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PubMedDate not supplied

Methylene chloride poisoning: a paradigmatic review.

The incidence of reported cases of toxicity resulting from methylene chloride exposure has increased within the last decade. A vast majority of these reports involve acute episodes, and the prevalence of domestic poisoning is relatively high. Diverse pathologic sequelae attributed to methylene chloride or its metabolites have been reported, although a distinct bias for central nervous system effects is evident. paradoxically, detoxification of methylene chloride via the mixed-function oxidase pathway is an inherently intoxicating event. Although the anomalous conversion of methylene chloride into carbon monoxide has increased the popular awareness of methylene chloride poisoning among medical personnel, lack of experience in diagnosis and treatment of methylene chloride poisoning is widespread. This review of 26 cases spanning 50 years reveals that the industrial and domestic use of methylene chloride is equally widespread. A compendium of the clinical experience with methylene chloride poisoning is presented.

Animals↗
PubMed2005

Rapid fixation of methylene chloride by a macrocyclic amine.

A simple macrocyclic amine is alkylated by methylene chloride to give a quaternary ammonium chloride salt. When methylene chloride is the solvent, the reaction exhibits pseudo-first-order kinetics, and the reaction half-life at 25.0 degrees C is 2.0 min. The reaction half-life for a structurally related, acyclic amine is approximately 50 000 times longer. Detailed calculations favor a mechanism where the methylene chloride associates with the macrocycle to form an activated prereaction complex. The macrocyclic nitrogen subsequently attacks the methylene chloride with a classic SN2 trajectory, and although the carbon-chlorine bond breaks, the chloride leaving group does not separate from the newly formed cationic macrocycle, such that the product is a tightly associated ion-pair. X-ray crystal structures of the starting amine and the product salt, as well as kinetic data, support this mechanism.

Journal Article↗
PubMed1995

Hepatic and pulmonary carcinogenicity of methylene chloride in mice: a search for mechanisms.

An inhalation study utilizing over 1400 female B6C3F1 mice was undertaken to study mechanistic factors associated with liver and lung tumor induction following exposure to 2000 ppm of methylene chloride. Mice were exposed to methylene chloride (treated) or chamber air (controls) 6 h per day, for varying durations up to 104 weeks. Several interim sacrifices and 'stop exposures' were included. Exposure to 2000 ppm methylene chloride caused an increase in liver and lung neoplasia in the absence of overt cytotoxicity. Measurement of replicative DNA synthesis done after 13, 26, 52 and 78 weeks of exposure showed a significant decrease in the hepatocyte labeling index at 13 weeks. Replicative DNA synthesis in pulmonary airways after 1, 2, 3, 4, 13 and 26 weeks of exposure to methylene chloride was significantly lower than in air-exposed controls. Likewise, the increase in tumor induction in treated mice was not associated with increased replicative DNA synthesis in liver foci or in alveolar parenchyma. The frequency and pattern of H-ras gene activation were similar in control and methylene chloride-induced liver neoplasms. Similarly, the frequency and pattern of K-ras activation in lung neoplasms were not altered by exposure to methylene chloride. Early exposure to methylene chloride for only 26 weeks was sufficient to cause an increase in lung tumors by 2 years, suggesting that methylene chloride may cause early and persistent loss of growth control in lung cells. This implies that risk management strategies should be aimed at minimizing or eliminating exposure to methylene chloride. Liver neoplasms continued to increase in incidence and multiplicity as exposure continued, suggesting that methylene chloride-induced hepatocarcinogenesis is facilitated by continuing exposure to methylene chloride. Since methylene chloride is a more potent inducer of lung than liver neoplasia, it is recommended that health risk assessment be based on the lung data. While no novel molecular lesions have been found to explain the induction of lung and liver neoplasia in mice, ongoing studies may identify other molecular changes that are important in the genesis of these neoplasms. Hence, it may be necessary to revise risk assessment and management strategies in light of future research findings.

Administration, Inhalation↗
PubMed1982

Fate and effects of methylene chloride in activated sludge.

