Quantitative aspects in the assessment of liver injury.
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Liver function data are usually difficult to use in their original form when one wishes to compare the hepatotoxic properties of several chemical substances. However, procedures are available for the conversion of liver function data into quantal responses. These permit the elaboration of dose-response lines for the substances in question, the calculation of median effective doses and the statistical analysis of differences in liver-damaging potency. These same procedures can be utilized for estimating the relative hazard involved if one compares the liver-damaging potency to the median effective dose for some other pharmacologie parameter. Alterations in hepatic triglycerides, lipid peroxidation, and the activities of various hepatic enzymes can also be quantitiated in a dose-related manner. This permits the selection of equitoxic doses required for certain comparative studies and the selection of doses in chemical interaction studies. The quantitative problems involved in low-frequency adverse reactions and the difficulty these present in the detection of liver injury in laboratory animals are discussed. (+info)
The importance of measured end-points in demonstrating the occurrence of interactions: a case study with methylchloroform and m-xylene.
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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. (+info)
Aerobic degradation of 1,1,1-trichloroethane by Mycobacterium spp. isolated from soil.
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Two strains of 1,1,1-trichloroethane (TCA)-degrading bacteria, TA5 and TA27, were isolated from soil and identified as Mycobacterium spp. Strains TA5 and TA27 could degrade 25 and 75 mg. liter of TCA(-1) cometabolically in the presence of ethane as a carbon source, respectively. The compound 2,2,2-trichloroethanol was produced as a metabolite of the degradation process. (+info)
Utility of real time breath analysis and physiologically based pharmacokinetic modeling to determine the percutaneous absorption of methyl chloroform in rats and humans.
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Due to the large surface area of the skin, percutaneous absorption has the potential to contribute significantly to the total bioavailability of some compounds. Breath elimination data, acquired in real-time using a novel MS/MS system, was assessed using a PBPK model with a dermal compartment to determine the percutaneous absorption of methyl chloroform (MC) in rats and humans from exposures to MC in non-occluded soil or occluded water matrices. Rats were exposed to MC using a dermal exposure cell attached to a clipper-shaved area on their back. The soil exposure cell was covered with a charcoal patch to capture volatilized MC and prevent contamination of exhaled breath. This technique allowed the determination of MC dermal absorption kinetics under realistic, non-occluded conditions. Human exposures were conducted by immersing one hand in 0.1% MC in water, or 0.75% MC in soil. The dermal PBPK model was used to estimate skin permeability (Kp) based on the fit of the exhaled breath data. Rat skin K(p)s were estimated to be 0.25 and 0.15 cm/h for MC in water and soil matrices, respectively. In comparison, human permeability coefficients for water matrix exposures were 40-fold lower at 0.006 cm/h. Due to evaporation and differences in apparent Kp, nearly twice as much MC was absorbed from the occluded water (61.3%) compared to the non-occluded soil (32.5%) system in the rat. The PBPK model was used to simulate dermal exposures to MC-contaminated water and soil in children and adults using worst-case EPA default assumptions. The simulations indicate that neither children nor adults will absorb significant amounts of MC from non-occluded exposures, independent of the length of exposure. The results from these simulations reiterate the importance of conducting dermal exposures under realistic conditions. (+info)
Biphasic effects of 1,1,1-trichloroethane on the locomotor activity of mice: relationship to blood and brain solvent concentrations.
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Despite the central nervous system (CNS) being a target of virtually all solvents, few solvents have been thoroughly studied for their effects on unlearned animal behaviors. Of the solvents that have been studied, little is known about the relationship of exposure concentration to behavioral effect, and quantitative data relating the toxicologically important target organ (i.e., brain) dose to behavioral effect are almost non-existent. To examine the concentration- and time-dependency of effects of 1,1, 1-trichloroethane (TRI) on behavior, male albino Swiss-Webster mice were exposed to TRI (500-14,000 ppm) in static inhalation chambers for 30 min, during which locomotor activity was measured. Separate mice were exposed to the same concentrations under identical conditions for 6, 12, 18, 24, and 30 min, to determine blood and brain concentrations versus time profiles for TRI. This allowed for the relationships between blood and brain concentrations of TRI and locomotor activity to be discerned. The lowest TRI concentrations studied (500-2000 ppm) had no statistically significant effect on activity, intermediate concentrations (4000-8000 ppm) increased activity immediately to levels that remained constant over time, and higher concentrations (10,000-14,000 ppm) produced biphasic effects, i.e., increases in activity followed by decreases. 1,1, 1-Trichloroethane concentrations in blood and brain approached steady-state equilibria very rapidly, demonstrated linear kinetics, and increased in direct proportion to one another. Locomotor activity increased monophasically ( approximately 3.5-fold) as solvent concentrations increased from approximately 50-150 microg/g brain and microg/ml blood. As concentrations exceeded the upper limit of this range, the activity level declined and eventually fell below the control activity level at approximately 250 microg/g brain and microg/ml blood. Regression analyses indicated that blood and brain concentrations during exposure were strongly correlated with locomotor activity, as were measures of internal dose integrated over time. The broad exposure range employed demonstrated that TRI, like some classical CNS depressants, is capable of producing biphasic effects on behavior, supporting the hypothesis that selected solvents are members of the general class of CNS depressant drugs. By relating internal dose measures of TRI to locomotor activity, our understanding of the effects observed and their predictive value may be enhanced. (+info)
Effects of volatile solvents on recombinant N-methyl-D-aspartate receptors expressed in Xenopus oocytes.
