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PubMed1984

Does chloroform exposure while showering pose a serious public health concern?

The problem of organic chemicals in drinking water has been well known since 1974-1975 when the National Organics Reconnaissance Survey (NORS) and the National Organics Monitoring Survey (NOMS) showed that drinking water contaminated by organics could be found throughout the nation. Of special concern are the trihalomethanes (THMs) one of which, chloroform, is a suspected human carcinogen, and has been proven to be carcinogenic in test animals. In addition to chloroform exposure from drinking water, inhalation of chloroform from air while showering may constitute an additional source of exposure. Since the EPA has not included exposure to airborne chloroform in their risk-assessment calculations, the actual cancer risk to the population due to chloroform in drinking water may be significantly higher than the EPA estimated. It is suggested that a major research effort be directed at the determination of airborne chloroform levels in the domestic shower environment. Effort should also be made to determine what variables affect the magnitude of the chloroform levels if present. Once these variables are known it may be possible to educate the public about the potential hazard and ways to eliminate or reduce it.

Air Pollutants↗

PubMed2006

The antimicrobial effect of chloroform on Enterococcus faecalis after gutta-percha removal.

The purpose of this in vitro study was to evaluate the antimicrobial effectiveness of chloroform on Enterococcus faecalis when used as a gutta-percha solvent during endodontic retreatment. Bilaterally matched human teeth were instrumented, infected with E. faecalis, and obturated. The gutta-percha was then removed using either chloroform or saline. Bacterial samples were collected after gutta-percha removal and following additional apical enlargement. A significant difference was seen (p<0.05) between the number of colony forming units (CFU) of E. faecalis for teeth retreated using chloroform (mean 21+56 CFU/ml) versus saline (mean 280+480 CFU/ml). Negative cultures were obtained in 11 of 17 chloroform samples and none of the saline samples. Samples taken after apical enlargement two sizes larger than the original master apical file showed a significant difference (p<0.05) between teeth retreated using chloroform versus saline. Negative cultures were seen in 9 of 17 chloroform samples and 1 of 17 saline samples. This study demonstrated that the use of chloroform during endodontic retreatment significantly reduced intracanal levels of cultivatable E. faecalis.

Anti-Bacterial Agents↗

PubMed1998

Chloroform and carbon tetrachloride induce intrachromosomal recombination and oxidative free radicals in Saccharomyces cerevisiae.

Chlorination of drinking water results in the generation of low levels of numerous chlorinated hydrocarbons due to the reaction of chlorine with naturally occurring organic compounds in the water. Concern has been raised about the safety of these chlorinated contaminants as several of them, most notably chloroform (trichloromethane), have been shown to be carcinogenic in long-term rodent bioassays and weak correlations between trihalomethane levels in drinking water and an increased risk of bladder and colorectal cancer in humans have been found. Chloroform and carbon tetrachloride induce liver cancer in rats and mice only at doses where significant hepatotoxicity is observed and have been classed as non-genotoxic carcinogens. We have investigated the ability of chloroform, carbon tetrachloride and 1,1,1-trichloroethane to induce deletions via intrachromosomal recombination in the yeast Saccharomyces cerevisiae. Chloroform and carbon tetrachloride induced this genotoxic recombination event at similar doses, 1,1,1-Trichloroethane gave only a weak response in the DEL recombination assay and only at the highest dose. We further show that chloroform and carbon tetrachloride, but not trichloroethane, induced oxidative free radical species in our yeast strain. The free radical scavenger N-acetylcysteine reduced chloroform-induced toxicity and recombination, and both chloroform and carbon tetrachloride were able to oxidize the free radical-sensitive reporter compound dichlorofluorescein diacetate in vivo. The implications of these findings to the carcinogenic activities of the three compounds are discussed.

Carbon Tetrachloride↗

PubMed2003

Copper catalysis in chloroform formation during water chlorination.

