Haschek and Rousseaux's Handbook of Toxicologic Pathology, Volume 3 : Environmental Toxicologic Pathology and Major Toxicant Classes

Haschek and Rousseaux's Handbook of Toxicologic Pathology, recognized by many as the most authoritative single source of information in the field of toxicologic pathology, has been extensively updated to continue its comprehensive and timely coverage. The fourth edition has been expanded to five separate volumes due to an explosion of information in this field requiring new and updated chapters. Completely revised with a number of new chapters, Volume 3,"Environmental Toxicologic Pathology and Major Toxicant Classes,'' covers the toxicologic pathology of major classes of environmental toxicants. Other volumes in this work round out the depth and breadth of coverage. Volume 1, Principles and the Practice of Toxicologic Pathology, covers the practice of toxicologic pathology in three parts: Principles of Toxicologic Pathology, Methods in Toxicologic Pathology, and the Practice of Toxicologic Pathology. Volume 2 encompasses "Toxicologic Pathology in Safety Assessment" and the application of toxicologic pathology in developing specific product classes, principles of data interpretation for safety assessment. Volumes 4 and 5 provide deep and broad treatment of "Target Organ Toxicity", emphasizing the comparative and correlative aspects of normal biology and toxicant-induced dysfunction, principal methods for toxicologic pathology evaluation, and major mechanisms of toxicity. These volumes comprise the most authoritative reference on toxicologic pathology for pathologists, toxicologists, research scientists, and regulators studying and making decisions on drugs, biologics, medical devices, and other chemicals, including agrochemicals and environmental contaminants. Each volume is being published separately. Cover Haschek and Rousseaux’s Handbook of Toxicologic Pathology Copyright Dedication Contents Contributors About the Editors Editors Associate Editors Illustrations Editor Preface PART 1 Toxicologic Pathology in Environmental and Food Protection 1 . Environmental Toxicologic Pathology and Human Health 1 Introduction 2 History of Carcinogenic Testing in Animal Species 3 Principles of Evaluations for Carcinogenic Potential 4 Examples of Environmental Pollutants 4.1 Workplace Exposure 4.2 General Environmental Contaminants 4.3 Air Pollutants (also see Respiratory Tract, Vol 5, Chap 4) 4.4 Water Pollutants 4.5 Ground and Soil Contamination 4.6 Radiofrequency Radiation (also see Radiation and Other Physical Agents, Vol 3, Chap 14) 4.7 Microplastics and Nanoplastics 5 The Role of Lifestyle and the Environment on Human Health 6 Methods of Toxicity and Carcinogenicity Testing 6.1 Fish Models 6.2 Transgenic Mouse Models 7 Current Considerations for Environmental Toxicity and Carcinogenicity Testing 7.1 Mechanism of Action versus Mode of Action 7.2 Human Relevancy 7.3 Alternative Testing Strategies 8 New Directions for Environmental Toxicity and Carcinogenicity Testing 8.1 Safe and Sustainable Alternatives References 2 . Food and Toxicologic Pathology 1 Introduction 1.2 Overview 2 Chemicals Intentionally Added to Food 2.1 Preservatives 2.2 Food Coloring 2.3 Flavor Enhancers Natural Flavoring Substances Artificial Flavoring Substances 2.4 Emulsifiers, Stabilizers, and Thickeners Emulsifiers Stabilizers Thickeners 2.5 Functional Foods 2.6 Medicated Feed 2.7 Dietary Supplements 3 Contamination of Food 3.1 Environmental Contaminants 3.2 Food Packaging and Food Processing Contaminants/Food Contact Substances Food Packaging Food Processing Food Contact Substances 3.3 Natural Toxins as Food Contaminants Algal Compounds in Food Phycotoxins in Food Cyanotoxins Marine Algal Toxins Domoic Acid and Amnesic Shellfish Poisoning Mycotoxins Bacterial Toxins 4 Compounds with Toxic Properties Naturally Present in Certain Foods 4.1 Cyanogenic Glycosides 4.2 Glucosinolates Brassica sp. 5 Novel Foods 5.1 Genetically Modified Food 5.2 Novel Food Colors—Anthocyanins 5.3 Novel Preservatives—Amygdalin 5.4 Novel Emulsifiers—Yeast 5.5 Novel Sweeteners—Stevia 5.6 Novel Proteins—Cell-Based Meats 5.7 Novel