CONTENTS
PREFACE TO THE FOURTH EDITION
CONTRIBUTORS
PART I INTRODUCTION
CHAPTER 1 Introduction to Toxicology
1.1 DEFINITION AND SCOPE
1.2 RELATIONSHIP TO OTHER SCIENCES
1.3 A BRIEF HISTORY OF TOXICOLOGY
1.4 DOSE—RESPONSE RELATIONSHIPS
1.5 SOURCES OF TOXIC COMPOUNDS
1.6 MOVEMENT OF TOXICANTS IN THE ENVIRONMENT
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
CHAPTER 2 Introduction to Biochemical and Molecular Methods in Toxicology
2.1 INTRODUCTION
2.2 CELL CULTURE TECHNIQUES
2.3 MOLECULAR TECHNIQUES
2.4 IMMUNOCHEMICAL TECHNIQUES
2.5 PROTEOMICS
2.6 METABOLOMICS
2.7 BIOINFORMATICS
2.8 SUMMARY AND CONCLUSIONS
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
PART II CLASSES OF TOXICANTS
CHAPTER 3 Exposure Classes, Toxicants in Air, Water, Soil, Domestic, and Occupational Settings
3.1 AIR POLLUTANTS
3.2 WATER AND SOIL POLLUTANTS
3.3 OCCUPATIONAL TOXICANTS
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
CHAPTER 4 Classes of Toxicants: Use Classes
4.1 INTRODUCTION
4.2 METALS
4.3 AGRICULTURAL CHEMICALS (PESTICIDES)
4.4 FOOD ADDITIVES AND CONTAMINANTS
4.5 TOXINS
4.6 SOLVENTS
4.7 THERAPEUTIC DRUGS
4.8 DRUGS OF ABUSE
4.9 COMBUSTION PRODUCTS
4.10 COSMETICS
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
PART III TOXICANT PROCESSING IN VIVO
CHAPTER 5 Absorption and Distribution of Toxicants
5.1 INTRODUCTION
5.2 CELL MEMBRANES
5.3 MECHANISMS OF TRANSPORT
5.4 PHYSICOCHEMICAL PROPERTIES RELEVANT TO DIFFUSION
5.5 ROUTES OF ABSORPTION
5.6 TOXICANT DISTRIBUTION
5.7 TOXICOKINETICS
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
CHAPTER 6 Metabolism of Toxicants
6.1 INTRODUCTION
6.2 PHASE I REACTIONS
6.3 PHASE II REACTIONS
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
CHAPTER 7 Reactive Metabolites
7.1 INTRODUCTION
7.2 ACTIVATION ENZYMES
7.3 NATURE AND STABILITY OF REACTIVE METABOLITES
7.4 FATE OF REACTIVE METABOLITES
7.5 FACTORS AFFECTING TOXICITY OF REACTIVE METABOLITES
7.6 REACTIVE OXYGEN SPECIES
7.7 EXAMPLES OF ACTIVATING REACTIONS
7.8 SUMMARY AND CONCLUSIONS
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
CHAPTER 8 Chemical and Physiological Effects on Xenobiotic Metabolism
8.1 INTRODUCTION
8.2 NUTRITIONAL EFFECTS
8.3 PHYSIOLOGICAL EFFECTS
8.4 COMPARATIVE AND GENETIC EFFECTS
8.5 CHEMICAL EFFECTS
8.6 ENVIRONMENTAL EFFECTS
8.7 SUMMARY AND CONCLUSIONS
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
CHAPTER 9 Elimination of Toxicants
9.1 INTRODUCTION
9.2 TRANSPORT
9.3 RENAL ELIMINATION
9.4 HEPATIC ELIMINATION
9.5 RESPIRATORY ELIMINATION
9.6 CONCLUSION
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
PART IV TOXIC ACTION
CHAPTER 10 Acute Toxicity
10.1 INTRODUCTION
10.2 ACUTE EXPOSURE AND EFFECT
10.3 DOSE—RESPONSE RELATIONSHIPS
10.4 NONCONVENTIONAL DOSE—RESPONSE RELATIONSHIPS
10.5 ALTERNATIVE METHODS
10.6 MECHANISMS OF ACUTE TOXICITY
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
CHAPTER 11 Chemical Carcinogenesis and Mutagenesis
11.1 DNA DAMAGE AND MUTAGENESIS
11.2 GENERAL ASPECTS OF CANCER
11.3 HUMAN CANCER
11.4 CLASSES OF AGENTS THAT ARE ASSOCIATED WITH CARCINOGENESIS
11.5 GENERAL ASPECTS OF CHEMICAL CARCINOGENESIS
11.6 ONCOGENES
11.7 TUMOR SUPPRESSOR GENES
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
CHAPTER 12 Teratogenesis
12.1 INTRODUCTION
12.2 OVERVIEW OF EMBRYONIC DEVELOPMENT
12.3 PRINCIPLES OF TERATOGENESIS
12.4 MECHANISMS OF TERATOGENESIS
12.5 FUTURE CONSIDERATIONS
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
PART V ORGAN TOXICITY
CHAPTER 13 Hepatotoxicity
13.1 INTRODUCTION
13.2 SUSCEPTIBILITY OF THE LIVER
13.3 TYPES OF LIVER INJURY
13.4 MECHANISMS OF HEPATOTOXICITY
13.5 EXAMPLES OF HEPATOTOXICANTS
13.6 METABOLIC ACTIVATION OF HEPATOTOXICANTS
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
CHAPTER 14 Nephrotoxicity
14.1 INTRODUCTION
14.2 FACTORS CONTRIBUTING TO NEPHROTOXICITY
14.3 EXAMPLES OF NEPHROTOXICANTS
14.4 SUMMARY
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
CHAPTER 15 Toxicology of the Nervous System
15.1 INTRODUCTION
15.2 THE NERVOUS SYSTEM
15.3 TOXICANT EFFECTS ON THE NERVOUS SYSTEM
