The use of quantitative histological and molecular data for risk assessment and biologically based model development

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.