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At least 19 recordsLinked to original sources
PubMed1986

Enhancement of the hepatotoxicity of chloroform in B6C3F1 mice by corn oil: implications for chloroform carcinogenesis.

A recent study of the ability of chloroform in drinking water to produce cancer reported that male Osborne-Mendel rats developed renal tumors, but that female B6C3F1 mice failed to develop hepatocellular carcinomas. The results obtained in the male Osborne-Mendel rats were comparable to those observed in an earlier study sponsored by the National Cancer Institute (NCI). On the other hand, the lack of an increased incidence of hepatocellular carcinomas in female B6C3F1 mice was in sharp contrast to previously reported results. The doses of chloroform used were comparable to that which produced an 85% incidence in the NCI study. We have investigated the extent to which the vehicle might be responsible for the different results in these two studies by examining the differential effects of chloroform when it was administered by gavage using corn oil versus a 2% Emulphor suspension as the vehicle. Male and female B6C3F1 mice were administered chloroform at 60, 130, and 270 mg/kg per day for 90 days. At sacrifice, body and organ weights were measured, and blood was recovered to perform the following serum chemistry measurements (in order of priority): glutamate oxalacetate transaminase (SGOT), lactate dehydrogenase (LDH), blood urea nitrogen (BUN), and triglyceride (TG) levels. The liver was sectioned for histopathological examination. Chloroform increased SGOT levels significantly only when administered in corn oil at a dose of 270 mg/kg in both male and female mice. It had no effect on LDH activity. There was a small increase in BUN when chloroform was administered in corn oil, but not when administered in 2% Emulphor. When administered in corn oil, chloroform significantly decreased serum TG levels but was without effect on this parameter when administered in 2% Emulphor. Chloroform decreased body weight and increased liver weight with both vehicles, but the effects were significantly greater when it was administered in corn oil. Mice administered chloroform in corn oil displayed a significant degree of diffuse parenchymal degeneration (5 of 10 males and 1 of 10 females) and mild to moderate early cirrhosis (5 of 10 males and 9 of 10 females); significant pathological lesions were not observed in the animals administered corn oil without chloroform nor in mice receiving chloroform in 2% Emulphor. These data indicate that administration of chloroform by corn oil gavage results in more marked hepatotoxic effects than observed when it is provided in an aqueous suspension.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Distribution of chloroform and methyl chloroform and their metabolites in pregnant mice.

The distribution of radioactivity in pregnant mice was registered at different time intervals (0-24 h) after a 10-min period of inhalation of 14C-labelled chloroform and methyl chloroform. Autoradiographic and liquid scintillation methods were used to make possible the distinction between volatile (non-metabolized), water-soluble and firmly tissue-bound radioactivity. Methyl chloroform was retained longer in fat as compared to chloroform. Metabolites of chloroform were present in a much greater abundance than those of methyl chloroform and they were found preferentially in the respiratory tract (nasal mucosa, trachea and bronchi), liver and excretory organs. Tissue-bound activity after chloroform inhalation or i.p. injection to newborn mice was found in the respiratory tract and centrilobular areas of the liver. Volatile radioactivity was observed in the placenta and fetuses at short time intervals after inhalation of both chloroform and methyl chloroform at all stages of gestation. While a low level of radioactive metabolites of methyl chloroform was observed in the fetoplacental unit, metabolites of chloroform accumulated with time. This fact was especially marked in the amniotic fluid, where the peak level of radioactivity was observed at 4 h. In early gestation, metabolites accumulated in the embryonic neural tissues. Tissue-bound metabolites of chloroform were observed in the fetal respiratory epithelium in late gestation, indicating a capacity for drug metabolism in these cells in the late fetal period.

Animals↗
PubMed1997

Chloroform in drinking water prevents hepatic cell proliferation induced by chloroform administered by gavage in corn oil to mice.

Chloroform administered by gavage in corn oil, but not when administrated in drinking water, has been shown to induce liver cancer in female B6C3F1 mice and to enhance cell proliferation. Since humans are exposed to chloroform in their drinking water, we evaluated whether exposure by this route would interact with the activity of chloroform when administered by gavage in corn oil. Female B6C3F1 mice were exposed to chloroform in drinking water for 33 days at 0, 300, or 1800 ppm (Experiment 1) or for 31 days at 0, 120, 240, or 480 ppm (Experiment 2) and for 3 days prior to termination also received a daily dose of 263 mg/kg chloroform administered by gavage in corn oil. Exposure to chloroform in drinking water reduced both the hepatotoxicity and the enhanced cell proliferation (bromodeoxyuridine-labeling index and mitotic index) elicited in response to chloroform administered by gavage in corn oil. Hence, chloroform administered in drinking water reduced the activity of chloroform administered by gavage in corn oil, suggesting that it would also reduce the hepatocarcinogenic activity of chloroform administered by gavage.

