Pharmacological characterization of the discriminative stimulus of inhaled 1,1,1-trichloroethane.

The present study examined the involvement of the GABAA, N-methyl-D-aspartate (NMDA), nicotinic acetylcholine, and mu-opioid receptor systems in the transduction of the discriminative stimulus effects of the abused inhalant 1,1,1-trichloroethane (TCE). Sixteen B6SJLF1/J mice were trained to discriminate 10 min of exposure to 12,000-ppm inhaled TCE vapor from air. Substitution and antagonism tests and TCE blood concentration analysis were subsequently conducted. TCE blood concentrations decreased rapidly after cessation of exposure, falling by 66% within 5 min. TCE vapor concentration-dependently substituted for the 12,000-ppm training stimulus. The volatile anesthetic halothane concentration-dependently and fully substituted for TCE. The benzodiazepine midazolam partially substituted for TCE, producing a maximum of 68% TCE-lever selection. The benzodiazepine antagonist flumazenil attenuated midazolam substitution for TCE, but not the discriminative stimulus effects of TCE itself. The noncompetitive NDMA receptor antagonists phencyclidine and dizocilpine failed to substitute for TCE. Nicotine and the central nicotinic receptor antagonist mecamylamine also failed to produce any TCE-lever selection, nor did they antagonize the discriminative stimulus of TCE. The mu-opioid receptor agonist morphine did not substitute for TCE. The opioid antagonist naltrexone failed to antagonize the discriminative stimulus of TCE. Overall, the present results, combined with previous studies, suggest that the discriminative stimulus effects of TCE are mediated primarily by positive GABAA receptor modulatory effects though a mechanism distinct from the benzodiazepine binding site.

Ethanol-induced increase in the metabolic clearance of 1,1,1-trichloroethane in human volunteers.

This study evaluated the effect of moderate doses of ethanol over a short period of time on the toxicokinetics of an organic solvent, 1,1,1-trichloroethane. A group of 10 moderate drinkers were recruited and exposed via inhalation for 2 h to a low concentration of 1,1,1-trichloroethane (175 ppm) on two separate occasions. Subjects were administered ethanol (0.35 g/kg body weight) on each of the 7 days preceding one of the exposures. Blood and urine samples were collected during and following each exposure, with blood analyzed for 1,1,1-trichloroethane and urine analyzed for the metabolites of 1,1,1-trichloroethane: trichloroethanol and trichloroacetic acid. Prior ethanol consumption resulted in a significant increase in apparent metabolic clearance of 1,1,1-trichloroethane (mean increase = 25.4%). The results of this study demonstrate that ethanol consumption over time can affect the rate at which an organic solvent is cleared through metabolism in humans. For chemicals with toxic metabolic products, this inductive effect of ethanol consumption on the rate of biotransformation could be potentially harmful to exposed individuals. Metabolic clearance of compounds with high hepatic extraction may not be affected by enzyme induction as it is likely that these compounds are essentially completely metabolized while passing through the liver.

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.

Inflammatory and cardiometabolic risk on obesity: role of environmental xenoestrogens.

CONTEXT: Some chemicals used in consumer products or manufacturing (eg, plastics, pesticides) have estrogenic activities; these xenoestrogens (XEs) may affect immune responses and have recently emerged as a new risk factors for obesity and cardiovascular disease. However, the extent and impact on health of chronic exposure of the general population to XEs are still unknown. OBJECTIVE: The objective of the study was to investigate the levels of XEs in plasma and adipose tissue (AT) depots in a sample of pre- and postmenopausal obese women undergoing bariatric surgery and their cardiometabolic impact in an obese state. DESIGN AND PARTICIPANTS: We evaluated XE levels in plasma and visceral and subcutaneous AT samples of Portuguese obese (body mass index ≥ 35 kg/m(2)) women undergoing bariatric surgery. Association with metabolic parameters and 10-year cardiovascular disease risk was assessed, according to menopausal status (73 pre- and 48 postmenopausal). Levels of XEs were determined by gas chromatography with electron-capture detection. Anthropometric and biochemical data were collected prior to surgery. Adipocyte size was determined on tissue sections obtained during surgery. RESULTS: Our data show that XEs are pervasive in this obese population. Distribution of individual and concentration of total XEs differed between plasma, visceral AT, and subcutaneous AT, and the pattern of accumulation was different between pre- and postmenopausal women. Significant associations between XE levels and metabolic and inflammatory parameters were found. In premenopausal women, XEs in plasma seem to be a predictor of 10-year cardiovascular disease risk. CONCLUSIONS: Our findings point toward a different distribution of XE between plasma and AT in pre- and postmenopausal women, and reveal the association between XEs on the development of metabolic abnormalities in obese premenopausal women.

