Veterinary Toxicology Basic and Clinical Principles

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xii FOREWORD

rodenticides and avicides, as well as the brief part on her- food sources. Other dietary contaminants are reviewed in
bicides and fungicides, highlight the array of agricultural the part dealing with “Feed and water contaminants”.
chemicals that have spurred not only the long-term devel- Ionophores and nonprotein nitrogen dietary supplements
opments in toxicology but also the environmental impact are highlighted. Not to be overlooked, water quality and
of widespread use of these groups of compounds. contaminants of water sources alert diagnosticians to the
The environmental areas of veterinary toxicology are hazards and often animal-threatening risks involved with
discussed by reviewing industrial toxicants and the resid- these aqueous contaminants.
ual impacts of the biphenyls, dioxins and dibenzofurans. The concluding parts in this book of facts and knowl-
The environmental impact of these and other chemicals edge address how current methodology allows confirma-
found in the environment are highlighted by extensive tion of specific poisonings and the appropriate means by
chapters dealing with their toxicity in birds, an introduc- which poisoned animals may be treated and managed.
tion to ecotoxicology, and the distribution of chemicals in After reviewing the basic concepts of analyses, appropri-
the global marine environment through aquatic toxicol- ate sample submission requirements for such procedures,
ogy, and the adverse effects of cyanobacterial toxins and the use of proteomics for diagnostic application, the
others affecting marine animals. application of microscopic analyses of feeds and animal
Although reviewed in only two chapters, the extensive ingesta for toxic components, and the complementing
information on botulinum neurotoxin and the enterotox- role of pathology in the diagnostic process are presented.
ins are not overlooked. Neither are the poisonous and ven- To wrap it all up, a concluding part on therapeutic mea-
omous compounds generated by animals in the terrestrial sures offers recommendations on how to prevent poison-
environment. The chapter on “Caterpillars and mare ings and, if necessary, what treatments may be applied to
reproductive loss syndrome” presents up-to-date infor- treat individual intoxications.
mation on this event’s disastrous effect on equine breed- In a full circle, the basic principles of veterinary toxicol-
ing stables and the puzzling origin of these problems. An ogy have been utilized to understand the mechanisms of
in-depth discussion on chemically induced estrogenicity toxicology, to relate to the numerous and challenging
brings readers current with this unique toxic hazard in all individual chemical constituents that offer risk and pro-
animal species including humans. duce injury to animals and indirectly to humans, and to
Part 14 is another expansive discussion of the still impor- offer current information and recommendations for iden-
tant poisonous plant concerns that contributed to and con- tifying such problems and specifically managing their
tinue to stimulate the interests and skills of veterinary animal and public health effects.
toxicologists. The groups of important United States’ poi- It should be apparent that Veterinary Toxicology is
sonous plants are reviewed, and then specific categories of about everything – from initial concerns of animal illness
plant toxins are presented: cyanide; nitrate/nitrite; oxalates; to specific molecular and genomic impacts in all of soci-
Datura and related plants; fescue; mushrooms; cottonseed ety. The veterinary toxicologist is well equipped and
toxicity; and the Taxus alkaloids. All these are common and active in identifying the opportunities and challenges
highly concerning dietary risks for livestock and other ani- presented. The discipline stands increasingly ready to
mal species existing in the natural environment. contribute to medical science by utilizing its broad talents
Fungal toxins are grouped under the “Mycotoxins” to have significant impacts for the health of all animals on
part where aflatoxins, trichothecenes, zearalenone, fumon- this globe.
isins, ochratoxins/citrinin, slaframine, ergot, and the inter- What’s Veterinary Toxicology all about? Those answers
estingly and dynamic tremorgenic mycotoxins are nicely are what this encyclopedic volume offers! Enjoy them and
presented. These compounds present not only animal use the information to the benefit of society and science!
hazards, but are also important public health concerns for
the dietary contamination of grains and other human Frederick W. Oehme
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Preface

Veterinary toxicology is a very complex, yet fascinating, have the tremendous task ahead of facing new challenges
subject as it deals with a wide variety of poisons of chem- of the 21st century.
ical, mineral, plant, fungal, and animal origins. Presently, The primary objective of this book, Veterinary Toxicology:
synthetic compounds constitute the largest class of chem- Basic and Clinical Principles, is to offer a comprehensive
icals that are most frequently encountered in animal poi- text/reference source to research veterinary toxicologists,
sonings. Veterinary toxicology is greatly complicated by students, teachers, clinicians, and environmentalists. The
the wide variations in responses of domestic, aquatic, volume is organized into 18 parts, with a total of 91 chap-
wild, and exotic animal species to toxicants. In the last ters, in order to offer a stand alone chapter on as many
few decades, veterinary toxicologists have faced the enor- topics as possible. Although the book is heavily focused
mous task of dealing with a flood of new farm chemicals on target organ toxicity (Part 2), it has many novel chap-
and household products. Understanding the complete ters on timely topics, such as veterinary toxicology and
profile, especially the mechanism of toxicity, of each toxi- the law, physiologically based pharmacokinetic model-
cant is the biggest challenge for today’s veterinary toxi- ing, in vivo/in vitro toxicity testing models, neurotoxic
cologists. At the present time, toxicologists are facing oxidative stress, nanoparticles, radiation, immunotoxic-
many new problems. For example, during the incident of ity, reproductive/endocrine/placental toxicity, chemical
September 11, 2001, a large number of pets died in the col- terrorism, and carcinogenesis. Poisonous plants, myco-
lapse of the World Trade Center in New York City, while toxins, feed, and water contaminants are covered exten-
the survivors continue to suffer from respiratory illnesses sively. Several chapters provide the latest information on
(Ground Zero Illnesses) caused by dust, debris, and toxic problems related to industrial, environmental, aquatic,
chemicals. In 2005, Hurricanes Katrina and Rita, devas- marine, avian, and zoo toxins. A significant part of the
tated the lives of many animals in the Gulf coast states book (Part 16) is devoted to diagnostic toxicology, which
(Louisiana and Mississippi). Thousands of animals died, includes basic principles, method validation and QA/QC,
while a large number of others suffered from intoxication sample submission, current diagnostic criteria, toxicopro-
with high levels of metals, pesticides, mold, and other teomics, pathology, and microscopic analysis of feed.
toxic substances. Recently, a fatal food from Diamond Pet Finally, the last part of the book emphasizes prevention
Foods Company has sparked concern as more than 125 and therapeutic measures of common poisonings.
dogs died in more than 25 states in the United States. In the past few years, veterinary toxicologists from
Aflatoxin was proven to be the culprit. From time to time, many parts of the world have realized the need for a stan-
unusual toxicological problems are encountered on a dard book that can provide a detailed coverage of the
large scale, and this trend is likely to continue in the basic and clinical principles of veterinary toxicology. This
future. Around the world, animals and humans are living book addresses global as well as regional toxicological
in a more polluted environment today than ever before. problems, and offers practical solutions. A stand alone
Many of the toxicological problems are global, while oth- chapter is provided on every major topic, with major
ers are regional. Unfortunately, antidotes for common references for further reading. This book represents the
poisons are not readily available, resulting in either collective wisdom of more than 75 authors, and offers
delayed or no treatment. Thus, veterinary toxicologists a unique text/reference source for those involved in

