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PubMed1987

A review of the mutagenicity of chloroform.

Although chloroform (CHCl3) is metabolized in vivo and in vitro to a substance that covalently interacts with protein and lipid, its potential for binding to DNA is low. In addition, most of the assays for genotoxicity are negative. However, many of the genotoxicity results are inconclusive because of inadequacies in the experimental protocols. The types of genotoxicity tests this report is based on include bacterial, yeast, host-mediated, Drosophila sex-linked recessive lethal, mammalian cell mutagenicity, sperm head abnormality, cytogenetic, and DNA damage. On the basis of presently available information, no definitive conclusion on the mutagenic potential of CHCl3 can be reached.

Animals↗
PubMed1994

Multiple activation of chloroform in kidney microsomes from male and female DBA/2J mice.

Microsomes from the renal cortex of DBA/2J mice can metabolize chloroform through oxidative and reductive pathways, similar to hepatic microsomes. The oxidative or reductive nature of CHCl3 activation is strictly dependent on the oxygenation of the incubation mixture, as indicated by the formation of qualitatively different adducts to phospholipids (PLs). The protein and lipid binding levels measured in kidney microsomes from control females differed significantly from the binding levels observed with kidney microsomes from male and testosterone-treated female DBA/2J mice in aerobic conditions only. Therefore, the sex-dependent CHCl3-induced acute nephrotoxicity seems related only with the oxidative CHCl3 activation. The levels of adducts to PL polar heads and to protein showed a strict correlation with each other. Therefore, the assay of adducts to PL polar heads may be used as a substitute for the assay of adducts to protein. This might be especially convenient when studying the effects of both phosgene and the trichloromethyl radicals.

Animals↗
PubMed1984

Improved techniques for the photometric determination of partition coefficients, with particular reference to the chloroform-ammonia solvent system.

Accurate partition coefficients K = Corg/Caq in chloroform-ammonia can be obtained by measuring the absorbance of the aqueous layer, replenishing with fresh aqueous solvent, and remeasuring the absorption after reequilibration. Provided the solute has a reasonably strong UV absorption, only 0.1-5 mg of material is required. Neither the amount, the extinction coefficient, nor (in most cases) the purity of the substrate material need be known. In general, K values ranging from 100 to 0.01 can be measured with a precision of greater than or equal to 10%. A detailed analysis of the absorbance and volumetric error sources permits the optimum combination of experimental conditions such as volume ratios, cell lengths, and absorbance (either direct or differential, or with scale expansion) to be predicted a priori. Quantitative estimates for all primary error sources, such as photometric precision, baseline error, stray light, and volumetric errors were also experimentally determined. The theoretical error model was tested by determining K for aniline under widely ranging experimental conditions and by comparing the experimental standard deviations with those calculated from the theoretical model. The agreement was found to be satisfactory. The method described appears to be of particular usefulness for the determination of extraction or chromatographic parameters of basic drugs.

Ammonia↗
PubMed1992

Analysis of phospholipids in brain tissue by 31P NMR at different compositions of the solvent system chloroform-methanol-water.

Brain phospholipids can be quantitated by high-resolution 31P NMR of crude brain tissue extracts in the solvent system chloroform-methanol-water (+EDTA) which was introduced recently (P. Meneses and T. Glonek, J. Lipid Res. 29, 679 (1988)). Phospholipid resonance positions depend on the type of tissue extract and on solvent composition. The effects of systematic variation of the solvent system on phospholipid NMR profiles are presented. Resolution can be optimized by adjustment of the solvent composition. Virtually all phospholipid classes can be resolved, and the major phospholipids in brain: sphingomyelin and phosphatidyl-choline, -serine, -inositol, -ethanolamine, and -ethanolamine plasmalogen can be quantitated easily. Additional resonances have been assigned to phosphatidylcholine plasmalogen, alkylacyl-phosphatidylcholine and phosphatidylinositolbisphosphate. NMR offers a rapid method for quantitative analysis of the phospholipid composition in brain tissue which requires minimum sample handling.

Aged↗
PubMed2002

Toxicity of chloroform extract of prunus africana stem bark in rats: gross and histological lesions.

