The 2-year rodent bioassay in drug and chemical carcinogenesis testing. 1. Sensitivity according to the frame of carcinogenic action.

The long-term rodent bioassay (RCB) has been the gold-standard for the pre-marketing prediction of chemical and drug carcinogenicity to humans. Nonetheless, the validity of this toxicity test has remained elusive for several decades. In the quest to uncover the performance of the RCB, its sensitivity (SEN) was charted as the first step. This appraisal was based on (a) chemicals with sufficient epidemiological evidence of carcinogenicity, and (b) other substances with limited epidemiological evidence, or with remarkable classifications of carcinogenicity based on mechanistic or pharmacological data. In the present study, chemicals evaluated for their carcinogenicity to humans in IARC Monographs volumes 1-123, U.S. EPA IRIS Assessments, and U.S. NTP RoC were considered. This investigation gathered additional evidence supporting that, in hazard identification, the RCB is unwarranted for mutagenic or direct-acting genotoxicants. However, for purposes of risk assessment or management, the RCB might be justified for those chemicals whenever there is a lack of reliable epidemiological data. The RCB exhibited a significantly different SEN for threshold human carcinogens compared to non-threshold-based ones. With threshold-based chemicals, to increase the SEN of the testing from 80% (rat-RCB) to 90%, the 2-species RCB might be warranted. Nevertheless, the resolve would depend on the viewpoint. In terms of SEN, the comparison between the RCB and alternative methods (e.g., rasH2 mouse, Tg.AC mouse) is now enabled.