Methylene chloride: A 2-year inhalation toxicity and oncogenicity study in rats*1

Nitschke, K.D.; Burek, J. D.; Bell, T.J.; Kociba, R.J.; Rampy, L. W.; McKenna, Michael J.

doi:10.1016/0272-0590(88)90269-2

Cited by 41 publications

(8 citation statements)

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“…[46], the statistical results are presented in the full report of the study (Hazleton Laboratories, [45]): the trend p-value was 0.058; p-values for the pair-wise comparisons with the combined control group were p = 0.071, 0.023, 0.019, and 0.036 for the 50, 125, 185, and 250 mg/kg per day dose groups, respectively. None of the chronic exposure studies in rats have shown a relation between dichloromethane exposure and liver or lung tumors [3,45,47–49]. …”

Section: Discussionmentioning

confidence: 99%

“…in which dichloromethane levels in the brain were much higher with a higher intensity exposure scenario compared with a constant exposure period with an equivalent time-weighted average [57]. A statistically significant increased incidence of brain or central nervous system tumors has not been observed in any of the animal cancer bioassays, but a 2-year study using relatively low exposure levels (0, 50, 200, and 500 ppm) in Sprague-Dawley rats observed a total of six astrocytoma or glioma (mixed glial cell) tumors in the exposed groups (in females, the incidence was 0, 0, 0, and 2 in the 0, 50, 200, and 500 ppm exposure groups, respectively; in males, the incidence was 0, 1, 2, and 1 in the 0, 50, 200, and 500 ppm exposure groups, respectively; sample size of each group was 70 rats) [49]. These tumors are exceedingly rare in rats, and there are few examples of statistically significant trends in animal bioassays [58].…”

Section: Discussionmentioning

confidence: 99%

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Insights from Epidemiology into Dichloromethane and Cancer Risk

Cooper

Scott

Bale

2011

IJERPH

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Dichloromethane (methylene chloride) is a widely used chlorinated solvent. We review the available epidemiology studies (five cohort studies, 13 case-control studies, including seven of hematopoietic cancers), focusing on specific cancer sites. There was little indication of an increased risk of lung cancer in the cohort studies (standardized mortality ratios ranging from 0.46 to 1.21). These cohorts are relatively small, and variable effects (e.g., point estimates ranging from 0.5 to 2.0) were seen for the rarer forms of cancers such as brain cancer and specific hematopoietic cancers. Three large population-based case-control studies of incident non-Hodgkin lymphoma in Europe and the United States observed odds ratios between 1.5 and 2.2 with dichloromethane exposure (ever exposed or highest category of exposure), with higher risk seen in specific subsets of disease. More limited indications of associations with brain cancer, breast cancer, and liver and biliary cancer were also seen in this collection of studies. Existing cohort studies, given their size and uneven exposure information, are unlikely to resolve questions of cancer risks and dichloromethane exposure. More promising approaches are population-based case-control studies of incident disease, and the combination of data from such studies, with robust exposure assessments that include detailed occupational information and exposure assignment based on industry-wide surveys or direct exposure measurements.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Insights from Epidemiology into Dichloromethane and Cancer Risk

Cooper

Scott

Bale

2011

IJERPH

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“…Hepatic effects are commonly observed forms of toxicity following inhalation ( Burek et al 1984 ; Nitschke et al 1988 ) or oral ( Serota et al 1986a ) dichloromethane exposure in rodents. Changes observed in animals following dichloromethane exposure include liver foci/areas of alteration, hepatocyte vacuolation (vacuolation of lipids in the hepatocyte), fatty liver, and necrosis, with effects seen beginning at 500 ppm ( Burek et al 1984 ; Nitschke et al 1988 ). Available human studies do not provide an adequate basis for evaluation of hepatic effects, particularly given the limitations of serological measures of hepatic damage ( Ott et al 1983 ; Soden 1993 ).…”

