The Principles of Toxicology: Environmental and Industrial Applications 2nd Edition

The Principles of Toxicology: Environmental and Industrial Applications 2nd EditionA fully updated and expanded edition of the bestselling guide on toxicology and its practical application. The field of toxicology has grown enormously since Industrial Toxicology: Safety and Health Applications in the Workplace was first published in 1985. And while the original edition was hugely popular among occupational health professionals, the time is ripe to address toxic agents not only in the industrial setting but also in the environment at large.

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Renamed Principles of Toxicology: Environmental and Industrial Applications, this new edition provides health protection professionals as well as environmental scientists with precise, up-to-date, practical information on how to apply the science of toxicology in both the occupational and environmental setting. Through contributions from leading experts in diverse fields, Principles of Toxicology, Second Edition features:

  • Clear explanations of the fundamentals necessary for an understanding of the effects of chemical hazards on human health and ecosystems
  • Coverage of occupational medicine and epidemiological issues
  • The manifestation of toxic agents such as metals, pesticides, organic solvents, and natural toxins
  • Special emphasis on the evaluation and control of toxic hazards
  • Specific case histories on applying risk assessment methods in the modern workplace
  • Ample figures, references, and a comprehensive glossary of toxicological terms

The Principles of Toxicology: Environmental and Industrial Applications 2nd Edition

by Phillip Williams (Author), Phillip L. Williams (Editor), Robert C. James (Editor), Stephen M. Roberts (Editor)
ISBN-13: 978-0471293217
ISBN-10: 0471293210

The Principles of Toxicology: Environmental and Industrial Applications 2nd Edition CONTENTS

