Summary Toxicologie

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This is the summary of the book "Toxicologie". The author(s) of the book is/are Rientjes. This summary is written by students who study efficient with the Study Tool of Study Smart With Chris.

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Summary - Toxicologie

  • 1 History&Scope

  • Bijdrage Paracelsus = introduction of the concept of “dose”

    Bijdrage Orfilla = introduction  of the concept “target organ”

    Van Hasselt =  eerste NL  toxicoloog

    welke periodes zijn  belangrijk  geweest voor de opntwikkelingen  van  de moderen  toxicologie?

    industriele revolutie en WOII;ontdekking en  gebruik  van  gassen

     

    DDT = insecticide (ontdekt in  de late jaren '20)

    thalidomide/softanon  & Rachel  Carson's boek “Silent spring” =Slaapmiddel in  1956; was een  aanleiding om  effecten  van  chemicalien  te bestuderen op embryo's en  foetussen. Na de incident met softanon  zijn  er duizenden  kinderen  met geboortedefecten  ter wereld gekomen.

     

    Agent orange/TCDD/dioxine = malformation  in  unborn  children.Gebruikt in  1960 in  Vietnam.Eind jaren  '70 Seveso  incident in Italie. Hoge waardes in  de omgeving. Mensen hebben  last “chloral  acne”

     

    POP's = toxic presistent organic pollutants = DDT,dioxine, PCB. Stapelen op  in  moeder-melk & in  vet van  de dieren  op  de noordpool.

     Polyciclische aromatische hydrocarbons = in 1775 is het erkend dat roet een  bijdrage levert aan  zaadbalkanker onder de schoorsteen  vegers.

     

    Twee  voorbelden  van  toxinen  uit de geschiedenis :

    1)                  Drinken  van  hemlock(dolle krevel) . Griekse staat gif. Socrates moest het drinken.Neurotoxine.

    2)                  Atropa Belladonna. Tollkirsche.Veroorzaken  hallucinaties. In  de middeleeuwen  was het bewijs van heksen.

     

    Erbes papyrus uit 1500BC,  ontdekt in  1873. Egyptische verzameling van  ca. 700 magische formules en  volksremedies. Hoe krokodil/schorpioen beten te behandelen. Ook  bevat het document  informatie over vele erkende gifstoffen&metalen.

     

     

  • 2 Principles of Toxicology

  • Takken van  toxicologie:

    Klinische = diagnose en  therapie van vergiftigingen.Met klinische geneeskunde& klinisch-analytische chemie.

    Forensische(juridische) = aan  de hand van chemich-toxische bevindingen worden uitspraken  gedaan  in juridische zaken  mbt.misbruik  en verwaarlozing van gifstoffen

    Occupational   =  Geeft adviesen  mbt maximale blootstelling aan  gifstoffen op het werkplek. Betrokken in biological  monitoring. Dit houdt in  dat interne blootstelling van  de werknemers systematisch  gemeten  wordt .

    Food toxicology = onderzoek  en  advisering over chemische stoffen  in het voedsel. O.a Additieven.

    Environmental = effects on populations & eco-systhems.

     

    Risk = the probability that the adverse effect will occur.

    Hazard = a potential  danger of a compound or a process.

    Risk Assesment = integrating hazard characteristics with actual  exposure levels(exposure assesment). Evaluation  of the health and environmental risks of chemicals.

    Risk management = integrating risk  assesment with social , economic and political aspects.

    Hazard Indentification – Hazard characterisation -  Risk  assesment – Risk management.

     

    Qualitative principles  describing nature of the effect:

    local  effects =  occur at the site of first contact. Produces by ingestion or inhalation.

    Systemic effects = deleriant effects  at a distant site due to absorbtion & distribution.

    Target organs = where the  major toxicity occurs. Often affected: CNS.

    Bloed-lever-niern- longen-huid.

    Spieren  en  botten zijn minst vaak  aangetast als systemisch effect.

    Primary lesion = reaction  at molecular level. Symptomen  van de vergiftiging zijn  het resultaat van deze reacties.

    Receptors = molecular structures affected by the substances.

    Electrofiele agenten = reageren  met alle nucleophiele groepen.DNA kan optreden  als een  toxicologische receptor.

    Reversible/ irreversible = vermogen om te regenereren bepaalt dit. Carcinogene&teratogene effecten  zijn  niet omkeerbaar.

     

    Variation in  toxic response INTER-(between) species: lichaamsafmetingen,verschil  in  fysiologie, metabolisme toxine kan varieeren.

    Variation in  toxic response INTRA -(tussen) species: genetische polymorfismes, leeftijd, voeding&lifestyle, ziekses, gender.

     

    Quantitative principles:derempelwaardes -  tresholds

    ED50=Mediaan  effectieve dose. Afgeleid door interpolatie.

    LD50=Statistisch  afgeleide single-dose van  de stof  that can  be expected to cause death in  50% of the animals tested.

