Veterinary toxicology : basic and clinical principles

__Veterinary Toxicology, 2nd Edition,__ is a unique single reference that teaches the basic principles of veterinary toxicology and builds upon these principles to offer an essential clinical resource for those practicing in the field. This new edition brings together insights from qualified and well-experienced authorities across all areas of veterinary toxicology to provide an authoritative and in-depth look at all facets of veterinary toxicology, including target organ toxicity, melamine and cyanuric acid, toxicogenomics, chemical terrorism and nanoparticles. While most comparable texts are primarily directed toward the field of human toxicology, this is the one text needed to thoroughly prepare future veterinarians on the newest approaches for diagnosing poisoning cases in all animals from chemicals and plants of a diverse nature as a result of inadvertent, accidental, or malicious intents. It is thoroughly updated with new chapters and the latest coverage of topics not tackled in any previous books such as target organ toxicity, radiation and radioactive materials, FDA regulatory issues, and ethics in veterinary toxicology. There are also expanded discussions on international topics such as epidemiology of animal poisonings and regulatory guidelines and poisonous plants in Europe. Problem solving strategies are offered for treatment. This volume will be of interest to practitioners, professors and students of veterinary medicine and veterinary toxicology, poison control centers, marine biologists, environmentalists and animal scientists. 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 Back