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

Abstract

A long-term study was conducted to determine the possible chronic toxicity and oncogenicity of methylene chloride. Rats and hamsters were exposed by inhalation to 0, 500, 1500, or 3500 ppm of methylene chloride for 6 hr per day, 5 days a week, for 2 years. No exposure-related cytogenetic effects were present in male or female rats exposed to 500, 1500, or 3500 ppm. Females rats exposed to 3500 ppm had an increased mortality rate while female hamsters exposed to 1500 or 3500 ppm had decreased mortality rates. Carboxyhemoglobin values were elevated in rats and hamsters exposed to 500, 1500, or 3500 ppm with the percentage increase in hamsters greater than in rats. Minimal histopathologic effects were present in the livers of rats exposed to 500, 1500, or 3500 ppm. Decreased amyloidosis was observed in the liver and other organs in hamsters exposed to 500, 1500 or 3500 ppm. While the number of female rats with a benign tumor was not increased, the total number of benign mammary tumors was increased in female rats in an exposure-related manner. This effect was also evident in male rats in the 1500- and 3500-ppm exposure groups. Finally, male rats exposed to 1500 or 3500 ppm had an increased number of sarcomas in the ventral neck region located in or around the salivary glands. Therefore, in this 2-year study, some effects were observed in male and female rats exposed to 500, 1500, or 3500 ppm of methylene chloride. In contrast, hamsters exposed to the same exposure concentrations had less extensive spontaneous geriatric changes, decreased mortality (females), and lacked evidence of definite target organ toxicity.

Formation and Mass Spectrometric Analysis of DNA and Nucleoside Adducts by S-(1-Acetoxymethyl)glutathione and by Glutathione S-Transferase-Mediated Activation of Dihalomethanes

“…Adduct levels were normalized to the GST DM11 concentration. Adduct yields formed from GST human T1-1 (Figure F) were multiplied by 1.1, and adduct yields formed by rat 5-5 (D) were multiplied by 1.7 …”

“…However, because the concentrations of the original GST enzyme preparations were different, it was not possible to use the same concentrations of bacterial, rat, and human GSTs in the experiments: the rat GST 5-5 concentration was 15 μΜ, the human T1-1 concentration was 24 μM, and the bacterial DM11 concentration was 26 μM. Adduct levels were thus normalized to the GST DM11 concentration . If this dGuo value is denoted as unity, then the relative efficiency of adduct formation to other bases or by other enzymes can be approximated from Figure .…”

“…The annual U.S. production of CH 2 Cl 2 is currently about 3 × 10 8 kg ( , ). Under certain conditions, high doses of CH 2 Cl 2 can produce liver and lung tumors in mice ( − ). These findings have led to regulation of the limits of human exposure to CH 2 Cl 2 ( , ).…”

Human Health Effects of Dichloromethane: Key Findings and Scientific Issues

“…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 ).…”

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

“…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 ( − ).…”