15.4 NEUROTOXICITY TESTING
15.5 SUMMARY
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
CHAPTER 16 Reproductive System
16.1 INTRODUCTION
16.2 THE HYPOTHALAMIC-PITUITARY-GONADAL AXIS
16.3 MALE REPRODUCTIVE PHYSIOLOGY
16.4 DISRUPTION OF MALE REPRODUCTION BY TOXICANTS
16.5 FEMALE REPRODUCTIVE PHYSIOLOGY
16.6 DISRUPTION OF FEMALE REPRODUCTION BY TOXICANTS
16.7 SUMMARY
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
CHAPTER 17 Endocrine Toxicology
17.1 INTRODUCTION
17.2 ENDOCRINE SYSTEM
17.3 ENDOCRINE DISRUPTION
17.4 INCIDENTS OF ENDOCRINE TOXICITY
17.5 CONCLUSION
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
CHAPTER 18 Respiratory Toxicology
18.1 INTRODUCTION
18.2 ANATOMY AND FUNCTION OF THE RESPIRATORY TRACT
18.3 TOXICANT-INDUCED LUNG INJURY, REMODELING, AND REPAIR
18.4 OCCUPATIONAL AND ENVIRONMENTAL LUNG DISEASES
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
CHAPTER 19 Immune System*
19.1 INTRODUCTION
19.2 THE IMMUNE SYSTEM
19.3 IMMUNE SUPPRESSION
19.4 CLASSIFICATION OF IMMUNE-MEDIATED INJURY (HYPERSENSITIVITY)
19.5 EFFECTS OF CHEMICALS ON ALLERGIC DISEASE
19.6 OTHER ISSUES: AUTOIMMUNITY AND THE DEVELOPING IMMUNE SYSTEM
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
PART VI APPLIED TOXICOLOGY
CHAPTER 20 Toxicity Testing
20.1 INTRODUCTION
20.2 EXPERIMENTAL ADMINISTRATION OF TOXICANTS
20.3 CHEMICAL AND PHYSICAL PROPERTIES
20.4 EXPOSURE AND ENVIRONMENTAL FATE
20.5 IN VIVO TESTS
20.6 IN VITRO AND OTHER SHORT-TERM TESTS
20.7 ECOLOGICAL EFFECTS
20.8 RISK ANALYSIS
20.9 THE FUTURE OF TOXICITY TESTING
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
CHAPTER 21 Forensic and Clinical Toxicology
21.1 INTRODUCTION
21.2 FORENSIC TOXICOLOGY
21.3 CLINICAL TOXICOLOGY
21.4 ANALYTICAL METHODS IN FORENSIC AND CLINICAL TOXICOLOGY
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
CHAPTER 22 Prevention of Toxicity
22.1 INTRODUCTION
22.2 LEGISLATION AND REGULATION
22.3 PREVENTION IN DIFFERENT ENVIRONMENTS
22.4 EDUCATION
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
CHAPTER 23 Human Health Risk Assessment
23.1 INTRODUCTION
23.2 RISK ASSESSMENT METHODS
23.3 NONCANCER RISK ASSESSMENT
23.4 CANCER RISK ASSESSMENT
23.5 PBPK MODELING
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
PART VII ENVIRONMENTAL TOXICOLOGY
CHAPTER 24 Toxicant Analysis: Analytical Methods and Quality Assurance
24.1 INTRODUCTION
24.2 ENVIRONMENTAL SAMPLE COLLECTION METHODS
24.3 ANALYTICAL TECHNIQUES
24.4 QUANTIFICATION, QA, AND QC
24.5 SUMMARY
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
CHAPTER 25 Basics of Environmental Toxicology
25.1 INTRODUCTION
25.2 ENVIRONMENTAL PERSISTENCE
25.3 BIOACCUMULATION
25.4 TOXICITY
25.5 CONCLUSION
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
CHAPTER 26 Transport and Fate of Toxicants in the Environment
26.1 INTRODUCTION
26.2 SOURCES OF TOXICANTS TO THE ENVIRONMENT
26.3 TRANSPORT PROCESSES
26.4 EQUILIBRIUM PARTITIONING
26.5 TRANSFORMATION PROCESSES
26.6 ENVIRONMENTAL FATE MODELS
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
CHAPTER 27 Environmental Risk Assessment
27.1 INTRODUCTION
27.2 FORMULATING THE PROBLEM
27.3 ANALYZING EXPOSURE AND EFFECTS INFORMATION
27.4 CHARACTERIZING RISK
27.5 MANAGING RISK
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
PART VIII NEW APPROACHES IN TOXICOLOGY
CHAPTER 28 Perspectives on Informatics in Toxicology
28.1 INTRODUCTION
28.2 TRANSCRIPTOMICS
28.3 ANNOTATION RESOURCES
28.4 GENOME SEQUENCING, RESEQUENCING AND GENOTYPING
28.5 EPIGENOMIC PROFILING
28.6 COMPUTATIONAL TOXICOLOGY
28.7 INFORMATICS TOOLS IN TOXICOLOGY
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTION
CHAPTER 29 Future Considerations
29.1 INTRODUCTION
29.2 RISK ASSESSMENT
29.3 RISK MANAGEMENT
29.4 RISK COMMUNICATION
29.5 IN VIVO TOXICITY
29.6 IN VITRO TOXICITY
29.7 MOLECULAR AND BIOCHEMICAL TOXICOLOGY
29.8 DEVELOPMENT OF SELECTIVE TOXICANTS
29.9 SUMMARY AND CONCLUSIONS
BIBLIOGRAPHY AND SUGGESTED READING
SAMPLE QUESTIONS
GLOSSARY
INDEX
Copyright © 2010 John Wiley & Sons, Inc. All rights reserved.
