: this course aims to transmit to students in master 1 the basic knowledge about:
- The different types of toxic substances and their sources (medication, organic and mineral pollutants, food additives, pesticides, toxins of plant and microorganisms). Exposure to environmental pollutants from air, water and occupational exposure.
- The routes of penetration of xenobiotics to the organism (absorption, distribution, metabolism, excretion, toxicokinetic, toxicodynamic,…).
- The molecular mechanisms of xenobiotics metabolism, and the involved enzymatic systems (phase I, phase II, phase III).
- The molecular effects of toxic substances, particularly on DNA (genotoxicity, teratogenesis) and on some target organs (liver, immune system, nervous system,).
- Basic knowledge about the principles and methods of toxicity evaluation (toxicity testing)
Chapter 1: General introduction
History of toxicology – terminology definitions of terms related to toxicology – evolution of toxicology domains – toxicity evaluation procedures (dose effect relationship, LD50, …) – inventory of classes of toxic compounds and their sources – brief introduction of international organizations concerned with quality control.
Chapter 2: Toxic effects (toxicodynamic) and their testing
Diversity of toxic effects – acute, subchronic and chronic toxicity - review of target organs – mechanism of action of toxic compounds – principle and examples of antidotes.
Apoptotic parameters (morphology, DNA fragmentation, caspases activity, membrane alteration) – detection of cytotoxicity (LDH release, BrdU incorporation) – proliferation tests (measurement of tetrazolium salt conversion)
Chapter 3: Elements of toxicokinetic (1)
Xenobiotics penetration routes - passage des xenobiotics through biological membranes -– penetration (intestinal absorption, pulmonary inhalation, cutaneous diffusion,) – distribution in blood and tissues).
Chapter 4: Elements of toxicokinetic (2)
Metabolism (biotransformation) of xenobiotics – major organs - description of phase I enzymes (cytochromes P450 family and other enzymes of fonctionalization), phase II enzymes (glutathions transferases family, glucoronidase, others) and phase III enzymes (membrane pumps such as MDR) – one or two detailed examples of each phase – elimination of xenobiotics (excretion in bile, in urine, etc…).
Chapter 5: Toxicology of the liver - hepatotoxicity
Overview - main hepatic lesions – evaluation procedure (clinical presentation) – in vitro tests – factors affecting biotransformation of xenobiotics (inflammations, cytokines and other hormones, xenobiotics themselves).
Chapter 6: Immunotoxicology – effects of toxic compounds at the blood level
Xenobiotics and immune system – direct toxicity on the immune system - hypersensitivity – cytokines, inflammation and metabolism of xenobiotics.
Chapter 7: Genotoxicity and its testing – chemical mutagenesis and cancerogenesis
Cancer and carcinogenic substances – process of cancerogenesis – DNA lesions and mutations – genotoxicity – detection and characterization of genotoxic substances. Micronucleus test - sister chromatid exchange test - comets test – Ames test
Chapter 8 : Teratogenesis and fetotoxicity
Mechanisms of teratogenesis – evidences and examples of teratogenic substances.
Chapter 9: Factors influencing toxicity and xenobiotics effects: environment, target, genetic factors
Sexual dimorphism of xenobiotics metabolizing enzymes (different sensitivity of males and female) – genetic polymorphism of xenobiotics metabolizing enzymes and its relationship with effects of toxic compounds (for instance cancer development) – Example of benzo(a)pyrene, parathion or others– genetic polymorphism of xenobiotics metabolizing enzymes and its relationship with effects of therapeutic drugs (example of debrisoquine, warfarin, or others).
Chapter 10: Review of effects of toxic compounds on other organs
Endocrine system - lungs – kidney – cardiovascular system –nervous system – skin – eye – bones.
Chapter 11: Toxicity of heavy metals and other minerals
Notion of physiological concentrations and of excess - lead – iron – bismuth – cadmium – strontium – uranium - aluminum – mercury – zinc - cobalt – arsenic – etc.
Chapter 12: Complete description of toxico(pharmaco)kinetic and toxico(pharmaco)dynamic of an example of toxic compound and medicines
Options : ethanol – methanol – caffeine – chlorinated solvents (chloroform) - others Options : salicylic acid (aspirin) – paracetamol – others.
Chapter 13: Food toxicology
Food safety, food additives, phytoestrogens, food contamination with heavy metals and mycotoxins, pesticide residues, wrapping products, GMO, nitrates and nitrites,
Lab and tutorial sessions of toxicology (24 hours)
- Presentation of scientific articles and/or preparation of mini-projects related to toxicology (monography of some xenobiotics, physicochemical properties, toxicokinetic and toxicodynamic, intoxication symptoms)
- exercise of toxicity investigation: ADI, NOEL, etc
- initiation to factors of conversion in toxicology (air, water, food)
- define and estimate the following parameters: half-life, Vd, Clearance, LC50 and LD50, Vmax, Km, NOEL, LOEL, RfD, RfC, ADI,
- Investigation of hydrogen peroxide toxicity on a eukaryotic cell culture (exposure and MTT test). dose-effect relationship.
- Paracetamol measurement in urine
- Free phenols measurement in urine