Oils—Olestra 5.8 Novel Carbohydrates—PrecticX 5.9 Recombinant Bovine Somatotropin 5.10 Cannabis—Cannabidiol 5.11 Nanomaterials 5.12 Probiotics and Prebiotics—Intelligent Labs Probiotics with Prebiotics 6 Adverse Reactions to Food Constituent 6.1 Food Allergies 6.2 Allergy-like Food Poisoning 6.3 Adverse Reactions to Gluten and Gluten-Related Disorders Celiac Disease “Leaky Gut” Nonceliac Gluten Sensitivity Wheat Allergy 6.4 Exposure of a Susceptible Population 6.5 Direct Chemical Toxicity 6.6 Nonallergic Food Hypersensitivity and Intolerance 6.7 Food Color and Food Allergy 7 Mechanism of Action of Clinical Disorders Related to Food 7.1 Gut Microbiota and Adverse Reactions to Food Microbiome and Cytochrome P450 Microbiome and Immunity Microbiome and Food Additives 7.2 Neurotransmission Excitatory Amino Acids Excitotoxicity of Glutamate Glutamate, GABA, and Glutamate Receptors Monosodium Glutamate Domoic Acid Gulf War Illness Serotonin Psilocybin—Mushrooms Other Hallucinogens that May Contaminate Food Cannabinoids 7.3 Channel Blockers Saxitoxin Tetrodotoxin 7.4 Endocrine Modifiers Goitrogens Phytoestrogens Estrogenic Mycotoxins 8 Safety Assessment of Food 8.1 Risk/Safety Assessment in Food 8.2 Food Additives Acceptable Daily Intake Food Colors 8.3 Food Contaminants Residues Maximum Residue Limit Withdrawal Periods Antimicrobial Resistance: More than Residues Clenbuterol: Withdrawal because of Residues rBST: Minimal Residues, Withdrawn because of Animal Welfare Issues Functional Foods Genetically Modified Plants and Organisms 9 Regulation of Food 9.1 History of Food-Related Disease 9.2 History of Food Regulation 9.3 Food Regulations Around the World Regulation and Approval of Foods Meant for Human Consumption United States Food and Drug Administration USDA Environmental Protection Agency Center for Disease Control State and Local Regulatory Systems Canada Europe Japan Other Countries China Brazil Australia and New Zealand United Kingdom South Africa Feed for Animal Consumption United States Ingredients and the Approval Process Production, Storage, and Distribution of Safe Animal Feed Ingredients and Mixed Feed Reporting Tools of Animal Food Hazards and Unsafe Animal Food Feed Standards Regulation of Pet Food and Its Labeling Other Countries Canada European Union Australia and New Zealand Japan China South Africa 10 Challenges and Future Developments in Food Safety 11 Conclusions Glossary References 3 . Nutritional Toxicologic Pathology 1 Introduction 2 Caloric Excess and Obesity 3 Caloric Restriction 4 Macronutrients and Micronutrients 4.1 Introduction 4.2 Macronutrients Proteins Deficiency Excess Amino Acids Deficiency Excess Carbohydrates Deficiency Excess Fiber Lipids Deficiency Excess 4.3 Micronutrients (for General Background References See Table 3.1) Vitamins (see Table 3.2) Vitamin A (All Trans-Retinol) Deficiency Excess Vitamin D (Calcitrol) Deficiency Excess Vitamin E Deficiency Excess Vitamin K Deficiency Excess Vitamin C (Ascorbic Acid) Deficiency Excess The B Vitamins Thiamine (Vitamin B1) Deficiency Excess Riboflavin (Vitamin B2) Deficiency Excess Niacin (Nicotinic Acid, Vitamin B3) Deficiency Excess Pyridoxine (Vitamin B6) Deficiency Excess Biotin (Vitamin B7) Deficiency Excess Folic Acid (Folate, Vitamin B9, Folacin) Deficiency Excess Cobalamin (Vitamin B12) Deficiency Excess Choline Deficiency Excess Minerals Major Minerals Calcium Deficiency Excess Phosphorus Deficiency Excess Magnesium Deficiency Excess Sodium/Potassium Deficiency Excess Sulfur Deficiency Excess Trace Minerals Chromium Deficiency Excess Cobalt Deficiency Excess Copper Deficiency Excess Fluorine Deficiency Excess Iodine Deficiency Excess Iron Deficiency Excess Manganese Deficiency Excess Molybdenum Deficiency Excess Selenium Deficiency Excess Zinc Deficiency Excess 5 Dietary Contaminants (Also See Issues In Laboratory Animal Science that Impact Toxicologic Pathology, Vol 1, Chap 29) 5.1 Analyses for Contaminants 5.2 Pesticides 5.3 Mycotoxins, Heavy Metals, Phytoestrogens, and Other Contaminants References PART 2 Selected Toxicant Classes in the Environment 4 . Herbal Remedies 1 Introduction 1.1 Nomenclature 2 Apothecary