Use of rasH2 transgenic mice for carcinogenesis testing of medical implants.

Several transgenic mice models are accepted by regulatory agencies to determine the carcinogenic potential and predict the human response to exposure of chemicals, as an alternative to the conventional 2-year rodent bioassay. The rasH2 transgenic mouse model has been proposed to evaluate the carcinogenic potential of medical devices, but few data are currently available regarding study design--namely appropriate positive and negative controls to be used--as well as historical pathology data. BIOMATECH-NAMSA recently conducted a 26-week carcinogenicity study following subcutaneous implantation in the transgenic rasH2 mouse model. This paper describes the study design and the main results obtained in the positive and negative control groups. The survival rate statistical (Kaplan-Meier) analysis showed that the survival rate was significantly affected by the occurrence of tumors in the positive control group when compared to the negative control group, in both genders. Thymic malignant lymphomas and squamous cell papillomas were reported to occur at a higher incidence in rasH2 mice exposed to a known chemical carcinogen, for terminally sacrificed animals as well as for unscheduled and terminally sacrificed animals considered together. Background and age-related lesions were few. Taken together, these data confirmed the reliability and usefulness of the rasH2 transgenic model in the assessment of carcinogenic properties of medical devices. A major beneficial property of this animal model consisted in the ability to demonstrate chemical carcinogenesis response without the solid-state tumorigenesis response seen in traditional 2-year rodent bioassays.