The importance of measured end-points in demonstrating the occurrence of interactions: a case study with methylchloroform and m-xylene.

Mixed exposures may result in significant changes in one biomarker of exposure without altering another biomarker, and this may have unknown significance in terms of exposure assessment and overall toxicity of the mixture. Results from a previous investigation showed that human exposure to methylchloroform (MC, 400 ppm) and m-xylene (XYL, 200 ppm) during 4 h did not result in any significant effect on blood concentrations of these solvents, suggesting the absence of interaction between MC and XYL. Those results were adequately described by conducting a physiologically-based toxicokinetic (PBTK) modeling of the MC-XYL interaction in humans; however, the model suggested that urinary excretion of MC metabolites would be reduced as a result of combined exposure, whereas that of XYL metabolites would not be modified. An experimental verification of this model prediction was then undertaken with rats. In this study, Sprague-Dawley rats (n, 5) were exposed during 4 h to MC (400 ppm) or XYL (200 ppm), alone or as a mixture. Results showed that combined exposure did not affect the blood concentration of MC whereas that of XYL was increased throughout the 2-h blood collection period following exposure. The excretion of MC metabolites during a period of 48 h following the onset of exposure, i.e., trichloroethanol (TCE: -71%) and trichloroacetic acid (TCA: -73%), were significantly reduced. Methylhippuric acid (MHA) was not affected by co-exposure to MC as expected from the PBTK model forecasts. These results exemplify the use of a priori PBPK modeling for designing interaction studies and choosing appropriate/sensitive end-points for demonstrating the occurrence of potential interactions.

Effect of alterations in drug metabolism on epinephrine-induced cardiac arrhythmias in rabbits exposed to methylchloroform.

Control rabbits or those treated with the drug-metabolism inducer, phenobarbitol, or the inhibitors, 2-diethylaminoethyl-2,2-diphenylvalerate-HCI (SKF-525A) or 2,4-dichloro-6-phenylphenoxyethyldiethyl-amine-HBr (Lilly 18947) were exposed to 5600 ppm methylchloroform in an inhalation chamber under dynamic airflow conditions. Phenobarbital treatment slightly decreased blood levels of methylchloroform and the incidence of cardiac arrhythmias. The two inhibitors decreased the metabolism of methylchloroform and increased the incidence of arrhythmias. Methylchloroform rather than its metabolites appeared responsible for the arrhythmias. This arrhythmogenicity was altered by agents which affect the disposition and hence the blood levels of the compound.

Inter-individual variability in blood/air partitioning of volatile organic compounds and correlation with blood chemistry.

In vitro blood/air partition coefficients (KB/A) for acetone, 1,1,1-trichloroethane, toluene, and styrene were measured in blood samples from 73 human subjects and correlated with blood chemistry parameters (hematocrit, total cholesterol, serum triglycerides, serum albumin, total plasma proteins, Na+, K+, Cl-, and HCO3-). Statistically significant inter-individual variation existed in KB/A between some subjects. Substitution of group or generic in vitro KB/A values for values determined in some individuals could introduce errors of up to 50%. However, most subjects could be well represented by group averages (mean +/- SD; acetone, 301 +/- 22; 1,1,1-trichloroethane, 6.0 +/- 0.8; toluene, 19 +/- 3; styrene, 62 +/- 10). The KB/A values for acetone, 1,1,1-trichloroethane and toluene were normally distributed. The data for styrene appeared to deviate from a normal distribution and may have been bimodal. The KB/A values for the two structurally related compounds, toluene and styrene, were strongly correlated within individuals, while the KB/A values for compounds with less structural similarity, such as acetone and styrene, were poorly correlated. At most, 15% of the variation in KB/A among individuals could be explained by variation in the measured blood chemistry parameters. When the entire sample group was considered, blood chemistry parameters were not significantly correlated with KB/A for any compound. The KB/A of 1,1,1-trichloroethane was significantly correlated with the concentration of cholesterol and triglycerides in females. Sex was a significant grouping variable for the correlation of albumin concentration with the KB/A of styrene. Age was not a significant correlation variable. Blood chemistry parameters which previously have been correlated with KB/A in small sample groups do not appear to be significantly correlated in our larger sample group.

