دانلود کتاب Veterinary Toxicology: Basic and Clinical Principles

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Cover Front matter Dedication Preface List of Contributors Section I: General 1 Veterinary toxicology: a historical perspective The Emergence of Veterinary Toxicology Professional Organization and Academic Recognition of Veterinary Toxicology Published Veterinary Toxicology Literature …And Where Will Veterinary Toxicology Go From Here? References 2 Concepts in veterinary toxicology Introduction Historical Perspective Historical events Textbooks Organizations Evolution of Veterinary Toxicology Roots in veterinary medicine and toxicology Emergence of science-based toxicology Toxicology joined to the risk paradigm A Framework for Acquiring Information Linkages from sources to health impacts Toxicokinetics Toxicodynamics Veterinary toxicology is multi-faceted Sources of Information Case observations in the species of interest Epidemiological/epizootiological studies Experimentation Schematic experimental designs Acquiring toxicokinetic data Acquiring exposure (dose)–response data Toxicologic Descriptors Toxicology rooted in observations Quantifying exposure Describing absorption, distribution, metabolism and excretion Toxicant-induced responses Describing exposure–response relationships for non-cancer endpoints Cancer as an endpoint New potential endpoints Conclusions and Summary Dedication Acknowledgments REFERENCES 3 Toxicokinetics Introduction Underlying Physiology Absorption Distribution Biotransformation Excretion Traditional (Compartmental) Toxicokinetic Models Introduction Measures of absorption Volume of distribution Clearance Half-life Flip-flop kinetics Residues Physiologically Based Toxicokinetics Introduction Model construction Parameter estimation and identifiability Model validation Applications Conclusions References 4 Factors affecting chemical toxicity Introduction Individual Factors Species Anatomical and physiological features Enzyme expression and biotransformation pathways Breed Age Pathophysiological conditions Stress Disease Pregnancy Lactation Non-Individual Factors Physico-chemical characteristics of the poison Environmental conditions Diet Routes of exposure Previous or coincident exposure to other chemicals (drug–drug interactions) Conclusion References 5 Toxicological testing: in vivo and in vitro models Introduction In Vivo Models in Toxicity Testing Introduction Animal welfare in toxicity testing Routes of test compound administration Reproductive toxicity tests Developmental toxicity testing Cutaneous toxicity testing Genotoxicity testing Carcinogenicity tests Neurotoxicity Immunotoxicity Transgenic animals in toxicity testing Limitations and implications of animal use in toxicological testing In Vitro Models of Toxicity Testing Introduction Types of cell culture system used in toxicity testing Endpoint determination for in vitro testing systems Cell viability Membrane leakage Cell growth and proliferation Cloning efficiency Mitogenicity DNA synthesis Protein synthesis Cell morphology Cell volume Cell shape Membrane integrity Growth patterns Metabolic assay ATP levels Dehydrogenase activity Calcium homeostasis Cell or tissue specific markers of toxicity Antibody-based detection Enzyme assays Proteomic analysis Genomic analysis General Summary and Conclusions References 6 Epidemiology of animal poisonings in the United States Introduction Background Demographics Dogs Cats Other Species Agents Involved Signs and Outcomes Conclusions References 7 Epidemiology of animal poisonings in Europe Introduction Species Involved Toxic Classes Non-Metals and Metalloids Metals Copper Lead Other metals and minerals Pesticides Insecticides Rodenticides Other pesticides Oil Feed Associated Toxicants Drugs and Related Compounds Household Products Toxins Plants Other toxins Conclusions References 8 Chemicals of terrorism Introduction Chlorine Gas Background Pharmacokinetics/toxicokinetics Mechanism of action Toxicity Treatment Concluding remarks Phosgene Background Pharmacokinetics/toxicokinetics Mechanism of action Toxicity Treatment Concluding remarks Mustard Gas Background Pharmacokinetics/toxicokinetics Mechanism of action Toxicity Treatment Concluding remarks Lewisite Background Pharmacokinetics/toxicokinetics Mechanism of action Toxicity Treatment Concluding remarks Phosgene Oxime Background Pharmacokinetics/toxicokinetics Mechanism of action Toxicity Treatment Concluding remarks Cyanide and Hydrogen Cyanide Background Pharmacokinetics/toxicokinetics Mechanism of action Toxicity Treatment Concluding remarks Military Nerve Agents Background Pharmacokinetics/Toxicokinetics Mechanism of action Toxicity Treatment Concluding remarks References 9 Regulatory considerations in veterinary toxicology Introduction Section I. Food and Drug Administration and the Center for Veterinary Medicine Creation and organization of the FDA and CVM Approving and monitoring animal drugs Testing methods for animal drugs CVM target animal safety and product efficacy testing requirements Introduction Good laboratory practices and general study requirements Drug tolerance test Toxicity study FDA-required toxicological testing in food-producing animals General considerations Testing requirements Acceptable daily intake and safety factors Sex steroids Synthetic sex steroids Animal efficacy studies Regulatory requirements for reporting animal adverse drug events Introduction Pharmacovigilance FDA/CVM adverse drug event reporting system for approved animal drugs The future of global pharmacovigilance reporting Section II. Environmental Protection Agency Creation of the EPA Pesticides and the federal insecticide, fungicide and rodenticide act Pesticide residues in foods EPA companion animal safety testing Chronic toxicity testing: pesticides in animal-derived food Introduction Reproduction toxicity testing Combined chronic toxicity/carcinogenicity testing Organization for Economic Cooperation and Development EPA adverse effects information reporting Section III. U.S. Department of Agriculture Regulatory authority and mission Definition and functions Animal immunobiologic vigilance program Animal care and welfare requirements Section IV. Drug Enforcement Administration Mission and public health impact Illicit veterinary drugs of public health concern DEA regulatory requirements for veterinarians Section V. Occupational Safety and Health Administration Organization and mission Offices and district offices Exposure limits Section VI. Statutes, Regulations and Guidelines Notice and comment rulemaking procedures and access to agency records Freedom of information and public access to regulatory agency records References 10 Regulatory aspects for the drugs and chemicals used in food-producing animals in the European Union Introduction Veterinary Medicinal Products Legislation Marketing authorization procedures Centralized or community procedure Decentralized procedure and mutual recognition procedure Decentralized procedure Mutual recognition procedure Independent national procedures Human Health Risks from Drug Residues in Foods Acute toxicity effects Hypersensitivity Pharmacological effects Teratogenic effects Long-term chronic effects (carcinogenesis) Antimicrobial effects Hormonal effects Carry-over or cross-contamination of the feed of coccidiostats Reference point for action Technological additives Sensory additives Nutritional additives Zootechnical additives Biocidal Substances Used in Animal Husbandry Feed Additives Legislation Comparative Setting Toxicological Standards for Food Safety Establishment of European Community maximum residue limits for drugs and feed additives Maximum residue level (MRL) Establishment of codex maximum residue limits for drugs and feed additives Changes in calculation of MRLs United States of America Food and Drug Administration tolerance setting Drug withdrawal/withholding periods Industrial Chemicals Conclusions References 11 Safety evaluation of new molecular entities for pharmaceutical