In vivo effects of naproxen, salicylic acid, and valproic acid on the pharmacokinetics of trichloroethylene and metabolites in rats.

It was recently demonstrated that some drugs modulate in vitro metabolism of trichloroethylene (TCE) in humans and rats. The objective was to assess in vivo interactions between TCE and three drugs: naproxen (NA), valproic acid (VA), and salicylic acid (SA). Animals were exposed to TCE by inhalation (50 ppm for 6 h) and administered a bolus dose of drug by gavage, equivalent to 10-fold greater than the recommended daily dose. Samples of blood, urine, and collected tissues were analyzed by headspace gas chromatography coupled to an electron capture detector for TCE and metabolites (trichloroethanol [TCOH] and trichloroacetate [TCA]) levels. Coexposure to NA and TCE significantly increased (up to 50%) total and free TCOH (TCOHtotal and TCOHfree, respectively) in blood. This modulation may be explained by an inhibition of glucuronidation. VA significantly elevated TCE levels in blood (up to 50%) with a marked effect on TCOHtotal excretion in urine but not in blood. In contrast, SA produced an increase in TCOHtotal levels in blood at 30, 60, and 90 min and urine after coexposure. Data confirm in vitro observations that NA, VA, and SA affect in vivo TCE kinetics. Future efforts need to be directed to evaluate whether populations chronically medicated with the considered drugs display greater health risks related to TCE exposure.

[To the question of the optimization of methods for detection of vinyl chloride and 1,2-dichloroethane, and their metabolites in biological fluids in workers involved in production of polyvinyl chloride].

There is considered the improvement of methodological approaches to the gas chromatographic methods- of the detection of vinyl chloride and 1,2-dichloroethane and their metabolites--chloroethanol and monochloroacetic acid in biological fluids. There were evaluated such metrological characteristics of methods, as repeatability, interlaboratoty precision, relevance and accuracy. The value of relative expanded uncertainty does not exceed 30%. There are reported optimal regimes of gas chromatographic analysis, conditions for sample preparation. The results of the contents ofthese chemical compounds and their metabolites in biological fluids from persons working in contact with chlorinated hydrocarbons are presented These techniques can be used for the detection ofthe fact of exposure to toxic substances, assessment of the level of exposure and biomonitoring.

Urinary biomarkers of exposure to glycol ethers and chlorinated solvents during pregnancy: determinants of exposure and comparison with indirect methods of exposure assessment.

OBJECTIVES: To describe urine levels of metabolites of glycol ethers and chlorinated solvents in a sample of pregnant women from the general population, to study their occupational and non-occupational determinants and to compare them with the results of indirect assessment methods of solvent exposure. METHODS: A sample of 451 pregnant women was randomly selected from a general population cohort. At inclusion, the women in this sample completed a self-administered questionnaire about their social and medical characteristics, occupation and exposure to different products at work and in non-occupational activities. Occupational exposure to solvents was assessed from the woman's self-report and from a job-exposure matrix. Eight alkoxycarboxylic acids and trichloroacetic acid and trichloroethanol were measured with chromatography in urine samples collected at inclusion. Associations between metabolite levels and job titles, exposure to products used at work, and solvent exposure were studied. RESULTS: The different glycol ether metabolites were detected in 5.3%-96.4% of the urine samples, trichloroacetic acid in 6.4% and trichloroethanol in 5.5%. Nurses had butoxyacetic acid and phenoxyacetic acid in their urine most often, whereas methoxyethoxyacetic acid was the most frequent among nursing aides. Among cleaners, ethoxyacetic acid and ethoxyethoxyacetic acid were the most frequent. The occupation of hairdresser was associated with urinary excretion of ethoxyacetic acid, ethoxyethoxyacetic acid, butoxyacetic acid and phenoxyacetic acid. Among the women classified as exposed to solvents, the agents identified most often were ethoxyacetic acid, ethoxy-ethoxyacetic acid, butoxyacetic acid, phenoxyacetic acid, trichloroacetic acid and trichloroethanol. Ethoxyethoxyacetic acid was the only metabolite associated with non-occupational exposure. CONCLUSIONS: Metabolites of glycol ethers and chlorinated solvents were present at low levels in the urine of pregnant women. Most metabolites were associated with occupational exposure.

