Course Syllabus ¿TOXICOLOGY¿ THEORY SYLLABUS (4.5 CREDITS)
STUDY BLOCK I: GENERAL TOXICOLOGY (1.5 CREDITS) 1. HISTORY Poisons, poisoners and antidotes in the ancient times: poisons for darts and arrows; animal, vegetable and mineral poisons. Pioneering figures in the history of Toxicology. Poisoners of ancient times. The first search for the universal antidote. The Theriac and the Mithridate. The Holy Land. Enchantment. The Middle Ages and the Renaissance: relevant figures; poisoners and poisons. The Eighteenth and Nineteenth Centuries. Abused drugs. 2. TOXIC INCIDENTS Incidents related to gases. Agents involved in food poisoning. Toxic Oil Syndrome (TOS) 3. TOXIC INCIDENTS Poisoning by drugs. Poisoning by alcohol and drugs. Occupational poisoning. Environmental and radiation incidents. Mass suicide. Chemical and biological warfare. Dioxins 4. TOXICOLOGY, XENOBIOTICS, CLASSIFICATION OF TOXIC AGENTS, TOXIC RESPONSE AND PHASES OF THE TOXIC PHENOMENON Areas and objectives of toxicology. The concept of Toxicology, toxicity, poisoning, toxic, toxin and xenobiotic. Classification of toxic agents. The general aetiology of poisoning. Forms of poisoning. Types of toxic response. Tolerance. Interactions. Dose-response relationships. Potency vs. Maximum efficacy. Phases of the toxic phenomenon. 5. PASSAGE OF XENOBIOTICS THROUGH THE ORGANISM. TOXICOKINETICS Definitions. Absorption: characteristics. Main absorption pathways: the skin, the gastrointestinal tract, and the lungs. Distribution: characteristics. Elimination. Elimination pathways. Compartments. Kinetics. Compartmental models. Examples. 6. BIOTRANSFORMATION OF XENOBIOTICS I: GENERAL PRINCIPLES Concepts and general principles. The general principles that govern the systems and reactions of the biotransformation of xenobiotics. Biotransformation of xenobiotics versus the immune system. Elimination as the final purpose of biotransformation. Differentiation between Phase I (oxidation, reduction or hydrolysis) and Phase II reactions (conjugation): chemical characteristics and toxicological consequences. Inclusion of Phase I and Phase II biotransformation within the general framework of the biokinetics of xenobiotics. Subcellular and tissue distribution of the biotransformation enzymes. Classification and nomenclature. Concepts of toxic bioactivation and detoxification. Phase I reactions: oxidation, reduction and hydrolysis. Epoxide hydrolases. Esterases. Monoaminooxidase. Alcohol and Aldehyde dehydrogenase 7. BIOTRANSFORMATION OF XENOBIOTICS II The Cytochrome P-450 Superfamily: general aspects, classification and nomenclature, structural peculiarities such as haemoproteins and the characteristic absorption spectrum. Reactions. Enzymatic induction. Genetic polymorphisms. Bioactivation The Cytochrome P-450 Superfamily: subdivision into families, subfamilies and isoforms, classification criteria and nomenclature. Constituting elements of the P450 microsomal. The general mechanism of the oxidative catalytic cycle. Types of oxidation reactions catalyzed by P450. 8. BIOTRANSFORMATION OF XENOBIOTICS III Final purpose of the Phase II biotransformation reactions and how they facilitate detoxification and/or the elimination of xenobiotics. Phase II as a set of biosynthetic reactions that consume ATP. Endogenous conjugation molecules. Elimination pathways preferred by the different types of conjugates. Phase II reactions: glucuronidation, sulphation, methylation, acetylation, conjugation of amino acids, conjugation of glutathione. Factors that affect biotransformation. 