Schedule-controlled operant behavior of rats during 1,1,1-trichloroethane inhalation: relationship to blood and brain solvent concentrations.

The central nervous system is the principal target of 1,1,1-trichloroethane (TRI), and several studies of this volatile solvent have demonstrated effects on learned animal behaviors. There have been few attempts, however, to quantitatively relate such effects to blood or target organ (brain) solvent concentrations. Therefore, Sprague-Dawley rats trained to lever-press for evaporated milk on a variable interval 30-s reinforcement schedule were placed in an operant test cage and exposed to clean air for 20 min, followed by a single concentration of TRI vapor (500-5000 ppm) for 100 min. Additional rats were exposed to equivalent TRI concentrations for 10, 20, 40, 60, 80, or 100 min to determine blood and brain concentration vs. time profiles. Inhalation of 1000 ppm slightly increased operant response rates, whereas 2000, 3500, and 5000 ppm decreased operant response rates in a concentration- and time-dependent manner. Accumulation of TRI in blood and brain was rapid and concentration dependent, with the brain concentration roughly twice that of blood. Plots of blood and brain TRI concentrations against operant performance showed responding in excess of control rates at low concentrations, and decreasing response rates as concentrations increased. Linear regression analyses indicated that blood and brain concentrations, as well as measures of time integrals of internal dose, were strongly correlated with operant performance. Neurobehavioral toxicity in laboratory animals, as measured by changes in operant performance, can therefore be quantitatively related to internal measures of TRI exposure to enhance its predictive value for human risk assessment.

Regional brain dosimetry of trichloroethane in mice and rats following inhalation exposures.

While certain neuroactive volatile organic compounds (VOCs) have been reported to have an uneven distribution in various anatomically distinctive brain regions, this has not yet been reported for the short-chain aliphatic halogenated hydrocarbons. Therefore, the uptake and regional brain distribution of 1, 1, 1-trichloroethane (TRI) in mice and rats following inhalation exposure were examined. Male Sprague-Dawley rats and CD-1 mice were exposed to TRI at either 3500 or 5000 ppm for 10, 30, 60, or 120 min. Seven brain regions from rats and three from mice were sampled, and TRI concentrations in the blood and brain tissues were determined by headspace gas chromatography. In both species, the medulla oblongata was found to have the highest TRI concentrations, while cortex (in both species) and hippocampus (only sampled in rats) contained the lowest TRI concentrations. Substantial differences were also observed between the two species, as the mice exhibited higher capacity to accumulate TRI in the blood as well as in the brain regions. It appears that lipid content is a main factor influencing the differential disposition of TRI among the brains regions. Physiological differences in the respiratory systems of the two species and the physiochemical properties of the chemical favoring diffusion toward lipid-rich compartments could also have been expected to account for the patterns of regional distribution and species differences.

Skin absorption as a source of error in biological monitoring.

Concentrations of toluene, tetrachloroethylene, and 1,1,1-trichloroethane were determined in blood collected from both forearms of subjects after one of their hands was soaked for 5 min in the corresponding solvent or in a thinner containing toluene, as a simulation of the washing of hands with solvent after work. The concentrations of toluene, tetrachloroethylene, and 1,1,1-trichloroethane on the soaked side were high, maximally 5.4, 9.0, and 4.0 mumol/l, respectively, and 20-, 130-, and 35-fold, respectively, compared to the contralateral side. Intraindividual differences were very marked, and dramatic changes were detected within a short period of time. It was not until after 3 h with toluene and 5 h with the chlorinated solvents that the difference between the two arms vanished. It is concluded that analyses of solvents in blood specimens drawn during or immediately after the workday may lead to markedly erroneous estimations of exposure.

