RESUMEN
The plasticizer di(2-ethylhexyl) phthalate (DEHP) is suspected to induce antiandrogenic effects in men via its metabolite mono(2-ethylhexyl) phthalate (MEHP). However, there is only little information on the kinetic behavior of DEHP and its metabolites in humans. The toxikokinetics of DEHP was investigated in four male volunteers (28-61y) who ingested a single dose (645±20µg/kg body weight) of ring-deuterated DEHP (DEHP-D(4)). Concentrations of DEHP-D(4), of free ring-deuterated MEHP (MEHP-D(4)), and the sum of free and glucuronidated MEHP-D(4) were measured in blood for up to 24h; amounts of the monoesters MEHP-D(4), ring-deuterated mono(2-ethyl-5-hydroxyhexyl) phthalate and ring-deuterated mono(2-ethyl-5-oxohexyl) phthalate were determined in urine for up to 46h after ingestion. The bioavailability of DEHP-D(4) was surprisingly high with an area under the concentration-time curve until 24h (AUC) amounting to 50% of that of free MEHP-D(4). The AUC of free MEHP-D(4) normalized to DEHP-D(4) dose and body weight (AUC/D) was 2.1 and 8.1 times, that of DEHP-D(4) even 50 and 100 times higher than the corresponding AUC/D values obtained earlier in rat and marmoset, respectively. Time courses of the compounds in blood and urine of the volunteers oscillated widely. Terminal elimination half-lives were short (4.3-6.6h). Total amounts of metabolites in 22-h urine are correlated linearly with the AUC of free MEHP-D(4) in blood, the parameter regarded as relevant for risk assessment.
Asunto(s)
Dietilhexil Ftalato/análogos & derivados , Adulto , Área Bajo la Curva , Biotransformación , Peso Corporal , Deuterio , Dietilhexil Ftalato/sangre , Dietilhexil Ftalato/farmacocinética , Dietilhexil Ftalato/orina , Relación Dosis-Respuesta a Droga , Glucurónidos/sangre , Glucurónidos/orina , Semivida , Humanos , Indicadores y Reactivos , Cinética , Masculino , Persona de Mediana EdadRESUMEN
A urinary trichloroacetic acid (TCA) concentration of 100 mg/l at the end of the last work shift (8 h/day, 5 days/week) of the week has been established in workers as exposure equivalent for the carcinogenic substance trichloroethene (EKA for TRI) at an exposure concentration of 50 ppm TRI. Due to the continuous reduction of atmospheric TRI concentrations during the last years, the quantitative relation given by the EKA for TRI is revised for exposures to low TRI concentrations. A physiological two-compartment model is presented by which the urinary TCA concentrations are calculated that result from inhaled TRI in humans. The model contains one compartment for trichloroethanol (TCE) and one for TCA. Inhaled TRI is metabolized to TCA and to TCE. The latter is in part further oxidized to TCA. Urinary elimination of TCA is modeled to obey first order kinetics. All required model parameters were taken form the literature. In order to evaluate the model performance on the urinary TCA excretion at low exposure concentrations, predicted urinary TCA concentrations were compared with data obtained in two volunteer studies and in one field study. The model was evaluated at exposure concentrations as low as 12.5 ppm TRI. It is demonstrated that the correlation described by the hitherto used EKA for TRI is also valid at low TRI concentrations. For TRI exposure concentrations of 0.6 and 6 ppm, the resulting urinary TCA concentrations at the end of the last work shift of a week are predicted to be 1.2 and 12 mg/l, respectively.
