Alternative mouse models for carcinogenicity assessment: industry use and issues with pathology interpretation.
The Carcinogenicity Alternative Mouse Models (CAMM) Working Group of the Society of Toxicologic Pathology (STP) surveyed the membership to define current practices and opinions in industry regarding the use of alternative mouse models for carcinogenicity testing. The results of the survey indicated that CAMM are used most often to fulfill a regulatory requirement (e.g., to replace the two-year mouse bioassay) and are being accepted by regulatory agencies. Alternative models are also sometimes used for internal decision making or to address a mechanistic question. The CAMM most commonly used are the p53+/- and rasH2. The rasH2 appears to be the currently accepted model for general carcinogenicity testing. Problems with study interpretation included lack of historic background data, unexpected tumor finding, and tumor identification/characterization of early lesions. Problems with implementation or conduct of the study included extent of the pathology evaluation, numbers of animals, survival, and study duration. Recommendations were developed for, frequency and type of positive control testing, extent of histopathologic examination of test article-treated and positive control animals, current use and future development of diagnostic criteria; increased availability and use of historic data, and use of other genetically modified mice in carcinogenicity testing.
Long
Gerald G
GG
Lilly Research Laboratories, Indianapolis, Indiana 46225, USA. Long_gerald_g@lilly.com
Morton
Daniel
D
Peters
Terry
T
Short
Brian
B
Skydsgaard
Mikala
M
D000818:Animals; D015197:Carcinogenicity Tests / Q000379:methods*; D004195:Disease Models, Animal; D011905:Genes, ras; D008770:Methylnitrosourea / Q000633:toxicity; D051379:Mice; D009374:Neoplasms, Experimental / Q000473:pathology*; D009626:Terminology as Topic; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D016159:Tumor Suppressor Protein p53; D008770:Methylnitrosourea