Boorman's Pathology of the Rat

Reference and Atlas

Andrew W. Suttie, Gary A. Boorman, Joel R. Leininger, Scot L. Eustis, Michael R. Elwell, William F. MacKenzie, Alys Bradley

• Publisher: Academic Press
• Year: 2017
• ISBN:
  9780123914897
• Edition: 2
• Topic: Medicine
• Subtopic: Veterinary Medicine

Boorman's Pathology of the Rat: Reference and Atlas, Second Edition, continues its history as the most comprehensive pathology reference on rat strains for researchers across science and medicine using rat models in the laboratory. It offers readers an added emphasis on the Sprague-Dawley and Wistar rat strains that is consistent with current research across academia, government, and industry.

In addition, the book provides standard diagnostic criteria, basic content on histology, histological changes that result from drug toxicity and neoplasm, pathology terminology, and four-color photographs from the NTP archive and database. With updated references and photographs, as well as coverage of all rat strains, this book is not only the standard in the field, but also an invaluable resource for toxicologists, biologists, and other scientists engaged in regulatory toxicology who must make the transition from pathology results to the promulgation of meaningful regulations.

• Contains full, four color photographs from the NTP archive and database and coverage of all rat strains
• Provides an organ-by-organ and system-by-system approach that presents standard diagnostic criteria and basic content on histology and histological changes
• Includes comprehensive and detailed background incidence data
• Presents detailed descriptive content regarding changes in rat models during research

Chapter 1

Introduction

Andrew W. Suttie,    Covance Inc., Chantilly, VA, United States

Boorman’s Pathology of the Rat, edited by Andrew Suttie with associate editors Joel Leininger and Alys Bradley, is the second edition of the classic pathology reference, Pathology of the Fischer Rat, Reference and Atlas. The first edition was edited by Gary Boorman, Scott Eustis, Michael Elwell, Charles Montgomery, and William MacKenzie.

The title of the second edition is dedicated to Dr. Gary Boorman who was one of the editors of the first edition and a coauthor on many chapters. This title honors the service, leadership, scholarship, mentoring, and teaching that Gary has shown in his long and distinguished career in toxicologic pathology, especially rodent pathology. Over the years, many pathologists referred to the first edition as Boorman’s Rat Book and hence inclusion of Gary’s name in the title of the second edition identifies the second edition as successor to the Pathology of the Fischer Rat.

Although the title of first edition referred specifically to the Fischer Rat, it has been an invaluable resource to pathologists and scientists working with all rat strains. A major difference between rat strains is in the incidence of the various lesions, rather than their histopathological appearance, hence the relevance of the book to all rat strains. The second edition contains material predominantly from the Sprague Dawley, Wistar, and Fischer rat strains, therefore the book title is not specific to one strain.

Numerous excellent books on toxicologic pathology are available, with many more planned. Some books concentrate on induced lesions while others contain spontaneous background lesions and neoplasms. In most cases, these books include lesions from all species used in toxicity studies. Boorman’s Pathology of the Rat deals entirely with the rat, currently the predominant species utilized in toxicity studies. The book is divided into organ specific chapters and presents a summary of embryological development, normal microscopic anatomy, and physiology, in addition to variations on normal anatomy, common aging and background lesions, hyperplastic lesions, neoplasia, and toxicologic changes. The book is an invaluable addition to the libraries of toxicologic pathologists early in their careers as they become familiar with the normal anatomic variation and background in short-term toxicity studies, and also aging changes, hyperplasia, and neoplasia in carcinogenicity studies. Experienced pathologists will also find the book useful particularly in identifying lesions they have not encountered previously, and also in refreshing themselves with the basics of rat pathology.

Chapters are predominantly in the same format as the first edition. Some chapters have been extensively rewritten, while others have used the narrative format from the first edition with minimal revision. The inclusion of color photomicrographs required new examples of lesions, except when the original slide used in the first edition was available.

The first edition contained control tumor incidence tables for F344 rats from NTP carcinogenicity studies. Incidence tables are not included in the second edition since data is more readily available from the NTP website, websites of rat suppliers, and from contract research organizations’ historical control databases, and also from publications. Furthermore, background data searches can be refined by rat strain suppler identity, dose route, and study duration and this information is updated frequently.

