Historical Control Data of Spontaneous Tumors in Transgenic CByB6F1-Tg(HRAS)2Jic (Tg.rasH2) Mice

Abstract

The Tg.rasH2 mouse is a hemizygous transgenic mouse, approved by regulatory agencies for carcinogenicity assessment. However, the absence of a historical database for the incidence of spontaneous neoplasms has subsequently led to reluctance by some pharmaceutical companies to adopt the use of this short-term carcinogenicity assay. Our laboratory has generated a database summarizing the mortality, body weights, and the incidence of spontaneous tumors in 1420 male and female mice assigned to 26 studies conducted at our facility. In addition, we present the incidence of tumors in positive control mice treated with urethane from these studies. Mortality in the vehicle-treated Tg.rasH2 mouse was low (average of 1% in each study). The most common spontaneous tumors in the Tg.rasH2 mice were alveolar bronchiolar adenoma of the lungs (10.14% in males and 5.77% in females) and hemangiosarcoma of the spleen (3.66% in both males and females). The incidence of all other tumors was generally very low. In the positive control, urethane-treated animals, the incidence of alveolar bronchiolar adenomas and alveolar bronchiolar carcinomas in the lungs was 93.69% and 42.88% in males and 92.43% and 72.79% in females, respectively. In addition, the incidence of splenic hemangiosarcomas in urethane-treated males was 89.18% and 92.25% in females. The 6-month Tg.rasH2 assay is more precise, faster, and more economical than the conventional 2-year mouse assays because of the low incidence of background tumors, very high survival, shorter duration, and the lower number of animals used.

Incidence of Spontaneous Non-Neoplastic Lesions in Transgenic CBYB6F1-Tg(HRAS)2Jic Mice

“…In our studies, we have not seen any progression of these basophilic foci toward the tumors. We have seen only 2 hepatocellular adenomas in the 710 male mice that we examined and none in the 710 female mice (Paranjpe et al 2013). Low incidence of hepatocellular adenoma has been recorded by others also in male mice but not in the female mice (Nambiar et al 2012).…”

“…Similar lesions in Tg.rasH2 mice (Takaoka et al 2003) and in other strains of mice have been diagnosed as acidophilic macrophage pneumonia (Pettan-Brewer and Treuting 2011; Murray and Luz 1990). The incidence of alveolar epithelial hyperplasia parallels the incidence of pulmonary adenomas noted in male and female mice, with hyperplasia generally of lower incidence than adenomas (Paranjpe et al 2013).…”

“…The incidence involving specifically the uterus only was not stated (Morton et al 2002). We have recorded hemangiosarcomas and hemangiomas as common spontaneous tumors of the Tg.rasH2 mouse with incidence being 5.91% in males and 7.18% in females and incidence of splenic hemangiosarcoma in males and females being identical at 3.66% (Paranjpe et al 2013). Uterus is the most commonly affected organ other than spleen in the female mice (Paranjpe et al 2013).…”

“…We have recorded hemangiosarcomas and hemangiomas as common spontaneous tumors of the Tg.rasH2 mouse with incidence being 5.91% in males and 7.18% in females and incidence of splenic hemangiosarcoma in males and females being identical at 3.66% (Paranjpe et al 2013). Uterus is the most commonly affected organ other than spleen in the female mice (Paranjpe et al 2013). Others have also shown that this strain of mouse is in general predisposed to splenic hemangiosarcomas or hemangiosarcomas in different organs (Morton et al 2002;Nambiar et al 2012;Usui et al 2001).…”

“…The low acceptance of the 26-week short-term carcinogenicity assays has been primarily due to the lack of a historical control database (Long et al 2010;Storer et al 2010). There have been few published reports on the incidence of spontaneous tumors in Tg.rasH2 mice (Nambiar et al 2012;Paranjpe et al 2013;Usui et al 2001), and few reports pertaining to non-neoplastic lesions such as skeletal muscle myopathy and vascular anomalies (De Jonghe et al 2000;Kanno et al 2003;Morton et al 2002;Tsuchiya et al 2001). There also have been published reports on the non-neoplastic lesions in the parent strains of Tg.rasH2, C57BL/6, and BALB/c mice (Frith et al 1983;Frith and Ward 1988;Pettan-Brewer and Treuting 2011).…”