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PubMed1991

Halothane and eucalyptol as alternatives to chloroform for softening gutta-percha.

Because chloroform was identified as a potential carcinogen by the Food and Drug Administration, interest has been revived to identify an alternative solvent to soften gutta-percha for removal from obturated root canals. This study compared the effectiveness of halothane, eucalyptol, and chloroform in softening gutta-percha in simulated root canals. One milliliter of a solvent was placed into a small glass funnel whose stem was obturated with a 30-mm column of gutta-percha. After 30 s, softening was evaluated for each solvent by recording the time required to reach a depth of 10 mm by hand filing with a #100 Hedstrom file. The depth of penetration of a #40 finger plugger under constant weight for 15 min was also determined for each solvent. By using a one-way analysis of variance and Scheffe's test, all comparisons were not significant except for the depth of penetration with constant weight between chloroform and halothane (p less than 0.05). The results indicate that halothane and eucalyptol are suitable alternatives to chloroform as gutta-percha softening solvents.

Analysis of Variance↗

PubMed2000

Risk assessment case study--chloroform and related substances.

Chlorine, used as an important disinfectant for drinking water, can react with naturally occurring organic matter to form chloroform, bromodichloromethane, chlorodibromomethane and bromoform. Chloroform and other trihalomethanes have been shown to increase tumours of the liver, kidney or large intestine in rats or mice. The risk to man from these contaminants must be assessed carefully since there is considerable benefit associated with the use of chlorine. The weight of evidence suggests that chloroform is non-genotoxic and there are data, for each site, to indicate that tumours only occur at high doses where there is also tissue damage. Bromodichloromethane has also been shown to increase liver and kidney tumours but this and bromoform have been shown to increase large intestinal tumours in rats. The weight of evidence is that they are only weak genotoxins and they do not appear to be active in vivo. It is probable that the mechanism for the liver and kidney tumours is the same as for chloroform but the mechanism for the large intestinal tumours is uncertain. However, the toxicity and carcinogenicity of these substances is profoundly affected by dosing in corn oil. New studies suggest that dosing in drinking water would not result in increases in tumours. The evidence suggests that the use of a threshold approach, based on a tolerable daily intake, would be the most appropriate way of determining safe levels in drinking water.

Animals↗

PubMed1996

Chloroform-induced cytotoxicity and regenerative cell proliferation in the kidneys and liver of BDF1 mice.

In a 2-year chloroform inhalation bioassay, an increased incidence of tumors was observed in the kidneys of male BDF1 mice and the liver of female BDF1 mice exposed to the highest exposure concentration of 90 ppm. To investigate the role of cytotoxicity and regenerative cell proliferation in tumor formation, male and female BDF1 mice were exposed to chloroform vapor concentrations of 0, 0.3, 5, 30, or 90 ppm 6 h/day for 4 days. Bromodeoxyuridine (BrdU) was administered via osmotic pumps implanted 3.5 days prior to necropsy, and the labeling index (LI), or percentage of cells in S-phase, was quantified using BrdU immunohistochemistry. To assess longer-term responses, additional male mice were exposed 5 days/week for 2 weeks to 0, 30, or 90 ppm. Degenerative lesions and an increase in the LI of seven- to ten-fold over controls were observed in the kidneys of male but not female mice exposed to 30 or 90 ppm. Liver lesions and increased hepatocyte LI were observed in male mice exposed to 30 or 90 ppm and in female mice exposed to 90 ppm. In the 2-week exposure groups 40% of the 30 ppm group and 80% of the 90 ppm group died with severe kidney damage, indicating that both 30 and 90 ppm exceed a maximum tolerated dose. Thus, in the 2-year bioassay chloroform concentrations had to be stepped-up over a period of weeks in order for the male mice exposed to 30 or 90 ppm to survive. The extrapolation of tumor data from such an unusual procedure is questionable. These observations are consistent with a substantial database that indicates that tumor induction by chloroform occurs via a non-genotoxic-cytotoxic mode of action and is secondary to organ-specific toxicity. These data further support the premise that doses that do not induce regenerative cell proliferation do not present an increased risk of cancer.

Animals↗

PubMed2003

Adduction of the chloroform metabolite phosgene to lysine residues of human histone H2B.

