P15: Use of rasH2 transgenic mice for carcinogenesis testing of medical implants

Abstract

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. Regarding medical device evaluation, ISO 10993-3 lists several situations that require carcinogenicity testing: absorbable materials, materials that obtained positive results in genetic toxicity on mammalian cells or materials with a permanent or cumulative contact of 30 days or longer in the body, except when significant and adequate human-use history is available. The rasH2 transgenic mouse model has been proposed to evaluate the carcinogenic potential of medical devices, but very few data are currently available regarding study design-namely appropriate positive and negative controls to be used-, as well as pathology historical data. From in-house pre-existing experience and active collaboration with our rasH2 mouse breeder, BIOMATECH-NAMSA recently conducted a 26 week carcinogenicity study following subcutaneous implantation in the transgenic rasH2 mouse model. This poster depicts 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. Incidence tables were obtained and discussed for hyperplastic and neoplastic findings in control groups. The positive control group revealed an increase in the incidence of neoplastic lesions. 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.