[Effect of chlorinated hydrocarbons on ascorbic acid content in the internal organs in white rats. II. Effect of methylene chloride].
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Animals↗
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PHOTOMETRIC DETERMINATION OF AMINES AND QUATERNARY AMMONIUM COMPOUNDS WITH BROMOTHYMOL BLUE. 3. PARTITION OF BROMOTHYMOL BLUE BETWEEN WATER AND METHYLENE CHLORIDE.
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Amines↗
Capillary gas chromatography with cryogenic oven temperature for headspace samples: analysis of chloroform or methylene chloride in whole blood.
A new and sensitive gas chromatography (GC) method for measurement of chloroform or methylene chloride in whole blood is presented. Trace levels of these analytes present in the headspace of samples were cryogenically trapped prior to on-line GC analysis. After heating of a blood sample containing chloroform and methylene chloride (internal standard, and vice versa) in a 7.0-mL vial at 55 degrees C for 20 min, 5 mL of the headspace vapor was drawn into a glass syringe. All vapor was introduced into an Rtx-Volatiles middle-bore capillary column in the splitless mode at -30 degrees C oven temperature to trap the entire analytes, and the oven temperature was programmed up to 280 degrees C for detection of the compounds and for cleaning of the column. The present conditions gave sharp peaks for both chloroform and methylene chloride and very low background noises for whole blood samples. As much as 11.5 and 20.0% of chloroform and methylene chloride, respectively, which had been added to whole blood in a vial, could be introduced into the GC column. The calibration curves showed linearity in the range of 0.05-5.0 micrograms/0.5 mL of whole blood. The detection limit was estimated to be about 2 ng/0.5 mL. The coefficients of intraday and interday variations were 1.31 and 8.90% for chloroform and 1.37 and 9.03% for methylene chloride, respectively. The data on chloroform or methylene chloride in rat blood after inhalation of each compound were also presented.
Animals↗
Derivation of an occupational exposure limit (OEL) for methylene chloride based on acute CNS effects and relative potency analysis.
The Occupational Safety and Health Administration (OSHA) methylene chloride Permissible Exposure Level (PEL) or 25 ppm is quantitatively derived from mouse tumor results observed in a high-exposure National Toxicology Program bioassay. Because this approach depends on controversial interspecies and low-dose extrapolations, the PEL itself has stimulated heated debate. Here, an alternative safety assessment for methylene chloride is presented. It is based on an acute human lowest-observed-adverse-effect level (LOAEL) of 200 ppm for subtle central nervous system (CNS) depression. Steep, parallel exposure-response curves for anesthetic and subanesthetic CNS effects associated with compounds mechanistically and structurally related to methylene chloride are shown to support a safety factor of two to account for inter-individual variability in response. LOAEL/no-observed-adverse-effect ratios for subtle CNS effects associated with structurally related solvents are shown to support a safety factor range of two to four to account for uncertainty in identifying a subthreshold exposure level. Anesthetic relative potencies and anesthetic/subanesthetic effect level ratios are shown to be constant for the compounds evaluated, demonstrating that subanesthetic relative potencies are also constant. Relative potencies among similarly derived occupational exposure limits (OELs) for solvents structurally related to methylene chloride are therefore used to validate the derived methylene chloride OEL range of 25-50 ppm. Because this safety assessment is based on human (rather than rodent) data and empirical (rather than theoretical) exposure-response relationships and is supported by relative potency analysis, it is a defensible alternative to to the OSHA risk assessment and should positively contribute to the debate regarding the appropriate basis and value for a methylene chloride PEL.
Anesthetics↗
Secondary substrate utilization of methylene chloride by an isolated strain of Pseudomonas sp.
Secondary substrate utilization of methylene chloride was analyzed by using Pseudomonas sp. strain LP. Both batch and continuously fed reactors demonstrated that this strain was capable of simultaneously consuming two substrates at different concentrations: the primary substrate at the higher concentration (milligrams per liter) and the secondary substrate at the lower concentration (micrograms per liter). The rate of methylene chloride utilization at trace concentrations was greater in the presence of the primary substrate, acetate, than without it. However, when the substrate roles were changed, the acetate secondary substrate utilization rate was less when methylene chloride was present. Thus, substrate interactions are important in the kinetics of secondary substrate utilization. Pseudomonas sp. strain LP showed a preference toward degrading methylene chloride over acetate, whether it was the primary or secondary substrate, providing it was below an inhibitory concentration of ca. 10 mg/liter.