Asunto(s)
Contaminantes Ocupacionales del Aire/metabolismo , Exposición Profesional/análisis , Ácido Tricloroacético/orina , Tricloroetileno/metabolismo , Contaminantes Ocupacionales del Aire/análisis , Humanos , Exposición por Inhalación/análisis , Modelos Biológicos , Tricloroetileno/análisisRESUMEN
Propylene oxide (PO) concentrations >or=300 ppm induced cell proliferation and tumors in rat nasal respiratory epithelium (NRE). Cell proliferation was suggested to result from depletion of glutathione (GSH) in NRE. In order to substantiate this hypothesis, cell proliferation - measured by bromodeoxyuridine incorporation into DNA of the epithelium lining middle septum, dorsal medial meatus, and medial and lateral surfaces of the nasoturbinate in transverse nasal sections taken immediately posterior to the upper incisor teeth - and water-soluble non-protein thiol (NPSH) in NRE were determined after exposing male Fischer 344 rats to 50 ppm, 100 ppm, 200 ppm, or 300 ppm PO (6 h/day, 3 days). Both parameters were also investigated after treating rats for 3 days with diethylmaleate (DEM; 2 x 250 mg/kg/day or 500 + 150 mg/kg/day) or buthionine sulfoximine (BSO; 500 mg/kg/day). Exposure to 50 ppm PO and treatment with 2 x2 50 mg/kg/day DEM resulted in NPSH levels approximating 50% and 80% of the level in untreated controls, respectively. Cell proliferation did not increase. After exposures to >or= 100 ppm PO or treatment with BSO or 500 + 150 mg/kg/day DEM, NPSH was depleted to Asunto(s)
Contaminantes Atmosféricos/toxicidad
, Proliferación Celular/efectos de los fármacos
, Compuestos Epoxi/toxicidad
, Glutatión/metabolismo
, Mucosa Nasal/efectos de los fármacos
, Compuestos de Sulfhidrilo/metabolismo
, Agua/química
, Animales
, Butionina Sulfoximina/farmacología
, Relación Dosis-Respuesta a Droga
, Masculino
, Maleatos/farmacología
, Mucosa Nasal/patología
, Neoplasias Nasales/inducido químicamente
, Neoplasias Nasales/metabolismo
, Neoplasias Nasales/patología
, Ratas
, Ratas Endogámicas F344
, Solubilidad
, Factores de Tiempo
RESUMEN
Ethylene glycol (EG) is a widely used liquid. Limited data are published regarding inhaled EG and no data regarding transdermal EG uptake in humans. In order to gain information on the quantitative fate of EG, four male volunteers inhaled between 1340 and 1610 micromol vaporous 13C-labeled EG (13C2-EG) for 4h. Separately, three of these subjects were epidermally exposed for up to 6h to liquid 13C2-EG (skin area 66 cm2). Plasma concentrations and urinary amounts of 13C2-EG were determined by gas chromatography with mass selective detection. Additionally, plasma was assayed for 13C-labeled glycolic acid 13C2-GA) and urine for 13C2-GA and 13C-labeled oxalic acid (13C2-OA). Both EG metabolites were nephrotoxic in animals and humans and embryotoxic in rodents. 13C-labels enabled to differentiate from also determined endogenous EG, glycolic acid (GA), and oxalic acid (OA). Of 13C2-EG inhaled, 5.5+/-3.0%, 0.77+/-0.15%, and 0.10+/-0.12% were detected in urine as 13C2-EG, 13C2-GA, and 13C2-OA, respectively. The skin permeability constant of liquid EG was 2.7 x 10(-5)+/-0.5 x 10(-5)cm/h. Of the dose taken up transdermally, 8.1+/-3.2% and up to 0.4% were excreted in urine as 13C2-EG and 13C2-GA, respectively. It is calculated that equally long-lasting exposure to 10 ppm vaporous EG or wetting of both hands by liquid EG leads to about the same body burden by EG and metabolites. The amounts of GA and OA excreted daily in urine as a result of exposure (8h/day) to 10 ppm EG are about 15% and 2%, respectively, of those excreted from naturally occurring endogenous GA and OA.
