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PubMed1985

Gassings due to methylene chloride, xylene, toluene, and styrene reported to Her Majesty's Factory Inspectorate 1961-80.

For the period 1961-80, 118 cases of industrial gassings caused by the solvents methylene chloride, xylene, toluene, and styrene were reported to Her Majesty's Factory Inspectorate. The data have been collated and analysed according to the predetermined criteria of age, sex, mode and circumstances of use, clinical effect, and outcome. The means of collection of the data and their objectivity is discussed. The study shows the narcotic effect of these solvents and underlines the dangers of their use in confined spaces. Symptoms were most commonly attributable to the nervous and respiratory systems. The problem of addiction and the vulnerability of the younger worker is also discussed.

Adolescent↗
PubMedDate not supplied

Stability of methylene chloride spiked passive samplers: an international shipping and transportation study.

A stability study was carried out by dynamically spiking Assay Technology Model 541 passive samplers with known amounts of methylene chloride (MeCl2) and shipping them to facilities around the world. Once arrived, these samples remained on site briefly and then were returned to the laboratory in North Chicago, III. A total of 22 sets of samples was prepared. Each sample set contained four passive samplers: blank, low (2.5 ppm), medium (25 ppm), and high (125 ppm) concentrations. Twelve of the 22 sets were separated into 4 groups of 3 sets, with each group defined as a cluster. One cluster was shipped to a pharmaceutical production facility in each country--South Africa, Pakistan, and Indonesia--and then shipped back to the lab, under normal shipping conditions. The fourth cluster was carried by one of the authors, who traveled through all three countries. The remaining 10 sets of samples were kept in the lab as controls. Each returning cluster was analyzed with two lab sets on arrival in the lab. Results obtained were evaluated using a t-test at a 95% confidence level. No significant differences were found in MeCl2 spiked passive samplers between traveled and lab controls, samples stored at room temperature and in the freezer, or analyzed right after being spiked and stored up to 7 weeks. It was concluded that MeCl2 spiked passive samplers were stable for at least 4 weeks at room temperature. There was no impact observed from international shipping and transportation on MeCl2 spiked passive samplers without temperature control.

Environmental Monitoring↗
PubMed1992

Methylene chloride--an inhalation study to investigate pathological and biochemical events occurring in the lungs of mice over an exposure period of 90 days.

Male B6C3F1 mice were exposed to 4000 ppm methylene chloride (MC) for 6 hr/day, 5 days/week for up to 13 weeks. Groups of mice were killed at intervals from Day 2 to Week 13. Whole lungs were examined morphologically, immunocytochemically, and biochemically. Biochemical and morphological examination was also performed on isolated Clara cells. The major initial morphological effect seen in lungs was acute Clara cell damage after one exposure to MC. However, this damage appeared to resolve after five consecutive daily exposures to MC. After a 2-day interval the Clara cell lesion reappeared on subsequent reexposure to MC. However, the severity of the lesion decreased over the duration of the study. The appearance and disappearance of the lesion in the Clara cell correlated well with the activity of cytochrome P450 monooxygenase in the Clara cell as assessed immunocytochemically (cytochromes P450IIB 1 and 2) in the whole lung and biochemically in the freshly isolated Clara cell (determined by ethoxycoumarin O-dealkylation and aldrin epoxidation). When there was a marked decrease in cytochrome P450 monooxygenase activity the lesion was not present. This suggested that with time the lung (Clara cell) has developed tolerance to MC possibly due to the inactivation of a cytochrome P450 isozyme. The glutathione S-transferase metabolism of MC by the lung cytosol remained virtually unaltered throughout the study. Events accompanying the discussed changes include (1) a significant increase in nonprotein sulfhydryl in the lungs of all exposed animals, (2) altered plating characteristics of the isolated Clara cells from exposed lungs after 24 hr in culture, and (3) an increase in the number of bronchiolar cells in the S-phase after the first exposure to MC. The study also demonstrates the advantages of target cell isolation and study over whole lung biochemical investigation alone.

Administration, Inhalation↗
PubMed2004

Methylene chloride fraction of Spatholobi Caulis induces apoptosis via caspase dependent pathway in U937 cells.