Published by John Wiley & Sons, Inc., Hoboken, New Jersey.
Published simultaneously in Canada.
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, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008, or online at http://www.wiley.com/go/permission.
Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.
For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317) 572-4002.
Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com.
Library of Congress Cataloging-in-Publication Data:
A textbook of modern toxicology/edited by Ernest Hodgson. —4th ed.
p. cm.
ISBN 978-0-470-46206-5 (cloth)
1. Toxicology. I. Hodgson, Ernest, 1932-
RA1211.H62 2010
615.9—dc22
2009045883
PREFACE TO THE FOURTH EDITION
There are some excellent general reference works in toxicology, including Casarett and Doull’s Toxicology, 6th edition, edited by Curt Klaassen, and the 13-volume Comprehensive Toxicology, the second edition currently being edited by Charlene McQueen, as well as many specialized monographs on particular topics. However, the scarcity of textbooks designed for teacher and student to use in the classroom setting that impelled us to produce editions 1 through 3 of this work is still apparent and the choice continues to be limited. The authors are, or have been, involved in teaching general toxicology at North Carolina State University and thus have insights into the actual teaching process and in the broader scope of toxicology as well as the subject matter of their areas of specialization.
Rapid advances are occurring in toxicology, particularly in the molecular and integrative aspects, and we hope these are reflected in this textbook. As an aid to students and teaching faculty, we have added sample questions to each chapter. Answering these questions not only indicates that the material presented has been understood but is, in itself, a learning experience.
At North Carolina State University, we continue to teach a course in general toxicology (TOX801) that is open to graduate students and undergraduate upperclassmen. Our experience leads us to believe that this textbook is suitable, in the junior or senior year, for undergraduate students with some background in chemistry, biochemistry, and animal physiology. For graduate students, it is intended to lay the foundation for subsequent specialized courses in toxicology, such as those in biochemical and molecular toxicology, environmental toxicology, chemical carcinogenesis, risk assessment, and so forth.
We share the view that an introductory text must present all of the necessary fundamental information to fulfill this purpose, but in as uncomplicated a manner as possible. To enhance readability, references have been omitted from the text, although Suggested Reading or Bibliography is recommended at the end of each chapter.
As with previous editions, the amount of material and the detail with which some of it is presented, is more than is needed for the average general toxicology course. This, however, will permit each instructor to select and emphasize those areas they feel need particular emphasis. The obvious biochemical and molecular bias of some chapters is not accidental; rather, it is based on the philosophy that progress in toxicology continues to depend on further understanding of the fundamental basis of toxic action at the cellular and molecular levels. The depth of coverage of each topic represents that chapter author’s judgment of the amount of material appropriate to the beginning level as compared to that appropriate to a more advanced course or text such as Smart and Hodgson, Molecular and Biochemical Toxicology, 4th edition (John Wiley and Sons, 2008).
Thanks to all of the authors and to the students and faculty of the Department of Environmental and Molecular Toxicology at North Carolina State University. Particular thanks to Jonathan Rose of John Wiley and Sons, who facilitated the project by his hard work, his goodwill and, not least, for his patience.
