Abstract
Toxicology of the Pancreas, edited by Parviz M. Pour, is a multiauthored, overdue volume in the Target Organ Series of Hayes, Thomas, and Gardner. As a first edition, it includes substantial introductory information and insight into an organ that has both exocrine and endocrine functions. The authors are well versed in their areas of expertise and provide, for the most part, informative overviews of their assigned chapters. Those expecting a comprehensive, all-inclusive book on the toxicology of the pancreas, however, will be disappointed, as the topic is too large to be reviewed in one volume of 695 pages. Nevertheless, the book is a good introduction into an often-overlooked field of toxicology.
As in the preceding volumes of this series, figures are presented in black and white only. This is a definite disadvantage as tissue histology and pathology as well as bar graphs acquire an extra-added dimension and perspective when viewed in color. Many publishers of lay newspapers, for example, have resisted incorporating color for many years. However, once they have relented to this growing trend, they and their readers have benefited greatly from the change. This may be an opportune time, therefore, for Taylor & Francis to move into the forefront and provide color to enhance future volumes of this series.
The book can be viewed as divided into six sections, namely, (1) structure, embryology, physiology, and function of the pancreas in the first 13 chapters; (2) the role of pancreatic enzymes in pancreatic injury, including pancreatitis, in the next five chapters; (3) effect of environmental factors on the pancreas in Chapters 19 to 22; (4) immunological and genetic defects of the pancreas in the subsequent four chapters; (5) two chapters that review the toxicology of the endocrine pancreas; and (6) Chapter 29 on pancreatic cancer and diabetes, although there is additional information on genetic and environmental causes of pancreatic malignancy scattered throughout several of the earlier chapters.
In fairness, Pour notes in the Foreword “pancreatic cancer was limited because (of) the rapid progress in this area . . . and requires a separate book.” However, pancreatic cancer is the third most common malignancy of the gastrointestinal tract, the fourth leading cause of cancer-related deaths in the United States, and patients with this disease have an overall 5-year survival rate of less than 5%. Therefore, a book on toxicology of the pancreas with only one or two chapters on pancreatic cancer, a topic that is of great concern to patients whose survival time after diagnosis ranges, on average, from 3 to 6 months, may, in retrospect, be a significant oversight. Rapid publication of a supplemental volume covering both exocrine and endocrine pancreatic carcinogenesis can rectify this deficiency in an otherwise very useful review of pancreatic function and disease.
That a significant portion of the book (about 45%) is spent on background material at the expense of a discussion of toxicological examples may reflect Pour’s need to comprehensively describe the pancreas, an organ he labels in Chapter 5 “the most complex structure of the body,” or the paucity of definitive information on pancreatic toxicology. An example is alcohol consumption, which is discussed in Chapter 15. Although it has been known for a very long time that alcohol is a leading cause of chronic pancreatitis in industrialized countries, satisfactory animal models that represent the human disease still have not been developed.
The introductory section comprised of 13 chapters includes the obligatory reviews of anatomy (Chapter 2), structure (Chapter 3), and vasculature (Chapter 4) of the pancreas, a standard staple of most organ-specific toxicology books. Chapter 1 by Lin and Leach attempts to cover everything you always wanted to know about developmental biology of the pancreas but were afraid to ask, whereas Chapter 6, “Physiology of Exocrine Pancreas,” omits a discussion of the role or importance of asparagine synthetase in regulating the concentration of asparagine within the pancreas. Chapter 12, “Pathological Perspectives of Pancreatic Mucins,” contains nearly 145 references, most from the last decade, a testament to the renewed interest in the unique characteristics and properties of this family of large multifunctional glycoproteins. The chapter on growth factors (Chapter 13) with over 200 references is an excellent summary of research on molecular biology of pancreatic disease.