development Introduction Nonclinical Safety Evaluation Pharmacokinetic and toxicokinetic studies Biological activity/pharmacodynamics (PD) Safety pharmacology studies General toxicity studies Acute toxicity studies Subchronic and chronic toxicity studies Local tolerance studies Genotoxicity studies Carcinogenicity studies Developmental and reproductive toxicity (DART) studies Pediatric drugs studies Immunotoxicity studies Phototoxicity studies Abuse liability testing Impurities qualification Estimation of the First Dose in Humans Concluding Remarks and Future Directions References and Further Reading 12 Statistics in veterinary toxicology Introduction Core concepts and vocabulary Relationship between variables Statistical significance and statistical error Degrees of freedom Objective of the Analysis Types of Data Changing the data Coding ordinal variables Imputation Transformations Outliers Identifying Constraints Graphing and Summarizing Data Choosing Appropriate Techniques Parametric versus non-parametric tests Balance Repeated-measures analysis Trend analysis Complex curves Final choice of hypothesis testing procedure Performing the Analysis Hypothesis testing Analysis of survival and time-to-event data ANOVA and ANCOVA Student’s t-test Mann-Whitney U test Kruskall-Wallace Logistic regression Exact tests and chi-square tests Cochran-Mantel-Haenszel tests MANOVA and MANCOVA Model selection Interpreting and Displaying the Results Learning More References 13 Toxicology and the law Introduction Reasons for Conducting Toxicology Analyses When the reason for testing the sample is known When the reason for testing the sample is not known or changes after testing Hypothetical case Jurisdiction – What are the Rules in this Fight and Who Decides the Winner? Standard of Proof – How Sure do I Need to Be? Evidence Documents Specimens Testimony Admissibility of Expert Testimony Frye Daubert Is the Expert Qualified? Has the Person Been Trained and Educated in the Discipline of Toxicology? Has the Person Been Certified as a Toxicologist? Do other Criteria Support an Argument that the Person is a Toxicologist? General Causation Specific Causation – The Differential Diagnosis Application of Daubert in Toxicology Cases Some Questions to Consider When Using Laboratory Results in a Legal Case Acknowledgment suggested reading Further Reading Section II: Organ Toxicity 14 Nervous system toxicity Introduction Structural Toxicoses Neuronopathy Axonopathy Myelinopathy Functional Toxicoses Acetylcholine Catecholamine neurotransmitters Serotonin Glycine GABA Glutamate/aspartate Histamine Mixed neurotransmitter effects Ion Channels Sodium channels Potassium channels Chloride channels Other Mechanisms of Neurotoxicity Conclusions References 15 Respiratory toxicity Introduction The Upper Airways Normal function Toxic diseases of the nasal passages Toxic diseases of the conducting airways The Gas Exchange Region Normal function Ventilation Perfusion Diffusion Avian respiration General Principles in the Pathogenesis Of Lung Damage Caused by Chemicals Oxidant burden Toxic inhalant gases Chlorine Ammonia Anhydrous ammonia Carbon dioxide Carbon monoxide Methane Hydrogen sulfide Nitrogen dioxide and ozone Particle size and clearance Particle size and deposition mechanisms Particle clearance Lung to Injury Acute responses to lung injury Airway reactivity Pulmonary edema Nasal and upper airway reactivity Mediators of lung toxicosis Cell proliferation Chronic responses of the lung to injury Fibrosis Emphysema Asthma Lung cancer Agents known to produce lung injury in animals Zinc phosphide Smoke Overheated frying pans Tryptophan and Perilla frutescens References 16 Cardiovascular toxicity Introduction Plant-Related Cardiotoxicity Glycoside-Containing Plants (See Table 16.1) Digitalis purpurea (foxglove) Asclepias spp. (milkweeds) Persea americana (avocado) Nerium spp. (oleander) Convallaria majalis (lily of the valley) Rhododendron spp. (azalea, rhododendron) Kalmia spp. (laurel, lambkill) Cyanide-Containing Plants Alkaloid-Containing Plants (See Table 16.2) Delphinium spp. (larkspurs) Aconitum (monkshood) Taxus spp. (yew) Zigadenus venenosus (death camas) Cicuta maculata (water hemlock) Eupatorium rugosum (white snakeroot) Astragalus (locoweed) Oxalates Gousiekte Mushrooms Xenobiotics That May Cause Cardiac Toxicity Arsenic Ionophores Fertilizers Herbicides Pesticides Organophosphates and carbamates Amitraz Ancillary Causes of Cardiac Toxicity Arthropods Scorpions and spiders Bees, wasps, hornets, yellow jackets and ants Snakes Blister beetles Conclusions and Future Directions References 17 Liver toxicity Introduction Structural and Functional Organization of the Liver Lobule and acinus Diverse function of the liver Cell types of the liver Factors Influencing Toxic Liver Injury Uptake and concentration Bioactivation and metabolism Inflammation Types of Toxicant-Induced Liver Injury Cell death Hepatic steatosis Steatohepatitis Hepatic fibrosis Cirrhosis Pigment accumulation Hepatic neoplasia Megalocytosis Mechanisms of Liver Damage Oxidative stress mediated by free radicals Disruption of calcium homeostasis and cell membrane damage Mitochondrial injury Disruption of cytoskeleton Cholestasis Hepatogenous photosensitization Inhibition of tissue repair response Idiosyncratic Reactions Concluding Remarks and Future Directions References 18 Renal toxicity Introduction Functional Anatomy Toxic Effects on the Kidney Acute renal failure Chronic renal failure Patterns of toxic renal injury Glomerular injury Proximal tubular injury Distal nephron/renal papillary injury Nephrotoxic Agents Mycotoxins Ochratoxins Citrinin Drugs Aminoglycoside antibiotics NSAIDs Metals Cadmium Lead Plants Amaranthus spp. Lilium spp. and Hemerocallis spp. Quercus spp. Vitis spp. Miscellaneous Ethylene glycol Melamine:cyanuric acid Conclusions References 19 Reproductive toxicity and endocrine disruption Introduction Important Definitions and Concepts Reproduction Reproductive toxicity Teratogenesis Wilson’s general principles of teratology Mechanisms of reproductive toxicity and teratogenesis Reproductive toxicants and teratogens Hormones and hormone receptors Gonadal steroid hormones and their “nuclear” receptors Genomic and non-genomic mechanisms of action of gonadal steroid hormones Endocrine disruption Mechanisms of endocrine disruption “Classic” receptor-mediated endocrine disruption Endocrine disruption independent of receptor-mediated interactions “Androgenic” and “estrogenic” effects of xenobiotics Endocrine disrupting chemicals, endocrine disruptors and hormonally active agents Aryl hydrocarbon receptor-mediated endocrine disruption Aryl hydrocarbon receptor agonists Mechanisms of aryl hydrocarbon receptor-mediated endocrine disruption Epigenetic mechanisms of action of endocrine disrupting chemicals Disruption of “non-reproductive” endocrine systems Normal Animal Reproduction Neuroendocrine control of reproduction Puberty The onset of puberty The endocrinology of puberty The susceptibility of the pubertal process to reproductive toxicants Normal male reproductive anatomy and physiology Reproductive anatomy of the male Testicular structure Excurrent duct system Accessory sex glands External genitalia Spermatogenesis Proliferation (mitosis or spermatocytogenesis) Meiosis Differentiation (spermiogenesis) The cycle of the seminiferous epithelium Male reproductive physiology Gonadal steroid synthesis in the testes Endocrine regulation of spermatogenesis Positive and negative feedback loops involved in male reproduction Epididymal and accessory sex gland function Sexual behavior, erection, emission and ejaculation Normal female reproductive anatomy and physiology Reproductive anatomy of the female Female reproductive physiology The estrous cycle Follicular development Ovarian follicular synthesis of estrogens The effects of estrogenic feedback on the hypothalamic–pituitary–gonadal axis Ovulation Formation and function of a CL Summary of the effects of estrogens and progesterone during