When chemicals that are nongenotoxic in conventional assays produce increases in tumor incidence in rodents in chronic bioassays, the determination of the significance of these data for human safety is a challenging task. An important first step in this process is consideration of available data on the mechanism of action and biological properties of the chemical as well as pharmacokinetic and metabolism data in the species showing the response. In recent years, there has been an increase in the understanding of so-called "secondary mechanisms" of carcinogenesis (e.g., thyroid tumors in rats following exposure to enzyme inducers). Application of these data may assist in determination of human risk. There are 2 important questions that will be explored and developed: Are there biological effects produced in the test species that could explain the increase in tumor incidence, and will these effects be reproduced in humans? What is the exposure to the chemical that is associated with the increase in tumors, and how does this relate to exposure in humans?