Table Of ContentPharmaceutical Science SAHOTA • POPP
HARDISTY
TOX ICOLOGIC
GOPINATH
TOXICOLOGIC PATHOLOGY
PAT HOLO GY
NONCLINICAL SAFETY ASSESSMENT
T
O
As drug development shifts over time to meet unmet medical needs and more N
targeted therapies are developed, previously unseen, exaggerated pharmacologi-
OX
cal or off-target effects may occur. Designed to provide practical information for
the bench toxicologic pathologist working in pharmaceutical drug research, NI
Toxicologic Pathology: Nonclinical Safety Assessment presents histopatho- CC NONCLINICAL SAFETY ASSESSMENT
logic description of lesions observed during drug development and discusses
L
their implication in the drug development process. O
I
N
Divided into two sections, the book systematically assists the pathologist in
L
making a determination as to the origin and potential importance of a lesion and I
its relevance for assessing human risk. The first section includes eight “concept” CO
chapters selected to orient the pathologist in areas that are important for effective A
G
interaction with other pathologists as well as the many non-pathologists involved L
in drug development. The second section is made up of organ-based chapters,
SI
each including light microscopic and electron microscopic descriptions of patho-
AC
logical lesions, differential diagnoses, biological consequences, pathogenesis,
F
mechanism of lesion formation, and the expected clinical pathology correlates.
E
P
Toxicologic Pathology: Nonclinical Safety Assessment is designed to T
present important information—both published and unpublished as gained YA
through personal experience—to improve the quality of drug safety evaluation and
A
T
to expedite and improve the efficiency of the process. This book is crafted to
S
assist students, residents, and toxicologic pathologists in their early career phase
SH
by serving as a resource that can effectively be used as a ready reference next to
E
the microscope. Nevertheless, more experienced pathologists will most certainly
SO
find this volume to be invaluable during their assessments. This book is also a
S
valuable reference for toxicologists to assist in understanding compound-related
ML
pathological findings and to provide background for interaction with pathologists.
EO
N
edited by
G
T
Pritam S. Sahota
Y
James A. Popp
Jerry F. Hardisty
K13314
Chirukandath Gopinath
TOX ICOLOGIC
PAT HOLO GY
NONCLINICAL SAFETY ASSESSMENT
TOX ICOLOGIC
PAT HOLO GY
NONCLINICAL SAFETY ASSESSMENT
edited by
Pritam S. Sahota
James A. Popp
Jerry F. Hardisty
Chirukandath Gopinath
Boca Raton London New York
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Version Date: 20121003
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Contents
Preface..............................................................................................................................................vii
Acknowledgments .............................................................................................................................ix
Editors ...............................................................................................................................................xi
Contributors ...................................................................................................................................xiii
Section i concepts in Drug Development
Chapter 1 Overview of Drug Development ..................................................................................3
James A. Popp and Jeffery A. Engelhardt
Chapter 2 Nonclinical Safety Evaluation of Drugs .....................................................................25
Thomas M. Monticello and Jeanine L. Bussiere
Chapter 3 Toxicokinetics and Drug Disposition .........................................................................55
David D. Christ
Chapter 4 Introduction to Toxicologic Pathology .......................................................................77
Judit E. Markovits, Page R. Bouchard, Christopher J. Clarke,
and Donald N. McMartin
Chapter 5 Routine and Special Techniques in Toxicologic Pathology .......................................97
Daniel J. Patrick and Peter C. Mann
Chapter 6 Principles of Clinical Pathology...............................................................................133
Robert L. Hall
Chapter 7 Toxicogenomics in Toxicologic Pathology ...............................................................175
Mark J. Hoenerhoff and David E. Malarkey
Chapter 8 Spontaneous Lesions in Control Animals Used in Toxicity Studies .......................209
Robert C. Johnson, Robert H. Spaet, and Daniel L. Potenta
Section ii organ Systems
Chapter 9 Gastrointestinal Tract ...............................................................................................257
Judit E. Markovits, Graham R. Betton, Donald N. McMartin, and Oliver C. Turner
v
vi Contents
Chapter 10 Liver, Gallbladder, and Exocrine Pancreas ..............................................................313
Russell C. Cattley, James A. Popp, and Steven L. Vonderfecht
Chapter 11 Respiratory System ..................................................................................................367
David J. Lewis and Tom P. McKevitt
Chapter 12 Urinary System.........................................................................................................421
Kendall S. Frazier and John Curtis Seely
Chapter 13 Hematopoietic System ..............................................................................................485
Kristin Henson, Glenn Elliott, and Gregory S. Travlos
