RESUMO
There is increasing concern for the potential adverse health effects of human exposures to chemical mixtures. To better understand the complex interactions of chemicals within a mixture, it is essential to develop a research strategy which provides the basis for extrapolating data from single chemicals to their behavior within the chemical mixture. 1,3-Butadiene (BD) represents an interesting case study in which new data are emerging that are critical for understanding interspecies differences in carcinogenic/genotoxic response to BD. Knowledge regarding mechanisms of BD-induced carcinogenicity provides the basis for assessing the potential effects of mixtures containing BD. BD is a multisite carcinogen in B6C3F1 mice and Sprague-Dawley rats. Mice exhibit high sensitivity relative to the rat to BD-induced tumorigenesis. Since it is likely that BD requires metabolic activation to mutagenic reactive epoxides that ultimately play a role in carcinogenicity of the chemical, a quantitative understanding of the balance of activation and inactivation is essential for improving our understanding and assessment of human risk following exposure to BD and chemical mixtures containing BD. Transgenic mice exposed to 625 ppm BD for 6 hr/day for 5 days exhibited significant mutagenicity in the lung, a target organ for the carcinogenic effect of BD in mice. In vitro studies designed to assess interspecies differences in the activation of BD and inactivation of BD epoxides reveal that significant differences exist among mice, rats, and humans. In general, the overall activation/detoxication ratio for BD metabolism was approximately 10-fold higher in mice compared to rats or humans.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Butadienos/metabolismo , Mutação , Animais , Bacteriófagos/genética , Benzeno/metabolismo , Butadienos/farmacocinética , Butadienos/farmacologia , Interações Medicamentosas , Etanol/metabolismo , Humanos , Pulmão/ultraestrutura , Masculino , Camundongos , Camundongos Transgênicos , Microssomos/metabolismo , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Estireno , Estirenos/metabolismoRESUMO
A physiological toxicokinetic (PT) model is presented describing disposition and metabolism of 1,3-butadiene (BU) and 1,2-epoxy-3-butene (BMO) in rat, mouse and man, and of 1,2:3,4-diepoxybutane (BDI) in mice. It contains formation of BMO and BDI, intrahepatocellular first-pass hydrolysis of BMO, conjugation of BMO with glutathione (GSH) and GSH-turnover in the liver. Tissue:air partition coefficients of BU and BMO were determined experimentally. Haemoglobin (HB) adducts of BMO in rodents following exposure to BU were simulated and compared with published data. The model is compared with those published earlier. An attempt was made to compare the carcinogenic potential of BU in mice and rats with respect to the carcinogenic potentials of both epoxides.
Assuntos
Butadienos/farmacocinética , Carcinógenos/farmacocinética , Compostos de Epóxi/sangue , Glutationa/metabolismo , Hemoglobinas/metabolismo , Animais , Carga Corporal (Radioterapia) , Butadienos/toxicidade , Feminino , Humanos , Masculino , Camundongos , Modelos Biológicos , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Especificidade da EspécieRESUMO
Propylene oxide (PO) is used as an intermediate in the chemical industry. Human exposure to PO may occur in the work place. Propylene, an important industrial chemical and a component of, for example, car exhausts and cigarette smoke, is another source of PO exposure. Once taken up in the organism, this epoxide alkylates macromolecules, such as haemoglobin and DNA. The aim of the present investigation was to compare two methods for determination of in vivo dose, the steady state concentration of PO in blood of exposed rats and the level of haemoglobin adducts. Male Fischer 344 rats were exposed for 4 weeks (6 h/day, 5 days/week) to PO at a mean atmospheric concentration of 500 ppm (19.9 micromol/l). Immediately after the last exposure blood was collected in order to determine the steady state concentration of PO. Free PO was measured in blood samples of three animals by means of a head space method to be 37 +/- 2 micromol/l blood (mean +/- S.D.). Blood samples were also harvested for the measurement of haemoglobin adducts. N-2-Hydroxypropyl adducts with N-terminal valine in haemoglobin were quantified using the N-alkyl Edman method with globin containing adducts of deuterium-substituted PO as an internal standard and N-D,L-2-hydroxypropyl-Val-Leu-anilide as a reference compound. Tandem mass spectrometry was used for adduct quantification. The adduct levels were < 0.02 and 77.7 +/- 4.7 nmol/g globin (mean +/- S.D.) in control animals (n = 7) and in exposed animals (n = 34), respectively. The adduct levels expected at the end of exposure were calculated to be 71.7 +/- 4.1 nmol/g globin (mean +/- S.D.) using the measured steady state concentration of PO in blood and taking into account the growth of animals, the life span of erythrocytes, the exposure conditions and the second order rate constant for adduct formation. The good agreement between the estimated and measured adduct levels indicates that both end-points investigated are suitable for biological monitoring.