Chloroform extract of Prunus africana (Hook f. (Rosaceae) did not cause clinical signs or pathology in rats at daily oral doses of up to 1,000 mg/kg for 8 weeks. The extract caused marked clinical signs, organ damage and a 50% mortality rate at a dose of 3.3 g/kg for 6 days. The main lesions observed at this dose were marked centrilobular hepatocellular degeneration and necrosis, diffuse nephrosis, myocardial degeneration, lymphocytic necrosis and neuronal degeneration. The morphological damage in these tissues caused a corresponding rise in blood biochemical parameters namely, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, creatine kinase and blood urea nitrogen. The target organs of toxicity of this extract are the liver, kidney and heart. Overt toxicity occurred only after the administration of multiple doses of 3.3 g/kg body weight. These findings confirm the suitability of this extract for therapeutic use, since the doses used in the therapy of prostate gland are much lower than those used in this study and would therefore not be expected to cause pathological changes.

Alanine Transaminase↗
PubMed1995

Uncertainty in fitted estimates of apparent in vivo metabolic constants for chloroform.

It has become common practice to rely on fitted estimates of apparent in vivo metabolic constants (e.g., Vmax and KM) in the parameterization of PBPK models. Yet, quantitative estimates of precision in these fitted parameters are not routinely reported. Such information is needed to assess the reliability of model predictions. The purpose of this study was to assess the precision in estimates of Vmax and KM for chloroform, accounting for both the statistical uncertainties in parameter estimates from individual data sets and any additional uncertainty due to differences in the parameter estimates derived from various experiments. Joint confidence regions for Vmax and KM from each experiment, generated using maximum likelihood techniques, were used to evaluate these questions. Three previously published data sets were considered. Estimates of Vmax and KM obtained from these data sets differed more than could be explained as a consequence of a limited number of observations, measurement error, or stochastic error. Issues associated with the use of maximum likelihood techniques to estimate joint confidence regions, the estimation of metabolic constants from individual experiments within a gas uptake study versus the full data set, the degree of overlap in the joint confidence regions for metabolic constants obtained from separate data sets, and the implications for risk assessment are discussed.

Animals↗
PubMed1997

Trihalomethane comparative toxicity: acute renal and hepatic toxicity of chloroform and bromodichloromethane following aqueous gavage.

Bromodichloromethane (BDCM) and chloroform (CHCl3) are by-products of drinking water chlorination and are the two most prevalent trihalomethanes (THMs) in finished drinking water. To date, no comprehensive comparison of the acute renal and hepatic effects of BDCM and CHCl3 following oral gavage in an aqueous dosing vehicle has been conducted. To characterize BDCM- and CHCl3-induced nephro- and hepatotoxicity following aqueous gavage and compare directly the responses between these THMs, 95-day-old male F-344 rats were given single oral doses of 0.0, 0.75, 1.0, 1.5, 2.0, or 3.0 mmol BDCM or CHCl3/kg body wt in an aqueous 10% Emulphor solution. Compound-related hepatic and renal damage was evaluated by quantitating clinical toxicity markers in the serum and urine, respectively. Both THMs appear to be equally hepatotoxic after 24 h, but BDCM caused significantly greater elevations in serum hepatotoxicity markers than CHCl3 at 48 h following exposure to 2.0 and 3.0 mmol/kg. In addition to causing more persistent liver toxicity than CHCl3, BDCM also appears to be slightly more toxic to the kidney at lower doses. Potency differences between the two THMs may be due to pharmacokinetic dissimilarities such as greater metabolism of BDCM to reactive metabolites or more extensive partitioning of BDCM into kidneys and fat depots, resulting in prolonged target tissue exposure.

Animals↗
PubMed1995

The ability of predicted internal dose measures to reconcile tumor bioassay data for chloroform.

PBPK models are developed in the hope that they will improve our ability to extrapolate from one species to another and from one exposure regime to another. Evidence that a dose measure was successful at reconciling the available animal bioassay data would be encouraging. It would give us some confidence that the dose measure (as evaluated by a PBPK model) might yield reasonable predictions for yet other species (e.g., humans) and other dose routes. We have investigated the ability of a modified version of the Corley et al. (R. A. Corley, A. L. Mendrala, F. A. Smith, D. A. Staats, M. L. Gargas, R. B. Conolly, M. E. Andersen, and R. H. Reitz, 1990, Toxicol. Appl. Pharmacol. 103, 512-527) PBPK model for chloroform to reconcile the available bioassay data. Two rate-dependent dose measures, maximal rate of metabolism in the liver, and percentage of hepatocytes killed per day performed well at reconciling the rodent liver bioassay data, while all rate-independent dose measures performed less well. In contrast, none of the PBPK dose measures were capable of reconciling the rat and mouse kidney tumor response data. Here, administered dose scaled to body surface area performed the best.

