Comparative Hepatic Toxicity: Prechronic/Chronic Liver Toxicity in Rodents

Abstract

The morphologic assessment of the gross and microscopic appearance of the liver can provide a broad base of knowledge concerning the potential toxicity of a drug or chemical. This information may either lead to an understanding of the underlying mechanism of toxicity or guide further study to discern the mode of action of the hepatotoxicity. In standard regulatory bioassays, toxicity studies are conducted during phase 1 and phase 2 of the development process to define the acute, subchronic and chronic toxicity of the test compound. In the liver, there are a limited number of morphologic changes that can be identified using conventional light microscopy. These morphologic alterations are often characterized as “adaptive,” consisting of an exaggerated normal physiologic response; “pharmacologic,” consisting of an expected alteration in response to the desired action of the test article; or “adverse,” consisting of morphologic alterations that are generally undesired, progressive and deleterious to the normal function of the cell(s) involved. Morphologic evidence of adverse effects may involve hepatocytes, the biliary system, hepatic vasculature, Kupffer cells, or stellate cells (Ito cells). In drug discovery and development programs, it is necessary to utilize a multidisciplinary approach, using different endpoints, to investigate the same or similar biological responses in the liver. This results in large amounts of data that must be organized in a retrievable fashion. In order for such a multidisciplinary approach to succeed, each discipline must organize and generate their data in a manner that is easily used by others in the process. The toxicologic pathologist must develop and use standardized nomenclature and diagnostic criteria when examining the liver so that data from various investigators can be compared in a useful manner.