Abstract
High doses in Tg.rasH2 carcinogenicity studies are usually set at the maximum tolerated dose (MTD), although this dose selection strategy has not been critically evaluated. We analyzed the body weight gains (BWGs), mortality, and tumor response in control and treated groups of 29 Tg.rasH2 studies conducted at BioReliance. Based on our analysis, it is evident that the MTD was exceeded at the high and/or mid-doses in several studies. The incidence of tumors in high doses was lower when compared to the low and mid-doses of both sexes. Thus, we recommend that the high dose in male mice should not exceed one-half of the estimated MTD (EMTD), as it is currently chosen, and the next dose should be one-fourth of the EMTD. Because females were less sensitive to decrements in BWG, the high dose in female mice should not exceed two-third of EMTD and the next dose group should be one-third of EMTD. If needed, a third dose group should be set at one-eighth EMTD in males and one-sixth EMTD in females. In addition, for compounds that do not show toxicity in the range finding studies, a limit dose should be applied for the 26-week carcinogenicity studies.
Highlights
The 2-year rodent carcinogenicity assays involving conventional rats and mice have been conducted for over 3 decades
We have recently evaluated the body weight parameters, trend analysis, mortality, and spontaneous tumors in the Tg.rasH2 mice (Paranjpe, Elbekai et al 2013; Paranjpe, Shah, et al 2013; Paranjpe, Denton, and Elbekai 2014; Paranjpe, Denton, et al 2014a; Paranjpe Denton et al 2014b) and demonstrated that problems associated with increasing initial body weights (IBW), high mortality, and high incidence of background tumors that exist in the conventional 2-year rodent model do not exist in the Tg.rasH2 mouse model
The data pertaining to studies in which the maximum tolerated dose (MTD) was exceeded or MTD was not exceeded, and the percentages of tumors associated with these studies are presented in Tables 7 and 8
Summary
The 2-year rodent carcinogenicity assays involving conventional rats and mice have been conducted for over 3 decades. As an alternative to the 2-year rodent carcinogenicity bioassays, 26-week short-term carcinogenicity bioassays were approved using transgenic mouse strains, including Tg.rasH2 (International Conference on Harmonisation [ICH] 1998). 26-week transgenic Tg.rasH2 mouse studies have replaced more than half of all mouse carcinogenicity studies (Jacobs and Hatfield 2013; Nambiar, Turnquist, and Morton 2012; Paranjpe, Elbekai, et al 2013). The Tg.rasH2 model predicts neoplastic findings relevant to human cancer risk assessment, produces fewer nonbiologically significant neoplastic outcomes, and is often preferable to a 2-year rodent study (Morton et al 2013)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
