The 26-Week Tg.Rash2 Mice Carcinogenicity Studies

Abstract

A typical 26-week Tg.rasH2 mouse carcinogenicity study usually has 4 dose groups, composed of 25 mice/sex, which include 1 control and 3 test article-treated groups. In every study, there is a protocol required full tissue list of 49 tissues which is examined microscopically in all animals of these 4 dose groups. Based on retrospective analysis of the historical control data collected from studies conducted in Tg.rasH2 mice from 2004 to 2012, we propose that a full tissue list be examined as usual in the control and high-dose groups; however, in the low-and mid-dose groups, only select tissues should be examined. The select tissue list is generated after analyzing common tumors, uncommon tumors seen grossly, uncommon tumors not seen grossly, organ weight variations with accountable microscopic lesions, and target organs identified in the high-dose groups. The proposed changes to the International Conference on Harmonization S1 guidance may lead to an increased need for 26-week Tg.rasH2 mice studies. The time savings resulting from processing and evaluating a select tissue list rather than a full tissue list from low-and mid-dose groups of Tg.rasH2 mouse studies will further accelerate early completion of these studies without compromising the quality and integrity.

Carcinogenicity Evaluation of Baclofen in TgrasH2 Mice

“…In the other low-dose male, enlarged cyst (left) with red discoloration correlated with testicular hemangiosarcoma, which has been reported as an uncommon tumor seen grossly, among others of this type accounting for up to 28% of all background tumors in males of this strain. 16 Due to the very-low incidence, previous reporting of these findings in this mouse strain, lack of dose-relationship and nonmalignant mass found in the high-dose baclofen male, a relationship to baclofen could not be established. Palpable masses were also found in 3 male and 4 female positive control animals (time of onset and incidence consistent with reference data 14 ).…”

“…The overall findings were consistent with previously reported spontaneous occurrences of the observed tumor types found in historical control data of this strain. 5,[14][15][16]19 The incidence of forestomach squamous cell papilloma, which is among the most common tumors in this strain, minimally exceeded reported spontaneous occurrence (group ranges in males up to 4%-6.7% 14,19 and 3% incidence in males 15 ) in high-dose baclofen-treated males (2/25 males [8%] at 180 mg/kg/d) and was statistically significantly different from the vehicle control by a Cochran-Armitage trend test (P .05). However, there were no predominant or differentiating preneoplastic changes such as dose-related squamous cell hyperplasia to support a carcinogenic mechanism of induction, and minimal or slight squamous cell hyperplasia in the forestomach was observed in 1 control male, 2 control females, and 4 baclofen-treated animals (1/25 males at 45 mg/kg/d, 1/25 females at 90 mg/kg/d, and 1/25 males and 1/26 females at 180 mg/kg/d).…”