Cancer develops because of multiple permanent genetic errors arising in a single stem cell, a clonal disease. Every time DNA replicates, spontaneous mistakes can occur. Thus, the risk of cancer can be increased by either directly damaging DNA each time it replicates (DNA reactive) or increasing the number of DNA replications (cell proliferation), or both. Some have indicated that the “spontaneous” errors that occur during DNA replication are the basis for cancer being due to “bad luck,” and are the cause of most cancers. However, it is well-known that numerous environmental factors can increase the risk of cancer. This dilemma is readily resolved by realizing that the number of stem cells and the rate of their proliferation can be markedly influenced by the environment. Over the course of more than a 50-year career in carcinogenesis research, I have been actively involved in research on DNA reactive carcinogens (nitrofurans, aromatic amines, nitrosamines) and non-DNA reactive carcinogens (saccharin, PPARγ agonists, arsenicals, others). Based on the fundamentals of carcinogenesis, a mode of action (MOA) approach, and the accumulated knowledge of carcinogenesis in animals and humans, carcinogenic risk can be readily evaluated today without utilizing the two-year bioassay.
Lecturer: Samuel M. Cohen, University of Nebraska Medical Center, Omaha, NE
This SOT Merit Award Lecture was delivered during the SOT 56th Annual Meeting and EUROTOX 2018.