Animals↗
PubMed1993

In vivo metabolism of chloroform in B6C3F1 mice determined by the method of gas uptake: the effects of body temperature on tissue partition coefficients and metabolism.

Mice exposed to various chemicals have been shown to respond by decreasing their core body temperature. To examine what effect such a response might have on the determination of in vivo metabolism, core body temperatures of B6C3F1 mice were recorded with temperature telemetry devices during exposure to chloroform (CHCl3) in a closed, recirculating chamber (100 to 5500 ppm). Significant decreases in body temperature occurred in all mice exposed to greater than 100 ppm CHCl3, with the greatest decrease of 14 degrees C occurring at 5500 ppm. A starting CHCl3 concentration of 4000 ppm had no effect on the 7-ethoxycoumarin O-deethylase (ECOD) activity or P450 levels determined at the end of a 5-hr gas uptake exposure. A physiologically based pharmacokinetic (PB-PK) model was developed to describe the effects of decreased body temperature on the analysis of metabolic data. In vitro ECOD activity as a measure of in vivo P450 metabolism was determined for temperatures ranging from 24 to 40 degrees C. In vitro enzyme activity decreased linearly from a maximum at 37 degrees C to one-third of this activity at 24 degrees C. A linear equation describing this enzymatic activity-temperature correlation was incorporated into the PB-PK model structure to describe decreases in metabolic activity resulting from decreases in core body temperature. In vitro blood/air and tissue/air partition coefficients were determined for CHCl3 at temperatures ranging from 24 to 40 degrees C. All blood/air and tissue/air partitions increased with decreasing temperature, while the tissue/blood partition coefficients calculated from the tissue/air and blood/air partitions decreased with decreasing temperature. Adding these temperature corrections to the model greatly improved the overall fit of the gas uptake curves at all concentrations. Incorporation of a first-order metabolic rate constant was also required to provide an adequate representation of the data at high concentrations. The analysis of gas uptake data by the use of a PB-PK computer model is a very powerful technique for determining in vivo metabolism of many volatile compounds, but the incorporation of significant deviations from a generally used model structure (i.e., Ramsey-Andersen model) to account for shortcomings of the model's ability to adequately analyze a gas uptake data set should be based on data collection when possible.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1995

Dose- and route-dependent alteration of metabolism and toxicity of chloroform in fed and fasting rats.

Effects of overnight food deprivation on the metabolism and toxicity of chloroform (CHCl3) administered to rats per os (po), intraperitoneally (ip), or by inhalation (inh) at different doses were investigated. Rats that had been either deprived of food overnight or normally fed were challenged with CHCl3 either po (0, 100, 200, or 400 mg/kg), ip (0, 100, 200, or 400 mg/kg), or inh (0, 50, 100, or 500 ppm for 6 hr). Overnight fasting increased CHCl3 metabolism in vitro about threefold with a decrease of liver glutathione content to 67%. The fasting caused route- and dose-dependent alteration in the metabolism and toxicity of CHCl3. The area-under-the-curve (AUC) of blood CHCl3 concentration was invariably smaller following po than ip administration, and CHCl3 administered po caused more severe hepatic damage than did the same amount of CHCl3 administered ip. With po administration, the AUC (toxicity) of CHCl3 in fasting rats was significantly smaller (higher) than that of fed rats at a dose as small as 100 mg/kg, whereas, with ip administration at such a small dose, fasting caused no significant alteration in the AUC (toxicity). When rats were exposed by inhalation to CHCl3 vapor, food deprivation had little or no effect on either the blood concentration or the toxicity until the exposure concentration was raised to 500 ppm. The present study indicates that po administration is different from both ip and inh administration with regard to the effect of enzyme induction on the toxicokinetics of CHCl3, mainly due to the first-pass metabolism unique to po administration.

Administration, Inhalation↗
PubMed1997

Dose- and route-dependent alterations in metabolism and toxicity of chemical compounds in ethanol-treated rats: difference between highly (chloroform) and poorly (carbon tetrachloride) metabolized hepatotoxic compounds.