the female reproductive cycle Oocyte/sperm transport, normal capacitation of sperm and fertilization Transport of the ovulated oocyte Transport and capacitation of spermatozoa Transport of spermatozoa Capacitation of spermatozoa Fertilization The endocrinology of pregnancy and placentation Gestational hormones Maternal recognition of pregnancy Placentation Types of placentas Placental function The “placental barrier” Normal embryonic and fetal development Blastocyst formation and differentiation of the germ cell layers Sex determination and sexual differentiation of reproductive function Genotypic sex and development of the primitive sex cords Gonadal sex determination and phenotypic sexual differentiation Development of the male phenotype Development of the female phenotype Sexual differentiation of the brain Parturition and lactation Physiology of parturition Physiology of lactation Lactogenesis Control of prolactin secretion The Mechanisms and Effects of Reproductive Toxicants The effects of EDCs on wildlife species, humans and domestic animals Endocrine disruption in wildlife species “Androgenic” and “estrogenic” effects of EDCs on wildlife species Endocrine disruption in humans The effects of reproductive toxicants on domestic animals Abortion, teratogenesis and impaired fertility in domestic animals Endocrine disruption in domestic animals Toxicants affecting the male reproductive function Selected male reproductive toxicants and mechanisms of action Cell-specific reproductive toxicants Heavy metals Gossypol Xenoestrogens and antiestrogens Xenoandrogens and antiandrogens Phthalates Toxicants affecting the female reproductive function Selected female reproductive toxicants and mechanisms of action Cell-specific reproductive toxicants Heavy metals Phytoestrogens Zearalenone Synthetic xenoestrogens and antiestrogens Xenoandrogens Teratogenesis and abortion Mechanisms of actions of teratogenesis and abortion Heavy metals Selected plant-associated teratogens and abortifacients Veratrum californicum Multiple congenital contractures Pine needle abortion Concluding Remarks References 20 Placental toxicity Introduction Role of the Placenta Types of Placenta Metabolism in Placenta Placental Susceptibility to Toxicants Placental Barrier for Chemical Toxicants Factors that May Influence the Placental Toxicity Maternal toxicity Placental transfer of toxicants Placental/Fetal metabolism Placental Toxicity of Metals Aluminum Arsenic Cadmium Lead Mercury Placental Toxicity of Insecticides Organophosphates and carbamates Organochlorines Pyrethrins and pyrethroids Mycotoxins Aflatoxins Fumonisins Ochratoxin A Rubratoxins Secalonic acid D Trichothecenes DON DAS T-2 toxin Zearalenone Tobacco Conclusions and Future Directions Acknowledgments References 21 Dermal toxicity Introduction Absorption Plants Causing Dermal Toxicity in Animals Photosensitization Topical Chemicals Causing Dermal Toxicity in Animals PAHs VOCs Pesticides Detergents, Solvents, Corrosives and Other Household Preparations Systemic Compounds Causing Dermal Toxicity in Animals Heavy metals Assessment Methods References 22 Blood and bone marrow toxicity Introduction Bone Marrow Hematopoietic Stem Cells Blood Components Erythrocyte, leukocyte and platelet formation Erythropoiesis Granulopoiesis Platelet formation Erythrocyte, leukocyte and platelet biology Erythrocyte Erythrocyte function Morphology of erythrocytes Heme synthesis Iron metabolism Red blood cell energy requirements and hemoglobin breakdown Leukocyte Leukocyte biology Morphology of leukocytes Neutrophils Eosinophils Basophils Monocytes Lymphocytes Platelet biology Platelet function Morphology of platelets Hemostasis Biochemical Basis of Hematopoietic Toxicity Toxicity-Induced Alterations of Hematopoietic Elements Myelosuppression Anemia Immune-mediated hemolytic anemia Oxidative or nonimmune hemolysis Basophilic stippling Neutrophilia and neutropenia Eosinophilia, monocytosis and lymphocytosis Erythrocytosis and thrombocytosis Thrombocytopenia/blood loss/coagulation inhibition Toxic leukemogenesis Conclusions and Future Directions References 23 Immunotoxicity Introduction Historical background Immunotoxicity in animal health Infectious diseases Interference with vaccination Immunotoxicity and cancer Autoimmunity Immune System Cellular components of the immune system Neutrophils Macrophages Dendritic cells Natural killer (NK) cells B cells and T cells General features of innate immunity General features of adaptive immunity Specificity Immunological memory Diversity Immunological tolerance Division of labor Relationship between innate and adaptive immune responses Possible mechanisms of immunotoxicity Cooperation and interactions between immune and other systems Immune mechanisms subsequent to pathologic damage Control of the immune system by nervous system Endocrine mechanisms The complement system Immunotoxic Agents Mycotoxins Metals Pesticides Industrial and environmental chemicals Other chemicals and drugs Testing for Immunotoxicity Conclusions and Future Directions References Section III: Nanoparticles, Radiation and Carcinogens 24 Toxicity of nanomaterials Introduction Nanomaterials Characterization Animal or Tissue Exposures In vitro exposures to nanomaterials Intratracheal instillation and pharyngeal aspiration Ultrafine particles Carbon nanotubes Intranasal exposure Inhalation exposure Epidemiological Data Sulfur dioxide (oxides of sulfur particles) Swine barn dust exposure Nanoparticles exposure in the home Dog exposures to automobile exhaust aerosols Emerging Challenges References 25 Ionizing radiation and radioactive materials in health and disease Introduction Historical Perspective Types of Ionizing Radiation Alpha and beta particles Gamma rays X-rays Measuring Ionizing Radiation Devices for Measuring Ionizing Radiation Film Thermoluminescent dosimeter Gas-filled detectors Scintillation counters Semiconductor detectors Ionizing Radiation: Risks AND Benefits Mechanisms of injury and their consequences Natural sources Nuclear weapons Nuclear power Sterilization of food products Medical diagnostics and treatments Dose–response curves for accessing risk Current recommendations regarding exposure limits Conclusions Acknowledgments References 26 Carcinogenesis: mechanisms and models1 Introduction Terminology Cancer Epidemiology Agents Causing Carcinogenesis Chemical carcinogenesis Chemical carcinogens Biological process of chemical carcinogenesis Initiation Promotion Progression Mode of action of chemical carcinogens Alkylation and alkylating agents Arylamination and arylaminating agents Aralkylation and aralkylating agents Cellular defense against DNA damage    DNA repair and removal of DNA adducts Viral carcinogenesis Tumor viruses, oncogenes and tumor suppressor genes Retroviral oncogenes and their evolution Activation of oncogenes Inactivation of tumor suppressor genes Functions of oncogene and tumor suppressor gene products Radiation carcinogenesis Radiation dose and risk Mechanism of radiation-induced carcinogenesis Epigenetic Basis of Carcinogenesis Classification of Carcinogens Assays for Carcinogens Long-term bioassays Short-term assays Structure–activity relationships and carcinogenicity Qualitative structure–activity relationships Quantitative structure–activity relationships Conclusions References 27 Oxidative stress and chemical toxicity Introduction Oxidative Stressors: Heavy Metals and Environmental Toxicants Chromium, lead, cadmium and other heavy metals Chromium Lead Iron, copper, manganese and zinc Oxidative stress by organophosphate and carbamate pesticides In vitro and in vivo generation of ROS and lipid peroxidation in the brain tissue by structurally dissimilar pesticides Chemiluminescence response by chlorpyrifos, fenthion and other structurally diverse pesticides for generation of ROS Lactate dehydrogenase leakage by chlorpyrifos, fenthion and other pesticides Genotoxicity of organophosphate In vitro and in vivo protein kinase c activation by structurally diverse pesticides