Hygiene guide series. Dichloromethane (methylene chloride, methylene dichloride).
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Occupational Medicine↗
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Results for “METHYLENE CHLORIDE”
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The role of formaldehyde and S-chloromethylglutathione in the bacterial mutagenicity of methylene chloride.
Methylene chloride was less mutagenic in Salmonella typhimurium TA100/NG-11 (glutathione-deficient) compared to TA100, indicating that glutathione is involved in the activation of methylene chloride to a mutagen in bacteria. In rodents, the pathway of methylene chloride metabolism utilizing glutathione produces formaldehyde via a postulated S-chloromethylglutathione conjugate (GSCH2Cl). Formaldehyde is known to cause DNA-protein cross-links, and GSCH2Cl may act as a monofunctional DNA alkylator by analogy with the glutathione conjugates of 1,2-dihaloalkanes. The lack of sensitivity of Salmonella TA100 towards formaldehyde (Schmid et al., Mutagenesis, 1 (1986) No. 6, 427-431) suggests that GSCH2Cl is responsible for methylene chloride mutagenicity in Salmonella. In Escherichia coli K12 (AB1157), formaldehyde was mutagenic only in the wild-type, a characteristic shared with cross-linking agents, whereas 1,2-dibromoethane (1,2-DBE) was more mutagenic in uvrA cells (AB1886). Methylene chloride, activated by S9 from mouse liver, was mutagenic only in wild-type cells, suggesting a mutagenic role for metabolically derived formaldehyde in E. coli. Mouse-liver S9 also enhanced the cell-killing effect of methylene chloride in the uvrA, and a recA/uvrA double mutant (AB2480) which is very sensitive to DNA damage. This pattern was consistent with formaldehyde damage. However, a mutagenic role in bacteria for the glutathione conjugate of methylene chloride cannot be ruled out by these E. coli experiments because S9 fractions did not increase 1,2-DBE mutagenicity, suggesting lack of cell wall penetration by this reactive species. Rat-liver S9 did not activate methylene chloride to a bacterial mutagen or enhance methylene chloride-induced cell-killing, which is consistent with the carcinogenicity difference between the species.
Animals↗
Ras proto-oncogene activation in liver and lung tumors from B6C3F1 mice exposed chronically to methylene chloride.
Methylene chloride has been the subject of recent toxicological and carcinogenesis studies because of significant human exposure and widespread use in industrial processing, food preparation and agriculture. In this study, liver and lung tumors, induced in female B6C3F1 mice by inhalation of 2000 p.p.m. methylene chloride (6 h/day, 5 days/week continuous exposure), were examined for the presence of activated ras proto-oncogenes. DNA was isolated from 49 spontaneous and 50 methylene chloride-induced liver tumors and screened by oligonucleotide hybridization of PCR amplified H-ras gene fragments for codon 61 mutations. In the chemically induced tumors, 38 mutations were detected, 16 C to A transversions in base 1, 16 A to G transitions in base 2 and 6 A to T transversions in base 2. This mutation profile was similar to that identified for the H-ras gene in the spontaneous liver tumors and suggests that methylene chloride acts in liver by promoting cells with spontaneous lesions. Tumors in which H-ras codon 61 mutations were not detected were examined for the presence of transforming genes by the nude mouse tumorigenicity assay. Except for activated K-ras genes detected in DNA from two methylene chloride induced tumors and one spontaneous tumor, no other transforming genes were identified. DNA from 54 lung tumors was screened by direct sequencing of PCR amplified DNA fragments of the K-ras gene for first and second exon mutations, and 12 mutations were identified, 5 in exon one and 7 in exon 2. The low number of spontaneous tumors available in this study limits the interpretation of the data, and thus the frequency and spectrum of K-ras activation in the methylene chloride induced tumors was not significantly different from that in the seven spontaneous tumors analyzed. Since K-ras activation was not detected in 80% of the tumors, the nude mouse tumorigenicity assay was used to examine the lung tumors for the presence of other transforming genes. At present no transforming genes other than ras genes were identified in either liver or lung tumors.
3T3 Cells↗
Physiologically based pharmacokinetics and the risk assessment process for methylene chloride.