The dose and route dependency of the metabolism and the toxicity of chloroform (CHCl3) and carbon tetrachloride (CCl4) was investigated in ethanol-treated rats. Rats that had been kept on either an ethanol (containing ethanol at 2 g/rat/day) or a control (containing no ethanol) liquid diet for 3 weeks were challenged with CHCl3 or CCl4 by inhalation (0, 50, or 500 ppm x 6 hr), or by p.o. or i.p. administration (0, 0.105, or 1.675 mmol/kg). Ethanol consumption, which increased the in vitro metabolism of both compounds six- to sevenfold, affected the metabolism and toxicity of CCl4 differently from those of CHCl3. Ethanol increased the metabolism and toxicity of CHCl3 at 500 ppm only, whereas it increased the metabolism and toxicity of CCl4 at either 50 or 500 ppm. In addition, the effect of ethanol consumption differed between CHCl3 and CCl4 depending on the route of administration (p.o. or i.p.) and the dose (0.105 or 1.675 mmol/kg). For the p.o. route, ethanol increased the metabolism and toxicity of both compounds at either dose. For the i.p. route, however, ethanol increased the metabolism and toxicity of the high dose of CHCl3 only, but of both CCl4 doses. The dose- and route-dependent differences in the effect of enzyme induction on the metabolism and toxicity between CHCl3 and CCl4 can be explained by a supposition that the hepatic blood flow rate-limits the metabolism of a low dose of CHCl3 (perfusion-limited metabolism), whereas the metabolic capacity of the liver limits the metabolism of CCl4 (capacity-limited metabolism) irrespective of dose.

Administration, Inhalation↗
PubMed1997

Glutathione S-transferase-mediated mutagenicity of trihalomethanes in Salmonella typhimurium: contrasting results with bromodichloromethane off chloroform.

Trihalomethanes (THMs) are the most prevalent disinfection by-products identified in chlorinated drinking water. Among the THMs, chloroform (CHCl3) generally occurs at the highest concentration in finished water, but the concentrations of each of the brominated THMs (CHBrCl2, CHBr2Cl, and CHBr3) can exceed that of CHCl3. Each of these four THMs was carcinogenic in rodents in chronic oral dosing studies. This study assessed THM mutagenicity in a strain of Salmonella typhimurium TA1535 that was transfected with rat theta-class glutathione S-transferase T1-1 (+GST). The +GST strain and its nontransfected parent strain (-GST) were employed in a plate-incorporation assay and exposed for 24 hr to the vapor of individual THMs at concentrations up to 25,600 ppm in sealed Tedlar bags. Base-substitution revertants were produced in the +GST strain in a dose-dependent fashion by CHBrCl2 but not by CHCl3. At 4800 ppm CHBrCl2, which produced a calculated agar concentration of 0.67 mM, there were 419 +/- 75 revertants per plate compared to a spontaneous level of 23 +/- 5. CHCl3 produced a doubling of revertants only at the two highest concentrations tested (19,200 and 25,600 ppm). These results indicate that bromination of THMs confers the capability for theta-class GST-mediated transformation to mutagenic intermediates at low substrate concentrations, suggesting the possibility of a similar activation route in humans. Further, the very low affinity of the GSH-dependent pathway for CHCl3 demonstrates that different THMs can induce adverse effects via different mechanisms, indicating that risk evaluations of THMs should not treat members of this class as if they shared a common mode of action.

Animals↗
PubMed2000

Hepatoprotection by dimethyl sulfoxide. III. Role of inhibition of the bioactivation and covalent bonding of chloroform.