xiii
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xiv PREFACE

veterinary medicine in general and toxicology in particu- appreciated. The editor and the authors would like to
lar. Contributing authors for chapters of this book are the thank Renske Van Dijk, Keri Witman, Mara Conner, and
most qualified and well-experienced authorities in their Tari Broderick, the editors at Academic Press/Elsevier, for
respective areas of veterinary toxicology. their vital input in preparation of this book.
The editor is deeply indebted to all the authors for their
sincere and dedicated contributions. Technical assistance Ramesh C. Gupta
of Joan Jenkins, Debra Britton and Robin Doss is immensely
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List of Contributors

Manoj Aggarwal, MVSc, PhD Steven I. Baskin, Pharm D, PhD, FACC, FCP, DABT,
Institute for Occupational Physiology FATS
(Dortmund University) Deputy Research Coordinator
Dortmund, Germany Cyanide Medical Countermeasures
Division of Pharmacology and Toxicology US Army Medical Research
Indian Veterinary Research Institute Institute of Chemical Defense
Izatnagar, UP, India USAMRICD, Analytical Toxicology Division
Aberdeen Proving Ground, MD, USA
Jaime B. Anderson, DVM, PhD
USAMRICD, Analytical Toxicology Division Lynn S. Bates, BS Chemistry, MS Biochemistry,
Ricketts Point Road PhD Grain Science
Aberdeen Proving Ground, MD, USA ALTECA Ltd,
Manhattan, KS, USA
Beverly Arnold, BS, MST, EDS, PhD
Quality Assurance Manager/Laboratory Supervisor Val R. Beasley, DVM, PhD, DABVT
Athens Diagnostic Laboratory Professor of Veterinary, Wildlife and
College of Veterinary Medicine Ecological Toxicology
University of Georgia Executive Director, Envirovet Program in Wildlife and
Athens, GA, USA Ecosystem Health
Assistant Head, Department of Veterinary Biosciences
Kirk Arvidson, PhD College of Veterinary Medicine
Organic Chemist University of Illinois, Urbana-Champaign
US Food and Drug Administration Urbana, IL, USA
Division of Food Contact Notifications
College Park, MD, USA William Bernard, DVM, Diplomate ACVIM
Chief of Medicine
Debasis Bagchi, PhD, FACN, CNS Rood and Riddle Equine Hospital
Professor Lexington, KY, USA
Department of Pharmacy Sciences
School of Pharmacy & Allied Health Professions Karyn Bischoff, DVM, MS, DABVT
Creighton University Medical Center Population Medicine and Diagnostic Sciences
Omaha, NE, USA College of Veterinary Medicine, Cornell University
Ithaca, NY, USA
Manashi Bagchi, PhD, FACN
Director of Research Dennis J. Blodgett, DVM, PhD, DABVT
Research and Development Associate Professor
InterHealth Research Center College of Veterinary Medicine
Benicia, CA, USA Blacksburg, VA, USA

xv
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xvi LIST OF CONTRIBUTORS

Steven Bursian, BS, MS, PhD Steven E. Czerwinski

Professor US Army Center for Health Promotion and
Michigan State University Preventive Medicine
Department of Animal Science Aberdeen Proving Ground, MD, USA
East Lansing, MI, USA
Camille DeClementi, VMD, DABT
Jennifer L. Buur, DVM, PhD, DACVCP
Director, Content and Records Management
North Carolina State University
ASPCA Knowledge Management
College of Veterinary Medicine
University of Illinois Allied Agency
Center for Chemical Toxicology Research and
Urbana, IL, USA
Pharmacokinetics
Raleigh, NC, USA
Rakesh Dixit, PhD, DABT
Michael P. Carlson, MS, PhD Senior Director & Head, Toxicology
Lecturer Translational Sciences
Diagnostic Toxicologist/Analytical Chemist MedImmune, Inc.
Toxicology Laboratory Gaithersburg, MD, USA
University of Nebraska Lincoln
Veterinary Diagnostic Center
Lincoln, NE, USA Eric K. Dunayer, VMD, MS, DABT, DABVT
Senior Toxicologist
Ronald Chanderbhan, PhD ASPCA Animal Poison Control Center
Biochemist/Toxicologist Urbana, IL, USA
US Food and Drug Administration
Division of Biotechnology & GRAS Notice Review Steve Ensley, DVM, MS, PhD
College Park, MD, USA Veterinary Toxicologist
College of Veterinary Medicine
Supratim Choudhuri, PhD Veterinary Diagnostic Laboratory
Toxicologist/Molecular Biologist Iowa State University
US Food and Drug Administration Ames, IA, USA
Division of Biotechnology & GRAS Notice Review
College Park, MD, USA
Tim J. Evans, DVM, MS, PhD,
Ralph G. Christian, DVM, Diplomate ACVP Diplomate ACT and ABVT
President, Ralph Christian Consulting Inc. Toxicology Section Head
Edmonton, Alberta, Canada Veterinary Medical Diagnostic Laboratory
Assistant Professor
Julie A. Coffield, DVM, PhD Department of Veterinary Pathobiology
The University of Georgia College of Veterinary Medicine
Department of Physiology & Pharmacology University of Missouri-Columbia
College of Veterinary Medicine Columbia, MO, USA
Athens, GA, USA
D.R. Gardner, PhD
Robert W. Coppock, DVM, PhD, DABVT, DABT
USDA-ARS
President and CEO
Poisonous Plant Research Laboratory
Toxicologist and Associates, Ltd
Logan, UT, USA
Adjunct Professor
Department of Public Health Sciences
School of Public Health Tam Garland, DVM, PhD
University of Alberta Director for the Joint Agro Defense Office
Edmonton, Alberta Program Manager for Agriculture Security for the
Adjunct Professor Science and Technology
Environmental Health Directorate of the Department of Homeland
Concordia University College Security
Edmonton, Alberta, Canada Greenfield, IN, USA
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LIST OF CONTRIBUTORS xvii

