Mechanisms of nongenotoxic carcinogenesis and assessment of the human hazard.

Regulatory toxicologists in the pharmaceutical area are faced with many chemical entities to be classified as rodent carcinogens, in most cases on the basis of a nongenotoxic mechanism. The purpose of this paper is to describe some mechanisms for nongenotoxic tumorigenicity and to indicate which type of testing should be done to substantiate why in those cases such a mechanism is not relevant to humans. The increasing attention being given to epigenetic carcinogenesis points at the need for a thorough evaluation during the toxicological program for safety assessment, enabling adequate assessment of the human hazard posed by such compounds. Data to support the nongenotoxic carcinogenesis may be obtained by collecting specific information from current safety assessment programs or from future, separate studies.