1 General Principles of Toxicology 3
Robert C. James, Stephen M. Roberts, and Phillip L. Williams
1.1 Basic Definitions and Terminology 3
1.2 What Toxicologists Study 5
1.3 The Importance of Dose and the Dose–Response Relationship 7
1.4 How Dose–Response Data Can Be Used 17
1.5 Avoiding Incorrect Conclusions from Dose–Response Data 19
1.6 Factors Influencing Dose–Response Curves 21
1.7 Descriptive Toxicology: Testing Adverse Effects of Chemicals and Generating
Dose–Response Data 26
1.8 Extrapolation of Animal Test Data to Human Exposure 28
1.9 Summary 32
References and Suggested Reading 32
2 Absorption, Distribution, and Elimination of Toxic Agents 35
Ellen J. O’Flaherty
2.1 Toxicology and the Safety and Health Professions 35
2.2 Transfer across Membrane Barriers 37
2.3 Absorption 41
2.4 Disposition: Distribution and Elimination 45
2.5 Summary 53
References and Suggested Reading 54
3 Biotransformation: A Balance between Bioactivation and Detoxification 57
Michael R. Franklin and Garold S. Yost
3.1 Sites of Biotransformation 62
3.2 Biotransformation Reactions 65
3.3 Summary 85
Suggested Reading 86
4 Hematotoxicity: Chemically Induced Toxicity of the Blood 87
Robert A. Budinsky Jr.
4.1 Hematotoxicity: Basic Concepts and Background 87
4.2 Basic Hematopoiesis: The Formation of Blood Cells and their
Differentiation 88
4.3 The Myeloid Series: Erythrocytes, Platelets, Granulocytes (Neutrophils),
Macrophages, Eosinophils, and Basophils 91
4.4 The Lymphoid Series: Lymphocytes (B and T Cells) 94
4.5 Direct Toxicological Effects on the RBC: Impairment of Oxygen Transport
and Destruction of the Red Blood Cell 95
4.6 Chemicals that Impair Oxygen Transport 97
4.7 Inorganic Nitrates/Nitrites and Chlorate Salts 99
4.8 Methemoglobin Leading to Hemolytic Anemia: Aromatic Amines and
Aromatic Nitro Compounds 100
4.9 Autoimmune Hemolytic Anemia 101
4.10 Bone Marrow Suppression and Leukemias and Lymphomas 102
4.11 Chemical Leukemogenesis 104
4.12 Toxicities that Indirectly Involve the Red Blood Cell 105
4.13 Cyanide (CN) Poisoning 105
4.14 Hydrogen Sulfide (H2S) Poisoning 105
4.15 Antidotes for Hydrogen Sulfide and Cyanide Poisoning 107
4.16 Miscellaneous Toxicities Expressed in the Blood 108
4.17 Summary 108
References and Suggested Reading 108
5 Hepatotoxicity: Toxic Effects on the Liver 111
Stephen M. Roberts, Robert C. James, and Michael R. Franklin
5.1 The Physiologic and Morphologic Bases of Liver Injury 111
5.2 Types of Liver Injury 116
5.3 Evaluation of Liver Injury 124
References and Suggested Reading 127
6 Nephrotoxicity: Toxic Responses of the Kidney 129
Paul J. Middendorf and Phillip L. Williams
6.1 Basic Kidney Structures and Functions 129
6.2 Functional Measurements to Evaluate Kidney Injury 135
6.3 Adverse Effects of Chemicals on the Kidney 137
6.4 Summary 142
References and Suggested Reading 143
7 Neurotoxicity: Toxic Responses of the Nervous System 145
Steven G. Donkin and Phillip L. Williams
7.1 Mechanisms of Neuronal Transmission 146
7.2 Agents that Act on the Neuron 149
7.3 Agents that Act on the Synapse 151
7.4 Interactions of Industrial Chemical with Other Substances 151
7.5 General Population Exposure to Environmental Neurotoxicants 152
7.6 Evaluation of Injury to the Nervous System 152
7.7 Summary 154
References and Suggested Reading 155
8 Dermal and Ocular Toxicology: Toxic Effects of the Skin and Eyes 157
William R. Salminen and Stephen M. Roberts
8.1 Skin Histology 157
8.2 Functions 158
8.3 Contact Dermatitis 160
8.4 Summary 167
References and Suggested Reading 168
9 Pulmonotoxicity: Toxic Effects in the Lung 169
Cham E. Dallas
9.1 Lung Anatomy and Physiology 169
9.2 Mechanisms of Industrially Related Pulmonary Diseases 181
9.3 Summary 185
References and Suggested Reading 186
10 Immunotoxicity: Toxic Effects on the Immune System 189
Stephen M. Roberts and Louis Adams
10.1 Overview of Immunotoxicity 189
10.2 Biology of the Immune Response 189
10.3 Types of Immune Reactions and Disorders 194
10.4 Clinical Tests for Detecting Immunotoxicity 195
10.5 Tests for Detecting Immunotoxicity in Animal Models 197
10.6 Specific Chemicals that Adversely Affect the Immune System 199
10.7 Multiple-Chemical Sensitivity 203
10.8 Summary 205
References and Suggested Reading 205
11 Reproductive Toxicology 209
Robert P. DeMott and Christopher J. Borgert
11.1 Male Reproductive Toxicology 210
11.2 Female Reproductive Toxicology 218
11.3 Developmental Toxicology 224
11.4 Current Research Concerns 232
11.5 Summary 236
References and Suggested Reading 236
12 Mutagenesis and Genetic Toxicology 239
Christopher M. Teaf and Paul J. Middendorf
12.1 Induction and Potential Consequences of Genetic Change 239
12.2 Genetic Fundamentals and Evaluation of Genetic Change 241
12.3 Nonmammalian Mutagenicity Tests 251
12.4 Mammalian Mutagenicity Tests 253
12.5 Occupational Significance of Mutagens 257
12.6 Summary 261
References and Suggested Reading 263
13 Chemical Carcinogenesis 265
Robert C. James and Christopher J. Saranko
13.1 The Terminology of Cancer 266
13.3 Carcinogenesis by Chemicals 268
13.4 Molecular Aspects of Carcinogenesis 280