P.K. Gupta, BVSc, MSc VM & AH, PhD, PGDCA, James Hungerford, PhD
FNA VS, FASc AW, FST, FAEB, FACVT Chair of AOAC Task Force on Marine and Freshwater
Director, Toxicology Consulting Services Inc. Toxins
and former Adviser to WHO (Geneva) and Chief Research Chemist
Division of Pharmacology and Toxicology FDA Seafood Products Research Center
Indian Veterinary Research Institute Bothell, WA, USA
Bareilly, UP, India
Anant V. Jain, BSc, MSc, PhD
Ramesh C. Gupta, DVM, MVSc, PhD, DABT, FACT Head, Toxicology Section (Retired)
Professor and Head, Toxicology Department Athens Diagnostic Laboratory
Breathitt Veterinary Center College of Veterinary Medicine
Murray State University University of Georgia
Hopkinsville, KY, USA Athens, GA, USA

L.F. James, PhD

Sharon M. Gwaltney-Brant, DVM, PhD, DABVT, DABT
USDA-Agricultural Research Service
Vice President
Poisonous Plant Research Laboratory
ASPCA Animal Poison Control Center
Logan, UT, USA
Urbana, IL, USA
Shaheen Khan, PhD
Jeffery O. Hall, DVM, PhD, DABVT Postdoctoral
Utah State University Department of Veterinary Physiology and Pharmacology
Utah Veterinary Diagnostic Laboratory Texas A&M University
Logan, UT, USA College Station, TX, USA
and
Dwayne W. Hamar, PhD Institute of Biosciences and Technology
Professor Houston, TX, USA
Colorado State University
Colorado State Diagnostic Lab S.T. Lee, PhD
Ft. Collins, CO, USA USDA-Agricultural Research Service
Poisonous Plant Research Laboratory
Alan J. Hargreaves, BSc, PhD Logan, UT, USA
Reader
Interdisciplinary Biomedical Research Centre Jeffrey M. Levengood, PhD
School of Biomedical and Natural Sciences Research Ecotoxicologist
Nottingham Trent University Division of Ecology and Conservation Science
Nottingham, UK Illinois Natural History Survey
Program in Veterinary, Wildlife and Ecological Toxicology
Department of Veterinary Biosciences
Lenn R. Harrison, DVM, Diplomate ACVP
University of Illinois, Urbana-Champaign
Director, Livestock Disease Diagnostic Center
Urbana, IL, USA
University of Kentucky,
Lexington, KY, USA
Xiangrong Li, PhD
Postdoctoral
Stephen B. Hooser, DVM, PhD, DABVT Department of Veterinary Physiology and
Head, Toxicology Sect. & Asst. Director Pharmacology
Purdue University Texas A&M University
Animal Disease Diagnostic Lab College Station, TX, USA
West Lafayette, IN, USA and
Institute of Biosciences and Technology
Jean-François Humbert, PhD Houston, TX, USA
Research Director
Institut Pasteur Roger O. McClellan, DVM, DABT, DABVT, FATS
Unité des cyanobactèries Advisor, Toxicology and Human Health Risk Analysis
Paris, France Albuquerque, NM, USA
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xviii LIST OF CONTRIBUTORS

Donna Mensching, DVM Steven S. Nicholson, DVM, DABVT

Resident, Veterinary Toxicology Professor Emeritus
University of Illinois Department of Veterinary Science
College of Veterinary Medicine LSU, AG Center
Department of Veterinary Biosciences Baton, Rouge, LA, USA
Urbana, IL, USA
Meliton N. Novilla DVM, MS, PhD, ACVP
Michelle S. Mostrom, DVM, MS, PhD, DABVT, DABT Adjunct and Graduate Faculty
Veterinary Toxicologist Department of Pathology & Microbiology
North Dakota State University Faculty of Veterinary Medicine
Veterinary Diagnostic Laboratory University of Prince Edward Island
Fargo, ND, USA Charlottetown, P.E.I., Canada

Faqir Muhammad, DVM, PhD Frederick W. Oehme, DVM, PhD, ATS, DABT, DABVT
Assistant Professor Kansas State University
University of Agriculture Comparative Toxicology Laboratories
Department of Physiology and Pharmacology Denison Avenue
Faisalabad, Pakistan Mosier Hall, Manhattan, KS, USA

Michael J. Murphy, DVM, PhD, JD, DABVT, DABT Kip E. Panter, PhD
Professor of Toxicology USDA-Agricultural Research Service
Department of Veterinary Population Medicine Poisonous Plant Research Laboratory
College of Veterinary Medicine Logan, UT, USA
University of Minnesota
Saint Paul, MN, USA
Sangeeta Patel, PhD
Technical Director, Food and Beverage
Mary B. Nabity, DVM, DACVP Interhealth Research Center
Clinical Pathologist Benicia, CA, USA
College of Veterinary Medicine
Texas A&M University
College Station, TX, USA J.A. Pfister, PhD
USDA-Agricultural Research Service
Poisonous Plant Research Laboratory
V. Naidoo, BVMCh, MSc
Logan, UT, USA
Section of Pharmacology and Toxicology
Department of Paraclinical Sciences
Faculty of Veterinary Science John A. Pickrell, DVM, MS, PhD, DABT
University of Pretoria Comparative Toxicology Laboratories
Onderstepoort, South Africa Diagnostic Medicine/Pathobiology
College of Veterinary Medicine
Kansas State University
P.N. Nation, DVM, PhD, DACVP
Manhattan, KS, USA
Nation Animal Pathology Services (APS) Ltd
Adjunct Associate Professor
Department of Laboratory Medicine and Pathology Robert H. Poppenga, DVM, PhD, DABVT
University of Alberta Professor of Clinical Veterinary Toxicology
Edmonton, Alberta, Canada CAHFS Toxicology Laboratory
School of Veterinary Medicine
University of California
Theuns W. Naudé, BVSc, MSc
Davis, CA, USA
Professor Emeritus Toxicology
Department of Paraclinical Sciences
Vet. Faculty at Onderstepoort Lynn O. Post, DVM, PhD, DABVT
University of Pretoria FDA/CVM
Onderstepoort, South Africa Falling Waters, WV, USA
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LIST OF CONTRIBUTORS xix

