ESTIMATE OF THE MAXIMUM INVIVO COVALENT BINDING OF 2,3,7,8-TETRACHLORODIBENZO-PARA-DIOXIN TO RAT-LIVER PROTEIN, RIBOSOMAL-RNA, AND DNA

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an extraordinarily potent toxin, was recently found to be a potent carcinogen producing mucosal, lung and liver tumors in female rats. In light of this carcinogenicity, the in vivo covalent binding of [3H]TCDD to rat liver macromolecules was studied. Immature Sprague-Dawley rats, receiving [3H]TCDD (0.87 mCi/kg; specific activity, 39 Ci/mmol) concentrated 18-64% of the total administered dose in their livers, but virtually all of this radioactivity (> 99.9%) was extractable. The maximum unextractable radioactivity was: protein, 60 pmol TCDD/mol of amino acid residue; rRNA, 12 pmol TCDD/mol of nucleotide residue; and DNA, 6 pmol TCDD/mol of nucleotide residue. If this small residual amount of radioactivity represents covalent binding, this binding is 4-6 orders of magnitude lower than that of most chemical carcinogens, and the binding to DNA is equivalent to 1 molecule of TCDD/DNA, equivalent to 35 cells. TCDD-induced oncogenesis may not be through a mechanism of covalent binding to DNA and somatic mutation.