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  • 1
    Electronic Resource
    Electronic Resource
    Species-specific pharmacokinetics of styrene in rat and mouse (1993)
    Springer
    Archives of toxicology 67 (1993), S. 517-530 
    Details
    ISSN: 1432-0738
    Keywords: Pharmacokinetics ; Styrene ; Diethyl dithiocarbamate ; Species scaling ; Allometric extrapolation ; Mouse ; Rat ; Man ; Closed chamber technique
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The pharmacokinetics of styrene were investigated in male Sprague-Dawley rats and male B6C3F1 mice using the closed chamber technique. Animals were exposed to styrene vapors of initial concentrations ranging from 550 to 5000 ppm, or received intraperitoneal (i.p.) doses of styrene from 20 to 340 mg/kg or oral (p.o.) doses of styrene in olive oil from 100 to 350 mg/kg. Concentration-time courses of styrene in the chamber atmosphere were monitored and analyzed by a pharmacokinetic two-compartment model. In both species, the rate of metabolism of inhaled styrene was concentration dependent. At steady state it increased linearly with exposure concentration up to about 300 ppm; more than 95% of inhaled styrene was metabolized and only small amounts were exhaled unchanged. At these low concentrations transport to the metabolizing enzymes and not their metabolic capacity was the rate limiting step for metabolism. Pharmacokinetic behaviour of styrene was strongly influenced by physiological parameters such as blood flow and especially the alveolar ventilation rate. At exposure concentrations of styrene above 300 ppm the rate of metabolism at steady state was progressively limited by biochemical parameters of the metabolizing enzymes. Saturation of metabolism (Vmax) was reached at atmospheric concentrations of about 700 ppm in rats and 800 ppm in mice, Vmax being 224 μmol/(h·kg) and 625 μmol/(h·kg), respectively. The atmospheric concentrations at Vmax/2 were 190 ppm in rats and 270 ppm in mice. Styrene accumulates preferentially in the fatty tissue as can be deduced from its partition coefficients in olive oil∶air and water∶air which have been determined in vitro at 37°C to be 5600 and 15. In rats and mice exposed to styrene vapors below 300 ppm, there was little accumulation since the uptake was rate limiting. The bioaccumulation factor body:air at steady state (K′st*) was rather low in comparison to the thermodynamic partition coefficient body:air (Keq) which was determined to be 420. K′st* increased from 2.7 at 10 ppm to 13 at 310 ppm in the rat and from 5.9 at 20 ppm to 13 at 310 ppm in the mouse. Above 300 ppm, K′st* increased considerably with increasing concentration since metabolism became saturated in both species. At levels above 2000 ppm K′st* reached its maximum of 420 being equivalent to Keq. Pretreatment with diethyldithiocarbamate, administered intraperitoneally (200 mg/kg in rats, 400 mg/kg in mice) 15 min prior to exposure of styrene vapours, resulted in effective inhibition of styrene metabolism, indicating that most of the styrene is metabolized by cytochrome P450-dependent monooxygenases. In order to simulate chronic exposure rats and mice were exposed to 150 and 500 ppm styrene on 5 consecutive days (6 h/day). On day 6, inhalation kinetics were studied. No change in the rate of styrene metabolism was detected compared to non-pretreated controls. Intraperitoneal administration of styrene to rats and mice led to concentration-time courses in the atmosphere of the closed chamber with agreed with those predicted by the applied pharmacokinetic model. After p.o. administration of styrene to rats and mice concentration time-courses showed considerable inter-animal variability. The pharmacokinetic model was extended by a first order absorption from the gastrointestinal tract with half-lives of 0.87 h (rat) and 0.41 h (mouse) to obtain reasonable fits through the measured data. The pharmacokinetic parameters of inhaled styrene were extrapolated allometrically from rat to mouse and from rat and mouse to man. A good agreement was obtained with experimentally determined values indicating similar pharmacokinetic behaviour of styrene in these species.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01969264
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  • 2
    Electronic Resource
    Electronic Resource
    New scientific arguments for regulation of ethylene oxide residues in skin-care products (1994)
    Springer
    Archives of toxicology 68 (1994), S. 401-405 
    Details
    ISSN: 1432-0738