and chromium (VI) and cadmium (II) Developmental neurotoxicity of chlorpyrifos on cultured PC-12 and Gliotypic C6 cells Naphthalene (a bicycylic aromatic hydrocarbon) Naphthalene-induced membrane microviscosity Mycotoxins, Oxidative Stress, Dna Damage and Apoptosis Conclusions References Section IV: Drugs of Use and Abuse 28 Toxicity of over-the-counter drugs Introduction Suspected OTC Drug Reactions Analgesics Acetaminophen Toxicity Toxicokinetics Mechanism of action Clinical signs Clinical chemistry Diagnosis and management Postmortem findings Nonsteroidal anti-inflammatory drugs (NSAIDs) Toxicity Toxicokinetics Mechanism of action Clinical signs Clinical chemistry Diagnosis and management Postmortem findings Aspirin and other salicylates Toxicity Toxicokinetics Mechanism of action Clinical signs Clinical chemistry and postmortem findings Management Cold, Cough and Allergy Medications Decongestants Toxicity Pharmacokinetics Mechanism of action Clinical signs Clinical chemistry Diagnosis and management Antihistamines Toxicity Pharmacokinetics Mechanism of action Clinical signs Management Drugs Used to Treat Gastrointestinal Symptoms Antacids H2 histamine receptor antagonists Pharmacokinetics Mechanism of action Clinical signs Mineral antacids Laxatives, cathartics and enemas Bulk-forming laxatives Lubricant laxatives Irritant laxatives Hyperosmotic cathartics Enemas Antidiarrheal drugs Topical Drugs Conclusions References 29 Toxicity of drugs of abuse Introduction Illicit drugs and small animals Illicit drugs and large animals The veterinarian and the Drug Enforcement Administration (DEA) Depressants Marijuana Toxicity Toxicokinetics Mechanism of action Clinical signs Treatment Pathology Barbiturates Toxicity Toxicokinetics Mechanism of action Clinical signs Treatment Opioids Toxicity Toxicokinetics Mechanism of action Clinical signs Treatment Other CNS depressants Flunitrazepam GHB Stimulants Cocaine Toxicity Toxicokinetics Mechanism of action Clinical signs Treatment Amphetamines Toxicity Toxicokinetics Mechanism of action Clinical signs Treatment Other stimulants MDMA Khat, mephedrone and methylenedioxypyrovalerone Betel quid Hallucinogens and Dissociative Drugs LSD and LSA Toxicity Toxicokinetics Mechanism of action Clinical signs Treatment Phencyclidine and ketamine Toxicity Toxicokinetics Mechanism of action Clinical signs Treatment Other compounds Mescaline Salvia divinorum Conclusions References Section V: Metals and Micronutrients 30 Aluminum Introduction Background Toxicokinetics Mechanism of Action Toxicity Diagnosis Treatment Conclusions Acknowledgments References 31 Arsenic Introduction Background Pharmacokinetics/Toxicokinetics Mechanism of Action Toxicity Treatment Conclusions References 32 Cadmium Introduction Background Pharmacokinetics/Toxicokinetics Mechanism of Action Toxicity Treatment Concluding Remarks/Future Directions References 33 Chromium, iodine and phosphorus Chromium Iodine Phosphorus References 34 Copper Introduction Background Pharmacokinetics Mechanism of Action Toxicity Treatment Conclusion References 35 Fluoride Introduction Background Pharmacokinetics and Mechanism of Action Toxicity Treatment Concluding Remarks References 36 Iron Introduction Background Pharmacokinetics/Toxicokinetics Mechanism of Action Toxicity General Acute toxicity in dogs, cattle, pigs and adult horses Neonatal pigs Neonatal horses Iron storage disease Treatment Concluding Remarks References 37 Lead Introduction Background Toxicokinetics Mechanism of Action Toxicity Treatment Concluding Remarks References 38 Manganese Introduction and Background Pharmacokinetics/Toxicokinetics Mechanism of Action Toxicity Diagnosis Treatment Concluding Remarks and Future Directions Acknowledgments References 39 Mercury Introduction Background Toxicokinetics Mechanism of Action Toxicity Nervous system Renal system Cardiovascular system GI tract Hematopoietic system Other effects Diagnosis Treatment Conclusions Acknowledgment References 40 Molybdenum Introduction Background Pharmacokinetics/Toxicokinetics Absorption Distribution Elimination Mechanism of Action Toxicity Treatment Concluding Remarks and Future Directions References 41 Selenium Introduction Background Pharmacokinetics/Toxicokinetics Absorption Distribution Metabolism Elimination Mechanism of Action Toxicity Treatment Concluding Remarks and Future Directions References 42 Sodium chloride (salt) Introduction Background Pharmacokinetics and Mechanism of Action Toxicity Treatment Concluding Remarks References 43 Sulfur Introduction Background Pharmacokinetics/Toxicokinetics Mechanism of Action Toxicity Treatment Concluding Remarks and Future Directions References 44 Zinc Introduction Background Pharmacokinetics/Toxicokinetics Mechanism OF Action Toxicity Treatment Conclusions References Section VI: Insecticides and Molluscicides 45 Organophosphates and carbamates Introduction Background OP Pesticides OP Nerve Agents/Gases Carbamates Pharmacokinetics of OPs And CMs Mechanism of Action Toxicity Treatment of Acute Poisoning OP-Induced Intermediate Syndrome Chronic Toxicity Tolerance Development Conclusions and Future Directions References 46 Organochlorines Introduction Background Pharmacokinetics/Toxicokinetics Mechanism of Action Toxicity Treatment Concluding Remarks and Future Directions References 47 Pyrethrins and pyrethroids Introduction Background Pharmacokinetics/Toxicokinetics Mechanism of Action Toxicity Treatment Concluding Remarks and Future Directions References 48 Neonicotinoids Introduction Background Pharmacokinetics/Toxicokinetics Mechanism of Action Treatment Concluding Remarks and Future Directions References 49 Amitraz Introduction Background Pharmacokinetics/Toxicokinetics Mechanism of Action Toxicity Acute toxicity Chronic toxicity Diagnosis Treatment Conclusions Acknowledgments References 50 Fipronil Introduction Background Pharmacokinetics/Toxicokinetics Mechanism of Action Toxicity Laboratory animals Dogs and cats Birds and fish Diagnosis Treatment Conclusions References 51 Macrocyclic lactone endectocides Introduction Background Pharmacokinetics/Toxicokinetics Mechanism of Action Toxicity Toxicity data Clinical effects Diagnosis Treatment Conclusions Acknowledgments References 52 Rotenone Introduction Background Pharmacokinetics/Toxicokinetics Mechanism of Action Toxicity Diagnosis Treatment conclusions Acknowledgments References 53 Metaldehyde Introduction Background Toxicokinetics Mechanism of Action Toxicity Diagnosis Treatment Conclusions Acknowledgments References Section VII: Herbicides and Fungicides 54 Toxicity of herbicides Introduction Background Toxicokinetics Mechanism of Action Toxicity Inorganic herbicides Phenoxy acid derivatives Bipyridyl derivatives Ureas and thioureas Phosphonomethyl amino acids or inhibitors of aromatic acid biosynthesis Protoporphyrinogen oxidase inhibitors Triazines and triazoles Substituted anilines Amides and acetamides Dinitrophenol compounds Triazolopyrimidine herbicides Imidazolinones Benzoic acids Carbamates, thiocarbamates and dithiocarbamate compounds Others Endocrine Disruption Treatment Conclusions References 55 Toxicity of fungicides Introduction Background Toxicokinetics Mechanism of Action Toxicity Inorganic fungicides Metallic fungicides Halogenated substituted monocyclicaromatics Chloroalkylthiodicarboximides (phthalimides) Anilinopyrimidines Carbamic acid derivatives Benzimidazoles Conazoles Morpholines Amides Others Endocrine Disruption Treatment Conclusions and Future Directions References Section VIII: Rodenticides and Avicides 56 Anticoagulant rodenticides Introduction Background Hydroxycoumarins Bromadiolone Brodifacoum Coumatetralyl Coumafuryl Difenacoum Warfarin Indanedione group Chlorophacinone Diphacinone Target species Brodifacoum Bromadiolone Chlorophacinone Coumafuryl Coumatetralyl Diphacinone Difenacoum Flocoumafen Flupropadine Warfarin Non-Target Species Environmental Wildlife Avian Mechanism of Action Biochemistry Resistance Antioxidant Metabolism Toxicokinetics Bioavailability