Asunto(s)
Glicol de Etileno/toxicidad , Glicolatos/farmacocinética , Oxalatos/farmacocinética , Absorción Cutánea/fisiología , Administración Tópica , Adulto , Área Bajo la Curva , Cromatografía de Gases , Difusión , Glicol de Etileno/farmacocinética , Femenino , Glicolatos/metabolismo , Glicolatos/orina , Semivida , Humanos , Exposición por Inhalación , Radioisótopos de Yodo , Riñón/metabolismo , Masculino , Persona de Mediana Edad , Oxalatos/metabolismo , Oxalatos/orina , FarmacocinéticaRESUMEN
Chronic exposure to high concentrations of PO induced inflammation in the respiratory nasal mucosa (RNM) of rodents and, for concentrations >or= 300 ppm, caused nasal tumors. Considering the nose to be the most relevant target organ for PO-induced tumorigenicity, we developed a physiological toxicokinetic model for PO in rats and humans. It includes compartments for arterial, venous, and pulmonary blood, liver, muscle, fat, richly perfused tissues, lung, and nose. It simulates inhalation of PO, its distribution into tissues by blood flow, and its elimination by exhalation and metabolism. In nose, lung, and liver of rats, PO conjugation with glutathione (GSH), PO-induced GSH depletion, and formation of PO adducts to DNA are described. Also modeled are PO adducts to hemoglobin of rats and humans. Required partition coefficients and metabolic parameters were derived experimentally or from publications. In rats, simulated PO concentrations in blood and GSH levels in tissues agreed with measured data. If compared with reported values, levels of adducts with hemoglobin were underpredicted up to a factor of about 2. Adducts with DNA differed up to a factor of 3. Hemoglobin adducts predicted for PO-exposed workers were 1.5-1.9 times higher than the reported ones. Considering identical conditions of PO exposure, similar PO concentrations in RNM were modeled for rats and humans. Also, PO concentrations in blood, about 1/30th of those in RNM, were similar in both species. Since the model was evaluated on all available data in rats and humans, we consider it to be useful for estimating the risk from inhalation exposure to PO.
Asunto(s)
Contaminantes Atmosféricos/farmacocinética , Compuestos Epoxi/farmacocinética , Exposición por Inhalación , Modelos Biológicos , Mucosa Nasal/metabolismo , Neoplasias Nasales/inducido químicamente , Contaminantes Atmosféricos/sangre , Contaminantes Atmosféricos/toxicidad , Animales , Biomarcadores/metabolismo , Calibración , Simulación por Computador , Aductos de ADN/metabolismo , Relación Dosis-Respuesta a Droga , Compuestos Epoxi/sangre , Compuestos Epoxi/toxicidad , Estudios de Evaluación como Asunto , Glutatión/metabolismo , Hemoglobinas/metabolismo , Humanos , Masculino , Nariz/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Reproducibilidad de los Resultados , Medición de Riesgo , Sensibilidad y Especificidad , Factores de Tiempo , Distribución TisularRESUMEN
Styrene (ST) is an important industrial chemical. In long-term inhalation studies, ST-induced lung tumors in mice but not in rats. To test the hypothesis that the lung burden by the reactive metabolite styrene-7,8-oxide (SO) would be most relevant for the species-specific tumorigenicity, we investigated the SO burden in isolated lungs of male Sprague-Dawley rats and in-situ prepared lungs of male B6C3F1 mice ventilated with air containing vaporous ST and perfused with a modified Krebs-Henseleit buffer (37 degrees C). Styrene vapor concentrations were determined in air samples collected in the immediate vicinity of the trachea. They were almost constant during each experiment. Styrene exposures ranged from 50 to 980 ppm (rats) and from 40 to 410 ppm (mice). SO was quantified from the effluent perfusate. Lungs of both species metabolized ST to SO. After a mathematical translation of the ex-vivo data to ventilation and perfusion conditions as they are occurring in vivo, a species comparison was carried out. At ST concentrations of up to 410 ppm, mean SO levels in mouse lungs ranged up to 0.45 nmol/g lung, about 2 times higher than in rat lungs at equal conditions of ST exposure. We conclude that the species difference in the SO lung burden is too small to consider the genotoxicity of SO as sufficient for explaining the fact that only mice developed lung tumors when exposed to ST. Another cause is considered as driving force for lung tumor development in the mouse.