Chapter 2

Introduction to First Edition

Gary A. Boorman¹, Michael R. Elwell¹, Scot L. Eustis² and Joel R. Leininger³, ¹Covance Laboratories, Inc., Chantilly, USA, ²Las Vegas, NM, USA, ³JRL Consulting, LLC, Chapel Hill, NC, USA

Abstract

This chapter, the introduction to the first edition of this book entitled Pathology of the Fischer Rat, Reference and Atlas, describes the role of the toxicologic pathologist in the evaluation of safety assessment studies. The approach to evaluation of short-term and carcinogenicity studies is discussed along with the approprate use of diagnostic terminology. Comparisons between the role of the diagnostic pathologist and the toxicologic pathologist are discussed.

Keywords

Pathology evaluation; Short term studies; Carcinogenicity studies

The pathology evaluation of toxicity studies involves not only the recognition of obvious treatment-related lesions, but also the identification of spontaneous lesions that may be increased in severity and/or frequency in treated animals. It is not uncommon to find lesions that are a direct effect of the test substance (such as renal tubular cell necrosis), as well as secondary changes resulting from toxicity. The latter may be a reflection of primary toxicity in another tissue (hemosiderin in the spleen secondary to erythrocyte destruction) or a physiologic response (myeloid hyperplasia associated with skin ulcerations in the skin paint study). In some instances, toxicity is manifested not as a unique lesion, but as an increase in the severity and/or incidence of a lesion or physiologic effect that is a common spontaneous alteration (nephropathy or splenic hematopoiesis).

Short-term studies are often conducted to establish doses for chronic toxicity and carcinogenicity studies. When it is necessary to identify a “no observable effect” level, the differences between control and treatment groups can be extremely subtle. For this reason, it is often helpful to examine tissues from high-dose groups followed by controls. When minimal effects are suspected, alternate comparison of the target organ from treatment and control rats is useful, but it may be more important to reexamine the target organs without knowledge of the dose groups (“blinded evaluation”). Reexamination of selected tissues after a period away from the study is also helpful in confirming the presence or absence of subtle effects in target organs.

The histopathology evaluations of toxicity/carcinogenicity studies require an approach that may seem at variance with the training and background of most pathologists. The main objective is not simply determination of morphological changes in a single animal, but rather comparison of incidences and/or severity of lesions in populations of animals that vary only in their exposure to a test compound. A traditional case-by-case diagnostic approach may cause difficulties in interpretation of the data unless careful attention is given to consistency in the application of diagnostic criteria and the use of terminology.

Traditionally, pathologists are taught that a diagnosis includes a topography (organ/site), a morphologic diagnosis, a duration qualifier (if appropriate), a distribution qualifier (focal or diffuse), and a severity grade (for nonneoplastic lesions). Although descriptive diagnoses are necessary for accurate recording of the pathological findings, the use of synonymous terms or the excessive use of qualifiers can hinder the interpretation of the data. For example, if a pathologist uses the terms acute inflammation, purulent inflammation, and suppurative inflammation (of a particular organ in an individual study), other scientists evaluating may be left wondering if the pathologist deliberately distinguished between these lesions (i.e., the lesions are different) or simply used different terms to describe the same type of lesion. If several similar diagnostic terms are used, it is imperative that a good rationale is clearly presented in the pathology narrative.

Similar problems result from inconsistent or excessive use of qualifiers as necessary to distinguish a lesion from others having differing pathogenesis and/or biological significance. For example, it is unnecessary to record spontaneous lesions such as cardiomyopathy or nephropathy in rats as focal, multifocal or diffuse is simply a reflection of the severity of organ involvement. Thus, the extent of organ involvement can be considered when assigning a severity grade to the lesion. A distribution qualifier should be used only to describe or identify an inherent feature of the lesion that distinguishes its pathogenesis. For example, necrosis that has a centrilobular distribution in the liver has a pathogenesis different from necrosis that is focal and occurs randomly throughout the liver; therefore, centrilobular is an appropriate and necessary qualifier. In this context, focal and multifocal are often used synonymously; for nearly all spontaneous and induced lesions seen in rats, the multifocal occurrence (of a focal lesion) is only a reflection of the extent of organ involvement. Accurate and interpretable presentation of the pathology data is facilitated by developing a dictionary of terms for each study and maintaining both consistency and simplicity of terminology for topography and morphology.