Assuntos
Monitoramento Ambiental , Compostos de Epóxi/sangue , Animais , Hemoglobinas/metabolismo , Masculino , Ratos , Ratos Endogâmicos F344RESUMO
A physiological toxicokinetic model (PT model) was developed for inhaled isoprene in mouse, rat and man. Partition coefficients blood:air and tissue:blood were determined in vitro by a headspace method. Parameters of a saturable isoprene metabolism in B6C3F1 mice, Sprague-Dawley rats and volunteers were obtained from gas uptake experiments in closed systems, analyzed by means of a two-compartment model. Incorporation of these parameters into the PT model revealed that isoprene was metabolized not only in the liver but also in extrahepatic organs. Endogenous production of isoprene in man was quantified from experiments with volunteers breathing into a closed system. The PT model was validated for mice, rats and humans by comparing simulated values with data determined by other authors.
Assuntos
Butadienos/farmacocinética , Hemiterpenos , Pentanos , Adulto , Animais , Feminino , Humanos , Masculino , Camundongos , Modelos Biológicos , Ratos , Ratos Sprague-Dawley , Ratos Wistar , SolubilidadeRESUMO
Isoprene (IP) is ubiquitous in the environment and is used for the production of polymers. It is metabolized in vivo to reactive epoxides, which might cause the tumors observed in IP exposed rodents. Detailed knowledge of the body and tissue burden of inhaled IP and its intermediate epoxides can be gained using a physiological toxicokinetic (PT) model. For this purpose, a PT-model was developed for IP in mouse, rat, and human. Experimentally determined partition coefficients were taken from the literature. Metabolic parameters were obtained from gas-uptake experiments. The measured data could be described by introducing hepatic and extrahepatic metabolism into the model. At exposure concentrations up to 50 ppm, the rate of metabolism at steady-state is 14 times faster in mice and about 8 times faster in rats than in humans (2.5 micromol/h/kg at 50 ppm IP in air). IP does accumulate only barely due to its fast metabolism and its low thermodynamic partition coefficient whole body:air. IP is produced endogenously. This production is negligible in rodents compared to that in humans (0.34 micromol/h/kg). About 90% of IP produced endogenously in humans is metabolized and 10% is exhaled unchanged. The blood concentration of IP in non-exposed humans is predicted to be 9.5 nmol/l. The area under the blood concentration-time curve (AUC) following exposure over 8 h to 10 ppm IP is about 4 times higher than the AUC resulting from the unavoidable endogenous IP over 24 h. A comparison of such AUCs can be used for establishing workplace exposure limits. For estimation of the absolute risk, knowledge of the body burden of the epoxide intermediates of IP is required. Unfortunately, such data are not yet available.