Raleigh, North Carolina
March 2010
ERNEST HODGSON
CONTRIBUTORS
Jill A. Barnes, Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina
Ronald E. Baynes, Center for Chemical Toxicology Research and Pharmacokinetics, North Carolina State University, Raleigh, North Carolina
Bonita L. Blake, Department of Pharmacology and Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
James C. Bonner, Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina
David B. Buchwalter, Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina
W. Gregory Cope, Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina
Helen Cunny, National Institute for Environmental Health Sciences, Research Triangle Park, North Carolina
Ernest Hodgson, Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina
Chris Hofelt, Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina
Seth W. Kullman, Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina
Gerald A. LeBlanc, Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina
Carolyn J. Mattingly, Mount Desert Island Biological Laboratory, Salisbury Cove, Maine
Joel N. Meyer, Nicholas School of the Environment, Duke University, Durham, North Carolina
Sharon A. Meyer, Department of Toxicology, University of Louisiana, Monroe, Louisiana
Heather Patisaul, Department of Biology, North Carolina State University, Raleigh, North Carolina
Randy L. Rose, (deceased), Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina
MaryJane Selgrade, National Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina
Damian Shea, Departments of Biology and Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina
Robert C. Smart, Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina
Joan Tarloff, Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, Philadelphia, Pennsylvania
Andrew D. Wallace, Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina
Ida M. Washington, Department of Comparative Medicine, University of Washington School of Medicine, Seattle, Washington
Andrew Whitehead, Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana
PART I
INTRODUCTION
CHAPTER 1
Introduction to Toxicology
Since the publication of the 3rd edition of this textbook (2004) major changes have been initiated in toxicology as the tools of molecular biology, genomics, proteomics, metabolomics, bioinformatics, and systems biology are increasingly brought to bear on the critical areas of mode of action, toxicity testing, and risk analysis. Chapter 2 provides information on new methodology and Part VIII—New Approaches in Toxicology is composed of two chapters of commentary on the current and expected impact of these new methods. While the traditional aspects and subdisciplines of toxicology, as outlined below, are still active and viable, during the next few years all are likely to be impacted and their development accelerated by these new approaches.
1.1 DEFINITION AND SCOPE
Toxicology can be defined as that branch of science that deals with poisons, and a poison can be defined as any substance that causes a harmful effect when administered, either by accident or by design, to a living organism. By convention, toxicology also includes the study of harmful effects caused by physical phenomena, such as radiation of various kinds, noise, and so on. In practice, however, many complications exist beyond these simple definitions, both in bringing more precise definition to the meaning of poison and to the measurement of toxic effects. Broader definitions of toxicology, such as “the study of the detection, occurrence, properties, effects, and regulation of toxic substances,” although more descriptive, do not resolve the difficulties. Toxicity itself can rarely, if ever, be defined as a single molecular event, but is, rather, a cascade of events starting with exposure, proceeding through distribution and metabolism, and ending with interaction with cellular macromolecules (usually DNA or protein) and the expression of a toxic end point (Figure 1.1). This sequence may be mitigated by excretion and repair. It is to the complications, and to the science behind them and their resolution, that this textbook is dedicated, particular to the how and why certain substances cause disruptions in biologic systems that result in toxic effects. Taken together, these difficulties and their resolution circumscribe the perimeter of the science of toxicology.
Figure 1.1 Fate and effect of toxicants in the body.
The study of toxicology serves society in many ways, not only to protect humans and the environment from the deleterious effects of toxicants, but also to facilitate the development of more selective toxicants such as anticancer and other clinical drugs, pesticides, and so forth.
Poison is a quantitative concept, almost any substance being harmful at some doses but, at the same time, being without harmful effect at some lower dose. Between these two limits, there is a range of possible effects, from subtle long-term chronic toxicity to immediate lethality. Vinyl chloride may be taken as an example. It is a potent hepatotoxicant at high doses, a carcinogen with a long latent period at lower doses, and apparently without effect at very low doses. Clinical drugs are even more poignant examples because, although therapeutic and highly beneficial at some doses, they are not without deleterious side effects and may be lethal at higher doses. Aspirin (acetylsalicylic acid), for example, is a relatively safe drug at recommended doses and is taken by millions of people worldwide. At the same time, chronic use can cause deleterious effects on the gastric mucosa, and it is fatal at a dose of about 0.2–0.5 g/kg. Approximately 15% of reported accidental deaths from poisoning in children result from ingestion of salicylates, particularly aspirin.
The importance of dose is well illustrated by metals that are essential in the diet but are toxic at higher doses. Thus, iron, copper, magnesium, cobalt, manganese, and zinc can be present in the diet at too low a level (deficiency), at an appropriate level (maintenance), or at too high a level (toxic). The question of dose—response relationships is fundamental to toxicology (see Section 1.4).
The definition of a poison, or toxicant, also involves a qualitative biological aspect because a compound, toxic to one species or genetic strain, may be relatively harmless to another. For example, carbon tetrachloride, a potent hepatotoxicant in many species, is relatively harmless to the chicken. Certain strains of rabbit can eat Belladonna with impunity while others cannot. Compounds may be toxic under some circumstances but not others or, perhaps, toxic in combination with another compound but nontoxic alone. The methylenedioxyphenyl insecticide synergists, such as piperonyl butoxide, are of low toxicity to both insects and mammals when administered alone, but are, by virtue of their ability to inhibit xenobioticmetabolizing enzymes, capable of causing dramatic increases in the toxicity of other compounds.
The measurement of toxicity is also complex. Toxicity may be acute or chronic, and may vary from one organ to another as well as with age, genetics, gender, diet, physiological condition, or the health status of the organism. As opposed to experimental animals, which are highly inbred, genetic variation is a most important factor in human toxicity since the human population is highly outbred and shows extensive genetic variation. Even the simplest measure of toxicity, the LD50 (lethal dose; the dose required to kill 50% of a population under stated conditions) is highly dependent on the extent to which the above variables are controlled. LD50 values, as a result, vary markedly from one laboratory to another.