Asunto(s)
Contaminantes Ocupacionales del Aire/farmacocinética , Compuestos Epoxi/farmacocinética , Pulmón/metabolismo , Estireno/farmacocinética , Administración por Inhalación , Contaminantes Ocupacionales del Aire/toxicidad , Animales , Relación Dosis-Respuesta a Droga , Residuos de Medicamentos , Compuestos Epoxi/toxicidad , Gases , Técnicas In Vitro , Exposición por Inhalación , Pulmón/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos , Perfusión , Ratas , Ratas Sprague-Dawley , Respiración Artificial , Estireno/toxicidadRESUMEN
To evaluate an adequate strategy for biological monitoring of aluminium (Al), a group of 62 Al welders (age in 1999: 23-51 years, median 35 years) was surveyed annually from 1999 to 2003 by determination of pre- and post-shift Al in urine and plasma. Biomonitoring was supplemented by personal air measurements of the total dust concentration. The welders' internal exposure was compared to the exposure of 60 non-exposed assembly workers (age in 1999: 21-51 years, median: 36 years) who were surveyed in 1999, 2001 and 2003. Having a nearly constant dust exposure, median concentrations of Al in urine (Al in plasma) of the welders decreased from 40.1 microg/g to 19.8 microg/g creatinine (8.7 to 4.6 microg/l). For the control group the median levels of Al in urine (plasma) ranged from 4.8 microg/g to 5.2 microg/g creatinine (2.4-4.3 microg/l) indicating a higher sensitivity for the marker Al in urine. No systematic differences have been found between pre- and post-shift internal exposure. This might be caused by the slow elimination kinetics and low systemic bioavailability of Al. A correlation analysis did not yield close relationships between dust exposure, Al in plasma and Al in urine underlining the importance of biomonitoring for assessment of Al exposure.
Asunto(s)
Contaminantes Ocupacionales del Aire/orina , Aluminio/orina , Exposición Profesional/análisis , Soldadura , Adulto , Contaminantes Ocupacionales del Aire/análisis , Contaminantes Ocupacionales del Aire/sangre , Aluminio/sangre , Polvo/análisis , Monitoreo del Ambiente , Humanos , Exposición por Inhalación/análisis , Persona de Mediana EdadRESUMEN
High concentrations of propylene oxide (PO) induced inflammation in the respiratory nasal mucosa (RNM) of rodents. Concentrations > or =300 ppm caused nasal tumors. In order to investigate if glutathione depletion could be relevant for these effects, we determined in PO exposed male Fischer 344/N rats PO in blood and soluble nonprotein SH-groups (NPSH) in RNM and other tissues. Rats were exposed once (6 h) to PO concentrations between 0 and 750 ppm, and repeatedly for up to 20 days (6 h, 5 days/week) to concentrations between 0 and 500 ppm. At the end of the exposures, PO in blood and NPSH in tissues were determined. PO in blood was dependent on concentration and duration of exposure. After the 1-day exposures, NPSH depletion was most distinctive (RNM > liver > lung). Compared to controls, NPSH levels were 43% at 50 ppm PO in RNM and 16% at > or =300 ppm in both RNM and liver. Lung NPSH fell linearly to 20% at 750 ppm. After repeated exposures over 3 and 20 days to 5, 25, 50, 300, and 500 ppm, NPSH losses were less pronounced. At both time points, NPSH were 90%, 70%, 50%, 30%, and 30% of the control values in RNM. Liver NPSH decreased to 80% and 50% at 300 and 500 ppm, respectively. After 20 days, lung NPSH declined to 70% (300 ppm) and 50% (500 ppm). We conclude that continuous, severe perturbation of GSH in RNM following repeated high PO exposures may lead to inflammatory lesions and cell proliferation, critical steps on the path towards tumorigenicity.
