Pathology for Toxicologists

Principles and Practices of Laboratory Animal Pathology for Study Personnel

Elizabeth McInnes

• Publisher: Wiley-Blackwell
• Year: 2017
• Print ISBN:
  9781118755402
  9781118755419
• Edition: 1
• eBook ISBN:
  9781118755310
• Topic: Physical Sciences
• Subtopic: Chemistry
• Index: Chemistry

Non-pathologists, such as toxicologists and study personnel, can find it difficult to understand the data they receive from pathologists. Toxicological pathologists write long, detailed and highly technical reports. Study personnel are under daily pressure to decide whether lesions described in pathology reports are treatment-related and thus important  to the pharmaceutical company or whether the lesions are background changes and thus of little significance.

Written by experienced toxicological pathologists, Pathology for Toxicologists: Principles and Practices of Laboratory Animal Pathology for Study Personnel serves to bridge the gap in the understanding of pathology data, enabling non-pathologists to more easily comprehend pathology reports, better integrate pathology data into final study reports and ask pathologists relevant questions about the test compound.

This succinct, fully referenced, full colour book is suitable for toxicologists at all stages of their training or career who want to know more about the pathology encountered in laboratory animals used in safety studies.  Key features include important chapters on  spontaneous and target organ lesions in rats, mice, non-human primates, mini pigs, rabbits and beagle dogs as well as information on general pathology, macroscopic target organ lesions, ancillary pathology techniques, haematology, biochemistry and adversity.

Pathology for Toxicologists: Principles and Practices of Laboratory Animal Pathology for Study Personnel includes:

• Colour diagrams explaining how lesions are caused by either external compounds or spontaneously
• The anatomic variations and background lesions of laboratory animals
• Advice on sampling tissues, necropsy, ancillary pathology techniques and recording data
• A chapter on the haematology and biochemistry of laboratory animals
• Full colour photographs of common macroscopic lesions encountered in laboratory animals
• A comprehensive glossary

Chapter 1
An Introduction to Pathology Techniques

Elizabeth McInnes

Cerberus Sciences, Thebarton, SA, Australia

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Learning Objectives

• Understand the role of study personnel in necropsies.
• Understand the various steps involved in producing glass slides from harvested tissues.
• Understand the ancillary techniques used in toxicological pathology.
• Discover what carcinogenicity, inhalation and crossreactivity studies entail.

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This book is aimed at all study personnel – including study monitors, study directors and toxicologists – who are exposed to pathology reports, necropsies, peer review, haematology and biochemistry results and adversity on a regular basis. The secret to an informative, relevant and useful pathology report is an open and collegial relationship between the study director and the study pathologist (Keane, 2014). This chapter aims to describe the various stages of the pathological process (e.g. necropsy, fixation of tissues, cutting of slides) in order to demonstrate where crucial errors which can cause problems at a later stage, may arise. In addition, it includes a brief overview of ancillary techniques that pathologists sometimes use (e.g. electron microscopy). Finally, it discusses carcinogenicity studies, digital pathology, biological drugs and crossreactivity studies, and their impact on study personnel. Throughout the chapter, the client is referred to as the ‘sponsor’ of a particular pharmaceutical study.

Pathology is the study of disease, particularly the structural and functional changes in tissues and organs. Toxicological pathology is concerned predominantly with cell and tissue injury in animals treated with introduced chemical compounds or biological drugs. Studies are regulated by international bodies such as the Organisation for Economic Co-operation and Development (OECD), the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Animal testing to determine the safety of pharmaceuticals, medical devices and food/colour additives is required by the FDA before it will give approval to begin clinical trials in humans. Pathology data may be quantitative (haematology, chemistry data, organ weights) or qualitative (microscopic diagnoses), and the toxicological pathology report is divided into macroscopic and microscopic findings. Study personnel are ultimately responsible for the study report, including the pathology report and data. Thus, study personnel need to understand what the pathology report means and how it has been generated. This chapter aims to help the study director understand the processes involved in a study, from harvesting tissues from the animal to generating glass slides to producing a pathology report.

