TOXICOLOGY AND APPLIED PHARMACOLOGY 138, 20–30 (1996) ARTICLE NO. 0093 Modeling the Number and Size of Hepatic Focal Lesions Following Exposure to 2,3,7,8-TCDD C. J. PORTIER,* C. D. SHERMAN,* M. KOHN,* L. EDLER,² A. K OPP-SCHNEIDER,² R. M. M ARONPOT,‡ AND G. LUCIER§ *Statistics and Biomathematics Branch, ‡Laboratory of Experimental Pathology, and §Laboratory of Biochemical Risk Assessment, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709; and ² Biostatistiks, Deutsches Krebsforschungzentrum, D6900 Heidelberg 1, Germany Received November 23, 1994; accepted December 6, 1995 observed tumor incidence. For TCDD, the use of this model Modeling the Number and Size of Hepatic Focal Lesions Follow- has resulted in a very stringent standard for exposure (EPA, ing Exposure to 2,3,7,8-TCDD. PORTIER, C. J., SHERMAN, C. D., 1985). KOHN, M., EDLER, L., KOPP-SCHNEIDER, A., MARONPOT, R. M., Long-term rodent carcinogenicity studies have shown that AND LUCIER, G. (1996). Toxicol. Appl. Pharmacol. 138, 20–30. TCDD is a potent carcinogen with the most seriously af- Data on the size and number of placental glutathione S-trans- fected organ being the liver in female rodents (Kociba et ferase-positive (PGST/) foci were collected from a two-stage hep- al., 1978; NTP, 1982; Portier et al., 1984). In humans, epide- atocarcinogenesis model in female Sprague–Dawley rats. The miological data have suggested increases in soft-tissue sarco- study consisted of multiple 2,3,7,8-tetrachlorodibenzo-p-dioxin mas, respiratory system tumors, and all cancers combined (TCDD)-exposed dose groups including both diethylnitrosomine (Eriksson et al., 1990; Fingerhut et al., 1991); there is some (DEN)-initiated and uninitiated animals. Groups were observed evidence that these cancers may arise via a receptor-based after 15 or 31 weeks of TCDD exposure. The parameters in the mechanism (Lucier, 1991). Completed quantitative risk as- first half of a two-stage mathematical model of carcinogenesis sessments for TCDD have been based upon rodent carcino- were estimated from these data. If the model is valid, the results genicity data due to lack of exposure estimates in the human suggest that TCDD stimulates the production of PGST/ foci and promotes the growth of PGST/ foci. This finding suggests a com- population. However, human data have been shown to be plicated mechanism for TCDD-induced production of hepatic foci consistent with the animal-based risk estimates. Thus, for that we refer to as activation, labeling TCDD as an activator. The risk assessment and dose – response purposes, the mechanism analysis also indicates that there is an interaction between DEN by which TCDD induces liver tumors in female rodents is and TCDD which results in dose-related formation of initiated of paramount concern. cells throughout the study period. Best-fitting curves (using maxi- In the rodent liver model, it is believed that cells go mum likelihood methods) for TCDD-induced activation and pro- through a number of changes which eventually lead to carci- motion reached saturation levels at low doses of TCDD. In sum- nogenesis (Goldsworthy et al., 1986; Kunz et al., 1983; Mar- mary, the model fit the data well, but leads to an interpretation onpot, 1993). There are a number of possibilities concerning of the data which either questions the validity of the model or the pathogenesis of these changes leading to these premalig- implies that our understanding of the effects of TCDD and DEN nant lesions, some of which may be the result of genetic is incomplete.  1996 Academic Press, Inc. mutations. For simplicity of presentation, the term mutation will be used to encompass any changes which result in the 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has re- formation of new premalignant lesions. The ability to detect ceived considerable attention in the past two decades in both these changes in precancerous rodent livers is somewhat the scientific and the public media. This strong interest in controversial. However, most researchers believe that he- TCDD is due to its apparent ability to elicit toxic responses patic changes in the expression of a number of biochemical in rodents at extraordinarily small exposure levels. There markers indicate a transformation of a cell into a premalig- is considerable controversy concerning the setting of safe nant state. Clonal colonies of cells with these types of altered exposure levels for TCDD. At the heart of this controversy expressions can be detected by histochemical staining. One is the utilization of a log-linear model for estimating low- such marker is a positive stain for the placental form of dose risks from high-dose animal experiments. Without data glutathione S-transferase (PGST/). It has been demonstrated to the contrary, the U.S. Environmental Protection Agency (Dragan et al., 1990; Maronpot et al., 1993) that TCDD (EPA) has adopted the use of a ‘‘linearized multistage modifies the observed number and size of focal lesions model’’ for risk estimation (Anderson et al., 1983) by re- (PGST/ and others) in the livers of female rats. If these lesions indicate a premalignant change in normal liver cells, gressing daily administered dose (e.g., mg/kg/day) against 20 0041-008X/96 $18.00 Copyright  1996 by Academic Press, Inc. All rights of reproduction in any form reserved.