Kinetics of chloral hydrate and its metabolites in male human volunteers.

Chloral hydrate (CH) is a short-lived intermediate in the metabolism of trichloroethylene (TRI). TRI, CH, and two common metabolites, trichloroacetic acid (TCA) and dichloroacetic acid (DCA) have been shown to be hepatocarcinogenic in mice. To better understand the pharmacokinetics of these metabolites of TRI in humans, eight male volunteers, aged 24-39, were administered single doses of 500 or 1,500 mg or a series of three doses of 500 mg given at 48 h intervals, in three separate experiments. Blood and urine were collected over a 7-day period and CH, DCA, TCA, free trichloroethanol (f-TCE), and total trichloroethanol (T-TCE=trichloroethanol and trichloroethanol-glucuronide [TCE-G]) were measured. DCA was detected in blood and urine only in trace quantities (<2 microM). TCA, on the other hand, had the highest plasma concentration and the largest AUC of any metabolite. The TCA elimination curve displayed an unusual concentration-time profile that contained three distinct compartments within the 7-day follow-up period. Previous work in rats has shown that the complex elimination curve for TCA results largely from the enterohepatic circulation of TCE-G and its subsequent conversion to TCA. As a result TCA had a very long residence time and this, in turn, led to a substantial enhancement of peak concentrations following the third dose in the multiple dose experiment. Approximately 59% of the AUC of plasma TCA following CH administration is produced via the enterohepatic circulation of TCE-G. The AUC for f-TCE was found to be positively correlated with serum bilirubin concentrations. This effect was greatest in one subject that was found to have serum bilirubin concentrations at the upper limit of the normal range in all three experiments. The AUC of f-TCE in the plasma of this individual was consistently about twice that of the other seven subjects. The kinetics of the other metabolites of CH was not significantly modified in this individual. These data indicate that individuals with a more impaired capacity for glucuronidation may be very sensitive to the central nervous system depressant effects of high doses of CH, which are commonly attributed to plasma levels of f-TCE.

Green chemistry in urinalysis for trichloroethanol and trichloroacetic acid as markers of exposure to chlorinated hydrocarbon solvents.

The aim of the present study was to develop a method of urinalysis for trichloroacetic acid (TCA) and trichloroethanol (TCE), and therefore total trichloro-compounds (TTC) as the sum, with least use of hazardous chemicals, being green in that sense. After acid hydrolysis followed by dilution with an ethanol (EtOH)-methanol (MeOH)-water mixture, capillary gas-choromatography with an electron-capture detector can quantify TCA and TCE in the diluted hydrolyzate. Comparison studies showed that the results were identical among three methods, i.e., 1. the method developed in the present study, 2. a head-space GC with acid hydrolysis of conjugated TCE and methyl-esterification of TCA, and 3. traditional colorimetry with Fujiwara reaction. When applied to exposure-excretion analysis, the three methods gave results reproducible to each other. Over-all evaluation therefore was such that the method developed in the present study is as equally reliable as previously developed methods. It should be further noted that the procedures are very simple, with minimum use of occupationally or environmentally hazardous chemicals. In case the determination of only TCA is requested, it is possible to skip the hydrolysis step so that the treatment prior to the GC analysis is even simpler, i.e., just a 60-fold dilution of the urine sample with the EtOH-MeOH-water mixture. It was also demonstrated that correction of urinary analyte levels for urine density in terms of creatinine or specific gravity did not improve the correlation with the intensity of TRI exposure.

Evaluation of dynamic headspace with gas chromatography/mass spectrometry for the determination of 1,1,1-trichloroethane, trichloroethanol, and trichloroacetic acid in biological samples.

A sensitive and reproducible method is described for the analysis of trichloroacetic acid in urine and 1,1,1-trichloroethane in blood using dynamic headspace GC/MS. Samples were analyzed using the soil module of a modified purge and trap autosampler to facilitate the use of disposable purging vessels. Coefficients of variation were below 3.5% for both analytes, and response was linear in the range of 0.01-7.0 microg/ml for trichloroacetic acid and 0.9 ng/ml-2.2 microg/ml for 1,1,1-trichloroethane. Attempts at using dynamic headspace for the analysis of trichloroethanol in urine were unsuccessful.

The biological exposure index: its use in assessing chemical exposures in the workplace.

