Mechanisms of the Dose-Dependent Kinetics of Trichloroethylene: Oral Bolus Dosing of Rats

doi:10.1006/taap.2000.8892

Toxicology and Applied Pharmacology

Volume 164, Issue 1, 1 April 2000, Pages 55-64

https://doi.org/10.1006/taap.2000.8892 Get rights and content

Abstract

Trichloroethylene (TCE), a common contaminant of drinking water, is oxidized by high-affinity, low-capacity cytochrome P450 isozymes and subsequently converted to metabolites, some of which are carcinogenic in mice and rats. Although the initial oxidation step is known to be rate-limiting and saturable, the oral dosage-range over which saturation materializes is unclear. One objective of this study was to characterize the dose-dependency of gastrointestinal (GI) absorption of TCE and its kinetics over a wide range of oral bolus doses. A related objective was to investigate cause(s) of the apparent saturation kinetics observed. Cannulas were surgically implanted into a carotid artery and the stomach of male Sprague–Dawley rats. TCE was incorporated into a 5% aqueous Alkamuls emulsion and given in doses of 2 to 1200 mg/kg bw via the stomach tube. Serial blood samples were taken from the arterial cannula for up to 14 h postdosing and analyzed for TCE content by headspace gas chromatography. The rate of GI absorption of TCE diminished as the dosage increased. Pharmacokinetic analysis indicated that TCE was eliminated by capacity-limited hepatic metabolism, with incursion into nonlinear kinetics with bolus doses ≥8 to 16 mg/kg. Effects of p-nitrophenol, a competitive metabolic inhibitor, were manifest at a high, but not at a low TCE dose. Gavage bolus doses as high as 1200 mg/kg did not cause rapid elevation of serum enzyme levels, typical of the solvation of hepatocellular membranes observed after portal vein administration of TCE (Lee et al., Toxicol. Appl. Pharmacol. 163, 000–000, 2000). No evidence of cytochrome P4502E1 (CYP2E1) destruction was seen with oral doses up to 1000 mg/kg. Instead, CYP2E1 activity was induced as early as 1 h postdosing. Induction was maximal at 12 h, then returned toward controls during the next 12 h. Pretreatment with cycloheximide did not reduce CYP2E1 activity in rats given 432 or 1000 mg TCE/kg, suggesting that binding of TCE to CYP2E1 may stabilize the isozyme. Metabolic saturation, in concert with relatively slow GI absorption, are responsible for the prolonged elevation of blood TCE levels in rats given high TCE doses, while suicidal inactivation of CYP2E1 and hepatocellular injury apparently play little role.

