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Summary Lectures General Toxicology (TOX-20303) (TOX20303)
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Summary lectures General Toxicology. Contains notes of the powerpoints, images and notes of the teacher.
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General ToxicologyCollege 1 History and principles
Toxicology: study of adverse/toxic effects of chemicals on living organisms → necessary: safe use of
chemicals, including drugs, additives, novel food ingredients, etc.
Historical perspective
Phase 1: Hunting, fishing, gathering
Had some knowledge on acute toxic properties of plants, mushrooms and some minerals, but
probably less knowledge of chronic effects. They used Aconitum sp. (Monkshood) as a poison while
hunting. It caused cardiac arrythmias (slowing heart rate) and hypotension (lowering blood pressure).
Phase 2: Agricultural development
Started cooking which allowed cultivation of new plants that contained natural toxins as crops.
Storage and transport introduced new toxic compounds such as molds → mycotoxins.
Hippocrates: description of poisons and clinical toxicology like bioavailability.
Middle ages
Ergot alkaloids produced by Claviceps purpurea (ergot) fungus on Rey (rogge). → caused by humidity
during storage. These toxins caused St. Anthony’s fire:
• Black limbs= gangrene due to vasoconstrictions of blood vessels
• Madness
• Pilgrimage to St. Antionius
!Paracelsus! (1439-1541): swiss alchemist. He made the notion of dose: everything is toxic, it is the
dose which determines whether something is toxic or non-toxic. → example: botulinum toxin, blocks
ACh release. Used for: facial rejuvenation, treatment spasticity and treatment Spasmodic dysphonia
(spasticity vocal cords).
Phase 3: Industrial development
Developments:
• 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
!Percivall Pott!: report in 1775 on chimney sweeps who had a very high incidence of scrotal cancer.
He found out that it was related to constant exposure to soot which contained (we know now)
polycyclic aromatic hydrocarbons.
!Orfila!: tried to find out the cause of death by looking at the body instead of eye witnesses. Found
out something with arsenic. Introduced target organ concept= where the toxin accumulates, and
animal experiments.
20th century toxicology
• Industrial revolution & World War II:
• Many pesticides: chlorinated hydrocarbon insecticides: DDT
• War gasses, munition: sarin, soman, uranium, agent orange (dioxins)
• Drugs: softenon (thalidomide), diethylstilbestrol (DES)
• Industrial chemicals
• Synthetic fibers.
Toxins used in history
DDT= diclorodiphenyltrichloroethane and other organohalides. It was to spray over nature. it
accumulated in bugs and birds. It is still found in the world, even in the polar regions. Rachel Carson
challenged the notion that man was destined to control nature. specifically to control pests through
use of chlorinated hydrocarbons such as DDT.
,Dioxins (TCDD) Agent orange (Vietnam) 1960’s: was used by US forces to spray over trees so that all
the leaves fell out and they could see underneath. It caused a lot of different problems for people →
malformations, etc.
Softenon (thalidomide): introduced as a medicine against morning sickness, but it caused
malformation to babies. It inhibited the growth of blood vessels → thalidomide inhibits angiogenesis.
It had two isomers of which only one was toxic. This caused the future emphasis on:
• Reproduction & development toxicity
• Stereochemistry: analytic techniques
• Safety testing and risk assessment
Aims of modern toxicology
The major aims of modern toxicology are:
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 management: select type of actions that has to be taken. This is based on assessment and social,
economic and political aspects. Example: Bisphenol A (BPA): EFSA says the health concern for BPA is
low at the current level of exposure, but still there is a ban on BPA in baby bottles and in some
countries (France) all food containers.
Risk assessment and exposure assessment: exposure assessment:
1. Route and site of exposure
a. gastrointestinal tract (oral)
b. lungs (inhalation)
c. skin (dermal)
d. injections
2. Duration and frequency of exposure.
a. Acute: < 24 hours, single dose
b. Subacute: 1 month or less, repeated exposure
c. Subchronic: 1-3 months, 10% of life span
d. Chronic: >3 month, 80-90% of life span
, The effects varies with dose and exposure
regimen.
EDI= estimated daily intake
The novel method uses a normal distribution.
Exposure assessment: duration and frequency
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.
• Doubling the concentration will halve the time needed to produce an adverse effect.
Hazard identification and hazard characterization
Hazard: dose response relationship. Establishes
causality that the chemical has in fact induced the
observed effects. Determines the rate at which
injury builds up: slope of dose response curve
ADI; acceptable daily intake, for avoidable
contaminates additives, pesticides
TDI: tolerable daily intake, for unavoidable
contaminants dioxins, mycotoxins, heavy metals.
Risk characterization/assessment:
• Integrate hazard characterization and exposure characterization
• Define exposure levels based on toxicological studies: ADI or TDI
• Define the actual exposure: EDI
• Calculate if actual exposure is safe
• Exception: initiating genotoxic carcinogens: only risk assessment (no safety, priority setting)
, College 2 Mechanisms of interaction of chemicals
Delivery to the site of action (ADME)
Reaction ultimate toxicant with target molecule
Cellular dysfunction and resultant toxicities.
Reaction of ultimate toxicant with target
1. Non covalent binding
a. Structural similarity with natural ligand: competition for physiological receptor
i. agonist: stimulates signal transduction, transcription, etc.
ii. antagonist; blocks signal transduction, etc.
b. No structural similarity natural ligand
i. blocker: reduced permeability activity. → tetrodotoxin: poison from puffer fish which
blocks Na+ channel neurons.
ii. modulator: increased permeability activity
2. Covalent binding: reactions with macromolecules. An electrophile reacts with a
macromolecule and makes the macromolecule a radical. An example: acetylcholinesterase
(AChE) irreversible inhibition. AChE catalyzes the hydrolysis of neurotransmitter
acetylcholine to form choline and acetate prevents overstimulation of postsynaptic
receptors.
3. Reactive oxygen species (hydrogen abstraction). Especially dangerous in organs where there
is a lot of O2
a. Reactive oxygen species (ROS) and other radicals
i. hydroxyl radicals *OH
ii. superoxide anion radicals O2-*
iii. hydrogen peroxide H2O2
b. Damage to:
i.proteins: inactivation
ii. DNA: mutation
iii. lipids: lipid peroxidation
Lipid peroxidation disturbs membrane structure.
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