Acetates↗
Engineering controls for furniture strippers to meet the OSHA methylene chloride PEL.
This case study demonstrates how methylene chloride exposures during furniture stripping can be reduced to below the Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL) of 25 ppm (as an 8-hour time-weighted average). Five surveys were conducted at one facility; the first four resulted in employee exposure geometric means from 39 to 332 ppm. For the fifth survey local exhaust ventilation was used at the stripping tank and the rinsing area, which together exhausted 138 m3/min (4860 ft3/min). Additional controls included providing adequate make-up air, adding paraffin wax to the stripping solution, raising the level of the stripping solution in the tank, and discussing good work practices with the employee. The employees' methylene chloride exposures during the fifth survey resulted in a geometric mean of 5.6 ppm with a 95% upper confidence limit of 8.3 ppm, which was found to be significantly lower than the OSHA PEL and the OSHA action level of 12.5 ppm. The cost of the ventilation system was $8900.
Data Collection↗
Health evaluation of employees occupationally exposed to methylene chloride.
General study design and environmental considerations. Scand j work environ health 9 (1983): suppl 1, 1-7. Recent concern regarding health hazards of methylene chloride stem primarily from the discovery of its metabolism to carboxyhemoglobin. In this report, a research program is described, the purpose of which was to assess potential health effects of methylene chloride exposure in an occupational setting. Particular attention was given to evaluating possible direct and carboxyhemoglobin-mediated effects on the hematopoietic and circulatory systems. The study involved one fiber production plant which used a methylene chloride/methanol mixture and acetone as solvents and a second fiber production plant that used acetone only. The research design included a retrospective cohort mortality study and several health evaluation studies, as well as an environmental assessment of the two plants. Industrial hygiene monitoring indicated that typical methylene chloride exposures ranged from an 8-h time-weighted average of 140 ppm in areas of low methylene chloride use to a corresponding average of 475 ppm in areas of high methylene chloride use and that methanol was present in about a one to ten ratio to methylene chloride. Acetone exposures in both plants ranged from 100 to over 1,000 ppm (time-weighted average).
Adult↗
Effects in the liver of methylene chloride inhaled alone and with ethyl alcohol.
When high concentrations of methylene chloride in combination with high concentrations of ethanol were inhaled for one day by guinea pigs, the extent of the hepatic damage induced suggested an antagonism between the effects of the two agents. However, exposure for five days to approximately 500 ppm of methylene chloride plus high concentrations of ethanol suggested ethanol may potentiate the effects of methylene chloride.
Animals↗
Hyperbaric oxygen for methylene chloride poisoning: report on two cases.
Two cases of methylene chloride poisoning treated with hyperbaric oxygen are presented and discussed. Both patients were found unconscious in an occupational setting. Carboxyhemoglobin level determination and neuropsychological evaluation confirmed a diagnosis of carbon monoxide intoxication subsequent to methylene chloride exposure. The serial carboxyhemoglobin levels and Carbon Monoxide Neuropsychological Screening Battery scores obtained from these patients suggest that toxicity from methylene chloride-derived carbon monoxide responds well to treatment with hyperbaric oxygen.
Adult↗
Extraction of chloroform and methylene chloride in human whole blood and urine by headspace solid phase microextraction (SPME).
Chloroform and methylene chloride were extracted from human whole blood and urine by headspace solid phase microextraction (SPME) using a Carboxen/polydimethylsiloxane (Carboxen/PDMS) fibre before capillary gas chromatography (GC)/flame ionization detection (FID). Whole blood or urine was placed in a vial and mixed with distilled water. The vial was heated at 30 degrees C, and the solvents were extracted from the headspace by SPME. The extraction efficiencies of chloroform and methylene chloride from whole blood were 40.3% and 35.8%, respectively; those for urine were 57.0% and 43.6%, respectively. The calibration curves for chloroform were linear in the range of 1-8 micrograms/ml for blood and urine samples, and those for methylene chloride in the range of 0.5-8 micrograms/ml. The detection limits for both compounds were 0.3 microgram/ml for whole blood and 0.2 microgram/ml for urine. The headspace SPME with Carboxen/PDMS fibre coupled with GC/FID seems useful for analyses of chloroform and methylene chloride in forensic toxicology and environmental chemistry.
Blood Chemical Analysis↗
Effect of subtoxic amounts of furan, acetylfuran and methylene chloride on some serum enzymes of rat.