13.5 Testing Chemicals for Carcinogenic Activity 289
13.6 Interpretation Issues Raised by Conditions of the Test Procedure 292
13.7 Empirical Measures of Reliability of the Extrapolation 299
13.8 Occupational Carcinogens 301
13.9 Cancer and Our Environment: Factors that Modulate Our Risks to
Occupational Hazards 304
13.10 Cancer Trends and Their Impact on Evaluation of Cancer Causation 319
13.11 Summary 321
References and Suggested Reading 323
14 Properties and Effects of Metals 325
Steven G. Donkin, Danny L. Ohlson, and Christopher M. Teaf
14.1 Classification of Metals 325
14.2 Speciation of Metals 327
14.3 Pharmacokinetics of Metals 328
14.4 Toxicity of Metals 331
14.5 Sources of Metal Exposure 334
14.6 Toxicology of Selected Metals 336
14.7 Summary 343
References and Suggested Reading 343
15 Properties and Effects of Pesticides 345
Janice K. Britt
15.1 Organophosphate and Carbamate Insecticides 346
15.2 Organochlorine Insecticides 352
15.3 Insecticides of Biological Origin 353
15.4 Herbicides 356
15.5 Fungicides 358
15.6 Rodenticides 360
15.7 Fumigants 361
15.8 Summary 362
References and Suggested Reading 363
16 Properties and Effects of Organic Solvents 367
Christopher M. Teaf
16.1 Exposure Potential 367
16.2 Basic Principles 368
16.3 Toxic Properties of Representative Aliphatic Organic Solvents 377
16.4 Toxic Properties of Representative Alicyclic Solvents 378
16.5 Toxic Properties of Representative Aromatic Hydrocarbon Solvents 379
16.6 Toxic Properties of Representative Alcohols 382
16.7 Toxic Properties of Representative Phenols 384
16.8 Toxic Properties of Representative Aldehydes 385
16.9 Toxic Properties of Representative Ketones 388
16.10 Toxic Properties of Representative Carboxylic Acids 389
16.11 Toxic Properties of Representative Esters 390
16.12 Toxic Properties of Representative Ethers 390
16.13 Toxic Properties of Representative Halogenated Alkanes 391
16.14 Toxic Properties of Representative Nitrogen-Substituted Solvents 398
16.15 Toxic Properties of Representative Aliphatic and Aromatic Nitro
Compounds 402
16.16 Toxic Properties of Representative Nitriles (Alkyl Cyanides) 404
16.17 Toxic Properties of the Pyridine Series 405
16.18 Sulfur-Substituted Solvents 405
16.19 Summary 407
References and Suggested Reading 407
17 Properties and Effects of Natural Toxins and Venoms 409
William R. Kem
17.1 Poisons, Toxins, and Venoms 409
17.2 Molecular and Functional Diversity of Natural Toxins and Venoms 410
17.3 Natural Roles of Toxins and Venoms 411
17.4 Major Sites and Mechanisms of Toxic Action 411
17.5 Toxins in Unicellular Organisms 415
17.6 Toxins of Higher Plants 417
17.7 Animal Venoms and Toxins 423
17.8 Toxin and Venom Therapy 430
17.9 Summary 432
Acknowledgments 432
References and Suggested Reading 432
18 Risk Assessment 437
Robert C. James, D. Alan Warren, Christine Halmes, and
Stephen M. Roberts
18.1 Risk Assessment Basics 437
18.3 Exposure Assessment: Exposure Pathways and Resulting Dosages 445
18.4 Dose–Response Assessment 449
18.5 Risk Characterization 460
18.6 Probabilistic Versus Deterministic Risk Assessments 462
18.7 Evaluating Risk from Chemical Mixtures 464
18.8 Comparative Risk Analysis 468
18.9 Risk Communication 472
18.10 Summary 474
References and Suggested Reading 475
19 Example of Risk Assessment Applications 479
Alan C. Nye, Glenn C. Millner, Jay Gandy, and Phillip T. Goad
19.1. Tiered Approach to Risk Assessment 479
19.2. Risk Assessment Examples 480
19.3. Lead Exposure and Women of Child-bearing Age 481
19.4. Petroleum Hydrocarbons: Assessing Exposure and Risk to Mixtures 483
19.5. Risk Assessment for Arsenic 486
19.6. Reevaluation of the Carcinogenic Risks of Inhaled Antimony Trioxide 490
19.7. Summary 496
References and Suggested Reading 497
20 Occupational and Environmental Health 499
Fredric Gerr, Edward Galaid, and Howard Frumkin
20.1 Definition and Scope of the Problem 499
20.2 Characteristics of Occupational Illness 502
20.3 Goals of Occupational and Environmental Medicine 502
20.4 Human Resources Important to Occupational Health Practice 503
20.5 Activities of the Occupational Health Provider 503
20.6 Ethical Considerations 507
20.7 Summary and Conclusion 508
References and Suggested Reading 509
21 Epidemiologic Issues in Occupational and Environmental Health 511
Lora E. Fleming and Judy A. Bean
21.1 A Brief History of Epidemiology 511
21.2 Epidemiologic Causation 512
21.3 Types of Epidemiologic Studies: Advantages and Disadvantages 513
21.4 Exposure Issues 514
21.5 Disease and Human Health Effects Issues 515
21.6 Population Issues 516
21.7 Measurement of Disease or Exposure Frequency 516
21.8 Measurement of Association Or Risk 517
21.9 Bias 519
21.10 Other Issues 520
21.11 Summary 520
References and Suggested Reading 520
22 Controlling Occupational and Environmental Health Hazards 523
Paul J. Middendorf and David E. Jacobs
22.1 Background and Historical Perspective 523
22.2 Exposure Limits 524
22.3 Program Management 530
22.4 Case Studies 541
22.5 Summary 552
References and Suggested Reading 553
Glossary 555
Index 575

