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General Toxicology – TOX-20303College 1
Toxicology:
- The study of the adverse effects of chemicals on living organisms
- This knowledge is essential for safe use of chemicals including drug, additives, novel food
ingredients, etc.
What is toxic?
- Toxicology is part of our daily life
History of toxicology:
- Greek and Roman:
o Hippocrates: description of poisons and clinical toxicology principles like
bioavailability
o Socrates: drinking Hemlock Greek state poison
o Poisoning via dinner of drinks:
Became a common practice every social class
Used to dispose of unwanted political of economic opponents
Cyanide, mushrooms, poison herbs
Poisoning became so epidemic that a law against poisoning was issued
- Middle ages:
o Atropos: Greek goddess of the death
o Bella-donna: use atropine to widen eye pupils hallucinations, used by witches
o Mycotoxicoses from ergot alkaloids present in grains
o Cause of alkaloids: St. Anthony’s fire:
Black limbs (= gangrene, tissue death) due to vasoconstriction of blood
vessels and extremes
Madness
o Aconitum sp. (Monkshood):
Aconitin very potent poison 3-6 mg fatal
o Ancient Europe & Asia used to poison hunting spears and enemy water supplies
during war:
Cardiac arrythmias (slowing heart rate)
Hypotension (lowering blood pressure)
o Paracelsus:
Philippus Aureolus Theophrastus: note the dose!
Dose:
- Botulinum toxin blocks acetylcholine in the nerves
- Is used to treat spasticity
- Is used for facial rejuvenation (botox)
- The compound has an effect on the muscles
1
,History of toxicology:
- Renaissance:
o People wondered what the cause of illness/death was can it have a relation to
living/working habits
o Percivall Pott:
Noted that people that sweeped chimneys had a high incidence of cancer
Related to their exposure to soot
o Orfila:
Spanish toxicologist
Related to poisoning, in Spain they used poison (Arsenic)
Introduction “target organ” concept and animal experiments
o Van Hasselt = first Dutch toxicologist wrote a book
20th century toxicology:
- Industrial revolution and World War 2
- Many pesticides
o Chlorinated hydrocarbon insecticides: DDT
- War gasses, munition
o Sarin, soman, uranium, agent orange (dioxins)
- Drugs
o Softenon (thalidomide), diethylstilbestrol (DES)
- Industrial chemicals and spread them in the environment
- Synthetic fibers
DDT Dichlorodiphenyltrichloroethane:
- Late 1920’s
- Sprayed directly on people, clothing and bedding, even sprayed by air over entire cities
- To protect against insects and infectious diseases (typhus)
- Highly persistent
- Still used as insecticide to fight malaria
- Search for alternatives (WHO: permethrin)
- Birds:
o Fragile egg shells: reproduction problems
Softenon (thalidomide):
- Introduced 1956 (sleeping aid) quite effective, but caused malformation
- 1960/1961: recognized as cause of malformations
- Thalidomide inhibits angiogenesis (formation of blood vessels)
- Only one of the stereoisomers toxic
- Future emphasis on:
o Reproduction and developmental toxicity
o Stereochemistry: analytical techniques
o Safety testing and risk assessment
Modern toxicology: major aims:
1. Define toxicity, mechanisms of action and structure activity relationships for chemicals (try to
understand why a chemical compound causes an effect)
2. Evaluation of health and environmental hazards and risks
3. Advisory task for authorities, industries and consumers (giving advice to the government,
should it be used or banned?)
2
,Modern toxicology:
- Multidisciplinary field of science
o Biology, chemistry, biochemistry, physiology, mathematics and physics
- Strong link between science and society
- New emerging technologies/topics
o Omics technology
o Alternatives for animal testing
o In vitro and in silico testing
o Role of epigenetics
o Newly emerging risks
- Ever increasing:
o Faster
o More sensitive
o Newer
- Analytical methods:
o Apparently more residue problems
o Newly emerging problems
- Define safe levels of exposure and acceptable instead of zero risk
Introduction History and Scope of Toxicology: Conclusions:
- Use toxic compounds already for many ages
- Paracelsus founder modern toxicology: concept of dose
- Orfila: concepts of target organ and animal testing
- Incidences due to use of chemicals during industrial revolution and World War II stimulated
modern Toxicology
- Modern Toxicology:
o Define toxicity and modes of action learn more about the chemicals of action
o Risk assessment
o Provide advice
College 2A
Modern toxicology: major fields:
1. Clinical / Forensic Toxicology
2. Occupational Toxicology
3. Food Toxicology
4. Environmental / Ecotoxicology
3
, Process of risk evaluation as defined by the FAO and WHO:
- Risk assessment = an overall process why a compound has that effect, to identify the hazards
- Hazard identification
- Hazard characterisation:
o At which dose level is a compound toxic
- Exposure assessments: how much are you exposed to (eat or inhale)
o Route and site of exposure
Gastrointestinal tract (oral)
Lungs (inhalation)
Skin (dermal)
Injections
o Duration and frequency of exposure
< 24 hours = acute, single dose
1 month or less = subacute
1-3 months = subchronic 10% of life span
> 3 months = chronic 80%-90% of life span
Effect varies with dose & exposure regimen
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: Example: doubling the concentration will halve the time
needed to produce an adverse effect
- Risk characterisation
- Risk management:
o Select type of actions to be taken
o Based on risk assessment and social, economic and political aspects
o Example:
Bisphenol A (BPA)
EFSA: health concern for BPA is
low at the current level of
exposure
In spite of this: ban on BPA in baby
bottles in some countries all food
containers
Acrylonitrile:
- For synthesis rubbers /plastics
- Acute effects: irritation, nausea, anemia, leucocytosis, renal effects, damage to the skin,
lethal at high dose levels
- Chronic effects: Class 2B carcinogen (IARC)
Example:
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