Biological Bases for the Dose-Response Assessment of 2,3,7,8-TCDD in Multistage Hepatocarcinogenesis in the Rat. H. C. Pitot, Y. P. Dragan, J. Teeguarden, and H. Campbell, McArdle Laboratory, University of Wisconsin, Madison, WI 53706
Chronic administration of TCDD to several rodent species indicate the ability of this compound to induce neoplasms in a number of tissues, including the rat liver. The lack of cell or molecular biological evidence that TCDD is an initiating agent and substantial evidence from rodent models that dioxin is potent promoting agent has led to the hypothesis that the carcinogenic action of TCDD is related to its effectiveness as a promoting agent. In the rat liver, TCDD is the most potent promoting agent known, having the largest promotion index of any compound tested in this laboratory. Characteristic of promoting agents, TCDD exhibits a dose-response relationship with an apparent threshold dose, below which TCDD either has no effect or inhibits the development of preneoplastic foci (AHF). Further, the dose-response relationship also exhibits a region where the response is dependent on the dose, and at higher doses, a plateau where increasing doses have no further effect on AHF development. In vivo, the promoting effects of TCDD have been shown, to a degree, to be functionally reversible. In the multistage model of rat hepatocarcinogenesis, TCDD is thought to promote the development of initiated cells into altered hepatic foci by selectively inducing the proliferation of the initiated cell population through increased cell proliferation, decreased apoptosis, or a combination of these mechanisms. While there is no evidence that TCDD acts as a progressor agent, TCDD could function in this role either by causing oxidative stress through induction of xenobiotic metabolizing enzymes or by increasing cell proliferation and the associated probability of replicative errors in the initiated cell population or both. Improvement of current biologically-based models of the carcinogenic action of TCDD will ultimately depend on improving our quantitative understanding of the promoting action of TCDD and the known spontaneous occurrence of both initiation and progression. At present use of the multistage model of rat hepatocarcinogenesis represents the most useful tool for developing such a model from quantitative biological data.
Work supported by grants from the National Cancer Institute, a Cooperative Agreement from the Environmental Protection Agencies, and the MITRE Corporation.