Human exposure to chemicals in the workplace has traditionally been assessed by determining the concentration of an airborne chemical in the workroom air. More recently, biological monitoring has been used to assess worker uptake of chemicals by all routes of exposure. Both approaches for the assessment of exposure and uptake are complementary. This relationship is examined, along with the advantages and limitations of using biological monitoring. The concept of the biological exposure index (BEI), developed by the American Conference of Governmental Industrial Hygienists (ACGIH), and information on the intended use and interpretation of BEIs are described. Examples are presented on the use of biological monitoring in NIOSH Health Hazard Evaluations (e.g., carboxyhemoglobin in blood to assess exposure to carbon monoxide, urinary metabolites of trichloroethylene to assess exposure to trichloroethanol, and 2-ethoxyacetic acid in urine to assess exposure to 2-ethoxyethanol). The progress of current research studies on the biological monitoring of volunteers exposed to paint spray solvents is presented, along with speculation on the future directions of biological monitoring research.

Tetrachloroethylene and trichloroethylene fatality: case report and simple headspace SPME-capillary gas chromatographic determination in tissues.

We describe a simple, precise, and sensitive assay of tetrachloroethylene and trichloroethylene in tissues, suitable both for emergency cases and forensic medicine. The method employs headspace solid phase microextraction-capillary gas chromatography and electron capture detection. The case is relative to a 45-year-old woman discovered unconscious in a laundry area. The concentrations of the solvents in tissues were determined and compared to other previously published fatalities.

Concentrations of trichloroethylene and its metabolites in blood and urine after acute poisoning by ingestion.

A 58-year-old man fell into a trichloroethylene reservoir bath head first, during a maintenance degreasing bath and accidentally ingested the solvent. Although he showed deep coma, chemical burns and pneumonia on admission, these symptoms gradually subsided. The concentrations of trichloroethylene (TRI) and its metabolites, trichloroethanol (TCE) and trichloroacetic acid (TCA) in blood and urine were measured during hospitalization. Eight hours after the accident, the concentrations of TRI and its metabolites in serum were 31.4 micrograms/ml TRI, 16.5 micrograms/ml TCE and 79.5 micrograms/ml TCA. The serum TRI concentration decreased to 4.3 micrograms/ml on the following day. Elimination of TCE and TCA from serum occurred biphasically, the estimated half-lives of each metabolites being about 52.6 and 50.4 h in an initial fast phase and 268.3 and 277.2 h in a subsequent slow phase, respectively. Urinary TRI excretion persisted for the first 2 days. The urinary TCE and TCA excretions were longer than that of TRI with a biphasic decrease and the total amount of TCE excreted during the first 2 days was about two times that of TCA. The half-life of urinary TCE excretion (t1/2 25.7 h) was shorter than that of TCA (t1/2 52.1 h) in the fast phase but did no difference during the slow phase, with each half-time being about 166.3 h. The kinetics of TRI metabolites in blood and urine in this case were in slight agreement with the results following inhalation exposure previously reported in the literature.

Fatal intoxications with chloral hydrate.

An alcoholic man, treated with chloral hydrate (CH) syrup to which he was dependent, was discovered comatose and in respiratory arrest. Death occurred on the ninth day of hospitalization following cerebral oedema. A woman, alcohol addicted, depressed, and epileptic was admitted in the Intensive Care Unit with heart and respiratory failure following CH absorption. She died three days later after a deep coma. In these two cases, CH intoxication was confirmed by toxicological analysis: CH and its major metabolite, trichloroethanol (TCE), were identified and determined in serum and urine using headspace-capillary gas chromatography-mass spectrometry. The concentrations measured were compared with those found in previously published fatalities. The analytical method used can be proposed for both clinical and forensic cases.

Sex differences in metabolism of trichloroethylene and trichloroethanol in guinea pigs.

