Neonatal Mouse Tumorigenicity Bioassay
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Drug Information J o u m l . Vol. 32, pp. 711-728. 1998 Printed in the USA. All rights reserved.
NEONATAL MOUSE TUMORIGENICITY BIOASSAY* PETERP. Fu, PHD Research Chemist
LINDAs. VON TUNGELN Research Chemist
PINGYI Visiting Scientist
QINGSUXIA Visiting Scientist Division of Biochemical Toxicology, United States Food and Drug Administration, National Center for Toxicological Research, Jefferson, Arkansas
DANIELA. CASCIANO, PHD Director, Division of Genetic & Reproductive Toxicology, United States Food and Drug Administration, National Center for Toxicological Research, Jefferson, Arkansas
THOMASJ. FLAMMANG, PHD Special Assistant, Office of the Director, United States Food and Drug Administration, National Center for Toxicological Research, Jefferson, Arkansas
FREDF. KADLUBAR, FWD Director, Division of Molecular Epidemiology, United States Food and Drug Administration, National Center for Toxicological Research, Jefferson, Arkansas
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 theformation of covalently bound DNA adducts (exogenous d u c t s ) of the administered compound and the processing of these adducts to mutations. Mechanistic studies, including metabolism, DNA adductformation, and ras-oncogene activation, presented in this paper aid in the interpretation of tumor experiments. By comparison, the data thusfar obtained suggest that this bioassay is very likely insensitive to some indirect-actingchemical carcinogens. Ongoing studies arefocused on the sensitivity of this bioassay to indirect-actingcarcinogens 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 Presented at the DIA Workshop "Testing Human Pharmaceuticals For Carcinogenic Potential: New Approaches after ICH 4," October 27-28. 1997, Noordwijk, the Netherlands. Reprint address: Dr. Peter P. Fu, U.S. FDA/NCTR, 3900 NCTR Road, HFT-110.Jefferson, AR 72079. *This article is not an official Food and Drug Administration guidance or policy statement. No official support or endorsement by the Food and Drug Administration is intended or should be inferred. 711
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Fu, Von Tungeln, Yi, Xia, Casciano, Flammang, and Kadlubar peroxisome proliferation. A systematic approach to validate the neonatal mouse tumorigenicity 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, indirectacting carcinogens, and noncarcinogens can be distinguished. Key Words: Neonatal mouse tumo
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