Chapter 14 Lymphoid System .....................................................................................................517
Patrick J. Haley
Chapter 15 Bone, Muscle, and Tooth ..........................................................................................561
John L. Vahle, Joel R. Leininger, Philip H. Long, D. Greg Hall, and
Heinrich Ernst
Chapter 16 Cardiovascular System .............................................................................................589
Calvert Louden and David Brott
Chapter 17 Endocrine Glands .....................................................................................................655
Sundeep Chandra, Mark J. Hoenerhoff, and Richard Peterson
Chapter 18 Reproductive System and Mammary Gland ............................................................717
Justin D. Vidal, Michael L. Mirsky, Karyn Colman, Katharine M. Whitney,
and Dianne M. Creasy
Chapter 19 Skin ..........................................................................................................................831
Zbigniew W. Wojcinski, Lydia Andrews-Jones, Daher Ibrahim Aibo,
and Robert Dunstan
Chapter 20 Nervous System ........................................................................................................895
Mark T. Butt, Robert Sills, and Alys Bradley
Chapter 21 Special Senses: Eye and Ear .....................................................................................931
James A. Render, Kenneth A. Schafer, and Richard A. Altschuler
Preface
Toxicologic Pathology: Nonclinical Safety Assessment is the result of careful planning and dili-
gence by the editors and authors. When entering the field of toxicologic pathology related to drug
development, the authors recognize the currently limited and scattered resources available to assist
the toxicologic pathologist, despite the best of basic diagnostic training and committed mentor-
ship. The editors have each served as mentors to toxicologic pathologists entering the arena of drug
development over the years and were struck by these shortcomings. Therefore, the current text has
been specifically designed to assist the students/residents and toxicologic pathologists in the early
phase of their careers by serving as a resource that can effectively be used as a ready reference next
to the microscope. Of course, even the most experienced pathologist in drug development has not
“seen it all,” as areas of drug emphasis shift over time and more targeted therapies are developed,
resulting in previously unseen, exaggerated pharmacologic or off-target effects. Since the initiation
of this book, toxicologists have expressed great interest in such a resource to better appreciate the
gravity of pathological lesions and processes described by the pathologist in toxicology reports and
to promote a much more fruitful dialog with pathologists toward a common understanding.
Toward these ends, the editors have organized this volume into two major sections, each com-
posed of multiple chapters. Since it is critical that the toxicologic pathologist has a basic understand-
ing of areas beyond diagnostic pathology to function effectively in an ever-increasing, integrated
approach to drug development, eight concept chapters are included. While numerous concept chap-
ters are possible, the current book includes those eight topics that have been judiciously selected to
orient the pathologist in areas that are important for effective interaction with other pathologists as
well as the many nonpathologists involved in drug development. The second major section is com-
posed of 13 chapters oriented by organ system. While this approach is generally used in pathology
texts, the limitation of presenting material on a multiorgan pathologic entity (e.g., phospholipidosis)
presented across several chapters is recognized. In such instances, information in various sections
should be identifiable from the index.
Any book of this nature is only as good as the authors who prepare the specific sections, thus
their selection was given very careful consideration. They were obviously chosen for their knowl-
edge, expertise, and focused interest on a topic. While multiple potential authors may be able to
develop a solid treatise on a topic based on literature review, we also know that extensive knowledge
and expertise based on the experience of working through toxicologic pathology issues that often
do not appear in the literature add a critical dimension. Therefore, the book was designed to pre sent
important information, both published and unpublished, as gained through personal experience,
so this knowledge can be used by others to improve the quality of drug safety evaluation and, as
importantly, to expedite and improve the efficiency of the process. The editors and the future read-
ers are indebted to the authors for sharing such personal knowledge in addition to organizing and
summarizing the latest information available in the literature.
While extensive care has been taken by the authors to identify the most important topics and
effectively address them within the constraints of this book, there will inevitably be topics that have
been missed or have not been given enough space, and there will certainly be unforeseen topics that
will need to be added in the future. Therefore, the editors solicit input from readers as they use the
text. The goal is to continually upgrade and update the book at reasonable intervals so it can be of
even greater value to future users. Creators and users of future revisions will surely benefit from
the contributions made by the readers and users of this initial edition of Toxicologic Pathology:
Nonclinical Safety Assessment.
vii
