Role and potential of histopathological specimens in the toxicological evaluation of pharmaceuticals and chemicals

Abstract

With the development of molecular-targeted drugs, the demand for utilization of histopathological specimens and pathological diagnosis is increasing in the field of clinical pathology. In particular, in case of companion diagnostics, the results of immunohistochemical staining have become beyond diagnostic assistance, definitive diagnosis, and now indispensable for selection of therapeutic agents. Histopathological examination also serves an important role in non-clinical toxicological evaluation. Particularly, it is pivotal for obtaining data on organ-specific toxicity and carcinogenicity. On the other hand, a weight of evidence approach is currently being considered in International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) S1 as an option to replace the 2-year rat carcinogenicity study, in which case the evaluation of the 26-week-repeated dose toxicity study will be more important. In this article, We would like to introduce the usefulness of γ-H2AX-based rat bladder carcinogenicity evaluation using histopathological specimens obtain from 28-day repeated-dose study and the application of mass spectrometric imaging currently under consideration in our laboratory, thus discuss the role of histopathological examination in non-clinical toxicological and safety evaluation and its future perspective.