes of cytochrome P-450. The significance of the result was suggested in the biological monitoring of exposure to toluene.
PMCID: PMC1012074  PMID: 1536817
2.  Ethanol and food deprivation induced enhancement of hepatotoxicity in rats given carbon tetrachloride at low concentration. 
Effects of chronic ethanol consumption and one day food deprivation on the hepatotoxicity of low dose carbon tetrachloride (CCl4; 0 to 100 ppm inhalation for eight hours) in rats were investigated by using biochemical and histopathological methods. Liver malondialdehyde (MDA) contents were significantly increased by exposure to 5 ppm to 50 ppm CCl4 in ethanol treated rats or by exposure to 25 ppm to 50 ppm CCl4 in food deprived rats but not in rats without ethanol or food deprivation. The MDA concentrations reached a maximum at 10 ppm and 50 ppm CCl4 in ethanol treated and food deprived rats, respectively, and decreased to the non-exposed concentration at 100 ppm CCl4. At greater than or equal to 50 ppm CCl4 plasma MDA contents increased significantly only in ethanol treated rats. None of the exposure concentrations influenced plasma glutamic-oxaloacetic transamidase (GOT) and glutamic-pyruvic transaminase (GPT) activities in rats that were only exposed to CCl4 whereas exposure to 10 ppm or higher concentrations combined with ethanol increased both activities. To a lesser extent food deprivation combined with exposure to greater than or equal to 25 ppm CCl4 had the same effect. No histopathological changes were found in the liver of rats exposed to less than or equal to 10 ppm CCl4, and only a few ballooned hepatocytes were seen in centrilobular areas when exposure was 25 ppm or higher. The presence of ballooned and hepatocytes became a regular feature of mid-zonal areas in ethanol treated rats and in the centrilobular areas of food deprived rats after exposure to /=25 ppm and >/=50 ppm respectively. These results indicate that consumption of ethanol and food deprivation potentiate CCl(4) induced hepatic damage even at low concentrations of CCl(4) by promoting lipid peroxidation. Thus heavy drinking may be a risk factor for CCl(4) induced hepatic damage even though the CCl(4) concentration is as low as the threshold limit value.
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PMCID: PMC1035437  PMID: 1911407
3.  Effects of chronic ethanol consumption on hepatic metabolism of aromatic and chlorinated hydrocarbons in rats. 
The activities of liver drug-metabolising enzymes for 16 aromatic or chlorinated hydrocarbons were measured in male rats after a three-week daily intake of ethanol amounting to 30% of total energy intake. Although the ethanol feeding produced only a slight increase in the microsomal cytochrome P-450 content, it increased the in-vitro metabolism of most hydrocarbons three-to six-fold. That a major part of this enhanced activity disappeared after one-day withdrawal of ethanol suggests that recent intake of ethanol plays an important part in accelerating the metabolism of hydrocarbons. The enzyme activity enhanced by ethanol was found to be related with changes occurring not in the soluble but in the microsomal fractions. A metabolism study using toluene as a model substrate indicated that chronic ethanol consumption increases the in-vivo metabolism of this hydrocarbon in rats.
PMCID: PMC1008756  PMID: 7192567
4.  Partition coefficients of some aromatic hydrocarbons and ketones in water, blood and oil. 
Water/air, blood/air, oil/air, oil/water, and oil/blood partition (or solubility) coefficients of 17 aromatic hydrocarbons and ketones were measured by a newly developed vial-equilibration method, which needs no direct measurements of the concentration either in the liquid or in the air phase, but only the gas chromatographic peak heights of the air in the sample (in which a test material is contained) and reference vessels (containing no test material). It was found that the blood/air partition coefficients for aromatic hydrocarbons are correlated closely with the product of water/air and oil/air partitiion coefficients, whereas those for ketones are almost in the same range as the water/air, irrespective of the oil/air partition coefficients.
PMCID: PMC1008570  PMID: 500783
5.  Differences following skin or inhalation exposure in the absorption and excretion kinetics of trichloroethylene and toluene. 
The concentrations of trichloroethylene in breath and blood and the urinary excretion of its metabolites following 30 minutes' direct immersion of one hand in the liquid, were compared with those obtained after four hours' inhalation exposure to the vapour of 100 ppm, described in a previous paper. The comparison shows that the end-tidal air concentrations during the first two hours of the post-exposure period were about twice as high in the case of skin exposure as in that of inhalation exposure, although the uptake of the solvent through the skin was only about one-third of the inhaled uptake. A kinetic approach suggested that differences in trichloroethylene movement in the body would be a principal cause of this discrepancy. The results of a similar series of experiments using toluene suggested that it is less readily taken up than trichloroethylene through the skin. It was concluded from the present investigation that analyses of not only breath but also of blood or urine are necessary and toluene would rarely be absorbed through the skin in toxic quantities during normal industrial use.
PMCID: PMC1008323  PMID: 629888
6.  A pharmacokinetic model to study the excretion of trichloroethylene and its metabolites after an inhalation exposure. 
For a better understanding of absorption, distribution, excretion, and metabolism of trichloroethylene the time-course of blood concentration of the vapour and urinary excretion of its metabolites was examined using a pharmacokinetic model. After a single experimental exposure in which four men inhaled 100 parts per million (ppm) of trichloroethylene for four hours an elimination curve showed three exponential components, that is, X=1-0005e(-16.71t)+0-449e(-1.710t)+0-255e(-0.2027t), where X is that blood concentration in mg/l and t the time in hours from 0 to 10. The overall rate constant for the disappearance of trichloroethylene was found to a agree with the theoretical one, estimated by means of a mathematical model for the blood concentration data. A D8- XD plot, developed from a mathematical model for urinary excretion, could also give a good estimate of rate constant for the transfer of trichloroethylene in the body. The rate constant thus estimated from urinary excretion was consistent with data on the blood concentration.
PMCID: PMC1008172  PMID: 843464
7.  Kinetic studies on sex difference in susceptibility to chronic benzene intoxication--with special reference to body fat content. 
The sex difference in the susceptibility to haematopoietic disorders induced by benzene was studied kinetically with a special reference to its relation with the body fat content. In rats of both sexes with a large body fat content, benzene was eliminated more slowly and remained in the body for a longer time than in rats with a small body fat content. In accord with this finding, the decrease in white blood cell numbers during a chronic benzene exposure was observed only in the groups of rats which had a large volume of fat tissue. In an experimental human exposure, the elimination of benzene was slower in the females than in the males. The kinetic study revealed that the slower elimination in the females is due primarily to the bulky distribution of body fat tissue in that sex. From these results obtained from the experimental exposure of men and rats to benzene, it was concluded that the human female, with her massive body fat tissue, shows an inherent disposition to be susceptible to a chemical such as benzene which has a high affinity with fat tissue.
PMCID: PMC1008083  PMID: 1103957
8.  Determination of benzene and toluene in blood by means of a syringe-equilibration method using a small amount of blood. 
A gas chromatographic determination of benzene and toluene in blood with a small amount of blood sample, 0.02 or 0.1 ml, is described. In the method an aliquot of the blood sample in a sealed hypodermic syringe of 2 ml capacity is equilibrated at 37 degrees C in a thermo-regulated water-bath. After establishing equilibrium 1 ml of overlying air is submitted to gas chromatographic analysis. The value of this method was verified by experiments in which men, rabbits, and rats were exposed to benzene and toluene mixtures of various concentrations.
PMCID: PMC1008060  PMID: 1171695

Results 1-8 (8)