Atlas of Experimental Toxicological Pathology

175 Pages·1987·34.96 MB·English

by  C. Gopinath

Atlas of Experimental
Toxicological Pathology
To Cora P. Cherry
for sharing with us her wealth of
experience in the field of
toxicological pathology
Current Histopathology
Consultant Editor
Professor G. Austin Gresham, TO, SeD, MO, FRC Path.
Professor of Morbid Anatomy and Histology, University of Cambridge
Volume Thirteen
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EXPERIMENTAL
TOXICOLOGICAL
PATHOLOGY
BY
C. GOPINATH
Director of Pathology
Huntingdon Research Centre
Huntingdon, UK
D. E. PRENTICE
Head of Pathology Group
Deputy Head of Toxicology Department
Pharmaceutical Division
Sandoz Ltd
Basle, Switzerland
D. J. LEWIS
Deputy Head of Pathology
Huntingdon Research Centre
Huntingdon, UK
l\tI.TP PRESS LI.M.ITED .....
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~ a member of the KLUWER ACADEMIC PUBLISHERS GROUP
". LANCASTER / BOSTON / THE HAGUE / DORDRECHT .'IIIIIIII
Published in the UK and Europe by
MTP Press Limited
Falcon House
Queen Square
Lancaster. England
Copyright © 1987 C. Gopinath. D. E. Prentice
and D. J. Lewis
All rights reserved. No part of this publication may be
reproduced. stored in a retrieval system. or
transmitted in any form or by any means. electronic.
mechanical. photocopying. recording or otherwise.
without prior permission from the publishers.
British Library Cataloguing in Publication Data
Gopinath. C.
Atlas of experimental toxicological pathology. -
(Current histopathology; v.13)
1. Toxicology - Technique
I. Title II. Prentice. D. E. III. Lewis. D. J.
IV. Series
615.9'0028 RA 1211
ISBN-13: 978-94-010-7930-3 e-ISBN-13: 978-94-009-3189-3
001: 10.1007/978-94-009-3189-3
Published in the USA by
MTP Press
A division of Kluwer Academic Publishers
101 Philip Drive
Norwell. MA 02061. USA
Library of Congress Cataloging in Publication Data
Gopinath. C. . MRC Path.
Atlas of experimental toxicological pathology.
(Current histopathology; v. 13)
Includes bibliographies and index.
1. Toxicology. Experimental-Atlases. 2. Histology.
Pathological-Atlases. 3. Laboratory animals-
Histology-Atlases. 4. Diseases-Animal
models-Atlases.
I. Prentice. D. E. II. Lewis. D. J. III. Title.
IV. Series. [DNLM: 1. Pathology-atlases.
2. Toxicology-atlases.
WI CU788JBA v.13 /QZ 17 G659al
RA1199.G67 1987 615.9'07 87-21448
Phototypesetting by Titus Wilson. Kendal.
Colour origination by Laserscan. Stretford. Manchester.
Contents
Consultant Editor's Note 7
Acknowledgements 8
Introduction 9
1 The cardiovascular system 11
2 The respiratory system 22
3 The liver 43
4 The alimentary system and pancreas 61
5 The urinary system 77
6 The reproductive system 91
7 The endocrine glands 104
8 The lymphoid system 122
9 The nervous system 137
10 The eye and ear 145
11 The musculoskeletal system and skin 156
Index 167
Cu rrent Histopathology Series
Already published in this series:
Volume 1 Atlas of Lymph Node Pathology
Volume 2 Atlas of Renal Pathology
Volume 3 Atlas of Pulmonary Pathology
Volume 4 Atlas of Liver Pathology
Volume 5 Atlas of Gynaecological Pathology
Volume 6 Atlas of Gastrointestinal Pathology
Volume 7 Atlas of Breast Pathology
Volume 8 Atlas of Oral Pathology
Volume 9 Atlas of Skeletal Muscle Pathology
Volume 10 Atlas of Male Reproductive Pathology
Volume 11 Atlas of Skin Pathology
Volume 12 Atlas of Cardiovascular Pathology
Other volumes currently scheduled in this series
include the following titles:
Atlas of Articular Pathology
Atlas of Bone Pathology
Atlas of Connective Tissue Pathology
Atlas of ENT Pathology
Atlas of General Cytology
Atlas of Neuropathology
Atlas of Ophthalmic Pathology
Atlas of Serous Fluid Cytology
Consultant Editor's Note
Toxicological pathology is a subject which attracts the species of animals. An extensive bibliography has con
interests of a wide variety of workers. Human and veter tributed greatly to the usefulness of this book.
inary pathologists often need access to the information Texts on toxicological pathology are not numerous.
provided by this book. It will be of especial value to This is a welcome addition to the series and follows the
those working in the fields of drug testing, experimental tradition of being a bench manual for workers in the
pathology and clinical pharmacology. field.
This is a comprehensive volume dealing with changes G. Austin Gresham
that are induced by a wide variety of agents in many
Acknowledgements
We are greatly indebted to many people who have We also wish to thank our wives for their tolerance
assisted us over several years in the preparation of during the long preparation of the book and we particu
this atlas. Our helpers are too numerous to mention larly wish to thank Mrs Ann Lewis for typing the various
individually, but we are particularly grateful to Hunting forms of the manuscript.
don Research Centre and Sandoz pathologists for ideas
and histological slides, and to the technical staff of both
companies for excellent assistance.
Introduction
Our aim in producing a colour atlas of toxicological guidelines itemize the investigations to be carried out
pathology was to present a catalogue of histopathologi during the course of the study and they normally include:
cal lesions which we had encountered over the years in clinical observations and behaviour; food intake and body
various laboratory animal species exposed to a vast weight measurements; serum biochemistry; haema
range of pharmaceuticals, agrochemicals and industrial tology; ECG and ophthalmology. At the end of a study,
chemicals. While we believe a colour atlas is the ideal full macroscopic and microscopic examinations of the
way to share our experiences with others, it quickly organ weight analyses together with tissues are essen
became clear to us that for the atlas to be meaningful tial. By far the greater part of the material used in this
the associated text must be comprehensive and contain book is from toxicity studies conducted in recent years
ample literature references. and performed in compliance with the Good Laboratory