Distribution Elimination Duration Toxicity Occurrence Dose Diagnosis History Clinical signs Coagulopathy Hematology Necropsy/autopsy Response to vitamin K1 treatment Analytical chemistry Treatment General Supportive Specific Conclusions References 57 Non-anticoagulant rodenticides Strychnine Introduction Background Toxicokinetics Mechanism of action Toxicity Diagnosis Treatment Conclusion Bromethalin Introduction Background Toxicokinetics Mechanism of action Toxicity Diagnosis Treatment Conclusion Cholecalciferol Introduction Background Toxicokinetics Mechanism of action Toxicity Treatment Conclusion Red Squill Introduction Background Toxicokinetics Mechanism of action Toxicity Treatment Conclusions Fluoroacetate Introduction Background Toxicokinetics Mechanism of action Toxicity Diagnosis Treatment Conclusion Alpha-Naphthyl Thiourea Introduction Toxicokinetics and mechanism of action Toxicity Diagnosis Treatment Zinc Phosphide Introduction Background Toxicokinetics Mechanism of action Toxicity Diagnosis Treatment Conclusion Thallium Introduction Background Toxicokinetics Mechanism of action Toxicity Diagnosis Treatment Conclusion References 58 Avitrol Introduction Background Toxicokinetics Mechanism of Action Toxicity Diagnosis Treatment Conclusions Acknowledgments References Section XI: Gases, Solvents and Other Industrial Toxicants 59 Toxic gases Introduction General Principles Toxicokinetics Absorption and distribution Metabolism Excretion of gases via the respiratory tract Basic dosimetric adjustments for human risk assessment Specific Toxic Gases Carbon monoxide Overview, uses, and sources of exposure Toxic dose Toxicokinetics and toxicodynamics Pathophysiology Vulnerable populations Clinical presentation Diagnostic testing Postmortem findings Treatment Prognosis Prevention Hydrogen sulfide Overview, uses, and sources of exposure Toxic dose Toxicokinetics and toxicodynamics Pathophysiology Vulnerable populations Clinical presentation Diagnostic testing Postmortem findings Treatment Prognosis Prevention Oxides of nitrogen (silo filler’s disease) Overview, uses, and sources of exposure Toxic dose Toxicokinetics and toxicodynamics Pathophysiology Vulnerable populations Clinical presentation Diagnostic testing Postmortem findings Treatment Prognosis Prevention Gaseous ammonia Overview, uses, and sources of exposure Toxic dose Toxicokinetics and toxicodynamics Pathophysiology Vulnerable populations Clinical presentation Diagnostic testing Postmortem findings Treatment Prognosis Prevention Smoke inhalation Overview, uses, and sources of exposure Toxic dose Pathophysiology Vulnerable populations Clinical presentation Diagnostic testing Treatment Prognosis References 60 Alcohols and glycols Introduction Background Alcohol Toxicoses Ethanol toxicosis Toxicokinetics Mechanism of action Diagnosis and treatment Methanol toxicosis Toxicokinetics Mechanism of action Diagnosis and treatment Isopropanol toxicosis Toxicokinetics Diagnosis and treatment Glycol Toxicoses Propylene glycol toxicosis Toxicokinetics Diagnosis and treatment Butylene glycol toxicosis Toxicokinetics Mechanism of action Treatment Ethylene glycol toxicosis Toxicokinetics Mechanism of action Toxicity Clinical signs Early laboratory abnormalities Late laboratory abnormalities Treatment Prognosis Conclusions References 61 Petroleum Introduction Oil and Gas Well Drilling and Completing Drilling Completion and formation fracturing (fracking) Coal bed Methane and Shale Gas Sources of Toxic Substances Emissions Production water Well rework and pipeline maintenance Sumps and contaminated soil Ions Lubricant additives Antihydrates and antifreezes Chromate Grease and Motor Oil Toxicology of Crude and Refined Petroleum Experimental studies Ingestion of petroleum Experimental studies on ingestion of petroleum Clinical observations and findings Dermal toxicity of petroleum Biochemical toxicology Veterinary Medical and Pesticide Uses of Petroleum White oils Kerosene and diesel oils Sour Gas Sour gas well blowouts Hydrogen Sulfide Gasotransmitter Effects on metabolism and the endocrine system Reproductive toxicology Biochemical toxicology Pathology of hydrogen sulfide Experimental studies: cattle Exposure to Environmental Sulfur Toxicology of Sulfur Dioxide in Cattle Pathology of Petroleum and Oil Field Chemicals Clinical pathology Pulmonary pathology of petroleum Hepatic pathology of petroleum Gastrointestinal pathology of petroleum Renal pathology of petroleum Nervous system pathology of petroleum Cardiac pathology of petroleum Pathological effects of petroleum in embryos Sour gas and sour condensate Nonpesticide organophosphorus esters Sulfur Epidemiological Studies: Cattle Wildlife Analytical Toxicology Differential Diagnosis Conclusions and Future Directions References 62 Polychlorinated biphenyls, polybrominated biphenyls, polychlorinated dibenzo-p-dioxins, and polychlorinated dibenzofurans Introduction Background Sources of PCBs, PCDDs, PCDFs, and PBBs PCBs PCDDs and PCDFs PBBs Environmental fate of PCBs, PCDDs, PCDFs, and PBBs Exposure to PCBs, PCDDs, PCDFs, and PBBs PCBs Michigan PBB incident PCDDs and PCDFs Differential toxicity TEFs Toxicokinetics PCBs and PBBs PCDDs and PCDFs Mechanism of Action Toxicity PBBs PCBs, PCDDs, and PCDFs Treatment Conclusions and Future Directions References 63 Polycyclic aromatic hydrocarbons Introduction Exposure of Farm Animals to PAHs Uptake, Disposition, Bioaccessibility, and Bioavailability of PAHs in Farm Animals Transfer of PAHs in cows Transfer of PAHs in pigs Transfer of PAHs in sheep and goats Biotransformation of PAHs in Farm Animals Effect of sexual maturity on BaP metabolism Health Effects of PAHs in Farm Animals Reproductive and developmental toxicity Treatment Conclusion and Future Directions Acknowledgments References 64 Brominated flame retardants and perfluorinated chemicals Introduction Background Physicochemical Properties Brominated flame retardants Perfluorinated compounds Pharmacokinetics and Toxicokinetics Brominated flame retardants Perfluorinated compounds Mechanism of Action and Toxicity Brominated flame retardants Perfluorinated compounds Conclusion and Future Directions Acknowledgments References Section X: Environmental Toxicology 65 Veterinary geology Introduction Medical Geology Veterinary Geology Problems In Animals Associated With Geochemistry Problems Associated with Water Conclusions References 66 Principles of ecotoxicology Introduction and Core Concepts Definitions Successes and challenges Sources of pollution Environmental fate and bioavailability of chemicals Chemical disasters: ecological, economic, and societal factors Ecotoxicants in Concert with Other Mechanisms of Ecosystem Disease Wasting carbon, inducing climate change, and increasing toxic exposures Direct Toxicity of Nutrients, Stimulation of Harmful Algal Blooms, and Facilitation of Lethal Outbreaks of Botulism Petroleum Disasters, Wildlife Toxicology, and Human Impacts Aromatic Hydrocarbons Persistent Organic Pollutants Contaminants from E-Wastes Pesticides Organochlorine insecticides Concurrent exposures of frogs to DDT analogs and other persistent organochlorines Cholinesterase-inhibiting insecticides Other insecticides Indirect effects of insecticides Herbicides Interactions among pesticides, nutrients, and pathogens Anticoagulant rodenticides Organotin biocides Endocrine-Disrupting Mixtures in Surface Waters Metals, Minerals, and Mining Oxides of Nitrogen and Sulfur and Their Interactions with Metals Radiation/Radionuclides The Future of Ecotoxicology References 67 Avian toxicology Introduction Pet and aviary birds Wild birds Poultry Physiologic differences of birds relevant to toxicology Respiratory system Metabolic system Excretion General Comments About Diagnosing Avian Intoxications Natural Toxicants Algal toxins Avian vacuolar myelinopathy Plants Mycotoxins Aflatoxins Fusariotoxins T-2 toxin Deoxynivalenol (vomitoxin) Fumonisins Ochratoxin and citrinin Zootoxins Bacterial toxins Botulinum toxin Biogenic amines Feed