Assuntos
Butadienos/farmacocinética , Butadienos/toxicidade , Hemiterpenos , Pentanos , Administração por Inalação , Animais , Carga Corporal (Radioterapia) , Butadienos/administração & dosagem , Butadienos/metabolismo , Simulação por Computador , Humanos , Camundongos , Modelos Biológicos , Exposição Ocupacional , Ratos , Medição de Risco , Especificidade da EspécieRESUMO
First-pass metabolism of 1,3-butadiene (BD) leading to 1,2-epoxy-3-butene (EB), 1,2:3,4-diepoxybutane (DEB), 3-butene-1,2-diol (B-diol), 3,4-epoxy-1,2-butanediol (EBD) and crotonaldehyde (CA) was studied quantitatively in the once-through BD perfused liver of mouse and rat by means of an all-glass gas-tight perfusion system. Metabolites were analyzed using gas chromatography equipped with mass selective detection. The perfusate consisted of Krebs-Henseleit buffer (pH 7.4) containing bovine erythrocytes (40%v/v) and BD. The perfusion flow rates through the livers were 3-4 ml/min (mouse) and 17-20 ml/min (rat). The BD concentrations in the liver perfusates were 330 nmol/ml (mouse) and 240 nmol/ml (rat) being high enough to reach almost saturation of BD metabolism. The mean rates of BD transformation were about 0.014 and 0.055 mmol/h per liver of a mouse and a rat, respectively, being similar to the values expected from in-vivo measurements. There were marked species differences in the formation of BD metabolites. In the effluent of mouse livers, all three epoxides (EB: 9.4 nmol/ml; DEB: 0.06 nmol/ml; EBD: 0.07 nmol/ml) and B-diol (8.2 nmol/ml) were detected. In the perfusate leaving naïve rat livers, only EB and B-diol were found. In that of rat liver, EB concentration was 8.5 times smaller than in that of mouse liver, whereas B-diol concentrations were similar in the effluent liver perfusate of both species. CA was below the limit of its detection (60 nmol/l) in the liver perfusate of mice and of naïve rats. Of BD metabolized, the sum of the metabolites investigated in the effluent amounted to only 30% (mouse) and 20% (rat). In first experiments with rat liver, glutathione (GSH) was depleted by pretreating the animals with diethylmaleate. With the exception of EBD (not quantifiable due to an interfering peak), all other metabolites including CA were found in the effluent perfusate summing up to about 70 and 100% of BD metabolized, which indicates the quantitative importance of the GSH dependent metabolism. In summary, the results demonstrate the relevance of an intrahepatic first-pass metabolism for metabolic intermediates of BD, which undergo further transformation immediately after their production in the liver before leaving this organ. Hitherto, the occurrence of this first-pass metabolism was only hypothesized. The findings will help to explain the drastic species difference between mice and rats in the carcinogenic potency of BD.
Assuntos
Butadienos/metabolismo , Fígado/metabolismo , Aldeídos/metabolismo , Animais , Biotransformação , Butadienos/toxicidade , Compostos de Epóxi/metabolismo , Glicóis/metabolismo , Cinética , Masculino , Camundongos , Perfusão , Ratos , Ratos Sprague-Dawley , Especificidade da EspécieRESUMO
Two approaches of compartmental toxicokinetic modeling of gaseous compounds are presented which are suitable for kinetic analysis of concentration-time data measured in the air of closed exposure systems. The first approach is based on a two-compartment model with physiological gas uptake, the second on a physiologically-based toxicokinetic model. Both models can be used for the description of inhalation, accumulation, exhalation and metabolism of gaseous compounds together with the toxicokinetics of metabolites. Interspecies extrapolation is based on physicochemical, physiological and biochemical parameters. The advantage of the two-compartment model is its limited number of variables and its experimentally easy applicability. Its disadvantage is the impossibility to predict tissue specific concentrations. The advantage of the physiologically-based model is its usability for predictions and for the description of tissue specific concentrations. However, it entails great effort, since a series of parameters has to be determined before meaningful model calculations can be carried out.