1.1 Animal Considerations

The main species of animal used in the pharmaceutical industry are rats, mice, dogs, non-human primates, minipigs and rabbits. Occasionally, farm animals, hamsters, cats and gerbils are also used. There are no absolute reasons for selecting a particular animal species for systemic toxicity, but for acute oral, intravenous, dermal and inhalation studies and studies of medical devices, the mouse or rat is preferred, with the option of the rabbit in the case of dermal and implantation studies. Non-rodent species may also need to be considered for testing, although a number of factors might dictate the number and choice of species. Carcinogenicity studies generally use rats and mice.

All animal studies must be conducted according to the animal welfare laws of the country in which they are based, and in general studies may use protected animals only if there are no other reasonable, practicable choices for achieving a satisfactory result. Laboratory animals may only be used in minimal numbers, where they have the lowest possible degree of neurophysiological sensitivity and where the study causes minimal pain, suffering, distress and lasting harm. Animal suffering must be balanced against the likely benefits for humanity, other animals and the environment. In general, in the planning of all preclinical studies, due consideration must be given to reduction, refinement and replacement (the ‘3 Rs’) (Tannenbaum and Bennett, 2015).

Generally, only healthy purpose-bred young adult animals of known origin and with defined microbiological health status should be used in pathology studies (i.e. health monitoring of sentinel animals must be performed before the study starts). Health monitoring involves testing for the various bacteria, viruses, parasites and protozoa that may infect experimental animals and compromise study results (McInnes et al., 2011). The weight variation within a sex should not exceed 20% of the mean weight, and when female animals are used, they should be non-pregnant and should never have borne young.

Laboratory animals should be given a short acclimatisation period at the start of the study. Control of environmental conditions and diet and proper animal care techniques are necessary throughout the study in order to produce meaningful results. The number of animals needed per dose group depends on the purpose of the study. Group sizes should increase with the duration of treatment, such that at the end of the study sufficient animals are available in every group for a thorough biological evaluation and statistical analysis.

1.2 Necropsy

Necropsies or post mortem examinations (Figure 1.1) on experimental animals are a fundamental part of toxicological pathology (Fiette and Slaoui, 2011). They generally take place at the end of a study, but are also conducted if an animal dies early. The necropsy and pathology data are the single most important aspect of the pathology process, and study personnel get only one chance to retrieve them: once the tissues have been discarded, potentially valuable information is lost forever. At the necropsy, all macroscopic findings and abnormalities visible to the naked eye (e.g. enlarged liver, ulcerated skin, the presence of diarrhoea) are noted and recorded. In addition, tissues are collected for examination under the microscope. The pathologist, necropsy supervisor, prosector, phlebotomist and weighing assistant are all responsible for the recording the macroscopic data (Keane, 2014). Some studies collect all tissues (a full tissue list is indicated in the study plan or protocol), while others harvest only a limited list. A copy of the study plan should be available in the necropsy room to ensure that study personnel collect the correct tissues. Sometimes, all the tissues are collected into formalin, but slides are only cut if the sponsor decides there is a need later on. Harderian glands and draining lymph nodes are examples of tissues that are not always collected: study personnel should check the study plan before beginning the necropsy.

Figure 1.1 Necropsies or post mortem examinations on experimental animals such as this mouse are a fundamental part of toxicological pathology.

Study directors and toxicologists are often required to attend the necropsies of the animals on their studies. Although not directly involved in the necropsy process, it is nevertheless important that study personnel understand the process and are ab...

Table of contents

• Cover
• Title Page
• copyright
• Table of Contents
• List of Contributors
• Preface
• Chapter 1: An Introduction to Pathology Techniques
• Chapter 2: Recording Pathology Data
• Chapter 3: General Pathology and the Terminology of Basic Pathology
• Chapter 4: Common Spontaneous and Background Lesions in Laboratory Animals
• Chapter 5: Target Organ Pathology
• Chapter 6: Clinical Pathology
• Chapter 7: Adversity: A Pathologist's Perspective
• Chapter 8: Limitations of Pathology and Animal Models
• Glossary
• Index
• End User License Agreement