to Pharmacy 3 Evidence for Herbal Remedy Efficacy 3.1 Empirical Evidence – Traditional Knowledge (Botanical) 3.2 Experimental Evidence – Controlled (Single Active Compound) 4 The Active Pharmaceutical ingredient(s) 4.1 Influencing Factors on the Concentration of the API(s) in the Plant 4.2 Dose and Response 4.3 Contaminants 4.4 Adulterants 4.5 A Comparison Between Properties of Herbal Remedies and Conventional Drugs 4.6 Acceptability of Herbal Remedies 5 Quality, Efficacy and Safety 6 Quality 6.1 The Active Pharmaceutical Ingredient 6.2 Quality Control 6.3 Manufacturing Processes and Controls 7 Efficacy and Effectiveness 7.1 Traditional Knowledge of Efficacy 7.2 Experimental Evidence 7.3 Randomized Clinical Trials Using Herbal Remedies 8 Safety 8.1 Safety, Side Effects and Toxicity 8.2 Adverse Reactions 8.3 Interactions Herb–Drug Interaction 8.4 Herb-Herb Interaction 8.5 Direct Toxicity 8.6 Indirect Toxicity 8.7 Hypersensitivity – Idiopathic Allergic Reactions 9 Toxicology of Herbal Remedies 9.1 Lethality 9.2 Genotoxicity and Carcinogenesis 9.3 Herbal Toxicokinetics 9.4 Microbiome 9.5 Herbal Pharmacodynamics 9.6 Organ Toxicity Hepatotoxicity Renal Toxicity Cardiotoxicity Neurotoxicity Dermal Toxicity Primary Irritant Dermatitis Allergic Contact Dermatitis Photosensitization Dermatitis 10 Toxicologic Pathology of Select Herbal Remedies 10.1 Aloe vera – Aloe barbadensis Whole Leaf Extract Latex Gel 10.2 Cannabis – Cannabis sativa and Cannabis indica 10.3 Chamomile – Chamomilla recutita 10.4 Coffee – Coffea arabica and C. Canephora Pharmacokinetics Human Health Animal Studies 10.5 Cocoa – Theobroma cacao 10.6 Echinacea – Echinacea purpurea 10.7 Ephedra – Ephedra sinica 10.8 Garlic – Allium sativum 10.9 Ginkgo Biloba – Ginkgo biloba 10.10 Ginger – Zingiberis rhizome 10.11 Ginseng – Panax ginseng 10.12 Goldenseal – Hydrastis canadensis 10.13 Green Tea – Camellia sinensis 10.14 Indole-3-Carbinol – Brassica sp. Glucosinolates 10.15 Kava kava – Piper methysticum 10.16 Milk Thistle – Silybum marianum 10.17 Mint Mentha sp. [Contains Pulegone] 10.18 Rattlepods, Yellow Burrweed, and Groundsel—Crotalaria, Amsinckia, and Senecio Containing [Contains Riddelliine a Pyrrolizid ... 10.19 Saw Palmetto – Serenoa repens 10.20 Senna – Senna alexandrina 10.21 St. John's Wort – Hypericum perforatum 10.22 Tobacco – Nicotiana tabacum 10.23 Turmeric Oleoresin – Curcuma longa 11 International Regulatory Overview 11.1 Select List of Countries and Their Regulatory Requirements Australia Canada China European Union India Japan Korea Malaysia Philippines United States of America 12 Discussion 13 Summary References 5 Phycotoxins 1 INTRODUCTION 1.1 Harmful Algal Blooms 1.2 Aquatic Hypoxia 1.3 Some Important Marine and Freshwater Toxins 1.4 The Need for Greater Access to and Reliance on Diagnostic Expertise and Instrumentation 1.5 A Future with Fewer Harmful Algal Blooms and Phycotoxin Poisonings 1.6 Rationale for the Subsequent Discussions of Phycotoxins 2 SAXITOXINS 2.1 Source/Occurrence 2.2 Toxicology 2.3 Clinical Signs and Pathology 2.4 Human Exposure and Disease 2.5 Diagnosis, Treatment, and Control 3 CYCLIC IMINES 3.1 Source/Occurrence 3.2 Toxicology 3.3 Clinical Signs and Pathology 3.4 Human Exposure and Disease 3.5 Diagnosis, Treatment, and Control 4 DOMOIC ACID 4.1 Occurrence and Species Susceptibility 4.2 Toxicology 4.3 Clinical Signs and Pathology 4.4 Human Exposure and Disease 4.5 Diagnosis, Treatment, and Control 5 BREVETOXINS 5.1 Source/Occurrence 5.2 Toxicology 5.3 Clinical Signs 5.4 Gross and Histologic Findings 5.5 Human Exposure and Disease 5.6 Diagnosis, Treatment, and Control 6 CIGUATOXINS 6.1 Source/Occurrence 6.2 Toxicology 6.3 Maitotoxins 6.4 Clinical Signs and Pathology 6.5 Human Exposure and Disease 6.6 Diagnosis, Treatment, and Control 7 OKADAIC ACID AND DINOPHYSISTOXINS 7.1 Source/Occurrence 7.2 Toxicology 7.3 Clinical Signs and Pathology 7.4 Human Exposure and Disease 7.5 Diagnosis, Treatment, and Control 8 AZASPIRACID TOXINS 8.1 Source/Occurrence 8.2 Toxicology 8.3 Clinical Signs and Pathology 8.4 Human Exposure and Disease 8.5 Diagnosis, Treatment, and Control 9 CYLINDROSPERMOPSINS 9.1 Source/Occurrence 