9. MOLECULAR AND CELLULAR MECHANISMS OF TOXICITY I Main mechanisms. Classification. Reaction of the toxic agent with the target molecule. Alterations of cell structure and/or function. Apoptosis and necrosis. The concept of final toxic. Processes that favour the release of the final toxic to the molecular target versus those that oppose it. The difference between electrophilic molecules and free radicals. Formation mechanisms of electrophiles, free radicals and reactive oxygen species: formation and detoxification of the superoxide anion, the Fenton reaction. 10. MOLECULAR AND CELLULAR MECHANISMS OF TOXICITY II The effects of toxic agents on target molecules: dysfunction, destruction: the example of lipid peroxidation initiated by the hydroxyl radical, formation of neoantigens. Toxicity not initiated by reaction with target molecules. Alterations of cell structure and/or function. Toxicity resulting from dysfunction at cell level: disruption of gene expression and/or of cell activity, alteration of the functions of cell maintenance. Primary metabolic disorders that threaten cell survival: depletion of ATP, accumulation of intracellular calcium and generation of reactive oxygen species or nitrogen. The interrelationships between primary metabolic disorders, phases of toxic cell death. Mitochondria as the final target in the process of cell death. 11. MOLECULAR AND CELLULAR MECHANISMS OF TOXICITY III Types of cell death: necrosis and apoptosis. ¿Decision plan¿ of the cell that suffers toxic damage. Toxicity resulting from faults in cell repair mechanisms: necrosis and tissue fibrosis, carcinogenesis. 12. MUTAGENESIS AND CARCINOGENESIS I Definition of mutagen. Mutation. Types: Substitution of a base. Deletion or insertion of a base; insertion or deletion of a codon. Examples. Ames Test. Definition of neoplasia. The biology and biochemistry of tumoral cells. Definition of carcinogen. Mortality from cancer. 13. CARCINOGENESIS II Early discoveries in chemical carcinogenesis. Action mechanisms. The example of polycyclic aromatic hydrocarbons, other compounds, nitrosamines, heterocyclic amines, fibres and other inorganic compounds, hormones. Concept of initiator and promoter. Pathogenesis of cancer: phases of induction plus fixation, promotion and progression, the biological and clinical characteristics of each phase and their correspondence at the molecular level. 14. CARCINOGENESIS AND DEVELOPMENTAL TOXICOLOGY III Pathogenesis of cancer: phases of induction plus fixation, promotion and progression, biological and clinical characteristics of each phase and their correspondence at the molecular level. Formation of macromolecular adducts between the final carcinogen and the DNA. Molecular basis of the reversibility of the phase of tumoral promotion. Genotoxic and epigenetic mechanisms. Molecular genetics of carcinogenesis: proto-oncogenes, oncogenes and tumour suppressor genes, functions of the proteins that codify in the control of the cell cycle. Carcinogenesis as a multi-step process: the colon carcinoma model. System of definitions of carcinogenic power. Modulating factors: diet and cancer. Developmental Toxicology: concepts. Teratogen. Toxic agents. 15. BASIC TOXICITY ASSAYS Physico-chemical properties and short-term toxicity assays. Metabolism and degradation in plants and animals. Structure-activity relationships. Acute toxicity assays: oral, dermal and by inhalation. The LD50 and ED50 concepts. Subchronic toxicity after 28 days. Evaluation and indicative parameters of general effects after medium-term and long-term exposure. Studies of the effects on reproduction after three generations. The concepts of NOAEL, NOEL, LOAEL. The experimental deduction of the lowest or critical value for NOAEL in the evaluation of risks. Establishing the value for Acceptable Daily Intake (ADI). STUDY BLOCK II: SYSTEMATIC TOXICOLOGY (0.4 CREDITS)