Asunto(s)
Compuestos Epoxi/sangre , Glutatión/metabolismo , Mucosa Nasal/metabolismo , Neoplasias Nasales/inducido químicamente , Compuestos de Sulfhidrilo/farmacocinética , Administración por Inhalación , Animales , Relación Dosis-Respuesta a Droga , Compuestos Epoxi/toxicidad , Masculino , Mucosa Nasal/efectos de los fármacos , Neoplasias Nasales/metabolismo , Ratas , Ratas Endogámicas F344 , Solubilidad , Factores de Tiempo , Distribución TisularRESUMEN
Concerns of a tumorigenic risk of styrene (ST) originate from the findings that styrene (ST) is metabolized to the genotoxic intermediate styrene-7,8-oxide (SO). Therefore, it was hypothesized that results of animal long-term studies with ST and SO together with the SO tissue burden are sufficient for conducting a 'worst case' estimate of the tumorigenic risk of ST. On this basis we predicted the excess human lifetime risk for lung tumors (p(EXL)) and the highest possible risk for other systemic tumors (p(HPS)) resulting from daily intake of ST via food and ambient air. As measures for p(EXL) the mean lifetime concentration of SO in the transitional zone of the lung and for p(HPS) the mean lifetime concentration of SO in blood were calculated using a physiological toxicokinetic model. For a daily oral intake of 12 microST, p(EXL) was obtained to be between 5x10(-9) and 2x10(-8) and p(HPS) to be between 7x10(-9) and 2x10(-8). Lifetime risks calculated for continuous exposure to 3 microg/m(3) ST in ambient air were between 8x10(-7) and 3x10(-6) (p(EXL)) and between 2x10(-8) and 4x10(-8) (p(HPS)). Although these values indicate very low risks, the actual risks are expected to be even by far smaller. This is discussed in detail for lung tumorigenesis.
Asunto(s)
Compuestos Epoxi/toxicidad , Contaminación de Alimentos , Neoplasias Pulmonares/inducido químicamente , Modelos Biológicos , Estireno/toxicidad , Adulto , Contaminantes Atmosféricos/efectos adversos , Animales , Relación Dosis-Respuesta a Droga , Compuestos Epoxi/farmacología , Humanos , Masculino , Ratones , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Medición de Riesgo , Estireno/farmacologíaRESUMEN
The industrial chemical 1,3-butadiene (BD) is a potent carcinogen in mice and a weak one in rats. This difference is generally related to species-specific burdens by the metabolites 1,2-epoxy-3-butene (EB), 1,2:3,4-diepoxybutane (DEB), and 3,4-epoxy-1,2-butanediol (EBD), which are all formed in the liver. Only limited data exist on BD metabolism in the rodent liver. Therefore, metabolism of BD, its epoxides, and the intermediate 3-butene-1,2-diol (B-diol) was studied in once-through perfused livers of male B6C3F1 mice and Sprague-Dawley rats. In BD perfusions, predominantly EB and B-diol were found (both species). DEB and EBD were additionally detected in mouse livers. Metabolism of BD showed saturation kinetics (both species). In EB perfusions, B-diol, EBD, and DEB were formed with B-diol being the major metabolite. Net formation of DEB was larger in mouse than in rat livers. In both species, hepatic clearance (Cl(H)) of EB was slightly smaller than the perfusion flow. In DEB perfusions, EBD was formed as a major metabolite. Cl(H) of DEB was 61% (mouse) and 73% (rat) of the perfusion flow. In the B-diol-perfused rat liver, EBD was formed as a minor metabolite. Cl(H) of B-diol was 53% (mouse) and 34% (rat) of the perfusion flow. In EBD-perfused rat livers, Cl(H) of EBD represented only 22% of the perfusion flow. There is evidence for qualitative species differences with regard to the enzymes involved in BD metabolism. The first quantitative findings in whole livers showing intrahepatic first-pass metabolism of BD and EB metabolites will improve the risk estimation of BD.