Exposure of humans and other organisms to toxicants may result from many activities: intentional ingestion, occupational exposure, environmental exposure, as well as accidental and intentional (suicidal or homicidal) poisoning. The toxicity of a particular compound may vary with the portal of entry into the body, whether through the alimentary canal, the lungs, or the skin. Experimental methods of administration such as injection may also give highly variable results; thus, the toxicity from intravenous (IV), intraperitoneal (IP), intramuscular (IM), or subcutaneous (SC) injection of a given compound may be quite different. Thus, toxicity may vary as much as 10-fold with the route of administration. Following exposure, there are multiple possible routes of metabolism, both detoxifying and activating, and multiple possible toxic end points (Figure 1.1).
Attempts to define the scope of toxicology, including that which follows, must take into account that the various subdisciplines are not mutually exclusive and are frequently interdependent. Due to overlapping of mechanisms as well as use and chemical classes of toxicants, clear division into subjects of equal extent or importance is not possible.
Many specialized terms are used in the various subdisciplines of toxicology as illustrated in the Dictionary of Toxicology, 2nd edition (Hodgson et al., 1998). However, some terms are of particular importance to toxicology in general; these and some more recent terms are defined in the glossary to be found at the end of this volume.
Although B through F (following) include subdivisions that encompass essentially all of the many aspects of toxicology, there are two new approaches (A, following) that serve to integrate the discipline as a whole.
A. Integrative Approaches
1. Bioinformatics. In the narrow and original meaning, bioinformatics was the application of information technology to molecular biology. While this is still the most important aspect of bioinformatics, it is increasingly applied to other fields of biology, including molecular and other aspects of toxicology. It is characterized by computationally intensive methodology and includes the design of large databases and the development of techniques for their manipulation, including data mining.
2. Systems Biology. Although systems biology has been defined in a number of ways, some involving quite simple approaches to limited problems, in the currently most commonly accepted sense, it is an integrative approach to biological structure and function that will be of increasing importance to biology in general and toxicology in particular. In large part, biology has been reductionist throughout its history, studying organs as components of organisms, cells as components of organs, enzymes, nucleic acids, and so on, as components of cells, with the goal of describing function at the molecular level. Systems biology, on the other hand, is holistic and has the objective of discerning interactions between components of biological systems and describing these interactions in rigorous mathematical models. Furthermore, the proponents of systems biology aim to integrate these models at higher and higher levels or organization in order to develop an integrated model of the entire organism.
Clearly, systems biology is in its infancy; however, the ultimate value of having an integrative model that could clarify all of the effects, from the most proximate to the ultimate, of a toxicant on a living organism, will provide enormous benefits not only for fundamental studies but in such applied areas as human health risk assessment.
B. Modes of Toxic Action. This includes the consideration, at the fundamental level of organ, cell, and molecular function, of all events leading to toxicity in vivo: uptake, distribution, metabolism, mode of action, and excretion. The term mechanism of toxic action is now more generally used to describe an important molecular event in the cascade of events leading from exposure to toxicity, such as the inhibition of acetylcholinesterase in the toxicity of organophosphorus and carbamate insecticides. Important aspects include the following:
1. Biochemical and molecular toxicology consider events at the biochemical and molecular levels, including enzymes that metabolize xenobiotics, generation of reactive intermediates, interaction of xenobiotics or their metabolites with macromolecules, gene expression in metabolism and modes of action, signaling pathways in toxic action, and so on.
2. Behavioral toxicology deals with the effects of toxicants on animal and human behavior, which is the final integrated expression of nervous function in the intact animal. This involves both the peripheral and central nervous systems, as well as effects mediated by other organ systems, such as the endocrine glands.
3. Nutritional toxicology deals with the effects of diet on the expression of toxicity and with the mechanisms of these effects.
4. Carcinogenesis includes the chemical, biochemical, and molecular events that lead to the large number of effects on cell growth collectively known as cancer.
5. Teratogenesis includes the chemical, biochemical, and molecular events that lead to deleterious effects on development.
6. Mutagenesis is concerned with toxic effects on the genetic material and the inheritance of these effects.
7. Organ toxicity considers effects at the level of organ function (e.g., neurotoxicity, hepatotoxicity, and nephrotoxicity).
C. Measurement of Toxicants and Toxicity. These important aspects deal primarily with analytical chemistry, bioassay, and applied mathematics, and are designed to provide the methodology to answer certain critically important questions. Is the substance likely to be toxic? What is its chemical identity? How much of it is present? How can we assay its toxic effect, and what is the minimum level at which this toxic effect can be detected? A number of important fields are included:
1. Analytical toxicology is a branch of analytical chemistry concerned with the identification and assay of toxic chemicals and their metabolites in biological and environmental materials.
2. Genomics. The sometimes stated distinction that genomics deals with genomes while molecular biology deals with single genes is unrealistic and unnecessary; it is more appropriate to regard genomics as an aspect of molecular biology that deals not only with genomes and gene expression but also such important aspects as genetic polymorphisms, particularly single nucleotide polymorphisms (SNPs). Techniques, such as microarrays, are now available to examine simultaneously the expression of very large numbers of genes.
