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  • 1
    Electronic Resource
    Electronic Resource
    Methodological investigations on the determination of n-hexane metabolites in urine (1986)
    Springer
    International archives of occupational and environmental health 57 (1986), S. 149-158 
    Details
    ISSN: 1432-1246
    Keywords: n-Hexane ; Urine ; 2-Hexanone ; 2-Hexanol ; 2,5-Hexanedione
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Male Wistar rats were exposed to 1000 ppm n-hexane, and the excreted urinary metabolites were analyzed by capillary gas chromatography-mass spectrometry (GC-MS). 1-Hexanol, 2-hexanol, 3-hexanol, 2-hexanone, 2,5-hexanedione, 2,5-dimethyltetrahydrofuran, 2,5-dimethyl2,3-dihydrofuran and γ-valerolactone were identified by their retention times and their mass spectra. Quantitative gas chromatographic analyses were performed using an FID. Experiments on the hydrolysis of conjugated n-hexane metabolites revealed that enzymatic hydrolysis (in addition to acid hydrolysis) was not required, as treatment with HCl hydrolyzed conjugates sensitive to acid as well as conjugates sensitive to β-glucuronidase. By incorporating acid hydrolysis only and by using C18-cartridges for sample extraction, a method was developed that allowed the determination of n-hexane metabolites with a sample preparation time of only 45 min. Assay precision was assessed by repeated analyses of the same urine sample. Coefficients of variation for the individual metabolites ranged from between 1.8 and 3.3.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00381383
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  • 2
    Electronic Resource
    Electronic Resource
    Experimental toxicology of formaldehyde (1987)
    Springer
    Journal of cancer research and clinical oncology 113 (1987), S. 305-309 
    Details
    ISSN: 1432-1335
    Keywords: Formaldehyde ; Mutagenicity ; Metabolism ; Biochemistry ; Carcinogenicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Formaldehyde is a reactive chemical which undergoes spontaneous reactions with various cellular constituents. Mutagenicity data may be interpreted on the background of this behavior. Mice are better able to reduce the irritating effect of formaldehyde than rats and to reduce their ventilation rate when formaldehyde acts on the respiratory tract. Subacute exposure of rats to concentrations higher than 2 ppm inhibits mucociliary clearance of the nasal epithelium and leads to progressive histological and ultrastructural lesions at this site. The occurrence of squamous cell carcinomas of the nasal epithelium of rats after 2 years inhalation of 14.3 ppm formaldehyde (CIIT study) is probably the result of chronic and recurrent local toxicity; this is supported by species differences in susceptibility to the tissue damaging and carcinogenic effect of formaldehyde (rat, mouse, hamster). Data on formaldehyde-DNA interaction further support the argument that a direct risk extrapolation from the formaldehyde effects in rats to those expected for man is not possible.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00397713
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  • 3
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of halogenated ethylenes in rats (1978)
    Springer
    Archives of toxicology 42 (1978), S. 123-136 
    Details
    ISSN: 1432-0738
    Keywords: Halogenated ethylenes ; Vinyl fluoride ; Vinylidene fluoride ; Vinyl chloride ; Vinylidene chloride ; Cis-dichloroethylene ; Trans-dichloroethylene ; Trichloroethylene ; Perchloroethylene ; Vinyl bromide ; Pharmacokinetics ; Metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Inhalation pharmacokinetics of the halogenated ethylenes vinyl fluoride (VF), vinylidene fluoride (VF2), vinyl chloride (VC1), vinylidene chloride (VC12), cis- and trans-dichloroethylene (cis-DCE and trans-DCE), trichloroethylene (Tri), perchloroethylene (Per), and vinyl bromide (VBr) have been comparatively studied in the rat. Rats were exposed in a closed inhalation system to various initial atmospheric levels of halogenated ethylenes, and the decline of atmospheric concentration was followed using gas Chromatographic analysis. From pharmacokinetic analysis of the experimental curves the following general patterns of the halogenated ethylenes were derived. Distribution of the compounds in the organism and in the gas phase is determined by physical factors. For practical purposes, a relation of the equilibrium constants with the volatilities of the compounds, expressed by the boiling points, may be used: compounds with a low boiling point are enriched in tissues much less than those of a higher boiling point, and vice versa. Compounds with high accumulation in tissues (Tri, Per) need much more time for completion of the equilibration process than more volatile compounds. Metabolic elimination of halogenated ethylenes is a saturable, dose-dependent process. If animals are exposed to atmospheric concentrations of a halogenated ethylene which exceed the “point of saturation (Sp)”, elimination is determined by a zero-order law, i.e., its rate is independent of the concentration of the compound. In