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Samenvatting - Class notes - TOX20303
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1504562400 College 1 + 2
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ToxicologyStudy of the adverse toxic effects of chemicals on living organisms
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What is toxicology?Study of the adverse (toxic) effects of chemicals on living organisms
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HemlockState poison of the Greek
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Historical perspective
phase 1: hunting, fishing, gathering
phase 2: agricultural development
phase 3: industrial development -
Belladonna (atropin)To create wide pupils and cause hallucination in 'witches'
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Wat voor kennis hadden we/ze in de periode 'hunting, fishing and gathering'?
- Knowledge on acute toxic properties of plants, mushrooms and some minerals
- probably less knowledge of chronic effects
- used to poison hunting spears and enemy water supplies during war (monkshood)
- Knowledge on acute toxic properties of plants, mushrooms and some minerals
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Mycotoxicoses (of fungi)Reduce bloodsupply to hands and feed --> black limbs
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Wat voor kennis hadden we/ze in de periode 'agricultural development'
- Cooking allowed cultivation of new plants containing natural toxins as crop
- storage and transport introduced new toxic compounds such as moulds (mycotoxins)
- Cooking allowed cultivation of new plants containing natural toxins as crop
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St. Antony's firePeople went to France to visit St. Antony. They went away from the source and got better (poison due to mycotoxicoses)
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Greek and roman
hippocrates
description of poisons and clinical toxicology principles like bioavailability
Socrates drinking hemlock greek state poison -
MonkshoodCauses cardiac arrhytmias en hypertention. Used as a poison on hunting spears or enemy watersupplies
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Paracelsus (1493-1541) ontdekte/nam waar dat:The dose matters
de dose maakt uit, alles is giftig de dose bepaald alleen wanneer het giftig is. -
Percivall PottScrotal cancer in chimney sweeps
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Botulinum toxinIt blocks ach release
you can find it in lakes and in vacuum potjes die niet goed zijn afgesloten
het wordt gebruikt voor medische treatment (botox) -
OrfillaTarget organ (if its safe, the rest is also safe)
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Wat voor kennis hadden we/ze in de periode 'industrial development'
- Distance between food sources and consumer increases
- new preservation methods such as canning
- addition of chemical additives for preservation or coloring
- legal steps to guarantee good quality of food (end 19th century)
- Distance between food sources and consumer increases
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DDTInsecticide to fight malaria or thyphus --> fragile egg shells --> reproduction problems in birds
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Wat heeft Percivall Pott ontdekt in 1775Chimney sweeps (schoorsteenvegers) had a very high incidence of scrotal cancer. Related to their constant exposure to soot (roet)
We now know that it contains: polycyclic aromatic hydrocarbons (PAHs) -
Agent orange (Dioxins)Causes malformations in unborn children
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Orfila (1814)Introduction 'target organ' concept and animal experiments
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SoftanonInhibits formation of bloodvessels
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Welke toxische stoffen zijn er in de 20th eeuw ontstaan/ontdekt.
- Many pesticides
- chlorinated hydrocarbon insecticides: DDT
- war gasses, munition
- Sarin, soman, uranium, agent orange (dioxins)
- Drugs
- Softenon (thalidomide), diethylstilbestrol (DES)
- industrial chemicals
- synthetic fibers
- Many pesticides
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DESSleeping aid/prevention miscarriages. It causes malformations in arms and legs in children
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DDT (dichlorodiphenyltrichloroathane)
- Het dood alle insecten maar niet ons de mens.
- het maakt eierschalen heel kwetsbaar en breekbaar waardoor er geen kuiken in kan groeien.
- Het dood alle insecten maar niet ons de mens.
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ParacelsusThe dose makes the poison
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Rachel Carson 'Silent Spring' (boek) 1962Alles was dood gegaan en het gebruik van DDT was uit de hand gelopen. Silent spring niet veel vogels en insecten...
challenged the notion that man was destined to control nature -
Major aims toxicology1. Toxicity, mechanisms of action, structure activity relationships
2. Health and environmental hazards and risks
3. Advise for authorities, industries and consumers -
Dioxins (TCDD)agent orange (vietnam)
- alle bladeren vielen van de bomen waardoor ze goed konden zien wat hun vijanden aan het doen waren.
