HEPATIC FOCI IN RATS AFTER DIETHYLNITROSAMINE INITIATION AND 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN PROMOTION - EVALUATION OF A QUANTITATIVE 2-CELL MODEL AND OF CYP 1A1 1A2 AS A DOSIMETER/

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent hepatic tumor p romoter in female rats. We used a quantitative, stochastic initiation- promotion model based on R. B. Conolly and J. S. Kimbell (Toxicol. App l. Pharmacol. 124, 284-295, 1994) to analyze initiation-promotion resu lts from a previously published study (H. C. Pitot et al., Carcinogene sis 8, 1491-1499, 1987) within the context of a negative selection mod el of tumor promotion. In this model, two types of initiated cells (ca lled A and B cells) are produced by DEN initiation. Visually excellent correspondence between model predictions and data (i.e., foci/cm(3) l iver and percentage of liver occupied by foci) are obtained when TCDD is described as having dose-responsive effects on division and death ( apoptotic) rates of these two cell types. For A cells, both the divisi on and the death rates increase while the difference between division and apoptotic rates decreases, For B cells, the difference between div ision and apoptotic rates increases, primarily due to a decrease in th e apoptotic rate, We also linked these alterations in cell kinetics to a pharmacokinetic model for TCDD incorporating a five subcompartment model of the liver acinus with induction of CYP1A1 and 1A2 genes in th e subcompartments, Alterations in A cell kinetics correlate with effec ts of TCDD in the region most sensitive to induction (subcompartment 5 -centrilobular region); B cell dynamics correlate with induction in su bcompartments 3-5 (centrilobular and mid-zonal regions). In summary, t hese modeling exercises show that (1) the two-cell model, without pres uming effects of TCDD on the mutation rate of normal hepatocytes, repr oduces the data of Pitot ef al, (1987) and (2) induction of CYP1A1/1A2 in different regions of the hepatic acinus can be used as a general c orrelate of these presumed changes in cell growth kinetics. (C) 1997 A cademic Press.