Spatholobi Caulis has been used in Oriental medicine to treat cancer and blood stasis. In this study, the methylene chloride fraction of Spatholobi Caulis (MCSC) was examined to determine if it possesses anti-cancer activity via its apoptosis-inducing activity. MCSC exhibited a strong cytotoxic effect against human monocyte leukemia U937 cells (IC(50)=15.1 microg/ml). A TUNEL assay showed that the MCSC caused a characteristic ladder pattern of discontinuous DNA fragments and apoptotic bodies. Flow cytometric analysis confirmed that MCSC significantly increases the number of apoptotic cells stained by annexin V(+)/PI(-) cells. Western blotting revealed that MCSC activated caspase-3 expression and cleaved poly (ADP-ribose) polymerase (PARP) in a concentration-dependent manner. An enzyme-linked immunosorbent assay (ELISA) demonstrated that MCSC significantly activated the caspase-3 activity compared with the untreated control by. Taken together, these results suggest that MCSC can induce apoptosis in U937cells via the caspase dependent pathway.

Annexin A5↗
PubMed1998

Field validation of passive monitors for the determination of employee exposures to methylene chloride in pharmaceutical production facilities.

A series of field evaluations was performed to estimate the overall uncertainty of three manufacturers' passive monitors (Assay Technology Model 541 and 546, 3M Model 3520, and SKC Model 575-001) to determine methylene chloride (MeCl2) concentrations. Area samples were exposed in a pharmaceutical production facility at five MeCl2 air concentrations for both permissible exposure limit (PEL) and short-term exposure limit (STEL) periods. A specially designed evaluation chamber was used to concurrently expose six of each type of passive monitor while concurrently collecting six active samples from locations surrounding the dosimeter array. The active samples were used to estimate the actual concentration during the evaluation period. The precision, bias, and overall uncertainty were estimated for each monitor type at concentrations bracketing the Occupational Safety and Health Administration proposed exposure limits. The actual MeCl2 concentrations for the PEL sampling periods ranged from 0.9 to 63 ppm. The pooled overall uncertainty results for all the passive monitors evaluated under PEL sampling conditions met the NIOSH accuracy recommendations. Pooled overall uncertainty for PEL evaluations for the monitors were: Assay Technology Model 546 +/- 17%; 3M +/- 13%; and SKC +/- 17%. Actual MeCl2 concentrations for the STEL sampling periods ranged from 14 to 357 ppm. Pooled overall uncertainty results for Assay Technology and 3M monitors evaluated under STEL sampling conditions met the NIOSH accuracy recommendations; however, the SKC passive monitor was slightly greater than the NIOSH recommendation. Pooled overall uncertainty for STEL evaluations for the monitors were: Assay Technology Model 541 +/- 18%; 3M +/- 16%; and SKC +/- 27%.

Air Pollutants, Occupational↗
PubMed2006

The methylene chloride fraction of Trichosanthis Fructus induces apoptosis in U937 cells through the mitochondrial pathway.

Trichosanthis kirilowii MAXIM has been used as a folk remedy to treat diabetes, leukemia, and breast cancer. In the present study, the apoptotic mechanism of the methylene chloride fraction of Trichosanthis Fructus (MCTF) was investigated in human leukemic U937 cells. MCTF exhibited antiproliferative effectsagainst U937 cells (IC50=ca. 8 microg/ml). Apoptotic bodies were observed in MCTF-treated U937 cells in the TUNEL assay. We also confirmed that MCTF significantly increases annexin V(+)/propidium iodide-cells using FACS analysis. MCTF treatment activated caspase-8, -9 and -3, and led to cleaved poly (ADP-ribose) polymerase and release of cytochrome c into cytosol in a concentration-dependent manner, while MCTF did not affect Bax or Bcl-2 protein levels as shown by Western blot analysis. Taken together, these results indicate that MCTF can induce apoptosis in U937 cells chiefly via a mitochondrial-mediated pathway and suggest that Trichosanthis Fructus can be used in cancer treatment as a chemopreventive agent.

Antineoplastic Agents, Phytogenic↗
PubMedDate not supplied

Modeling methylene chloride exposure-reduction options for home paint-stripper users.