Activated sludge obtained from a municipal wastewater treatment plant was acclimated to methylene chloride at concentrations between 1 and 100 mg/liter by continuous exposure to the compound for 9 to 11 days. Acclimated cultures were shown to mineralize methylene chloride to carbon dioxide and chloride. Rates of methylene chloride degradation were 0.14, 2.3, and 7.4 mg of CH2Cl2 consumed per h per g of mixed-liquor suspended solids for cultures incubated in the presence of 1, 10, and 100 mg/liter, respectively. Concentrations of methylene chloride between 10 and 1,000 mg/liter had no significant effect on O2 consumption or glucose metabolism by activated sludge. A hypothetical model was developed to examine the significance of volatilization and biodegradation for the removal of methylene chloride from an activated sludge reactor. Application of the model indicated that the rate of biodegradation was approximately 12 times greater than the rate of volatilization. Thus, biodegradation may be the predominant process determining the fate of methylene chloride in activated sludge systems continuously exposed to the compound.

Bacteria↗
PubMed1988

Macromolecular interactions of inhaled methylene chloride in rats and mice.

The in vivo interaction of methylene chloride and its metabolites with F344 rat and B6C3F1 mouse lung and liver DNA was measured after inhalation exposure to 4000 ppm [14C]methylene chloride for 3 hr. DNA was isolated from the tissues 6, 12, and 24 hr after the start of exposure and analyzed for total radioactivity and the distribution of radioactivity within enzymatically hydrolyzed DNA samples. Covalent binding to hepatic protein was also measured. A further group of rats and mice were dosed intravenously with [14C]formate after exposure to nonradiolabeled methylene chloride for 3 hr to determine the pattern of labeling resulting from incorporation of formate into DNA via the C-1 pool. Low levels of radioactivity were found in DNA from lungs and livers of both rats and mice exposed to [14C]methylene chloride. Two- to fourfold higher levels were found in mouse DNA and protein than in rat. Chromatographic analysis of the DNA nucleosides showed the radioactivity to be associated with the normal constituents of DNA. No peaks of radioactivity were found that did not coincide with peaks of radioactivity present in hydrolyzed DNA from formate-treated rats and mice. Under the conditions of this study there was no evidence for alkylation of DNA by methylene chloride in either rats or mice.

Administration, Inhalation↗
PubMed1999

Methylene chloride poisoning in a cabinet worker.

More than a million workers are at risk for methylene chloride exposure. Aerosol sprays and paint stripping may also cause significant nonoccupational exposures. After methylene chloride inhalation, significant amounts of carbon monoxide are formed in vivo as a metabolic by-product. Poisoning predominantly affects the central nervous system and results from both carboxyhemoglobin formation and direct solvent-related narcosis. In this report, we describe a case of methylene chloride intoxication probably complicated by exogenous carbon monoxide exposure. The worker's presentation of intermittent headaches was consistent with both methylene chloride intoxication and carbon monoxide poisoning. The exposures and symptoms were corroborated by elevated carboxyhemoglobin saturations and a workplace inspection that documented significant exposures to both methylene chloride and carbon monoxide. When both carbon monoxide and methylene chloride are inhaled, additional carboxyhemoglobin formation is expected. Preventive efforts should include education, air monitoring, and periodic carboxyhemoglobin determinations. Methylene chloride should never be used in enclosed or poorly ventilated areas because of the well-documented dangers of loss of consciousness and death.

Adult↗
PubMed1993

Inhalation exposure to a hepatocarcinogenic concentration of methylene chloride does not induce sustained replicative DNA synthesis in hepatocytes of female B6C3F1 mice.

