Abstract
Toxicologic Pathology: Nonclinical Safety Assessment is the first edition of an exceptionally high-quality book. Overall, the book abounds with useful figures, tables, mini-glossaries, and extremely high-quality photomicrographs from the light and transmission electron microscope perspective. As I read through many of the chapters, I would happen upon the name of a feature or lesion and wonder “I wonder what THAT looks like,” only to find a figure or picture of the feature or lesion presented. This is truly a comprehensive production. The book is organized into 2 sections: Section 1 is entitled “Concepts in Drug Development” and consists of 8 chapters, while Section 2 covers 21 organ systems. Each chapter begins with a detailed list of the contents of the chapter and ends with an expansive reference list.
In section 1, Chapter 1 provides a detailed overview of drug development (J. A. Popp and J. A. Engelhardt) with topics including the scientific and regulatory histories of drug development, a sequence of small-molecule drug development, approaches to development of biotherapeutics, time and resource utilization in drug development, and future changes in drug development, with some comments on potential expansion of personalized medicine.
Chapter 2 discusses nonclinical safety evaluation of drugs (T. M. Monticello and J. L. Bussiere), beginning with introductory comments, followed by information on lead optimization safety assessment, followed by descriptions of nonclinical animal toxicology studies for small molecules and biopharmaceuticals as well as a comparison of biopharmaceuticals to traditional small-molecule drugs. Various toxicity testing paradigms (immunotoxicology, developmental and reproductive toxicology, genetic, with reference to relevant guidelines) are then presented, followed by a discussion of safety assessment of oncology products and challenges with nonclinical safety assessment in the nonhuman primate. The chapter ends with comments on reporting of pathology data.
Chapter 3 “Toxicokinetics and Drug Disposition” (D. D. Christ) is enhanced with a number of very useful equations, tables, diagrams, and graphs. In particular, Table 3.3, showing important differences in gastrointestinal physiology that affect toxicokinetics, is particularly valuable. The chapter also covers gender and species differences in drug metabolism and cytochrome P450 metabolism and induction.
Chapter 4 “Introduction to Toxicologic Pathology” (J. E. Markovits, P. R. Bouchard, C. J. Clarke, and D. N. McMartin) is the only chapter in the book without any figures or tables. The discussion of the various topics is, however, very clearly presented, with coverage of topics including “integration of exposure, drug metabolism, and histopathology findings,” “reporting and risk assessment,” and “novel models.”
Chapter 5 “Routine and Special Techniques in Toxicologic Pathology” (D. J. Patrick and P. C. Mann) provides a very useful discussion of routine and special techniques. Contemporary techniques such as laser microdissection, fluorescence-activated cell sorting, and laser scanning cytometry are among the techniques discussed in the special techniques section. I appreciated that the reference section for this chapter was broken out into separate reference lists for routine and special techniques.
Chapter 6 “Principles of Clinical Pathology” (R. L. Hall) covers the topics that would be expected in a chapter so-titled, starting with study design factors and data interpretation, followed by “interpretation of hematology data,” “clinical chemistry tests and interpretation,” and “urinalysis and urine chemistry tests and interpretation.” This chapter is filled with very practical advice on many aspects of clinical pathology.
M. J. Hoenerhoff and D. E. Malarkey tackle “Toxicogenomics in Toxicologic Pathology” in Chapter 7, beginning with an overview of the “-omics,” followed by a discussion of basic array technologies, the “toxicologic pathologist’s role in toxicogenomics,” “pathway and network analysis,” and ending with various examples and applications.
In Chapter 8, R. C. Johnson, R. H. Spaet, and D. L. Potenta present extensive (nearly 50 pages!) of tabulated spontaneous lesion data in the Wistar rat, CD-1 mice, Beagle dogs, and cynomolgus monkeys for studies of varying duration. For those working with these species, this chapter will serve as a valuable repository of spontaneous lesion data.
Section 2 of Toxicologic Pathology: Nonclinical Safety Assessment begins with the “Gastrointestinal Tract” (Chapter 9; J. E. Markovits, G. R. Betton, D. N. McMartin, and O. C. Turner). This chapter is particularly well embellished with beautiful diagrams and photomicrographs (including routine and immunohistochemically stained sections). In Chapter 10, R. C. Cattley, J. A. Popp, and S. L. Vonderfecht provide an exhaustive overview of “Liver, Gallbladder, and Exocrine Pancreas,” which includes several high-quality photomicrograph panels. Chapter 11 (“Respiratory System” by D. J. Lewis and T. P. McKevitt) begins with the embryology and functional anatomy of the respiratory system and then goes on to cover nonneoplastic and neoplastic lesions of the nasal cavity, followed by lesions of the larynx, trachea, and bronchi, the bronchioles, including Clara cell changes are covered next, followed by the lung parenchyma, including a discussion of macrophage responses.