Methylene chloride (dichloromethane, DCM) is metabolized by two pathways: one dependent on oxidation by mixed function oxidases (MFO) and the other dependent on glutathione S-transferases (GST). A physiologically based pharmacokinetic (PB-PK) model based on knowledge of these pathways was used to describe the metabolism of DCM in four mammalian species (mouse, rat, hamster, and humans). Kinetic constants for the model were derived from in vivo experiments or the literature. The model was constructed to distinguish contributions from the two pathways of metabolism in lung and liver tissue, and to permit extrapolation from rodents to humans. Model validation was conducted by comparing predicted blood concentration time-course data in rats, mice, and humans with experimental data from these species. The tumor incidence in two chronic studies of DCM toxicity in mice was correlated with various measures of target tissue dose calculated with the PB-PK model. Tumor incidence correlated well with tissue AUC (area under the concentration/time curve) and amount of DCM metabolized by the GST pathway. However, tumor incidence did not correlate with the amount of DCM metabolized by the MFO pathway. Because of its low chemical reactivity, DCM is unlikely to be directly involved in carcinogenesis. Consequently, metabolism of DCM by GST appears to be important in carcinogenesis. The PB-PK model was used to estimate target doses of presumed toxic chemical species in humans exposed to DCM by inhalation or by drinking water. Target tissue doses in humans exposed to low concentrations of DCM are 140- to 170-fold lower (inhalation) or 50- to 210-fold lower (drinking water) than would be expected from the linear extrapolation and body surface area factors which have been used in conventional risk assessment methods (D. V. Singh, H. L. Spitzer, and P. D. White (1985). Addendum to the Health Assessment Document for Dichloromethane (Methylene Chloride). EPA/600/8-82/004F). The PB-BK analysis thus suggests that conventional risk analyses greatly overestimate the risk in humans exposed to low concentrations of DCM. PB-PK considerations provide a scientific basis for risk assessment, improve experimental design in chronic studies, and structure collection of quantitative metabolic constants required for risk assessment.
Animals↗
Influence of cytochrome P-450 inhibitors on the inhalative uptake of methyl chloride and methylene chloride in male B6C3F1 mice.
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Administration, Inhalation↗
Exposure to methylene chloride. III. Metabolism of 14C-labelled methylene chloride in rat.
The accumulation of methylene chloride and its metabolites in different organs and tissues was studied in an experimental series comprising 10 rats. Each rat was exposed for 1 h to radioactive methylene chloride (14C) in a concentration amounting to 1,935 mg/m3 in inspiratory air. Radioactive carbon atoms were found in the isolated carbon monoxide after exposure. There was also a close correlation between the activity of carbon monoxide extracted from the blood sample and the amount of carboxyhemoglobin (COHb) in the specimen. The largest concentration of methylene chloride and its metabolites per gram of tissue was found in white adipose tissue. This concentration had declined by more than 90% 2 h after exposure, whereas the concentration in the liver declined by about 25% during the same period. The amount accumulated in the brain displayed a decline of about 75% 2 h after exposure. Thus the examination showed that the increased concentration of COHb in the blood during exposure to methylene chloride is due to the metabolism of methylene chloride into carbon monoxide.
Adipose Tissue↗
Estimating the risk of human cancer associated with exposure to methylene chloride.
Dichloromethane (methylene chloride, CH2Cl2) has been shown to significantly increase the incidence of malignant lung and liver tumors in B6C3F1 mice inhaling high concentrations of CH2Cl2 vapor for the majority of their natural lifetime. CH2Cl2 is extensively metabolized in mammalian species through two competing pathways: (1) oxidation by the mixed function oxidase enzymes, and (2) conjugation with glutathione catalyzed by glutathione-S-transferase(s)(GST). Since elevated tumor incidences have not been observed in B6C3F1 mice exposed to 1,1,1-trichloroethane, a halogenated solvent with similar physical-chemical properties (but only minor amounts of mammalian metabolism), it appeared that biologically reactive intermediates (BRIs) from one or both of the pathways of CH2Cl2 metabolism were involved in the tumorigenic process. Development of an integrated pharmacokinetic model incorporating quantitative measures of mammalian physiology, chemical solubility, and metabolic rate constants permitted formulation of a plausible hypothesis for the tumorigenic effects of CH2Cl2: namely that BRIs formed by the CH2Cl2/GST(s) may react with critical molecules in the target organs. This hypothesis is consistent with the dose-dependency, route-dependency, and species-specificity of CH2Cl2 for the induction of lung and liver tumors. Based on this hypothesis as well as in vivo and in vitro measurements of CH2Cl2 metabolism in humans, it was possible to prepare quantitative estimates of the cancer risk in human populations. Examination of these risk estimates indicates that development of quantitative procedures for describing the production of BRI in target tissues may cause significant changes in the levels of estimated risk.