Assuntos
Farmacocinética , Animais , Humanos , Modelos Biológicos , VolatilizaçãoAssuntos
Heptanos/farmacocinética , Heptanos/toxicidade , Hexanos/farmacocinética , Hexanos/toxicidade , Doenças do Sistema Nervoso/induzido quimicamente , Administração por Inalação , Adulto , Animais , Carga Corporal (Radioterapia) , Reagentes de Ligações Cruzadas/química , Reagentes de Ligações Cruzadas/metabolismo , Meia-Vida , Hexanonas/química , Hexanonas/metabolismo , Hexanonas/urina , Humanos , Cetonas/química , Cetonas/metabolismo , Cetonas/urina , Masculino , Doenças do Sistema Nervoso/patologia , Pirróis/metabolismo , Ratos , Ratos Wistar , Medição de RiscoRESUMO
Inhalation is the most important route of absorption for many volatile substances. The inhaled chemical is distributed via the bloodstream into the organs and tissues. It is eliminated mainly unchanged by exhalation and also via metabolism. The blood concentration can be considered as a surrogate for the body burden of the chemical. It depends on the rate of uptake and on the rate of elimination. The rate of uptake by inhalation is determined by the blood:air partition coefficient of the gaseous compound, the actual concentration of the chemical already in the blood entering the lungs, the blood flow through the lungs, and the alveolar ventilation. The latter is greatly influenced by physical activity, which thus has a crucial impact on the rate of uptake. Consequently, the blood concentration of an inhaled chemical and the resulting alveolar retention, representing the rate of metabolism at steady-state, are dependent on the intensity of physical work. Both parameters can be calculated for steady-state conditions using simple algebraic equations, if one assumes that the rate of metabolic elimination is limited by the blood flow through the metabolizing organs. This assumption is valid for many rapidly metabolized inhaled gases and vapours at low concentrations present under workplace conditions. The derived equations give the theoretical background for the observations presented from a series of experimental studies which demonstrate that physical activity can be a major determinant of the toxicokinetics of inhaled compounds. Practical examples illustrate the procedure. We conclude that workplace-related physical activity should be taken into account for compounds with blood:air partition coefficients above 6 in the determination of occupational limit concentrations in air.
Assuntos
Poluentes Ocupacionais do Ar/farmacocinética , Exposição por Inalação , Esforço Físico/fisiologia , Carga Corporal (Radioterapia) , Humanos , Alvéolos Pulmonares/metabolismo , Volatilização , Local de TrabalhoRESUMO
A relationship between the partition coefficient (P) and the boiling point (TBp, expressed in degrees Kelvin) was derived as TBp = alpha *ln(P) + beta. The relationship is based on the Clausius-Clapeyron equation and is valid for volatile lipophilic compounds, when one of the phases is air. Specific tissue/air and whole animal/air partition coefficients, as published in the literature, were used to validate the equation.
Assuntos
Termodinâmica , Toxicologia/métodos , Lipídeos , Relação Estrutura-Atividade , VolatilizaçãoRESUMO
1,3-Butadiene (BD), a widely used monomer in the production of synthetic rubber and other resins, is one of the 189 hazardous air pollutants identified in the 1990 Clean Air Act Amendments. BD induces tumors at multiple organ sites in B6C3F1 mice and Sprague-Dawley rats; mice are much more susceptible to the carcinogenic action of BD than are rats. Previous in vivo studies have indicated higher circulating blood levels of butadiene monoepoxide (BMO), a potential carcinogenic metabolite of BD, in mice compared to rats, suggesting that species differences in the metabolism of BD may be responsible for the observed differences in carcinogenic susceptibility. The metabolic fate of BD in humans is unknown. The objective of these studies was to quantitate in vitro species differences in the oxidation of BD and BMO by cytochrome P450-dependent monooxygenases and the inactivation of BMO by epoxide hydrolases and glutathione S-transferases using microsomal and cytosolic