Asunto(s)
Butadienos/farmacocinética , Carcinógenos/farmacocinética , Hígado/metabolismo , Animales , Masculino , Redes y Vías Metabólicas , Ratones , Perfusión , Ratas , Ratas Sprague-Dawley , Pruebas de ToxicidadRESUMEN
Propylene (PE) was not carcinogenic in long-term studies in rodents. However, its biotransformation to propylene oxide (PO) raises questions about a carcinogenic risk. PO alkylates macromolecules, is a direct mutagen, and caused tumors in rodents at high concentrations. In order to acquire knowledge on the species-specific PO concentrations in blood resulting from PE exposure, we exposed male Fischer 344/N rats in closed exposure chambers to constant PE concentrations, between 20.1 and 3000 ppm (7 h at least), and four male volunteers to mean constant PE concentrations of 9.82 and 23.4 ppm (180 min) in inhaled air. In the animal experiments, PE and PO were measured in the chamber atmosphere, PE by gas chromatography with flame ionization detection (GC/FID), PO by GC/FID or GC with mass-selective detection (GC/MSD). In the human studies, PE was measured in inhaled and exhaled air by GC/FID. PO was quantified by GC/MSD from exhaled breath collected in gasbags. Blood concentrations of PO were calculated based on the measured PO concentrations in air using the blood-to-air partition coefficients of 60 (rat) and 66 (human). In rats, PO blood concentrations ranged from 53 nmol/l at 20.1 ppm PE to 1750 nmol/l at 3000 ppm PE. In humans, mean blood concentrations of PO were 0.44 and 0.92 nmol/l at mean PE concentrations of 9.82 and 23.4 ppm, respectively. These findings should be taken into consideration when estimating the carcinogenic risk of PE to humans based on carcinogenicity studies in PE- or PO-exposed rats.
Asunto(s)
Alquenos/farmacocinética , Carcinógenos/metabolismo , Compuestos Epoxi/sangre , Administración por Inhalación , Adulto , Alquenos/análisis , Animales , Biotransformación , Pruebas Respiratorias , Cromatografía de Gases , Relación Dosis-Respuesta a Droga , Humanos , Exposición por Inhalación , Masculino , Persona de Mediana Edad , Ratas , Ratas Endogámicas F344 , Medición de Riesgo , Especificidad de la EspecieRESUMEN
The "Tuebingen desiccator," a gas-tight all-glass closed chamber system (CCS), has been established in Herbert Remmer's Institute of Toxicology, University of Tuebingen, to investigate the mechanisms underlying the exhalation of endogenous volatile hydrocarbons in rats under oxidative stress. Remmer and associates confirmed the former view that ethane and n-pentane were derived from polyunsaturated fatty acids, and they demonstrated that propane, n-butane and isobutane were released from amino acids. Hydrocarbons exhaled following acute ethanol treatment of rats resulted predominantly from ethanol-dependent inhibition of their metabolism and partly from oxidation of proteins. Exhalation of alkanes in carbon tetrachloride exposed rats did not reflect liver damage, which was, however, directly linked to the amount of carbon tetrachloride metabolized. As has first been shown in Herbert Remmer's institute by investigating the fate of inhaled vinyl chloride in rats, the CSS proved to be also an excellent tool for studying toxicokinetics of inhaled gaseous xenobiotics by means of gas uptake experiments. Based on results gained by such studies, it was recently demonstrated that knowledge of compound-specific physicochemical and species-specific physiological parameters are often sufficient to predict important toxicokinetic properties of inhaled chemicals such as tissue burdens at steady state. By means of the CCS, not only kinetics of a parent gaseous substance but also of gaseous metabolites can be investigated in vivo, as exemplified for ethylene oxide and 1, 2-epoxy-3-butene, metabolites of ethylene and 1,3-butadiene, respectively. Gas uptake studies in closed chamber systems are now worldwide used for determining toxicokinetic parameters relevant for physiological toxicokinetic modeling.