Administration, Inhalation↗
Observed versus predicted carboxyhemoglobin levels in cellulose triacetate workers exposed to methylene chloride.
BACKGROUND: Occupational exposure to methylene chloride, together with carboxyhemoglobin concentrations, has not been studied previously. METHODS: Carboxyhemoglobin levels were measured in non-smoking employees exposed to varying concentrations of methylene chloride during the manufacture of cellulose triacetate fibers. The observed carboxyhemoglobin levels were compared to predicted concentrations using a pharmacokinetic model. RESULTS: The presence of carboxyhemoglobin in non-smokers exposed to methylene chloride results primarily from the metabolism of methylene chloride in the liver and exhibits a linear dose-response relationship. The observed levels of carboxyhemoglobin in non-smokers at the end of an 8-hour shift depend upon exposures to methylene chloride that day but are independent of occupational exposures on previous days. The observed daily concentrations of carboxyhemoglobin are consistent with predicted concentrations using a pharmacokinetic model. While varying exposure patterns were shown to change the rate of metabolite formation at the end of shift, these same exposure patterns had almost no effect on the total amount of carbon monoxide in the blood. CONCLUSION: While the present study addresses the relationship between methylene chloride, carbon monoxide, carboxyhemoglobin and ischemic heart disease, it does not address the issue of tumorigenicity, which is also the basis for the current U.S. Occupational Health and Safety workplace exposure limit of 25 ppm. This study provides support for the conclusion that the current American Conference of Governmental Industrial Hygienists 8-hour Threshold Limit Value of 50 ppm adequately protects human health with regard to ischemic heart disease and carboxyhemoglobin formation among non-smokers.
Carbon Monoxide↗
Substitutes for methylene chloride as dental softening agent.
Methylene chloride is used as softening agent for guttapercha and as adhesion promotor for polymethylmethacrylate (PMMA). However, methylene chloride has been found to be carcinogenic. It was the aim of the present work to search for harmless substitutes for methylene chloride in these situations. A number of possible candidates with structural similarities to guttapercha or PMMA were selected. The efficacy in softening of guttapercha of these compounds was measured by the depth of penetration of a needle under the load of 2 N. The effect of the compounds on the adhesion between PMMA and an acrylic rebasing material was measured in shear. It was found that a number of alkenes or dialkenes of moderate molecular weight (1,3-pentadiene, cyclopentene, isoprene, 2-methyl-2-butene, and 1,5-hexadiene) were as effective as methylene chloride as softening agent for guttapercha. As adhesion promotor in bonding to PMMA, it was found that low molecular weight methyl esters (methyl formate and methyl acetate) were as effective as methylene chloride. Because of the variation in polarity, the calculated solubility parameter was not a reliable predictor of softening efficacy of the investigated compounds.
Acetates↗
Case study: control of methylene chloride exposures during furniture stripping.
Methylene chloride, a potential occupational carcinogen, is one of the principal solvents used for furniture stripping. Methylene chloride exposures among workers in furniture stripping operations have been found to be high. This article describes a furniture stripping operation at a sheltered workshop before and after the ventilation system was modified. Previous to ventilation system modifications, workers who were stripping furniture had exposures to methylene chloride ranging from 600 to 1150 ppm. These high exposures and an evaluation of the ventilation system prompted the design and installation of a modified ventilation system. Primary modifications included installing a local ventilation hood, decreasing the velocity of makeup air entering the stripping area, removing a contaminated charcoal adsorption bed and improving work practices. The modified system was arranged into three configurations that included a slot hood, a downdraft hood, and a combination slot and downdraft hood. The three configurations were evaluated over a three-day period, and it was found that they controlled the worker's personal exposures to methylene chloride while stripping to 28 ppm for the combination configuration, 30 ppm for the downdraft configuration, and 34 ppm for the slot configuration. Although the exposures are above the proposed Occupational Safety and Health Administration permissible exposure level of 25 ppm, these results show a substantial improvement over the existing ventilation system. The ventilation system described is applicable to other furniture stripping facilities if rinse area local ventilation is improved.
Equipment Design↗
Diverse manifestations of oral methylene chloride poisoning: report of 6 cases.