Birgit Puschner, DVM, PhD, DABVT Raghubir P. Sharma, DVM, PhD, CIH,
CAHFS-Toxicology Laboratory DABT, DABVT
School of Veterinary Medicine Professor Emeritus
University of California University of Georgia
Davis, CA, USA Department of Physiology and Pharmacology
College of Veterinary Medicine
Merl F. Raisbeck, BS, DVM, PhD, DABVT Athens, GA, USA
Professor Veterinary Sciences
University of Wyoming Geoffrey W. Smith, DVM, PhD, Dipl. ACVIM
Laramie, WY, USA Assistant Professor of Ruminant Medicine
Department of Population Health & Pathobiology
M.H. Ralphs, PhD College of Veterinary Medicine
USDA-Agricultural Research Service North Carolina State University
Poisonous Plant Research Laboratory Raleigh, NC, USA
Logan, UT, USA

Shashi K. Ramaiah, DVM, PhD, DACVP, DABT B.L. Stegelmeier, PhD

Assistant Professor USDA-Agricultural Research Service
Faculties of Pathobiology and Toxicology Poisonous Plant Research Laboratory
Texas Veterinary Medical Center Logan, UT, USA
College of Veterinary Medicine
Texas A&M University Patricia A. Talcott, MS, DVM, PhD, DABVT
College Station, TX, USA Associate Professor
Department of Veterinary Comparative Anatomy,
Jim E. Riviere, DVM, PhD, FATS Pharmacology and Physiology
Distinguished Professor and Director Veterinary Diagnostic Toxicologist
Center for Chemical Toxicology Research and Washington Animal Disease Diagnostic
Pharmacokinetics Laboratory
College of Veterinary Medicine Pullman, WA, USA
North Carolina State University
Raleigh, NC, USA Larry J. Thompson, DVM, PhD, DABVT, CBSP
Clinical Toxicologist
Magda Sachana, DVM, MSc, PhD University of Georgia
Lecturer Veterinary Diagnostic & Investigational Lab
Laboratory of Biochemistry and Toxicology Tifton, GA, USA
Faculty of Veterinary Medicine
Aristotle University of Thessaloniki
Thessaloniki, Greece Mary Anna Thrall, DVM, MS, DACVP
President
Stephen H. Safe, D.Phil American College of Veterinary Pathologists
Professor Department of Microbiology, Immunology and
Department of Veterinary Physiology and Pathology
Pharmacology Colorado State University
Texas A&M University Fort Collins, CO, USA
College Station, TX, USA and
and Department of Pathobiology
Institute of Biosciences and Technology Ross University School of Veterinary Medicine
Houston, TX, USA Basseterre, St. Kitts, West Indies

Manu M. Sebastian, DVM, MS, PhD, Aurelia Tubaro, PhD

Diplomate ACVP Professor, DEMREP
Assistant Professor of Pathology Department of Materials and Natural
College of Veterinary Medicine Substances
University of Georgia University of Trieste
Tifton, GA, USA Trieste, Italy
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xx LIST OF CONTRIBUTORS

Deon van der Merwe, BVSc, PhD Tina Wismer, DVM, DABVT, DABT
Assistant Professor of Toxicology Senior Director of Veterinary Outreach and Education
College of Veterinary Medicine ASPCA Animal Poison Control Center
Kansas State University Urbana, IL, USA
Manhattan, KS, USA
Fei Wu, BS
Petra A. Volmer, DVM, MS, DABVT, DABT Graduate Research Assistant
Assistant Professor, Toxicology Department of Veterinary Physiology and
Director, Veterinary Toxicology Residency Program Pharmacology
Toxicology Section Head, Veterinary Diagnostic Texas A&M University
Laboratory College Station, TX, USA
University of Illinois and
College of Veterinary Medicine Institute of Biosciences and Technology
Veterinary Diagnostic Laboratory Houston, TX, USA
Department of Veterinary Biosciences
Urbana, IL, USA Hany Y. Youssef, DVM, MS
ASPCA Animal Poison Control Center
Dorothy D. Whelchel S. Philo Rd, Suite 36
The University of Georgia Urbana, IL, USA
College of Veterinary Medicine
Athens, GA, USA Shirley Zafra-Stone, BS
Research Associate
Christina R. Wilson, MS, PhD Research and Development
Purdue University InterHealth Research Center
Animal Disease Diagnostic Lab Benicia, CA, USA
West Lafayette, IN, USA
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C H A P T E R

Concepts in veterinary
toxicology
Roger O. McClellan

INTRODUCTION
the syndrome of adverse health effects that result from
exposure to a toxicant. During the last several decades,
Toxicology, from the Greek words toxicon for poison and increased concern has developed for the effects of long-
logos for scientific study, is the study of poisons. Veterinary term low-level exposures to toxicants. With these expo-
medicine is that branch of medical science concerned with sures, adverse health effects, if they occur, may be manifest
the diagnosis, treatment and prevention of diseases of ani- in a non-specific manner as an increase in the incidence of
mals. The adjective veterinary is derived from Latin – common diseases in a population.
veterinae, beasts of burden. Obviously, the modern field A wide range of materials produces toxic effects when
of veterinary medicine extends beyond the “beasts of exposure occurs at sufficiently high levels. Indeed, with
burden” to include all the domesticated animal species, extreme levels of exposure most agents can produce adverse
both livestock and companion animals, as well as non- effects. For example, while both water and oxygen are
domesticated species. Indeed, it has expanded to include required to sustain life, they are toxic when the level of
non-mammalian species. While the focus of toxicology intake is excessive. The nature of the toxic responses
remains on chemicals, it is generally acknowledged that depends not only on the toxicant, but also the route of
the study of effects of ionizing radiation is a part of the field exposure, the duration and intensity of the exposure and
or at least a closely related specialty. Pharmacology, from the characteristics of the exposed individual, i.e. species,
the Greek words pharma for drugs and logos for scientific gender, age, pre-existing disease states, nutritional status
study, is a closely related field concerned with the science and prior exposure to the agent or related compounds. The
of drugs: their preparation, properties, effects and uses in exposure may be brief or prolonged. The response may
the diagnosis, treatment and prevention of disease. occur acute or chronic and occur soon after exposure or
The field of toxicology is very broad including the iden- much later and only after prolonged exposure. The response
tification and characterization of poisons, their physical may be relatively unique to the toxicant, i.e. a specific tox-
and chemical properties, their fate in the body and their icosis, or distinguishable from common diseases caused
biological effects. In addition, toxicology is concerned by natural processes or exposure to other agents. In many
with the treatment of disease conditions caused by poi- cases, sophisticated statistical methods are required to
sons. The terms toxicant and poison are used interchange- associate some excess health risk, over and above that
ably. A toxicant is a material that when it contacts or enters caused by other factors, with a particular toxicant expo-
the body via ingestion, inhalation, dermal contact or injec- sure. This is especially true today after much progress has
tion, interferes with the normal biological processes and been made in controlling exposure to toxic materials.
causes adverse health effects. The term toxin is used to In this chapter, I first provide a brief historical perspec-
describe poisons originating from biological processes. tive on the development of veterinary toxicology as a sub-
The term toxic is used to describe the effects of a poison on specialty of the veterinary medical profession and as a
biological systems. Toxicosis is the term used to describe specialized area within the general field of toxicology. This