Although all 13 introductory chapters contain background information on the pancreas that is of great interest, three chapters deserve special mention. In Chapters 7 and 8 dealing with drug metabolizing enzymes, the reader is dispelled of the notion that the liver first must activate chemicals before they can cause injury to the pancreas. In these chapters, the pancreas is introduced as an organ that is well equipped with its own drug-metabolizing enzymes and can metabolize toxins and carcinogens directly. Thus, studies on the metabolic pathways of xenobiotics within the pancreas may now lead to the development of preventive strategies for pancreatitis and pancreatic cancer. Similarly, in Chapter 9, Go and Wang discuss the pancreas, an organ that traditionally has been described as two separate organs, as an integrated organ with substantial exocrine-endocrine interactions. This, in turn, has significant implications for the clinical diagnosis and management of numerous exocrine and endocrine pancreatic disorders.
Of the several chapters on pancreatic injury (Chapters 14 to 18), those on toxicology of hormone-like chemicals and pancreatitis directly relate to causes of pancreatic disease that impact society in a significant way. Chapter 14 on hormone-like chemicals is timely since currently there is intense interest by regulatory agencies such as the U.S. Environmental Protection Agency in the toxicology of endocrine disrupters, e.g., chemicals with hormone-like activity present in the environment. The possibility that hormone-like chemicals in the environment may be toxic to the exocrine pancreas indicates that further research is needed to elucidate the mechanism by which these agents exert their toxic effects on this organ. Chapters 15 and 16 on pancreatitis shed no new light into or clarify the mechanisms underlying chronic pancreatitis, even though it has long been established that alcohol is one of the leading causes of chronic pancreatitis and is responsible for nearly 70% of all cases.
Chapter 17 on chemically induced exocrine degeneration in rats is particularly lacking, with only four examples of dioxin-like compounds being associated with increased incidences of nonneoplastic changes of the exocrine pancreas after 2 years of chemical administration. This may reflect the absence of chemically induced injury to the pancreas by the over 300 of the remaining chemicals that have been screened by the U.S. National Toxicology Program or because of the Program’s focus on toxicology to other organs at the expense of the pancreas. In any case, this chapter, along with chapters dealing with pancreatic metabolism, clearly show that the pancreas has been neglected much too long in chemically induced experimental toxicology and that efforts must be renewed to more fully understand the effects of environmental toxicants on the function of this important organ.
Chapters 19 to 22 identify and discuss several environmental risk factors that affect the exocrine pancreas, including smoking tobacco, diet and nutrients, and environmental pollutants. Pancreatic cancer is discussed to some extent in Chapters 19, 20, and 22, mainly as it relates to tobacco smoke, but there is much overlap and the discussions are not exhaustive. Thus, Chapters 19 and 20, although informative in other areas, such as in discussions of diet and nutrition, they cannot substitute for an in-depth review of pancreatic carcinogenesis that can only be accomplished in a volume that is specifically dedicated to the subject. Chapter 21 on nutrients and pancreatic malignancy extends the discussion of nutrition presented in the earlier chapters, but is much too short (5 pages) to be helpful. Perhaps the material from all four chapters should have been presented in at most two chapters and overlaps, which in a multiauthored book often cannot be avoided without strict editorial oversight, eliminated.
In the next group of four chapters, the role of genetics in pancreatic disease is examined. In Chapter 23, Okazaki reviews the autoimmune mechanistic hypothesis that has been proposed for idiopathic pancreatitis, which accounts for about 30% to 40% of chronic pancreatitis and for which obvious causes have not been detected. Weiss and Lerch further expand on this concept in Chapter 24. Okazaki discusses autoimmune pancreatitis mainly from a pathophysiological perspective, displaying several computer generated tomography and other electronic images and discussing their attributes and limitations in support of the hypothesis. In contrast, Weiss and Lerch review genetic factors in inflammatory diseases of the pancreas mainly from a molecular toxicological viewpoint. They hypothesize on the mechanism of pancreatitis by viewing a person’s genetic makeup as an indicator of his/her susceptibility to environmental toxins. Thus, the views expressed by Okazaki supplemented by those of Weiss and Lerch make for interesting reading and bring a unique perspective to the understanding of cellular and genetic mechanisms that may trigger acute pancreatitis and induce a progression of the disease to a chronic condition.
