Samenvatting - Class notes - TOX20303

• 1504562400 College 1 + 2

• Toxicology

  Study of the adverse toxic effects of chemicals on living organisms
• What is toxicology?

  Study of the adverse (toxic) effects of chemicals on living organisms
• Hemlock

  State poison of the Greek
• 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'
• 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)
• Mycotoxicoses (of fungi)

  Reduce bloodsupply to hands and feed --> black limbs
• 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)
• St. Antony's fire

  People went to France to visit St. Antony. They went away from the source and got better (poison due to mycotoxicoses)
• Greek and roman 
  
  hippocrates
  
  description of poisons and clinical toxicology principles like bioavailability 
  
  Socrates drinking hemlock greek state poison 
• Monkshood

  Causes cardiac arrhytmias en hypertention. Used as a poison on hunting spears or enemy watersupplies
• 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 Pott

  Scrotal cancer in chimney sweeps
• Botulinum toxin

  It 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)
• Orfilla

  Target organ (if its safe, the rest is also safe)
• 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)
• DDT

  Insecticide to fight malaria or thyphus --> fragile egg shells --> reproduction problems in birds
• Wat heeft Percivall Pott ontdekt in 1775

  Chimney 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
• Orfila (1814)

  Introduction 'target organ' concept and animal experiments
• Softanon

  Inhibits formation of bloodvessels
• 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 
• DES

  Sleeping aid/prevention miscarriages. It causes malformations in arms and legs in children
• 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. 
    
• Paracelsus

  The dose makes the poison
• Rachel Carson 'Silent Spring' (boek) 1962

  Alles 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 toxicology

  1. 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. 
• Hazard

  Potential danger
• Softenon (thalidomide)

  For morning sickness, maar het had vele bijwerkingen, de kinderen raakte helemaal misvormd met rare ledematen.
• Risk

  Probability that adverse effects will occure
• 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 
• Risk management

  Based 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)

  1. Define toxicity, mechanisms of action and structure activity relationships for chemicals 
     
  2. evaluation of health and environmental hazards and risks 
  3. advisory task for authorities, industries and consumers 
• Risk assessment

  Based on hazard, exposure and risk
• 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 
• Exposure assessment

  1. 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)
• Benzene

  - Acute: CNS depression
  - Chronic: Leukemia
• Exposure assessment

  1. Route and site of exposure 
     
  2. duration and frequency of exposure 
• Ethanol

  - Acute: CNS depression
  - Chronic: fatty liver
• Exposure assessment: route & site of exposure

  • Gastrointestinal tract (oral)
    
  • lungs (inhalation)
  • skin (dermal)
  • injections
• Arsenic

  - Acute: gastrointestonal damage
  - Chronic: skin/liver cancer
• Exposure assessment: duration and frequency

  Acute: <24 hours, single dose 
  subacute: 1 month or less
  subchronic: 1-3 months 
  chronic: >3
  
  effect varies with dose & exposure regimen 
• Harber's rule

  C * t = k
  
  C = concentration chemical
  t = time untill effect
  k = constant
• Estimated daily intake

  Classical method:
  

  • EDI = [compound] in product X consumption of product 

  
  
  nogal method:
  

  • probabilistic exposure assessment (Monte Carlo simulations)
  • zie afbeelding
• Receptor

  Part of the molecule affected by the toxic agent
• Haber's rule

  C 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 lesion

  Primairy molecular damage
• Zie de afbeelding 
  
  
  hazard: types of biological responses