The seminal work of Rook initiated a considerable body of research regarding the formation of trihalomethanes (THMs) and other by-products of chlorine-based disinfection. Since that time, a broad spectrum of compounds has been identified as precursors to THM formation. More recently, it has been demonstrated that the presence of copper in solution enhances THM formation. Copper is known to catalyze a number of reactions that are similar to the conventional haloform reaction. A study was therefore initiated to investigate the specific role played by copper in the formation of chloroform during chlorination of water supplies. Aqueous solutions containing a number of known THM precursors were chlorinated in the presence and absence of copper, and subjected to time-course monitoring of chloroform concentration. The results of experiments with humic acid demonstrated an apparent catalytic effect on the part of copper in chloroform formation. To examine the role of copper in greater detail, a series of experiments involving aqueous solutions of pure compounds of humic substance structural units was conducted. Of the pure compounds investigated as THM precursors, only citric acid demonstrated enhanced chloroform formation in the presence of copper. A detailed matrix of experiments conducted with citric acid as a precursor demonstrated that copper, at environmentally relevant concentrations, can have a profound effect on chloroform formation. Based on previously published information regarding the mechanism of chloroform formation from citric acid and the results of these experiments, it is hypothesized that copper promotes chloroform formation from chlorination of citric acid through catalysis of oxidative decarboxylation, and the subsequent chlorination of beta-ketoglutaric acid.

Catalysis↗

PubMed1998

Effects of singly administered betaine on hepatotoxicity of chloroform in mice.

Effects of a single dose of betaine on the chloroform-induced hepatotoxicity were examined in adult male ICR mice. Administration of betaine (1000 mg/kg, ip) 1 to 7 hr prior to a chloroform challenge (0.25 ml/kg, ip) resulted in remarkable enhancement of hepatotoxicity as indicated by increases in serum sorbitol dehydrogenase (SDH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. The potentiation of hepatotoxicity was most significant when mice were treated with betaine 4 hr earlier than chloroform. However, a 24 hr prior administration of betaine protected the animals from induction of the chloroform hepatotoxicity. Thus, its effect appeared to be highly dependent on the time lapse from the betaine pretreatment to the challenge of mice with chloroform. Betaine treated either 4 or 24 hr prior to sacrifice did not alter the hepatic contents of cytochrome P-450, cytochrome b5, or NADPH cytochrome P-450 reductase activity. Accordingly the hepatic microsomal p-nitroanisole O-demethylase, aminopyrine N-demethylase, or p-nitrophenol hydroxylase activities were not influenced by the betaine pretreatment. Betaine was shown not to affect any of the enzyme activities associated with glutathione (GSH) conjugation reaction, such as glutathione S-transferases (GSTs), glutathione disulfide (GSSG) reductase and GSH peroxidase irrespective of the time of its administration. When betaine was administered to mice 2-6 hr prior to sacrifice, hepatic GSH level, but not plasma GSH, was decreased significantly. Enhancement of the chloroform hepatotoxicity by betaine correlated well with the reduction in hepatic GSH levels. Both hepatic and plasma GSH levels were elevated in mice 24 hr following the betaine treatment. The results suggest that betaine affects induction of the chloroform hepatotoxicity by modulating the availability of hepatic GSH, which appears to be associated with its role in the transsulfuration pathway in the liver.

Alanine Transaminase↗

PubMed1997

Vehicle-dependent oral absorption and target tissue dosimetry of chloroform in male rats and female mice.

