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.

The extracellular pH and temperature of Walker 256 carcinoma and of normal subcutaneous tissue were measured continuously in unanesthetized female Sprague-Dawley rats for up to 20 hours following glucose or galactose administration. The pH was monitored with flexible glass electrodes contained in micropore chambers implanted in the flank of a rat. Temperature was measured with miniature thermistor probes incorporated in the tumor or in subcutaneous tissue. The pH in the untreated Walker 256 carcinoma decreased linearly from approximately 7.3 to 6.2 with increasing tumor mass up to 50 g. Administration of glucose (6 g/kg body wt, ip) in tumor-bearing rats increased glucose concentrations in blood and tumor, as well as lactic acid concentration in tumor, and had no significant effect on lactic acid concentration in blood. Plasma volume was not affected by either glucose or galactose loading as compared to that in rats given saline alone. However, the blood viscosity increased by up to 30% within 30 minutes after galactose injection, but not after glucose injection, and this significant difference in viscosities persisted for approximately 6 hours after glucose and galactose injections. In small tumors (less than 10 g), a decrease of up to 1 pH unit was observed within 6 hours after glucose administration, and the return of pH to pretreatment values began about 10 hours after glucose injection. Response of large ulcerated tumors (greater than 20 g) was not as uniform; the pH decreased by about 0.5 to 1 pH unit for only a brief period. After galactose injection, pH in some tumors remained unchanged, whereas in others an average decrease of about 0.2 pH units was observed. The pH in normal tissue was not affected by glucose or galactose administration. Both glucose and galactose decreased tumor temperature by about 7 degrees C.

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Since 2003, the Tg.rasH2 model has been accepted by regulatory agencies worldwide for 26-week short-term carcinogenicity assays as an alternative to the standard 2-year assays in conventional mice. However, over the decade, the number of actual studies conducted with alternative mouse models has remained low. The primary cause for low acceptance of this model has been lack of a historical database for the incidence of spontaneous lesions. Recently, we published the historical control database on spontaneous tumors in the Tg.rasH2 mice. The purpose of this publication is to present a large database pertaining to the non-neoplastic spontaneous lesions noted in Tg.rasH2 mice from studies conducted at our facility. Lesions that are considered unique in Tg.rasH2 mice are skeletal muscle myopathy, vascular anomalies involving various organs, and mesenteric arterial thrombosis. Other notable lesions are extramedullary hematopoiesis of spleen, subacute inflammatory foci in the liver, and infiltration of histiocytes in the lungs.