preparations of livers and lungs obtained from Sprague-Dawley rats, B6C3F1 mice and humans. Maximum rates for BD oxidation (Vmax) were highest for mouse liver microsomes (2.6 nmol/mg protein/min) compared to humans (1.2) and rats (0.6). The Vmax for BD oxidation by mouse lung microsomes was similar to that of mouse liver but greater than 10-fold higher than the Vmax for the reaction in human or rat lung microsomes. Correlation analysis revealed that P450 2E1 is the major P450 enzyme responsible for oxidation of BD to BMO. Only mouse liver microsomes displayed quantifiable rates for metabolism of BMO to butadiene diepoxide (Vmax = 0.2 nmol/mg protein/min), a known rodent carcinogen. Human liver microsomes displayed the highest rate of BMO hydrolysis by epoxide hydrolases. The Vmax in human liver microsomes ranged from 9 to 58 nmol/mg protein/min and was at least 2-fold higher than the Vmax observed in mouse and rat liver microsomes. The Vmax for glutathione S-transferase-catalyzed conjugation of BMO with glutathione was highest for mouse liver cytosol (500 nmol/mg protein/min) compared to human (45) or rat (241) liver cytosol. In general, the KMs for the detoxication reactions were 1000-fold higher than the KMs for the oxidation reaction. Because of the low solubility of the BD and the relatively high KM for oxidation, it is likely that the Vmax/KM ratio will be important for BD and BMO metabolism in vivo. In vivo clearance constants were calculated from in vitro data for BD oxidation and BMO oxidation, hydrolysis and GSH conjugation.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Butadienos/metabolismo , Carcinógenos/metabolismo , Compostos de Epóxi/metabolismo , Fígado/metabolismo , Pulmão/metabolismo , Animais , Biotransformação , Butadienos/farmacocinética , Citosol/metabolismo , Compostos de Epóxi/farmacocinética , Humanos , Cinética , Masculino , Matemática , Camundongos , Camundongos Endogâmicos , Microssomos/metabolismo , Microssomos Hepáticos/metabolismo , Modelos Biológicos , Especificidade de Órgãos , Ratos , Ratos Endogâmicos , Especificidade da EspécieRESUMO
1,3-Butadiene is carcinogenic to rats and mice, although mice are more sensitive than rats. It is not known if butadiene poses a carcinogenic risk to humans. Butadiene requires metabolic activation to reactive epoxides that can bind to DNA to initiate a series of events that lead to tumour formation. Species differences in activation and detoxification must be considered in estimating human risks from exposure to butadiene. A research strategy for assessing the role of metabolic factors in the carcinogenicity of butadiene involves studies in laboratory animals in vivo, supplemented with studies in vitro with tissues from both laboratory animals and humans. In experiments conducted on liver and lung tissues from Sprague-Dawley rats, B6C3F1 mice and humans, we characterized the oxidation of butadiene and butadiene monoepoxide by cytochrome P450-dependent mono-oxygenases and the detoxification of butadiene monoepoxide by epoxide hydrolases and glutathione transferases. B6C3F1 mouse liver microsomes displayed a capacity for butadiene oxidation exceeding that seen in either human or rat liver microsomes. Except in mice, oxidation of butadiene occurred at rates significantly lower with lung than with liver microsomes. In general, human liver microsomes hydrolysed butadiene monoepoxide at higher rates than either rats or mice. The capacity for glutathione conjugation with butadiene monoepoxide was higher in mice than in humans or rats. The ratios of butadiene activation (P450):detoxication (hydrolysis and conjugation) are markedly different in mouse (74:1), rat (6:1) and human (6:1) liver tissues. The differences in the ratios between mice and rats are consistent with the higher carcinogenic sensitivity of mice than rats to butadiene. Factors in addition to metabolism, however, probably play a role in the carcinogenicity of butadiene in rats and mice. Metabolic rate constants for butadiene and butadiene monoepoxide oxidation and for butadiene monoepoxide hydrolysis and conjugation with glutathione, determined from physiological pharmacokinetic model simulations of butadiene-exposed rats and mice, were for the most part similar to the constants determined in vitro. The same trends that were noted in vitro were seen in vivo. The physiological dosimetry model for butadiene that includes in-vitro vitro metabolic constants can stimulate behaviour in vivo and can be used to predict blood and tissue concentrations of butadiene and its monoepoxide.