- Historical Control Database of Spontaneous Tumors in Transgenic TG.rasH2 Mice

The incidence of spontaneous tumors in control animals is important in understanding the background incidence of neoplasia in a model. The Tg.rasH2 mouse model has been used only over the past two decades. The historical control incidence in 55 studies conducted in Tg.rasH2 mice between 2014 and 2018 is presented, representing a total of 1,615 male mice and 1,560 female mice. Common neoplasias (>1% incidence) include pulmonary adenomas and adenocarcinomas, vascular neoplasms, and harderian gland adenomas, with other neoplasias seen rarely (<1% incidence).

- A Proposal for New Strategies in Dose Selection for 26-Week Tg.Rash2 Carcinogenicity Studies

Maximum tolerated dose (MTD) is a commonly used factor in determining dose levels for carcinogenicity studies. In the Tg.rasH2 mouse model, MTD derived from four-week dose range finding (DRF) studies conducted in the wild-type CByB6F1 is used to determine high-dose levels in the 26-week Tg.rasH2 mouse carcinogenicity studies. MTD determined through the CByB6F1 mouse DRF may overpredict tolerability and undermine utility of the high-dose group in Tg.rasH2 mouse carcinogenicity studies, primarily because the wild-type mice weigh around 20% more than the Tg.rasH2 mice. Fifty-five studies conducted at the BioReliance facility between 2003 and 2018 were evaluated for initial body weights (IBW), terminal body weights (TBW), food consumption, mortality, decrease in body weight gains, and cause of deaths (COD). Our analysis showed that the MTD derived from ChyB6F1 mice and applied to TG.rasH2 mice is overestimated and causes high mortality, decreases in numbers of tumors, and decreases in body weight gain % that are greater than 10%, defeating the purpose of the assay. Thus, we propose that the rule of thumb of no greater than 10% drop should be scaled down to no greater than 5% body weight gain. Thus, setting the doses in males at 1/2, 1/4, and 1/8 of MTD and those in females at 2/3, 1/3, and 1/6 of MTD derived from in CbyB6F1 studies.