A study on the distribution of methylchloroform and n-octane in the mouse during and after inhalation.

The distribution of methylchloroform and n-octane, respectively, in the blood, liver, kidney, and brain of mice was studied at different inspired air concentrations and after different exposure times. The air concentration varied between 10 and 10,000 ppm; and the exposure time, between 0.5 and 24 h. The resulting solvent concentrations in kidney and brain were about the same, but the liver concentrations were usually somewhat higher for both solvents. There was a linear dependence between inspired air concentration and tissue concentrations at fixed exposure times. A correlation between blood and organ concentrations was observed in animals exposed at different inhalation air concentrations but not in animals exposed only at one fixed concentration. The ratios between the concentrations of the solvents in the organs and blood were higher for n-octane than for methylchloroform. The ratios increased as the exposure concentration increased for all organs studied in the case of n-octane but only for the liver in the case of methylchloroform. When the exposure dose, i.e., inspired air concentration X time, was generated in different ways, a high concentration during a short exposure resulted in a ten times higher organ concentration than a low concentration during a long exposure. The liver, kidney, and brain concentrations generally did not differ more than twice between methylchloroform and n-octane after exposure of the same concentration and duration. The blood concentration, however, was much less in n-octane exposed animals than in methylchloroform exposed ones. A pharmacokinetic model with both uptake and elimination of the first order fitted the empirical data better for methylchloroform than a model with zero order uptake and first order elimination. Postexposure concentrations of methylchloroform were linear in a semilog graph. A one-compartment pharmacokinetic model was in accordance with the experimental data for methylchloroform. For n-octane, however, at least a two-compartment model must be assumed.

Residuals of beta-hexachlorocyclohexane, dichlorodiphenyltrichloroethane, and hexachlorobenzene in serum, and relations with consumption of dietary components in rural residents in Japan.

To estimate levels of organochlorine residuals in the Japanese population and the contribution of dietary factors to these levels, we determined serum levels of beta-hexachlorocyclohexane (beta-HCH), hexachlorobenzene (HCB), p,p'-dichlorodiphenyldichloroethane (p,p'-DDD), 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene (p,p'-DDE) and p,p'-dichlorodiphenyltrichloroethane (p,p'-DDT) in 41 volunteers (14 men and 27 women) in a rural area of Northern Japan. These organochlorine levels were measured using gas-chromatography mass-spectrometry. By a self-administered dietary history questionnaire, the usual dietary intake was estimated. Their median levels (range) were as follows: beta-HCH, 0.50 (0.05-1.50); HCB, 0.20 (0.02-0.70); and total DDT (p,p'-DDE + p,p'-DDT), 5.0 (0.9-31.0) ng/ml serum. Levels of p,p'-DDD were detected in only seven subjects (0.05-0.6 ng/ml serum). The beta-HCH levels were increased with rice and milk intakes, but the least squares means were not simply increased according to the quartile of the intakes. Concerning HCB, fish intake showed a borderline significant correlation (0.20, P = 0.052). In terms of total DDT, intakes of meat, fish, vegetable and milk showed a positive relationship, although none of them provided statistically significant results. No other statistically significant relation between any organochlorines and any food intakes examined was observed in this study. The present study suggests that organochlorine compounds are transported into the human body via foods in the Japanese population. Their effects on health should thus be investigated and monitored.

Metabolites of chlorinated solvents in blood and urine of subjects exposed at environmental level.

After a two-level selection, 141 blood donors living in Milan, Italy, were analyzed for their content of plasma and urinary trichloroacetic acid (TCA) and trichloroethanol (TCE). Environmental levels of exposure to trichloroethylene (TRI) and tetrachloroethylene (PER) through drinking water and air were also measured. The plasma TCA levels were in the range of previously found concentrations. Relationships among plasma and urinary metabolites were found and discussed.

