Dioxin hepatic carcinogenesis: biologically motivated modeling and risk assessment.
There are several key portions of the exposure-dose-response continuum with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) that have to be described quantitatively in developing a comprehensive mechanistically based dose-response model. These include: (i) the accumulation of TCDD in the target tissue, (ii) formation of a complex between dioxin and the Ah receptor, (iii) activation of transcription of growth regulatory genes by the TCDD-Ah receptor complex, (iv) cellular events on tumor initiation, promotion, and progression. Physiologically based pharmacokinetic (PBPK) models have been used as tools to integrate knowledge of the determinants of dioxin disposition, including specific binding to dioxin-inducible hepatic cytochromes, and to link TCDD tissue dosimetry with gene activation by pharmacodynamic (PD) models crafted to examine dioxin-regulated gene expression. Biological studies on growth factor regulation suggest hypotheses for the role of these gene products in transient cell proliferation, prolonged growth suppression, and hepatic tumor promotion. We have used these hypotheses as the basis for stochastic cell growth models of the promotional events with TCDD and to suggest experimental strategies for future research. The combination of PBPK, PBPD and stochastic cell growth models provides a seamless exposure-dose-response model for TCDD induction of liver tumors in rodents. This comprehensive exposure-dose-response model should prove useful for risk assessment, experimental design, and analysis of noncancer endpoints with this potent, ubiquitous environmental contaminant. This paper outlines progress in formulating and evaluating these models for TCDD.
Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709.
J J
JJ
Mills
M E
ME
Andersen
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation; D008113:Liver Neoplasms / Q000139:chemically induced*; D008954:Models, Biological; D000072317:Polychlorinated Dibenzodioxins / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D012307:Risk Factors; D015533:Transcriptional Activation
D000072317:Polychlorinated Dibenzodioxins