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

Abstract

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.

Critical Pathways in Heart Function: Bis(2-chloroethoxy)methane-Induced Heart Gene Transcript Change in F344 Rats

“…RESULTS CEM induced heart toxicity in all regions of the heart (Figure 2) (Dunnick et al, 2004a(Dunnick et al, , 2004b. The CEM-induced heart damage occurred as early as day 2, and began to resolve by day 5, and by day 16 had completely resolved (Figure 2).…”

“…Histologic and ultrastructural analysis of hearts from male rats after 2, 3, 5, and 16 days of CEM treatment have previously been reported (Dunnick et al, 2004a(Dunnick et al, , 2004b. RESULTS CEM induced heart toxicity in all regions of the heart (Figure 2) (Dunnick et al, 2004a(Dunnick et al, , 2004b.…”

“…111-91-1; lot B004160277; Figure 1) (Karl Industries, Aurora, OH) ( Figure 1) was 98.5% pure (Dunnick et al, 2004a(Dunnick et al, , 2004b. Solutions of CEM were prepared in 95% ethanol for daily dermal administration to male F344 rats (Taconic Laboratories, Germantown, NY), 5 days per week, excluding weekends, for 2 weeks plus 2 consecutive dosages before sacrifice on study-day 16.…”

“…CEM is an organic compound used in the production of polysulfide polymers for sealant applications. CEM cardiotoxicity is characterized by cytoplasmic vacuolation of myocytes, necrosis, and inflammation (Dunnick et al, 2004a(Dunnick et al, , 2004b. Thiodiglycolic acid is a metabolic product of several chemicals that target the heart in humans and/or rodents (Hofmann et al, 1991), and, thus, our model of CEM-induced cardiotoxicity also serves to characterize heart damage from other environmental chemicals.…”

“…Chemicals that are metabolized to thiodiglycolic acid have been associated with cardiotoxicity in rodents and humans including bis(2-chloroethoxy)methane (Dunnick et al, 2004a(Dunnick et al, , 2004b) (CEM), Ifosfamide (Visarius et al, 1998), monochloroacetic acid (National Toxicology Program, 1992), chloroacetaldehyde (Joqueviel et al, 1997), trichloroethane (Yllner, 1971), trichloroethylene (Anderson et al, 1987), 1,1-dichloroethylene (Anderson et al, 1987), cyclophosphamide (Joqueviel et al, 1997), vinylidene chloride (Jones and Hathway, 1978), and vinyl chloride (Green and Hathway, 1975). Fatty acids are a major source of energy in the heart (Ala- Rami et al, 2005), and because thiodiglycolic acid interferes with fatty acid metabolism (Visarius et al, 1998), CEM mitochondria damage may be due in part to depletion of nutrients (Edinger and Thompson, 2004;Lum et al, 2005).…”