- de ledematen van kinderen groeide niet goed (erg klein), vervormde gezichten.
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HazardPotential danger
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Softenon (thalidomide)For morning sickness, maar het had vele bijwerkingen, de kinderen raakte helemaal misvormd met rare ledematen.
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RiskProbability that adverse effects will occure
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Door de bijwerkingen op het kind, nadat de moeder softenon slikte voor morning sickness werd er voor de toekomst meer nadruk gelegd op: (3)
- Reproduction & developmental toxicity
- stereochemistry: analytical techniques
- safety testing and risk assessment
- Reproduction & developmental toxicity
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Risk managementBased on risk assessment, social, economic and political aspects
For example: BPA is safe, but in France there is a ban because of political reasons -
The major aims of modern toxicology (3)
- Define toxicity, mechanisms of action and structure activity relationships for chemicals
- evaluation of health and environmental hazards and risks
- advisory task for authorities, industries and consumers
- Define toxicity, mechanisms of action and structure activity relationships for chemicals
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Risk assessmentBased on hazard, exposure and risk
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Wat komt er allemaal bij risk assessment kijken? Hoe komt dit tot stand
- Hazard identification
- hazard characterisation
- risk characterisation
- exposure assessment
- risk management
- risk communication
- Hazard identification
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Exposure assessment1. Route and site of exposure: oral, inhalation, dermal, injections
2. Duration and frequency of exposure: acute, subacute, subchronic, chronic -
Risk management =-->Select type of actions to be taken
- based on risk assessment and social, economic and political aspects
example:- fipronil in eggs (august 2017)
- Bisphenol A (BPA)
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Benzene- Acute: CNS depression
- Chronic: Leukemia -
Exposure assessment
- Route and site of exposure
- duration and frequency of exposure
- Route and site of exposure
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Ethanol- Acute: CNS depression
- Chronic: fatty liver -
Exposure assessment: route & site of exposure
- Gastrointestinal tract (oral)
- lungs (inhalation)
- skin (dermal)
- injections
- Gastrointestinal tract (oral)
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Arsenic- Acute: gastrointestonal damage
- Chronic: skin/liver cancer -
Exposure assessment: duration and frequencyAcute: <24 hours, single dose
subacute: 1 month or less
subchronic: 1-3 months
chronic: >3
effect varies with dose & exposure regimen -
Harber's ruleC * t = k
C = concentration chemical
t = time untill effect
k = constant -
Estimated daily intakeClassical method:
- EDI = [compound] in product X consumption of product
nogal method:- probabilistic exposure assessment (Monte Carlo simulations)
- zie afbeelding
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ReceptorPart of the molecule affected by the toxic agent
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Haber's ruleC x t = k
C = concentration or dose
t = time of exposure needed to produce a given toxic effect
K: a constant, depending on chemical and effect
example: doubling the concentration will halve the time needed to produce an adverse effect -
Primairy lesionPrimairy molecular damage
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Zie de afbeelding
hazard: types of biological responses
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Laatst toegevoegde flashcards
Absorption: passing cell membranes via
- Phospholipid
- intergral proteins
- cholesterol
- ion channel
- ligand
Toxicokinetics (ADME) de letters staan voor...?
Absorption
Distribution
Metabolism
Excretion
Distribution
Metabolism
Excretion
Variation in toxic response (hangt af van)
- Intra species or between individuals of one species
- age
- nutrition and life style diseases
- gender
- combined exposures
Target organ =
Most sensitive organ
Primary lesion =
Primary molecular damage
Receptor =
The molecular structure affected by the toxic agent (DNA, protein like enzyme, ion channel)
Fibrosis
Excessive accumulation of extracellular matrix (collagen)
Necrosis
Severe damage
- loss membrane integrity
- swelling cytoplasm/mitochondria
- cell lysis
- no energy requirement
- inflammatory response
- non physiological stimuli
Apoptosis
Programmed cell death
- membrane intact
- shrinking cytoplasm/nucleus
- cell fragmentation
- ATP dependent
- no inflammatory response
- physiological stimuli
Cellular repair:
Apoptosis of necrosis