Abstract
The goal of Biological Concepts and Techniques in Toxicology: An Integrated Approach “is to highlight new methods and concepts that may have a major impact on toxicology and present how such concepts and techniques migrate into the mainstream of toxicology.” The book contains 17 chapters written primarily by U.S. authors.
The book is divided into three major parts. The first part is intended to provide a timely introduction to new approaches and concepts that will have a major impact on the practice of toxicology. The second part is designed to show how biological data and test systems are integrated into the practice of toxicology. The third part “reviews applications of toxicology to specific and more focused topics that represent current issues facing society today.”
The organizing principles as defined in the preface and the introduction and overview are vague and are not apparent throughout the book. There is no effort to relate chapters to one another. The result is overlap in material and lack of continuity. The individual chapters, which range in length from 3 to 67 pages, differ from each other in the extent of background and introductory material provided and the breadth and depth of material covered. It is unclear who the intended audience is.
Part I, “New Concepts and Approaches,” contains a brief introduction and overview, three chapters dealing with the “-omics” (toxicogenomics, proteomics, and metabonomics), and one chapter each on quantitative structure-activity relationships (QSAR) and hormesis. With the editor’s emphasis on “new” disciplines and concepts, it is surprising that there are very few 2005 references cited in this section and only one is cited in the three “-omics” chapters.
Chapter 1, the introduction and overview, does not significantly expand on the preface. It would be helpful to understand why topics are chosen to the exclusion of others and how the assignments to Parts II and III are made.
Chapter 2 on toxicogenomics suffers from brevity and eight coauthors. It is densely packed and a difficult read for someone with a cursory knowledge of the area. A list of Web-based database resources is useful as are some of the figures. The authors provide an example from an in vivo study that is very helpful. The figure to demonstrate a hierarchical tree with clustering of validated genes, however, is too small and indistinct to be illustrative for anyone who is not already familiar with microarrays.
Chapter 3 on proteomics is well suited to introducing someone to the topic. The author guides the reader through the goals of proteomic analysis, the problems related to its use for toxicology, and the shortcomings of various separation and analytical techniques. The figures are helpful and complement the text, but some concepts are still difficult to follow from the information given. In one place, Figure 5 is mistakenly cited for Figure 8. The author successfully uses studies of jet propulsion fuel (JP-8) to highlight toxicoproteomic applications. The lack of integration in the book is clear, however, because there is no reference to Chapter 13, which is devoted to this same fuel.
Chapter 4 on metabonomics is a short chapter that would benefit greatly from expanded discussion. The figures are very useful but their explanation is mostly limited to figure legends, which makes them difficult to follow and interpret. Overall, the chapter suffers from a lack of editing; for example, references 2 and 30 only contain author names and date of publication and the text on several pages intrudes into the lower margin by two to three lines.
Chapter 5 presents hierarchical QSAR (HiQSAR). This approach starts with topological (structural and chemical) descriptors and progresses to geometrical, quantum chemical, and biological descriptors, which are more computationally complex and demand more computational resources. A three-page table that defines calculated molecular descriptors may be useful to someone working in the field, but it is overkill for the average toxicologist. The authors give brief examples of HiQSAR modeling for cell toxicity estimation and describe how information at the level of the cell and the whole animal relates to predictive toxicology. They discuss the future of QSAR integrated with proteomics and genomics.
Chapter 6, the shortest chapter of the book apart from the introduction, deals with the concept of hormesis. The author explains how the concept has been misunderstood and that the hormetic dose-response model is neither threshold nor linear, but is either an inverted U-shape or J-shape. The author asserts that the hormetic dose response is the dominant dose response. He discusses the evolution of toxicologic thought that significantly influences generations of toxicologists and regulators and the implications of hormesis for toxicology and risk assessment.
Part II, “Integration into Practice,” is intended to show how scientific techniques and concepts are integrated in the practice of toxicology and how specific basic research test systems are validated for use in the regulatory setting. This section contains two chapters on risk assessment, and one each on toxicokinetic (TK) analysis for drugs and in vitro methodology validation.
Chapter 7 discusses chemical risk assessment that is instructive for those not engaged in risk assessment. The chapter examines issues such as dose-response assessment, carcinogen and noncarcinogen risk quantification, weight-of-evidence approaches, and risk assessment for dermal exposure. There is a brief, informative discussion of how various agencies approach risk assessment. The authors devote several pages discussing the mathematical basis for assessing mixtures, but do not reference Chapter 10, which is devoted to chemical mixtures. Approximately one-fourth of the chapter is allocated to physiologically based pharmacokinetic (PBPK) modeling, which is also thoroughly discussed in Chapter 8.
Chapter 8 on the fundamentals and applications of TK in drug development and safety assessment is a well-balanced, 43-page chapter that explains basic concepts of TK/PK and PBPK models. The author applies concepts of absorption, distribution, metabolism, and excretion (ADME) to identify lead drug candidates and TK to select species and doses for toxicology and safety studies.
