[Experimental studies of trichloroethylene toxicity. II. Changes in trichloroethylene metabolites in blood serum and in urine during and after exposure to trichloroethylene].
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[Studies of trichloroethylene-induced glycosuria: blood glucose and renal glucose reabsorption in rats exposed to trichloroethylene].
In our previous experiments, a remarkable increase in urinary excretion of glucose was found in rats exposed to 821 ppm trichloroethylene for 12 wk. This was not accompanied with proteinuria, aminoaciduria, phosphaturia and definite histological changes in renal tubular structure. In order to ascertain the mechanism of the increase in urinary glucose excretion, blood glucose level and renal glucose reabsorption were studied in 10 male rats exposed to 783 ppm trichloroethylene for more than 3 wk. Another 10 male rats were studied as control. The following results were obtained: 1. Urine glucose of the trichloroethylene group increased after exposure for 2 wk. All the rats showed glycosuria (above 250 mg/dl) by the 4th week of exposure. 2. Plasma glucose levels were depressed by trichloroethylene to as low as 77% of that of the control group. Glycohemoglobin was similarly decreased. 3. Intravenous glucose tolerance tests (0.5 g/kg load) revealed that decreasing constant of plasma glucose (K value) was elevated by trichloroethylene, suggesting that induced hyperglycemia in the exposed rats improved more rapidly than in the controls. Trichloroethylene did not modify the secretion of insulin after glucose load, regardless of the depression in plasma insulin level before load. 4. Glucose titration tests revealed that tubular transport maximum for glucose (TmG) was decreased by trichloroethylene to as low as 46% of that of the control group. The ratio of TmG to glomerular filtration rate (the theoretical renal threshold for glucose) was also depressed to as low as 55% of that of the control group. The foregoing results indicate that trichloroethylene-induced glycosuria is attributable to deteriorated tubular reabsorption of glucose, and not to hyperglycemia. However, the mechanism for the selective disturbance of renal reabsorption of glucose is yet unknown.
Animals↗
Acute trichloroethylene poisoning with additional ingestion of ethanol--concentrations of trichloroethylene and its metabolites during hyperventilation therapy.
One hour after suicidal ingestion of about 150 g of trichloroethylene, a 32-year-old male was admitted to hospital. On admission, the patient's state of consciousness deteriorated from somnolence to coma. Based on blood level data, an absorbed trichloroethylene dose of at least 35 g was estimated. Additionally, ethanol, which is a strong inhibitor of trichloroethylene metabolism, had been ingested. With respect to the high dose of trichloroethylene, hyperventilation therapy was performed for 28 h. Concentrations of trichloroethylene and its metabolites in blood and urine were determined by gas chromatography. Due to hyperventilation and inhibition of trichloroethylene metabolism, not more than 30% of the absorbed dose was metabolized and excreted via kidneys. Under normal respiratory conditions and in the absence of ethanol, this fraction amounts to about 75%. Obviously, hyperventilation and ethanol-induced inhibition of metabolism led to considerably enforced pulmonary elimination of the absorbed trichloroethylene.
Adult↗
Hepatotoxicity of trichloroethylene-carbon tetrachloride mixtures in rats. A possible consequence of the potentiation by trichloroethylene of carbon tetrachloride-induced lipid peroxidation and liver lesions.
Liver histology was normal 24 h after the administration of trichloroethylene (1 ml . kg-1) in rats. It was normal, or showed necrosis of a few hepatocytes, after the administration of carbon tetrachloride (64 microliters . kg-1). In rats receiving both solvents, there was extensive centrilobular necrosis. In vitro, trichloroethylene did not initiate lipid peroxidation but potentiated that initiated by carbon tetrachloride; a similar potentiating effect was observed for a wide range of trichloroethylene concentrations (0.19-12 mM). In vivo, a wide range of trichloroethylene doses (0.064-1 ml . kg-1) similarly potentiated the hepatotoxicity of carbon tetrachloride. Administration of trichloroethylene (1 ml . kg-1), 5 h earlier, increased carbon tetrachloride-induced lipid peroxidation in vitro, and increased the hepatotoxicity of a subsequent dose of carbon tetrachloride (64 microliters . kg-1). Previous administration of carbon tetrachloride failed to modify lipid peroxidation and to increase the hepatotoxicity of trichloroethylene. We conclude that trichloroethylene potentiates the hepatotoxicity of carbon tetrachloride, possibly by increasing carbon tetrachloride-induced lipid peroxidation.
