A physiologically based toxicokinetic model for inhaled ethylene and ethylene oxide in mouse, rat, and human.

Ethylene (ET) is the largest volume organic chemical. Mammals metabolize the olefin to ethylene oxide (EO), another important industrial chemical. The epoxide alkylates macromolecules and has mutagenic and carcinogenic properties.

An evaluation of concentrations of styrene-7,8-oxide in rats and humans resulting from exposure to styrene or styrene-7,8-oxide and potential genotoxicity.

There is potential for oral exposure of humans to styrene (ST) such as from migration of residual levels in polystyrene food containers. After absorption, ST is metabolised to styrene-7,8-oxide (SO), an alkylating epoxide. Hence, a comparison of blood burdens of SO resulting from oral exposures to ST was made with SO burdens possibly warranting genotoxic concern.

Novel and existing data for a future physiological toxicokinetic model of ethylene and its metabolite ethylene oxide in mouse, rat, and human.

The olefin ethylene is a ubiquitously found gas. It originates predominantly from plants, combustion processes and industrial sources. In mammals, inhaled ethylene is metabolized by cytochrome P450-dependent monooxygenases, particularly by cytochrome P450 2E1, to ethylene oxide, an epoxide that directly alkylates proteins and DNA.

Ethylene oxide in blood of ethylene-exposed B6C3F1 mice, Fischer 344 rats, and humans.

The gaseous olefin ethylene (ET) is metabolized in mammals to the carcinogenic epoxide ethylene oxide (EO). Although ET is the largest volume organic chemical worldwide, the EO burden in ET-exposed humans is still uncertain, and only limited data are available on the EO burden in ET-exposed rodents. Therefore, EO was quantified in blood of mice, rats, or 4 volunteers that were exposed once to constant atmospheric ET concentrations of between 1 and 10 000 ppm (rodents) or 5 and 50 ppm (humans).

Kinetics of di(2-ethylhexyl) phthalate (DEHP) and mono(2-ethylhexyl) phthalate in blood and of DEHP metabolites in urine of male volunteers after single ingestion of ring-deuterated DEHP.

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)).

1,2:3,4-Diepoxybutane in blood of male B6C3F1 mice and male Sprague-Dawley rats exposed to 1,3-butadiene.

The important industrial chemical 1,3-butadiene (BD; CAS Registry Number: 106-99-0) is a potent carcinogen in B6C3F1 mice and a weak one in Sprague-Dawley rats. This difference is mainly attributed to the species-specific burden by the metabolically formed 1,2:3,4-diepoxybutane (DEB). However, only limited data exist on the DEB blood burden of rodents at BD concentrations below 100 ppm.

Analysis of carcinogenic polycyclic aromatic hydrocarbons in complex environmental mixtures by LC-APPI-MS/MS.

Here we developed a highly sensitive, fast and reliable liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the detection and analysis of 16 different polycyclic aromatic hydrocarbons (PAHs) and nitro-PAHs that have been identified as carcinogens and classified according to their biological potency. Comparison to standard analysis procedures based on gas chromatography-mass spectrometry (GC-MS) instrumentation demonstrated an improved easiness of sample preparation and sensitivity of detection achieved with the new LC-MS/MS method employing an atmospheric pressure photoionization (APPI) source attached to an API 4000 mass spectrometer (LC-APPI-MS/MS). The favorable outcome could be confirmed by analyzing complex mixtures such as certain Standard Reference Materials (SRMs) obtained from the National Institute of Standards & Technology (NIST), i.

Kinetics of ethylene and ethylene oxide in subcellular fractions of lungs and livers of male B6C3F1 mice and male fischer 344 rats and of human livers.

Ethylene (ET) is metabolized in mammals to the carcinogenic ethylene oxide (EO). Although both gases are of high industrial relevance, only limited data exist on the toxicokinetics of ET in mice and of EO in humans. Metabolism of ET is related to cytochrome P450-dependent mono-oxygenase (CYP) and of EO to epoxide hydrolase (EH) and glutathione S-transferase (GST).

Trichloroacetic acid in urine as biological exposure equivalent for low exposure concentrations of trichloroethene.

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.

Quantitative investigation on the metabolism of 1,3-butadiene and of its oxidized metabolites in once-through perfused livers of mice and rats.

