|
Sign In to gain access to subscriptions and/or personal tools.
|
The Use of Quantitative Histological and Molecular Data for Risk Assessment and Biologically Based Model Development
Melvin E. Andersen
International Center for Risk Assessment, Colorado State University, Ft. Collins, Colorado 80523, Melvin.Andersen{at}ColoState.edu
In organs with diverse cell populations, it is not uncommon for one type of cell to respond while others are spared. Even in an organ with common cell types, such as hepatocytes within the liver, the population of cells may respond with different sensitivities for injury or for biochemical responses to toxicants. In the liver, many tumor promoters induce cytochrome P450 enzymes and other proteins in centrilobular cells at much lower doses than required to cause induction in periportal cells. In addition, these induction responses appear to occur at the level of individual cells—a 50% response of the liver for induction does not represent 50% induction in all cells. Instead, half of the cells are fully induced and half are unaffected. Cells "switch" from one phenotypic state to another. Over the past 10 years, several attempts have been made to model these cellular switches and to understand their relevance for hepatic tumor promotion and risk assessment. The data used for analyzing these switches include responses of the entire liver (total induction), responses of individual cells in the liver (regional induction), and cellular responses such as proliferation and apoptosis. This brief overview describes the development of biologically based, dose-response (BBDR) models for protein induction and tumor promotion in liver by 2,3,7,8-tetrachlorodibenzo -p-dioxin (TCDD) with emphasis on the role of specific types of histological and molecular data in providing insights about mechanisms for cellular switches and their implications for tumor promotion. As the biological basis of these switches become unraveled and incorporated into the models, these BBDR models should eventually serve to improve risk assessments with a variety of liver tumor promoters with receptor-based modes of action.
Key Words: Tumor promotion • 2,3,7,8-tetrachlorodibenzo -p-dioxin • dioxin • immunohistochemistry • phenotypic switching • regional induction • cell proliferation.
References
- Andersen ME, Birnbaum LS, Barton HA, Eklund C. (1997). Regional hepatic CYP1A1 and CYP1A2 induction with 2,3,7,8-tetrachlorodibenzo -p-dioxin evaluated with a multi-compartment geometric model of hepatic zonation. ToxicolApplPharmacol144: 145—155.
- Andersen ME, Conolly RB (1998). Mechanistic modeling of rodent liver tumor promotion at low levels of exposure: An example related to dose-response relationships for 2,3,7,8-tetrachlorodibenzo-p-dioxin. BELLE Newsletter 7: 2—8.
- Andersen ME, Mills JJ, Gargas ML, Kedderis L., Birnbaum LS, Neubert D., Greenlee WF (1993). Modeling receptor-mediated processes with dioxin: Implications for pharmacokinetics and risk assessment. J Risk Anal 13: 25—36.[CrossRef]
- Andersen ME, Mills JJ, Jirtle RL, Greenlee WF (1995). Negative selection in hepatic tumor promotion in relation to cancer risk assessment. Toxicology 102: 223—237.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Bars RG, Elcombe CR (1991). Dose-dependent acinar induction of cytochrome P450 in rat liver. Evidence for a differential mechanism of induction of P450IA1 by b-naphthoflavone and dioxin. Biochem J 277: 577—580.[Web of Science][Medline]
[Order article via Infotrieve]
- Bars RG, Mitchell AM, Wolf CR, Elcombe CR (1989). Induction of cytochrome P-450 in cultured hepatocytes. The heterogeneous localization of specificisoenzymes using immunocytochemistry. Biochem J 262: 151—158.[Web of Science][Medline]
[Order article via Infotrieve]
- Bell DR, Bars RG, Gibson GG, Elcombe CR (1991). Localization and differential induction of cytochrome P450IVa and acyl-CoA oxidase in rat liver. Biochem J 275: 247— 252.[Web of Science][Medline]
[Order article via Infotrieve]
- Conolly RB, Andersen ME (1997). 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. Toxicol Appl Pharmacol 146: 281—293.
- Conolly RB, Kimbell JS (1994). Computer simulation of cell growth governed by stochastic processes: Application to clonal growth cancer models. Toxicol Appl Pharmacol 124: 284—295.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Hall JC (1990). Genetics of circadian rhythms. Annu Rev Genet 24: 659— 687.[Web of Science][Medline]
[Order article via Infotrieve]
- Jirtle RL, Hankins GR, Reisenbichier H., Boyer IJ (1994). Regulation of mannose-6-phosphate /insulin-like growth factor-II receptors and transforming growth factor beta during liver tumor promotion with phenobarbital. Carcinogenesis 15: 1473—1478.[Abstract/Free Full Text]
- Jirtle RL, Meyer SA, Brockenbrough JS (1991). Liver tumor promoter phenobarbital: A biphasic modulator of hepatocyte proliferation. In: Chemically Induced Cell Proliferation: Implications for Risk Assessment. Wiley-Liss Inc, New York, pp 209—216.