additives Arsenicals Sodium Vitamin A Vitamin D Ionophores Drugs Pesticides Insecticides Organochlorine insecticides Cholinesterase inhibitors (organophosphorus and carbamate insecticides) Pyrethrins/pyrethroids Boric acid Nicotine Rodenticides Anticoagulants Avicides Metals Lead Zinc Mercury Iron Selenium Environmental Toxicants Pentachlorophenol Petroleum Cyanide Toxic Gases Ammonia Carbon monoxide Polytetrafluoroethylene: Teflon Concluding Remarks and Future Directions References 68 Aquatic toxicology Introduction Background Water Safety Nitrogen cycle Ammonia Nitrite Nitrate Metals Copper Chlorine Feed Mycotoxins Fumonisins and moniliformin Aflatoxins Ochratoxins Contaminants in aquaculture fish Chlorinated dioxins Methylmercury Toxicology Investigations Concluding Remarks And Future Directions References 69 Toxicology and diversity of marine toxins Introduction Saxitoxins Background Pharmacokinetics/toxicokinetics Mechanism of action Toxicity Human toxicity Experimental toxicity Single administration Treatment Concluding remarks Tetrodotoxin Background Pharmacokinetics/toxicokinetics Mechanism of action Toxicity Human toxicity Experimental toxicity Single administration Treatment Concluding remarks Ciguatoxins and Maitotoxins Background Ciguatoxins Pharmacokinetics/toxicokinetics Mechanism of action Toxicity Human toxicity Experimental toxicity Single administration Repeated administration Treatment Concluding remarks Maitotoxins Pharmacokinetics/toxicokinetics Mechanism of action Toxicity Human toxicity Experimental toxicity Single administration Repeated administration Concluding remarks Domoic Acid and Analogs Background Pharmacokinetics/toxicokinetics Mechanism of action Toxicity Human toxicity Experimental toxicity Single administration Repeated administration Teratogenicity Genotoxicity Treatment Concluding remarks Brevetoxins Background Pharmacokinetics/toxicokinetics Mechanism of action Toxicity Human toxicity Experimental toxicity Single administration Repeated administration Toxicity for fish and other marine animals Treatment Concluding remarks Palytoxin and its Analogs Background Pharmacokinetics/toxicokinetics Mechanism of action Toxicity Human toxicity Experimental toxicity Single administration Repeated administration Mutagenic and genotoxic activity Tumor-promoting activity Treatment Concluding remarks Okadaic Acid and its Derivatives Background Pharmacokinetics/toxicokinetics Mechanism of action Toxicity Human toxicity Experimental toxicity Single administration Repeated administration Mutagenic and genotoxic activity Tumor-promoting activity Treatment Concluding remarks Azaspiracids Background Pharmacokinetics/toxicokinetics Mechanism of action Toxicity Human toxicity Experimental toxicity Single administration Repeated administration Treatment Concluding remarks Other Lipophilic Toxins Yessotoxins Background Pharmacokinetics/toxicokinetics Mechanism of action Toxicity Human toxicity Experimental toxicity Single administration  Repeated administration  Concluding remarks Pectenotoxins Background Pharmacokinetics/toxicokinetics Mechanism of action Toxicity Human toxicity Experimental toxicity Single administration Concluding remarks Cyclic Imine Toxins Background Pharmacokinetics/toxicokinetics Toxicity Human toxicity Experimental toxicity Single administration Mechanism of action Concluding remarks References Section XI: Bacterial and Cyanobacterial Toxins 70 Botulinum neurotoxins Introduction Background Mechanism of Action Clinical Botulism Laboratory Diagnosis Species-Specific Disease Equine botulism Clinical signs, diagnosis, and treatment Prevention Avian botulism Clinical signs, diagnosis, and treatment Prevention Bovine botulism Clinical signs, diagnosis, and treatment Public health Canine and feline botulism Clinical signs, diagnosis, and treatment References 71 Enterotoxins Introduction Background Pharmacokinetics and Mechanism of Action Toxicity Treatment Concluding Remarks References 72 Cyanobacterial (blue-green algae) toxins Introduction Background Microcystins Pharmacokinetics/toxicokinetics Mechanism of action Toxicity Treatment Anatoxins Pharmacokinetics/toxicokinetics Mechanism of action Toxicity Treatment Miscellaneous Freshwater Cyanobacterial Toxins Concluding Remarks and Future Directions References Section XII: Poisonous and Venomous Organisms 73 Terrestrial zootoxins Introduction Arthropoda Araneae: Spiders Introduction Widow spiders (Latrodectus Spp.) Background Mechanism of action Toxicity Treatment Recluse or violin spiders (Loxesceles Spp.) Background Mechanism of action Toxicity Treatment Hobo Spiders (Tegenaria Agretis) Background Toxicity Treatment Funnel web spiders (Atrax and Hadronyche Spp.) Background Mechanism of action Toxicity Tarantulas Scorpiones: scorpions Background Mechanism of action Toxicity Treatment Ixodida: Ticks Background Mechanism of action Toxicity Treatment Myriapoda: Centipedes and millipedes Insecta: insects Introduction Coleoptera: Meloidae (Blister Beetles) Background Mechanism of action Toxicity Treatment Coleoptera: Fireflies Background Mechanism of action Toxicity Treatment Coleoptera: Other toxic beetles Hymenoptera: Bees, Wasps, And Hornets Background Mechanism of action Toxicity Treatment Hymenoptera: Ants Background Mechanism of action Toxicity Treatment Hymenoptera: Sawflies Background Mechanism of action Toxicity Treatment Lepidoptera: Butterflies and moths Phasmatodea: Walking sticks Introduction Background Toxicokinetics Mechanism of action Toxicity Treatment Amphibia, Anura: Toads Reptilia Snakes Introduction Crotalids Background Toxicokinetics Mechanism of action Toxicity Clinical effects Treatment Elapids Background Toxicokinetics Mechanism of action Toxicity Treatment Lizards Background Mechanism of action Toxicity Treatment Aves Mammalia Conclusions References 74 Mare reproductive loss syndrome Introduction Clinical Manifestations Mechanism of Action Treatment and Prevention Conclusions References Section XIII: Estrogenic Toxicants 75 Chemical-induced estrogenicity Introduction Estrogens Play a Role in Normal Physiological Function and Disease Background Estrogens and women’s health Risks for breast cancer: genetic factors Hormonal risk factors for breast cancer Lifestyle and dietary risk factors Estrogens as Risk Factors for Male Reproductive Tract Problems Estrogenic Chemicals of Concern Case study: bisphenol A Mechanisms of Estrogen-Induced Transactivation ERα and ERβ domain structure Xenoestrogens and Phytoestrogens as Selective Er Modulators Complexity of estrogenic activity Development of bioassays for clinically relevant SERMs Xenoestrogens and phytoestrogens as SERMs Xenoestrogens and Phytoestrogens as SermS and Implications for Risk Assessment Acknowledgments References 76 Phytoestrogens Introduction Description Historical background Pharmacokinectics/Toxicokinetics Plant impact Animal biotransformation Absorption Tissue distribution Excretion Mechanism of Action Estrogen receptors Impact on steroidogenesis Additional impact on cell functions Altered signal transduction and cell proliferation Adverse Health Effects Developmental effects Hormones and estrous cycles Infertility Male infertility Risk Assessment Treatment Concluding Remarks and Future Directions References Section XIV: Poisonous Plants 77 Poisonous plants of the United States Introduction Astragalus and Oxytropis Species (Locoweeds, Nitro spp., and Selenium spp.) Locoweeds Description Distribution and ecology Toxicology Toxin Conditions of grazing Prevention of poisoning and management recommendations Summary Nitro-containing Astragalus (milkvetches) Description Distribution Toxicology Prevention and treatment Seleniferous Astragalus Description Distribution Toxicity Prevention of poisoning Larkspurs (Delphinium spp.) Description Distribution and habitat Toxicology Prevention and management of poisoning Grazing management Graze sheep before cattle Drug intervention Herbicidal control Lupines (Lupinus spp.) Description Distribution Toxicology Cattle grazing