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.

Derivation of inhalation toxicity reference values for propylene oxide using mode of action analysis: example of a threshold carcinogen.

Propylene oxide (PO) is an important industrial chemical used primarily in the synthesis of other compounds. Inhalation carcinogenesis studies in rodents, with no-observed-adverse-effect levels (NOAELs) of 100 and 200 ppm, have revealed that chronic, high exposure to PO can induce tumors at the site of contact. Despite these characteristics, there is no evidence that typical environmental or occupational exposures to PO constitute a health risk for humans.

Is propylene oxide induced cell proliferation in rat nasal respiratory epithelium mediated by a severe depletion of water-soluble non-protein thiol?

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).

Inhalation and epidermal exposure of volunteers to ethylene glycol: kinetics of absorption, urinary excretion, and metabolism to glycolate and oxalate.

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.

Suppression of peroxisomal enzyme activities and cytochrome P450 4A isozyme expression by congeneric polybrominated and polychlorinated biphenyls.

The purpose of this study was to determine the effects of PCBs and PBBs on peroxisome proliferator-activated receptor-alpha-(PPARalpha-) associated enzyme activities or protein levels. Male Sprague-Dawley rats were administered a single IP injection (150 mu mol/kg) of either 3,3',4,4'-tetrabromobiphenyl, 3,3',4,4'-tetrachlorobiphenyl, 3,3',5,5'-tetrabromobiphenyl, 2',3,3',4,5-pentachlorobiphenyl, 3,3',4,4',5-pentachlorobiphenyl, 2,2',3,3',5,5'-hexachlorobiphenyl, or 3,3',4,4',5,5'-hexabromobiphenyl in corn oil (10 ml/kg). One week later, the activities of catalase, peroxisomal fatty acyl-CoA oxidase, and peroxisomal beta-oxidation as well as cytochrome P450 4A (CYP4A) protein content were determined in subcellular liver fractions.

Concentrations of the propylene metabolite propylene oxide in blood of propylene-exposed rats and humans--a basis for risk assessment.

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.

A physiological toxicokinetic model for inhaled propylene oxide in rat and human with special emphasis on the nose.

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.

Metabolism of 1,3-butadiene to toxicologically relevant metabolites in single-exposed mice and rats.

1,3-Butadiene (BD) was carcinogenic in rodents. This effect is related to reactive metabolites such as 1,2-epoxy-3-butene (EB) and especially 1,2:3,4-diepoxybutane (DEB). A third mutagenic epoxide, 3,4-epoxy-1,2-butanediol (EBD), can be formed from DEB and from 3-butene-1,2-diol (B-diol), the hydrolysis product of EB.

Styrene-7,8-oxide burden in ventilated, perfused lungs of mice and rats exposed to vaporous styrene.

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).

Biological monitoring of welders exposed to aluminium.

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.

The "Tuebingen desiccator" system, a tool to study oxidative stress in vivo and inhalation toxicokinetics.

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.

Propylene oxide in blood and soluble nonprotein thiols in nasal mucosa and other tissues of male Fischer 344/N rats exposed to propylene oxide vapors--relevance of glutathione depletion for propylene oxide-induced rat nasal tumors.

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.

Blood burden of di(2-ethylhexyl) phthalate and its primary metabolite mono(2-ethylhexyl) phthalate in pregnant and nonpregnant rats and marmosets.

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.

Dosimetry by means of DNA and hemoglobin adducts in propylene oxide-exposed rats.

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.

Effects of propylene oxide exposure on rat nasal respiratory cell proliferation.

Long-term exposure of rodents to propylene oxide (PO) induced inflammation, respiratory cell hyperplasia, and nasal tumors at concentrations >/= 300 ppm, suggesting a possible role for cytotoxicity and compensatory cell proliferation in PO carcinogenesis. In this study, the effects of PO exposure on histopathology and cell proliferation in nasal and hepatic tissues were studied in male F344 rats exposed by inhalation for 3 or 20 days (0, 5, 25, 50, 300, and 500 ppm). Histopathology revealed an increase in mucous cell hyperplasia in the anterior nasal passages after 20 days of exposure (>/=300 ppm).

Human inhalation exposure to ethylene glycol.

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.