The atlas is intended for both the trainee and the Practice standards of governmental regulatory bodies in
experienced toxicological pathologist working with lab Europe, Japan and North America.
oratory animals in the pharmaceutical, agrochemical or Toxicity studies are commonly carried out in rats,
chemical environment. In addition, it is aimed at exper mice, dogs or monkeys, but the range of species used
imental pathologists, toxicologists and pharmacologists is extensive and may include larger animals such as
who may wish to obtain further insights into toxicological sheep and pigs or non-mammalian species like the dom
pathology. It may also be of value to veterinary pathol estic hen. The selection of species, dose levels, route
ogists in academic institutes who may encounter toxic of administration (oral, parenteral, inhalation) and dur
lesions from time to time in domestic animals or who ation of study are all determined by the proposed use of
may be required to deal occasionally with laboratory the compound and the perceived potential risk. Conven
animals. tionally, studies have an untreated control group and
The history of modern toxicology and therefore of three groups of animals exposed to low, intermediate
toxicological pathology is relatively short and, as a conse and high levels of the test compound. The rationale
quence, the number of books and texts dealing solely for using three dose levels in toxicity studies is well
with the subject are few. Those books which are avail established. The highest dose utilized should show
able to the practitioner tend to concentrate on spon some evidence of toxicity, ideally identifying target or
taneous and induced neoplasia in laboratory rodents. gans and thereby indicating the area of risk for man. The
ThLs atlas deals exclusively with induced, non-neoplas lowest dose, on the other hand, should be free of toxicity
tic, morphological lesions in the tissues and organs of as this is often close to the level of expected exposure
laboratory animals. Although most of the photomicro for man. The intermediate dose may either be free of
graphs used in this book were taken from routine haem a toxicity or show toxic changes similar to the highest
toxylin and eosin stained paraffin sections, a small dose, but minor in degree. The majority of the photo
number of special stains, enzyme histochemical prep micrographs in this atlas are examples of high dose
arations, resin sections and electron micrographs are effects on target organs. The establishment of a clear
also included. 'no toxic effect level' (NTEL) in a toxicity study is of
We wish to emphasize that the lesions presented in paramount importance; it allows the calculation of a
this atlas were encountered during the histopathological safety factor for use of the compound in the human
evaluation of routine toxicity studies. These studies were situation. For a pharmaceutical preparation, for example,
undertaken to assess whether a substance could pre the NTEL from the toxicity study, expressed as mg of
sent a health hazard to man and his environment. In compound per kg body weight per day, should ideally
essence, toxicity tests are considered as safety assess be at least several times the proposed therapeutic dose
ment studies. The types of compound involved in testing in man.
and the immediate aims of the assessment vary con The full nature of toxic change is beyond the scope of
siderably. Studies witA novel pharmaceutical prep this book. We do not attempt to give details of basic
arations, for example, are designed to predict possible pathological responses to injury, but when the pathogen
side effects in human patients, while studies with indus esis of a particular lesion is known it is mentioned and
trial chemicals are performed to determine whether referenced in the text. Here we are dealing primarily
worker contamination constitutes a health hazard. with morphological changes which follow administration
Although the requirements for and the conduct of toxicity of test substances. Toxicity manifesting as morphologi
studies are today controlled by governmental regulatory cal changes is produced by numerous pharmaceuticals
bodies and health authorities, the aims were, and are, and industrial chemicals. In fact, in our experience, there
to ensure human safety from potentially noxious chemi are few completely inert industrial chemicals or indeed
cals. Guidelines on the conduct and design of toxicity pharmaceuticals. Most compounds will induce a toxic
studies are issued by governmental authorities. These reaction under experimental conditions in which a sus-
9
10 INTRODUCTION
ceptible species is exposed at a sufficiently high dose This book has been compiled with material from nu
level via a specific route of administration. There are, merous sources and because of the confidential nature
however, some toxic manifestations which have no his of the work we are unable to divulge the chemical names
topathological counterpart. The interpretation of a mor of many compounds. For many of the lesions illustrated
phological response may be difficult for the toxicologist the individual chemical or pharmaceutical agent respon
as there is often only a fine distinction between a toxic sible is, therefore, not named but whenever possible we
response, an exaggerated pharmacological response have given the general class of the compound, e.g. novel
and a physiological response. In a few well publicized corticosteroid, contraceptive steroid, neuroleptic. In a
examples evidence of induced toxicity in man has been few other instances we have only been able to use
established in the absence of similar findings in labora extremely vague terms such as agrochemical or indus
tory animal species. However, it should perhaps be trial chemical. As our aim was to include the widest
stressed that toxicity studies are on the whole predictive possible spectrum of induced lesions, it is hoped that
for man and that the majority of induced morphological this constraint does not detract from the value of the
changes encountered in these studies do have counter
atlas.
parts in man.