Human exposure to trihalomethanes such as chloroform has been associated with both cancer and reproductive toxicity. While there is little evidence for chloroform mutagenicity or DNA adduct formation, in vivo studies in rats have demonstrated adduction to histones and other nuclear proteins. Histones play a key role in controlling DNA expression particularly through the acetylation of lysine residues in their N-termini. Therefore, we studied the reaction of phosgene, the major active metabolite of chloroform, with the N-terminus of human histone H2B (Hpep, Pro-Glu-Pro-Ala-Lys-Ser-Ala-Pro-Ala-Pro-Lys-Lys-Gly-Ser-Lys-Lys-Ala-Val-Thr-Lys-Ala-Gln-Lys) in a model chemical system. The aim of this study was to assess whether phosgene is able to form irreversible adducts with this peptide and to investigate which residues are most susceptible. Hpep was reacted with a range of phosgene concentrations (0.03-36 mM) at 37 degrees C, pH 7.4. The products of these reactions, analyzed by matrix-assisted laser desorption ionization MS, showed that up to three CO moieties could be adducted to the peptide. The singly and doubly adducted peptides were purified by HPLC and then hydrolyzed with trypsin to produce a series of fragments that were analyzed by HPLC-MS. The tryptic products showed that adduction occurred principally at lysine residues, and that all seven lysine residues of the peptide were subject to adduction. Collision-induced dissociation analysis using ion trap MS-MS of the tryptic fragment [Pro-Glu-Pro-Ala-Lys-Ser-Ala-Pro-Ala-Pro-Lys + CO] and of the full-length singly adducted peptide supported the role of lysine residues in adduction; the data also indicated that the N-terminal proline and the serine residues are susceptible. Addition of glutathione to the reaction mixture only partially attenuated adduct formation and allowed production of another adducted species, i.e., Hpep-CO-glutathione. The occurrence of such reactions to the N-termini of histones, if confirmed by in vivo studies, could help to explain the mechanism of chloroform carcinogenicity.

Amino Acid Sequence↗

PubMed1999

Reversible azoospermia by oral administration of the benzene chromatographic fraction of the chloroform extract of the seeds of Carica papaya in rabbits.

Contraceptive efficacy, reversibility and toxicity, if any, of the benzene, chloroform and ethyl acetate chromatographic fractions of the chloroform extract of the seeds of Carica papaya have been investigated in adult male rabbits at a dose regimen of 50 mg/animal/day for 150 days of treatment. Body weight, semen analysis, hematology, serum clinical biochemistry and the fertility status of control and treated animals were evaluated. Chloroform and ethyl acetate chromatographic fractions did not produce appreciable changes in these parameters. However, the benzene chromatographic fraction resulted in uniform azoospermia after 15 days of treatment, which was maintained for the remainder of the 150-day observation period. The levels of fructose, glycerophosphocholine, acid phosphatase and lactate dehydrogenase in the seminal plasma were within the control range. Hematology and the serum clinical parameters showed no appreciable changes, indicating lack of toxicity. The libido of the treated animals was normal and the fertility rate was zero. Complete normalcy of altered parameters was observed 60 days following withdrawal of treatment. It is concluded that the benzene chromatographic fraction of the chloroform extract of the seeds of Carica papaya possesses reversible male contraceptive potential and the effects appear to be mediated through the testis.

Acetates↗

PubMed2005

Dermal uptake of chloroform and haloketones during bathing.

Dermal contact with some organic disinfection by-products (DBPs) such as trihalomethanes in chlorinated drinking water has been established to be an important exposure route. We evaluated dermal absorption of two haloketones (1,1-dichloropropanone and 1,1,1-trichloropropanone) and chloroform while bathing, by collecting and analyzing time profiles of expired breath samples of six human subjects during and following a 30-min bath. The DBP concentrations in breath increased towards a maximum concentration during bathing. The maximum haloketone breath concentration during dermal exposure ranged from 0.1 to 0.9 microg / m(3), which was approximately two orders of magnitude lower than the maximum chloroform breath concentration during exposure. Based on a one-compartment model, the in vivo permeability of chloroform, 1,1-dichloropropanone, and 1,1,1-trichloropropanone were approximated to be 0.015, 7.5 x 10(- 4), and 4.5 x 10(- 4) cm / h, respectively. Thus, haloketones are much less permeable across human skin under normal bathing conditions than is chloroform. These findings will be useful for future assessment of total human exposure and consequent health risk of these DBPs.

Acetone↗

PubMed1979

Purification and properties of the adenosine triphosphatase released from the liver mitochondrial membrane by chloroform.

