Hepatic foci in rats after diethylnitrosamine initiation and 2,3,7,8-tetrachlorodibenzo-p-dioxin promotion: evaluation of a quantitative two-cell model and of CYP 1A1/1A2 as a dosimeter.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent hepatic tumor promoter in female rats. We used a quantitative, stochastic initiation-promotion model based on R. B. Conolly and J. S. Kimbell (Toxicol. Appl. Pharmacol. 124, 284-295, 1994) to analyze initiation-promotion results from a previously published study (H. C. Pitot et al., Carcinogenesis 8, 1491-1499, 1987) within the context of a negative selection model of tumor promotion. In this model, two types of initiated cells (called A and B cells) are produced by DEN initiation. Visually excellent correspondence between model predictions and data (i.e., foci/cm3 liver 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 division and the death rates increase while the difference between division and apoptotic rates decreases. For B cells, the difference between division and apoptotic rates increases, primarily due to a decrease in the 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 the subcompartments. Alterations in A cell kinetics correlate with effects of TCDD in the region most sensitive to induction (subcompartment 5-centrilobular region); B cell dynamics correlate with induction in subcompartments 3-5 (centrilobular and mid-zonal regions). In summary, these modeling exercises show that (1) the two-cell model, without presuming effects of TCDD on the mutation rate of normal hepatocytes, reproduces the data of Pitot et al. (1987) and (2) induction of CYP1A1/1A2 in different regions of the hepatic acinus can be used as a general correlate of these presumed changes in cell growth kinetics.

[1]  R. Jirtle,et al.  Liver tumor promoter phenobarbital: a biphasic modulator of hepatocyte proliferation. , 1991, Progress in clinical and biological research.

[2]  A. Buchmann,et al.  Inhibition of apoptosis during 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated tumour promotion in rat liver. , 1995, Carcinogenesis.

[3]  M. Andersen,et al.  Negative selection in hepatic tumor promotion in relation to cancer risk assessment. , 1995, Toxicology.

[4]  S H Moolgavkar,et al.  A stochastic two-stage model for cancer risk assessment. II. The number and size of premalignant clones. , 1989, Risk analysis : an official publication of the Society for Risk Analysis.

[5]  R B Conolly,et al.  Computer simulation of cell growth governed by stochastic processes: application to clonal growth cancer models. , 1994, Toxicology and applied pharmacology.

[6]  Paul Bratley,et al.  A guide to simulation , 1983 .

[7]  W. Bursch,et al.  Induction of apoptosis in cultured hepatocytes and in regressing liver by transforming growth factor beta 1. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[8]  S. Safe,et al.  Organ-specific effects of long term feeding of 2,3,7,8-tetrachlorodibenzo-p-dioxin and 1,2,3,7,8-pentachlorodibenzo-p-dioxin on I-compounds in hepatic and renal DNA of female Sprague-Dawley rats. , 1988, Carcinogenesis.

[9]  C. Wade,et al.  Results of a two-year chronic toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats. , 1978, Toxicology and applied pharmacology.

[10]  E Farber,et al.  Sequential alterations in growth control and cell dynamics of rat hepatocytes in early precancerous steps in hepatocarcinogenesis. , 1986, Cancer research.

[11]  R. Jirtle,et al.  Regulation of mannose 6-phosphate/insulin-like growth factor-II receptors and transforming growth factor beta during liver tumor promotion with phenobarbital. , 1994, Carcinogenesis.

[12]  H. Pitot,et al.  Application of quantitative stereology to the evaluation of phenotypically heterogeneous enzyme-altered foci in the rat liver. , 1986, Journal of the National Cancer Institute.

[13]  M E Andersen,et al.  Regional hepatic CYP1A1 and CYP1A2 induction with 2,3,7,8-tetrachlorodibenzo-p-dioxin evaluated with a multicompartment geometric model of hepatic zonation. , 1997, Toxicology and applied pharmacology.

[14]  R. Maronpot,et al.  A method to quantitate the relative initiating and promoting potencies of hepatocarcinogenic agents in their dose-response relationships to altered hepatic foci. , 1987, Carcinogenesis.

[15]  W. Bursch,et al.  Determination of the length of the histological stages of apoptosis in normal liver and in altered hepatic foci of rats. , 1990, Carcinogenesis.

[16]  G. Higgins,et al.  Experimental pathology of the liver , 1931 .

[17]  J. Southon,et al.  Accelerator mass spectrometry in biomedical dosimetry: relationship between low-level exposure and covalent binding of heterocyclic amine carcinogens to DNA. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[18]  K. Ohno,et al.  Transforming growth factor beta 1 preferentially induces apoptotic cell death in rat hepatocytes cultured under pericentral-equivalent conditions. , 1995, Toxicology and applied pharmacology.

[19]  G. Clark,et al.  Dose response for TCDD promotion of hepatocarcinogenesis in rats initiated with DEN: histologic, biochemical, and cell proliferation endpoints. , 1993, Environmental health perspectives.

[20]  D. Paustenbach,et al.  A critical evaluation of the use of mutagenesis, carcinogenesis, and tumor promotion data in a cancer risk assessment of 2,3,7,8-tetrachlorodibenzo-p-dioxin. , 1987, Regulatory toxicology and pharmacology : RTP.

[21]  William H. Press,et al.  Numerical Recipes: FORTRAN , 1988 .

[22]  E. Farber,et al.  Possible etiologic mechanisms in chemical carcinogenesis. , 1987, Environmental health perspectives.

[23]  C. Elcombe,et al.  Dose-dependent acinar induction of cytochromes P450 in rat liver. Evidence for a differential mechanism of induction of P450IA1 by beta-naphthoflavone and dioxin. , 1991, The Biochemical journal.

[24]  E Farber,et al.  Induction of resistant hepatocytes as a new principle for a possible short-term in vivo test for carcinogens. , 1980, Cancer research.

[25]  E G Luebeck,et al.  Quantitative analysis of enzyme-altered liver foci in rats initiated with diethylnitrosamine and promoted with 2,3,7,8-tetrachlorodibenzo-p-dioxin or 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin. , 1996, Toxicology and applied pharmacology.

[26]  L Edler,et al.  Modeling the number and size of hepatic focal lesions following exposure to 2,3,7,8-TCDD. , 1996, Toxicology and applied pharmacology.

[27]  M. Kastan,et al.  Induction of apoptosis by tumor suppressor genes and oncogenes. , 1995, Seminars in cancer biology.

[28]  M. Tatematsu,et al.  Reciprocal relationship between development of glutathione S-transferase positive liver foci and proliferation of surrounding hepatocytes in rats. , 1988, Carcinogenesis.

[29]  Hans Rudolf Gnägi,et al.  CORRELATED MORPHOMETRIC AND BIOCHEMICAL STUDIES ON THE LIVER CELL , 1969, The Journal of cell biology.

[30]  G. Clark,et al.  Dioxin-responsive genes: examination of dose-response relationships using quantitative reverse transcriptase-polymerase chain reaction. , 1994, Cancer research.

[31]  C J Portier,et al.  Dose-response relationships for chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in a rat tumor promotion model: quantification and immunolocalization of CYP1A1 and CYP1A2 in the liver. , 1992, Cancer research.