Serum transaminases (GOT and GPT) and ornithincarbamyltransferase (OCT) were determined in rats treated with subtoxic doses of furan, acetylfuran, and methylene chloride. Significant increases of all enzymes were observed in methylene chloride treated rats, while only GOT increased in rats treated with acetylfuran and with furan + methylene chloride. Calculation of the GOT/GPT ratios indicated a pattern of toxic hepatitis only for rats treated with acetylfuran and furan + methylene chloride.
Alanine Transaminase↗
Methylene chloride: two-generation inhalation reproductive study in rats.
Reproductive parameters in Fischer 344 rats were evaluated following inhalation of methylene chloride (MeCl2) for two successive generations. Thirty male and female rats were exposed to 0, 100, 500, or 1500 ppm MeCl2 for 6 hr/day, 5 days/week for 14 weeks and then mated to produce f1 litters. After weaning, 30 randomly selected f1 pups/sex/group were exposed to MeCl2 for 17 weeks and subsequently mated to produce f2 litters. Reproductive parameters examined included fertility, litter size and neonatal growth, and survival. All adults and selected weanlings were examined for grossly visible lesions. Tissues from selected weanlings were examined histopathologically. No adverse effects on reproductive parameters, neonatal survival, or neonatal growth were noted in animals exposed to methylene chloride in either the f0 or f1 generations. Similarly, there were no treatment-related gross pathologic observations in f0 or f1 adults or f1 and f2 weanlings. Histopathologic examination of tissues from f1 and f2 weanlings did not reveal any lesions attributed to methylene chloride. Thus, exposure of rats to concentrations as high as 1500 ppm methylene chloride, which has been shown in a 2-year study to produce treatment-related effects, did not affect any reproductive parameters.
Administration, Inhalation↗
Exposure to methylene chloride. I Its concentration in alveolar air and blood during rest and exercise and its metabolism.
Fourteen subjects were exposed to about 870 and 1,740 mg/m3 of methylene chloride in the air during rest and physical exercise on a bicycle ergometer. The duration of each exposure period was 30 min. Each subject was exposed during four periods. The concentration of methylene chloride in the alveolar air increased in the beginning but had a tendency to level off at the end of each period. There was a high correlation between the alveolar and arterial concentration of methylene chloride. The uptake of methylene chloride was about 55 % of the supplied amount at rest, about 40% at a work load of 50 W, and about 30 and 35 % at 100 and 150 W, respectively. The concentration of carboxyhemoglobin (COHb) increased both during and after exposure. With exposure to 1,740 mg/m3 a concentration of COHb in the blood of about 0.85 g/100 ml was reached. This value corresponds to about 5.5 % COHb.
Adult↗
Interindividual differences in the in vitro conjugation of methylene chloride with glutathione by cytosolic glutathione S-transferase in 22 human liver samples.
The interindividual variation in the in vitro conjugation of methylene chloride with glutathione by cytosolic glutathione S-transferase (GST) was investigated with 22 human liver samples. In three of the samples no activity towards methylene chloride was observed. Eleven samples showed an activity ranging from 0.20 to 0.41 (0.31 +/- 0.08) nmol/min/mg protein, and eight samples an activity of 0.82-1.23 (1.03 +/- 0.14) nmol/min/mg protein. The activities towards 1-chloro-2,4-dinitrobenzene (CDNB) of these three groups were 1.17 +/- 0.25, 1.12 +/- 0.35 and 1.20 +/- 0.53 mumol/min/mg protein, respectively. In nine of the liver samples, the alpha-, mu- and pi-class GST subunits were quantified. In two of these samples, no activity was observed towards methylene chloride, while alpha-, mu- and pi-class subunits were expressed in these human liver cytosolic samples. As the highest activity towards methylene chloride was still 1.4 times lower than the activity in rat cytosol, the existence of the three populations seems to be of little importance for human risk assessment.
Cytosol↗
Relevance of carcinogenicity bioassays in mice in assessing potential health risks associated with exposure to methylene chloride.
Considerable research has been conducted to identify possible mechanisms of the carcinogenicity of methylene chloride in rodents, and to ascertain whether the observed increased incidences of liver and lung tumours in mice exposed to this substance, are relevant in assessing the potential hazards and risks to human health. On the basis of a study that purported to show qualitative differences between murine and human tissues, in the subcellular localization of the Theta-class glutathione S-transferase enzyme responsible for converting methylene chloride to a putative highly unstable, but reactive genotoxic metabolite, it was suggested that the mouse is an inappropriate model for human health risk assessment. However, other studies conducted in vitro with intact cells do not support the hypothesis that a putatively reactive metabolite of methylene chloride must be generated only within the nucleus in order to be able to interact with genomic DNA. Moreover, investigations employing semi-quantitative methods of mRNA hybridization are not convincing in identifying the subcellular localization of active Theta class glutathione S-transferase, and do not support the hypothesis of the differential subcellular localization of this enzyme within the nucleus of mouse, but not human cells. There is therefore, insufficient evidence to support the view that qualitative differences between humans and mice in the subcellular distribution of Theta-class glutathione S-transferase, renders carcinogenicity studies conducted with mice irrelevant in human hazard identification and risk assessment.