Section: Major Toxic Effects Of Dichloromethanementioning

confidence: 99%

Human Health Effects of Dichloromethane: Key Findings and Scientific Issues

Schlosser

Bale²,

Gibbons³

et al. 2015

Environ Health Perspect

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Background: The U.S. EPA’s Integrated Risk Information System (IRIS) completed an updated toxicological review of dichloromethane in November 2011.Objectives: In this commentary we summarize key results and issues of this review, including exposure sources, identification of potential health effects, and updated physiologically based pharmacokinetic (PBPK) modeling.Methods: We performed a comprehensive review of primary research studies and evaluation of PBPK models.Discussion: Hepatotoxicity was observed in oral and inhalation exposure studies in several studies in animals; neurological effects were also identified as a potential area of concern. Dichloromethane was classified as likely to be carcinogenic in humans based primarily on evidence of carcinogenicity at two sites (liver and lung) in male and female B6C3F1 mice (inhalation exposure) and at one site (liver) in male B6C3F1 mice (drinking-water exposure). Recent epidemiologic studies of dichloromethane (seven studies of hematopoietic cancers published since 2000) provide additional data raising concerns about associations with non-Hodgkin lymphoma and multiple myeloma. Although there are gaps in the database for dichloromethane genotoxicity (i.e., DNA adduct formation and gene mutations in target tissues in vivo), the positive DNA damage assays correlated with tissue and/or species availability of functional glutathione S-transferase (GST) metabolic activity, the key activation pathway for dichloromethane-induced cancer. Innovations in the IRIS assessment include estimation of cancer risk specifically for a presumed sensitive genotype (GST-theta-1+/+), and PBPK modeling accounting for human physiological distributions based on the expected distribution for all individuals 6 months to 80 years of age.Conclusion: The 2011 IRIS assessment of dichloromethane provides insights into the toxicity of a commonly used solvent.Citation: Schlosser PM, Bale AS, Gibbons CF, Wilkins A, Cooper GS. 2015. Human health effects of dichloromethane: key findings and scientific issues. Environ Health Perspect 123:114–119; http://dx.doi.org/10.1289/ehp.1308030

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“…Haloalkanes can produce a variety of toxicities at high doses. One compound of interest is CH 2 Cl 2 , a high volume commodity chemical () that can cause liver and lung tumors in mice when administered at high doses by gavage ( , ). An issue is the relevance of the mouse results, in consideration of the lack of cancer in rats treated with the same doses ( − ).…”

Section: Introductionmentioning

confidence: 99%

Analysis of the Kinetic Mechanism of Haloalkane Conjugation by Mammalian θ-Class Glutathione Transferases

Guengerich

McCormick

Wheeler

2003

Chem. Res. Toxicol.

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Glutathione (GSH) transferases (GSTs) catalyze the conjugation of small haloalkanes with GSH. In the case of dihalomethanes and vic-1,2-dihaloalkanes, the reaction leads to the formation of genotoxic GSH conjugates. A generally established feature of the reaction of the mammalian theta-class GSTs, which preferentially catalyze these reactions, is the lack of saturability of the rate with regard to the substrate concentration. However, the bacterial GST DM11 catalyzes the same reactions with a relatively low K(m). Recently, DM11 has been shown to exhibit burst kinetics, with a rate-determining k(off) rate for product (Stourman et al. (2003) Biochemistry 42, 11048-11056). We examined rat GST 5-5 and human GST T1-1 and did not detect any burst kinetics in the conjugation of C(2)H(5)Cl, CH(2)Br(2), or CH(2)Cl(2), distinguishing these enzymes from GST DM11. The kinetic results were fit to a minimal mechanism in which the rate-limiting step is halide displacement. The differences in the steady state kinetics of conjugations catalyzed by bacterial GST DM11 and the mammalian GSTs 5-5 and T1-1 are concluded to be the result of differences in the rate-limiting steps and not to inherent enzyme affinity for the haloalkanes. The results may be interpreted in the context of a model in which the halide order affects the rate of carbon-halogen bond cleavage of all such reactions catalyzed by the GSTs. With GST DM11, the halide order is manifested in the K(m) parameter but not k(cat). With mammalian GSTs, the high K(m) is difficult to estimate. With all of the GSTs, the halide order is seen in the enzyme efficiency, k(cat)/K(m), with C-Br cleavage approximately 10-fold faster than C-Cl cleavage. The ratio k(cat)/K(m) is the most relevant parameter for issues of risk assessment.

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Methylene chloride: A 2-year inhalation toxicity and oncogenicity study in rats*1

Cited by 41 publications

References 8 publications

Insights from Epidemiology into Dichloromethane and Cancer Risk

Insights from Epidemiology into Dichloromethane and Cancer Risk

Human Health Effects of Dichloromethane: Key Findings and Scientific Issues

Analysis of the Kinetic Mechanism of Haloalkane Conjugation by Mammalian θ-Class Glutathione Transferases

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