Home improvement is a popular activity, but one that can also involve exposure to hazardous substances. Paint stripping is of particular concern because of the high potential exposures to methylene chloride, a solvent that is a potential human carcinogen and neurotoxicant. This article presents a general methodology for evaluating the effectiveness of behavioral interventions for reducing these risks. It doubles as a model that assesses exposure patterns, incorporating user time-activity patterns and risk-mitigation strategies. The model draws upon recent innovations in indoor air-quality modeling to estimate exposure through inhalation and dermal pathways to paint-stripper users. It is designed to use data gathered from home paint-stripper users about room characteristics, amount of stripper used, time-activity patterns and exposure-reduction strategies (e.g., increased ventilation and modification in the timing of stripper application, scraping, and breaks). Results indicate that the effectiveness of behavioral interventions depends strongly on characteristics of the room (e.g., size, number and size of doors and windows, base air-exchange rates). The greatest simple reduction in exposure is achieved by using an exhaust fan in addition to opening windows and doors. These results can help identify the most important information for product labels and other risk-communication materials.

Air Pollution, Indoor↗
PubMed2004

Methylene chloride fraction of Scutellaria barbata induces apoptosis in human U937 leukemia cells via the mitochondrial signaling pathway.

BACKGROUND: Scutellaria barbata D.Don has been applied to treat cancers, inflammation and urinary disease. However, its antitumor mechanism still remains unclear. METHODS: With methylene chloride fraction of Herba Scutellariae barbatae (MCSB), apoptosis-related experiments were carried out on human U937 leukemia cells by (a) 2,3-bis[2-4-nitro-5-sulphophenyl]2H-tetrazolium-5-carboxanilide (XTT) assay for cytotoxicity; (b) terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling (TUNEL) assay for morphological changes; (c) cell cycle analysis; (d) Western blot analysis of poly(ADP-ribose) polymerase (PARP), caspase-8, caspase-9, caspase-3 and Bax, Bcl-2 and cytochrome c expressions for apoptosis signaling pathway. RESULTS: MCSB inhibited the proliferation of human U937 leukemia cells in a dose-dependent manner (IC50 = approximately 10 microg/ml). MCSB dose-dependently increased the sub-G1 DNA contents by cell cycle analysis. DNA fragments indicating induction of apoptosis were observed in MCSB-treated U937 cells by TUNEL assay. Caspase-9 and caspase-3 were activated while caspase-8 was intact by MCSB. Similarly, MCSB effectively cleaved PARP, increased the ratio of Bax/Bcl-2 and released the cytochrome c from mitochondria during apoptosis in U937 cells. CONCLUSIONS: Our results suggest that MCSB can induce apoptosis via the mitochondria-mediated signaling pathway.

Apoptosis↗
PubMed1990

Reproducibility of carcinogenic potencies estimated in different rodent species. Methylene chloride: a useful example.

The aim of this study was to investigate the reproducibility of carcinogenic potencies estimated by multistage model (and its linearized form) fitting to dose-response relationships referring to different rodent species and strains, different sexes, target organs and severity of prognosis. Methylene chloride represented a useful example since there were 11 single dose-response relationships available for the same administration route (inhalation) and for the above-mentioned variables. The multistage mathematical model and the 'linearized multistage' model (EPA's conservative procedure), which are the mainly adopted models for regulatory purposes, were used for the dose-response fitting of single trends and other different cumulative trends. The reproducibility of response frequencies at equal exposure doses was also analyzed. The mathematical function best describing each trend showed the constant presence of a linear component (for low doses) and, in the majority of cases, a quadratic second order component. Carcinogenic potencies were fairly consistent for the various parameters. A good interspecies reproducibility of carcinogenic potencies was observed. A high intraspecies reproducibility was also observed, even though obtained from different sexes, as well as varying degrees of severity of prognosis and, in the case of rats, different strains. The fluctuation of the estimated carcinogenic potencies was lower in mice than in rats.

Animals↗
PubMed1988

Incorporation of in vitro enzyme data into the physiologically-based pharmacokinetic (PB-PK) model for methylene chloride: implications for risk assessment.

Physiologically-based pharmacokinetic (PB-PK) models provide a mechanism for reducing the uncertainty inherent in extrapolating the results of animal toxicity tests to man. This paper discusses a technique for incorporating data from in vitro studies of xenobiotic metabolism into in vivo PB-PK models. Methylene chloride is used as an example, and carcinogenic risk estimates incorporating PB-PK principles are presented.