9.2 Toxicology 9.3 Clinical Signs and Pathology 9.4 Human Exposure and Disease 9.5 Diagnosis, Treatment, and Control 10 MICROCYSTINS AND NODULARINS 10.1 Source/Occurrence 10.2 Toxicology 10.3 Clinical Signs and Pathology 10.4 Human Exposure and Disease 10.5 Diagnosis, Treatment, and Control 11 ANATOXINS 11.1 Source/Occurrence 11.2 Toxicology 11.3 Clinical Signs and Pathology 11.4 Human Exposure and Disease 11.5 Diagnosis, Treatment, and Control 12 GUANITOXIN [FORMERLY ANATOXIN-A(S)] 12.1 Source/Occurrence 12.2 Toxicology 12.3 Clinical Signs and Pathology 12.4 Human Exposure and Disease 12.5 Diagnosis and Treatment 13 LYNGBYATOXINS AND APLYSIATOXINS 13.1 Source/Occurrence 13.2 Toxicology 13.3 Clinical Signs and Pathology 13.4 Human Exposure and Disease 13.5 Diagnosis, Treatment, and Control 14 β-METHYLAMINOALANINE 14.1 Introduction 14.2 Sources/Occurrences/Exposures 14.3 Toxicology 14.4 Animal Studies 14.5 Mechanism of Action 14.6 Human Exposure and Disease 14.7 Analytical Methods for Detection and Quantification 14.8 Conclusion 15 EMERGING PHYCOTOXINS 15.1 Vacuolar Myelinopathy and Aetokthonotoxin 15.2 Palytoxins 15.3 Yessotoxins 16 CONCLUSIONS AND FUTURE NEEDS REFERENCES 6 . Mycotoxins 1 Introduction 2 Aflatoxins 2.1 Source/Occurrence 2.2 Toxicology Toxin Species Susceptibility Biodistribution, Metabolism, and Excretion Mechanism of Action 2.3 Manifestations of Toxicity in Animals Overview Laboratory Animals Poultry Livestock Other Species Liver Cancer in Laboratory Animals 2.4 Human Risk and Disease 2.5 Diagnosis, Treatment, and Control 3 Ochratoxins 3.1 Source/Occurrence 3.2 Toxicology Species Susceptibility Biodistribution, Metabolism, and Excretion Mechanism of Action 3.3 Manifestations of Toxicity in Animals Laboratory Animals Swine Poultry 3.4 Human Risk and Disease 3.5 Diagnosis, Treatment, and Prevention 4 Patulin 4.1 Source/Occurrence 4.2 Toxicology Toxin Biodistribution, Metabolism, and Excretion Mechanism of Action 4.3 Manifestations of Toxicity in Animals 4.4 Human Exposure and Disease 4.5 Diagnosis, Treatment, and Control 5 Trichothecene Mycotoxins 5.1 Sources/Occurrence 5.2 Toxicology Toxins Biodistribution, Metabolism, and Excretion Mechanism of Action Toxicity and Species Susceptibility 5.3 Manifestations of Toxicity in Animals General Deoxynivalenol T-2 Toxin and Diacetoxyscirpenol Overview Swine Ruminants Poultry Macrocyclic Trichothecenes (Stachybotryotoxicosis) 5.4 Human Risk and Disease Introduction Deoxynivalenol T-2 Toxin and Diacetoxyscirpenol Macrocyclic Trichothecenes 5.5 Diagnosis, Treatment, and Prevention General Livestock Chemical Warfare Considerations for T-2 Toxin 6 Zearalenone 6.1 Source/Occurrence 6.2 Toxicology Toxins Mechanism of Action Species Susceptibility Biodistribution, Metabolism, and Excretion 6.3 Manifestations of Toxicity in Animals Laboratory Animals Swine Cattle and Sheep 6.4 Human Risk and Disease 6.5 Diagnosis, Treatment, and Prevention 7 Fumonisins 7.1 Source/Occurrence/Exposure 7.2 Toxicology and Mode of Action (MOA) Toxins Species Susceptibility Biodistribution, Metabolism, and Excretion Mode of Action 7.3 Manifestations of Toxicity in Animals Overview Equidae Swine Laboratory Animals Nonhuman Primates 7.4 Human Risk and Disease 7.5 Diagnosis, Treatment, and Prevention 7.6 Regulations and Guidances 8 Ergot Alkaloids 8.1 Introduction 8.2 Source/Occurrence Claviceps spp. Epichloe spp. 8.3 Toxicology Toxins Biodistribution, Metabolism, and Excretion Mechanism of Action Species Susceptibility 8.4 Manifestations of Toxicity in Animals (Reviewed by EFSA, 2005; Gupta et al., 2018a) Laboratory Animals Food Animals and Horses (Reviewed by Blodgett, 2001; Strickland et al., 2011, Klotz, 2015: Coufal-Majeewski et al., 2016; G ... Gangrenous Syndrome Hyperthermic Syndrome (Summer Fescue Toxicosis, Summer Slump, Systemic Hyperthermia) Fat Necrosis Reproductive Failure Neurologic Syndrome 8.5 Human Risk and Disease 8.6 Pharmaceutical Use 8.7 Diagnosis, Treatment and Prevention 9 Emerging Mycotoxins 9.1 Introduction 9.2 Alternaria Toxins Source/Occurrence Toxicology Toxins Biodistribution, Metabolism, and Excretion Mechanism of Action Manifestations