1. Soluble ATPase (adenosine triphosphatase) activity is released when rat liver submitochondrial particles are shaken with chloroform, provided that ATP or glycerol is present in the suspending medium. The extraction is very rapid and appears to be complete. 2. The ATPase of the chloroform extract is about 50% pure and can be readily purified to a specific activity of 60-70mumol/min per mg of protein by (NH(4))(2)SO(4) fractionation and column chromatography on Sephadex G-200. 3. The particulate and soluble ATPases have many similar properties, including their K(m) values for ATP, activation by various metal ions, hydrolytic activity with other nucleotides and stimulation by bicarbonate ions. 4. Unlike the particulate enzyme, the soluble enzyme is cold-labile and insensitive to oligomycin. 5. The molecular weight indicated by the mobility of the soluble ATPase on Sepharose 6B is 360000. 6. The soluble ATPase combines very readily with liver submitochondrial particles depleted of ATPase by salt extraction, and oligomycin-sensitivity is restored. Very little recombination of the enzyme occurs with chloroform-extracted particles. 7. The soluble enzyme contains orcinol-reactive material, suggesting that it may be a glycoprotein. The carbohydrate content was estimated to be 1-2% by weight. 8. It is concluded that the liver ATPase obtained by the chloroform extraction method of Beechey, Hubbard, Linnett, Mitchell & Munn [(1975) Biochem. J.148, 533-537] is similar to other preparations described previously and that this method is superior in simplicity and speed.

Adenosine Triphosphatases↗

PubMedDate not supplied

Uptake of chloroform by skin on brief exposures to the neat liquid.

The uptake of chloroform into hairless rat's stratum corneum after application of the neat solvent directly to the skin has been studied. Tape stripping was used to determine amounts deposited within the stratum corneum and also the clearance of the compound from the skin following varied levels of exposure. Three minutes exposure to neat chloroform was adequate to achieve a limiting accumulation in the stratum corneum and thus it appears to take this long for the gradient of chloroform to be established fully across this structure. There was indication of progressively deeper penetration of chloroform as the exposure time was increased from 1 to 8 minutes. Local irritation and a loosening of the superficial layers of stratum corneum were apparent with as little as 2 minutes of exposure to the solvent and were exacerbated with further increases in exposure duration. Following exposure, clearance of the solvent from the skin surface was rapid. Interestingly, the rate of clearance, as followed by stripping, was comparable on live and freshly euthanized rats. This implies that once the exposure is terminated evaporation from the surface, and not systemic uptake by way of the local vasculature, is the predominant means of clearance at an open surface.

Analysis of Variance↗

PubMed1982

Trihalomethanes: II. Reversibility of toxicological changes produced by chloroform, bromodichloromethane, chlorodibromomethane and bromoform in rats.

Groups of 20 male and 20 female rats were fed 0, 5, 50, 500 or 2500 ppm trihalomethanes (chloroform, bromodichloromethane, chlorodibromomethane and bromoform) in their drinking water for 90 days. Ten rats from each group were killed at this time and the remaining animals were fed tap water for a further 90 days before they were sacrificed. Suppression of growth rate was observed in male and female rats fed 2500 ppm chloroform and bromodichloromethane (BDCM) for 90 days. After the subsequent 90-day recovery period, no effects on body weight gain in either sex were apparent. Food consumption was depressed in all groups of males and females receiving 2500 ppm chloroform, chlorodibromomethane (CDBM) and BDCM for 90 days and in these same groups during the recovery period. Bromoform at 2500 ppm suppressed food consumption of male rats but this effect was not evident 90 days after cessation of exposure. Decreased lymphocyte counts were only observed in the recovery groups fed chloroform (500 ppm, male), CDBM (2500 ppm, female) and bromoform (2500 ppm, females). Histological changes in the livers and thyroids of male and female rats were qualitatively and quantitatively similar for the four trihalomethanes. These changes were mild in nature, and were not evident 90 days after cessation of exposure. These data indicate that trihalomethanes can produce biochemical hematological and histological changes but most of these were reversible when exposure had terminated.

Animals↗

PubMed1988

Chloroform induction of ornithine decarboxylase antizyme (ODC-AZ) in male rat liver.

Chloroform stimulation of rat hepatic ODC is most dramatic at 18 h following a single injection. Repeated dosing, 1 dose/d for up to 7 d, results in a daily decline in the ability of the liver enzyme to respond 18 h after the final injection. We postulated that this decline was due to an increased synthesis and accumulation of the OCD-AZ protein. ODC-AZ was determined by measuring the inhibition of isolated ODC activity as described by Hayashi and Fujita and modified in our laboratory to use kidney ODC. Male and female Fischer 344 rats were injected daily for 1, 3, or 7 d with 3.0 mmol/kg chloroform. Chloroform induced ODC-AZ activity in males at 3 and 7 d (26% and 37% inhibition of the ODC activity in the incubation medium, respectively). While females exhibited a similar decline in ODC activity after repeated doses, ODC-AZ was not induced. Thus, it would appear that daily exposure of rats to chloroform results in a refractoriness of its induction of ODC activity accompanied by an induction of the ODC-AZ in males. However, in females these two responses were not directly related.