OBJECTIVES: Trichloroethylene (TRI) has the potential to cause generalized dermatitis complicated with hepatitis. The guinea pig maximization test (GPMT) also suggests that both TRI and its metabolite trichloroethanol (TCE) exhibit immunogenicity and possible sex differences in guinea pigs. However, TRI and TCE metabolisms in guinea pigs have not been elucidated in detail. The first issue to clarify may be the sex differences in relation to the immunogenicity. METHODS: We collected urine from Hartley male and female guinea pigs 24 hours after intracutaneous injection of TRI, TCE or trichloroacetic acid (TCA) during a GPMT and measured the urinary metabolites by gas chromatography-mass spectrometry. RESULTS: After TRI treatment, the amount of TCA was significantly greater in females than males, while there was no sex difference in the total amount (TCA + TCE). TCA was only detected in urine after TCA treatment. Interestingly, not only TCE but also TCA was detected in urine of both sexes after TCE treatment, and the amount of TCA was also greater in females than males. An additional experiment showed that TCE treatment did not result in the detection of urinary TCA in cytochrome P450 (CYP)2E1-null mice TCEbut did in wild-type mice, suggesting the involvement of CYP2E1 in the metabolism from TCE to TCA. The constitutive expression of CYP2E1 in the liver of guinea pigs was greater in females than males. CONCLUSIONS: The sex difference in urinary TCA excretion after TRI and TCE treatments may be due to variation of the constitutive expression of CYP2E1.

Acute, nonfatal intoxication with trichloroethylene.

Nonfatal acute inhalation of trichloroethylene (TRI) at work was described. The subject, male, 54 years old, was drawn unconscious by a metal-degreasing machine and immediately sheltered in intensive care unit. Other than basic life support and common laboratory indices, blood and urine were collected to measure dose and kidney effect parameters such as TRI in blood and urine, trichloroethanol (TCE) and trichloroacetic acid (TCA) in urine, and total urinary proteins (TUP), urinary glutamine synthetase (GS) and urinary N-acetyl-beta-D-glucosaminidase (NAG). Two hours after accident, TRI in blood was 9 mg/l, but after 38 h it was below 1 mg/l. TCE and TCA have a peak 11 and 62 h after poisoning, respectively. Acute renal involvement was revealed by a peak of urinary proteins and enzymes 7 h after exposure with a second peak 74 h after. Seven day after hospitalisation the patient was dismissed with complete recovery. This nonfatal intoxication with TRI shows that the exposure was approximately 150 ppm, three times the ACGIH TLV (50 ppm) and that kidney was the only organ affected. Urinary enzymes, in particular GS, are good indices to monitor transient effects of TRI on the kidney.

[Determination of trichloroacetic acid and trichloroethanol by head-space gas chromatography (HS.GC)].

Simultaneous determination of trichloroacetic acid (TCA) and trichloroethanol (TCE) in urine was made using head-space gas chromatography (HSGC). TCA was analyzed after methyl esterification by methanol, and TCE was measured with decomposition of conjugation adding sulfuric acid. (1) As preliminary treatment, 0.1 ml of urine and 0.6 ml of esterizer (pure water: sulfuric acid: methanol = 6:5:1, V/V/V) were mixed in a sample vial, which was sealed a septum. This was analyzed in HSGC. (2) By this method, the recovery, standard deviation and coefficient of variation of TCA were 95.7-104.3%, 0.001-0.783 mg/l and 0.8-4.0%, respectively, while those of TCE were 98.6-102.5%, 0.024-1.603 mg/l and 0.8-4.0%, respectively. (3) Calibration curves were linear up to 30 mg/l for TCA (y = 1.838x + 0.023, r = 0.999, n = 8) and 60 mg/l for TCE (y = 0.963x + 0.072, r = 0.999, n = 8). (4) A high correlation between HSGC and alkaline pyridine spectrophotometry was found for both TTC (TCA + TCE = TTC), (y = 0.917x - 3.08, r = 0.980, n = 100, p less than 0.001) and TCA (y = 0.891x - 2.36, r = 0.928, n = 100, p less than 0.001). The values for TCA and TCE obtained with HSGC were lower than those obtained with spectrophotometry. (5) The limits of the detection obtained with this method were 0.002 mg/l for TCA and 0.005 mg/l for TCE according to the formula recommended by International Union of Pure and Applied Chemistry (IUPAC). These results indicate that this simple method is accurate and useful in simultaneous detection of TCA and TCE.

Gas-uptake pharmacokinetics and biotransformation of 1,1-dichloro-1-fluoroethane (HCFC-141b).

