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
4.5 Endocrine System
Thyroid Gland
Parathyroid Gland
Pancreas
Adrenal Gland
4.6 Special Senses
General Reaction to Ionizing Radiation Injury
Ear
Eye
Lens
Retina
Other Ocular Structures
4.7 Respiratory System
General Reaction to Ionizing Radiation Injury
Upper Respiratory Tract
Lung
Neoplasia
4.8 Musculoskeletal System
General Reaction to Ionizing Radiation Injury
Bone
Skeletal Muscle
4.9 Cardiovascular System
General Reaction to Ionizing Radiation Injury
Coronary Arteries
Pericardium
Heart
4.10 Urinary System
General Reaction to Ionizing Radiation Injury
Kidney
Ureter
Urinary Bladder
4.11 Fetal Effects
4.12 Reproductive Tract
Testes
Ovary
4.13 Integumentary System
General Reaction to Ionizing Radiation Injury
Part II Ultraviolet Radiation
5 Nature and Action of Ultraviolet Radiation
6 Mechanisms of Ultraviolet Radiation Injury
7 Response to Injury Induced by Ultraviolet Radiation
7.1 Integument
7.2 Eye
7.3 Immune System
7.4 Ultraviolet Radiation Carcinogenesis
Epidemiologic Evidence
Animal Models
Mechanisms
Skin Neoplasms
Ocular Neoplasia
Part III Hyperthermia
8 Clinical Use of Hyperthermia
9 Mechanisms of Hyperthermia-Induced Injury
10 Response to Injury Induced by Hyperthermia
10.1 Reaction of Specific Organs and Tissue to Hyperthermia
Alimentary System
Musculoskeletal System
Nervous System
Eye
Cardiovascular System
Urinary System
Male Reproductive System
Integumentary System
Disclaimer
References
Chapter-11---Agrochemi_2023_Haschek-and-Rousseaux--s-Handbook-of-Toxicologic
Chapter-12---New-Frontiers-in-Endocrine-Disruptor-Research-_2023_Haschek-and
Chapter-13---Nanoparticu_2023_Haschek-and-Rousseaux--s-Handbook-of-Toxicolog
Chapter-14---Radiation-and-Other_2023_Haschek-and-Rousseaux--s-Handbook-of-T
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