    NOAEL= No Observed Adverse Effect Level

    LOAEL= Lowest Observed Adverse Effect Level

     

    Algemene begrippen:

    dose-response curve = illustrates  dose-effect relationship. Respons of a population of organisms to a Toxic substance is more or less normally distributed in  relation to  the logarithm of the dose.

    acute toxicity = exposure to  a chemical for less than  24h

    sub-acute = repeated exposure for 1 mnth or less.

    Sub-chronic = 1-3 mths

    chronic toxicity = more than 3 mnths

    carcinogen = inducing cancer.

    addition= if proportional summation of effects occurs.

    Synergism/potentiation = if combined effect is stronger, then to  be expected on  the separate effects.

    Antagonism/depotentiation = attenuation  of the effect.

    Haber's rule = effects of toxins depend on  the product of concentration and the duration of exposure. Concentration- time curve.

     

  • 3 Mechanisms ofToxicity

  • agonist\antagonist
    structural  similarity
  • CO2 &curare
    agonist Hb en  antagonist Ach - zet spiern  niet aan  tot ademhalen--> stikken
  • blocker&modulator
    no structural  similarity
  • saxitoxin & tetrodoxin
    Na-channel blokers
  • schorpieon gif
    modulator Na- channel -

  • mode of action  induction of cancer
    covalent binding to DNA
  • Non-covalent binding

    a) structural similarity with natural ligand: competition for physiological receptor

    antagonist= blocks signal- transduction etc

    agonist = stimulates signal- transduction, transcription

    EXP 1)CO binds 220 x stronger to heme Fe 2+ of hemoglobin than O2 : results in anemia; 2)curare

    binds strongly to acetylcholine receptors

    antagonist

    paralyzes skeletal muscles resulting in suffocation

  • Non-covalent binding

    b) no structural similarity natural ligand

    interaction with ion channels or enzymes without structural similarity natural ligand

    modulator= increased permeability activity

    Blocker= reduced permeability activity

    EXP 1) Tetrodotoxinfrom puffer fish blocks Na+ channels neurons 2)Saxitoxin Paralytic shellfish poison PSP blocks Na+ channel From Alexandrium spp 3) scorpion toxin(modulator) Na+ channels of neurons 4) inhibitionof cytochrome oxidase by CN-(cyanide) of H2S tothe heme group inthe active site of enzyme.-->Acute imparement of cellular respiration.

    2)covalent binding: reactions with nucleophilic macromolecule

    reactions with nucleophilic macromolecules-àalkylation DNA/protein/RNAàverlies vanfunctie.

    EXP 1) Afla-toxine mutation hotspots P53 tumor suppressor geneàliver cancer. Inductie van  kanker.

    2)Acetylcholinesterase irreversible inhibition(sarin,soman,tabun): ze vormencovalente binding met serineOH-moiety inde actieve site of enzym, that cannot easilybe hydrolised bywater.

    AChE: catalyzes the hydrolysis of NT acetylcholine to form choline and acetate prevents overstimulation of postsynaptic receptors.

    3) mostergas & lewisite. = alkylating chemicals.

    upon inhalation, blistering and chronic respiratory tract impairment, can become fatal

  • 3) hydrogen abstraction

    Reactive oxygen species (ROS)

    hydroxyl radicals --OH

    superoxide anion radicals O2- ?

    hydrogen peroxide H2O2

    Damage to - proteins: inactivation - DNA: mutation - lipids: lipid peroxidation

  • 4)electron transfer

    toxic action can be based ontheir oxidising potential

    electron transfer; pe methemoglobinemia Hb Fe 2+ Hb Fe 3+ no oxygen binding iron in hemoglobin unable to carry oxygen caused by pe nitrate/nitrite

     

  • what type of molecules are sensitive to  ROS
    protein,  DNa,  lipids
  • lipid peroxidation  is initiated by OH radicals
  • Mechanisms of repair:

    Many toxicants alter macromolecules, which, if not repaired, cause damage at higher levels of biologicalhierarchy in the organism. 3 levels of repair: molecular, cellular, tissue.

    1)Molecular

    oxidation of proteinthiols & methylation of DNA are simply reversible. Base excision, Nucleotid excision For removing damaged bases from Dna. Unshedulde DNA synthese = gat vullen met nucleotiden mbv dna -polymerase en complementaire streng als template.

    2)Cellular

    Repair of damaged cells is not a widly applied strategyfor repair. Mature neurons loss their abilitytomultiplie.

    3)Tissue

    Damaged cells maybe eliminated by apoptosis or necrosis.

    necrosis =When the damage is too advanced. loss membrane integrity’;swelling cytoplasm/mitochondria; cell lysis ;no energy requirement ; inflammatory response ; non physiological stimuli. Chaotisch process.

    Apoptosis = geprogrameerde celdood. membrane intact ;a shrinking cytoplasm/nucleus cell ; cell fragmentation ;small apoptotic bodies  that can  be easylly  cleaned by  macrophages.ATP dependent ; not inducing inflammatory response; physiological stimuli. Ordelijk.

    Following apoptosis - - profileration. Blalance between.Toxicity can  result in proliferation that gets out of hand,  induction of cancer.

  • n

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