Prevention, management, and treatment Summary Poison Hemlock (Conium Maculatum) Description Toxicology Prevention and treatment Water Hemlock (Cicuta spp.) Distribution Description Toxicology Prevention and treatment Ponderosa Pine Needles (Pinus spp.) Description Distribution Toxicology Prevention and treatment Broom Snakeweed (Gutierrezia spp.) Description and distribution Broom snakeweed (Gutierrezia sarothrae (Pursh) Britt. & Rusby) Threadleaf snakeweed (G. microcephala (DC) Gray) Ecology Toxicology Management and treatment Rayless Goldenrod (Haplopappus Heterophyllus) Description Distribution Toxicology Prevention and treatment Halogeton (Halogeton Glomeratus) Description and ecology Toxicology Treatment of poisoned animals Management to prevent poisoning Oak Poisoning Conditions of poisoning Prevention and treatment Pyrrolizidine Alkaloid-Containing Plants Toxicology Prevention and treatment Photosensitizing Plants Description and distribution Toxicology Primary Secondary Prevention and treatment Death Camas Description, habitat, and geographical distribution Toxicity of death camas to livestock Management and prevention Veratrum spp. Distribution Habitat and description Toxicology Prevention and treatment Bracken Fern (Pteridium and Aquilinum) Distribution and habitat Description Toxicology Treatment Milkweeds: Asclepias spp. Description Distribution and habitat Toxicology Treatment and control Nightshades Toxins Clinical signs Treatment Knapweeds: Centaurea spp. Habitat and distribution Toxicology Clinical signs Pathology Prevention and treatment Conclusions Acknowledgments References 78 Poisonous plants of Europe Introduction Plant identification Diagnosis of plant poisoning Pet animals Livestock Conditions conducive to plant poisoning Predictive and toxicity factors Age Species Boredom Changes in surroundings Behavioral abnormalities Plants Poisonous Plants Affecting Animals Aconitum napellus (Ranunculaceae family) Common names: aconite, monkshood, and wolfsbane Toxicity Clinical presentation Amianthium muscaetoxicum (Liliaceae family) Common names: fly poison, stagger grass, and crow poison Toxicity Clinical presentation Cannabis sativa (Cannabinaceae family) Common names: marijuana, marihuana, bhang, hashish, Ganja, and sinsemilla Active principle Conditions of poisoning Clinical presentation Colchicum autumnale L. (Liliaceae family) Common names: colchium, meadow saffron, autumn crocus, and naked ladies Toxicity Clinical presentation Conium maculatum (Umbillifereae family) Common name: hemlock Toxicity Clinical presentation Convallaria majalis (Liliaceae family) Common names: lily of the valley, may lily, Jacob’s lily, and our lady’s tears Toxicity Clinical presentation Coriaria myrtifolia (Coriariaceae family) Common names: tanner’s herb, Mediterranean coriaria, and redoul Toxicity Clinical presentation Datura spp. (Solanaceae family) Common name: thorn apple Toxicity Conditions of poisoning Clinical presentation Hypericum perforatum (Hypericaceae family) Common names: St. John’s wort, goatweed, and Klamath weed Toxicity Clinical presentation Galega officinalis L. (Papilionaceae family) Common name: goat’s rue Toxicity Clinical presentation Nerium oleander (Apocynaceae family) Common name: oleander Toxicity Clinical presentation Pteridium aquilinum L. or Pteris aquilina L. (Polypodiaceae family) Common name: Bracken fern Toxicity Clinical presentation Quercus spp. (Fagaceae family) Common names: live oaks (evergreens) and acorns Toxicity Clinical presentation Ricinus communis (Euphorbiaceae family) Common name: castor bean Toxicity Clinical presentation Robinia pseudoacacia (Papilionaceae family) Common names: false acacia, locust tree, and black locust tree Toxicity Clinical presentation Senecio spp. (Compositeae family) Common names: ragwort and groundsel Toxicity Clinical presentation Taxus baccata L. (Taxaceae family) Common name: yew Toxicity Clinical presentation Thuja occidentalis L. (Cupressaceae family) Common name: thuja Clinical presentation Treatment Nonspecific treatment Decontamination procedures Gastric decontamination Enemas Laxatives and purgatives (cathartics) Enhanced removal and elimination Specific treatment Supportive Therapy Conclusions References 79 Poisonous plants of Australia and New Zealand Introduction Reducing Livestock Losses Associated with Poisonous Plants in Australia and New Zealand Conclusions References 80 Cyanogenic plants Introduction Background Pharmacokinetics/Toxicokinetics Mechanism of Action Toxicity Treatment Concluding Remarks and Future Directions References 81 Nitrate and nitrite accumulating plants Introduction Background Pharmacokinetics/Toxicokinetics Mechanism of Action Toxicity Treatment Concluding Remarks References 82 Toxicity of yew (Taxus spp.) alkaloids Introduction Historical background Chemical characterization Pharmacokinetics/Toxicokinetics Physiology/Mechanism of Action Toxicity Diagnosis Treatment Conclusions References 83 Oxalate-containing plants Introduction Oxalate Chemistry Eating Behavior and Gastrointestinal Anatomy Monogastric carnivores Monogastric herbivores Ruminant herbivores Clinical Toxicosis Categories Species-Specific Toxicity Sheep Cattle Horses Other hindgut fermenters Dogs and cats A growing problem: canine and feline oxalate urolithiasis. Is it chronic oxalate toxicosis? Poultry Treatment Prophylaxis/Adaptation Conclusions Acknowledgments References 84 Mushroom toxins Introduction Background Hepatotoxic Cyclopeptides Pharmacokinetics/toxicokinetics Mechanism of action Toxicity Treatment Hydrazines Pharmacokinetics/toxicokinetics Mechanism of action Toxicity Treatment Muscarinic Agents Pharmacokinetics/toxicokinetics Mechanism of action Toxicity Treatment Isoxazoles Pharmacokinetics/toxicokinetics Mechanism of action Toxicity Treatment Psilocin and Psilocybin Pharmacokinetics/toxicokinetics Mechanism of action Toxicity Treatment Gastrointestinal Irritants Renal Toxic Mushrooms Ramaria Flavo-Brunnescens Concluding Remarks and Future Directions References 85 Datura species and related plants Introduction Chemistry Toxicity as Related to the Plant Part Toxicodynamics and Toxicokinetics of Tropane Alkaloids from Datura Spp. Clinical Signs of Poisoning Equines Cattle Sheep and goats Springbok Pigs Chickens Other species Treatment Conclusions and Future Directions Ruminants Toxicokinetics References 86 Cottonseed toxicity Introduction Background Pharmacokinetics/Toxicokinetics Mechanism of Action Toxicity Treatment Concluding Remarks References 87 Fescue toxicosis Introduction Background Endophyte name Mutualism (symbiosis) and endophyte survival Endophytic toxins Ergot alkaloids General classification and toxicity Role of ergovaline in fescue toxicosis Seasonal variation Interactions with Claviceps purpurea Pharmacokinetics/Toxicokinetics Absorption Distribution/metabolism Excretion Mechanisms of Action D1 dopaminergic antagonist D2 dopaminergic agonist Prolactin inhibition Lactation suppression Effect on other reproductive hormones Effect on hypothalamic thermoregulatory center Effect on lipogenesis Effect on winter hair loss Effect on immunity Miscellaneous neurologic effects α1 Adrenergic antagonist α2 Adrenergic agonist Vasoconstriction Gangrene of extremities Decreased heat loss Serum enzyme decrease Oxidative stress Renal-related effects Serotonergic agonist Toxicity Seasonal variation and effects of decreased feed intake Cattle Summer slump Fescue foot Lipomatosis Small ruminants Horses Gestational abnormalities Subfertility Laminitis Camelids (llamas and alpacas) Laboratory rodents Treatment Nonspecific treatment/prevention for bovine fescue toxicosis Specific treatment for fescue toxicosis in various species Prevention Prevention of equine fescue toxicosis Breeding and foaling management D2 dopamine receptor antagonists Novel or non-endophyte-infected fescue Ammoniation of hay Feed supplements Pasture considerations Concluding Remarks References Section XV: Mycotoxins 88 Aflatoxins Introduction Background History of