Veterinary Toxicology, Edited by Ramesh C. Gupta Copyright © 2007, Elsevier Inc. All rights reserved.
ISBN: 978-0-12-370467-2
3
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4 1. CONCEPTS IN VETERINARY TOXICOLOGY

is followed by a section on the evolution of veterinary level of exposure, cause adverse health effects. As will be
toxicology from an observation-based profession and sci- noted at several places in this chapter, toxicology is increas-
ence to one that places increasing reliance on science devel- ingly concerned with low-level exposures for which the
oped through experimentation. This includes a discussion effects, if any are observed, may not be specific to a par-
of the risk paradigm which has become an integral part of ticular chemical.
toxicology in recent decades. In the next section, I offer Toxicology, in a sense, dates back to the earliest activities
several related paradigms for acquiring, organizing and of humans. By observation, people came to learn that
using knowledge in veterinary toxicology so as to maxi- which could be ingested without harm and, by contrast,
mize its potential impact. Next, there is a section on the the foodstuffs to be avoided because of their harmful
sources of knowledge that may be obtained either through properties. They also came to know which animal ven-
observation or experimentation. These sources may include oms, plant extracts and other materials could be used for
studies on the species of interest, i.e. people or some other hunting, warfare and assassination. No doubt as animals
specific animal species, controlled exposure studies in the were domesticated, it became apparent that the human
species of interest, studies in other species, investigations observations and practices could be extended to domestic
using tissues and cells and structure–activity analyses. This animals. Unfortunately, domestic animals are not always
is followed by a section discussing the design of experi- as astute as people in learning to avoid poisonous plants
mental studies to optimize the interpretation and use of and other harmful situations. Thus, veterinary practition-
the results. This chapter concludes with a discussion of key ers still encounter toxicoses involving animals ingesting
toxicological descriptors and a brief conclusion section. poisonous plants.
The history of toxicology has been well documented by
several contemporary authors (Milles, 1999; Borzelleca,
2001; Gallo, 2001). The history of veterinary toxicology has
HISTORICAL PERSPECTIVE not been as well documented, although it is apparent that
veterinary toxicology has been an integral part of veterinary
medicine since the origins. Veterinary medicine is a special-
Historical events
ized branch of medical science with formal programs of
The father of modern toxicology is generally acknowl- study leading to a professional degree. The history of vet-
edged to be Auroleus Phillipus Theostratus Bombastus erinary medicine has been reviewed by several authors
Von Hohenheim (1493–1541), who referred to himself as a (Smithcors, 1957; Stahlheim, 1994; Swabe, 1999; Wilkinson,
Paracelsus, from his belief that his work was beyond the 2005). The role of veterinary toxicology in the veterinary
work of Celsus, a first century Roman physician (Pagel, curriculum is well documented for one of the earliest vet-
1958). Paracelsus is credited with the well-known state- erinary medical colleges, that at the Free University of
ment: “All substances are poisons; there is none which is Berlin. Wilsdorf and Graf (1998) provide an account of the
not a poison. The right dose differentiates a poison from a development of veterinary toxicology at that University
remedy.” Paracelsus advanced many views that were rev- from 1790 to 1945. Oehme (1970) has briefly reviewed
olutionary for his time that are now accepted as funda- the development of veterinary toxicology as a discipline in
mental concepts for the field of toxicology. In contrast to the United States.
earlier emphasis on mixtures, he focused on the toxicon as
a specific primary chemical entity that was toxic. Paracelsus
advanced four fundamental concepts:
Textbooks
1 Experimentation is required for examining responses In the English language, the earliest veterinary toxicology
to chemicals. publication I could find was a synopsis of Veterinary
2 A distinction should be made between the therapeutic Materia Medica, Therapeutics and Toxicology (Quitman, 1905)
and toxic properties of chemicals. apparently used at Washington State University College
3 The therapeutic and toxic properties are something of Veterinary Medicine in the early part of the 20th cen-
closely related and distinguishable by dose. tury. I am uncertain of the extent to which this synopsis is
4 It is possible to ascertain a degree of specificity for based on a French text by Kaufmann (1901). The earliest
chemicals and their therapeutic or toxic effects. English language veterinary toxicology textbook I was able
to locate was that authored by an Englishman, Lander
It is obvious from the foregoing that toxicology and phar- (1912). This book was also prepared in a second edition
macology are closely related fields of scientific endeavor. (1926) and a third edition was prepared by an Irishman,
Pharmacology is focused on drugs, including both their Nicholson (1945). I am uncertain how widely it was used
effectiveness and safety. Toxicology is concerned with all in the United States. The text included four sections: a
kinds of chemicals and other agents that may, at some brief introduction to toxicology followed by sections on
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HISTORICAL PERSPECTIVE 5