Animals↗
Mutagenicity of trichloroethylene and its metabolites: implications for the risk assessment of trichloroethylene.
This article addresses the evidence that trichloroethylene (TCE) or its metabolites might mediate tumor formation via a mutagenic mode of action. We review and draw conclusions from the published mutagenicity and genotoxicity information for TCE and its metabolites, chloral hydrate (CH), dichloroacetic acid (DCA), trichloroacetic acid (TCA), trichloroethanol, S-(1, 2-dichlorovinyl)-l-cysteine (DCVC), and S-(1, 2-dichlorovinyl) glutathione (DCVG). The new U.S. Environmental Protection Agency proposed Cancer Risk Assessment Guidelines provide for an assessment of the key events involved in the development of specific tumors. Consistent with this thinking, we provide a new and general strategy for interpreting genotoxicity data that goes beyond a simple determination that the chemical is or is not genotoxic. For TCE, we conclude that the weight of the evidence argues that chemically induced mutation is unlikely to be a key event in the induction of human tumors that might be caused by TCE itself (as the parent compound) and its metabolites, CH, DCA, and TCA. This conclusion derives primarily from the fact that these chemicals require very high doses to be genotoxic. There is not enough information to draw any conclusions for trichloroethanol and the two trichloroethylene conjugates, DCVC and DCVG. There is some evidence that DCVC is a more potent mutagen than CH, DCA, or TCA. Unfortunately, definitive conclusions as to whether TCE will induce tumors in humans via a mutagenic mode of action cannot be drawn from the available information. More research, including the development and use of new techniques, is required before it is possible to make a definitive assessment as to whether chemically induced mutation is a key event in any human tumors resulting from exposure to TCE.
Animals↗
Mechanism of trichloroethylene-induced elevation of individual serum bile acids. I. Correlation of trichloroethylene concentrations to bile acids in rat serum.
The temporal relationship between trichloroethylene (TRI) and individual serum bile acids (SBA) has been investigated to gain insight into the mechanism of solvent-induced increases in SBA. Male Sprague-Dawley rats were treated with 1 mmol/kg TRI in corn oil, while control rats received only corn oil. Blood samples were collected from the abdominal aorta at 2, 4, 8, and 16 hr after dosing. Individual SBA were determined by high-performance liquid chromatography (HPLC). Liver and blood concentrations of TRI and one of its metabolites, trichloroethanol (TCEOH), were determined by gas chromatography. SBA levels reached their peak at 4 hr and returned to control levels by 16 hr. There was a relationship between SBA levels and TRI concentrations, which were also at their peak 4 hr after dosing. By 16 hr the levels were undetectable. However, peak blood concentrations of TCEOH were reached 8 hr after dosing, and remained high at 16 hr. Cholic acid and taurocholic acid showed the highest levels of bile acids. Some other bile acids were also elevated, including deoxycholic acid, taurodeoxycholic acid, ursodeoxycholic acid, chenodeoxycholic acid, and taurochenodeoxycholic acid. Determination of total bile acids in serum using an enzymatic/colorimetric method showed a similar pattern of response to that obtained with the HPLC analysis. The data are consistent with TRI having a rapid and specific effect on SBA levels by a mechanism other than liver cell damage.
Animals↗
Mechanism of trichloroethylene-induced elevation of individual serum bile acids. II. In vitro and in vivo interference by trichloroethylene with bile acid transport in isolated rat hepatocytes.
The effects of trichloroethylene (TRI) on bile acid transport in isolated rat hepatocytes have been studied using doses ranging from 0.5 to 4.0 microliters/flask and a 20-min equilibration period. It was found that TRI caused a dose-related suppression of initial rates of uptake of cholic acid (CA) and taurocholic acid (TC) with no significant effect on enzyme leakage and intracellular potassium ion contents. Accumulation over 30 min for each of those two bile acids was also inhibited. A noncompetitive inhibition of bile acid uptake was shown as indicated by a decrease in maximum velocity (Vmax) and unchanged Michaelis constant (Km). Thirty minutes after cessation of TRI exposure in vitro the uptake of bile acids had gradually returned to normal levels. No significant interference of efflux was found in cells preloaded with either CA or TC. After dosing rats with 1 mmol/kg TRI in vivo the inhibition of uptake of CA and TC by subsequently isolated hepatocytes was not detected until 4 hr. By 16 hr uptake had returned to normal. The accumulation of bile acids was also suppressed at 4 and 8 hr. The inhibition of uptake after in vivo treatment was also noncompetitive. The data are consistent with the reversible increase of serum bile acids (SBA) in experimental animals after exposure to TRI. Furthermore, they support the contention that it is an interference with bile acid uptake, rather than actual cell damage, that is responsible for TRI-induced increases in SBA. Thus, the changes in SBA seem to be the result of interference with a physiological process rather than an event associated with significant pathological consequences.