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This results in a disproportionate increase in AUC and a longer t1/2 in both the po and gi groups receiving 50 mg/kg than in those given 10 mg/kg. Lee et al. (2000) report initial incursion into nonlinear TK in rats at bolus TCE doses ≥8 to 16 mg/kg. In contrast, male mice gavaged daily for 6 weeks were reported to exhibit linear metabolism of TCE up to 1600 mg/kg (Buben and O'Flaherty, 1985).
Trichloroethylene (TCE) and 1,1,1-trichloroethane (TRI) are frequent contaminants of drinking water and of groundwater at hazardous waste sites. There is relatively little information on the target organ deposition of TRI, despite its ingestion and common occurrence in humans. An important aim of the study was to delineate and contrast the toxicokinetics (TK) and bioavailability (F) of TRI and its well metabolized congener, TCE. Blood profiles were obtained from male Sprague-Dawley rats given aqueous emulsions of 6 or 48 mg TRI/kg and 10 or 50 mg TCE/kg as an oral bolus (po) or by gastric infusion (gi) over 2 h. TCE exhibited nonlinear TK, with a disproportionate increase in AUC and decrease in clearance and F with increase in dose. TRI exhibited linear TK. F did not vary significantly with TRI dose or dosage regimen. F values were substantially higher for TRI than for the respective TCE groups. TRI was distributed widely to tissues of rats gavaged with 6 mg TRI/kg, with accumulation in fat. This experiment yielded tissue uptake and elimination profiles and in vivo tissue:blood partition coefficients (PCs). Finally, additional rats were given 10 mg/kg of TCE and TRI po, ia and iv, so that first-pass hepatic (FP_h) and pulmonary (FP_p) elimination could be measured directly. Total and FP_h elimination of TCE exceeded that of TRI. TRI, with its higher air:blood PC, exhibited the higher FP_p. TCE and TRI, despite several common physical and chemical properties resulting in similar absorption and systemic distribution, displayed dissimilar dosage and dose rate effects on their TK.
Trichloroethylene-induced formic aciduria: Effect of dose, sex and strain of rat
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In our studies low doses of TCE would be completely absorbed and quite extensively metabolised over 24 h to TCA and TCE-O-glucuronide. Lee et al. (2000) used an emulsifying solvent to administer TCE which enables rapid absorption, while we used corn oil, as in the cancer bioassays, which tends to slow and prolong the extent of absorption. Our findings at low doses of TCE may have relevance to TCE heavily contaminated drinking water.
The industrial solvent trichloroethylene (TCE) has been reported to increase the excretion of formic acid in the urine of male Fischer 344 (F-344) rats following large oral doses. We have examined the dose–response relationship for formic aciduria in male and female Fischer 344 rats, the effect of some known metabolites of TCE and examined the response in male Wistar rats to help understand its relevance to renal toxicity. We report that doses of TCE as low as 8 mg/kg for 3 days to both male and female F344 rats produced formic aciduria. The formic aciduria was time-dependent being more marked after 3 doses compared to one dose in male F344 rats and to a lesser extent in female F344 rats. TCE administration to male Wistar rats produced less formic aciduria than in male F344 rats, indicating a strain difference in response. As TCE is primarily metabolised by cytochrome P450 2E1, Wistar rats were administered inducers of cytochrome P450 2E1 followed by TCE, this increased formic acid excretion to a concentration similar to that observed in male F344 rats, indicating a role for P450. Administration of the major metabolites of TCE, trichloroethanol and trichloroacetic acid to male F344 rats also produced a marked and sustained formic aciduria, while the metabolite of TCE formed via glutathione conjugation had no effect on formic acid excretion. The mechanism whereby this response occurs is currently not understood, but the formic acid excreted is not a metabolite of TCE, but appears to be due to interference with the metabolic utilisation of formate by a down stream metabolite of TCE. Over the three days of the studies no histopathological evidence of kidney toxicity was observed in F344 rats given TCE, indicating that the perturbation of formate metabolism does not lead to acute renal injury.
Characterizing uncertainty and population variability in the toxicokinetics of trichloroethylene and metabolites in mice, rats, and humans using an updated database, physiologically based pharmacokinetic (PBPK) model, and Bayesian approach
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We have developed a comprehensive, Bayesian, PBPK model-based analysis of the population toxicokinetics of trichloroethylene (TCE) and its metabolites in mice, rats, and humans, considering a wider range of physiological, chemical, in vitro, and in vivo data than any previously published analysis of TCE. The toxicokinetics of the “population average,” its population variability, and their uncertainties are characterized in an approach that strives to be maximally transparent and objective. Estimates of experimental variability and uncertainty were also included in this analysis. The experimental database was expanded to include virtually all available in vivo toxicokinetic data, which permitted, in rats and humans, the specification of separate datasets for model calibration and evaluation. The total combination of these approaches and PBPK analysis provides substantial support for the model predictions. In addition, we feel confident that the approach employed also yields an accurate characterization of the uncertainty in metabolic