Chapter 12 (K. S. Frazier and J. C. Seely) covers the urinary system and focuses primarily on the kidney, with a few pages dedicated to the urinary bladder, ureters, and urethra. Although perhaps well known to the individuals who might have this book as a reference book, I found myself wanting to see pictures of lesions such as hyaline droplets, renal phospholipidosis, and some of the other common lesions that are often mentioned in drug safety evaluation studies.
Chapter 13 covers the “Hematopoietic System” (K. Henson, G. Elliott, and G. S. Travlos). This chapter contains beautiful photomicrographs as well as a colorful version of a figure depicting the general model of hematopoiesis. Chapter 14 covers the “Lymphoid System” (P. J. Haley) and is similarly very nicely illustrated. After taking the reader through the thymus, spleen, and lymph nodes, we are treated to a discussion of the “hobgoblin” of toxicologic pathology, immunotoxicants versus stress. The chapter concludes with discussions of various malignancies.
We move to “Bone, Muscle, and Tooth” in Chapter 15 (authored by J. L. Vahle, J. R. Leininger, P. H. Long, D. G. Hall, and H. Ernst). The chapter contains an excellent section on evaluation methods, as readers such as myself might not be aware of techniques such as fluorochrome labeling and histomorphometry. Useful photomicrograph panels are included for each subsection.
Chapter 16 is devoted to the “Cardiovascular System” (C. Louden and D. Brott). The chapter contains numerous useful tables (I found table 16.1 “Histological Special Stains…” and table 16.9 “Potential Biomarkers of the Vascular System” to be particularly useful). The chapter also includes some excellent photomicrographs and a convenient color figure of potential mode of action for drug-induced vascular injury.
Chapter 17 “Endocrine Glands” (S. Chandra, M. J. Hoenerhoff, and R. Peterson) contains subsections on the pituitary, thyroid, parathyroid, and adrenal glands as well as pancreatic islets. The chapter is extensively illustrated with nice photomicrograph panels and includes useful tables, including a compilation of reference range values for serum glucose and insulin levels from the literature for multiple species, including multiple rat strains, various dog breeds, ferret, minipig, and nonhuman primate.
Chapter 18 takes the prize for the longest (>80 pages) and most ambitious in the book. In “Reproductive System and Mammary Gland,” J. D. Vidal, M. L. Mirsky, K. Colman, K. M. Whitney, and D. M. Creasy team together to tackle male and female embryology and maturation and cover multiple species. Histological and nonmorphological end points are discussed. It is perhaps notable that only 10 pages of this chapter are devoted to the mammary gland. The chapter is extensively illustrated with high-quality photomicrographs.
Chapter 19 “Skin” (Z. W. Wojcinski, L. Andrews-Jones, D. I. Aibo, and R. Dunstan) presents extensive comparisons of skin morphology, thickness, and structural features across multiple species as well as a table containing minipig strain comparisons. I found section 19.2 on Dermatologic Drug Development to be quite useful. The chapter has a superb mix of tables and photomicrographs.
Chapter 20 “Nervous System” (M. T. Butt, R. Sills, and A. Bradley) begins with a discussion of “special considerations.” The “diagnostic neuropathology” subsections (covering nonproliferative and proliferative lesions) are beautifully illustrated with many useful photomicrographs, including a number of immunohistochemical stains.
We close Toxicologic Pathology: Nonclinical Safety Assessment with “Special Senses: Eye and Ear” (J. A. Render, K. A. Schafer, and R. A. Altschuler). This chapter presents a straightforward, region-by-region discussion of the substructures/regions of the eye and ear. The photomicrographs and figures, including a cytocochleogram, add greatly to the text descriptions of the structures of and lesions in these 2 tissues.
In summary, this book will serve as an outstanding contemporary resource for practicing and research toxicologists, whether in an industry or academic setting. It is expansive in its coverage and a pleasure to read. I appreciated that each chapter was compiled by true experts in the respective area, in that there are unique authors for nearly every chapter in this book.
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