Samenvatting Pien's aantekeningen

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Samenvatting - Pien's aantekeningen

  • 1.1 TOX intro

  • What is toxicology?
    The field that studies the adverse effects of chemicals on living organisms.
  • Which persons played an important role in the history of Toxicology?
    • Paracelsus
    • Rachel Carson
    • Orfila
  • Which chemicals played an important role in the history of Toxicology?
    • Dioxins
    • DDT
    • Softenon
  • The concept of dose was introduced in Toxicology by Paracelsus.
    The target organ concept was introduced in Toxicology by Orfila 
    The affair with softenon/thalidomide introduced emphasis on teratology and reproduction toxicology in safety testing of drugs and chemicals.
    Modern toxicology especially developed because of the many new drugs, pesticides, munitions and industrial chemicals developed during the industrial revolution and during world war 2 
  • Put in the right order: Risk management, Hazard characterization, risk assessment, hazard identification:
    1. Hazard identification
    2. Hazard characterisation
    3. Risk assessment
    4. Risk management
  • Risk assessment integrates risk characterisation and exposure assessment. Risk management follows risk assessment
  • What is risk assessment?
    Integrating hazard characteristic with exposure data.
  • What is hazard?
    A potential danger of a compound or a process
  • What is a receptor?
    The molecular structure affected by a toxic agent
  • What is risk?
    The probability that an adverse effect will occur
  • What is risk management?
    Integrating risk assessment with social, economic and political aspects
  • 1.2 TOX mechanisms

  • What are 2 possibilities in non-covalent bindings?
    1. Structural similarity with natural ligand: competition for physiological receptor(agonist/antagonist)
    2. no structural similarity natural ligand(blocker/modulator)
  • What is an agonist?
    Stimulates signal-transduction, transcription enz
  • What is an antagonist?
    Blocks signal-transduction enz
  • What is a blocker?
    Reduced permeability activity
  • What is a modulator?
    Increased permeability activity
  • What are covalent bindings?
    Reactions with macromolecules(ex DNA)
  • 4 options/ways of reactions between toxicant and target:
    • Non-covalent binding
    • covalent binding
    • reactive oxygen species(hydrogen abstraction)
    • electron transfer
  • What is the mechanism of action of AChE?
    AChE as an enzyme catalyzes the hydrolysis of neurotransmitter. This causes adverse effects.
  • How can you inhibit the function of AChE?
    To expose it to pesticides, they bind covalently to the enzyme. Result: neurotransmitter cannot be processed by this enzyme so it remains active in the body
  • Several classes of reactive oxygen species
    • Hydroxyl radicals OH
    • superoxide anion radicals O2-
    • hydrogen peroxide H2O2
  • Reactive oxygen species damage:
    • Proteins: inactivation
    • DNA: mutation(>development of cancer)
    • lipids: lipid peroxidation(disturbs membrane structure)
  • The Harber-Weiss reaction is a cyclic reaction, catalysed by enzymes. In the enzymes, de iron groups are important. Iron is a compound of Hemoglobin(binding oxygen).
  • What is the essence of the Harber-Weiss reaction?
    It changes some of the reactive oxygen species into more potent/toxic ones. The oxygen radicals are changed in more reactive radicals. Enzymes in the body are not able to remove these radicals(no time). But if they are formed by this reaction, they live longer and are more toxic.
  • How to repair a molecule:(7)
    • Oxidation protein thiols(reverse)
    • methylation of DNA(reverse)
    • peroxidized lipids(replace)
    • DNA excision repair: detection of altered deoxynucleosides in urine or in cell nuclei)
    • apoptosis
    • necrosis
    • proliferation
  • Apoptosis: what is it, what does it?
    • Programmed cell death
    • membrane is intact, shrinking cytoplams, cell fragmentation, ATP dependent, no inflammatory responsem physiological stimuli
  • Necrosis: what is it, what does it?
    • It gives severe damage to the cell
    • loss membrane integrity, swelling cytoplasm, cell lysis, no energy requirement, inflamatory response, non physiological stimuli
  • Proliferation: what is it, what does it?
    Novel tissue to replace damaged tissue removed by apoptosis or necrosis
  • What is a primary lesion?
    The first site where the chemical binds to. So it gives the primary molecular damage
  • What is a target organ?
    Most sensitive(to toxic compound) organ. Where the most dominant effects happen.
  • What are quantitative principles? And what is the goal?
    They establish causality that the chemical has in fact induced the observed effects, it determines the rate at which injury build up: slope of dose-response curve.
    Goal: derive a concentration that does not cause and adverse effect
  • How does the toxic response variate?(5)
    • Within species or between individuals of one species
    • age
    • nutrition and life style diseases
    • gender
    • combined exposures
  • What are qualitative principles?
    It distinguishes reversible and irreversible(carcinogenic/teratogenic) toxic effects. ALso, local(at site of first contact) and systemic toxicity(absorption and distribution from entry point to distnt site target organ)
  • Some facts about the mechanisms of toxicity:
    • inhibition of oxygen binding to hemoglobin by CO is an example of non covalent binding causing toxicity
    • methemoglobinemia is caused by chemicals that cause electron transfer that oxidizes the Fe in hemoglobin from Fe2+ to Fe3+
    • lipid peroxidation can be cause by reactive oxygen species(ROS)
  • Which chemicals act by non-covalent interactions?
    Sarin, soman and acetylcholine agonists
  • Facts about reactive oxygen species:
    • reactive oxygen species are toxic because they are able to cause hydrogen abstraction
    • in the Haber Weiss reaction superoxide anions and hydrogen peroxide are converted to hydroxyl radicals
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