Dimethyl sulfoxide (DMSO) has previously been shown to have the ability to attenuate chloroform (CHCl(3))-induced liver injury in the naive rat even when administered 24 h after the toxicant. These studies were undertaken to determine if the protective action by late administration of DMSO is due to an inhibition of the bioactivation of CHCl(3). This was done by comparing the cytochrome P450 inhibitors, diallyl sulfide (DAS), and aminobenzotriazole (ABT) to DMSO for their protective efficacy when administered 24 h after CHCl(3) exposure. In addition, (14)CHCl(3) was utilized to measure the effect of DMSO and ABT on the covalent binding of CHCl(3) in the liver following their late administration. Male Sprague-Dawley rats (300-350 g) received 0.75 ml/kg CHCl(3) po. Twenty-four hours later, they received ip injection of 2 ml/kg DMSO, 100 mg/kg DAS, or 30 mg/kg ABT. Plasma ALT activities and quantitation of liver injury by light microscopy at 48 h after CHCl(3) dosing indicated that all three treatments were equally effective at protecting the liver. A detailed study of the time course of injury development indicated that the protective action of DMSO was occurring within 10 h of its administration. Therefore, in the radiolabel studies, rats were killed 24-34 h after receiving 0.75 ml/kg CHCl(3) (30 microCi/kg (14)CHCl(3)) po. Treatment with ABT at 24 h after (14)CHCl(3) dosing decreased the covalent binding of (14)C to hepatic protein by 35% and reduced the amount of (14)C in the blood by 50% by 10 h after its administration. DMSO treatment did not significantly affect any of these parameters. The lack of effect by late administration of DMSO on the covalent binding of CHCl(3) would indicate that DMSO may offer protection by mechanisms other than inhibition of the bioactivation of CHCl(3). These studies also indicate that specific cytochrome P450 inhibitors may be of benefit in clinical situations to help treat the delayed onset hepatitis that can result following poisoning with an organohalogen, even if the antidotes are administered a number of hours after the initial exposure.

Alanine Transaminase↗
PubMed1984

Different pathways of chloroform metabolism.

Chloroform metabolism can occur in liver, under physiological pO2 conditions, with and without participation of O2. Although, under anaerobic conditions the protein covalent binding of CHCl3 metabolites is lowered, cytochrome P-450 decrease is more substantial. The loss of cytochrome P-450 cannot be accounted for either by heme destruction or lipid peroxidation under anaerobic conditions. It is not prevented by GSH. Different spectral changes occur between 400 and 500 nm, depending on the oxygen concentration; transition takes place at 1-6% pO2.

Animals↗
PubMed1977

Purification and properties of adenosine triphosphatase solubilized from beef heart mitochondria by chloroform.

Soluble, oligomycin-insensitive ATPase released from beef heart mitchondria by chloroform extraction can be further purified by Sepharose 6B gel filtration. This purification increases enzyme activity 4--5 times (100-130U/mg). According to specific activity, high purity and ability to reconstitute oligomycin-sensitive complex, isolated ATPase is quite comparable with enzyme preparations isolated by other methods.

Adenosine Triphosphatases↗
PubMed1985

Phosphorylation of chloroform soluble compounds in plasma membranes of human epidermoid carcinoma A431 cells.

This study investigated a possible role for the epidermal growth factor (EGF) receptor protein tyrosine kinase in phosphoinositide metabolism with plasma membrane vesicles from human epidermoid carcinoma (A431) cells. We found a novel chloroform-soluble product radiolabeled with [gamma-32P]ATP that did not migrate from the origin in the thin layer system designed to separate the phosphoinositides, appeared as a single band of Mr = 3500 on polyacrylamide gels in the presence of dodecyl sulfate, had an ultraviolet absorbance spectrum with a maximum at 275 nm and stained with Coomassie dye. Based on these properties this phosphorylation product is referred to as a proteolipid. The 32P label was not detected in phosphotyrosine [Tyr(P)], phosphoserine [Ser(P)] or phosphothreonine [Thr(P)] and was lost during acid or base hydrolysis. Phosphorylation of proteolipid was increased significantly by EGF, whereas phosphorylation of phosphatidic acid was decreased and labeling of phosphoinositides was unaffected. Thus, it appears that in A431 membranes the EGF receptor/kinase does not utilize phosphatidylinositol as a substrate, but does phosphorylate a membrane proteolipid.

Adenosine Triphosphate↗
PubMed1998

Molds on house walls and the effect of their chloroform-extractable metabolites on the respiratory cilia movement of one-day-old chicks in vitro.

The ciliostatic activity of the chloroform-extractable endo- and exometabolites of 5 strains of filamentous fungi--Alternaria sp., Aspergillus glaucus group, Aspergillus versicolor, Cladosporium sphoerospermum, Penicillium sp. and Ulocladium sp.--isolated from molded walls of a dwelling--on tracheal cilia from 1-d-old chicks in vitro was evaluated. Endometabolites of Alternaria sp. and A. versicolor and exometabolites of Ulocladium sp. were the most active, these extracts stopped the ciliary movement within 1 d. The results are discussed in relation to the health status of people living in "moldy" dwellings.

Age Factors↗