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Butadienos/farmacocinética , Mutagênicos/farmacocinética , Animais , Butadienos/análise , Butadienos/toxicidade , Sistema Enzimático do Citocromo P-450/metabolismo , Epóxido Hidrolases/metabolismo , Compostos de Epóxi/farmacocinética , Compostos de Epóxi/toxicidade , Glutationa/metabolismo , Glutationa Transferase/metabolismo , Humanos , Hidrólise , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos , Microssomos Hepáticos/metabolismo , Mutagênicos/análise , Mutagênicos/toxicidade , Ratos , Ratos Sprague-Dawley , Especificidade da EspécieRESUMO
Concern about the carcinogenic potential of styrene (ST) is due to its reactive metabolite, styrene-7,8-oxide (SO). To estimate the body burden of SO resulting from various scenarios, a physiologically based pharmacokinetic (PBPK) model for ST and its metabolite SO was developed. This PBPK model describes the distribution and metabolism of ST and SO in the rat, mouse and man following inhalation, intravenous (i.v.), oral (p.o.) and intraperitoneal (i.p.) administration of ST or i.v., p.o. and i.p. administration of SO. Its structure includes the oxidation of ST to SO, the intracellular first-pass hydrolysis of SO catalyzed by epoxide hydrolase and the conjugation of SO with glutathione. This conjugation is described by an ordered sequential ping-pong mechanism between glutathione, SO and glutathione S-transferase. The model was based on a PBPK model constructed previously to describe the pharmacokinetics of butadiene with its metabolite butadiene monoxide. The equations of the original model were revised to refer to the actual tissue concentration of chemicals instead of their air equivalents used originally. Blood:air and tissue:blood partition coefficients for ST and SO were determined experimentally and have been published previously. Metabolic parameters were taken from in vitro or in vivo measurements. The model was validated using various data sets of different laboratories describing pharmacokinetics of ST and SO in rodents and man. In addition, the influences of the biochemical parameters, alveolar ventilation and blood:air ventilation and blood:air partition coefficient for ST on the pharmacokinetics of ST and SO were investigated by sensitivity analysis.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Compostos de Epóxi/farmacocinética , Estirenos/farmacocinética , Administração por Inalação , Administração Oral , Animais , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/sangue , Glutationa/metabolismo , Humanos , Hidrólise , Injeções Intraperitoneais , Injeções Intravenosas , Absorção Intestinal , Camundongos , Modelos Biológicos , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/fisiologia , Ratos , Solubilidade , Especificidade da Espécie , Estireno , Estirenos/administração & dosagem , Estirenos/sangue , TermodinâmicaRESUMO
Gas uptake studies were carried out to evaluate kinetic interactions between 1,3-butadiene and styrene in Sprague-Dawley rats. The animals were co-exposed by inhalation to a mixture of 1,3-butadiene between 20 and 6000 ppm (v/v) and styrene between 0 and 500 ppm. The data demonstrate that metabolism of 1,3-butadiene was partially inhibited by styrene. The inhibition was competitive at atmospheric concentrations of styrene up to 90 ppm. Higher concentrations of styrene resulted in a small additional inhibition only. The apparent Michaelis-Menten constant for 1,3-butadiene, related to the average concentration in the organism of the animals, was Kmapp = 1.17 +/- 0.37 (mumol/l of tissue) and the corresponding atmospheric concentration at steady state was 560 ppm. The inhibition constant of styrene was found to be Ki = 0.23 +/- 0.30 (mumol/l of tissue). The maximal metabolic rate for 1,3-butadiene was 230 +/- 10 (mu/kg/h).