contrast, below saturation normal first-order kinetics apply. If the rate of metabolic elimination is related to the concentrations of the compounds in the tissue compartment, very similar rates for first-order elimination of the different halogenated ethylenes are found. This suggests a common rate limiting factor applicable for the lower concentration range. The maximal velocities (V max) of metabolic elimination of halogenated ethylenes which are reached above the “saturation points” depend on the chemical structures of the individual compounds. In general, with the exception of Tri, further halogen substitution inhibits metabolic conversion. Of the halogenated ethylenes, VF2 and Per are extremely slowly metabolized. The present report also provides the data necessary for calculation of the rates of metabolism of halogenated ethylenes in rats at a given concentration of atmospheric exposure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00316492
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  • 4
    Electronic Resource
    Electronic Resource
    Inhalation pharmacokinetics based on gas uptake studies (1981)
    Springer
    Archives of toxicology 47 (1981), S. 279-292 
    Details
    ISSN: 1432-0738
    Keywords: Pharmacokinetics ; Metabolism ; Halogenated ethylenes ; Vinyl fluoride ; Vinylidene fluoride ; Vinyl chloride ; Vinylidene chloride ; cis-Dichloroethylene ; trans-Dichloroethylene ; Trichloroethylene ; Vinyl bromide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract An improved pharmacokinetic model is described for inhalation of volatile xenobiotics from a closed gas phase system. This model is based on steady-state kinetics and covers metabolic elimination processes of either first-order, zero-order, or Michaelis-Menten characteristics. It is emphasized that the distribution of a volatile compound between gas phase and organism under steady-state conditions may be much different from a static equilibrium obtained in absence of metabolism, as it is observed after application of a metabolic inhibitor. A re-analysis of previous experimental data on dose-dependent pharmacokinetics of different haloethylenes reveals that, in general, the metabolic elimination processes of the rapidly equilibrating mono-haloethylenes (and vinylidene fluoride) can be resolved with excellent accuracy into sections of first-order and zero-order kinetics. Other compounds show a more smooth transition from first-order elimination (at lower atmospheric concentrations) into conditions of saturation (dichloroethylenes, trichloroethylene). The analyses are consistent with a recent concept of Andersen (1980) that metabolic elimination of inhaled xenobiotics is limited by either the capacity of metabolic enzymes or factors of transport to the metabolic sites.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00332394
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  • 5
    Electronic Resource
    Electronic Resource
    Species differences in butadiene metabolism between mice and rats evaluated by inhalation pharmacokinetics (1986)
    Springer
    Archives of toxicology 58 (1986), S. 235-238 
    Details
    ISSN: 1432-0738
    Keywords: 1,3-Butadiene ; Inhalation ; Pharmacokinetics ; Species differences ; Metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Metabolism of 1,3-butadiene to 1,2-epoxybutene-3 in rats follows saturation kinetics. Comparative investigation of inhalation pharmacokinetics in mice also revealed a saturation pattern. For both species “linear” pharmacokinetics apply at exposure concentrations below 1000 ppm 1,3-butadiene; saturation of butadiene metabolism is observed at atmospheric concentrations of about 2000 ppm. For mice metabolic clearance per kg body weight in the lower concentration range where first order metabolism applies was 7300ml×h−1 (rat: 4500 ml×h−1). Maximal metabolic elimination rate (Vmax) was 400 μmol×h−1 ×kg−1 (rat: 220 μmol ×h−1×kg−1). This shows that 1,3-butadiene is metabolized by mice at higher rates compared to rats. Based on these investigations, the metabolic elimination rates of butadiene in both species were calculated for the exposure concentrations applied in two inhalation bioassays with rats and with mice. The results show that the higher rate of butadiene metabolism in mice when compared to rats may only in part be responsible for the considerable difference in the susceptibility of both species to butadiene-induced carcinogenesis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00297112
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  • 6
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of the neurotoxin n-hexane in rat and man (1987)
    Springer
    Archives of toxicology 60 (1987), S. 77-80 
    Details
    ISSN: 1432-0738