Animals↗

PubMed1989

Chloroform-induced multiple forms of ornithine decarboxylase: differential sensitivity of forms to enhancement by diethyl maleate and inhibition by ODC-antizyme.

The role of glutathione (GSH) and ornithine decarboxylase-antizyme (ODC-AZ) in the regulation of the chloroform-mediated stimulation of rat hepatic ornithine decarboxylase (ODC) was investigated. We have previously implicated roles for each while examining the chloroform effect on crude cytosolic enzyme preparations. In this study we examined the effect of pretreatment with diethyl maleate (DEM), a GSH-depleting agent, on the chloroform stimulation of the two forms of the rat hepatic ODC enzyme and the sensitivity of these two forms to inhibition by the ODC-AZ. While the pretreatment with DEM provided a greater amount of the two forms of the ODC enzyme, it also resulted in a differential stimulation of each form when compared to chloroform alone. Additionally, Peak II was 20-25% more sensitive to the same amount of ODC-AZ then Peak I ODC activity.

Animals↗

PubMed1962

The enhancement of chloroform-induced plasma proteolytic activity by epsilon aminocaproic acid.

The proteolytic activity in chloroform-treated plasma euglobulins has been attributed to plasmin. Plasmin can digest both casein and fibrin. Epsilon aminocaproic acid, which inhibits the activation of plasminogen, the precursor of plasmin, by streptokinase, urokinase, and tissue activators enhanced the development of casein hydrolytic activity in a mixture of chloroform and plasma euglobulins. Fibrinolytic activity was also enhanced, but this was evident only if the epsilon aminocaproic acid was removed from the chloroform-treated euglobulins prior to assay. The reasons for the paradoxical enhancement of chloroform-induced casein hydrolysis by euglobulins containing epsilon aminocaproic acid are unclear. However, studies of optimal pH, heat stability, and the effect of ionic strength on the activation of the precursor of this proteolytic enzyme do not differentiate it from plasminogen.

Amino Acids↗

PubMed1976

Analysis of chloroform in blood.

A gas chromatographic method for the analysis of chloroform in blood has been developed in which the anaesthetic agent is extracted into carbon disulphide and trichlorethylene is used as an internal standard. Injection of the extract into a chromatograph resulted in a chloroform peak eluted after 165 s and a trichloroethylene peak at 310 s, both of which are much later than the solvent peak which is completely eluted in 100 s. The mean percentage recovery of chloroform from blood in the range of 1.4--38.12 mg/100 ml was 98.8+/-1.32. This is an improvement on all previous methods described for the estimation of chloroform.

Carbon Disulfide↗

PubMed1997

Clinical evidence for delayed chloroform poisoning.

From its introduction in 1847, chloroform proved to be a potent anaesthetic agent and over the next 50 yr its use became widespread. However, in 1912 the Committee on Anaesthesia of the American Medical Association stated that they were concerned with the occurrence of delayed chloroform poisoning in a number of cases. This conclusion was based on case reports and experimental animal data. However, subsequent studies and reported series of chloroform anaesthesia in humans have suggested a lower incidence of clinically significant liver injury. In this article we have investigated this discrepancy by analysing the published clinical data relating chloroform anaesthesia to liver damage.

Anesthesia, Inhalation↗

PubMed2006

An unusual autoerotic fatality associated with chloroform inhalation.

We report the death of a young male attributed to chloroform poisoning during autoerotic asphyxia. He was found lying on the floor of his apartment, prone on a piece of foam and a towel. His eyes were bound with a towel, his lower face and nose were almost entirely covered with duct tape surrounding a rubber hose in his mouth. The other end of the hose was loosely sitting inside an open bottle which was in a box beside him. He was bound-up by an intricate system of ropes, handles, and rods, ending with a noose around his neck. Toxicology testing indicated chloroform concentrations of 18.1 mg/L in femoral blood and 1.5 mg/L in urine. Chloroform was measured by headspace gas chromatography with flame-ionization detection using 1,1,1-trichloroethane as the internal standard. The cause of death was recorded as "chloroform toxicity" with "autoerotic asphyxia" as a contributing factor, and the manner of death was "accidental".

