Opinion on Maintaining In-House GLP Status for Toxicologic Pathology in Pharmaceutical and (Agro)Chemical Development.

Many pharmaceutical companies have recently elected to stop maintaining good laboratory practices (GLP) status of their R&D sites. Similar discussions have also been engaged in the (agro)chemical industry. This opinion paper examines the pros and cons of maintaining facility GLP status for the purposes of performing the pathology interpretation or peer reviews of GLP studies internally. The toxicologic pathologist provides gross and histomorphologic evaluation and interpretation of nonclinical exploratory and regulatory studies during drug and (agro)chemical development. This assessment significantly contributes to human risk assessment by characterizing the toxicological profile and discussing the human relevance of the findings. The toxicologic pathologist is a key contributor to compound development decisions (advancement or termination) and in the development of de-risking strategies for backup compounds, thus playing a critical role in helping to reduce the late attrition of drugs and chemicals. Maintaining GLP compliance is often perceived as a costly and cumbersome process; a common and short-term strategy to reduce the costs is to outsource regulatory toxicity studies. However, there are significant advantages in maintaining the GLP status for toxicologic pathology activities in-house including the sustainable retention of internal pathology expertise that has maintained the necessary training needed to manage GLP studies. [Box: see text].

Hepatic enzyme induction: histopathology.

Hepatic enzyme induction is generally an adaptive response associated with increases in liver weight, induction of gene expression, and morphological changes in hepatocytes. The additive growth and functional demands that initiated the response to hepatic enzyme induction cover a wide range of stimuli including pregnancy and lactation, hormonal fluctuations, dietary constituents, infections associated with acute-phase proteins, as well as responses to exposure to xenobiotics. Common xenobiotic enzyme inducers trigger pathways involving the constitutive androstane receptor (CAR), the peroxisome proliferator-activated receptor (PPAR), the aryl hydrocarbon receptor (AhR), and the pregnane-X-receptor (PXR). Liver enlargement in response to hepatic enzyme induction is typically associated with hepatocellular hypertrophy and often, transient hepatocyte hyperplasia. The hypertrophy may show a lobular distribution, with the pattern of lobular zonation and severity reflecting species, strain, and sex differences in addition to effects from specific xenobiotics. Toxicity and hepatocarcinogenicity may occur when liver responses exceed adaptive changes or induced enzymes generate toxic metabolites. These undesirable consequences are influenced by the type and dose of xenobiotic and show considerable species differences in susceptibility and severity that need to be understood for assessing the potential effects on human health from similar exposures to specific xenobiotics.