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1. We have previously shown that toluene dose-dependently inhibits recombinant N-methyl-D-aspartate (NMDA) receptors at micromolar concentrations. This inhibition was rapid, almost complete and reversible. The NR1/2B combination was the most sensitive receptor subtype tested with an IC(50) value for toluene of 0.17 mM. 2. We now report on the effects of other commonly abused solvents (benzene, m-xylene, ethylbenzene, propylbenzene, 1,1,1-trichlorethane (TCE) and those of a convulsive solvent, 2,2,2-trifluoroethyl ether (flurothyl), on NMDA-induced currents measured in XENOPUS oocytes expressing NR1/2A or NR1/2B receptor subtypes. 3. All of the alkylbenzenes and TCE produced a reversible inhibition of NMDA-induced currents that was dose- and subunit-dependent. The NR1/2B receptor subtype was several times more sensitive to these compounds than the NR1/2A subtype. 4. The convulsant solvent flurothyl had no effect on NMDA responses in oocytes but potently inhibited ion flux through recombinant GABA receptors expressed in oocytes. 5. Overall, these results suggest that abused solvents display pharmacological selectivity and that NR1/2B NMDA receptors may be an important target for the actions of these compounds on the brain. (+info)
Acute, short-term, and subchronic oral toxicity of 1,1,1-trichloroethane in rats.
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1,1,1-Trichloroethane (TRI) is a widely used solvent that has become a frequent contaminant of drinking water supplies in the U.S. There is very little information available on the potential for oral TRI to damage the liver or to alter its P450 metabolic capacity. Thus, a major objective of this investigation was to assess the acute, short-term, and subchronic hepatotoxicity of oral TRI. In the acute study, male Sprague-Dawley (S-D) rats were gavaged with 0, 0.5, 1, 2, or 4 g TRI/kg bw and killed 24 h later. No acute effects were apparent other than CNS depression. Other male S-D rats received 0, 0.5, 5, or 10 g TRI/kg po once daily for 5 consecutive days, rested for 2 days, and were dosed for 4 additional days. Groups of the animals were sacrificed for evaluation of hepatotoxicity 1, 5, and 12 days after initiation of the short-term experiment. This dosage regimen caused numerous fatalities at 5 and 10 g/kg, but no increases in serum enzymes or histopathological changes in the liver. For the subchronic study, male S-D rats were gavaged 5 times weekly with 0, 0.5, 2.5, or 5.0 g TRI/kg for 50 days. The 0 and 0.5 g/kg groups were dosed for 13 weeks. A substantial number of rats receiving 2.5 and 5.0 g/kg died, apparently due to effects of repeated, protracted CNS depression. There was evidence of slight hepatocytotoxicity at 10 g/kg, but no progression of injury nor appearance of adverse effects were seen during acute or short-term exposure. Ingestion of 0.5 g/kg over 13 weeks did not cause apparent CNS depression, body or organ weight changes, clinical chemistry abnormalities, histopathological changes in the liver, or fatalities. Additional experiments did reveal that 0.5 g/kg and higher doses induced hepatic microsomal cytochrome P450IIE1 (CYP2E1) in a dose- and time-dependent manner. Induction of CYP2E1 activity occurred sooner, but was of shorter duration than CYP2B1/2 induction. CYP1A1 activity was not enhanced. In summary, 0.5 g/kg po was the acute, short-term, and subchronic NOAEL for TRI, for effects other than transient CYP2E1 induction, under the conditions of this investigation. Oral TRI appears to have very limited capacity to induce P450s or to cause liver injury in male S-D rats, even when administered repeatedly by gavage in near-lethal or lethal dosages under conditions intended to maximize hepatic effects. (+info)
Antagonism of inhalant and volatile anesthetic enhancement of glycine receptor function.
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Recent studies suggest that alcohols, volatile anesthetics, and inhaled drugs of abuse, which enhance gamma-aminobutyric acid, type A, and glycine receptor-activated ion channel function, may share common or overlapping molecular sites of action on these receptors. To investigate this possibility, these compounds were applied singly and in combination to wild-type glycine alpha(1) receptors expressed in Xenopus laevis oocytes. Data obtained from concentration-response curves of the volatile anesthetic enflurane constructed in the presence and absence of ethanol, chloroform, or toluene were consistent with competition for a common binding pocket on these receptors. A mutant glycine receptor, insensitive to the enhancing effects of ethanol but not anesthetics or inhalants, demonstrated antagonism of anesthetic and inhalant effects on this receptor. Although ethanol (25-200 mm) had no effect on its own in this receptor, it was able to inhibit reversibly the enhancing effect of enflurane, toluene, and chloroform in a concentration-dependent manner. These data suggest the existence of overlapping molecular sites of action for ethanol, inhalants, and volatile anesthetics on glycine receptors and illustrate the feasibility of pharmacological antagonism of the effects of volatile anesthetics. (+info)