Chloroform-induced toxicity in rodents depends on oral dose regimen. We evaluated the absorption and tissue dosimetry of chloroform after gavage administration in various vehicles to male Fischer 344 rats and female B6C3F1 mice. Animals received a single dose of chloroform in corn oil, water, or aqueous 2% emulphor at doses (15-180 and 70-477 mg/kg for rats and mice) and dose volumes (2 and 10 ml/kg for rats and mice) used in previously reported toxicity studies. Blood, liver, and kidney chloroform concentration-time courses were determined. Gavage vehicle had minimal effects on chloroform dosimetry in rats. In mice, however, tissue chloroform concentrations were consistently greater for aqueous versus corn oil vehicle. At the low dose volume used for rats (2 ml/kg) gavage vehicle may not play a significant role in chloroform absorption and tissue dosimetry, at the higher dose volume used for mice (10 ml/kg), vehicle may be a critical factor.

Administration, Oral↗

PubMed1982

Toxicity of trihalomethanes: I. The acute and subacute toxicity of chloroform, bromodichloromethane, chlorodibromomethane and bromoform in rats.

In an acute study, groups of 10 male and 10 female rats were given single oral doses of chloroform, bromodichloromethane (BDCM), chlorodibromomethane (CDBM), or bromoform and were observed for clinical symptoms for the following 14 days. Median lethal doses (LD 50) of the four trihalomethanes were found to be between 848 and 1388 mg/kg. Some groups which survived the treatment for 14 days showed reduced food intake, growth retardation and increased liver and kidney weight. Elevated serum cholesterol levels were observed in the surviving male rats treated with chloroform and CDBM, and in the females treated with chloroform. Decreased liver protein content occurred in male but not female rats fed chloroform and bromoform. In contrast, increase aniline hydroxylase activity was observed in female rats fed chloroform but not bromoform. Hematological values which were altered by the four trihalomethanes were hemoglobin, hematocrit, RBC, WBC, neutrophil and lymphocyte counts. Treatment-related histologic changes were observed in the liver and kidney of rats. These changes were qualitatively and quantitatively similar for the four trihalomethanes. These data indicate that trihalomethanes at large single oral doses can produce a wide range of toxic changes in the rat. In a subacute study, groups of 10 male rats were fed four trihalomethanes at 0, 5, 50 or 500 ppm in their drinking water for 28 days. The growth rate and food intake were not affected by treatment. A slight increase in relative kidney weight was observed in the groups fed 5 ppm chloroform; 500 ppm bromoform, 5 and 500 ppm BDCM. The animals fed the highest dose of chloroform showed decreased neutrophils. Serum biochemical parameters and hepatic microsomal enzyme activities were not altered by any of the four trihalomethanes. No histopathological changes were seen in the tissues examined.

Animals↗

PubMed2000

Physiologically based pharmacokinetic modeling of the temperature-dependent dermal absorption of chloroform by humans following bath water exposures.

The kinetics of chloroform in the exhaled breath of human volunteers exposed skin-only via bath water (concentrations < 100 ppb) were analyzed using a physiologically based pharmacokinetic (PBPK) model. Significant increases in exhaled chloroform (and thus bioavailability) were observed as exposure temperatures were increased from 30 to 40 degrees C. The blood flows to the skin and effective skin permeability coefficients (Kp) were both varied to reflect the temperature-dependent changes in physiology and exhalation kinetics. At 40 degrees C, no differences were observed between males and females. Therefore, Kps were determined (approximately 0.06 cm/hr) at a skin blood flow rate of 18% of the cardiac output. At 30 and 35 degrees C, males exhaled more chloroform than females, resulting in lower effective Kps calculated for females. At these lower temperatures, the blood flow to the skin was also reduced. Total amounts of chloroform absorbed averaged 41.9 and 43.6 microg for males and 11.5 and 39.9 microg for females exposed at 35 and 40 degrees C, respectively. At 30 degrees C, only 2/5 males and 1/5 females had detectable concentrations of chloroform in their exhaled breath. For perspective, the total intake of chloroform would have ranged from 79-194 microg if the volunteers had consumed 2 liters of water orally at the concentrations used in this study. Thus, the relative contribution of dermal uptake of chloroform to the total body burdens associated with bathing for 30 min and drinking 2 liters of water (ignoring contributions from inhalation exposures) was predicted to range from 1 to 28%, depending on the temperature of the bath.