Assuntos
Butadienos/farmacocinética , Estirenos/farmacocinética , Ar/análise , Animais , Butadienos/análise , Cromatografia Gasosa , Interações Medicamentosas , Cinética , Masculino , Ratos , Ratos Endogâmicos , Estireno , Estirenos/análiseRESUMO
We measured the background levels of di(2-ethylhexyl) phthalate (DEHP) and its hydrolytic metabolite mono(2-ethylhexyl) phthalate (MEHP) in blood from naive female Sprague-Dawley rats and in de-ionized charcoal-purified water using an analytical procedure that is based on sample treatment with acetonitrile, n-hexane extraction and analysis by gas chromatography. In blood, blank values of 91.3 +/- 34.7 micrograms DEHP/l (n = 31) and 30.1 +/- 13.1 micrograms MEHP/l (n = 20) were obtained, and in water, values of 91.6 +/- 44.2 micrograms DEHP/l (n = 26) and 26.7 +/- 10.4 micrograms MEHP/l (n = 15) were found. Since there is no difference between the background valves obtained from blood of naive rats and water, we conclude that DEHP and MEHP result from contamination during the analytical procedure.
Assuntos
Dietilexilftalato/sangue , Animais , Cromatografia Gasosa , Dietilexilftalato/análogos & derivados , Feminino , Ratos , Ratos Sprague-Dawley , Água/análiseRESUMO
Metabolism of isobutene (2-methylpropene) in rats (Sprague Dawley) and mice (B6C3F1) follows kinetics according to Michaelis-Menten. The maximal metabolic elimination rates are 340 mumol/kg/h for rats and 560 mumol/kg/h for mice. The atmospheric concentration at which Vmax/2 is reached is 1200 ppm for rats and 1800 ppm for mice. At steady state, below atmospheric concentrations of about 500 ppm the rate of metabolism of isobutene is direct proportional to its concentration. 1,1-Dimethyloxirane is formed as a primary reactive intermediate during metabolism of isobutene in rats and can be detected in the exhaled air of the animals. Under conditions of saturation of isobutene metabolism the concentration of 1,1-dimethyloxirane in the atmosphere of a closed exposure system is only about 1/15 of that observed for ethene oxide and about 1/100 of that observed for 1,2-epoxy-3-butene as intermediates in the metabolism of ethene or 1,3-butadiene.
Assuntos
Alcenos/metabolismo , Administração por Inalação , Alcenos/administração & dosagem , Animais , Sistema Enzimático do Citocromo P-450/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos , Ratos , Ratos Endogâmicos , Especificidade da EspécieRESUMO
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 mumol/(h.kg) and 625 mumol/(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 degrees 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.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Estirenos/farmacocinética , Administração por Inalação , Administração Oral , Ar/análise , Animais , Ditiocarb/farmacologia , Meia-Vida , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos , Ratos , Ratos Sprague-Dawley , Solubilidade , Especificidade da Espécie , Estireno , Estirenos/administração & dosagem , Estirenos/análiseRESUMO
Co-exposure to vapours of 1,3-butadiene and styrene occurs in the styrene-butadiene polymer manufacturing industry. Both compounds are biotransformed during a first step by cytochrome P450-dependent mono-oxygenases to epoxides--intermediates which are proven carcinogens. In a previous publication, we reported that metabolism of butadiene in rats was inhibited by simultaneous exposure to styrene, whereas butadiene had no effect on the kinetics of styrene. In order to translate these results into conditions of human exposure, we developed a physiologically based pharmacokinetic (PBPK) model, which is presented here. Maximal metabolic rates (Vmax) and Ostwald's partition coefficients were obtained using liver microsomes and tissues from rat and man. Apparent Michaelis (Km) and inhibition (Ki) constants were derived from previously published data on rats and were considered to be species-independent. The model was used to simulate human exposure to atmospheric mixtures of 5 and 15 ppm butadiene with 0.20 and 50 ppm styrene. It predicts that the presence of styrene significantly inhibits butadiene metabolism in man: At exposures up to 15 ppm, the amounts of butadiene metabolized can be expected to be reduced to 81 and 63% with co-exposure to styrene at 20 and 50 ppm, respectively.