We have used methylene chloride as a model to study cellular and molecular processes responsible for liver tumor induction by chlorinated hydrocarbons. Because of current interest in the role of enhanced cell proliferation in tumor induction, measurement of S-phase hepatocytes was incorporated into recently conducted toxicity and carcinogenicity studies. In prechronic studies, female B6C3F1 mice were exposed to 0, 1000, 2000 or 8000 p.p.m. methylene chloride by inhalation, 5 days per week, for up to 4 weeks followed by a 1 and 2 week recovery period. Mice exposed to concentrations of 2000, 4000 or 8000 p.p.m. methylene chloride had sustained increased liver weight commencing after 1 week of exposure and returning to normal after the 1 or 2 week recovery period. The increased liver weight was attributed to hepatocellular hypertrophy secondary to intracellular glycogen accumulation. Tritiated thymidine was administered by osmotic minipumps to label S-phase hepatocytes over a 6 day period. At most intervals examined there was decreased hepatocyte labeling in mice exposed to methylene chloride. However, there was a transitory increased number of S-phase hepatocytes observed at the 2 week interval in the 1000, 4000 and 8000 p.p.m. methylene chloride groups. In a chronic study, female mice were exposed to 2000 p.p.m. methylene chloride for up to two years. Following labeling with BRDU using 6 day minipumps, a statistically significant decrease in S-phase hepatocytes was observed after 13 weeks of methylene chloride exposure. A minor increased labeling index (LI) observed at 52 weeks was not considered to be a methylene chloride treatment-related effect. Retrospective immunohistochemical staining for proliferating cell nuclear antigen (PCNA) in liver sections containing foci of cellular alteration allowed demonstration of S-phase hepatocytes in these clonally expanded preneoplastic lesions. While foci frequently had higher LI's than surrounding normal hepatocytes, there was no difference in the mean LI of foci from methylene chloride-treated mice versus foci occurring spontaneously in control mice. The absence of a sustained increase in S-phase hepatocytes in female B6C3F1 mice suggests that enhanced cell proliferation is not a major mechanistic factor associated with the observed hepatocarcinogenicity of methylene chloride.

Administration, Inhalation↗
PubMed1996

Isolation of a mouse theta glutathione S-transferase active with methylene chloride.

A glutathione S-transferase metabolizing methylene chloride has been isolated from mouse liver using a variety of chromatographic methods. N-terminal and internal amino acid sequences show that the enzyme, designated GST T1-1*, is closely related to the rat Theta-class GST 5-5. The mouse enzyme, molecular mass 25000 Da, has been isolated to homogeneity in active form with an approximate yield of 2% of the cytosolic activity towards methylene chloride. GST T1-1* has a specific activity of about 5.5 micromol/min per mg of protein whereas the rat GST 5-5 is reported to have a specific activity of about 11 micromol/min per mg of protein [Meyer, Coles, Pemble, Gilmore, Fraser and Ketterer (1991) Biochem. J. 274, 409-414], demonstrating that both the rat and mouse enzymes have similar activity with this substrate. Limited evidence was obtained for a second enzyme, with a similar molecular mass (25400 Da), which had an N-terminal sequence identical to that of rat GST 12-12. This protein, which was sequenced from a band on a gel, was extremely labile and could not be isolated to homogeneity. The partially purified enzyme was not active with methylene chloride.

Amino Acid Sequence↗
PubMedDate not supplied

Determination of methylene chloride acceptability and its "purification" for ethylenethiourea methodology.

A liquid chromatographic-electrochemical method for the determination of ethylenethiourea (ETU) residues uses methylene chloride in the cleanup. Distilled-in-glass grade methylene chloride produced erratic ETU recoveries ranging from 0 to 106% for vacuum rotary evaporation of the solvent. ETU recoveries were found to be dependent on the bottle of methylene chloride used, not on supplier or lot. When GC2 grade methylene chloride from Burdick & Jackson Laboratories was used, ETU recoveries ranged from 92 to 110%. "Acceptable" ETU recoveries were defined as those values between 90 and 110%. Passing "unacceptable" methylene chloride through a column containing anhydrous sodium sulfate, sodium carbonate, and alumina was found to adequately purify methylene chloride. Treated methylene chloride provided acceptable ETU recoveries for up to 1 month after "purification."

Chromatography, Liquid↗
PubMed1988

Methylene chloride: a 2-year inhalation toxicity and oncogenicity study in rats.