of Toxicity in Animals Human Exposure and Disease 9.3 Aspergillus and Penicillium Toxins Cyclopiazonic Acid Source/Occurrence Toxicology, Toxicokinetics and Mechanism of Action Manifestations of Toxicity in Animals Human Exposure and Disease Sterigmatocystin (Zingales et al., 2020) Source/Occurrence Toxicology, Toxicokinetics, and Mechanism of Action Manifestations of Toxicity in Animals Human Exposure and Disease 9.4 Tremorgenic Mycotoxins Source/Occurrence Toxicology, Toxicokinetics and Mechanism of Action Manifestations of Toxicity in Animals Human Exposure and Disease 9.5 Fusarium Toxins Beauvericin and Enniatins Source/Occurrence Toxicology, Toxicokinetics and Mechanism of Action Manifestations of Toxicity in Animals Human Exposure and Disease Moniliformin Butenolide Culmorin, Fusaproliferins and Fusaric Acid 9.6 Diagnosis, Treatment, and Control 10 Summary/Conclusion Acknowledgments References 7 . Poisonous Plants 1 Introduction 2 Selected Hepatotoxic Plants 2.1 Dehydropyrrolizidine Alkaloid–Containing Plants Chemical Structure and Diversity Plant Sources Toxicology Clinical Signs and Pathology Animal Species Susceptibility Human Exposure and Disease 2.2 Saponin-Containing Plants 2.3 Plants Containing Fungal Hepatotoxins Lupinosis Sporidesmin Plant/Mycotoxin-Related Liver Diseases and Syndromes 2.4 Alsike Clover 2.5 Lantana 2.6 Cocklebur (Xanthium strumarium) and Other Potent Hepatotoxic Plants 3 Selected Neurotoxic Plants 3.1 Plant-Induced Storage Diseases (Swainsonine/Calestegine/Castanospermine) Swainsonine or Locoweed Intoxication Toxin and Toxicity Clinical Disease Pathology Reproductive Effects Swainsonine in Human Health and Medicine Calystegines Castanospermine 3.2 Ryegrass Toxicity Perennial Ryegrass Staggers Annual Ryegrass Toxicity 3.3 Larkspur 3.4 Centaurea spp. 3.5 Nitro-Toxins 3.6 Hemlocks 3.7 Lupines 3.8 Death Camas 4 Selected Myotoxic Plants 4.1 Cardioactive Glycoside-Containing Plants 4.2 Rayless Goldenrod and White Snakeroot 4.3 Other Myotoxic Plants Thermopsis spp. Cassia or Senna spp. Erythroxylum coca Seleniferous Plants 5 Selected Teratogenic Plants 5.1 Lupine 5.2 Veratrum californicum 5.3 Poison Hemlock 6 Selected Nephrotoxic Plants 6.1 Oak 6.2 Lily and Grapes 6.3 Oxalate-Containing Plants 6.4 Amaranthus spp. 6.5 Calcinogenic Glycoside-Containing Plants 7 Other Toxic Plants 7.1 Pine Needles 7.2 Cyanogenic Plants 7.3 Nitrate-Accumulating Plants 7.4 Photosensitizing Plants Primary Photosensitization Hypericism Fagopyrism Furocoumarins Drugs and Other Toxicants Hepatogenous Photosensitization (Secondary Photosensitization) Photosensitization Sequelae 7.5 Bracken Fern Acute Hemorrhagic Disease and Enzootic Hematuria Bright Blindness Bracken Staggers Human Poisoning Treatment and Prevention 7.6 Ricinus spp. 8 Additional Resources References 8 . Animal Toxins 1 Introduction 2 Sources of Exposure 2.1 Poisoning Ingestion Dermal or Mucosal Contact Inhalation 2.2 Envenomation Bites Stings 2.3 Deliberate Administration Aggression and Defense Therapeutic Applications 3 Zootoxin Classification 3.1 Zootoxin Classification by Source 3.2 Zootoxin Classification by Molecular Structure 3.3 Zootoxin Classification by Function Coagulotoxins Necrotoxins Neurotoxins 3.4 Zootoxin Classification by Mechanism of Action Cell and Tissue Destruction Phospholipase A2 Cardiotoxins Metalloproteinases Sphingomyelinase D Circulatory Disturbances Vascular Permeability Enhancement Vascular Tone Modulation Vascular Wall Damage Hemostasis Abnormalities Coagulotoxic Zootoxins Coagulotoxic Mechanisms Inflammation Induction Innate Immune Responses to Zootoxins Adaptive Immune Responses to Zootoxins Neurotransmission Derangement Altered Neurotransmitter Levels Altered Neurotransmitter Availability Exogenous signaling molecules Altered synthesis and packaging Altered Neurotransmitter Release Inhibition of Na+ channels Inhibition of K+ channels Inhibition of Ca2+ channels Modified Presynaptic Receptor Activity Disruption of Axon Terminal Membranes Altered Acetylcholinesterase Activity Aberrant Postsynaptic Receptor Activation Altered Action Potential Propagation Altered Myofiber Integrity and Function 4 Clinical