Toxicology of the Exocrine Pancreas

The exocrine pancreas is not a common target organ for toxic drugs and chemicals. It is however the fifth most common human cancer in the western world, and acute and chronic pancreatitis, through various identifiable and unidentified causes, is a common disease in both the developed and developing countries of the world. Both inflammatory disease and cancer of the pancreas is correlated to lifestyle with poor diet and habits, such as moderate to high alcohol intake and smoking, having positive correlations to developing the disease. The chapter describes the functional anatomy of the organ together with its biochemistry that determines toxicity, in particular the role of oxidant damage in the development of cell and tissue damage is thought to be important. The consequences of toxic damage to the acinar cells are severe and primarily result from the auto-activation and hence autodigestion of the tissue by the digestive enzymes normally contained within the exocrine cells, a cascade of apoptosis/necrosis and fibrosis with the ultimate collapse of the organ, subsequent shock, multi-organ collapse and death. The organ has complex molecular mechanisms to prevent premature activation of the digestive enzymes and also has defence mechanisms present to neutralise any premature enzyme activation but these can be rendered ineffectual by factors such as alcohol abuse and a poor diet. Chemical exposure, through both occupational and consumer product usage, has been associated with the development of both pancreatic neoplastic and non-neoplastic disease but the relationship between exposure and disease has never developed further than a simple association and it is likely that the development of pancreatic disease is a multi-faceted combination of inter-related events, none of which in isolation can induce disease. The pancreas has its own array of phase 1 and 2 metabolic enzyme systems and the role of pancreatic drug and chemical activation and detoxification in inducing toxicity is discussed together with the possible secondary effects of hepatic drug/chemical activation and detoxification. Finally the role of animal models of pancreatic disease is discussed in terms of their contribution to understanding the aetiology of the human conditions and the possible use of therapeutic intervention in treating the disease. Keywords: acute pancreatitis; chronic pancreatitis; pancreatic cancer; drug metabolism; phase 1 and 2 enzymes; ethanol; chlorinated hydrocarbons; anti-oxidants; reactive oxidant species; acinar; ductal; exocrine; microanatomy; functional morphology; diet; occupation; glutathione; solvents; animal models