The 2-year rodent bioassay in drug and chemical carcinogenesis testing: Sensitivity, according to the framework of carcinogenic action

Abstract

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 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 whenever there is a lack of reliable and/or comprehensive epidemiological data. The RCB exhibited a significantly different SEN for threshold-based 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, and on the future analysis of the overall performance of the RCB. In terms of SEN, and cancer hazard identification, the comparison between the RCB and alternative methods (e.g. rasH2 mouse, Tg.AC mouse) is now enabled.

Keywords:

• Regulatory science
• carcinogenicity testing
• chemical carcinogenesis
• hazard identification

Acknowledgments

The corresponding author thanks (a) the Board of Directors of the Institute for Pharmaceutical Research of Universidad Central de Venezuela; (b) the Department of Toxicology of Universidad Nacional de Colombia, and (c) the research group Química de Productos Naturales y Alimentos from Universidad Nacional de Colombia, specifically because of their institutional support to this series of ongoing investigations. Besides, we thank Timberlake Ventures (Inc.) for the student-program access (for J.D. Suarez-Torres) to ToxPlanet, which has been of significant help to the research conducted by our academic office.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

This investigation was formulated and performed by J.D. Suarez-Torres. F.A. Jimenez-Orozco and C.E. Ciangherotti provided fundamental scientific guidance from applied pharmacology and toxicology. The three authors contributed to the elaboration of the article.

Additional information

Funding

This study was supported by the Ph.D. Scholarship 757 from Minciencias, Government of the Republic of Colombia.