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Toxicologic Pathology
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Cardiac Damage in Rodents after Exposure to Bis(2-chloroethoxy)methane

June K. Dunnick

Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA, dunnickj@niehs. nih.gov

Warren Lieuallen

Pathology Associates (PAI) Division of Charles River Laboratories, Durham, North Carolina, USA

Carolyn Moyer

Pathology Associates (PAI) Division of Charles River Laboratories, Durham, North Carolina, USA

Denise Orzech

Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA

Abraham Nyska

Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA

We report that an environmental agent, bis(2-chloroethoxy)methane (CEM), caused cardiac toxicity in male and female F344 rats and B6C3F1 mice exposed to the chemical by dermal administration at doses of 0, 50, 100, 200, 400 or 600 mg/kg 5 days a week for up to 14 weeks. Treatment-related deaths occurred in 10/10 male and 10/10 female rats at 600 mg/kg, in 2/10 female rats at 400 mg/kg, and in 3/10 female mice at 600 mg/kg. The heart lesions were more severe in rats than mice, and more severe in females than males. In rats, the no-observed-adverse-effect level (NOAEL) for the heart lesions was 200 mg/kg for males and 100 mg/kg for females; in mice, it was more than 600 mg/kg for males and 200 mg/kg for females. Multifocal, widespread vacuolization of the myocytes comprised the main morphological feature of the lesions, and only in rats was it accompanied by mononuclear cell infiltration, myocytic necrosis and atrial thrombosis. Hearts from male rats were immunohistochemically stained for troponin T (cTnT) protein. Loss of cytoplasmic cTnT correlated with histopathological damage only in the 600 mg/kg animals. CEM is metabolized to thiodiglycolic acid, a chemical that causes mitochondrial dysfunction. It is hypothesized that mitochondrial damage leads to the heart toxicity from bis(2-chloroethoxy)methane.

Key Words: Bis(2-chloroethoxy)methane • cardiotoxictiy • myocyte vacuolization • mitochondrial dysfunction • troponin T • rat • mouse.

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Toxicologic Pathology, Vol. 32, No. 3, 309-317 (2004)
DOI: 10.1080/01926230490431501
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