classes of toxicants; mineral or inorganic poisons; organic have edited two editions of Small Animal Toxicology. The
poisons and drugs; and poisonous plants. This last sec- present multi-authored text promises to be the most
tion represented half of the book. comprehensive text on veterinary toxicology published to
Many early students in veterinary medicine in the United date. A Veterinary Toxicology text edited by Chapman (2007)
States used textbooks prepared for physicians such as is in preparation.
Kobert (1897), Practical Toxicology for Physicians and Students. There are a number of comprehensive general toxicology
It was also common to use either textbooks in pharma- texts available today. I will note four that the serious stu-
cology or veterinary pharmacology that contained a brief dent of toxicology will find useful to have in their reference
coverage of toxicology. Indeed, few veterinary medical library. Casarett and Doull’s Toxicology: The Basic Science of
colleges prior to the 1950s had full-time veterinary toxi- Poisons edited most recently by Klaassen (2001) was first
cologists on their faculty. Lectures on toxicology were published in 1975 and is now in its sixth edition. Hayes
usually included in courses in pharmacology, pathology (2001), Principles and Methods in Toxicology, is now in its
and clinical medicine. fourth edition. Toxicology, edited by Marquadt et al. (1999),
The first veterinary toxicology text I personally used was built on an earlier German text by Marquadt and Schafer.
authored by Garner (1957) who was then a Senior Lecturer Biological Concepts and Techniques in Toxicology: An Integrated
in Chemical Pathology (Veterinary) at the University of Approach edited by Riviere (2006) was just released. Serious
Bristol in the United Kingdom and later Head of the students will also want to be aware of a 13 volume com-
Radiobiology Department at the Agricultural Research prehensive set of toxicology text edited by Sipes et al.
Council Field Station, Compton, Berks, UK. The text by (1997). Moreover, there are numerous text and reference
Garner (1957) was intended as a successor to the third edi- books available now covering various sub-specialty areas
tion of Lander’s Veterinary Toxicology. A second edition was such as Inhalation Toxicology, Reproductive and Developmental
prepared by Garner (1961) after he became Head of the Toxicology and Dermal Toxicology.
Public Health Section, Radiological Protection Division, In addition to text and reference books, there are numer-
UK Atomic Energy Authority, Harwell, Berks, UK. Later, ous journals published in the field of toxicology that regu-
Garner came to the United States where he was initially larly contain articles that relate recent findings in veterinary
associated with Colorado State University directing stud- toxicology. Many clinically oriented veterinary medical jour-
ies of the long-term effects of radiation on beagle dogs. nals contain articles on veterinary toxicology. The on-line
I recall asking Garner in the early 1970s about the possibil- search capabilities serving the medical sciences including
ity of preparation of a third edition of his Veterinary toxicology and veterinary toxicology are expanding at an
Toxicology text. He indicated that the field of veterinary tox- exponential rate. Of special note are those maintained
icology had become so broad that it was not readily feasible under the auspices of the National Library of Medicine,
for a single individual to author a text in veterinary toxicol- MEDLINE and TOXLINE.
ogy and he was not interested in “shepherding” a herd of
individual chapter authors with specialized knowledge of
various aspects of veterinary toxicology.
Organizations
Radeleff (1964) authored one of the first veterinary
toxicology texts published in the United States. A second A number of professional scientific organizations have
edition appeared in 1970. This was followed by a text pre- been created as the field of toxicology, including veterinary
pared by Osweiler et al. (1985). Several books published toxicology, has matured. The most noteworthy include
in the 1960s became classics on the effects of poisonous the American College of Veterinary Toxicology (ACVT),
plants (Kingsbury, 1954, 1964; Hulbert and Oehme, 1968). American Board of Veterinary Toxicology (ABVT), Society
Recent books on poisonous plants have been authored of Toxicology (SOT), American Board of Toxicology (ABT)
by Garland and Barr (1998), Burrows and Tyrl (2001, and Academy of Toxicological Sciences (ATS). The ACVT
2006) and Knight and Walter (2001). Murphy (1996) was one of the earliest scientific societies in the field being
has authored a field guide to common animal poison. It founded in 1958. It now exists as the American Academy
is organized by the organ system affected and then by of Veterinary and Comparative Toxicology (AAVCT).
toxicant. The ACVT was instrumental in fostering the creation of
Osweiler (1996) has authored a text focused on toxi- the ABVT and its recognition by the American Veterinary
cology as part of the National Veterinary Medical Series Medical Association (AVMA) as the approved certifying
for Independent Study. It has been widely used by indi- specialty organization for veterinary toxicology. Three
viduals preparing for the National Board Examinations well-known veterinary toxicologists, W. Binns, J.W.
for Veterinary Medical Licensing. Roder (2001) has pre- Dollahite and R. Radeleff, were accepted by the AVMA as
pared a text, Veterinary Toxicology, as part of a series The Charter Members of the ABVT. They prepared the first
Practical Veterinarian. Plumlee (2004) has edited Clinical certifying ABVT examination which was given in 1967
Veterinary Toxicology and Peterson and Talcott (2001, 2006) (see www.abvt. org). I was pleased to be one of seven
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6 1. CONCEPTS IN VETERINARY TOXICOLOGY

individuals in the first class certified, based on examina- specialized livestock endeavors. The second related to the
tion, as Diplomates of the ABVT. increased attention given to providing veterinary medical
The SOT, with the world’s largest membership of toxicol- services to a growing population of companion animals. In
ogists, was organized in 1961 (see www.sot.org). Many of both areas the science of veterinary medicine was strength-
the organizers of the SOT were members of the American ened as observation-based medical practice was comple-
Society for Pharmacology and Experimental Therapeutics mented and, ultimately, supplemented by science-based
(ASPET) who felt toxicologists needed a “home” of their medicine. During this period, veterinary toxicologists
own. I recall attending an organizational meeting of the began to play an important role in veterinary medical diag-
SOT held in conjunction with an ASPET meeting at the nostic laboratories, both in veterinary medical colleges and
University of Rochester and the excitement and enthusiasm in state and federal agencies. With the strengthening of the
of the attendees for creating the SOT. As an aside, it would science base of veterinary medicine, including the quality
be a few years before I felt my credentials were sufficient of the science in the veterinary medical curriculum, the
that I could apply for membership in the SOT. The SOT fos- third movement, the emergency of the comparative medi-
tered the creation of the ABT which held its first certifying cine character of veterinary medicine, became more appar-
examination in 1980 (see www.abtox.org). I was pleased to ent and was enhanced (Wilkinson, 2005). These changes in
be one of the first class of individuals certified, based on the profession were accompanied by increased involve-
examination, as Diplomates of the ABT. The SOT includes a ment of veterinarians in research on the species of tradi-
number of specialty sections including the Comparative tional concern to the profession, domestic and companion
and Veterinary Specialty Section. animals (Stahlheim, 1994), and to participation in a broader
A third certifying entity, the ATS, which accepts individ- range of biomedical research activities, involving use of the
uals as Fellows based on a review of credentials, was cre- traditional laboratory animal species, driven largely by
ated in 1981 (see www.acadtoxsci.org). Many veterinary concern for human health (Wilkinson, 2005).
toxicologists belong to all of the organizations noted above
and some have been certified by one or more of the certify-
ing organizations: the ABVT, ABT and ATS. Veterinary tox-
Emergence of science-based toxicology
icology has evolved greatly over the past several decades.
Toxicology, like veterinary medicine, was also rapidly
changing and evolving in the mid-20th century. The pre-
vious strong emphasis on field observations was first
EVOLUTION OF VETERINARY complemented and then supplemented by experimenta-
TOXICOLOGY tion. This led to the current strong mechanistic orienta-
tion of toxicology. With this shift in toxicology came an
increased awareness of the utility of a comparative medi-
Roots in veterinary medicine and toxicology
cine orientation in research directed primarily toward
The evolution of veterinary toxicology occurred concur- improving human health (Wilkinson, 2005). With this
rently with evolution of its two roots: the profession of comparative medicine orientation came increased oppor-
veterinary medicine and the science of toxicology. The tunities for individuals educated in veterinary medicine,
veterinary medicine profession was initially focused on including veterinary toxicology, to contribute to general
domestic animals, particularly those used for food, fiber, toxicology and biomedical science.
transportation and to provide power for agricultural These changes in the veterinary medical profession and
endeavors and transportation. With the growth of more the emergence of toxicology as a science came during a
specialized agriculture and production practices, the pro- period when the public was giving increased attention to
fession with its linkage to domestic livestock stimulated the health risks, and its counterpoint safety, of new tech-
growth of the profession. Veterinary toxicology focused nologies and products. A landmark of the era was publi-
on poisonous plants and then on antidotes for various cation of Rachel Carson’s book, Silent Spring (Carson,
toxins. The early part of the 20th century presented a spe- 1962). She focused on both human health impacts and
cial challenge for veterinary medicine as the use of horses impacts on the total ecosystem of which people were just
and mules in agriculture decreased in favor of the use of a part. Her book was certainly one of the key stimuli to a
equipment powered by internal combustion engines. tidal wave of legislative actions in the United States that
During this period of time, there must have been consid- focused broadly on the environment with concern for
erable uncertainty as to the future of the profession. clean air and water; safe food, pharmaceuticals, pesti-
By the mid-20th century three movements transformed cides, fungicides, rodenticides and consumer products;
veterinary medicine. The first related to the traditional and a safe working environment.
roots of the profession in animal agriculture and related The legislative actions and related administrative actions
to the increasing emphasis given to large-scale highly in the 1970s created the US Environmental Protection
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EVOLUTION OF VETERINARY TOXICOLOGY 7

