Samenvatting - General toxicology

• 1 Introduction history and scope of toxicology

• Toxicology
  

  • study of the adverse toxic effects of chemicals on living organisms
  • knowledge is essential for safe use of chemicals --> drugs/additives/novel food ingredients
• History of toxicology - Greek and Romans 
  

  • Hippocrates: 400 B.C., description of poisons and clinical toxicology principles --> bioavailability
  • Socrates: drinking hemlock --> Greek state poison 
    
  • Romans: poisonings via food by cyanide/mushrooms/herbs as common practice in all social classes to dispose political/economic opponents --> 82 B.C. law against poisoning due to epidemic of poisoning 
• History of toxicology - Middle Ages
  

  • Atropa belladonna: atropin/scopolamin causes widen eye pupils and hallucinations --> witches 
  • Claviceps purpurea: fungus on rey which produces mycotoxicoses from ergot alkaloids --> St. Anthony's fire (black limbs due to vasoconstriction, madness)
• History of toxicology - Ancient Europe and Asia
  

  • Aconitum sp.: poison of hunting spears and enemy water supplies
  • cardiac arrythmias (slowing heart rate) and hypotension
  • 3-6 mg is fatal 
• History of toxicology - Renaissance
  

  • Paracelsus
  • Vesalius
  • Pott
  • Orfila
  • van Hasselt
• History of toxicology - Paracelsus (1493-1541)
  

  • notion of dose: "Alle Ding' sind Gift, und nichts ohn' Gift; allein die Dosis mach, Daß ein Ding kein Gift ist"
  • example: botulinum toxin from Clostridium botulinum --> treatment spasticity/Spasmodic dysphonia, facial rejuvenation
• History of toxicology - Percivall Pott (1775)
  

  • report of polycyclic aromatic hydrocarbons (PAHs)
  • chimney sweeps with high incidence of scrotal cancer due to constant exposure to soot
• History of toxicology - Orfila (1818)
  

  • introduction of 'target organ' concept and animal experiments 
    
• History of toxicology - van Hasselt (1850)
  

  • first Dutch toxicologist 
    
• Modern toxicology - 20th century
  

  • industrial revolution and WWII
  • chlorinated hydrocarbon insecticides: DDT
  • war gasses/munition: dioxins --> sarin, soman, uranium, agent orange 
  • drugs: softenon (thalidomide), diethylstilbestrol (DES)
    
• Organochlorines (1945)
  

  • chemical used to protect against insects and infectious diseases --> DDT, dieldrin, aldrin
  • DDT: late 1920s, highly persistant, insecticide to fight malaria
  • birds: fragile egg shells --> reproduction problems
    
  • 'Silent spring' by Rachel Carson in 1962: challenged the notion that man was destined to control nature, specifically to control pests through the use of chlorinated hydrocarbons
• Dioxins (TCDD)
  

  • Agent Orange (Vietnam) in the 1960s 
• Softenon (thalidomide) 
  

  • 1956: sleeping aid --> 1960: recognized as cause of malformations in babies
  • thalidomide (one stereoisomeric toxic) inhibits angiogenesis 
  • future emphasis on reproduction/developmental toxicity, stereochemistry and safety testing and risk management
• Modern toxicology
  

  • multidisciplinary field of sciences
  • new technology: -omics technology, alternatives for animal testing, in vitro and in silico testing, role of epigenetics 
    
• Modern toxicology - major aims 
  

  1. define toxicity, mechanisms of action and structure activity relationships for chemicals 
     
  2. evaluation of health and environmental hazards and risks
  3. advisory tasks for authorities, industries and consumers 

• 2 Principles of toxicology

• Modern toxicology - major aims
  

  1. define toxicity, mechanisms of action and structure activity relationships for chemicals
  2. evaluation of health and environmental hazards and risks
  3. advisory taks for authorities, industries and consumers 
     
• Modern toxicology - major fields
  

  1. clinical/forensic toxicology
  2. occupational toxicology
  3. food toxicology
     
  4. environmental/ecological toxicology
• Principles of toxicology 
  

  • definition of hazard and risk 
  • hazard = potential danger of a compound or process
  • risk = probability that an adverse effect will occur 
  • risk assessment: the process of determination of  hazard, exposure and risk
• Risk management
  

  • selection of type of actions to be taken
  • based on risk assessment and social/economic/political aspects  
    
• Risk management - Bisphenol A (BPA)
  

  • EFSA: health concern for BPA is low at the current level of exposure 
  • ban on BPA in baby bottles 
  • ban on BPA in all food containers (France) 
    
• Exposure assessment
  

  1. route and site of exposure --> gasrtointestinal tract (oral), lungs (inhalation), skin (dermal), injections 
  2. duration and frequency of exposure --> acute (<24 hours, single dose), subacute, subchronic, chronic (>3 months, 80-90% of life span) --> effect varies with dose and exposure regimen 
     
• Acute toxicity - examples 
  

  • Bhopal 1989: methylisocyanate --> 5000 deaths, 30000 permanent disabled  
    
  • Gent 2013: acrylonitrille (synthesis rubber/plastic)--> 2 deaths, 14 injuries --> acute lethal at high dose levels, chronic class 2B carcinogen  
• Acute and chronic toxicants 
  

  • benzene: CNS depression versus leukemia
  • ethanol: CNS depression versus liver cirrhosis 
  • arsenic: gastrointestinal damage versus skin/liver cancer 
    
• Chronic toxicity - example 
  

  • Bangladesh 2001: arsenic poisoning from contaminated water wells 
  • chronic poisoning --> calluses on feet/hands --> skin cancers 
  • detection by field kits, cleaning by ferric hydroxide 
• Exposure assessment 
  

  • Haber's rule: C * t = k 
  • C = concentration/dose, t = time of exposure needed to produce a given toxic effect, k = constant depending on chemical and effect
  • doubling the concentration will halve the time needed for an adverse effect  
    
• Qualitative principles 
  

  • receptor = the molecular structure affected by the toxic agent
  • primary lesion = primary molecular damage 
  • target organ = most sensitive organ 
  • reversible versus irreversible effects  
    
  • local versus systemic toxicity 
  • dose-response relationship --> LD50 = lethal dose 50%, NOAEL = No Observed Adverse Effect Level
• Dose-response relationship
  

  • establishes of  causality that the chemical has induced the observed effects
  • establishes of the LOAEL, NOAEL
  • determinates of the rate at which injury builds up --> slope of curve
    
• Disadvantages LD50 approach
  

  • unethical --> lethal endpoint, many animals required, political issue
  • not a biological constant
  • intra and inter species variation in toxic responses
    
• Causes of varation in toxic response inter species
  

  • body size --> weight and surface area --> small animals with >surface area = >dermal uptake and >food intake 
    
  • different physiology 
  • variation in metabolism of toxic compound 
• Causes of variation in toxic response intra species
  

  • genetic polymorphisms 
  • age --> e.g. parathion more toxic to young animals, nitrosamines more carcinogenic to newborns 
    
  • nutrition and lifestyle
  • diseases
  • gender --> e.g. male rats more sensitive to liver damage from DDT, female rats more sensitive to parathion
  • combined exposures 
• Risk assessment
  

  • integration: hazard and exposure characterisation  
    
  • definition: safe exposure levels --> ADI or TDI = NOAEL * uncertainty factors
  • exception: initiating genotoxic carcinogens --> only risk assessment
  • uniform concepts required