Adult↗

PubMed2003

Biologically motivated computational modeling of chloroform cytolethality and regenerative cellular proliferation.

Chloroform is a nongenotoxic-cytotoxic carcinogen in rodents. As such, events related to cytotoxicity are the driving force for cancer induction. In this paper we extended an existing physiologically based pharmacokinetic (PBPK) model for chloroform to describe a plausible mechanism linking the hepatic metabolism of chloroform to hepatocellular killing and regenerative proliferation. The key aspects of this mechanism are (1) the production of damage at a rate proportional to the rate of metabolism predicted by the PBPK model, (2) the saturable repair of the damage, (3) the stimulation of the cell death rate by damage, and (4) the stimulation of the cell division rate as a function of the difference between the control and exposed numbers of cells. This extension allows the simulation of the labeling index and comparison with labeling index data. Data from a previously published chloroform-inhalation study with female B6C3F1 mice that determined cytolethality and regenerative cellular proliferation following exposures of varying concentrations and exposure durations were used for model calibration. Both threshold and low-dose linear linkages between chloroform-induced damage and cell death rate provided visually good fits to the labeling index data after formal optimization of the adjustable parameters, and there was no statistical difference between the fits of the two models to the data. Biologically motivated computational modeling of chloroform-induced cytolethality and regenerative proliferation is a necessary step in the quantitative evaluation of the hypothesis that chloroform-stimulated cell proliferation predicts the rodent tumor response.

Administration, Inhalation↗

PubMed1982

A new elution procedure using chloroform, a nonflammable organic solvent.

A new method for eluting red cell antibodies using chloroform has been shown to be effective. The method is similar to ether and xylene techniques but can be completed within 10 min after adequate cell washing. Comparison studies using ether, xylene and chloroform showed that antibodies eluted by chloroform yielded equivalent titration scores. Antibodies within the Ss blood group system were easily eluted using chloroform but not using ether. Also, the chloroform method yielded informative eluates when prepared from red cells of patients with warm antibody autoimmune hemolytic anemia, drug-induced immune hemolytic anemia, hemolytic disease of the newborn caused by ABO or Rh fetal maternal incompatibility, or from patients having a positive direct antiglobulin test as a result of alloantibodies stimulated by recent transfusion ("delayed transfusion reaction'). The advantages of chloroform elution are: (1) chloroform is nonflammable; (2) the eluate is readily obtained from the top layer after centrifugation; (3) no residual solvent remains in the eluate, and (4) the method is rapid.

Anemia, Hemolytic↗

PubMed1996

Systemic uptake and clearance of chloroform by hairless rats following dermal exposure. I. Brief exposure to aqueous solutions.

The systemic uptake of chloroform from dilute aqueous solutions into live hairless rats under conditions simulating dermal environmental exposure was studied. Whole blood was sampled during a 30-min immersion of an animal within water containing a known concentration of chloroform and then for 5.5 h following its removal from the bath. The amount of chloroform systemically absorbed was determined by comparing the AUCs of the blood concentration vs. time plots from dermal exposure to that obtained after i.v. infusion (for a period of 30 min) of an aqueous solution containing a known amount of chloroform (positive control). Although dermal data implied two-compartment disposition characteristics, i.v. infusion data fit best to a three-compartment disposition. Linear pharmacokinetics was observed both by i.v. administration and percutaneous absorption at the dose levels studied. Chloroform was detected in the rat blood as early as 4 min following exposure. Our findings suggest that about 10.2 mg of chloroform was systemically absorbed after dermal exposure of a rat to an aqueous solution of 0.44 mg/ml. This amount is substantially higher than the predictions of mathematical risk-models put forth by some investigators. However, when expressed as the "effective" permeability coefficient (Kpeff), close agreement was noticed between our value and those estimated by others using physiologically based pharmacokinetic (PBPK) models. Also, in terms of Kpeff, reasonable agreement existed between our and another investigator's past estimates of uptake based on depletion of bath level of chloroform and the actual uptake measured in our current experiments. The estimated onset of systemic entry seen here is entirely consistent with our estimate of how long it takes to establish the diffusion gradient across the stratum corneum based on tape stripping.