Animals↗
Metabolism of trichloroethylene in man. III. Interaction of trichloroethylene and ethanol.
Volunteers inhaled a constant concentration of 50 ppm trichloroethylene (Tri) for 6 hrs per day on 5 consecutive days. Simultaneous ethanol (EtOH) ingestion (blood level 0.6%) inhibits the metabolization of Tri to trichloroethanol (TCE) and trichloroacetic acid (TCA) by 40% on the average. Oxidation of Tri to TCA does not occur as long as EtOH is present. During this time period the blood Tri-concentration increases 2 1/2-fold, that in the expired air rising 4-fold, as compared to Tri inhalation without EtOH. TCE glucuronidation is not subject to inhibition. On concurrent inhalation of Tri, the EtOH and acetaldehyde levels are slightly increased over the control values without Tri. The mechanisms underlying the alternate inhibition of mixed-function oxygenases and aldehyde dehydrogenase on simultaneous intake of Tri and EtOH are discussed. The intolerance reaction occurring on combined exposure to Tri and EtOH can be interpreted as an accumulation of Tri in the CNS resulting from the complete depression of Tri oxidation.
Acetaldehyde↗
Oxidation of trichloroethylene by liver microsomal cytochrome P-450: evidence for chlorine migration in a transition state not involving trichloroethylene oxide.
Trichloroethylene (TCE) was metabolized by cytochrome P-450 containing mixed-function oxidase systems to chloral (2,2,2,-trichloroacetaldehyde), glyoxylic acid, formic acid, CO, and TCE oxide. TCE oxide was synthesized, and its breakdown products were analyzed. Under acidic aqueous conditions the primary products were glyoxylic acid and dichloracetic acid. The primary compounds formed under neutral or basic aqueous conditions were formic acid and CO. TCE oxide did not form chloral in any of these or other aqueous systems, even when iron salts, ferriprotoporphyrin IX, or purified cytochrome P-450 was present. Ferric iron salts catalyzed the rearrangement of TCE oxide to chloral only in CH2Cl2 or CH3CN. A 500-fold excess of iron was required for complete conversion. A kinetic model involving the zero-order oxidation of TCE to TCE oxide by cytochrome P-450 and the first-order degradation of the epoxide was used to test the hypothesis that TCE oxide is an obligate intermediate in the conversion of TCE to other metabolites. Kinetic constants fo the breakdown of TCE oxide and for the oxidative metabolism of TCE to stable metabolites were used to predict epoxide concentrations required to support the obligate intermediacy of TCE oxide. The maximum levels of TCE oxide detected in systems using microsomal fractions and purified cytochrome P-450 were 5-28-fold lower than those predicted from the model. The kinetic data and the discrepancies between the observed metabolites and TCE oxide breakdown products support the view that the epoxide is not an obligate intermediate in the formation of chloral, and an alternative model is presented in which chlorine migration occurs in an oxygenated TCE-cytochrome P-450 transition state.
Animals↗
Reaction of trichloroethylene and trichloroethylene oxide with cytochrome P450 enzymes: inactivation and sites of modification.