Concentration in blood and organs of dogs after high dose 1,1,1-trichloroethane inhalation.

Dogs were exposed to 1% (v/v) (10,000 ppm) vapor of 1,1,1-Trichloroethane (1,1,1-TCE) by inhalation for 3 min repeated four times at 4 hr intervals under continuous anesthesia. Changes in the 1,1,1-TCE concentration in blood with time, as well as distribution of 1,1,1-TCE in the organs and tissues (lungs, liver, kidneys, heart, brain, and fat around the kidneys and on the abdominal wall) upon completion of the four exposures were studied. Concentrations of 1,1,1-TCE in blood showed the highest level immediately after exposure, and fairly decreased in about 30 min after exposure. The half life of 1,1,1-TCE in blood was 4-12 min after exposure. Upon completion of the exposures (3 min inhalations repeated four times), 1,1,1-TCE concentrations per gram wet weight of each organ ranged from 0.1 to 0.5 microgram/g in the lungs, liver, kidneys, heart and brain. On the other hand, the 1,1,1-TCE concentration in fat ranged from 16.9 to 54.6 micrograms/g, greatly exceeding those in other organs.

Discriminative stimulus effects of inhaled 1,1,1-trichloroethane in mice: comparison to other hydrocarbon vapors and volatile anesthetics.

RATIONALE: Because the toxicity of many inhalants precludes evaluation in humans, drug discrimination, an animal model of subjective effects, can be used to gain insights on their poorly understood abuse-related effects. OBJECTIVES: The purpose of the present study was to train a prototypic inhalant that has known abuse liability, 1,1,1-trichloroethane (TCE), as a discriminative stimulus in mice, and compare it to other classes of inhalants. MATERIALS AND METHODS: Eight B6SJLF1/J mice were trained to discriminate 10 min of exposure to 12,000 ppm inhaled TCE vapor from air and seven mice were trained to discriminate 4,000 ppm TCE from air. Tests were then conducted to characterize the discriminative stimulus of TCE and to compare it to representative aromatic and chlorinated hydrocarbon vapors, volatile halogenated anesthetics as well as an odorant compound. RESULTS: Only the 12,000 ppm TCE versus the air discrimination group exhibited sufficient discrimination accuracy for substitution testing. TCE vapor concentration- and exposure time-dependently substituted for the 12,000 ppm TCE vapor training stimulus. Full substitution was produced by trichloroethylene, toluene, enflurane, and sevoflurane. Varying degrees of partial substitution were produced by the other volatile test compounds. The odorant, 2-butanol, did not produce any substitution for TCE. CONCLUSIONS: The discriminative stimulus effects of TCE are shared fully or partially by chlorinated and aromatic hydrocarbons as well as by halogenated volatile anesthetics. However, these compounds can be differentiated from TCE both quantitatively and qualitatively. It appears that the degree of similarity is not solely a function of chemical classification but may also be dependent upon the neurochemical effects of the individual compounds.

[Animal experiments on the detection of an exposure to "chemical mace" (author's transl)]. / Tierexperimentelle Untersuchungen zum Nachweis einer Anwendung der "chemischen Keule".

To answer the question whether a negative result of gas chromatographic blood analysis for components of chemical mace proves that no or at most only slight tear gas exposure can have occurred, animal experiments were carried out. In the blood of 10 guinea pigs, which were exposed to the contents of chemical mace for 1--6 h, the solvants 1,1,2-trichloro-1,2,2-trifluorethane (freon 113) and 1,1,1-trichloroethane could easily be detected--even 23 h after the end of exposure or after a storage of the blood samples for 18 weeks--whereas the lacrimator chloracetophenone (CN) could not be found at all. In vitro experiments showed that CN relatively quickly reacts with components of blood. Therefore, blood samples should be analyzed for CN after withdrawal as soon as possible. In case of inhalation of the contents of chemical mace, i.e., after the comparatively mildest form of CN application, most probably no traces of the lacrimator at all can pass into the blood due to the quick reaction of CN with proteins of the respiratory surface of the lung.

[Diminution of 1, 1, 1- and 1, 1, 2- trichloroethane in the blood and their excretion by the lungs (author's transl)].