OBJECTIVE: Methylene chloride is a solvent used in domestic and industrial preparations, such as paint removers and degreasing agents. Although it is considered of low toxicity, acute toxic manifestations have been reported following inhalation of methylene chloride, mainly from working in an enclosed environment. Oral ingestion of methylene chloride, however, remains rare and its consequences are less clearly understood. CASE REPORTS: The various clinical manifestations of 6 patients with oral ingestion of methylene chloride are reported. Central nervous system depression, tachypnea, and corrosive gastrointestinal injury were the most common presentations following ingestion. An elevated carboxyhemoglobin level was documented in only 2 patients (35% and 8.4% carboxyhemoglobin, respectively). Due to a frequent misleading history of "chloroform" ingestion and unawareness of probable carboxyhemoglobin production in these patients, carboxyhemoglobin was not routinely measured. Renal failure, hepatic failure, and acute pancreatitis occurred in the 2 most severe cases of methylene chloride ingestion. CONCLUSIONS: Ingestion of methylene chloride can result in diverse manifestations, including a high carboxyhemoglobin level. Corrosive gastrointestinal injury is common in oral poisoning and needs further therapeutic consideration. A high index of suspicion and appropriate laboratory studies are needed in those patients who allegedly ingest "chloroform" but do not present the incriminating solvent to their treating physicians. The presence of an elevated carboxyhemoglobin level suggests the diagnosis of methylene chloride poisoning. Symptomatic and supportive measures remain the mainstay in the treatment of patients with oral methylene chloride poisoning.
Administration, Oral↗
Inhalation exposure to methylene chloride does not induce systemic immunotoxicity in rats.
Methylene chloride (dichloromethane) is used in a variety of industrial applications. To date, there has been no formal assessment of immunotoxicity attributed to methylene chloride. Studies were undertaken to examine whether methylene chloride has any potential to influence the integrity of immune function. For this purpose, Sprague-Dawley rats of both genders were exposed by inhalation to a single high dose (5000 ppm) of methylene chloride for 6 h/d, 5 d/wk for 28 d. This was considered the relevant route of administration, as not only is inhalation a primary route for human exposure to methylene chloride, but, also, the chemical is absorbed rapidly via the lungs. Under these conditions of exposure, methylene chloride failed to influence absolute or relative thymus weights in either gender and produced a significant reduction in relative, but not absolute, spleen weight in female rats only. Immunocompetence was measured as a function of the ability of treated animals to mount immunoglobulin M (IgM) antibody responses to sheep red blood cells (SRBC) as determined by enzyme-linked immunosorbent assay (ELISA). Exposure to methylene chloride did not affect antibody production. Evidence indicates that under these conditions of exposure, methylene chloride did not compromise immune function.
Administration, Inhalation↗
Fatal gassing due to methylene chloride - a case report.
Methylene chloride is a major component of paint and varnish strippers. Due to its high volatility, its use in unventilated or poorly ventilated confined spaces poses a serious health hazard as a result of accumulation of the solvent vapour. At high levels, methylene chloride can cause severe central nervous system depression and ultimately death, as illustrated in this case report. The importance of adequate forced ventilation, utilisation of proper personal protective equipment and enforcement of a permit-to-work system during work with solvents in confined spaces is emphasised.
Adult↗
Induction of chromosome damage by methylene chloride in CHO cells.
The genotoxicity of methylene chloride was determined using sister-chromatid exchange (SCE) and chromosome aberration assays in cultured Chinese hamster ovary (CHO) cells. Methylene chloride caused extensive chromosome aberrations both with and without metabolic activation. However, the results of the SCE assay were negative for methylene chloride. These results agree with previously observed genotoxic effects of methylene chloride in Salmonella typhimurium and Saccharomyces cerevisiae. The fact that methylene chloride causes chromosome aberrations without increasing the SCE level indicates that complete reliance on the induction of SCE as a test system for assessing chromosomal effects is not valid.
Animals↗
Treatment of methylene chloride induced carbon monoxide poisoning with hyperbaric oxygenation.
Methylene chloride is an organic solvent with many industrial uses. Inhalation of methylene chloride fumes can result in toxicity, caused by hepatic biotransformation of methylene chloride to carbon monoxide. A case of acute methylene chloride poisoning is presented, including successful treatment of this patient with the use of hyperbaric oxygenation. The rationale for the use of hyperbaric oxygenation in the treatment of methylene chloride poisoning is discussed.