Agency (USEPA), the Consumer Product Safety Commis- risk paradigm built on the long-standing paradigm linking
sion, the National Institute of Occupational Safety and sources to exposure to dose to adverse health outcomes
Health (NIOSH), the National Center for Toxicological that had guided toxicology from its earliest days (Figure
Research, the National Institute of Environmental Health 1.1). I have reviewed elsewhere the development of the risk
Sciences and the Cancer Bioassay Program within the analysis paradigm (McClellan, 1999). The risk analysis par-
National Cancer Institute, which evolved into the National adigm originally proposed by the National Research
Toxicology Program (NTP) now administered by the Council (NRC, 1983) and used by the USEPA is shown in
National Institute for Environmental Health Sciences. This Figure 1.2. A later report Science and Judgment in Risk Assess-
was also a period of rapid expansion of research activities ment (McClellan, 1994; NRC, 1994) and reports from the
in the pharmaceutical food, chemical and petroleum indus- Risk Commission (1997) re-affirmed use of the risk para-
tries. The chemical industry in 1976 started the not-for- digm which continues to be a cornerstone of activities not
profit Chemical Industry Institute of Toxicology, which now just at EPA but in other national and international agencies
exists as the CIIT Center for Health Sciences, to test com- and in the private sector.
modity chemicals, investigate the mechanisms of chemical The original key elements of the risk paradigm were (1)
toxicity and train additional toxicologists. The Food and hazard identification, (2) exposure–response assessment,
Drug Administration (FDA) continued its traditional dual (3) exposure assessment and (4) risk assessment. The
emphasis of ensuring both the efficacy and the safety of NRC (1994) report emphasized the importance of a fifth
drugs and medical devices continued. Increased emphasis element – using the results of the risk analysis to guide
was given by the FDA to veterinary drugs and to the poten- future research and, thus, reduce uncertainty in future risk
tial for veterinary drugs to contaminate meat and milk. estimates. In addition, I have added a sixth over-arching
Increasing public concern for safety/risk and the result- element - risk communication. The hazard identification
ing legislation led to the development of increasingly for- element has been a source of contention and confusion
malized approaches to both safety and risk analysis. This both with the public and in the scientific community,
included more clearly defined roles for using the results of especially with regard to cancer as I will discuss later.
toxicological studies, including studies with laboratory Hazard is defined as the potential for an agent under
animals, to assess the safety, or conversely risk, to humans some conditions of exposure to cause an adverse effect
of the use of pharmaceuticals, other products in commerce, (NRC, 1983, 1994; McClellan, 1999). With this definition
and technologies. the level of exposure or dose required to produce an
adverse health effect is not considered. An agent may be
classified as a hazard irrespective of whether or not the
exposure conditions required to elicit adverse effects are
Toxicology joined to the risk paradigm
relevant to human situations. The exposure–response
As noted earlier, federal legislation passed in the 1970s assessment involves characterization of this relationship
focused on the health impacts of environmental and occu- as it may pertain to likely levels of human exposure. The
pational exposures and led to more formalized approaches exposure assessment quantifies, either retrospectively or
to evaluating the risks and safety of various exposures. The prospectively, the likely duration and intensity of human

Sources of Dose to Health

potential toxicants Exposure biological target responses

Industrial activities Mechanisms Presence of Mechanisms Dose at multiple Mechanisms Acute to chronic
Consumer products influencing toxicant influencing levels from critical leading to responses including
Agricultural practices transport via in different absorption, macro-molecular alterations in both functional
Forage multiple media, air, distribution, to tissues to total function and effects and cancer
Feed pathways water, food metabolism body structure
and excretion

Exposure assessment Toxicokinetics Toxicodynamics

Characterization of hazard and exposure–response relationships

Risk characterization

FIGURE 1.1 Critical linkages for integrating information from sources of toxicants to the development of adverse health effects.
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8 1. CONCEPTS IN VETERINARY TOXICOLOGY

Risk communication

Effectively communicate the total risk process

and risk characterization to all stakeholders

Risk research Risk assessment Risk management

Understanding the 1 Hazard identification Risk management
mechanistic linkages 2 Exposure, dose and decisions incorporate
between sources of response assessment the results of risk
toxicants, exposure, characterizations and
3 Exposure assessment
dose and response public health, economic
4 Risk characterization social and political
5 Identification of considerations
research needs

Action
Identification of research needs

FIGURE 1.2 Risk paradigm for evaluating potential health impacts of a toxicant.