Administration, Oral↗
PubMed1996

Chloroform uptake by gutta-percha and assessment of its concentration in air during the chloroform-dip technique.

The use of chloroform as an adjunct to the practice of endodontics has been a matter of debate. In the present study the chloroform uptake of gutta-percha cones was determined by a gravimetric assay for different times of chloroform dip. In conjunction with an assessment of the amount of gutta-percha dissolved during dip, this provided an estimate of the amount of chloroform that patients are exposed to in clinical conditions. An assay was also performed of the chloroform concentration in the air in a dental office. Chloroform uptake was shown to increase with an increasing dipping time. There also seems to be a difference in this uptake between pure chloroform and a chloroform preparation with colophonium. The concentration levels of chloroform evaporated during the practice of chloroform dip within a dental office do not exceed the safety limits.

Air Pollution, Indoor↗
PubMed1976

Solubility of phosphatidylcholine in chloroform. Formation of hydrogen bonding between phosphatidylcholine and chloroform.

The solubility of phosphatidylcholine (PC) was studied by the spectroscopic analysis and the measurement of the solubility. The qualitative analysis of infrared absorption spectra confirmed the existence of two types of hydrogen bondings between chloroform and PC, one between chloroform and the C=O group of PC and the other between chloroform and the phosphorylcholine group of PC. The quantitative analysis of the C-D stretching vibration bands of the chloroform-d solution of PC showed that the latter hydrogen bonding mainly contributes to the solubility and that PC dissolves in chloroform to form a complex consisting of a few or more molecules of chloroform and one molecule of PC. We discussed in this report about the molecular organization of PC in chloroform solution.

Chloroform↗
PubMed1980

Extraction and determination of chloroform in rat blood and tissues by gas chromatography-electron-capture detection: distribution of chloroform in the animal body.

We have developed a simple, sensitive, and accurate method for the determination of chloroform in rat blood, brain, kidney, liver, and fat. The detection limit is 2.5 ng of chloroform per gram of tissue. Studies of in vivo distribution of chloroform in rat blood and target tissues after intragastric intubation of chloroform/water show that the amount of chloroform accumulated in the different tissues increases with increasing doses. Fat tissue contains the greatest amount of chloroform. The accumulation of chloroform in rat blood and target tissues seems to be maximum 1.5 h after administration, and the apparent chloroform concentration is almost at baseline value 8 h later.

Adipose Tissue↗
PubMed1982

Hydrogen bonding in mechanisms of anaesthesia tested with chloroform and deuterated chloroform.

There has been recent speculation about the role of hydrogen bonding in molecular mechanisms of anaesthesia. We have tested this hypothesis by comparing the potencies of chloroform and deuterated chloroform in mice, using loss of righting reflex as the endpoint for anaesthesia. We found that the ED50 for chloroform was 0.297 +/- 0.03% (SD) and for deuterated chloroform 0.318 +/- 0.02% (SD). These values are not significantly different. However, there were some differences in toxicity with deuterated chloroform having less "acute" toxicity. This is compatible with an isotope effect in which deuterium interferes with the formation of reactive free radicals. We conclude from the potency data that hydrogen bonding can be excluded as the major mechanism of chloroform anaesthesia.

Anesthesia, Inhalation↗
PubMed1996

[Early contributions from Erlangen to the theory and practice of ether and chloroform anesthesia. 1. Heyfelder's clinical trial with ether and chloroform].

The era of modern anaesthesia in Germany began on January 24th, 1847. This day, professor in ordinary Johann Ferdinand Heyfelder anaesthetized a patient with sulphuric ether in the clinic of surgery and ophthalmology of the University of Erlangen. By March 17th, 1847, Heyfelder had performed 121 surgical procedures under ether. The operations in majority were teeth-extractions, and a few more complex operations such as the treatment of a harelip or of lip cancer or the resection of the shoulder joint. Heyfelder described in detail 108 of these inhalations in a little book entitled The experiments with sulphuric ether. This monograph published in March, 1847, represents one of the first complete dissertations on sulphuric ether in the German literature. In a special chapter he analyzed the development of various physiological and psychological parameters during etherization. Heyfelder also examined blood and urine of some etherized patients and reported that he did not find any important or specific alterations. In 1847, Heyfelder was probably the first to apply salt-ether in man. After 4 administrations he concluded that salt ether acted more quickly but shorter than sulphuric ether. Advantageous were its application without problems and ease of induction. Disadvantageous were its high volatility, its price and the difficulty of getting it in a pure form. From December, 1847, on Heyfelder started to use chloroform. He was now able to perform more major operations, for example, the total resection of the hip-joint. In his book The experiments with sulphuric ether, salt ether, and chloroform he describes a great number of anaesthetic administrations using these 3 agents. In his summary Heyfelder concluded, that chloroform was undoubtly superior to sulphuric ether mainly because it was a quicker acting and longer lasting agent and leads to deeper narcosis. Moreover its application was much easier for it needed no special apparatus. However, because of its great anaesthetic potency, Heyfelder particularly demanded great caution in the application of chloroform. Explicitely he expected an assistant for chloroformizations, whose only duty was to supervise the inhalations and the patient--a forerunner of the modern specialized anaesthesiologist.