    Keywords: Key words: Ethylene oxide – Polyglycol ethers – Skin-care products – Risk assessment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. Ethylene oxide (EO) occurs as a contaminant of skin-care products because current commercial preparations of polyglycol ethers may contain ethylene oxide monomer residues, up to the order of 1 ppm. Using current regulatory worst-case assumptions, the presence of EO in skin-care products might lead to a maximal human daily external ethylene oxide dose of about 2.8 μg, and a consecutive maximal daily absorbed dose of 0.39 μg. Two methods of toxicokinetic analysis have been used to compare this possible EO load by use of skin-care products with the inevitable load of EO which is produced endogenously in the organism. On the basis of a previous assessment of the endogenous production of ethylene and ethylene oxide (Filser et al. 1992) it is inferred that the absorbed EO dose of 0.39 μg is about 1/30 of the unavoidable human endogenous load by endogenous EO. Alternatively, for a second calculation molecular dosimetry data have been used which were based on experimental quantification of the hydroxyethyl adduct of EO to the N-terminal valine of hemoglobin (HOEtVal) in rats. If the worst-case assumptions for human EO absorption from skin-care products are transferred to the rat species, the associated internal EO doses are about 1/110 of the internal EO doses which were calculated from the background HOEtVal concentrations observed in untreated animals. The divergence between both lines of calculation is mainly due to differences in HOEtVal background concentrations between man and rat. It is concluded that the additional internal body burden of EO associated with the use of current skin-care products, even under a series of worst-case assumptions, is neglegible compared to the physiological and unavoidable internal EO burden of the organism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002040050089
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  • 3
    Electronic Resource
    Electronic Resource
    Experimental data from closed chamber gas uptake studies in rodents suggest lower uptake rate of chemical than calculated from literature values on alveolar ventilation (1992)
    Springer
    Archives of toxicology 66 (1992), S. 291-295 
    Details
    ISSN: 1432-0738
    Keywords: Inhalation ; Mouse ; Pharmacokinetic model ; physiologically-based, two-compartment ; Rat ; Acetone ; 1,3-Butadiene ; 2-Butanone ; 1,1-Dichloroethylene ; 1,1-Difluoroethylene ; 1,2-Epoxybutene-3 ; Ethylbenzene ; Ethylene oxide ; n-Hexane ; Isobutene ; Isoprene ; 2-Nitropropane ; Toluene ; 1,1,1-Trichloroethane ; 1,1,2-Trichloroethane ; Styrene ; m-Xylene
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Experimental data obtained in vivo with the closed-chamber gas uptake technique have been reported for a series of volatile chemicals. Pharmacokinetic analyses of these data have been performed either by using a two-compartment model or physiological models. In the former the transfer rate of chemical from ambient air to body is defined by the clearance of uptake. In the latter models the transfer rate depends on alveolar ventilation, cardiac output, and blood: air partition coefficient. In this communication we describe the quantitative relationship between clearance of uptake and alveolar ventilation, cardiac output, and blood: air partition coefficient. Theoretical values of clearance of uptake were calculated for a variety of volatile chemicals using literature data on alveolar ventilation, cardiac output, and blood: air partition coefficient. For most chemicals the experimentally determined values in rats and mice were about 60% of the theoretical values. This suggests that the inhalatory uptake rate of chemical may be overestimated if literature values of alveolar ventilation are used in physiological pharmacokinetic models for rodents.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02307176
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  • 4
    Electronic Resource
    Electronic Resource
    Species Differences in Butadiene Metabolism between Mouse and Rat (1988)
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 534 (1988), S. 0 
    Details
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1749-6632.1988.tb30156.x
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  • 5
    Electronic Resource
    Electronic Resource
    Spectrophotometric determination of pyrrole-like substances in urine of rat and man: An assay for the evaluation of 2,5-hexanedione formed fromn-hexane (1990)
    Springer
    Archives of toxicology 64 (1990), S. 242-246 
    Details
    ISSN: 1432-0738
    Keywords: n-Hexane ; 2,5-Hexanedione ; Pyrroles ; Spectrophotometry ; Biological monitoring
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Male Wistar rats exposed to atmosphericn-hexane excreted in their urine substances which gave rise to absorption spectra like those of pyrroles after the reaction with Ehrlich's reagent. A simple spectrophometric assay was developed to determine these “pyrrole-like substances” in urine. Their excretion kinetics were evaluated by exposing rats for 8 h to atmosphericn-hexane concentrations between 50 and 3000 ppm. The dose-response curve revealed saturation kinetics according to Michaelis-Menten, Vmax being 1.12 [ΔE 526ml urine/8 hn-hexane exposure] and “Km”, the atmosphericn-hexane concentration at Vmax/2, being 250 ppm. The excretion of pyrrolelike substances closely correlated with that of 2,5-hexanedione measured by Fedtke and Bolt (1987). Pyrrole-like substances were also found in the urine of a male volunteer. When exposing the person for 3 h to atmosphericn-hexane at a concentration of 146 ppm (equivalent to 55 ppm/8 h) the excreted amount was twice the background value. Due to the sensitivity of this assay it is possible to determine pyrrole-like substances in urine according to the present German MAK or US TLV conditions forn-hexane (50 ppm/8 h).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02010731