Trichloroethylene (TCE) has been shown to be toxic to experimental animals and humans. TCE oxide is a reactive electrophile formed during TCE oxidation and rearranges to acylating intermediates [Cai, H., and Guengerich, F. P. (1999) J. Am. Chem. Soc. 121, 11656-11663], which may be related to the toxicity. Mice treated with TCE have been reported to contain N(6)-dichloroacetylLys residues in P450 2E1, as detected by immunochemical methods. TCE can be oxidized by both P450 2E1 and (rat) 2B1. In this work, direct reaction of TCE oxide with either human P450 2E1, P450 2B1, or NADPH-P450 reductase was shown to lead to enzyme inactivation, and no recovery of the activity of either enzyme occurred, consistent with the view of inactivation reactions with Lys groups and not hydroxyls or Cys. Furthermore, Lys adducts were detected in the reaction of TCE oxide with both P450 2E1 and NADPH-P450 reductase, with a larger amount of N(6)-formylLys observed compared to N(6)-dichloroacetylLys in both cases. Inactivation of P450 2E1 during NADPH-dependent TCE oxidation was not observed, compared to control experiments. However, inactivation of P450 2B1 during NADPH-dependent TCE oxidation was detected. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry of tryptic peptides indicated that the direct reaction of TCE oxide with human P450 2E1 resulted in the modification of peptides containing Lys87 (AVKEALLDYK), Lys251 (VKEHHQSLDPNCPR), and Lys487 (YKLCVIPR), with either a formyl or dichloroacetyl group attached. Lys87 and Lys487 of human P450 2E1 appear to be modified during the oxidation of TCE, using the same approach. The results are considered in the context of comparison of species and P450s.
Amino Acid Sequence↗
Identification of trichloroethylene and its metabolites in human seminal fluid of workers exposed to trichloroethylene.
We have investigated the potential of the male reproductive tract to accumulate trichloroethylene (TCE) and its metabolites, including chloral, trichloroethanol (TCOH), trichloroacetic acid (TCA), and dichloroacetic acid (DCA). Human seminal fluid and urine samples from eight mechanics diagnosed with clinical infertility and exposed to TCE occupationally were analyzed. In in vivo experimental studies, TCE and its metabolites were determined in epididymis and testis of mice exposed to TCE (1000 ppm) by inhalation for 1 to 4 weeks. In other studies, incubations of monkey epididymal microsomes were performed in the presence of TCE and NADPH. Our results showed that seminal fluid from all eight subjects contained TCE, chloral, and TCOH. DCA was present in samples from two subjects, and only one contained TCA. TCA and/or TCOH were also identified in urine samples from only two subjects. TCE, chloral, and TCOH were detected in murine epididymis after inhalation exposure with TCE for 1 to 4 weeks. Levels of TCE and chloral were similar throughout the entire exposure period. TCOH levels were similar at 1 and 2 weeks but increased significantly after 4 weeks of TCE exposure. Chloral was identified in microsomal incubations with TCE in monkey epididymis. CYP2E1, a P450 that metabolizes TCE, was localized in human and monkey epididymal epithelium and testicular Leydig cells. These results indicated that TCE is metabolized in the reproductive tract of the mouse and monkey. Furthermore, TCE and its metabolites accumulated in seminal fluid, and suggested associations between production of TCE metabolites, reproductive toxicity, and impaired fertility.
Adult↗
Influence of endogenous and exogenous electron donors and trichloroethylene oxidation toxicity on trichloroethylene oxidation by methanotrophic cultures from a groundwater aquifer.
Trichloroethylene (TCE)-transforming aquifer methanotrophs were evaluated for the influence of TCE oxidation toxicity and the effect of reductant availability on TCE transformation rates during methane starvation. TCE oxidation at relatively low (6 mg liter-1) TCE concentrations significantly reduced subsequent methane utilization in mixed and pure cultures tested and reduced the number of viable cells in the pure culture Methylomonas sp. strain MM2 by an order of magnitude. Perchloroethylene, tested at the same concentration, had no effect on the cultures. Neither the TCE itself nor the aqueous intermediates were responsible for the toxic effect, and it is suggested that TCE oxidation toxicity may have resulted from reactive intermediates that attacked cellular macromolecules. During starvation, all methanotrophs tested exhibited a decline in TCE transformation rates, and this decline followed exponential decay. Formate, provided as an exogenous electron donor, increased TCE transformation rates in Methylomonas sp. strain MM2, but not in mixed culture MM1 or unidentified isolate, CSC-1. Mixed culture MM2 did not transform TCE after 15 h of starvation, but mixed cultures MM1 and MM3 did. The methanotrophs in mixed cultures MM1 and MM3, and the unidentified isolate CSC-1 that was isolated from mixed culture MM1 contained lipid inclusions, whereas the methanotrophs of mixed culture MM2 and Methylomonas sp. strain MM2 did not. It is proposed that lipid storage granules serve as an endogenous source of electrons for TCE oxidation during methane starvation.