Adult↗
Results of the Massachusetts methylene chloride end-users survey.
A survey of Massachusetts companies reporting use of methylene chloride between 1995 and 1999 was conducted to assess the status of industrial use of the chemical in 2000. Methylene chloride has had wide use in industry although it has been identified as potentially hazardous to exposed workers and the environment. New and tightened occupational and environmental regulations taking effect in the 1990s were hypothesized to have reduced use of the chemical in Massachusetts. Substitute technologies, especially aqueous cleaning, were expected to have replaced methylene chloride in many industries. Seventeen of the 21 Massachusetts manufacturing companies reporting use of over 10,000 lb/y of methylene chloride between 1995 and 1999 were surveyed by telephone regarding their experiences of methylene chloride use and elimination and/or replacement. Fifteen of the 17 companies had either eliminated (10) or reduced to below 10,000 lbs/yr (5) their use of methylene chloride at the time of the survey in 2000. Many of the surveyed companies moved to aqueous cleaning from methylene chloride degreasing operations. Environmental concerns were the most popular reason given for eliminating or reducing use of methylene chloride. Worker health and safety concerns, especially concern about compliance with the 1997 Occupational Safety and Health Administration methylene chloride standard, were also a motivation. In general, the companies associated many benefits and few problems with eliminating or reducing use of methylene chloride. Exposure reduction strategies based on toxics use reduction techniques appear to be feasible for many manufacturing companies. However, research should be conducted to assess the introduction of new hazards as a result of tightened regulations on methylene chloride.
Data Collection↗
Permeation of protective clothing materials by methylene chloride and perchloroethylene.
The permeation of methylene chloride and perchloroethylene through seven protective clothing materials was studied to determine the permeation parameters, and to investigate the effect of solubility (polymer weight gain) and material thickness on the permeation parameters. The materials tested were two different nitrile rubbers, neoprene, Combination (a blend of natural rubber, neoprene and nitrile), two different polyvinyl chlorides, and polyvinyl alcohol. Methylene chloride permeated through all materials, except PVA, with breakthrough times in the range of 2 to 8 min, and permeation rates in the range of 1250-5800 micrograms/cm2 X min. PVA and unsupported nitrile offered good protection against perchloroethylene with breakthrough time occurring after 2 hr. Perchloroethylene permeated through the other materials with breakthrough times in the range of 8 to 36 min and permeation rates in the range of 200 to 1600 micrograms/cm2 X min. It was shown that for both chemicals, there is a correlation between the solubility (weight gain) and the ratio of permeation rate to breakthrough time (PR/BT). For all material/chemical pairs, an increase in solubility, increased (PR/BT). The change in material thickness had an effect on breakthrough time and permeation rate, but no effect on normalized breakthrough time. An increase in thickness reduced permeation rate and increased breakthrough time.
Diffusion↗
Critical review of the epidemiology literature on the potential cancer risks of methylene chloride.
OBJECTIVE: To critically review and summarize the epidemiological evidence published to date on the carcinogenicity of methylene chloride to humans. METHODS: Papers for review were identified through Medline (National Library of Medicine) and were limited to epidemiology studies. Studies were classified using three categories. Primary studies focused on the association between methylene chloride and cancer among occupational cohorts primarily exposed to methylene chloride. Secondary studies identified methylene chloride a priori as a potential exposure of interest, and the investigators either characterized the methylene chloride exposure or described results for the methylene chloride-exposed workers separately. Tertiary studies evaluated cohorts either minimally exposed to methylene chloride or presumed exposed but for which no exposure estimation or separate classification was made. RESULTS: No strong or consistent finding for any site of cancer was apparent despite several studies of large occupational cohorts of workers potentially exposed to high concentrations of methylene chloride. Sporadic and weak associations were reported for cancers of the pancreas, liver and biliary passages, breast, and brain. Although these studies collectively cannot rule out the possibility of any cancer risk associated with methylene chloride exposure, they do support a conclusion of no substantive cancer risk. CONCLUSIONS: Continued follow-up of the established cohorts may elucidate the few and inconsistent relationships reported to date; however, it appears likely that risks associated with methylene chloride exposure, if any, are small and limited to rare cancers. The usefulness of additional cohort studies for the evaluation of cancer risks associated with methylene chloride exposure will depend largely on whether the relevant exposure period has passed and whether exposure characterization (e.g., peak or intermittent exposure or intensity) can be improved.
Adult↗