aflatoxins Aflatoxigenic fungi Conditions for aflatoxin production Moisture management of grain In vivo production of aflatoxins Provenance of Aflatoxins in Feedstuffs and Foods Sources and occurrences of aflatoxicosis Rapid formation Oilseeds Distiller’s grains and commodity byproducts Chemistry Sampling and Analysis Pharmacokinetics/Toxicokinetics Absorption Metabolism and excretion Residues Milk Residues in meat Toxicodynamics Mechanisms of action Immunotoxic effects Reproductive and teratogenic effects Clinicopathology Introduction Cattle Sheep and goats Swine Dogs Horses Poultry Humans Macroscopic and Microscopic Pathology Edema Hemorrhage Hepatic lesions Other lesions Differential Diagnosis Treatment and Outcomes Prevention of Aflatoxins Aflatoxin Interactions Concluding Remarks And Future Directions References 89 Ergot Introduction Background Pharmacokinetics/Toxicokinetics Mechanism of Action Toxicity Treatment Concluding Remarks References 90 Fumonisins Introduction Background Chemical structure Occurrence and distribution Pharmcokinetics/Toxicokinetics Mechanism of Action Sphingolipid alterations Toxicity Spontaneous and experimental fumonisin toxicosis in swine Fumonisins in swine – pulmonary effects Fumonisins in swine – hepatic effects Fumonisins in swine – cardiovascular effects Fumonisins in swine – immunologic effects Fumonisin toxicosis in horses – historical Spontaneous and experimental fumonisin toxicosis in horses Neurologic and hepatic effects in horses Fumonisin toxicity in cattle Fumonisin toxicity in poultry Diagnosis and Treatment Concluding Remarks and Future Directions References 91 Ochratoxins and citrinin Introduction Background Toxicokinetics Mechanism of Action Nephrotoxicity Neurotoxicity Immunotoxicity Carcinogenicity Toxicity Treatment Conclusions Acknowledgments References 92 Slaframine Introduction Background Chemistry and Toxicokinetics Mechanism of Action Toxicity Diagnosis and Treatment Conclusions References 93 Tremorgenic mycotoxins Introduction Background Penicillium-associated tremorgenic mycotoxins Aspergillus-associated tremorgenic mycotoxins Neotyphodium-associated tremorgenic mycotoxins Claviceps-associated tremorgenic mycotoxins Bermudagrass staggers Toxicokinetics Mechanism of Action Toxicodynamics Central effects Peripheral effects Genotoxicity Acute toxicity Potential interactions Clinical Aspects of Tremorgenic Mycotoxicoses Diagnosis Treatment Prevention Conclusions References 94 Trichothecenes Introduction Background Sources Toxicokinetics Microbial Metabolism Mechanism of Action and Toxicity Protein Synthesis Inhibition Lipid Peroxidation Neurotransmitter Effects Immunotoxicity IgA Apoptosis Cell Membrane Function Reproductive Toxicity Genotoxicity and Teratogenesis Clinical pathology Toxicity Swine Horses Dogs and cats Ruminants Poultry New trichothecene concern Treatment Conclusions References 95 Zearalenone Introduction Background Toxicokinetics Mechanism of Action TOXICITY Swine Ruminants Equine Poultry Treatment Conclusions References Section XVI: Feed and Water Contaminants 96 Melamine and cyanuric acid Introduction Source Pharmacokinetics/Toxicokinetics Mechanism of Action Toxicity Clinical Signs Clinical Pathology Pathology Diagnosis Treatment and Prognosis Conclusions References 97 Ionophores Introduction Background Pharmacology/Pharmacokinetics Pharmacology Pharmacokinetics Mechanism of Action Toxicity Pathogenesis Occurrence Clinical signs Post-mortem findings Histopathologic findings Other laboratory findings Diagnosis and differential diagnosis Treatment Conclusions References 98 Nonprotein nitrogen (urea) and hyperammonemia Introduction and Background Toxicity Clinical Signs Diagnostic Criteria Treatment Ammonia Conclusions References 99 Water quality and contaminants Introduction The Assessment of Water Quality Water Quality Standards for Animals U.S. EPA water quality criteria for animals National Academy of Sciences recommended limits in drinking water for livestock and poultry Canadian environmental quality guidelines Organic contaminants Drinking Water Quality Standards for Humans Water Consumption Tables Rationale for Livestock Recommendations Arsenic Cadmium Chromium Copper Fluorine (Author’s addendum: fluorine and fluoride seem to be used synonymously) Hardness (Authors’ addendum) Iron Lead Mercury Nitrate and nitrite Total dissolved solids (TDS) Selenium Sulfate Zinc Health Effects Of Cyanotoxins From Water Cyanotoxins Adverse health effects in humans Effects in animals Cyantoxins in drinking water Recreational water exposure Safe practices for drinking water Safe practices for recreational waters Monitoring strategy for freshwater cyanobacteria Conclusions References Section XVII: Diagnostic Toxicology 100 Basic concepts of analytical toxicology Introduction History of Chemical Analysis Early history of chemical analysis Recent history of chemical analysis Trueness (Accuracy) of Chemical Analytical Results Analytical Method Validation Performance tested methods Peer-verified programs Single laboratory validation An Example of an Slv for the Gas Chromatographic Determination of Selenium (Se) In Blood and Liver Calibration Curve: How to Measure a Quantity Of Interest Goodness of Linearity of Calibration Curve Recovery and accuracy Precision HorRat values Shewhart chart Example of an Interlaboratory (Collaborative) Study for the Validation of the Semi-Quantitative Method Outlier results Sensitivity rate Specificity rate (p) False positive rate (pf) False negative rate (pf) Performance parameters for the method Laboratory Quality Management Quality assurance Quality control Conclusions Acknowledgment References 101 Sample submission for toxicological analysis Introduction Required Information For Sample Submission History Clinical signs Post-mortem findings Chemical analysis Sample Collection and Submission for Toxicological Analysis Whole blood Serum Urine Liver biopsy specimen Milk Feces Vomitus or gastric aspirate Hair Brain, liver, kidney, fat and other tissue(s) with lesions Ocular fluid Ingesta (rumen content and stomach content) Baits Feedstuffs Forage (pasture) Forage (hay) Forage (silage) Mushrooms Plants Soil Water Samples for histological examination Samples for nutritional elemental analysis Submission forms Shipping Regulations for Diagnostic Specimens Packing diagnostic specimens for transport: summary Dispatch of samples Conclusions References 102 Toxicoproteomics in diagnostic toxicology Introduction Analytical Tools for Proteomic Analyses The proteome and sample complexity Two-dimensional gel electrophoresis High performance liquid chromatography Protein and peptide microarrays Mass spectrometry Bioinformatics tools Proteomics Applications In Diagnostic Toxicology Aquatic toxicology and pesticides Hepatotoxicity Toxins Conclusions References 103 Microscopic analysis of toxic substances in feeds and ingesta Introduction The Search for Clues Background: Principles of Feed Microscopy The Applications of Feed Microscopy Classification of Feed Ingredients by Sources Classification of Finished Formula Feeds by Processing Classification of Forages by Points of Contact or Potential Toxicants Identification of Ingesta Particles The Role of the Attending Veterinarian Feed Microscopy Training and Available Literature The Feed Microscopy Laboratory The Equipment Conclusions and Future Expectations References Section XVIII: Prevention and Treatment 104 Prevention and treatment of poisoning Prevention of Poisoning Stabilization and Monitoring Decontamination Ocular exposure Dermal exposure Oral exposure Dilution Emetics Lavage Adsorbents Cathartics Enemas Endoscopy/Gastrotomy Antidotal Therapies Antidotes for amitraz: atipamezole and yohimbine Antidotes for anticholinesterase agents: atropine and pralidoxime Cyproheptadine HCl Digoxin immune Fab Antidotes for ethylene glycol: ethanol and fomepizole Flumazenil Lipid emulsion Methocarbamol Naloxone HCl N-acetylcysteine Pamidronate disodium Phytonadione (vitamin K1) Conclusion References Index