16. TOXICITY OF TARGET ORGANISMS: NEUROTOXICOLOGY I The blood-brain barrier. Energy requirements of the nervous system. The problem of space. Maintenance of a medium rich in lipids. Transmission of information through the extracellular space. Neurotransmission: neurotransmitters 17. TOXICITY OF TARGET ORGANISMS: NEUROTOXICOLOGY II Transmission of information through the extracellular space: pathways. Patterns of neurotoxic lesion. Compounds associated with neuronopathies. Compounds associated with neuronopathies. Compounds associated with myelinopathies. Compounds associated with neurotransmission. 18. DIFFERENCES IN THE CONCEPTS OF DEPENDENCE, ADDICTION, TOLERANCE AND POISONING, DEFINED ACCORDING TO: THE DSM IV-TR AND THE ICD-10 DIAGNOSTIC CRITERIA; THE NATIONAL INSTITUTE ON DRUG ABUSE (NIDA); GOODMAN AND GILMAN¿S ¿THE PHARMACOLOGICAL BASIS OF THERAPEUTICS"; AND CASARETT AND DOULL'S ¿TOXICOLOGY: THE BASIC SCIENCE OF POISONS¿ Diagnosis of Dependence on Psychoactive Substances. The DSM IV-TR and ICD-10 Diagnostic Criteria. The DSM-IV-TR Criteria for Substance Dependence. The DSM-IV-TR Criteria for Substance Withdrawal. ICD-10 Guidelines for the Diagnosis of the Dependence Syndrome, WHO Criteria. ICD-10 Criteria for the Withdrawal Syndrome. Definitions of the National Institute on Drug Abuse of: Addiction, Substance Dependence and Tolerance. Goodman & Gilman ¿The Pharmacological Basis of Therapeutics¿: Concepts of Dependence and Tolerance. Diagnostic Characteristics for Substance Poisoning. The DSM IV-TR Diagnostic Criteria. The DSM-IV-TR Criteria for Substance Poisoning. Casarett and Doull's ¿Toxicology the Basic Science of Poisons¿: Definition of Poisoning. Comments 19. TOXICITY OF TARGET ORGANS: HEPATOTOXICITY I Functions and structural organization of the liver. Hepatotoxic Agents. Toxic responses of the liver. Mechanisms of hepatotoxicity .
STUDY BLOCK III: TOXICOLOGY OF RELEVANT CHEMICAL SUBSTANCES (2.1 CREDITS) 20. NATURAL TOXINS I Adverse reactions to foodstuffs or ingredients of the foodstuffs: adverse reaction (sensitivity); Hypersensitivity (allergy); Anaphylaxis; Intolerance; Toxicity (poisoning); Idiosyncrasy; Anaphylactoid reaction; Pharmacological food reaction; Metabolic reaction. Toxins of vegetable origin: Goitrogens. Cyanogenetic substances. Favism. Fungal toxins: Ergotism. Aflatoxins. Trichothecenes. Other micotoxins. 21. NATURAL TOXINS II Toxins of animal origin: Toxins of animal livers. Vitamin A. Toxins of marine animals: Scombroid poisoning. Poisoning by Tetraodontiform Fish. Poisoning by Shellfish: Neurotoxic Shellfish Poisoning (NSP), Paralytic Shellfish Poisoning (PSP), Amnesic Shellfish Poisoning (ASP), Ciguatera Fish Poisoning (CFP). Other types of poisoning by Shellfish. Other toxins. 22. TOXICITY OF PESTICIDES: ORGANOPHOSPHATES AND CARBAMATES I Introduction. Historical considerations. Pesticides in the food chain. Classifications. Anticholinesterase pesticides: organophosphates and carbamates. Classification and nomenclature. 23. TOXICITY OF PESTICIDES: ORGANOPHOSPHATES AND CARBAMATES II Cholinergic effects: action mechanism, treatment and main differences between organophosphates and carbamates. The neurodegenerative effects of organophosphates: Retarded Polyneuropathy and Neuropathy Target Esterase (NTE). Other toxic effects. Biotransformation: phosphotriesterases. Diagnosis. Treatment. 24. TOXICITY OF ORGANOCHLORIDES AND PYRETHROID PESTICIDES III Pesticides that affect the ionic channels: organochlorides and pyrethroids. Organochlorides: chemical structure. Historical perspective. Absorption. Distribution. Action mechanisms. Elimination. Action mechanisms. Signs and symptoms of poisoning. 25. TOXICITY OF ORGANOCHLORIDES AND PYRETHROID PESTICIDES. N,N-DIETHYL-3-METHYLBENZAMIDE (DEET) IV Pesticides that affect the ionic channels: organochlorides and pyrethroids. Organochlorides: Laboratory tests. Treatment. Pyrethrins and pyrethroids. Absorption. Distribution. Action mechanisms. Elimination. Signs and symptoms of poisoning. Treatment. N,N-diethyl-3-methylbenzamide (DEET).