3. Proteomics deals with the protein complement of organisms, the entire complement being known as the proteome. Thus, while genomics is concerned with gene expression, proteomics examines the products of the expressed genes.
4. Metabolomics is the next step in the sequence from genomics through proteomics and is concerned with the profile of small molecules produced by the metabolic processes of an organism. Changes in the profile in response to chemical stress are of importance to both fundamental and applied toxicology.
5. Toxicity testing involves the use of living systems to estimate toxic effects. It covers the gamut from short-term tests for genotoxicity such as the Ames test and cell culture techniques to the use of intact animals for a variety of tests from acute toxicity to lifetime chronic toxicity. Although the term “bioassay” is used properly only to describe the use of a living organism to quantitate the amount of a particular toxicant present, it is frequently used to describe any in vivo toxicity test.
6. Toxicologic pathology is that branch of pathology that deals with the effects of toxic agents manifested as changes in subcellular, cellular, tissue, or organ morphology.
7. Structure-activity studies are concerned with the relationship between the chemical and physical properties of a chemical and toxicity and, particularly, the use of such relationships as predictors of toxicity.
8. Biomathematics and statistics relate to many areas of toxicology. They deal with data analysis, the determination of significance, and the formulation of risk estimates and predictive models.
9. Epidemiology, as it applies to toxicology, is of great importance as it deals with the relationship between chemical exposure and human disease in actual populations, rather than in experimental settings.
D. Applied Toxicology. This includes the various aspects of toxicology as they apply in the field or the development of new methodology or new selective toxicants for early application in the field setting.
1. Clinical toxicology is the diagnosis and treatment of human poisoning.
2. Veterinary toxicology is the diagnosis and treatment of poisoning in animals other than humans, particularly livestock and companion animals, but not excluding feral species. Other important concerns of veterinary toxicology are the possible transmission of toxins to the human population in meat, fish, milk, and other foodstuffs, and the care and ethical treatment of experimental animals.
3. Forensic toxicology concerns the medicolegal aspects, including detection of poisons in clinical and other samples.
4. Environmental toxicology is concerned with the movement of toxicants and their metabolites and degradation products in the environment and in food chains, and with the effect of such contaminants on individuals and, especially, populations. Because of the large number of industrial chemicals and possibilities for exposure, as well as the mosaic of overlapping laws that govern such exposure, this area of applied toxicology is well developed.
5. Industrial toxicology is a specific area of environmental toxicology that deals with the work environment and constitutes a significant part of industrial hygiene.
E. Chemical Use Classes. This includes the toxicology aspects of the development of new chemicals for commercial use. In some of these use classes, toxicity, at least to some organisms, is a desirable trait; in others, it is an undesirable side effect. Use classes are not composed entirely of synthetic chemicals; many natural products are isolated and are used for commercial and other purposes and must be subjected to the same toxicity testing as that required for synthetic chemicals. Examples of such natural products include the insecticide, pyrethrin, the clinical drug, digitalis, and the drug of abuse, cocaine.
1. Agricultural chemicals include many compounds, such as insecticides, herbicides, fungicides, and rodenticides, in which toxicity to the target organism is a desired quality whereas toxicity to “nontarget species” is to be avoided. Development of such selectively toxic chemicals is one of the applied roles of comparative toxicology.
2. Clinical drugs are properly the province of pharmaceutical chemistry and pharmacology. However, toxic side effects and testing for them clearly fall within the science of toxicology.
3. Drugs of abuse are chemicals taken for psychological or other effects and may cause dependence and toxicity. Many of these are illegal but some are of clinical significance when used correctly.
4. Food additives are of concern to toxicologists only when they are toxic or being tested for possible toxicity.
5. Industrial chemicals are so numerous that testing them for toxicity or controlling exposure to those known to be toxic is a large area of toxicological activity.
6. Naturally occurring substances include many phytotoxins, mycotoxins, minerals, and so on, all occurring in the environment. The recently expanded and now extensive use of herbal “remedies” and dietary supplements has become a cause of concern for toxicologists and regulators. Not only is their efficacy frequently dubious, but their potential toxicity is also largely unknown.
7. Combustion products are not properly a use class but are a large and important class of toxicants, generated primarily from fuels and other industrial chemicals.
F. Regulatory Toxicology. These aspects, concerned with the formulation of laws, and regulations authorized by laws, are intended to minimize the effect of toxic chemicals on human health and the environment.
1. Legal aspects are the formulation of laws and regulations and their enforcement. In the United States, enforcement falls under such government agencies as the Environmental Protection Agency (EPA), the Food and Drug Administration (FDA) and the Occupational Safety and HealthAdministration (OSHA). Similar government agencies exist in many other countries.
2. Risk assessment is the definition of risks, potential risks, and the risk–benefit equations necessary for the regulation of toxic substances. Risk assessment is logically followed by risk communication and risk management. Risk assessment, risk communication, and risk management are frequently referred to as risk analysis.
1.2 RELATIONSHIP TO OTHER SCIENCES
Toxicology is a highly eclectic science and human activity drawing from, and contributing to, a broad spectrum of other sciences and human activities. At one end of the spectrum are those sciences that contribute their methods and philosophical concepts to serve the needs of toxicologists, either in research or in the application of toxicology to human affairs. At the other end of the spectrum are those sciences to which toxicology contributes.
