Abstract
In its first edition, Pathology for Toxicologists edited by Dr Elizabeth McInnes is a much welcomed addition to the basic literature bridging the 2 complementary sciences of pathology and toxicology, specifically within the context of drug, chemical, or device industries. Aimed at the wide spectrum of study personnel supporting investigational and routine toxicity studies, this book provides a broad yet succinct coverage of the bases underlying the generation and interpretation of pathology data and enables a better use, comprehension, and integration of these data into toxicology reports. In its paperback presentation (provided for this review), the book is illustrated and has a good print quality, is concise, portable, and thoroughly referenced. The 6 contributing authors are all adequately qualified and have hands-on experience on the topics they covered; the editor herself contributed with 4 chapters. The book structure is organized into 8 chapters and include an introduction to pathology techniques, recording pathology data, general pathology and the terminology of basic pathology, common spontaneous and background lesions in laboratory animals, target organ pathology, clinical pathology, adversity from the pathologist’s perspective, and limitations of pathology and animal models. Each chapter begins with a learning objectives section and ends with a comprehensive list of references; a chapter-by-chapter analysis is included below. The book also includes a glossary (always helpful when dealing with pathology terms and acronyms) and an index. In short, this book is a bridging reference between toxicology and pathology, broadly covering the bases of laboratory animal pathology generation, interpretation, and communication, and it should prove useful not only for early career as well as for practicing toxicologists.
Chapter 1 (E. McInnes) provides an introduction to pathology techniques, including things to consider at the study design stage, such as animal species selection, as well as at the sample collection stages, including macroscopic examination (necropsy), tissue sampling, processing, and microscopic examination. The chapter concludes with considerations on special study designs (eg, inhalation studies) and a discussion of the ultimate product of the pathologist’s support, the pathology report.
Chapter 2 (C. Scudamore) brings in an excellent review of how toxicologic pathology data are generated, organized, interpreted, and reported. The nuances of the qualitative, semiquantitative, and quantitative nature of pathology data are discussed and conveniently contrasted in a text table. Aspects of pathology data quality control and sources of variability are also presented. The understanding of all these concepts is a key to the toxicologist and required for navigating the many pathology reports generated by various authors and laboratories across the life span of a compound development program. The contents of this chapter are covered in sufficient detail that it would also be a suitable introductory reference to pathology trainees.
Chapter 3 (E. McInnes) offers an overview of general pathology. This chapter nicely complements chapter 2 and aims at providing the reader with a basic understanding of the mechanisms (and the terminology used to describe them) of how cells and tissues react to various types of injury and the possible outcomes of these exchanges. The concepts are illustrated with color macroscopic and microscopic images, as well as with concise diagrams. A few methods are listed that can be used to identify and differentiate biological phenomena that may be involved in pathological processes, such as lipid or fibrin accumulation and programmed cell death.
Chapter 4 (E. McInnes) covers the concept of background findings in laboratory animals, which are the many largely species-specific spontaneous findings, that can be present at birth (congenital), develop or progress with aging, or be related to aspects of the study other than the test article or device. The understanding of this paradigm and the familiarity of the particular findings in the species of interest are paramount in the appropriate recording and interpretation of the toxicologic pathology data and critically so in the setting of a test article-related exacerbation of background findings. Specific examples, with illustrations, are provided for the most common laboratory species, including the rat, mouse, dog, minipig, nonhuman primate, and rabbits.
Chapter 5 (E. McInnes) deals with target organ toxicity and pathology findings of various organs. The narrative focuses on the macroscopic level (ie, observed during necropsy), since these are the data that are often recorded by study personnel with or without the presence of a pathologist. Though noncomprehensive, this chapter is illustrated throughout and covers the major organ systems that are often the target of toxicity. Even though macroscopic findings noted during necropsy must be recorded descriptively, rather than interpretively, understanding the underlying processes that could result in such gross alterations enables the prosector to generate a more robust necropsy data set.
Chapter 6 (B. von Beust) provides an outstanding overview of clinical pathology in the context of nonclinical investigation and safety assessment, covering the routine aspects of hematology, clinical chemistry, urinalysis, coagulation, and customized biomarkers end points. This chapter is complete with considerations on data generation, quality control, good laboratory practice regulatory requirements, troubleshooting errors, and data interpretation and reporting. The section is very well illustrated and features helpful tables listing the recommended variables assessed in routine toxicology studies. In addition, this chapter offers tables with a few examples of common nonspecific patterns observed in toxicologic clinical pathology data sets.
Chapter 7 (B. Singh) presents the framework of adversity assessment in toxicologic pathology data sets, one of the most critical aspects of safety assessment. Beginning with the working definitions of adversity from the literature, followed by the strategies used to determine if a pathology finding is adverse or nonadverse, and including the bases of communicating adversity and overcoming the challenges in adversity assessment, the chapter is complete with a brief discussion of efforts to move from subjective expert opinion determinations to objective and mechanism-based charges. Familiarity with this framework is vital to the study personnel, especially the study director and toxicologists, in contextualizing the pathology narrative throughout the study reports.
Chapter 8 (N. Neef) wraps up the book with a must-have overview of the limitations of pathology and animal models in the context of compound research and development, including discussions on the limitations of animal disease models in testing compound efficacy, of acute and chronic animal studies in determining safety, and of the subjective nature of pathology data and the potential for pathologist error. The inclusion of a section addressing the limitations of pathology data, the potential pitfalls, and nuances of how pathology data are generated, interpreted, and communicated is complemented by a concluding section with a proposed framework for the study personnel and toxicologists for managing risks associated with subjectivity and pathologist errors.