Mechanism-Focused Research: The Foundation of Scientifically Based Carcinogen Risk Assessment

Abstract

This year, 2025, marks the 5th decade of my initiation into carcinogenesis research. Work in my laboratory has focused on understanding the mechanisms by which environmental and pharmaceutical chemical agents induce cancer. We have focused on the liver as the target organ, given that it is the predominate site of neoplasms induced by chemical in chronic rodent bioassays. Our work has utilized a multistage, multistep liver tumor model as the foundation for dissecting the key events of the carcinogenesis process in the liver. Historically, it was assumed that all chemical carcinogens were genotoxic/mutagenic in action producing DNA damage and mutation of key growth regulatory genes resulting in neoplasia. However, subsequent studies revealed that this simplest approach was not apparent seen with many agents that produced cancer in rodents and humans. While a mutational event is needed for neoplasia, the induction of cell proliferation by the carcinogen in the target tissue has been shown to be of utmost importance in the neoplastic process. In the case of liver carcinogenesis, the induction of cell growth either through increased cell proliferation or decreased apoptosis. In the liver this can occur through a mitogenic stimulus (nuclear receptor mediated) or through compensatory hyperplasia subsequent to cytotoxicity. My lab has combined these mechanistic concepts with the pathology of the multistep liver carcinogenesis process to further develop a mode of action approach. The importance of the multistep concept is that each step is defined by molecular and pharmacological attributes of the carcinogen and mechanisms. Therefore, each step has dose response and threshold characteristics that need to be considered for the entire neoplastic process to occur. We are faced to with an increasing number of new and untested chemicals that require proper risk evaluation for cancer. This coupled with the approach to reduce the animal usage in testing and the development of more molecular and cellular knowledge of the biological processes has put additional stress on developing modalities to properly perform cancer risk assessment. Although there is a tendency to streamline the process, it is important to note that proper risk evaluation is not easy and requires the input of multiple discipline and expertise. Understanding the mechanism(s) of chemical carcinogenesis in the context of the multistage model is important in developing scientifically based human risk evaluation of potential chemical carcinogens. In considering carcinogen risk evaluations several concepts need to be addressed based on Bradford Hills criteria. The development of a mode of action framework 20 years ago was an important step in utilizing the Bradford hill approach to chemical risk assessment. It is important that we as scientists don't default to poor science in an attempt to perform simpler and faster cancer risk assessment. The public and regulators in particular, need to have confidence that the evaluation of cancer risk is founded in proper science.