Assuntos
Poluentes Ocupacionais do Ar/farmacocinética , Butadienos/farmacocinética , Mutagênicos/farmacocinética , Estirenos/farmacocinética , Administração por Inalação , Poluentes Ocupacionais do Ar/toxicidade , Animais , Butadienos/toxicidade , Interações Medicamentosas , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Modelos Biológicos , Modelos Químicos , Mutagênicos/farmacologia , Mutagênicos/toxicidade , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Estireno , Estirenos/farmacologia , Estirenos/toxicidadeRESUMO
1,3-Butadiene (BD), a rodent carcinogen, is metabolized to mutagenic and potentially DNA-reactive epoxides, including butadiene monoepoxide (BMO) and butadiene diepoxide. A physiological model containing five tissue groups (liver, lung, fat, slowly perfused tissues and rapidly perfused tissues) and blood was developed to describe uptake and metabolism of inhaled BD and BMO. Maximal rates for hepatic and pulmonary metabolism of BD and hepatic metabolism of BMO incorporated into the model were extrapolated from in vitro data (Csanády et al., Carcinogenesis, 13, 1143-1153, 1992). Apparent enzyme affinities used in the model were identified to the values measured in vitro. Model stimulations for BD and BMO uptake were compared to results from experiments in which groups of male Sprague-Dawley rats and B6C3F1 mice were exposed to initial concentrations of 50-5000 p.p.m. BD in closed chamber experiments and published data on BMO uptake by rats and mice. Metabolic rate constants extrapolated from in vitro data stimulated both BMO and BD uptake from closed chambers. The Vmax for hepatic metabolism of BD extrapolated from in vitro studies was 62 mumol/kg/h for rats and 340 mumol/kg/h for mice, while the Vmax for pulmonary metabolism of BD was 1.0 and 22 for rats and mice, respectively. These results demonstrate the usefulness of data derived in vitro for predicting in vivo behavior. Model simulations were also conducted in which only hepatic metabolism of BD was incorporated. These simulations underestimated BD uptake for mice, but not rats. Inclusion of in vitro-derived rates of pulmonary metabolism of BD into the model improved the fit to the data for mice. Since mice, but not rats, develop lung tumors after exposure to BD, these results point to the need for further characterize the metabolic capacity and target cells in the lung for BD and its metabolites. Once characterized, these models can be extended to predict in vivo behavior of BD in humans.
Assuntos
Butadienos/metabolismo , Animais , Compostos de Epóxi/metabolismo , Glutationa/metabolismo , Masculino , Camundongos , Modelos Biológicos , Ratos , Ratos Sprague-Dawley , Solubilidade , Especificidade da EspécieRESUMO
1,3-Butadiene (BD) is carcinogenic in the B6C3F1 mouse in multiple organs, including lung and liver. We conducted a study to measure the frequency of BD mutations in mouse tissues using a transgenic mouse (Muta mouse; MM). MM is a BALB/c x DBA/2 (CD2F1) mouse that has a bacteriophage lambda shuttle vector with the target gene lacZ integrated into the mouse genome. Mice were exposed by inhalation to 625 ppm BD (6 hr/day) for 5 days and the lacZ- mutant frequency (mf) was determined in lung, bone marrow, and liver. The lacZ- mf in lung increased twofold above air-exposed control animals, but the bone marrow and liver samples did not exhibit an increase above background. N-ethyl-N-nitrosourea (250 mg/kg ip) was mutagenic in all three tissues examined. Studies on the biotransformation of BD using MM liver microsomes showed that the ratio between the rates of BD bioactivation to BD monoepoxide (BMO) and hydrolysis of BMO by epoxide hydrolases was approximately 40% less than this ratio using B6C3F1 mouse liver microsomes. Quantitation of adducts of BMO to N-terminal valine in hemoglobin (Hb) in the MM revealed an adduct level of 3.7 pmol/mg globin. Using this value, the predicted Hb adduct level in MM would be approximately one-half of that measured in the B6C3F1 mouse following similar exposures. These results indicate that BD induces mutations in vivo in a known murine target tissue, but strain differences in the biotransformation of BD should be considered in comparing the susceptibility of transgenic mouse strains to mutation.