Animals↗

PubMed1995

In vitro and in vivo percutaneous absorption of 14C-chloroform in humans.

Chloroform has been found in potable water and there is concern that significant dermal absorption may arise from daily bathing and other activities. The present study examines percutaneous absorption of 14C-chloroform in vivo using human volunteers and in vitro using fresh, excised human skin in a flow-through diffusion cell system. Fifty microlitre doses of either 1000 micrograms ml-1 chloroform in distilled water, (16.1 micrograms cm-2) or 5000 micrograms ml-1 of chloroform in ethanol, (80.6 micrograms cm-1) were applied to the forearm of volunteers with exhaled air and urine being collected for analysis. Single doses of either 0.4 microgram ml-1 chloroform in distilled water (low dose, 0.62 microgram cm-2, 1.0 ml dosed) or 900 micrograms ml-1 chloroform in distilled water (high dose, 70.3 micrograms cm-2, 50 microliters dosed) were applied to discs of the excised abdominal skin placed in flow-through diffusion cells and perfused with Hepes buffered Hank's balanced salt solution, with a wash at 4 h. In vivo absorption was 7.8 +/- 1.4% (water as vehicle) and 1.6 +/- 0.3% (ethanol as vehicle). Of the dose absorbed in vivo, more than 95% was excreted via the lungs (over 88% of which was CO2), and the maximum pulmonary excretion occurred between 15 min and 2 h after dosing. The percentage of dose absorbed in vitro (skin+perfusate) was 5.6 +/- 2.7% (low dose) and 7.1 +/- 1.4% (high dose). The above data demonstrate that a significant amount of the dissolved chloroform penetrates through the human skin, and that a higher percentage of the applied dose was absorbed using water as vehicle.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1994

Evaluation of dermal and respiratory chloroform exposure in humans.

Chloroform is a known contaminant of chlorinated drinking water and of swimming pool water disinfected with chlorine or one of its derivatives. Few data exist regarding the importance of dermal and inhalation exposure routes to the chloroform body burden resulting from domestic and recreational use of chlorinated water. In our experimental study involving 11 male swimmers, we quantified the body burden resulting from exposure to various concentrations of chloroform in water and air of an indoor swimming pool, during a daily 55-min exercise period. From the first to the sixth exercise period, CHCl3 mean concentration in water was increased from 159 micrograms/l to 553 micrograms/l. Corresponding mean air CHCl3 level ranged from 597 ppb to 1630 ppb. To dissociate the dermal exposure route from that of inhalation, swimmers used scuba tanks during an additional exercise period. Chloroform concentrations were measured in alveolar air before and after each exercise period, as well as after 35 min of physical activity. Chloroform levels in water and air were measured every 10 min. We examined the relationship between alveolar air concentration (a measure of body burden) at 35 and 55 min and environmental chloroform concentrations by using multiple regression models. The natural logarithm of alveolar air concentration was strongly correlated with aqueous chloroform concentration both at 35 (p2 < 0.001, r2 = 0.75) and 55 min (p < 0.001, r2 = 0.86). The relationship with air concentrations was also statistically significant (35 min: p < 0.001, r2 = 0.58, 55 min: p < 0.001, r2 = 0.63).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗

PubMed1982

Mechanistic considerations for carcinogenic risk estimation: chloroform.

