Effect of inhalation exposure regimen on DNA binding potency of 1,2-dichloroethane in the rat

Abstract

1,2-Dichloroethane (DCE) was reported to be carcinogenic in rats in a long-term bioassay using gavage in corn oil (24 and 48 mg/kg/day), but not by inhalation (up to 150–250 ppm, 7 h/day, 5 days/week). The daily dose metabolized was similar in the two experiments. In order to address this discrepancy, the genotoxicity of DCE was investigated in vivo under different exposure conditions. Female F-344 rats (183–188 g) were exposed to [1,2-¹⁴C]- DCE in a closed inhalation chamber to either a low, constant concentration (0.3 mg/l=80 ppm for 4 h) or to a peak concentration (up to 18 mg/l=4400 ppm) for a few minutes. After 12 h in the chamber, the dose metabolized under the two conditions was 34 mg/kg and 140 mg/kg. DNA was isolated from liver and lung and was purified to constant specific radioactivity. DNA was enzymatically hydrolyzed to the 3′-nucleotides which were separated by reverse phase HPLC. Most radioactivity eluted without detectable or with little optical density, indicating that the major part of the DNA radioactivity was due to covalent binding of the test compound. The level of DNA adducts was expressed in the dose-normalized units of the Covalent Binding Index, CBI = (μmol adduct per mol DNA nucleotide/mmol DCE per kg body wt. In liver DNA, the different exposure regimens resulted in markedly different CBI values of 1.8 and 69, for “constant-low” and “peak” DCE exposure levels. In the lung, the respective values were 0.9 and 31. It is concluded that the DNA damage by DCE depends upon the concentration-time profile and that the carcinogenic potency determined in the gavage study should not be used for low-level inhalation exposure.