In the first group, chemistry, biochemistry, pathology, physiology, epidemiology, immunology, ecology, and biomathematics have long been important while molecular biology has, in the last two or three decades, contributed to dramatic advances in toxicology.
In the group of sciences to which toxicology contributes significantly are such aspects of medicine as forensic medicine, clinical toxicology, pharmacy, and pharmacology, public health, and industrial hygiene. Toxicology also contributes in an important way to veterinary medicine, and to such aspects of agriculture as the development and safe use of agricultural chemicals. The contributions of toxicology to environmental studies have become increasingly important in recent years.
Clearly, toxicology is preeminently an applied science, dedicated to the enhancement of the quality of life and the protection of the environment. It is also much more. Frequently, the perturbation of normal life processes by toxic chemicals enables us to learn more about the life processes themselves. The use of dinitrophenol and other uncoupling agents to study oxidative phosphorylation and the use of α-amanitin to study RNA polymerases are but two of many examples. The field of toxicology has expanded enormously in recent decades, both in numbers of toxicologists and in accumulated knowledge. This expansion has brought a change from a primarily descriptive science to one which utilizes an extensive range of methodology to study the mechanisms involved in toxic events.
1.3 A BRIEF HISTORY OF TOXICOLOGY
Much of the early history of toxicology has been lost, and in much that has survived, toxicology is of almost incidental importance in manuscripts dealing primarily with medicine. Some, however, deal more specifically with toxic action or with the use of poisons for judicial execution, suicide, or political assassination. Regardless of the paucity of the early record, and given the need for people to avoid toxic animals and plants, toxicology must be one of the oldest practical sciences.
The Egyptian papyrus, Ebers, dating from about 1500 BC, must rank as the earliest surviving pharmacopeia, and the surviving medical works of Hippocrates, Aristotle, and Theophrastus, published during the period 400–250 BC, all include some mention of poisons. The early Greek poet Nicander treats, in two poetic works, animal toxins (Therica) and antidotes to plant and animal toxins (Alexipharmica). The earliest surviving attempt to classify plants according to their toxic and therapeutic effects is that of Dioscorides, a Greek employed by the Roman emperor Nero about 50 AD.
There appear to have been few advances in either medicine or toxicology between the time of Galen (131–200 AD) and that of Paracelsus (1493–1541). It was the latter who, despite frequent confusion between fact and mysticism, laid the groundwork for the later development of modern toxicology by recognizing the importance of the dose–response relationship. His famous statement “All substances are poisons; there is none that is not a poison. The right dose differentiates a poison and a remedy” succinctly summarizes that concept. His belief in the value of experimentation was also a break with earlier tradition.
There were some important developments during the eighteenth century. Probably the best known is the publication of Ramazini’s Diseases of Workers in 1700 which led to his recognition as the father of occupational medicine. The correlation between the occupation of chimney sweeps and scrotal cancer by Percival Pott in 1775 is almost as well-known although it was foreshadowed by Hill’s correlation of nasal cancer and snuff use in 1761.
Orfila, a Spaniard working at the University of Paris in the early nineteenth century, is generally regarded as the father of modern toxicology. He clearly identified toxicology as a separate science and, in 1815, published the first book devoted exclusively to toxicology. An English translation in 1817 was entitled A General System of Toxicology or, A Treatise on Poisons, Found in the Mineral, Vegetable and Animal Kingdoms, Considered in Their Relations with Physiology, Pathology and Medical Jurisprudence. Workers of the late nineteenth century who produced treatises on toxicology include Christian, Kobert, and Lewin. The recognition of the site of action of curare by Claude Bernard (1813–1878) began the modern study of the mechanisms of toxic action. Since then, advances have been numerous—too numerous to list in detail. They have increased our knowledge of the chemistry of poisons, the treatment of poisoning, the analysis of toxicants and toxicity, as well as modes of toxic action and detoxication processes, and specific molecular events in the poisoning process.
With the publication of her controversial book, The Silent Spring, in 1962, Rachel Carson became an important influence in initiating the modern era of environmental toxicology. Her book emphasized stopping the widespread, indiscriminate use of pesticides and other chemicals and advocated use patterns based on sound ecology. Although sometimes inaccurate and with arguments often based on frankly anecdotal evidence, her book is often credited as the catalyst leading to the establishment of the U.S. EPA and she is regarded by many as the mother of the environmental movement.
It is clear, however, that since the 1960s, toxicology has entered a phase of rapid development and has changed from a science that was largely descriptive to one in which the importance of mechanisms of toxic action is generally recognized. Since the 1970s, with increased emphasis on the use of the techniques of molecular biology, the pace of change has increased even further, and significant advances have been made in many areas, including chemical carcinogenesis and xenobiotic metabolism, among many others.
1.4 DOSE—RESPONSE RELATIONSHIPS
As mentioned previously, toxicity is a relative event that depends not only on the toxic properties of the chemical and the dose administered but also on individual and interspecific variation in the metabolic processing of the chemical. The first recognition of the relationship between the dose of a compound and the response elicited has been attributed to Paracelsus (see Section 1.3). It is noteworthy that his statement includes not only that all substances can be toxic at some dose, but that “the right dose differentiates a poison from a remedy,” a concept that is the basis for pharmaceutical therapy.