Asphyxia↗

PubMed1997

'My beloved chloroform'. Attitudes to childbearing in colonial Queensland: a case study.

In 1847 the anaesthetic and analgesic properties of chloroform were discovered. This technology generated a new era for midwifery: mothers could be relieved of pain in childbirth. The introduction of chloroform for childbirth saw increasing medical dominance in obstetrics, traditionally in the hands of the midwife. At the same time the use of chloroform sparked a medical and moral controversy which lasted for several decades. On the one hand women were destined by the 'curse of Eve' to experience pain during childbirth; on the other, medical humanitarians and practitioners believed that there were technical and moral reasons for alleviating pain in childbirth. In concentrating on the debate historians have largely ignored the reactions of mothers to the introduction of the technology. This paper explores changing attitudes to childbearing within the context of colonial Queensland society, 1860-90, by examining the correspondence of an upper-class mother. Her education and liberal outlook, and a certain ambivalence towards motherhood, all influenced her attitude to the use of chloroform and the process of childbirth.

Anesthesia↗

PubMed1992

The association of waterborne chloroform with intrauterine growth retardation.

The potential reproductive effects of long-term, low-dose exposure to chloroform have received little attention despite the known, acute toxicity of high exposures and the wide-spread occurrence of low concentrations in drinking water. We studied the association of waterborne chloroform with low birthweight (less than 2,500 gm), prematurity (less than 37 weeks gestation), and intrauterine growth retardation (less than 5th percentile of weight for gestational age). Cases were not mutually exclusive, but each outcome was analyzed independently. Birth certificates from January 1, 1989, to June 30, 1990, were used to identify cases and randomly selected controls. All were live, singleton infants born to non-Hispanic, white women from Iowa towns with 1,000-5,000 inhabitants. Exposures to chloroform and other trihalomethanes were ecologic variables based on maternal residence and a 1987 municipal water survey. After adjustment for maternal age, parity, adequacy of prenatal care, marital status, education, and maternal smoking by multiple logistic regression, residence in municipalities where chloroform concentrations were greater than or equal to 10 micrograms/liter was associated with an increased risk for intrauterine growth retardation (odds ratio = 1.8, 95% confidence interval = 1.1-2.9). The major limitations of this study involve the ascertainment and classification of exposures to trihalomethanes, including such issues as the imprecision of using aggregate municipal measures for classifying exposure at the level of the individual, the potential misclassification due to residential mobility, and the fluctuation of trihalomethane levels.

Adult↗

PubMed2025

A universal, high-quality, and high-yield DNA purification method for mycobacteria, including Mycobacterium tuberculosis: large-scale assessment of the chloroform-bead method.

UNLABELLED: Genomic analysis of mycobacteria has become increasingly crucial for understanding drug-resistance mechanisms, molecular epidemiology, and pathogenesis. However, efficient extraction of high-molecular-weight genomic DNA from these organisms remains challenging because of their thick mycolic acid-rich cell walls. In this study, we report the chloroform-bead method, a universal DNA extraction protocol that combines chemical and mechanical disruptions to overcome these challenges. Multi-laboratory evaluation (16 sites) demonstrated the chloroform-bead method's superiority over conventional methods for Mycobacterium tuberculosis (DNA yield: 17.9 vs 1.9 µg, purity A260/A230: 1.86 vs 1.22, both P < 0.001). Single-facility assessment extended these findings to >32 nontuberculous mycobacterial species (n = 1,058), showing performance comparable to M. tuberculosis (n = 1,000), with both achieving median yields of 22.2 µg DNA and consistent quality metrics. The chloroform-bead method significantly reduced the processing time from 2 to 3 days to 2 h while ensuring complete sample sterilization, eliminating the need for species-specific optimization. This streamlined and universally applicable protocol represents a practical advancement in mycobacterial DNA extraction methodology, ideal for high-throughput genomic studies and routine clinical diagnostics. IMPORTANCE: Mycobacterial genomics is crucial for understanding pathogenesis and drug resistance; however, DNA extraction remains a significant challenge because of its unique cell wall. Traditional methods rely on enzymatic treatments, resulting in complex and time-consuming protocols with variable results. The chloroform-bead method introduces a paradigm shift by chemically and mechanically disrupting the mycolic acid layer and eliminating the need for enzymatic treatment. This standardized approach ensures consistent, high-quality DNA extraction across diverse mycobacterial species, thereby enhancing research capabilities and clinical applications.

Chloroform↗