Terminology used by pathologists for the classification of neoplasms also plays a crucial role in the interpretation and statistical analysis of data from carcinogenicity studies. Evaluations of the potential carcinogenic effects of chemicals are based primarily on site-specific comparisons of tumors of the same or similar morphology or histogenesis rather than overall comparisons. Thus, it is extremely important that synonymous terms for topography or morphology are not introduced into the data by the pathologist. Excessive subclassification of neoplasms may also confuse the interpretation of the data and lead to erroneous conclusions and impaired hazard evaluation. The subclassification of neoplasms in human medicine has particular applicability because of prognostic significance for the patient, but this is not a consideration in toxicologic pathology. The goal of the toxicologic pathologist is to record pathology data in a format that lends itself to accurate biological and statistical interpretation.

There is considerable morphological and biochemical evidence that neoplasms in humans and animals progress through a series of stages and ultimately become completely autonomous, invade surrounding tissue, and metastasize widely. From a mechanistic point of view, this progression seems to be a multistep process in which the population of cells changes and diversifies with eventual dominance of subpopulations with properties of enhanced growth, survival, autonomy, and malignant potential. From a morphological point of view, carcinogenesis proceeds through transitory or progressive stages of growth including hyperplasia and/or dysplasia, benign neoplasia, and finally, overt malignant neoplasia. This progression, often, but not always, appears as a morphological continuum, and the terms used to represent each of the main stages of the carcinogenic process imply a certain biological behavior. The degree of certainty or confidence in the assumed biological behavior increases as the lesions proceed from hyperplasia, or other preneoplastic changes such as dysplasia, to overt malignant neoplasia.

The degree to which pathologists tacitly accept this concept of a biological and morphological continuum is evident in several different ways. The simple fact that pathologists use histologic criteria such as degree of cellular differentiation, cellular pleomorphism, cellular atypia, and other cellular characteristics in the absence of invasion or metastasis to make a diagnosis is a reflection of this continuum. The fact that grading systems and even staging systems are in common usage in medical pathology is also a reflection of the biological continuum.

Long-term toxicity and carcinogenicity studies are unique in terms of expense, time, and lack of repetition. In contrast to most other scientific endeavors, in which important experiments are usually repeated, societal regulatory decisions may be based on one or a few toxicity/carcinogenicity studies. Thus, it is important that pathology data be based on sound judgment and that they be subjected to peer review prior to presentation to the scientific, regulatory, and lay community. A panel of pathologists experienced with rodent tissues, and from varying backgrounds, can provide a broad view of the potential biological behavior of lesions induced by a chemical whose toxic and carcinogenic potentials are poorly understood.

Bibliography

1. Baker HJ, Lindsey JR, Weisboth SH, eds. The Laboratory Rat. vol. 1. New York, NY: Academic Press; 1979.

2. Baker HJ, Lindsey JR, Weisboth SH, eds. The Laboratory Rat. vol. 2. New York, NY: Academic Press; 1980.

3. Coleman GL, Barthold SW, Osbaldiston GW, Foster SJ, Jonas AM. Pathological changes during aging in barrier-reared Fischer 344 male rats. J Gerontol. 1977;32:258–278.

4. Cotchin E, Roe FJC, eds. Pathology of Laboratory Rats and Mice. Oxford: Blackwell; 1967.

5. Goodman DG, Ward JM, Squire RA, Chu...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• List of Contributors
• Preface
• Acknowledgements to Contributors of the First Edition
• Chapter 1. Introduction
• Chapter 2. Introduction to First Edition
• Chapter 3. The History of the Rat
• Section I: Digestive System
• Section II: Liver and Exocrine Pancreas
• Section III: Urinary Tract
• Section IV: Nervous System and Special Sense Organs
• Section V: Musculoskeletal System
• Section VI: Integumentary System
• Section VII: Mammary Gland
• Section VIII: Respiratory Tract
• Section IX: Immune System
• Section X: Bone Marrow
• Section XI: Female Reproductive Tract
• Section XII: Male Reproductive System
• Section XIII: Circulatory System
• Section XIV: Endocrine System
• Index