A physiologically based pharmacokinetic model was used to determine the in vivo metabolic constants of the candidate chlorofluorocarbon replacement 1,1-dichloro-1-fluoroethane (HCFC-141b). Rats were exposed by inhalation to HCFC-141b concentrations ranging from 1,000 to 10,000 ppm. Uptake studies of HCFC-141b in the rat indicated the involvement of saturable and first-order components. The in vivo metabolic constants for HCFC-141b were: KM = 7.0 mg liter-1 (59.9 mumol liter-1), Vmax = 0.2 mg kg-1 hr-1 (1.71 mumol kg-1 hr-1), and k = 0.5 hr-1. In rats exposed to HCFC-141b, 2,2-dichloro-2-fluoroethanol was excreted in the urine as its glucuronide conjugate, and the rate of 2,2-dichloro-2-fluoroethanol excretion increased linearly with increasing HCFC-141b exposure concentrations. Diallyl sulfide, a selective, mechanism-based inhibitor of cytochrome P-450 2E1, inhibited the metabolism of HCFC-141b, as indicated by a decreased uptake of HCFC-141b and by a lowered urinary excretion of 2,2-dichloro-2-fluoroethanol in diallyl-sulfide-treated rats. In vitro biotransformation studies with microsomes from rats treated with pyridine, an inducer of cytochrome P-450 2E1, confirmed that cytochrome P-450 2E1 is involved in the metabolism of HCFC-141b. The in vitro metabolic rate constants for the biotransformation of HCFC-141b to 2,2-dichloro-2-fluoroethanol were: KM = 0.39 +/- 0.11 mM and Vmax = 2.08 +/- 0.23 nmol mg protein-1 hr-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of intermittent trichloroethylene exposure in vapor degreasing.

To validate various sampling strategies in assessment of trichloroethylene (TCE) exposure, urine and air samples were obtained from 29 metal workers involved in vapor degreasing. Urinary trichloroacetic acid and trichloroethanol were useful metabolites to estimate TCE exposure on a group basis, but the predictive value of a single urine sample was low when related to the air concentration. With intermittent TCE exposure, the best information is obtained by analyzing both metabolites.

Determination of 2,2,2-trichloroethanol in plasma and urine by ion-exclusion chromatography.

A simple and rapid chromatographic method has been developed for the determination of 2,2,2-trichloroethanol (TCEOH) and its glucuronide in plasma and urine. A glass column (150 x 6.6 mm i.d.) packed with Aminex A-5 cation-exchange resin (potassium form) following the slurry method was used as the analytical column, and an admixture of 10 mmol l-1 potassium sulfate and 10 mmol l-1 potassium hydroxide solution as the eluent (pH 12.2). Diluted plasma samples and urine samples were directly injected into the chromatograph through a 0.45 micron membrane filter without deproteinization. The amount of TCEOH conjugated to glucuronide was determined following treatment with beta-glucuronidase (200 U) for 30 min at 37 degrees C. This allowed the concentration of free, total, and conjugated TCEOH to be determined. The calibration graph was rectilinear from 5 to 500 mg l-1 of TCEOH, with a detection limit of 3 mg l-1, 2 sigma, being the signal-to-noise ratio. The analytical recovery of TCEOH, obtained by analysing spiked plasma and urine samples, was in the range 98.4-102% and the relative standard deviation was less than 3.5%.

Intestinal absorption of chloral hydrate, free trichloroethanol and trichloroacetic acid in dogs.

In order to examine the intestinal absorption of chloral hydrate (CH), free trichloroethanol (F-TCE) and trichloroacetic acid (TCA), an intestinal circulation system in dogs was developed using jejunal, ileal and colonic loops, and solutions of CH, F-TCE and TCA were circulated within them. The concentrations of these substances and their metabolites in the serum, urine, bile and circulates were then measured. In all groups, the fraction of water absorbed from the intestine was about 10% of the administered volume two hours after administration. The absorbed fraction of CH was about 50% in the jejunum and ileum, and about 40% in the colon. The absorbed fraction of F-TCE was about 60% in the jejunum, 50-60% in the ileum and about 40% in the colon, while the figures for TCA were about 40-50% in the jejunum and about 30-40% in the ileum and colon. The combined biliary and urinary excretion ratios of the administered substances and their respective metabolites to the total amounts absorbed from the intestine were about 25-30% for F-TCE, 10-15% for CH and 0.1-0.2% for TCA in all parts of the intestine two hours after administration.