Animals↗
PubMed1996

A cohort mortality study of cellulose triacetate-fiber workers exposed to methylene chloride.

The purpose of this study of 3211 cellulose-fiber production workers was to evaluate earlier findings of excess biliary tract and liver cancer in a similarly exposed cohort reported in 1990. Mortality from biliary tract and liver cancer was not increased in this study population, and there was no excess mortality from pancreatic cancer. Mortality was not elevated for cancers of the lung or liver, sites at which tumors were induced in experimental animals exposed to methylene chloride. Men with 20 or more years of employment exhibited increased mortality from prostate cancer, whereas women who also had 20 or more years of employment experienced higher-than-expected mortality from cervical cancer. Although these apparent increases in mortality are difficult to interpret biologically and are not consistent with previous studies, they require further investigation.

Cause of Death↗
PubMed1989

Variability of safe dose estimates when using complicated models of the carcinogenic process. A case study: methylene chloride.

Advances in understanding carcinogenesis have led to the development of mathematical models that have biologically interpretable parameters. These models utilize more of the available scientific data than the empirical models routinely employed for quantifying carcinogenic risk. They also require consideration of sources of uncertainty in risk estimates that were previously ignored, such as animal-to-animal variability of physiological and pharmacological constants. A numerical technique is proposed for studying the consequences of incorporating the intrapopulation variability of biologically interpretable parameters into the risk assessment process. To demonstrate the technique, the variability of safe dose estimates for exposure to methylene chloride is considered. The results suggest that intrapopulation variability of the model parameters can increase the variability of safe dose estimates an appreciable amount.

Animals↗
PubMed2005

Simulation of the toxicokinetics of trichloroethylene, methylene chloride, styrene and n-hexane by a toxicokinetics/toxicodynamics model using experimental data.

The toxicokinetics/toxicodynamics (TKTD) model simulates the toxicokinetics of a chemical based on physiological data such as blood flow, tissue partition coefficients and metabolism. In this study, Andersen and Clewell's TKTD model was used with seven compartments and ten differential equations for calculating chemical balances in the compartments (Andersen and Clewell 1996, Workshop on physiologically-based pharmacokinetic/pharmacodynamic modeling and risk assessment, Aug. 5-16 at Colorado State University, U.S.A) . Using this model, the authors attempted to simulate the behavior of four chemicals: trichloroethylene, methylene chloride, styrene and n-hexane, and the results were evaluated. Simulations of the behavior of trichloroethylene taken in via inhalation and oral exposure routes were also done. The differences between simulations and measurements are due to the differences between the absorption rates of the exposure routes. By changing the absorption rates, the simulation showed agreement with the measured values. The simulations of the other three chemicals showed good results. Thus, this model is useful for simulating the behavior of chemicals for preliminary toxicity assessment.

Administration, Oral↗
PubMed1989

In vitro metabolism of methylene chloride in human and animal tissues: use in physiologically based pharmacokinetic models.

Physiologically based pharmacokinetic (PB-PK) models describe the dynamic behavior of chemicals and their metabolites in individual tissues of living animals. Because PB-PK models contain specific parameters related to the physiological and biochemical properties of different species as well as the physical chemical characteristics of individual chemicals, they are useful tools for performing high dose/low dose, dose route, and interspecies extrapolations in hazard evaluations. An example of such extrapolation has been presented by M. E. Andersen, H. J. Clewell III, M. L. Gargas, F. A. Smith, and R. H. Reitz (Toxicol. Appl. Pharmacol. 87, 185-205, 1987), who employed a PB-PK model for methylene chloride (CH2Cl2) to estimate the chronic toxicity of this material. However, one limitation of this PB-PK model was that the metabolic rate constants for the glutathione-S-transferase (GST) pathway in humans were estimated by allometric scaling rather than from experimental data. In this paper we report studies designed to estimate the in vivo rates of metabolism of CH2Cl2 from in vitro incubations of lung and liver tissues from B6C3F1 mice, F344 rats, Syrian Golden hamsters, and humans. A procedure for calculating in vivo metabolic rate constants from the in vitro studies is presented. This procedure was validated by making extrapolations with mixed function oxidase enzymes (MFO) acting on CH2Cl2, where both in vitro and in vivo rates of metabolism are known. The in vitro rate constants for the two enzyme systems are consistent with the hypothesis presented by Andersen et al. that metabolism of CH2Cl2 occurs in vivo by two competing pathways: a high-affinity saturable pathway (identified as MFO) and a low-affinity first-order pathway (identified as GST). The metabolic rate constants for GST obtained from these studies are also consistent with the hypothesis of Andersen et al. that production of large quantities of glutathione/CH2Cl2 conjugates in vivo may increase the frequency with which lung and liver tumors develop in some species of animals (e.g., B6C3F1 mouse). When in vivo studies in humans are unavailable, in vitro enzyme assays provide a reasonable method for estimating metabolic rate constants.