26. HERBICIDES Herbicides: chlorophenoxides, bipyridyl derivatives. The most important toxic effects and their action mechanisms. 27. SOLVENTS, VAPOURS AND INHALANTS Solvents, Vapours and Inhalants: classification. Levels of exposure. Categories proposed for encephalopathy induced by solvents. Abuse of inhalants. How they are used. Toxicity. Classification as a disease. Consumption disorder: Dependence, Abuse, Poisoning. Laboratory findings. Course. Prevalence. 28. SOLVENTS, VAPOURS AND INHALANTS Properties of solvents. Absorption. Distribution. Metabolism. Epidemiology. General toxic effects. Chemical compounds: benzene, toluene and ethylbenzene, xylenes, styrene, diesel, n-hexane, carbon disulphide, chlorine hydrocarbons, ethylenglicol. Main toxic effects. Toxic and carcinogenic action mechanisms. 29. METALS I Heavy metals: lead and mercury. Clinical case. History. Presence and importance. Sources of exposure. Epidemiology. Toxicology. Pharmacokinetics/Toxicokinetics. Action mechanism. Physiopathology. Acute poisoning. Chronic poisoning. Diagnosis. Treatment. 30. METALS II Heavy metals: cadmium and arsenic. Clinical case. History. Presence and importance. Sources of exposure. Epidemiology. Toxicology. Pharmacokinetics/Toxicokinetics. Action mechanism. Physiopathology. Acute poisoning. Chronic poisoning. Diagnosis. Treatment. 31. ETHANOL I Introduction. Cultural history of alcohol. Biological markers. Standard measures of alcohol intake. Pattern of consumption. Problems of some specific groups: women, young people and the elderly. Alcohol in legislation. Toxicokinetics. Alcoholism; Instruments of evaluation. Treatment. Interactions 32. ETHANOL II Organic pathology associated to the consumption of alcohol. Pathology associated to the consumption of alcohol. Liver. Central nervous system. Cancer. Alcohol and pregnancy. 33. PSYCHOACTIVE SUBSTANCES. OPIATES Opiates: degree and pattern of use; action mechanism; molecular tolerance mechanisms, dependence and withdrawal; agonists and antagonists. 34. ABUSED SUBSTANCES: COCAINE History. Epidemiology. Legislation. Pharmacology. Effects. Toxicokinetics. Manufacture and uses. Toxic effects: Neurological symptoms, cardiac symptoms, pulmonary symptoms, other symptoms. Tests. 35. ABUSED SUBSTANCES. HALLUCINOGENS: LSD, AND PHENCYCLIDINE (PCP). CANNABIS History. Pharmacology. Pharmacokinetics and toxicokinetics. Physiopathology. Clinical manifestations. Diagnosis. 36. ABUSED SUBSTANCES. AMPHETAMINES AND DESIGNER DRUGS Indications. History and epidemiology. Pharmacology. Clinical manifestations. Amphetamine derivatives. Toxicity. Mechanisms of neurotoxicity. Diagnosis. Treatment. 37. TOBACCO Consequences of tobacco smoking. Physiological effects of tobacco smoke. Components of tobacco products. General aspects of treatment. 38. ANALGESICS, ANTIPYRETICS AND NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs). General concepts: the problem. NSAIDs: Pharmacological groups. Physiopathology. General adverse effects. Specific toxicology. 39. ANTIDEPRESSANTS. Classification. Toxic effects. Interactions. 40. ANTIPSYCHOTIC NEUROLEPTICS Classification. Indications. Action mechanism: serotonin, acetylcholine, noradrenaline, dopamine. Pharmacokinetics. Toxic effects. Typical and atypical drugs. 41. ANTIPSYCHOTICS. LITHIUM Antipsychotic drugs. Endocrine effects. Metabolic anomalies. Interactions. Toxic effects of lithium. Treatment. Interactions.