Animals↗
Mortality of workers exposed to methylene chloride employed at a plant producing cellulose triacetate film base.
OBJECTIVE: To study mortality among 1785 employees of a factory that produced cellulose triacetate film base at Brantham in the United Kingdom. Also, to investigate patterns of mortality after exposure to methylene chloride; in particular, mortality from liver and biliary tract cancer, lung cancer, pancreatic cancer, and cardiovascular disease. SUBJECTS AND METHODS: All male employees with a record of employment at the film factory in 1946-88. A total of 1473 subjects worked in jobs that entailed exposure to methylene chloride. The mean duration of exposure was nine years at 19 ppm (eight hour time weighted average). RESULTS: In the cohort, 334 deaths were identified up to 31 December 1994. Mortalities for the cohort were compared with national and local rates and expressed as standardised mortality ratios (SMR). In the subcohort of workers exposed to methylene chloride, substantially reduced mortalities compared with national and local rates were found for all causes, all cancers, and the principal cancer sites of interest. The significantly reduced lung cancer mortalities in exposed workers (SMR 48) seemed to reflect the restrictions on smoking at the workplace. In contrast, mortality from ischaemic heart disease in exposed workers, although lower than national rates (SMR 92), was slightly increased compared with local rates. However, mortality from ischaemic heart disease was lower in active employees (SMR 83) where a direct effect of exposure to methylene chloride should be concentrated. No in service mortality due to ischaemic heart disease was found in workers with the highest cumulative exposure (> or = 800 ppm-years). CONCLUSIONS: The study provided no indication that employment at the plant, or exposure to methylene chloride, had adversely affected the mortalities of workers.
Cause of Death↗
Pulmonary toxicity following exposure to methylene chloride and its combustion product, phosgene.
Chemical paint removers containing methylene chloride are widely used in domestic and industrial settings where exposure to a heat source with conversion to phosgene is possible. We describe a case of noncardiogenic pulmonary edema and subsequent hyperreactive airways following such an exposure. In addition, the various problems that have been associated with exposure to methylene chloride and phosgene are reviewed.
Adult↗
PBPK modeling/Monte Carlo simulation of methylene chloride kinetic changes in mice in relation to age and acute, subchronic, and chronic inhalation exposure.
During a 2-year chronic inhalation study on methylene chloride (2000 or 0 ppm; 6 hr/day, 5 days/week), gas-uptake pharmacokinetic studies and tissue partition coefficient determinations were conducted on female B6C3F1, mice after 1 day, 1 month, 1 year, and 2 years of exposure. Using physiologically based pharmacokinetic (PBPK) modeling coupled with Monte Carlo simulation and bootstrap resampling for data analyses, a significant induction in the mixed function oxidase (MFO) rate constant (Vmaxc) was observed at the 1-day and 1-month exposure points when compared to concurrent control mice while decreases in glutathione S-transferase (GST) rate constant (Kfc) were observed in the 1-day and 1-month exposed mice. Within exposure groups, the apparent Vmaxc maintained significant increases in the 1-month and 2-year control groups. Although the same initial increase exists in the exposed group, the 2-year Vmaxc is significantly smaller than the 1-month group (p < 0.001). Within group differences in median Kfc values show a significant decrease in both 1-month and 2-year groups among control and exposed mice (p < 0.001). Although no changes in methylene chloride solubility as a result of prior exposure were observed in blood, muscle, liver, or lung, a marginal decrease in the fat:air partition coefficient was found in the exposed mice at p = 0.053. Age related solubility differences were found in muscle:air, liver:air, lung:air, and fat:air partition coefficients at p < 0.001, while the solubility of methylene chloride in blood was not affected by age (p = 0.461). As a result of this study, we conclude that age and prior exposure to methylene chloride can produce notable changes in disposition and metabolism and may represent important factors in the interpretation for toxicologic data and its application to risk assessment.
Administration, Inhalation↗