Predictive Value of Rodent Models in Human Carcinogenic Risk Assessment
Rodent bioassays have long served as the gold standard for evaluating the carcinogenic potential of pharmaceuticals, chemicals, and biologics. Chronic toxicity and carcinogenicity studies conducted in rats and mice over 18 to 24 months form the foundation of regulatory safety assessments and guide classification schemes used by global agencies. Despite their widespread use, the predictive accuracy of these models for human cancer risk remains a subject of ongoing debate, especially with the rise of alternative models and mechanistic testing strategies.
Rodents offer advantages in genetic uniformity, well-characterized tumor backgrounds, and the ability to monitor time-dependent progression of neoplasia. However, interspecies differences in metabolism, DNA repair capacity, hormone regulation, and immune surveillance can influence tumorigenic pathways. For example, certain hepatic tumors observed in rodents, such as peroxisome proliferator-activated receptor alpha (PPARα)-mediated hepatocellular carcinomas, are not considered relevant to humans due to species-specific activation.
To improve the relevance of rodent data, regulatory agencies encourage the integration of mode-of-action analysis, genotoxicity profiling, and dose–response modeling. Tools such as benchmark dose modeling, physiologically based pharmacokinetic (PBPK) modeling, and the use of historical control databases further refine interpretation. Advances in transgenic and knockout mouse models also allow researchers to examine humanized responses to oncogenic triggers, enhancing translational fidelity.
While rodent studies remain an essential component of carcinogenicity testing, their predictive value is maximized when combined with mechanistic understanding, human exposure estimates, and emerging in vitro tools. This integrated approach supports more accurate human risk assessment and regulatory decision-making.