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An Estimate of the Maximum in Vivo Covalent Binding of 2,3,7,8-Tetrachlorodibenzo-p-dioxin to Rat Liver Protein, Ribosomal RNA, and DNA¹

McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin 53706

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an extraordinarily potent toxin, has recently been found to be a potent carcinogen producing mucosal, lung, and liver tumors in female rats. In light of this carcinogenicity, we reexamined the in vivo covalent binding of [³H]TCDD to rat liver macromolecules. Immature Sprague-Dawley rats, receiving [³H]TCDD (0.87 mCi/kg; specific activity, 39 Ci/mmol) concentrated 18 to 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 per mol of amino acid residue; rRNA, 12 pmol TCDD per mol of nucleotide residue; and DNA, 6 pmol TCDD per mol of nucleotide residue. If one assumes that this small residual amount of radioactivity represents covalent binding, this binding is 4 to 6 orders of magnitude lower than that of most chemical carcinogens, and the binding to DNA is equivalent to one molecule of TCDD per DNA, equivalent to 35 cells. The results suggest it is unlikely that TCDD-induced oncogenesis is through a mechanism of covalent binding to DNA and somatic mutation.

¹ Research supported by National Institute of Environmental Health Sciences Grant 1-R01-ES-00965, National Cancer Institute Core Grant CA-07175, National Cancer Institute Program Project Grant CA-22484.

² Recipient of Research Career Development Award K-04ES-0017. To whom requests for reprints should be addressed.

Received 1/17/79. Accepted 5/22/79.

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