Asunto(s)
Desecación/métodos , Exposición por Inhalación , Exposición por Inhalación/historia , Estrés Oxidativo/fisiología , Animales , Desecación/instrumentación , Alemania , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Exposición por Inhalación/efectos adversos , FarmacocinéticaRESUMEN
Bisphenol A is a widely used industrial chemical with many potential sources of human exposure. Bisphenol A is a weak estrogen and has been implicated as an "endocrine disruptor". This term is used for a variety of chemicals encountered in the environment which have estrogenic activity. It has been postulated that human exposure to these chemicals may elicit unwanted estrogenic effects in humans such as reduced fertility, altered development and cancer. Up to now the body burden of bisphenol A in humans is unknown. Therefore, we investigated the metabolism and toxicokinetics of bisphenol A in humans exposed to low doses since systemic bioavailability has a major influence on possible estrogenic effects in vivo. Human subjects (three males and three females, and four males for detailed description of blood kinetics) were administered d(16)-bisphenol A (5 mg). Blood and urine samples were taken in intervals (up to 96 h), metabolites formed were identified by GC/MS and LC-MS/MS and quantified by GC/MS-NCI and LC-MS/MS. d(16)-Bisphenol A glucuronide was the only metabolite of d(16)-bisphenol A detected in urine and blood samples, and concentrations of free d(16)-bisphenol A were below the limit of detection both in urine (6 nM) and blood samples (10 nM). d(16)-Bisphenol A glucuronide was cleared from human blood and excreted with urine with terminal half-lives of less than 6 h; the applied doses were completely recovered in urine as d(16)-bisphenol A glucuronide. Maximum blood levels of d(16)-bisphenol A glucuronide (approximately 800 nM) were measured 80 min after oral administration of d(16)-bisphenol A (5 mg). The obtained data indicate major species differences in the disposition of bisphenol A. Enterohepatic circulation of bisphenol A glucuronide in rats results in a slow rate of excretion, whereas bisphenol A is rapidly conjugated and excreted by humans due to the absence of enterohepatic circulation. The efficient glucuronidation of bisphenol A and the rapid excretion of the formed glucuronide result in a low body burden of the estrogenic bisphenol A in humans following oral absorption of low doses.
Asunto(s)
Estrógenos no Esteroides/metabolismo , Estrógenos no Esteroides/farmacocinética , Fenoles/metabolismo , Fenoles/farmacocinética , Administración Oral , Adulto , Compuestos de Bencidrilo , Disponibilidad Biológica , Carga Corporal (Radioterapia) , Estrógenos no Esteroides/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenoles/administración & dosificaciónRESUMEN
A comparison of the dose-dependent blood burden of di(2-ethylhexyl) phthalate (DEHP) and mono(2-ethylhexyl) phthalate (MEHP) in pregnant and nonpregnant rats and marmosets is presented. Sprague-Dawley rats and marmosets were treated orally with 30 or 500 mg DEHP/kg per day, nonpregnant animals on 7 (rats) and 29 (marmosets) consecutive days, pregnant animals on gestation days 14-19 (rats) and 96-124 (marmosets). In addition, rats received a single dose of 1000 mg DEHP/kg. Blood was collected up to 48 h after dosing. Concentrations of DEHP and MEHP in blood were determined by GC/MS. In rats, normalized areas under the concentration-time curves (AUCs) of DEHP were two orders of magnitude smaller than the normalized AUCs of the first metabolite MEHP. Metabolism of MEHP was saturable. Repeated DEHP treatment and pregnancy had only little influence on the normalized AUC of MEHP. In marmosets, most of MEHP concentration-time courses oscillated. Normalized AUCs of DEHP were at least one order of magnitude smaller than those of MEHP. In pregnant marmosets, normalized AUCs of MEHP were similar to those in nonpregnant animals with the exception that at 500 mg DEHP/kg per day, the normalized AUCs determined on gestation days 103, 117, and 124 were distinctly smaller. The maximum concentrations of MEHP in blood of marmosets were up to 7.5 times and the normalized AUCs up to 16 times lower than in rats receiving the same daily oral DEHP dose per kilogram of body weight. From this toxicokinetic comparison, DEHP can be expected to be several times less effective in the offspring of marmosets than in that of rats if the blood burden by MEHP in dams can be regarded as a dose surrogate for the MEHP burden in their fetuses.