Animals↗
PubMed2000

Open circuit reactions complicating the electroprecipitation of poly(vinylferricinium) films from methylene chloride

We describe an electrochemical quartz crystal microbalance interfacial gravimetric study of the electroprecipitation and dissolution of PVF+ClO4- (PVF = poly(vinylferrocene)) films exposed to methylene chloride solutions. Film deposition is diffusion controlled by the supply of PVF from the solution. Film solvent content is markedly dependent upon the deposition potential. The self-exchange process between surface-bound ferricinium sites and solution-phase ferrocene sites, which is responsible for film deposition under conditions of positive applied potential, is also responsible for film dissolution under open circuit conditions. Dependent upon the deposition potential, releasing the electrode from potential control may (not) result in transient deposition processes that temporarily increase surface coverage. Under all conditions, opening the circuit ultimately leads to reductive stripping of the film by solution-phase PVF. The dissolution rate is independent of applied potential, and is not limited by electron transfer at the outer film interface or by electron (and coupled ion) transport within the film; we speculate that polymer-based processes, such as chain disentanglement, are rate limiting.

Journal Article↗
PubMed1990

Methylene chloride intoxication in a furniture refinisher. A comparison of exposure estimates utilizing workplace air sampling and blood carboxyhemoglobin measurements.

A 35-year-old furniture refinisher came to the occupational medicine clinic with complaints of upper respiratory irritation, fatigue, and lightheadedness occurring on a daily basis after using a methylene chloride-containing paint stripper. Determinations of blood carboxyhemoglobin (COHb) on three occasions showed an apparently linear elevation of COHb as a function of hours worked on the day of sampling. COHb levels predicted from spot industrial hygiene measurements were in close concordance with those observed in the patient, indicating the potential usefulness of COHb monitoring in estimating airborne exposure levels. Methylene chloride (or dichloromethane) is an organic solvent that has found wide use as a degreaser, paint remover, aerosol propellant, and a blowing agent for polyurethane foams, and as a solvent in food processing, photographic film production, and plastics manufacturing. Discovery of its unusual metabolic fate--conversion to carbon monoxide in vivo--has earned the compound a special place in the solvent toxicology literature. Demonstration of oncogenicity in experimental animals has occasioned a reconsideration of exposure limits, with emphasis upon stricter controls. In some workplaces, conditions prevail in which controls are inadequate to prevent even acute toxicity, much less long-term exposure risks.

Adult↗
PubMed1998

Determination of Key Flavor Components in Methylene Chloride Extracts from Processed Grapefruit Juice.

The relative correlation of 52 aroma and 5 taste components in commercial not-from-concentrate grapefruit juices with flavor panel preference was determined. Methylene chloride extracts of juice were analyzed using GC/MS with a DB-5 column. Nonvolatiles determined included limonin and naringin by HPLC, degrees Brix, total acids, and degrees Brix/acid ratio. Juice samples were classified into low, medium, or high categories, based on average taste panel preference scores (nine-point hedonic scale). Principal component analysis demonstrated that highest quality juices were tightly clustered. Discriminant analysis indicated that 82% of the samples could be identified in the correct preference category using only myrcene, beta-caryophyllene, linalool, nootkatone, and degrees Brix. Nootkatone alone was not strongly associated with preference scores. The most preferred juices were strongly associated with low myrcene, low linalool, and intermediate levels of beta-caryophyllene.

Journal Article↗