Chapter 25, “Genetic Disorders Associated with Exocrine and Endocrine Pancreatic Tumors,” is an excellent chapter that unfortunately, after reviewing in great detail the familial and hereditary forms of exocrine and endocrine pancreatic cancer, comes to the conclusion that “in spite of the great strides and advances made in genetic toxicology over the past decade, we remain in the dark.” Of course, it is the absence of knowledge that ensures that scientists continue to do basic research and strive for answers and here is no exception. The chapter would make an excellent addition to any volume on pancreatic carcinogenesis for it eloquently reviews the epidemiology, genetic-environmental interaction, and familial and hereditary risk factors associated with the disease.
Cystic fibrosis of the pancreas, one of the most common fatal genetic diseases in humans, is reviewed in Chapter 26. As Singh and Batra observe, although the disease has a poor prognosis, the median age of survival with cystic fibrosis of the pancreas has dramatically improved from 14 years in 1969 to a predicted 31.6 years in 2002, mainly because of advancements in our understanding about disease presentation, diagnosis, and supportive therapy. The authors describe the molecular, genetic, and pathophysiology of cystic fibrosis of the pancreas and briefly discuss the relationship between the disease and pancreatic cancer. Clearly, much more work needs to be done before there is sufficient knowledge on the cause of the disease that can be useful in developing new supportive therapies or changes in therapeutic strategies.
Section 5, comprised of Chapters 27 and 28, is a fairly complete and comprehensive discussion of the toxicology of the endocrine pancreas. The two chapters alone contain nearly 650 references, a good indicator of the depth and breadth of research that has been done over the years in this field. This can be contrasted with the 379 references that are cited, in total, in the five chapters on toxicology of the exocrine pancreas (Chapters 14, 17, 18, 19, and 20). Together, Chapters 27 and 28 summarize the toxicology of the endocrine pancreas from islet cell anatomy, development, maintenance, and survival to the effects of streptozotocin and alloxan, drugs that have been extensively studied for their toxic, tumorigenic, and antitumorigenic actions on the endocrine pancreas. My preference would have been to present Chapter 28 that discusses islet cells in great detail prior to Chapter 27 that mainly reviews the toxicology of two drugs that affect the endocrine pancreas. Nevertheless, the two chapters are worthy additions to the book and provide a good lead to Chapter 29, “Pancreatic Cancer and Diabetes—Cellular Origin of Adenocarcinoma.”
The final chapter of the book explores the controversy surrounding the association between pancreatic cancer and diabetes, specifically, whether pancreatic cancer is the cause of abnormal glucose metabolism or if hyperinsulinemia is a risk factor for pancreatic cancer. Fortunately, endocrine cancers of the pancreas are extremely rare, accounting for less than 1% of all pancreatic neoplasms. On the other hand, diabetes is a fairly common disease in advanced countries, with about 6% of the population in the United States having the disease. Therein lies the dilemma, which the authors explore in the remaining 4 to 5 pages of their chapter. The complexity of the hypotheses is clearly revealed by the authors as they describe the various lines of evidence that support or refute either hypothesis. Invariably, they reach the only possible conclusion, namely, that the etiology of pancreatic cancer remains elusive and detailed morphological and molecular biological studies are needed to settle the controversy. Therein lies no argument.
In summary, Toxicology of the Pancreas is an excellent first edition review of toxicological research on a multifunctional gastrointestinal organ of great importance. The editor and authors should be commended for their efforts, as the book is generally well edited and written by leading experts in the field. It highlights many areas of toxicological concern but leaves room for a much-needed second volume that concentrates on pancreatic cancer alone. I strongly recommend Toxicology of the Pancreas as an important addition to any library with an interest in gastrointestinal toxicology.