Neonatal Mouse Tumorigenicity Bioassay

Abstract

The International Conference on Harmonisation (ICH) has suggested the use of the newborn mouse bioassay as an alternative tumorigenicity assay. There are sufficient data to conclude that this animal model is highly sensitive to chemical carcinogens that exert their action through mechanisms involving the formation ofcovalently bound DNA adducts (exogenous adducts) of the administered compound and the processing of these adducts to mutations. Mechanistic studies, including metabolism, DNA adduct formation, and ras-oncogene activation, presented in this paper aid in the interpretation of tumor experiments. By comparison, the data thus far obtained suggest that this bioassay is very likely insensitive to some indirect-acting chemical carcinogens. Ongoing studies are focused on the sensitivity of this bioassay to indirect-acting carcinogens that are believed to exert their tumorigenicity through secondary mechanisms, including: 1. induction of lipid peroxidation and increases in endogenous DNA adducts, 2. endocrine disruption, and 3. induction of peroxisome proliferation. A systematic approach to validate the neonatal mouse tumorige-nicity bioassay as a part of a risk identification procedure is proposed. This approach combines the tumorigenicity bioassay with several simple and convenient supportive mechanistic experiments of study so that direct-acting chemical carcinogens, indirect-acting carcinogens, and noncarcinogens can be distinguished.