Chloroform has been reported to induce cancer in rodents after chronic administration of high doses by gavage. However, the interpretation of these findings is hampered by a lack of knowledge concerning the relative roles of genetic and nongenetic mechanisms in these bioassays. The present studies were carried out in male B6C3F1 mice in order to investigate the potential of chloroform to induce genetic damage and/or organ toxicity at the sites where tumors have been observed in the various bioassays. These studies revealed that carcinogenic doses of chloroform produced severe necrosis at the sites where tumors later developed. This was demonstrated by light microscopy as well as by determination of the cellular regeneration index following administration of 3H-thymidine. Noncarcinogenic doses of chloroform failed to induce these responses. In contrast, studies of DNA alkylation and DNA repair in vivo failed to give any indication that chloroform had produced the type of genetic alterations associated with known genotoxic chemicals. These data suggest that the primary mechanism of chloroform-induced carcinogenesis is nongenetic in nature. If the same mechanism predominates in man, there should be little to no carcinogenic risk associated with exposure to noncytotoxic levels of chloroform.

Alkylation↗

PubMedDate not supplied

Safety evaluation of toothpaste containing chloroform. III. Long-term study in beagle dogs.

Beagle dogs were given chloroform in a toothpaste base orally in gelatin capsules on 6 d/wk for 7 1/2 yr, followed by a 20-24 wk recovery period. Groups of 16 males and females received 0.5 ml/kg/d of the vehicle (toothpaste without chloroform) and 8 dogs of each sex remained untreated. Treated groups comprised 8 dogs of each sex remained untreated. Treated groups comprised 8 dogs of each sex, receiving doses equivalent to 15 and 30 mg CHCl3/kg/d in the toothpaste vehicle; another group of the same size received an alternative non-chloroform toothpaste (0.5 ml/kg/d). Eleven of the 96 dogs died during the study, only two of these being in the CHCl3-treated groups. The only significant toxic response during treatment was a moderate rise in serum enzyme levels (e.g. SGPT), reaching a peak in the sixth year of the study and probably corresponding to minimal liver damage. Few Palpable growths were noted while the dogs were alive. "Fatty cysts" were seen in the liver of several dogs at post mortem possibly associated with the chloroform treatment but the distribution of a nodular change in the liver was not obviously dose related. A small number of macroscopic and microscopic neoplasms were seen; one dog in each chloroform-treated group had a malignant tumour but there were no tumours in the liver or kidney of any dog. Overall, exposure to chloroform in a toothpaste base was not associated with any effect on the incidence of any kind of neoplasm. From this and related studies in mice and rats, it is concluded that repeated exposure to chloroform (3.5 percent) in toothpaste is unlikely to result in any hazard to human health.

Animals↗

PubMed1995

Homicide facilitated by inhalation of chloroform.

Three related homicides in which each decedent had significant concentrations of chloroform in blood, fat, brain and/or liver are described. The tissue concentrations of chloroform in one of three decedents were within reported lethal ranges. The concentrations in the remaining two decedents were less than lethal but were well above blood levels in nonoccupationally exposed, healthy subjects. The cause of death in one decedent with sublethal chloroform concentrations was suffocation; the cause of death in the other decedent could not be determined with certainty. The manner of death in each case was homicide. Through a review of the literature the authors discuss the history of chloroform as an inhalation anesthetic and the history of chloroform as an agent of abuse, suicide, assault, and homicide. Blood and/or tissue concentrations of chloroform in nonoccupationally exposed, healthy subjects and victims of suicide or homicide from previous reports are compared and contrasted with the amounts in blood and/or tissue in the three subjects described in this study. The authors conclude that, in addition to a direct lethal effect, chloroform may be used to incapacitate a victim of assault who then dies by another cause.

Adult↗

PubMed2005

Comparison of highly-fluorinated chloroformates as direct aqueous sample derivatizing agents for hydrophilic analytes and drinking-water disinfection by-products.

