Central nervous system tumors in 2-year rat carcinogenicity studies: perspectives on human risk assessment

Rodent in vivo carcinogenicity bioassays are required for human risk assessment and have been utilized in this capacity for decades. Accordingly, there is an abundance of data that could be accessed and analyzed to better understand the translatability of xenobiotic-induced rodent tumors to human risk assessment. In the past decade, various groups have published assessments of the value garnered by these life-time rodent studies. Results and recommendations from the International Council for Harmonization Expert Working Group (ICH-S1 EWG) on the predictability of the current testing paradigm and proposal for an integrated approach to human carcinogenicity risk assessment are pending. Central nervous system (CNS) tumors in rats are rare and translatability to human remains unknown. This review focuses on microglial cell tumors (MCT) of the CNS in rats including its classification, nomenclature, incidence and translatability to human risk assessment. Based on emerging immunohistochemistry (IHC) characterization, glial tumors previously thought of astrocytic origin are more likely MCTs. These may be considered rodent specific and glucose dysregulation may be one component contributing to their formation. Based on review of the literature, MCTs are rarely diagnosed in humans, thus this tumor type may be rat-specific. We propose to include MCTs as a tumor type in revised International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) classification and all glial tumors to be classified as MCTs unless proven otherwise by IHC.