Abstract
Our recent retrospective analysis of data, collected from 29 Tg.rasH2 mouse carcinogenicity studies, determined how successful the strategy of choosing the high dose for the 26-week studies was based on the estimated maximum tolerated dose (EMTD) derived from earlier 28-day dose range finding (DRF) studies conducted in CByB6F1 mice. Our analysis demonstrated that the high doses applied at EMTD in the 26-week Tg.rasH2 studies failed to detect carcinogenic effects. To investigate why the dose selection process failed in the 26-week carcinogenicity studies, the initial body weights, terminal body weights, body weight gains, food consumption, and mortality from the first 4 weeks of 26-week studies with Tg.rasH2 mice were compared with 28-day DRF studies conducted with CByB6F1 mice. Both the 26-week and the earlier respective 28-day studies were conducted with the exact same vehicle, test article, and similar dose levels. The analysis of our results further emphasizes that the EMTD and subsequent lower doses, determined on the basis of the 28-day studies in CByB6F1 mice, may not be an accurate strategy for selecting appropriate dose levels for the 26-week carcinogenicity studies in Tg.rasH2 mice. Based on the analysis presented in this article, we propose that the Tg.rasH2 mice and not the CByB6F1 mice should be used in future DRF studies. The Tg.rasH2 mice demonstrate more toxicity than the CByB6F1 mice, possibly because of their smaller size compared to CByB6F1 mice. Also, the Tg.rasH2 males appear to be more sensitive than the female Tg.rasH2 mice.
Highlights
The 2-year rodent carcinogenicity assays involving conventional rats and mice have been conducted for over 3 decades
To come to this conclusion, we evaluated additional data that included comparison of initial body weight (IBW), terminal body weight (TBW), body weight gains (BWGs), food consumption (FC), and mortality in the first 4 weeks of Tg.rasH2 mice used in the 26-week carcinogenicity studies and CByB6F1 wild type mice used in the prior 28-day dose range finding (DRF) studies with exact same vehicle, test article, and similar dose levels
For the purpose of this article, the parameters compared included IBW, TBW, BWG, FC, and mortality collected for 28-day DRF studies conducted in CByB6F1 mice and the same data collected for the first 28 days of the 26-week carcinogenicity studies conducted in Tg.rasH2 mice
Summary
The 2-year rodent carcinogenicity assays involving conventional rats and mice have been conducted for over 3 decades. 26-week transgenic Tg.rasH2 mouse studies have replaced more than 75% of all mouse carcinogenicity studies.[2,3,4] The Tg.rasH2 model predicts neoplastic findings relevant to human cancer risk assessment, produces fewer nonbiologically significant neoplastic outcomes, and is often is preferable to a 2-year mouse study.[5]. 5- and 28-day dose range finding (DRF) studies are conducted in CByB6F1 mice, the wild type littermates of Tg.rasH2 mice, to establish the doses used in the 26-week Tg.rasH2 carcinogenicity study. The CByB6F1 mouse has the same genetic background as the Tg.rasH2 mouse except for the omission of the transgene (Tg) element. For this reason, the nontransgenic wild type littermates CByB6F1 mice are used in earlier DRF studies. The purpose of the 5-day study is to estimate the doses for the 28-day study, and International Journal of Toxicology 36(4)
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