Male and female Sprague-Dawley rats were exposed to 0, 50, 200, or 500 ppm methylene chloride for 6 hr/day, 5 days/week for 2 years. Blood carboxyhemoglobin levels were elevated in a dose-dependent (less than linear) manner in rats exposed to 50-500 ppm methylene chloride. Histopathologic lesions related to methylene chloride exposure were confined to the liver and mammary tissue of rats. An increased incidence of hepatocellular vacuolization was observed in male and female rats exposed to 500 ppm methylene chloride. Female rats exposed to 500 ppm methylene chloride also had an increased incidence of multinucleated hepatocytes and number of spontaneous benign mammary tumors/tumor-bearing rat (adenomas, fibromas, and fibroadenomas with no progression toward malignancy); the incidence of benign mammary tumors in female rats exposed to 50 or 200 ppm methylene chloride was comparable to historical control values. No increase in the number of any malignant tumor type was observed in rats exposed to concentrations as high as 500 ppm methylene chloride. Additional groups of female rats were exposed to 500 ppm methylene chloride for the first 12 months or the last 12 months of the 24-month study. The response observed in female rats exposed to 500 ppm for the first 12 months was the same as that observed in female rats exposed to 500 ppm for 2 years. Conversely, the response observed in female rats exposed to 500 ppm during the last 12 months of the study was similar to that observed in control animals. Based upon the results of this study, the no-adverse-effect level for chronic inhalation exposure of Sprague-Dawley rats was judged to be 200 ppm methylene chloride.

Administration, Inhalation↗
PubMed1993

Comparing toxicologic and epidemiologic studies: methylene chloride--a case study.

Exposure to methylene chloride induces lung and liver cancers in mice. The mouse bioassay data have been used as the basis for several cancer risk assessments. The results from epidemiologic studies of workers exposed to methylene chloride have been mixed with respect to demonstrating an increased cancer risk. The results from a negative epidemiologic study of Kodak workers have been used by two groups of investigators to test the predictions from the EPA risk assessment models. These two groups used very different approaches to this problem, which resulted in opposite conclusions regarding the consistency between the animal model predictions and the Kodak study results. The results from the Kodak study are used to test the predictions from OSHA's multistage models of liver and lung cancer risk. Confidence intervals for the standardized mortality ratios (SMRs) from the Kodak study are compared with the predicted confidence intervals derived from OSHA's risk assessment models. Adjustments for the "healthy worker effect," differences in length of follow-up, and dosimetry between animals and humans were incorporated into these comparisons. Based on these comparisons, we conclude that the negative results from the Kodak study are not inconsistent with the predictions from OSHA's risk assessment model.

Animals↗
PubMedDate not supplied

Impact of methylene chloride on microorganisms and phenanthrene mineralization in soil.

This study investigated the effects of the quantity of methylene chloride, used as a carrier solvent for phenanthrene when added to soil, on phenanthrene mineralization kinetics, soil phospholipid fatty add profiles (PLFA), and phenanthrene distribution. Methylene chloride dosages of 25 microL/g soil or more resulted in an enrichment of saturated PLFAs, suggesting soil microorganisms had adjusted their cell membranes in response to the solvent. A greater fraction of phenanthrene mineralized when spiked in 5 microL/g than in 25 microL/g methylene chloride suggesting that the methylene chloride became toxic to phenanthrene-degrading organisms in soil. Phenanthrene was more equally distributed among 0.1 g soil subsamples if spiked in 25 than 5 or 1 microL methylene chloride per gram soil. Thus the amount of methylene chloride used to spike phenanthrene in soil strongly impacted the mineralization kinetics, phenanthrene distribution, and microbial community in soil. Because a variety of spiking methods are used in biodegradation research, scientists should consider the quantity of solvents used when comparing results among different studies.

Biodegradation, Environmental↗
PubMed1985

Methylene chloride inhalation: an unusual form of drug abuse.

Methylene chloride is a chlorinated hydrocarbon used widely in home and industry. Its intentional abuse has not been reported previously. We describe the case of a 14-year-old boy who presented with lethargy, nausea, and chills six hours after the intentional inhalation of a household product containing methylene chloride. The patient's elevated carboxyhemoglobin level responded well to 100% oxygen therapy. The pathophysiology and treatment of methylene chloride are discussed.

Absorption↗
PubMed1993

Methylene chloride toxicity.

The effects of acute exposure to methylene chloride (dichloromethane) are due to its central nervous system depressant properties, which have resulted in fatalities. Manifestations of acute exposure include mental confusion, fatigue, lethargy, headache and chest pain. Metabolic conversion of methylene chloride to carbon monoxide may place persons with preexisting coronary artery disease at increased risk. Sequelae following chronic exposure are unknown, but data suggest serious long-term effects. The Environmental Protection Agency considers methylene chloride to be a probable human carcinogen.

