[Toxicity evaluation of pharmaceuticals and mechanisms of their effects]

Preclinical studies are defined as experiments other than clinical trials that are conducted in test systems under laboratory conditions for determining the safety of test materials for anticipated human use. It is known that preclinical studies are an indispensable requisite for but constitute time/resource-consuming processes in research and development of new pharmaceuticals. Therefore, they must be designed and conducted in a manner to satisfy the criteria that the obtained data are mutually acceptable among various countries to avoid unnecessary duplication of testing. The purpose of the International Conference on Harmonisation (ICH) has been directed towards the resolution of this issue. Major scientific issues in preclinical studies comprise the interpretation of test data with respect to prediction of potential adverse effects of a test material in humans. Mechanistic consideration of the toxic effects occurring in animals given a test material can usually provide a scientific basis for evaluating the potential hazard of the material in humans. For example, when a test material was found to exhibit a carcinogenic effect in a long-term animal test, one will attempt to determine, on the basis of data from genotoxicity studies, repeated dose toxicity tests, toxicokinetic studies or pharmacology studies on the substance, whether the carcinogenic effect is due to its genotoxicity (genotoxic carcinogen) or a sequela of some secondary mechanisms (non-genotoxic carcinogen). In the cases where a test material was shown to exert toxic effects with either functional manifestation or non-neoplastic morphological manifestation, elucidation of the mechanism will also be useful for extrapolation of animal data to the human situation. It is known that pharmaceuticals induce their toxic effects through various mechanisms such as covalent binding of active intermediates with macrolecules of target cells, oxidative stress-mediated effects, hormone-mediated effects or cytokinemediated effects. As shown in hepatocarcinogenesis or elevation of plasma transaminase activities in rodents attributable to activation of PPAR-alpha, nuclear receptors or ligand-dependent transcription factors are, now, regarded as important targets for toxicity evaluation of pharmaceuticals.