- Kociba RJ, Keyes DG, Beyer JE, Carreon RM, Wade CE, Dittenber DA, Kalnins RP, Frauson LE, Park CN, Banard SD, Hummel RA, Humiston CG (1978). Results of a two-year chronic toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo -p-dioxin in rats. Toxicol Appl Pharmacol 46: 279—303.
- Kohn MC, Lucier GW, Clark GC, Sewall C., Tritscher A., Portier CJ (1993). A mechanistic model of the effects of dioxin on gene expression in the rat liver. Toxicol Appl Pharmacol 120: 138—154.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Lamers WH, Hilberts A., Furt E., Smith J., Jonges GN, Noorden CJFv, Gaasbeck-Janzen JW, Charles B., Moorman AFM (1989). Hepatic enzymic zonation: A reevaluation of the concept of the liver acinus. Hepatology 10: 72—76.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Leung HW, Paustenbach DJ, Murray FJ, Andersen ME (1990). Aphysiological pharmacokinetic description of the tissue distribution and enzyme inducing properties of 2,3,7,8-tetrachlorodibenzo -p-dioxin in the rat. Toxicol Appl Pharmacol 103: 399—410.
- Maronpot RR, Foley JF, Takahashi K., Goldsworthy T., Clark G., Tritscher A., Portier C., Lucier G. (1993). Dose response for TCDD promotion of hepatocarcinogenesi s in rats initiated with DEN: Histologic, biochemical, and cell proliferation endpoints. Environ Health Perspect 101: 634— 642.[Web of Science][Medline]
[Order article via Infotrieve]
- McGrath LF, Cooper KR, Georgopoulos P., Gallo MA (1995). Alternative models for low dose-response analysis of biochemical and immunological endpoints for tetrachlorodibenzo-p-dioxin. Regul Toxicol Pharmacol 21: 382—396.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Ohno K., AmmannP, Fasciati R., MaierP (1995). Transforming growth factor b1 preferentially induces apoptotic cell death in rat hepatocytes cultured under pericentral-equivalent conditions. Toxicol Appl Pharmacol 132: 227— 236.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Perdew GH (1992). Chemical cross-linking of the cytosolic and nuclear forms of the Ah receptor in hepatoma cell lines lele7. Biochem Biophys Res Comm 182: 55—62.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Pitot HC, Goldsworthy TL, Moran S., Kennan W., Glauert HP, Maronpot RR, Campbell HA (1987). A method to quantitate the relative initiating and promoting potencies of hepatocarcinogeni c agents in their dose-response relationships to altered hepatic foci. Carcinogenesis 8: 1491—1499.[Abstract/Free Full Text]
- Poland A., Knudson JC (1982). 2,3,7,8-Tetrachlorodibenzo -p-dioxin and related halogenated aromatic hydrocarbons: Examination of the mechanism of toxicity. Annu Rev Pharmacol Toxicol 32: 531—554.
- Portier C., Tritscher A., Kohn M., Sewall C., Clark G., Edler L., Hoel D., Lucier G. (1993). Ligand/receptor binding for 2,3,7,8-TCDD: Implications for risk assessment. Fundam Appl Toxicol 20: 48—56.
- Reyes H., Reisz-Porszasz S., Hankinson O. (1992). Identification of the Ah receptor nuclear translocator protein (Arnt) as a component of the DNA binding form of the Ah receptor. Science 256: 1193—1195.[Abstract/Free Full Text]
- Sarangapani RJ, Teeguarden Plotzke KP, McKim JE Jr, Andersen ME (2001). Dose-response modeling of cytochrome P450 induction in rats by octamethylcyclotetrasiloxane. Toxicol Sci., submitted.
- Sutter TR, Greenlee WF (1992). Classification of members of the AH gene battery. Chemosphere 25: 222—226.
- Tritscher AM, Goldstein JA, Portier CJ, McCoy Z., Clark GC, Lucier GW (1992). 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. Cancer Res 52: 3436—3442.
- Waxman DJ (1999). P450 gene induction by structurally diverse xenochemicals: Central role of nuclear receptors CAR, PXR, andPPAR. Arch Biochem Biophys 369: 11—23.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Whitlock JP (1990). Genetic and molecular aspects of 2,3,7,8-tetrchlorodibenzo-p-dioxin activity. Annu Rev Pharmacol Toxicol 30: 251—277.
Toxicologic Pathology, Vol. 30, No. 1,
106-111 (2002)
DOI: 10.1080/01926230252824789
 CiteULike  Complore  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter What's this?
|
|