Presentations and Pathologic Manifestations of Zootoxin-Mediated Diseases 4.1 Blood Vessels and Blood Components 4.2 Epithelium (Cutaneous and Mucosal Surfaces) 4.3 Kidney 4.4 Liver 4.5 Lung 4.6 Muscle (Cardiac and Skeletal) 4.7 Neuromuscular Junction and Other Peripheral Synapses 4.8 Systemic (Multi-Organ) Failure 5 Diagnosis and Treatment of Zootoxin-Mediated Diseases 5.1 Diagnosis History and Physical Examination Field Tests Molecular Procedures Pathology Procedures Clinical Pathology Histopathology 5.2 Treatment First Aid for Acute Exposures Supportive (Nonspecific) Care for Acute Exposures Curative (Specific) Therapies and Their Complications Antivenom Therapy Adverse Reactions to Antivenom Care for Chronic Complications Prophylactic Measures 6 Regulatory Guidance Regarding Zootoxins 6.1 Sources and Major Indications of Medicinal Zootoxins 6.2 Practices for Developing Zootoxin-Based Medical Products 6.3 Practices for Developing Antivenom Products 7 Summary Glossary Acknowledgments References 9 . Bacterial Toxins 1 Introduction 2 Exotoxins 2.1 Sources of Exposure Infection Ingestion Inhalation Therapeutic Products 2.2 Toxicology Exotoxin Classification by Function Cytolysins Bacterial Colonization Factors Exotoxin Classification by Mechanism of Action Type I Exotoxins—Superantigens Hijacking the Immune Response Type II Exotoxins—Membrane-Damaging Toxins Type III Exotoxins—Intracellular Effector Enzymes Exotoxin Classification by Target Organ Spectrum Enterotoxins Hemolysins Leukocidins Myotoxins Neurotoxins 3 Endotoxins 3.1 Sources of Exposure Infection Ingestion Inhalation Therapeutic Products 3.2 Toxicology Structure and Functional Attributes of Endotoxin Endotoxin-Mediated Cell Signaling Pathogenesis of Endotoxin-Induced Immune Dysfunction 4 Clinical Presentations and Pathologic Manifestations of Bacterial Toxin-Mediated Diseases 4.1 Enteric Effects (Intestine) 4.2 Fascial Effects (Connective Tissue) 4.3 Hepatic Effects (Hepatocytes and Hepatic Immune Cells) 4.4 Microvascular Effects (Blood Vessels) 4.5 Myotoxic Effects (Cardiac and Skeletal Muscle) 4.6 Neurotoxic Effects (Brain and Terminal Nerve Synapses) 4.7 Pneumotoxic Effects (Lung) 4.8 Systemic Effects (Sepsis and Toxic Shock Syndrome) 4.9 Miscellaneous Effects Attributed to Bacterial Toxins 5 Diagnosis and Treatment of Bacterial Toxin–Mediated Diseases 5.1 Diagnosis Imaging, Microbiological, and Molecular Procedures Pathology Procedures 5.2 Treatment Curative Therapies Prophylactic Measures 6 Regulatory Guidance Regarding Bacterial Toxins 6.1 Food and Beverage Production and Water Treatment 6.2 Manufacturing Biomedical Products 6.3 Safety Assessment of Immunotoxins Regulatory Guidance for Immunotoxin Safety Assessment Toxic Effects Associated with Immunotoxin Administration 7 Summary Glossary Acknowledgments References 10 . Metals 1 Introduction 2 Antimony 2.1 Sources and Exposure 2.2 Toxicology 2.3 Manifestations of Toxicosis 2.4 Diagnosis and Treatment 3 Arsenic 3.1 Inorganic Arsenic Sources and Exposure Toxicology Manifestations of Toxicosis 3.2 Organic Arsenic Sources and Exposure Toxicology Manifestations of Toxicosis 3.3 Arsine 3.4 Diagnosis and Treatment 3.5 Chemical Warfare Considerations 4 Beryllium 4.1 Sources and Exposure 4.2 Toxicology 4.3 Manifestations of Toxicosis 4.4 Diagnosis and Treatment 5 Bismuth 5.1 Sources and Exposure 5.2 Toxicology 5.3 Manifestations of Toxicosis 5.4 Diagnosis and Treatment 6 Cadmium 6.1 Sources and Exposure 6.2 Toxicology 6.3 Manifestations of Toxicosis 6.4 Diagnosis and Treatment 7 Chromium 7.1 Sources and Exposure 7.2 Toxicology 7.3 Manifestations of Toxicosis 7.4 Diagnosis and Treatment 8 Lead 8.1 Sources and Exposure 8.2 Toxicology 8.3 Manifestations of Toxicosis in Animals 8.4 Human Exposure and Disease 8.5 Diagnosis and Treatment 9 Mercury 9.1 Sources and Exposure 9.2 Toxicology 9.3 Elemental Mercury 9.4 Inorganic Mercury 9.5 Organic Mercury 9.6 Diagnosis and Treatment 10 Plutonium (See Also Volume 3, Chap 14, Radiation and Other Physical Agents) 10.1 Sources and Exposure 10.2 Toxicology 10.3 Manifestations of Toxicosis 10.4 Diagnosis and Treatment 11 Thallium 11.1 Sources and Exposure 