Aged↗
PubMed1993

Methylene chloride exposure in industrial workers.

Methods of environmental and biological monitoring were applied in order to evaluate exposure to methylene chloride in workers operating in a factory where this substance was used as a solvent. For the measurement of methylene chloride in environmental concentration, the ambient air was sampled by using personal passive dosimeters. The activated charcoal was desorbed with CS2 and injected into a gas chromatograph connected with a mass spectrometer. The biological monitoring of exposed workers was performed by determining the concentration of CO in alveolar air (CA, ppm) and methylene chloride in urine (Cu, mu/L). Immediately after the end of the exposure, a urine sample was collected avoiding solvent loss and using gas-tight samplers. Excretion level in urine was determined by using headspace gas chromatography linked to a mass spectrometer. The CO was determined at the end of the shift by using a portable instrument. A group of 20 workers (12 smokers and 8 nonsmokers) in the manufacturing plant were monitored. No significant correlation was observed among the CO of all subjects and the concentration of methylene chloride in ambient air. When those workers who smoked were removed from the analysis, a correlation between the methylene chloride concentration in air and the CO concentration in alveolar air was found. Significant linear correlation was found between the environmental concentration of methylene chloride in the breathing zone and methylene chloride concentration in urine.

Adult↗
PubMed1990

Comparison of the cancer risk of methylene chloride predicted from animal bioassay data with the epidemiologic evidence.

Methylene chloride has been shown to be a lung and liver carcinogen in the mouse; yet, the current epidemiologic data show no adverse health effects associated with chronic exposure to this compound. Hearne et al. have compared the results of a large mortality study on occupational exposure to methylene chloride to the human risk predictions based on the rodent bioassay to point out the inconsistency between the animal toxicologic and human epidemiologic data. The maximum number of lung and liver cancers predicted due to methylene chloride exposure based on the rodent bioassay data was 24 compared to 14 deaths from these cancers actually observed in the Hearne et al. epidemiology study. We assess the minimum risk detectable by the human study in order to calculate the upperbound potency of methylene chloride and compare it to the potency derived from the bioassay data. Results from the epidemiology study imply an upperbound potency of 1.5 x 10(-2) per ppm, compared to 1.4 x 10(-2) per ppm calculated using the most conservative analysis of the animal data. We conclude that the negative epidemiology study of Hearne et al. is not sufficiently powerful to show that the risk is inconsistent with the human risk estimated by modeling the rodent bioassay data. Specifically, the doses to which the workers were exposed, the population studied, and the latency period were not adequate to determine that the risks are outside the bounds of the risk estimates predicted by low-dose modeling of the animal data.

Air Pollutants, Occupational↗
PubMed1997

Methylene chloride induced mouse liver and lung tumours: an overview of the role of mechanistic studies in human safety assessment.

B6C3F1 mice exposed to high dose levels of methylene chloride by inhalation for 2 years had an elevated incidence of liver and lung tumours. These tumours were not increased in rats or hamsters exposed under the same or similar conditions. This paper gives an overview of research conducted over the last 10 years into the mechanism of action of methylene chloride as a mouse carcinogen and into the relevance of the mouse data to humans exposed to this chemical. Data are presented on the comparative metabolism and pharmacokinetics of methylene chloride in mice, rats, hamsters and humans, on the toxicity of methylene chloride to the target organs in the mouse, and on the genotoxicity of methylene chloride in vitro and in vivo. The enzyme which activates methylene chloride to its carcinogenic form has been isolated, sequenced, and cloned, and its distribution studied within cells, organs and between species. Evidence has been obtained to show the methylene chloride caused cancer in mice as a result of interactions between metabolites of the glutathione S-transferase pathway and DNA. Damage to mouse lung Clara cells and increased cell division are believed to have influenced the development of the lung tumours. The species specificity was a direct consequence of the very high activity and specific cellular and nuclear localisation of a theta class glutathione S-transferase enzyme which was unique to the mouse. Consequently, DNA damage was not detectable in rats in vivo, or in hamster and human hepatocytes exposed to cytotoxic dose levels of methylene chloride in vitro. These results provide evidence that the mouse is unique in its response to methylene chloride and that it is an inappropriate model for human health assessment.

Administration, Inhalation↗