    Keywords: n-Hexane ; Pharmacokinetics ; Man ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The pharmacokinetics of inhaled n-hexane in rat and man were compared. In the rat metabolism was saturable. Up to 300 ppm, the metabolic rate was directly proportional to the concentration in the atmosphere, reaching 47 μmol/(h· kg). Only 17% of n-hexane was exhaled unchanged. Above 300 ppm, the amount of n-hexane in the body rose with increasing atmospheric concentrations from 1.6 up to a limiting value of 9.6, which corresponded to the thermodynamic distribution coefficient of n-hexane between the organism and the atmosphere. Up to 3000 ppm, the rate of metabolism increased to 245 μmol/ (h· kg); only a slow further increase was found up to 7000 ppm (285μmol/(h· kg)). In man the steady-state concentrations of n-hexane were about 1 ppm. The metabolic clearance was 1321/h, and n-hexane accumulated to a factor of 2.3 in the organism. The thermodynamic distribution coefficient was calculated to be 12. Twenty per cent of n-hexane in the body was exhaled unchanged. At low concentrations the rate of metabolism of n-hexane is limited in both species by transport to the enzyme system. Under these conditions the rate of metabolism of n-hexane should not be influenced by xenobiotics which induce the n-hexane metabolizing enzyme system.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00296952
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  • 7
    Electronic Resource
    Electronic Resource
    The relevance of 4,5-dihydroxy-2-hexanone in the excretion kinetics ofn-hexane metabolites in rat and man (1987)
    Springer
    Archives of toxicology 61 (1987), S. 131-137 
    Details
    ISSN: 1432-0738
    Keywords: n-Hexane ; 2,5-Hexanedione ; 4,5-Dihydroxy-2-hexanone ; Biological monitoring
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Male Wistar rats were exposed ton-hexane concentrations between 50 and 3000 ppm for 8 h, and urinary excretion kinetics of then-hexane metabolites 1-hexanol, 2-hexanol, 3-hexanol, 2-hexanone, 2,5-hexanedione, and 4,5-dihydroxy-2-hexanone were assessed. The amounts of metabolites excreted were linearly dependent on then-hexane exposure concentration, up to an exposure of about 300 ppm. Above 300 ppm exposure the metabolite excretion indicated saturation kinetics in the metabolism ofn-hexane. In its quantity, the newly described 4,5-dihydroxy-2-hexanone was the second metabolite, its amount in the urine being about ten times higher than that of excreted 2,5-hexanedione. Using gas chromatography-mass spectrometry the occurrence of 4,5-dihydroxy-2-hexanone as ann-hexane metabolite in urine of man was confirmed after exposure of a male volunteer to a mean of 217 ppmn-hexane for 4 h (laboratory exposure). Twenty-six hours after starting this exposure the excretion of 4,5-dihydroxy-2-hexanone (as a result of then-hexane exposure) reached a level which was four times higher than the excretion of 2,5-hexanedione. The results in both rat and man indicate the relevance of 4,5-dihydroxy-2-hexanone as a metabolite ofn-hexane metabolism. Formation of this metabolite may be viewed as a route of detoxification.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00661371
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  • 8
    Electronic Resource
    Electronic Resource
    Inhalation pharmacokinetics of 1,2-epoxybutene-3 reveal species differences between rats and mice sensitive to butadiene-induced carcinogenesis (1987)
    Springer
    Archives of toxicology 61 (1987), S. 7-11 
    Details
    ISSN: 1432-0738
    Keywords: Butadiene ; Epoxybutene ; Inhalation ; Species differences ; Metabolism ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Comparative investigations of inhalation pharmacokinetics of 1,2-epoxybutene-3 (vinyl oxirane, the primary reactive intermediate of butadiene) revealed major differences in metabolism of this compound between rats and mice. Whereas in rats no indication of saturation kinetics of epoxybutene metabolism could be observed up to exposure concentrations of 5000 ppm, in mice saturation of epoxybutene metabolism becomes apparent at atmospheric concentrations of about 500 ppm. The estimated maximal metabolic rate (Vmax) in mice for epoxybutene was only 350 μmol×h−1×kg−1 (rats: 〉2600 μmol× h−1×kg−1). In the lower concentration range where first order metabolism applies (up to about 500 ppm) epoxybutene is metabolized by mice at higher rates compared to rats (metabolic clearance per kg body weight, mice: 24900 ml×h−1, rats: 13400 ml×h−1). Under these conditions the steady state concentration of epoxybutene in the mouse is about 10 times that in the rat. When mice are exposed to high concentrations of butadiene (〉2000 ppm; conditions of saturation of butadiene metabolism; closed exposure system) epoxybutene is exhaled by the animals, and its concentration in the gas phase increases with exposure time. At about 10 ppm epoxybutene signs of acute toxicity are observed. When rats are exposed to butadiene under similar conditions, the epoxybutene concentration reaches a plateau at about 4 ppm. Under these conditions hepatic non-protein sulfhydryl compounds are virtually depleted in mice but not in rats. We conclude that in addition to the higher rate of metabolism of butadiene in mice, limited detoxification and consequently accumulation of its primary reactive intermediate epoxybutene may be a major determinant for the higher susceptibility of mice to butadiene-induced carcinogenesis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00324541
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