11.2 Toxicology 11.3 Manifestations of Toxicosis 11.4 Diagnosis and Treatment 12 Uranium (See also Volume 3, Chap 14, Radiation and Other Physical Agents) 12.1 Sources and Exposure 12.2 Toxicology 12.3 Manifestation of Toxicosis 12.4 Diagnosis and Treatment 13 Summary and Conclusions References 11 . Agrochemicals 1 Introduction 2 Herbicides 2.1 Introduction 2.2 Inhibition of Cell Division and Growth Auxin Mimics Chlorophenoxy Herbicides Toxicology, Clinical Signs, and Pathology Human Risk Microtubule Organization Inhibitors Carbamates Toxicology, Clinical Signs, and Pathology 2.3 Activation of Reactive Oxygen Species Pyridiniums: Paraquat and Diquat Pyridiniums Development and Use Toxicology, Clinical Signs, and Pathology Phosphonic Acids Glufosinate Toxicology, Clinical Signs, and Pathology Human Risk Ureas and Thioureas Toxicology, Clinical Signs, and Pathology Human Risk Triazines Toxicology, Clinical Signs, and Pathology Hydroxyphenylpyruvate Dioxygenase Inhibitors 2.4 Inhibition of Cellular Metabolism Inhibition of Enolpyruvyl Shikimate Phosphate Synthase Glyphosate Toxicology, Clinical Signs, and Pathology Human Risk Thiocarbamates 3 Fungicides 3.1 Introduction 3.2 Triazole-Containing Azole Fungicides (Conazoles)/DMI-Fungicides (Demethylation Inhibitors)/C14-Demethylase Inhibitors Tebuconazole Prothioconazole Mefentrifluconazole 3.3 Succinate Dehydrogenase Inhibitor Fungicides 3.4 Strobilurins or Quinol Oxidation Site of Complex III Inhibitor Fungicides 4 Insecticides 4.1 Introduction 4.2 Organophosphates and Carbamates Toxicology Clinical Signs and Pathology Human Risk 4.3 Organochlorines Development and Use Toxicology Clinical Signs and Pathology Human Risk 4.4 Pyrethrins and Pyrethroids Development and Use Toxicology Clinical Signs and Pathology Human Risk 4.5 New Insecticides Neonicotinoids Phenylpyrazoles Macrocyclic Lactone Endectocides (Mectins) Diamide Insecticides Cyromazine Diafenthiuron Fenoxycarb Lufenuron Pymetrozine Spiropidion 5 Rodenticides 5.1 Introduction 5.2 Anticoagulant Rodenticides Development and Use Toxicology Metabolism Clinical Signs and Pathology Human Risk 5.3 Cholecalciferol Development and Use Toxicology Clinical Signs and Pathology Human Risk Medical Data Other Species 5.4 Inorganic Compounds: Metal Phosphides Aluminum Phosphide/Zinc Phosphide Development and Use Toxicology Absorption, Distribution, Excretion, and Metabolism Clinical Signs Other Species (Clinical Signs and Pathology) Human Risk 5.5 Alphachloralose Development and Use Toxicology Clinical Signs and Pathology Human Risk Risk to Environment/Other Species 5.6 Bromethalin Development and Use Toxicology Clinical Signs Other Species (Clinical Signs and Pathology) 5.7 Corn Cob Development and Use Toxicology Clinical Signs and Pathology Human Risk Risk to Other Species 5.8 Strychnine Toxicology Clinical Signs Risk to Other Species 6 Conclusions References 12 . New Frontiers in Endocrine Disruptor Research∗ 1 Introduction 2 Environmental Chemicals Can Disrupt Endocrine Signaling 2.1 History of Endocrine Disruptor Research 2.2 Types of Chemicals With Endocrine-Disrupting Activity 2.3 Routes of Exposure to Endocrine Disruptors 2.4 Regulatory Approaches to Endocrine Disruption 3 Mechanisms of Endocrine Disruption 4 Examples of Disruption of Endocrine Pathways by Some Environmental Contaminants and Emerging Endocrine Disruptors 4.1 Phthalates Disrupt Several Endocrine Pathways 4.2 Emerging Endocrine Disruptors: Glyphosate 4.3 Emerging Endocrine Disruptors: General Anesthetics as Endocrine Disruptors 5 Epigenetic Effects of EDCs 6 From Reactive to Proactive Endocrine Disruptor Analysis 7 Emerging Models in EDC Research 7.1 Zebrafish Model 7.2 CRISPR Screening 8 Omics Technologies to Evaluate Endocrine Disruption 8.1 Transcriptomics and Proteomics 8.2 Lipidomics and Metabolomics 8.3 Microbiome 8.4 Exposomics 9 New Frontiers in Bioinformatics and Integrative and Functional Enrichment Omics Approaches 9.1 Integrative Correlation Analyses 9.2 Integrative MultiOmics Pathway Resolution 10 Machine Learning and EDCs 10.1 How Machine Learning Works 10.2 Examples of Current Deep Learning Programs for Toxicology 11 