Anesthesiology↗
PubMed1999

Development of resistance to chloroform toxicity in male BDF1 mice exposed to a stepwise increase in chloroform concentration.

To investigate the development of resistance to chloroform toxicity, a 4-week inhalation study was conducted in which BDF1 male mice were exposed to a low level of chloroform for an initial two-week period, and thereafter the exposure concentration was increased for a second two-week period. The animals were exposed to inhalation of chloroform vapor 6 hr per day, 5 days per week, with clinical observation and measurement of body weight conducted. These results demonstrate that pre-exposure to chloroform at a low dose level induced resistance to a higher dose of chloroform in male mice. This resistance was dependent on the pre-exposure concentration.

Animals↗
PubMed1999

Correlation and estimation of gas-chloroform and water-chloroform partition coefficients by a linear free energy relationship method.

A linear free energy relationship, LFER, has been used to correlate 150 values of gas-chloroform partition coefficients, as log Lchl with a standard deviation, sd, of 0.23 log units, a correlation coefficient r2 of 0.985, and an F-statistic of 1919. The equation reveals that bulk chloroform is dipolar/polarizable, of little hydrogen-bond basicity, but as strong a hydrogen-bond acid as bulk methanol or bulk ethanol. However, the main influence on gaseous solubility in chloroform is due to solute-solvent London dispersion interactions. A slightly modified LFER has been used to correlate 302 values of water-chloroform partition coefficients, as log Pchl. The correlation equation predicts log Pchl for a further 34 compounds not used in the equation with sd = 0.17 log units. When the LFER is applied to all 335 log Pchl values, the resulting equation has sd = 0.25, r2 = 0.971, and F = 2218.

Chloroform↗
PubMed1988

Chloroform mediated refractory state against ornithine decarboxylase induction by serial chloroform treatment.

The chloroform mediated refractory state against ornithine decarboxylase induction in male and female rat liver was further studied. One aspect of the investigation was to determine the duration of the induced refractory period while the other component focused on the extent to which the inhibitory effect was dependent upon the concentration of the first dose. When the dosing interval between the first and second dose was varied from 1 to 31 days, the magnitude of the resistance to further stimulation by chloroform only decreased gradually. In studies where the concentration of the first dose was varied while the dosing interval was fixed, it was concluded that the extent of the inhibitory effect was dependent upon the concentration of the first dose.

Animals↗
PubMed1983

Mechanism of chloroform nephrotoxicity. I. Time course of chloroform toxicity in male and female mice.

Chloroform (CHCl3) nephrotoxicity in male mice could be detected as early as 2 hr after CHCl3 administration (250 microliter/kg, sc) as decreased ability of renal cortical slices to accumulate p-aminohippurate (PAH) and tetraethylammonium (TEA). The decrease was preceded and paralleled by a reduction of renal cortical nonprotein sulfhydryl (NPSH) concentration, an index of tissue reduced glutathione concentration. Histologic alterations were not observed until NPSH concentrations and PAH and TEA accumulation had reached the nadir, 5 hr after CHCl3 administration. Female mice exhibited no evidence of nephrotoxicity to CHCl3 even when the dose was increased to 1000 microliter/kg or when pretreated with diethyl maleate to reduce renal cortical NPSH concentrations prior to CHCl3 injection. The extent of hepatotoxicity was similar in male and female mice and decreases of hepatic NPSH concentrations also were detected by 1.5 hr after CHCl3 administration. The rapid response of the kidney to CHCl3 toxicity in male mice and the similarity of liver toxicity in both sexes suggests that nephrotoxicity occurs independently of hepatotoxicity. Furthermore, the ability to detect these early changes in vivo following CHCl3 administration may permit the development of an in vitro model to evaluate the mechanism of CHCl3 nephrotoxicity.

Animals↗
PubMed1983

Mechanism of chloroform nephrotoxicity. II. In vitro evidence for renal metabolism of chloroform in mice.