exposure to the hazardous agent. The risk assessment ele- 1

Region where
ment brings together information from the other three ele- excess health
ments to characterize risk as illustrated in Figure 1.1. Risk 10−1 risk can be
measured
is defined as the probability of occurrence of an adverse Supralinear
health effect from exposure to a hazardous agent at a spec- 10−2
U-shaped
Added risk

ified duration and intensity of exposure. As an aside, espe-

10−3
cially in Europe, the word hazard is used as risk has been Region where
defined in the United States. Safety is defined as being a extrapolation
10−4 is required
condition with a high probability of freedom from any
Linear
increase in adverse health outcome when the agent is used 10−5 Threshold
Sublinear
in a specified manner. Obviously, both safety and risk are
Range of ability to measure compounds
relative recognizing that it is not possible to ensure absolute 10−6
freedom from some small level of risk. 0 10−4 10−3 10−2 10−1 1 101 102
The more formalized risk analysis approaches devel- Exposure (ppm)
oped starting in the 1970s built on approaches developed
FIGURE 1.3 Schematic rendering of exposure–response
earlier for providing guidance for controlling occupational relationships for various toxicants.
exposures, the intake of contaminants in food and the
safety of pharmaceutical agents. Pre-World War II, the pri-
mary focus was on adverse health outcomes that caused relationship is shown in Figure 1.3 along with four other
functional impairment such as decreased respiratory func- relationships: sub-linear, linear, supralinear and a U-shaped
tion. As will be discussed later, the issue of carcinogenic or hormetic function. Note that both scales in this schematic
responses received limited attention before World War II. rendering are logarithmic.
The approach to developing guidance for the control of Technically, in hormesis there is a beneficial effect at
toxicants was based on the assumption that a threshold some low level of exposure which decreases with increas-
exists in the exposure (dose)–response relationship – just as ing exposure/dose and at yet higher levels adverse effects
discussed by Paracelsus. The threshold exposure–response become apparent. During the last decade, there has been
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EVOLUTION OF VETERINARY TOXICOLOGY 9

increased discussion of the concept of hormesis in which I worked with a joint AEC–National Aeronautical and
very low-level exposures have positive effects with nega- Space Administration assessing potential human cancer
tive effects observed only at higher exposure levels (Cal- risks of accidents involved with the launch of spacecraft
abrese and Baldwin, 2003; Calabrese and Blain, 2005). The containing plutonium-238 fueled thermal electric power
concept of hormesis is well known to veterinarians who systems.
are aware that certain agents, such as vitamins and min- Another factor influencing public concern was the
erals, are essential for life at low concentrations and can increasing incidence of total cancers being observed in all
produce toxicity with excess intake. of the economically developed countries including the US
As an aside, there has been on-going debate for decades driven largely by lung cancer. It is now well known that
as to whether linear exposure–response relationships, the increase in lung cancer, first observed in men and then
especially for cancer, are realistic, i.e. an added level of in women, was largely related to cigarette smoking. Rachel
exposure, regardless of how small, results in a calculable Carson’s book also helped to create concern for exposure
monotonic increase in cancer risk. It has been argued to man-made chemicals contributing to the increasing
by some that the linear exposure–response model is appro- incidence of cancer. It is now known that this is not the
priate for regulatory purposes for assessing cancer case (Gold et al., 2003).
risks because every dose of a new agent is added to a The experience with radiation soon resulted in its use as
background of genetic damage in somatic cells arising a proto-typical carcinogen in developing approaches to
from multiple agents and endogenous factors. risk analysis and risk regulation. Albert (1994) documented
The early development of threshold limit values (TLVs) the development of the USEPA’s approach to assessing
for control of occupational exposures by the American Con- cancer risks. Key assumptions in the approach were (a)
ference of Governmental Industrial Hygienists (ACGIH), cancer-causing chemical agents acted like radiation in
organized in 1938, assumed the existence of thresholds in causing cancer; (b) there was a linear relationship between
exposure–response relationships. The initial data were exposure (dose) and increased risk of cancer extending to
provided primarily by opportunistic studies of exposed the lowest levels of exposure; (c) agents causing cancer in
human populations. In the absence of human data, data laboratory animals could be viewed as also causing cancer
from controlled exposure studies in laboratory animals in people and (d) exposure–response relationships could
were used. This necessitated the use of safety factors to be extrapolated between species by considering differences,
account for inter-individual variability, inter-species extrap- body weight and surface area, i.e. metabolic activity. These
olation and duration of the study as will be discussed later. assumptions were viewed as default options to be used in
The original safety factors were formally proposed by the absence of specific scientific data to the contrary
Lehman and Fitzhugh (1954) of the FDA. Later, the USEPA (McClellan, 1994, 1999, 2003; NRC, 1994).
was organized and began using the same factors. However, In response to public concern for chemicals causing can-
the EPA identifies them as uncertainty factors apparently cer, the International Agency for Research on Cancer
out of a desire to avoid use of the potentially contentious (IARC) became the first organization to propose a scheme
word – safety. for classifying agents as to their carcinogenic potential
Post-World War II increased public concern developed (IARC, 1972). The view was that if cancer-causing chemi-
for the occurrence of cancer. This was stimulated by multi- cals or other agents, such as radiation, or workplace condi-
ple factors. Extensive research conducted during and after tions involving exposure to chemicals or other agents
the war on the effects of both external ionizing radia- could be identified, then these could be controlled and the
tion and internally deposited radionuclides emphasized occurrence of cancer in people reduced. The IARC carcino-
the importance of cancer as a radiation-induced disease. gen classification scheme considers human, laboratory ani-
Concern for radiation-induced cancer was further height- mal and supporting data to classify agents or workplace
ened when the intensive follow-up of Japanese A-bomb conditions as (1) carcinogenic to humans, (2) probably car-
survivors revealed an increase, first in hematopoietic cinogenic to humans, (3) possibly carcinogenic to humans,
neoplasms, and, later in solid cancers. These findings soon (4) not likely to be carcinogenic to humans or (5) not classi-
led to abandoning a threshold approach to evaluating fied as to carcinogenicity. The IARC classification is strictly
radiation risks in favor of using a probabilistic approach to hazard oriented, it does not formally evaluate the potency
assess the health risks of using radiation devices in space of these agents for causing cancer at a specific level of expo-
and nuclear power. The probabilistic approach using the sure. The USEPA, the NTP and other organizations have
linear exposure–response model discussed earlier was developed similar carcinogen classification schemes (EPA,
convenient to use because it could be readily applied to 1986, 2005a, b; NTP, 2005). In recent years, IARC (1991) has
assessing the risks to individuals or populations. My first made provision for increased use of mechanistic data in
experience with probabilistic risk assessment came in the classifying chemicals as human carcinogens. Both the EPA
mid-1960s when I was on a temporary assignment with and NTP now also give increased emphasis to the use of
what was then the US Atomic Energy Commission (AEC). mechanistic data in classifying chemicals as carcinogens