A typical dose–response curve is shown in Figure 1.2, in which the percentage of organisms or systems responding to a chemical is plotted against the dose. For many chemicals and effects, there will be a dose below where no effect or response is observed. This is known as the threshold dose. This concept is of significance because it implies that a no observed effect level (NOEL) can be determined and that this value can be used to determine the safe intake for food additives and contaminants such as pesticides. Although this is generally accepted for most types of chemicals and toxic effects, for chemical carcinogens acting by a genotoxic mechanism, the shape of the curve is controversial, and for regulatory purposes, their effect is assumed to be a no-threshold phenomenon. Dose—response relationships are discussed in more detail in Chapter 10—Acute Toxicity and Chapter 20—Toxicity Testing.
Figure 1.2 A typical dose-response curve.
1.5 SOURCES OF TOXIC COMPOUNDS
Given the enormous number of toxicants, it is difficult to classify them, either chemically, by function, or by mode of action since many of them would fall into several classes. Some are natural products, many are synthetic organic chemicals of use to society, while some are byproducts of industrial processes and waste disposal. It is useful, however, to categorize them according to the expected routes of exposure or according to their uses.
A. Exposure Classes. Exposure classes include toxicants in food, air, water, and soil as well as toxicants characteristic of domestic and occupational settings. Toxicant use classes are described in detail in Chapter 3.
B. Use Classes. Use classes include drugs of abuse, therapeutic drugs, agricultural chemicals, food additives and contaminants, metals, solvents, combustion products, cosmetics, and toxins. Some of these, such as combustion products, are the products of use processes rather than being use classes. All of these groups of chemicals are discussed in detail in Chapter 4.
1.6 MOVEMENT OF TOXICANTS IN THE ENVIRONMENT
Chemicals released into the environment rarely remain in the form, or at the location, of release. For example, agricultural chemicals used as sprays may drift from the point of application as air contaminants or enter run-off water as water contaminants. Many of these chemicals are susceptible to fungal or bacterial degradation and are rapidly detoxified, frequently being broken down to products that can enter the carbon, nitrogen, and oxygen cycles. Other agricultural chemicals, particularly halogenated organic compounds, are recalcitrant to a greater or lesser degree to metabolism by microorganisms and persist in soil and water as contaminants; they may enter biologic food chains and move to higher trophic levels or persist in processed crops as food contaminants. This same scenario is applicable to any toxicant released into the environment either for a specific use or as a result of industrial processes, combustion, and so on. Chemicals released into the environment are also susceptible to chemical degradation, a process often stimulated by ultraviolet light.
Although most transport between inanimate phases of the environment results in wider dissemination, but, at the same time, dilution of the toxicant in question, transfer between living creatures may result in increased concentration or bioaccumulation. Lipid-soluble toxicants are readily taken up by organisms following exposure in air, water, or soil. Unless rapidly metabolized, they persist in the tissues long enough to be transferred to the next trophic level. At each level, the lipophilic toxicant tends to be retained while the bulk of the food is digested, utilized, and excreted, thus increasing the toxicant concentration. At some point in the chain, the toxicant can become deleterious, particularly if the organism at that level is more susceptible than those at the level preceding it. Thus, the eggshell thinning in certain raptorial birds was almost certainly due to the uptake of DDT (1,1,1-trichloro-2,2bis(4-chlorophenyl) ethane) and DDE (1,1-dichloro-2,2-bis(4-chlorophenyl) ethane) and their particular susceptibility to this type of toxicity. Simplified food chains are shown in Figure 1.3.
Figure 1.3 Examples of simplified food chains.
It is clear that such transport can occur through both aquatic and terrestrial food chains, although in the former, higher members of the chains, such as fish, can accumulate large amounts of toxicants directly from the medium. This accumulation occurs because of the large area of gill filaments, their intimate contact with the water, and the high flow rate of water over them. Given these characteristics and a toxicant with a high partition coefficient between lipid membranes and water, considerable uptake is inevitable.
These and all other environmental aspects of toxicology are discussed in Part VII.
BIBLIOGRAPHY AND SUGGESTED READING
Hodgson, E., R. B. Mailman, and J. E. Chambers, eds. Dictionary of Toxicology, 2nd ed. London: Macmillan, 1998, 504 pp.
Klaassen, C. D., ed. Casarett and Doull’s Toxicology: The Basic Science of Poisons, 6th ed. New York: McGraw-Hill, 2001, 1236 pp.
Smart, R. C. and E. Hodgson, eds. Molecular and Biochemical Toxicology, 4th ed. Hoboken, NJ: Wiley, 2008, 901 pp.
Wexler, P., ed. Encyclopedia of Toxicology, 2nd ed. Oxford, UK: Elsevier, 2005, 4 volumes.
SAMPLE QUESTIONS
1. Briefly define the following terms:
a. Toxicology
b. Poison
c. Genomics
d. Proteomics
e. Metabolomics
2. Toxicity has been described as a cascade of events initiated by exposure to a harmful chemical. Name the principal steps in this cascade.
3. Name and define three important chemical use classes.