In order to investigate the diminution of 1, 1, 1-trichloroethane (1, 1, 1-TCE) and 1, 1, 2-trichloroethane (1, 1, 2-TCE) in the blood and the excretion of them by the lungs, 100 mg and 50 mg per kg body weight of 1, 1, 1-TCE were intravenously administered to 12 and 13 dogs, respectively, and the same amounts of 1, 1, 2-TCE to 5 and 8 dogs, respectively. The arterial blood gathered and the expired air collected by the time up to 60 minutes after the injection were analysed with a FID-gas-chromatography for the concentrations of the solvents. The results obtained are as follows. 1. Concentrations of 1, 1, 1-TCE in the blood were maintained significantly lower always from 2 to 60 minutes after the injection than those of 1, 1, 2-TCE. 2. While highest concentrations of the solvents in the expired air were found about 1 minute after the injection for both 1, 1, 1-and 1, 1, 2-TCE, values 1 minute after for the former were seven to ten times higher than those for the latter. However, no significant differences in the concentration were seen between both solvents after 15-40 minutes of administration in the expired air. 3. Ratios of the amounts expired by the lungs during 60 minutes after the injection to the total were 61-68% for 1, 1, 1-TCE, whereas only 21-32% for 1, 1, 2-TCE, respectively. 4. Highly significant linear regression was found between the concentrations of the solvent in the blood and those in the expired air for each of 1, 1, 1- and 1, 1, 2-TCE.

Variations in the blood concentration of 1,1,2-trichloroethane by percutaneous absorption and other routes of administration in the guinea pig.

The blood concentration of 1,1,2-trichloroethane was studied after epicutaneous application, by an intracutaneous, subcutaneous or intraperitoneal injection. An equation with three exponential terms was necessary for a satisfactory description of the experimental data in the case of intraperitoneal injection. Subcutaneous and intracutaneous injections seem to give essentially the same king of blood concentration curves as for intraperitoneal injection. In the case of percutaneous absorption an equation with three exponential terms and a constant was necessary to account for the experimental data. The complex toxicokinetics of 1,1,2-trichloroethane by percutaneous absorption was assumed to be associated with progressive skin damage observed in previously reported experiments, a damage apparently involving a change in barrier function.

[Experimental examinations and toxicokinetic analysis of the absorption and excretion of 1,1,1-trichloroethane by the lung].

Of fifteen dogs each five of them inhaled 1,1,1-trichloroethane (1,1,1-TCE) at the levels of 700, 1500 and 2,000 ppm respectively for one hour. Changes in 1,1,1-TCE concentrations in the expired air, arterial blood and venous blood of dogs were measured from the beginning of exposure until one hour after the end of exposure. The results obtained were as follows. 1. Cumulative uptakes of 1,1,1-TCE in one hour exposure were 27.3 mg/kg at 700 ppm, 44.7 mg/kg at 1,500 ppm and 71.2 mg/kg at 2,000 ppm. 2. Excretion ratios of 1,1,1-TCE in one hour after the exposure were 66-71% at all the three levels of exposure. 3. During the exposure, highly significant negative correlation was seen between arterial/venous blood concentration ratio and expired/inspired air concentration ratio. In the post-exposure period, highly significant positive correlations were seen between expired air concentration and venous or arterial blood concentration. 4. The mean ratio of the total absorption value to the total inspired value was 14% at all the three levels of exposure. 5. From these results, the authors examined the multiple regression equations with two independent variables x and z which are shown as follows. a) During the exposure period, Y1: Cumulative absorption solvent value by the dog (mg/kg) X1: Time of exposure (min) Z1: Level of the solvent value in the ambient air (microgram/ml) log Y1 = -0.526 + 0.622 log X1 + 0.905 log Z1 b) Post exposure period, Y2: Cumulative excreted solvent value by the dog (mg/kg) X2: Time after the end of exposure (min) Z2: Cumulative absorbed solvent value by the dog at the end of exposure (mg/kg) log Y2 = -2.300 + 0.609 log X2 + 0.858 log Z2 We assumed that both equations are very fit and significant.