PROMOTION OF PRENEOPLASTIC FOCI IN RAT-LIVER WITH 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN, 1,2,3,4,6,7,8-HEPTACHLORO-DIBENZO-P-DIOXIN AND A DEFINED MIXTURE OF 49 POLYCHLORINATED DIBENZO-P-DIOXINS

In a two-stage initiation-promotion experiment the hypothesis was inve stigated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equivalents ( TE), calculated from data of CYP1A induction in hepatocytes in primary culture, or international TCDD equivalents (ITE) are useful for evalu ating the tumor-promoting potency of 1,2,3,4,6,7,8-heptachlorodibenzo- p-dioxin (HpCDD) and of a defined mixture (M2) of 49 polychlorinated d ibenzo-p-dioxins (PCDDs) in comparison with TCDD. Therefore, female Wi star rats were treated with an initiating dose of N-nitroso-morpholine , and subsequently received daily doses of 2, 20 and 200 ng TCDD/kg or equivalent doses of HpCDD or M2, based on TE values. After a promotio n phase of 13 weeks, hepatic PCDD levels, CYP1A activity and the relat ive hepatic volume of adenosinetriphosphatase-negative or glutathione S-transferase P-positive preneoplastic foci were determined. After log arithmic transformation, linear PCDD level-response relationships were obtained for induction of CYP1A activity with TCDD, HpCDD or M2. Base d on TE values, inducing potencies of both HpCDD and M2 were overestim ated at higher doses, whereas induction was approximately equivalent a t the lowest dose. The best fit of PCDD level-response relationships o f relative hepatic volumes of preneoplastic lesions was achieved using a four-parameter logistic model. Significantly different functions we re calculated for promotion,vith TCDD or HPCDD. It is concluded that ( i) different PCDD level-response relationships exist for the induction of hepatic CYP1A activity and the promotion of preneoplastic liver fo ci, and (ii) that TE or ITE factors provide only a rough estimate of t he tumor-promoting potency of a PCDD mixture but may overestimate the risk from exposure to higher-chlorinated 2,3,7,8-substituted congeners such as HpCDD.