Preincubation of renal cortical slices with chloroform (CHCl3) from male, but not female, mice resulted in a subsequent decrease of the ability of the slices to accumulate the organic ions, p-aminohippurate (PAH) and tetraethylammonium (TEA). These sex-related differences, the time required for manifestation of this effect (60 to 90 min), and the concentration dependency (0 to 50 mumol, 0 to 4 microliter CHCl3) were similar to in vivo observations on CHCl3 nephrotoxicity in mice. Furthermore, an equimolar concentration of deuterated CHCl3 (CDCl3) in vitro was less effective than CHCl3 in decreasing PAH and TEA accumulation in male renal cortical slices. The effects of CHCl3 on PAH and TEA accumulation could be diminished or blocked by preincubation with CHCl3 in the presence of carbon monoxide or at 0 degrees C, respectively. The nephrotoxicity of CHCl3 in vitro was increased in renal cortical slices from male mice pretreated with diethyl maleate. Thus, this in vitro model with mouse renal cortical slices and the sex-related differences in CHCl3 nephrotoxicity suggests that the kidney may metabolize CHCl3 in situ to a nephrotoxic metabolite.

Animals↗
PubMed1984

Mechanism of chloroform nephrotoxicity. III. Renal and hepatic microsomal metabolism of chloroform in mice.

In vitro studies with male ICR mouse renal cortical slices have indicated that chloroform (CHCl3) is metabolized by the kidney to a nephrotoxic intermediate, possibly by a cytochrome P-450-dependent mechanism similar to that occurring in the liver. In this investigation, metabolism of 14CHCl3 by microsomes prepared from renal cortex and liver provided definitive evidence for a role of cytochrome P-450 in the renal metabolism and toxicity of CHCl3. 14CHCl3 was metabolized to 14CO2 and covalently bound radioactivity by male renal cortical microsomes; metabolism required oxygen, a NADPH regenerating system, was dependent on incubation time, microsomal protein concentration, and substrate concentration, and was inhibited by carbon monoxide. Consistent with the absence of CHCl3 nephrotoxicity in female mice, little or no metabolism of 14CHCl3 by female renal cortical microsomes was detected. CHCl3 produced a type I binding spectrum with oxidized male renal cortical and hepatic microsomes. Incubation of glutathione with microsomes and 14CHCl3 increased the amount of aqueous soluble metabolites detected with a concomitant decrease of metabolism to 14CO2 and covalently bound radioactivity, suggesting the formation of a phosgene conjugate as has been described for hepatic CHCl3 metabolism. These data support the hypothesis that renal cytochrome P-450 metabolizes CHCl3 to a nephrotoxic intermediate.

Animals↗
PubMed1984

Mechanism of chloroform nephrotoxicity. IV. Phenobarbital potentiation of in vitro chloroform metabolism and toxicity in rabbit kidneys.

Metabolism of chloroform (CHCl3) by a cytochrome P-450-dependent process to a reactive metabolite may be required to elicit hepatic and renal toxicities. Specific inducers or inhibitors of cytochrome P-450 have been employed frequently as tools to demonstrate this relationship between metabolism and toxicity in the liver. The experiments reported herein were designed to identify the relationship between metabolism and toxicity of CHCl3 in the kidney of rabbits, a species in which renal cytochrome P-450 is induced by phenobarbital. Pretreatment with phenobarbital enhanced the toxic response of renal cortical slices to CHCl3 in vitro as indicated by decreased p-aminohippurate and tetraethylammonium accumulation. Phenobarbital pretreatment also potentiated in vitro 14CHCl3 metabolism to 14CO2 and covalently bound radioactivity in rabbit renal cortical slices and microsomes. Addition of L-cysteine significantly reduced covalent binding in renal microsomes from both phenobarbital-treated and control rabbits and was associated with the formation of the radioactive phosgene-cysteine conjugate 2-oxothiazolidine-4-carboxylic acid (OTZ). Formation of OTZ was enhanced in renal microsomes from phenobarbital-pretreated rabbits. Thus, this in vitro model supports the hypothesis that the kidney metabolizes CHCl3 to the nephrotoxic metabolite, phosgene.

Animals↗
PubMedDate not supplied

Strain and sex differences in chloroform-induced nephrotoxicity. Different rates of metabolism of chloroform to phosgene by the mouse kidney.

It has been known for many years that there are species, strain, and sex differences in the incidence and severity of the nephrotoxicity caused by chloroform. However, the molecular basis for these differences has not been clearly understood. In this investigation, we have found that sensitivity to CHCl3 correlates with the capacity of the kidney to metabolize CHCl3 to the toxic metabolite phosgene (COCl2). For example, kidney homogenates of sensitive male DBA/2J mice metabolized CHCl3 to COCl2 more rapidly than did the less sensitive C57BL/6J mice. Similarly, kidney homogenates from male mice, which are sensitive to CHCl3-induced nephrotoxicity, metabolized CHCl3 to COCl2 at nearly an order of magnitude more rapidly than did those from female mice. Treatment of female mice with testosterone, however, reversed this trend. Cytochrome P-450 in the microsomal and mitochondrial fraction of the kidney appeared to catalyze the metabolism of CHCl3 to COCl2.

Animals↗