The Principles of Toxicology: Environmental and Industrial Applications 2nd Edition

1 General Principles of Toxicology


The intent of this chapter is to provide a concise description of the basic principles of toxicology and to illustrate how these principles are used to make reasonable judgments about the potential health hazards and the risks associated with chemical exposures. This chapter explains
• Some basic definitions and terminology
• What toxicologists study, the scientific disciplines they draw upon, and specialized areas of
interest within toxicology
• Descriptive toxicology and the use of animal studies as the primary basis for hazard
identification, the importance of dose, and the generation of dose–response relationships
• How dose–response data might be used to assess safety or risk
• Factors that might alter a chemical’s toxicity or the dose–response relationship
• The basic methods for extrapolating dose–response data when developing exposure guidelines of public health interest


The literal meaning of the term toxicology is “the study of poisons.” The root word toxic entered the English language around 1655 from the Late Latin word toxicus (which meant poisonous), itself derived from toxikón, an ancient Greek term for poisons into which arrows were dipped. The early history of toxicology focused on the understanding and uses of different poisons, and even today most people tend to think of poisons as a deadly potion that when ingested causes almost immediate harm or death.

As toxicology has evolved into a modern science, however, it has expanded to encompass all forms of adverse health effects that substances might produce, not just acutely harmful or lethal effects. The following definitions reflect this expanded scope of the science of toxicology:

  • Toxic—having the characteristic of producing an undesirable or adverse health effect.
  • Toxicity—any toxic (adverse) effect that a chemical or physical agent might produce within a living organism.
  • Toxicology—the science that deals with the study of the adverse effects (toxicities) chemicals or
    physical agents may produce in living organisms under specific conditions of exposure. It is
    a science that attempts to qualitatively identify all the hazards (i.e., organ toxicities) associated
    with a substance, as well as to quantitatively determine the exposure conditions under which
    those hazards/toxicities are induced. Toxicology is the science that experimentally investigates
    the occurrence, nature, incidence, mechanism, and risk factors for the adverse effects of toxic

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