Asunto(s)
Dietilhexil Ftalato/análogos & derivados , Dietilhexil Ftalato/sangre , Dietilhexil Ftalato/metabolismo , Administración Oral , Animales , Área Bajo la Curva , Carga Corporal (Radioterapia) , Callithrix , Relación Dosis-Respuesta a Droga , Femenino , Sangre Fetal , Embarazo , Efectos Tardíos de la Exposición Prenatal , Ratas , Ratas Sprague-Dawley , Especificidad de la Especie , Factores de TiempoRESUMEN
Two male volunteers (A and B) inhaled 1.43 and 1.34 mmol, respectively, of vaporous (13)C-labeled ethylene glycol ((13)C(2)-EG) over 4 h. In plasma, (13)C(2)-EG and its metabolite (13)C(2)-glycolic acid ((13)C(2)-GA) were determined together with the natural burden from background GA using a gas chromatograph equipped with a mass selective detector. Maximum plasma concentrations of (13)C(2)-EG were 11.0 and 15.8 micromol/l, and of (13)C(2)-GA were 0.9 and 1.8 micromol/l, for volunteers A and B, respectively. Corresponding plasma half-lives were 2.1 and 2.6 h for (13)C(2)-EG, and 2.9 and 2.6 h for (13)C(2)-GA. Background GA concentrations were 25.8 and 28.3 micro mol/l plasma. Unlabeled background EG, GA and oxalic acid (OA) were detected in urine in which the corresponding (13)C-labeled compounds were also quantified. Within 28 h after the start of the exposures, 6.4% and 9.3% (13)C(2)-EG, 0.70% and 0.92% (13)C(2)-GA, as well as 0.08% and 0.28% (13)C(2)-OA of the inhaled amounts of (13)C(2)-EG, were excreted in urine by volunteers A and B, respectively. The amounts of (13)C(2)-GA represented 3.7% and 14.2% of background urinary GA excreted over 24 h (274 and 88 micromol). The amounts of (13)C(2)-OA were 0.5% and 2.1% of background urinary OA excreted over 24 h (215 and 177 micromol). From the findings obtained in plasma and urine and from a toxicokinetic analysis of these data, it is highly unlikely that workplace EG exposure according to the German exposure limit (MAK-value 10 ppm EG, 8 h) could lead to adverse effects from the metabolically formed GA and OA.
Asunto(s)
Contaminantes Ambientales/toxicidad , Glicol de Etileno/toxicidad , Administración por Inhalación , Adulto , Cromatografía de Gases , Relación Dosis-Respuesta a Droga , Contaminantes Ambientales/sangre , Contaminantes Ambientales/orina , Glicol de Etileno/sangre , Glicol de Etileno/orina , Glicolatos/sangre , Glicolatos/orina , Semivida , Humanos , Masculino , Persona de Mediana Edad , Ácido Oxálico/sangre , Ácido Oxálico/orina , Factores de TiempoRESUMEN
The main purpose of the study was to establish the relation between exposure dose of propylene oxide (PO) and dose in various tissues of male F344 rats exposed to the compound by inhalation. The animals were exposed to 0, 5, 25, 50, 300, or 500 ppm PO in the air for 3 days (6 h/day) or 4 weeks (6 h/day, 5 days/week). Blood, nasal respiratory epithelium, lung, and liver were collected. 2-Hydroxypropylvaline (HPVal) in hemoglobin was quantified using the N-alkyl Edman method and gas chromatography/tandem mass spectrometry. 7-(2-Hydroxypropyl)guanine (7-HPG) in DNA was quantified using (32)P postlabeling. The levels of 7-HPG in DNA of nasal respiratory epithelium and lung increased linearly with concentration as measured both after 3 days and 4 weeks of exposure. Similarly, 7-HPG in liver DNA and HPVal in hemoglobin showed a linear increase with PO concentration in the 3-day exposure group, whereas a deviation from linearity was observed above 300 ppm in the 4-week exposure group. The new results confirm previous observations of a dose difference between tissues with the highest dose present in the nasal respiratory epithelium. The measured adduct levels were used for calculation of adduct increments and corresponding tissue doses per unit of external exposure dose. For this purpose, the buildup of adducts was modeled considering the different kinetics of formation and elimination of adducts with DNA and hemoglobin, respectively, and also considering the increasing body weight of the animals. The half-life of 7-HPG in vivo, as well as tissue doses, could be solved from DNA adduct data at the 3rd and 26th days. Within the range of concentrations where the dose-response curves for adduct formation are linear, the relationship between exposure dose and resulting tissue doses could be based equally well on adduct data from the short-term exposure as on adduct data from the prolonged exposure.