Conclusions Abbreviations References 13 . Nanoparticulates 1 Background 1.1 Definitions 1.2 Historical Perspective 1.3 Development of Nanotechnology 1.4 Current and Future Nanotechnology Applications 1.5 Human Exposures 2 Experimental Toxicologic Pathology of NPs 2.1 Enhanced Toxicity of Nanoscale Particulates Surface Area Solubility Quantum Chemistry Size 2.2 Visualizing NPs in Tissue Factors which Limit the Ability to Identify NPs in Tissue Sections Labeled NPs High-Resolution FESEM Enhanced Darkfield Microscopy 2.3 Cytopathology Cytoplasmic Membrane Damage Mitotic Spindle Interactions Overview of the Mitotic Spindle Centrosomal Interactions Microtubule Interactions Chromosomal Interactions Additional Cytopathologic Interactions 2.4 Target Organ and Tissue Toxicity Pulmonary Pathology Neurotoxicity/Neuropathology of NPs Cardiovascular Pathology Lymphatic Pathology 2.5 Human Relevance of Experimental Studies in Animals 3 Future Trends in Nanopathology and Nanotoxicology 4 Conclusions Acknowledgments References 14 . Radiation and Other Physical Agents 1 Introduction 1.1 Sources and Occurrence Ionizing Radiation External Radiation Internally Deposited Radionuclides Ultraviolet Radiation Hyperthermia 1.2 Impact of Household Technologies and Nonionizing Radiation (see also Environmental Toxicologic Pathology and Human Health, ... Part I Ionizing Radiation 2 Nature and Action of Ionizing Radiation 2.1 Radiation Biophysics 2.2 External Radiation and Internal Emitters External Radiation Internal Emitters Definition Emissions Chemical Form Metabolism Chemical Class Routes of Entry Ingestion Inhalation Dose Localization Health Effects 2.3 Chernobyl and Fukushima: Retrospective Overview of Pathology Associated with Ionizing Radiation Exposure 3 Mechanisms of Ionizing Radiation Injury 3.1 Interaction of Ionizing Radiation with Biological Materials 3.2 Subcellular and Cellular Effects of Ionizing Radiation 3.3 Cell and Tissue Radiosensitivity to Ionizing Radiation 3.4 General Tissue and Organ Effects of Ionizing Radiation 3.5 Molecular Mediators 3.6 Acute Radiation Syndromes and Combined Injury 3.7 Ionizing Radiation Carcinogenesis 4 Response to Injury Induced by Ionizing Radiation 4.1 Vascular and Connective Tissue Effects of Ionizing Radiation 4.2 Hematopoietic and Lymphoid Systems General Reaction to Ionizing Radiation Injury – Hematopoietic System Lymphoid Tissues Radiation Leukemogenesis 4.3 Alimentary System General Reaction to Ionizing Radiation Injury Salivary Tissue Small Intestine Esophagus Liver 4.4 Nervous System General Reaction to Ionizing Radiation Injury Peripheral/Cranial Nerves Spinal Cord Brain 4. Haschek and Rousseaux's Handbook of Toxicologic Pathology, Fourth Edition, recognized by many as the most authoritative single source of information in the field of toxicologic pathology, has been extensively updated to continue its comprehensive coverage. The fourth edition has been expanded to five separate volumes due to an explosion of information in this field requiring new and updated chapters. Completely revised with a number of new chapters, this book covers the toxicologic pathology of major classes of environmental toxicants. Volumes emphasize the comparative and correlative aspects of normal biology and toxicant-induced dysfunction, principal methods for toxicologic pathology evaluation, and major mechanisms of toxicity. This series comprises the most authoritative reference on toxicologic pathology for pathologists, toxicologists, research scientists, and regulators studying and making decisions on drugs, biologics, medical devices, and other chemicals, including agrochemicals and environmental contaminants. Each volume is being published separately. Provides updated and revised chapters for in-depth discussions of toxicologic pathology for the protection of the environment and food supplies Offers high-quality and trusted content in a multi-contributed work written by leading international authorities in all areas of toxicologic pathology Features hundreds of full-color images in both the print and electronic versions of the book to highlight difficult concepts with clear illustrations