Chapter 9 on the validation of in vitro methods for toxicology studies is concise, well written, and well referenced. It is a short chapter that seems oddly placed in the book apart from its logical partner, the validation of in vivo studies in Part III, Chapter 14, on drug safety.
Chapter 10 covers chemical mixtures and risk assessment. The authors discuss diseases caused by chemical mixtures and the Centers for Disease Control and Prevention biomonitoring program. The three-page list of chemicals monitored in the NHANES study is unnecessary. A small table with classes of chemicals is more suitable. The table defining types of mixtures is informative. Definitions of toxicologic interactions are given, but unfortunately, the source is not; there appears to be a conflict with common textbook definitions. The authors discuss terms and the weight-of-evidence approach and briefly address risk assessment models for complex mixtures.
Part III of the book is devoted to “Examples Applied to Problems” and includes seven chapters. The goal of this section is to look at “specific technologies, drugs, chemicals, issues, and disciplines to see how new scientific techniques have been incorporated into these areas.” The first two chapters, foods from genetically engineered (GE) animals and nanomaterials, are included because they “have potential for widespread exposure to humans.” The other five chapters deal with specific applications: JP-8 fuel, drug safety, statins, inhalation, and GC-MS in forensics. The result is a jumble. The selection of some topics to the exclusion of others and the placement of topics in Part III as opposed to Part II is puzzling.
Chapter 11 presents a risk-based approach to evaluating foods from GE animals. The chapter provides good background on GE animals, their derivation, and their intended use. The authors point out that the standard toxicology “dose-exaggeration studies” used to evaluate chemical toxicity are unsuitable to evaluate the adverse effects of foods. They discuss risk for the animal being transformed by the construct, risk for the human consuming food derived from the GE animal, and the unique challenges in hazard and risk analysis. Specific examples are instructive.
Chapter 12 provides useful information on the nomenclature, characteristics, and current and proposed uses of nanomaterials. Five nanomaterials that are likely candidates for industrial and biomedical applications are discussed with respect to their known toxicity. There is good discussion of some factors related to exposure conditions that affect health risk assessment. Environmental impact is also briefly mentioned.
Chapter 13 summarizes the toxicity of JP-8 fuel from experimental animal and cellular models. The authors examine pulmonary, dermal, and immune toxicity in light of changes in protein and gene expression and the release of inflammatory cytokines and other factors. The material on proteomics overlaps somewhat with that in Chapter 3, which provides some additional information on testes and renal proteomic responses to JP-8 exposure.
Chapter 14 examines the process of drug safety toxicology, its development and evolution, and how a new method or scientific approach becomes a standard tool in evaluating drug safety. This chapter is logically paired with Chapters 8 and 9 on TK and ADME in drug development and in vitro method validation, respectively. Chapter 14 is very instructive for those working outside the area of drug development. One table lists tests and techniques and how they are used in the drug approval process and whether they are the subject of a guidance document. A second summarizes why certain accepted tests are no longer routinely used. The authors discuss the FDA’s “critical path” concept with respect to the development of new methods for safety evaluation and the critical issues and challenges for emerging technologies and methodologies.
Chapter 15 discusses the potential toxicity of the statins, starting with a good overview of the pathogenesis of atherosclerosis and the issues related to statin therapy. The author highlights toxicity in a number of organ systems with evidence from experimental animal studies and human clinical and epidemiological studies. It is unclear why this one drug class is chosen to the exclusion of others.
Chapter 16 is an excellent review of concepts and techniques in inhalation and respiratory toxicology. At 67 pages, it is approximately 20 pages longer than any other chapter and is more what one would expect for a textbook. The authors discuss many aspects related to performing and interpreting inhalation toxicology studies, including biochemical and physiological evaluations; human health risks of inhaled particles; inhalation reference concentration (RfC); dose-response relationships for cancer and noncancer end points; quantitative estimates of carcinogen potency and cancer risk; criteria air pollutants; and EPA guidelines.
Chapter 17 explains the use of modern GC-MS in forensic toxicology and the different types of GC-MS and experimental setups. There is a good discussion of the screening capabilities of GC-MS and the limitations and pitfalls. The authors briefly touch on new technologies. Readers unfamiliar with GC-MS would benefit from reference of some earlier chapters to Chapter 17.
There are some very good chapters in the book, but the book lacks a convincing theme and a strong organizing principle. There is no attempt to interrelate the chapters except in a vague way in the introduction and overview. For any sense of organization, the reader must constantly refer to the introduction. An overview at the beginning of each of the three parts would help, but even then, the ordering of the chapters, the absence of cross-referencing between chapters, and the curious choice of some topics to the exclusion of others leaves the reader adrift.
The editor states at the conclusion of the introduction and overview that, “these developing fields and issues define the scope of toxicology in the 21st century.” Certainly, this comment is overreaching and the topics in this book only give us an inkling of what will come in the field of toxicology over the next few decades.