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Samenvatting - General toxicology
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1 Introduction history and scope of toxicology
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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
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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
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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)
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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
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History of toxicology - Renaissance
- Paracelsus
- Vesalius
- Pott
- Orfila
- van Hasselt
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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
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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
- report of
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History of toxicology -
Orfila (1818)- introduction of 'target organ' concept and animal experiments
- introduction of 'target organ' concept and animal experiments
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History of toxicology - van Hasselt (1850)
- first Dutch toxicologist
- first Dutch toxicologist
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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)
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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
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Dioxins (TCDD)
- Agent
Orange (Vietnam) in the1960s
- Agent
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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
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Modern toxicology
- multidisciplinary field of sciences
- new technology: -
omics technology, alternatives foranimal testing, invitro and insilico testing, role ofepigenetics
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Modern toxicology - major aims
- define toxicity, mechanisms of action and structure activity relationships for chemicals
- evaluation of health and environmental hazards and risks
- advisory tasks for authorities, industries and consumers
- define toxicity, mechanisms of action and structure activity relationships for chemicals
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2 Principles of toxicology
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Modern toxicology - major aims
- define
toxicity , mechanisms of action and structure activity relationships for chemicals - evaluation of health and environmental hazards and risks
- advisory
taks for authorities, industries and consumers
- define
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Modern toxicology - major fields
clinical /forensic toxicologyoccupational toxicologyfood toxicologyenvironmental /ecological toxicology
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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
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Risk management
- selection of type of actions to be taken
- based on risk assessment and social/economic/political aspects
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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)
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Exposure assessment
- route and site of exposure --> gasrtointestinal tract (oral), lungs (inhalation), skin (dermal), injections
- 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
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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
- Bhopal 1989: methylisocyanate --> 5000 deaths, 30000 permanent disabled
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Acute and chronic toxicants
- benzene: CNS depression versus leukemia
- ethanol: CNS depression versus liver cirrhosis
- arsenic: gastrointestinal damage versus skin/liver cancer
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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
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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
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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
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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
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Disadvantages LD50 approach
- unethical --> lethal endpoint, many animals required, political issue
- not a biological constant
- intra and inter species variation in toxic responses
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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
- body size --> weight and surface area --> small animals with >surface area = >dermal uptake and >food intake
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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
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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
- integration: hazard and exposure characterisation
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