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  • 6
    Electronic Resource
    Electronic Resource
    A physiologically based pharmacokinetic model for butadiene and its metabolite butadiene monoxide in rat and mouse and its significance for risk extrapolation (1993)
    Springer
    Archives of toxicology 67 (1993), S. 151-163 
    Details
    ISSN: 1432-0738
    Keywords: 1,3-Butadiene ; Closed-chamber technique ; 1,2-Epoxybutene-3 ; Glutathione ; Glutathione turnover ; Inhalation ; Mouse ; Pharmacokinetics ; Physiological model ; Ping-pong mechanism ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The gas 1,3-butadiene (BU) is an important industrial chemical and an environmental air pollutant. BU has been shown to be a weak carcinogen in the rat but a potent carcinogen in the B6C3F1 mouse. This species difference makes risk extrapolation to humans difficult and the underlying mechanism should be clarified before meaningful risk extrapolation to humans can be made. One possible explanation for the species differences in cancer response is that there are quantitative species differences in the formation of genotoxic epoxides. To investigate this possibility a physiologically based pharmacokinetic (pbpk) model for BU together with its first reactive metabolite l,2-epoxybutene-3 (butadiene monoxide, BMO) was developed. Previously reported values on hepatic glutathione (GSH) turnover, depletion of hepatic GSH in rodents exposed to BU, and in vitro metabolic data of BU and BMO were included in the model, which incorporates intrahepatic first-pass hydrolysis of BMO and the ordered sequential, ping-pong mechanism to describe the enzyme kinetics of BMO-GSH conjugation. In vitro studies were carried out to obtain tissue: air partition coefficients of BU and BMO in rat tissue homogenates. The simulated pharmacokinetics of BU, BMO, and GSH agreed with previously published experimental observations in rat and mouse obtained in closed and open chamber experiments. According to the model, the internal dose of BMO (expressed either as the concentration in mixed venous blood or as the area under the concentration-time curve) is approximately 1.6 times higher in the mouse than in the rat for exposure to BU below 1000 ppm. At higher exposure levels, GSH depletion occurs in the mouse, but not in the rat, after about 6–9 h. This GSH depletion results in up to 2–3 times higher internal doses in the mouse than in the rat. The clear but relatively small species difference in body burdens of BMO indicated from our model can only partly explain the marked species difference in cancer response between mice and rats exposed to BU.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01973302
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  • 7
    Electronic Resource
    Electronic Resource
    Changes in the classification of carcinogenic chemicals in the work area (1998)
    Springer
    International archives of occupational and environmental health 71 (1998), S. 566-574 
    Details
    ISSN: 1432-1246
    Keywords: Key words Chemical carcinogens ; List of MAK and BAT Values ; Cancer risk
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Carcinogenic chemicals in the work area are currently classified into three categories in section III of the German List of MAK and BAT Values (list of values on maximum workplace concentrations and biological tolerance for occupational exposures). This classification is based on qualitative criteria and reflects essentially the weight of evidence available for judging the carcinogenic potential of the chemicals. It is proposed that these categories – IIIA1, IIIA2, IIIB – be retained as Categories 1, 2, and 3, to correspond with European Union regulations. On the basis of our advancing knowledge of reaction mechanisms and the potency of carcinogens, these three categories are supplemented with two additional categories. The essential feature of substances classified in the new categories is that exposure to these chemicals does not contribute significantly to risk of cancer to man, provided that an appropriate exposure limit (MAK value) is observed. Chemicals known to act typically by nongenotoxic mechanisms and for which information is available that allows evaluation of the effects of low-dose exposures, are classified in Category 4. Genotoxic chemicals for which low carcinogenic potency can be expected on the basis of dose-response relationships and toxicokinetics, and for which risk at low doses can be assessed are classified in Category 5. The basis for a better differentiation of carcinogens is discussed, the new categories are defined, and possible criteria for classification are described. Examples for Category 4 (1,4-dioxane) and Category 5 (styrene) are presented.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004200050325
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