Four highly-fluorinated alkyl and aryl chloroformates, including 2,2,3,3,4,4,5,5-octafluoro-1-pentyl chloroformate (OFPCF), 2,3,4,5,6-pentafluorobenzyl chloroformate (PFBCF), 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluoro-1-octyl chloroformate (TDFOCF), and 2-(2,3,4,5,6-pentafluorophenoxy)-ethyl chloroformate (PFPECF), were synthesized and tested as reagents for the direct water derivatization of polar and hydrophilic analytes. The goal of this research was to develop an optimal derivatizing agent to aid in the identification of highly polar ozonation drinking water disinfection by-products (DBPs) that are believed to be missed with current analytical procedures. The chemical properties (reactivity, selectivity, derivatization products, and their chromatographic and spectral features) for the four chloroformates were investigated using a set of highly polar standard analytes, including malic and tartaric acids, hydroxylamine, valine, 2-aminoethanol, resorcinol, 1,3,5-trihydroxybenzene, and 2,4-dihydroxybenzoic acid. Upon derivatization, the analytes were extracted from the aqueous solvent and analyzed by gas chromatography (GC)-mass spectrometry (MS) in the electron capture negative ionization (ECNI) mode. Positive chemical ionization (PCI)-MS was used for confirmation of molecular ions that were weak or absent in ECNI mass spectra. Of the four derivatizing reagents tested, OFPCF showed the best performance, with good reaction efficiency, good chromatographic and spectroscopic properties, low detection limits (10-100 fmol), and a linear response more than two orders of magnitude. Further, the entire procedure from raw aqueous sample to ready-to-inject hexane solutions of the derivatives requires less than 10 min. PFBCF showed ideal applicability for derivatizing aminoalcohols and aminoacids. The two chloroformates with the highest intrinsic stability (TDFOCF and PFPECF) failed to derivatize some of the analytes. Finally, the OFPCF derivatizing agent was tested with simulated ozonated drinking water (aqueous fulvic acid treated with ozone), and three highly polar reaction by-products were determined.

Journal Article↗

PubMed1998

Long-term mutagenicity studies with chloroform and dimethylnitrosamine in female lacI transgenic B6C3F1 mice.

The weight of evidence indicates that chloroform induces cancer in the female B6C3F1 mouse liver via a nongenotoxic-cytotoxic mode of action. However, it is probable that DNA damage occurs secondary to events associated with cytolethality and regenerative cell proliferation. The purpose of the present study was to evaluate the potential mutagenic activity of chloroform in the B6C3F1 lacI transgenic mouse liver mutagenesis assay including mutagenic events that might occur secondary to cytolethality. The positive control, dimethylnitrosamine (DMN) is a DNA-reactive mutagen and carcinogen. DMN-induced mutations were anticipated to require only a brief exposure and without further treatment were predicted to remain unchanged over time at those frequencies. Chloroform-induced mutations secondary to toxicity were anticipated to require longer exposure periods and to occur only under conditions that produced sustained cytolethality and regenerative cell proliferation. Female B6C3F1 lacI transgenic mice were treated with daily doses of 2, 4, or 8 mg/kg of DMN by gavage for 4 days and then held until analysis 10, 30, 90, and 180 days postexposure. Livers from DMN-treated mice exhibited a dose-related 2- to 5-fold increase over control mutant frequencies and remained at those levels for 10 through 180 days postexposure. Thus, following the initial induction by DMN no selective mutation amplification or loss was seen for this extended period of time. Female B6C3F1 lacI mice were exposed daily for 6 hr/day 7 days/week to 0, 10, 30, or 90 ppm chloroform by inhalation, representing nonhepatotoxic, borderline, or overtly hepatotoxic chloroform exposures. Timepoints for determination of lacI mutant frequency were 10, 30, 90, and 180 days of exposure. No increase in lacI mutant frequency in the liver was observed at any dose or timepoint with chloroform, indicating a lack of DNA reactivity. DNA alterations secondary to toxicity either did not occur or were of a type not detectable by lacI mutant frequency analysis, such as large deletions.

Administration, Inhalation↗