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Published on: December 19, 2019
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A Proposal for New Strategies in Dose Selection for 26-Week Tg.Rash2 Carcinogenicity Studies
Madhav G Paranjpe1, Tom J Vidmar2, Melissa D Denton3
1Charles River, Mattawan, MI, USA.
International Journal of Toxicology
|March 30, 2021
Summary
Extrapolating maximum tolerated doses (MTD) from short-term studies overestimates tolerability in long-term carcinogenicity studies. This leads to toxicity in high-dose groups, rendering MTD estimations ineffective for Tg.rasH2 mouse studies.
Area of Science:
- Toxicology
- Carcinogenicity Studies
- Preclinical Drug Development
Background:
- Maximum tolerated dose (MTD) is crucial for carcinogenicity studies.
- Short-term dose range finding (DRF) studies are used to determine MTD.
- Tg.rasH2 mice are a common model for carcinogenicity testing.
Purpose of the Study:
- To evaluate the utility of MTD derived from 4-week DRF studies in 26-week carcinogenicity studies in Tg.rasH2 mice.
- To assess the impact of extrapolated MTD on toxicity and tumor incidence.
- To determine if MTD estimations from DRF studies are predictive for long-term studies.
Main Methods:
- Analysis of 26 carcinogenicity studies (2014-2018) in Tg.rasH2 mice.
- Evaluation of body weight gain, food consumption, mortality, and cause of death.
- Comparison of vehicle and test article-treated groups across different dose levels.
Main Results:
- Extrapolated MTD overpredicted tolerability, leading to decreased body weight gain and increased mortality in male mice.
- Mortality due to undetermined causes (potential toxicity) was highest in high-dose groups.
- Tumor-related mortality was lowest in high-dose groups, while undetermined causes were highest.
Conclusions:
- MTD derived from 4-week DRF studies is often exceeded in 26-week carcinogenicity studies in Tg.rasH2 mice.
- This overestimation undermines the utility of high-dose groups and does not serve the intended purpose.
- Revised strategies for dose selection in carcinogenicity studies are needed to ensure study validity and utility.