Biotransformation↗
Trichloroethylene. I. Carcinogenicity of trichloroethylene.
Trichloroethylene (TCE) as an industrial pollutant may damage human health and can be considered as carcinogen. TCE has been detected in the environment and in various human organs, e.g., liver, kidney and brain etc. There are histological alterations such as depletion of glycogen and hydropic degeneration in the liver, however, other signs of TCE effects can be found in various organs as well. TCE and its metabolites, e.g., trichlorethanol, trichloro-acetic acid and epoxides were recently identified as strong mutagens in Ames mutagenicity test inducing frameshift and base-substitution mutations. TCE induced predominantly hepatocellular carcinoma after long term administration in mice. In these animals, kidneys and liver were supposed to be primary target organs with low epoxy-hydrolase activity. A high level of mitotic gene conversion (or gene rearrangement) was indicated by the metabolism of TCE after repeated administration. Purified TCE by was a weak mutagen in the presence of S9 microsomal fraction of rats and as a consequence, the carcinogenic activity was low in the kidney of rats. However, a dose related increase of Leydig cell tumors was found in male rats.
Animals↗
Trichloroethylene. II. Mechanism of carcinogenicity of trichloroethylene.
The cancer inducing effect of trichloroethylene (TCE) was studied by various methods. DNA complexing activity and apoptosis inhibition were found to be the key elements of the carcinogenicity of TCE and its metabolites. The ability of TCE to interact with DNA was low, but its incorporation into the RNA and DNA of the brain, testis, pancreas, kidney, liver, lung and spleen, cannot be excluded. Exposure to TCE and its metabolites provides a selective growth advantage to spontaneously occurring mutations in some K- and H-ras oncogenes (as non specific results of secondary DNA or RNA damage). The amount of DNA-TCE adducts was higher in mouse hepatocytes than in rat hepatocytes. These differences may explain the species difference in carcinogenicity of TCE, which was dose dependent (due to metabolism) in mice but independent in rats. The blood level kinetics of TCE confirmed the faster metabolic rate in mice, including peroxisome proliferation and induction in hepatocytes. Dichloroacetic- and trichloroacetic acid were found to be hepatic carcinogens in mice, and the specificity depends on peroxisome proliferation induction. Possibly, TCE and related compounds down regulated apoptosis in mouse liver, and the reduced ability to remove initiated cells by apoptosis could be responsible for liver cancer induction by TCE.
Animals↗
Trichloroethylene. III. Prediction of carcinogenicity of investigated compounds including trichloroethylene.
The mutagenicity and carcinogenic properties of trichloroethylene (TCE) derivatives, and their correlation with its molecular properties were analyzed. The observed cancer incidence was compared to the predicted, calculated incidence. The predictions were based on the rodent bioassay results and were consistent with human data. The electrophilic data of molecules of the Ke system provided evidence for 205 rodent carcinogens, where Ke correlated with energy of the lowest unoccupied molecular orbital. The majority of carcinogenic compounds were found to be electron acceptors with decreased lowest unoccupied molecular orbital (LUMO) energy, indicating the particular DNA-reactivity leading to mutations and abnormal cell division. Based on the mutagenic activity in Ames test, the affinity of target organs for mutagens and non mutagens were compared in 351 rodent carcinogens. Nearly 80% of carcinogens (mutagenic and non mutagenic ones) were positive in the mouse and rat, in at least one of the most frequent target organs, i.e. liver, lung, mammary gland, stomach, kidney, hematopoietic system, urinary bladder and vascular system. Several predictive methods have been developed over the last 5 years based on structure-activity relationship studies known as US National Toxicology Program. One of these programs, called "PROGOL" is widely used for the prediction of carcinogenesis for a wide variety of compounds, e.g., nitro aromatics and suramin analogs. This program provides a simple model for predictive carcinogenesis, despite of the fact that the very first steps of carcinogenesis are not fully understood yet.
Animals↗
Trichloroethylene does not cause trigeminal neuropathy.
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Blinking↗
ACUTE TRICHLOROETHYLENE NARCOSIS. ACCIDENT INVOLVING THE USE OF TRICHLOROETHYLENE IN A CONFINED SPACE.
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Accidents↗
Trichloroethylene exposure and trichloroethylene metabolites in urine and blood.
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Chromatography, Gas↗