pathways for which available data were sparse or relatively indirect, such as GSH conjugation and respiratory tract metabolism. Key conclusions from the model predictions include the following: (1) as expected, TCE is substantially metabolized, primarily by oxidation at doses below saturation; (2) GSH conjugation and subsequent bioactivation in humans appear to be 10- to 100-fold greater than previously estimated; and (3) mice had the greatest rate of respiratory tract oxidative metabolism as compared to rats and humans. In a situation such as TCE in which there is large database of studies coupled with complex toxicokinetics, the Bayesian approach provides a systematic method of simultaneously estimating model parameters and characterizing their uncertainty and variability. However, care needs to be taken in its implementation to ensure biological consistency, transparency, and objectivity.
Trichloroethylene metabolism in the rat ovary reduces oocyte fertilizability
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Exposure to trichloroethylene (TCE, an environmental toxicant) reduced oocyte fertilizability in the rat. In vivo, TCE may be metabolized by cytochrome P450 dependent oxidation or glutathione conjugation in the liver or kidneys, respectively. Cytochrome P450 dependent oxidation is the higher affinity pathway. The primary isoform of cytochrome P450 to metabolize TCE in the liver, cytochrome P450 2E1, is present in the rodent ovary. Ovarian metabolism of TCE by the oxidative pathway and the production of reactive oxygen species (ROS) may occur given the presence of the metabolizing enzyme. The objectives of this study were to define the sensitive interval of oocyte growth to TCE exposure, and to determine if TCE exposure resulted in the formation of ovarian protein carbonyls, an indicator of oxidative damage. Rats were exposed to TCE in drinking water (0.45% TCE (v/v) in 3% Tween) or 3% Tween (vehicle control) during three 4–5 day intervals of oocyte development preceding ovulation. Oocytes from TCE-exposed females were less fertilizable compared with vehicle-control oocytes. Immunohistochemical labeling of ovaries and Western blotting of ovarian proteins demonstrated TCE treatment induced a greater incidence of protein carbonyls compared with vehicle controls. Protein carbonyl formation in the ovary is consistent with TCE metabolism by the cytochrome P450 pathway. Oxidative damage following ovarian TCE metabolism or the presence of TCE metabolites may contribute to reduced oocyte fertilizability. In summary, these results indicate maturing oocytes are susceptible to very short in vivo exposures to TCE.
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The diuretic activity of the stem-bark extracts of Steganotaenia araliacea (SbESa) and effects on urine electrolytes in rats was studied. Furthermore, a toxicological effect of the SbESa on several tissues was investigated. Groups of male Wister albino rats (170 ± 0.77 g) were employed. Four doses of 20 mg/kg body weight (b.w.), of SbESa (water, methanol, ethanol) and furosemide were administered intraperitoneally (IP). The control group received normal saline alone by oral administration.
The 24-h urine outputs per day (in ml) were: normal saline (1.57 ± 0.11); water extract (3.18 ± 0.24); methanol extract (3.22 ± 0.29); ethanol extract (3.62 ± 0.27) and furosemide (4.22 ± 0.23). The urine output among the extracts (water, methanol, ethanol) and the furosemide against the control was statistically significant, (P < 0.05), (P < 0.05), (P < 0.02), and (P < 0.01), respectively. The ethanol preparation gave the highest diuretic activity among the extracts. There was marked increase in K⁺ ion excretion (122 ± 7.3 mMol/l) in the ethanol extract as compared to control (95.8 ± 1.2 mMol/l) and furosemide (standard) (90.05 ± 0.1 mMol/l). The LD₅₀ of 1.75 g/kg body weight was observed and the histopathological examination reveals damage to vital organs.
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Trichloroethylene (TCE) is a common industrial chemical that has been heavily used as a metal degreaser and a solvent for the past 100 years. As a result of the extensive use and production of this compound, it has become prevalent in the environment, appearing at over 50% of the hazardous waste sites on the US EPA’s National Priorities List (NPL). TCE exposure has been linked to neurological dysfunction as well as to several types of cancer in animals. This paper describes the development and validation of a gas chromatography–mass spectrometry (GC–MS) method for the quantitation of trace levels of TCE in its target tissues (i.e. liver, kidney and lungs). The limit of quantitation (5 ng/ml) is substantially lower than currently published methods for the analysis of TCE in tissues. The % RSD and % Error for the assay falls within the acceptable range (<15% for middle and high QC points and <20% for low QC points), and the recovery is high from all tissues (>79%).

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Regular ArticleMechanisms of the Dose-Dependent Kinetics of Trichloroethylene: Oral Bolus Dosing of Rats

Abstract

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

J. Biol. Chem.

Arch. Biochem. Biophys.

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J. Biol. Chem.

J. Biol. Chem.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

J. Biol. Chem.

Toxicol. Appl. Pharmacol.

Chem.–Biol. Interact.

Chloroethylene mixtures: Pharmacokinetic modeling and in vitro metabolism of vinyl chloride, trichloroethylene, and trans-1,2-dichloroethylene in the rat

Toxicol. Appl. Pharmacol.

Acid phosphatase

Regular Article
Mechanisms of the Dose-Dependent Kinetics of Trichloroethylene: Oral Bolus Dosing of Rats