Overview
College 1 - toxicology part 1................................................................................................. 2
College 2 - toxicology part 2................................................................................................. 4
College 3 - modelling human organs in vitro...................................................................... 7
College 4 - alternative models.............................................................................................. 9
College 5 - teratogens & birth defects................................................................................11
College 6 - epigenetics and the DohAD............................................................................. 15
College 7 - Epidemiology.................................................................................................... 19
College 8 - human biomonitoring and the exposome...................................................... 26
College 9 - Human development II......................................................................................28
College 10 - hazard risk....................................................................................................... 34
College 11 - epidemiology in risk assessment..................................................................37
College 12 - effect directed analysis (EDA)....................................................................... 39
College 13 - Metabolomics.................................................................................................. 42
College 14 - RIVM Validation............................................................................................... 50
,College 1 - toxicology part 1
● History of toxicology > how toxicants have been explored throughout history
● General principle of toxic responses (ADME)
● Demonstrate an understanding of why barriers are important in toxic exposures
History of toxicology
Antiquity: Poisonous plants and animals were known
- Ebers papyrus: earliest documentation of pioson and their effects
- Hippocrates: poison for medical use
- Socrates: died of drinking hemlock (knowledge of poisons)
Renaissance:
- Paracelsus took the compound (toxicon) as a strating point and not the mixture.
Distinguishes between poisonous and therapeutic doses (not alays separated).
Enlightenment:
- Percoval Pott: related soot-scrotum cancer > occupational toxicology + prevention.
- Mathieu Orfila: founder of modern toxicology, systematic animal studies and the
autopsy and analytical chemistry.
Industrial revolution:
- More new compunds > increased occupational toxicoloy and enviromental pollution
20th century: Warfare, scandels and disasters with toxins and regulation (risk assessment).
- Neurological diseases from mercury poison
- Release of methylmercury into industrial wastewater from a factory
- Chemical bioaccumulate in shellfish and these were eaten by the population
Examples of toxicology disasters
Minimata disease: caused by mercury poisoning from industrial water. Symptoms:
ataxia, muscle weakness, cognitive disabilities. Mechanism: methylmercury bioaccumulates
in fish and shelfish, consumed by humans.
Diethylstilbestrol (DES) syndrome: synthetic estrogen prescribed to prevent
miscarriages. Effect: reproductive tract malformations, reduced fertility, increased cancer
risk. Legacy: effect also still shown in grandchildren (offspring)
Thalidomide (Softenon): prescribed to pregant women against morning sickness.
Did not show toxicity in animal tests but caused severe teratogenic effects (= developmental
effects caused by toxicants) in humans. Effect: limb malformations like no legs or arms.
Pollution: one of the largest risk factors for disease and premature death globally.
Much greater health impact than war, terrorism, malaria, drugs and alcohol. Number of
deatsh caused by polluation similar to those by smoking.
Phases in toxic responses
A. Kinetics: what does the body do to the compound?
- Toxicants do not end up in all organs at the same concentrations
- Example: Target site metabolism may lead to different levels of toxicants
- ADME (Absorption, Distribution, Metabolism, Elimination)
B. Dynamics: what does the compound do to the body?
- Toxicity depends on organ specialization and regenerative capacity.
- Example: Liver can regenerate, but CNS damage is often permanent.
,ADME process
1. Absorption
Toxicants enter the body via: oral, contact, respiratory
and special routes (injection or suppository) = exposure
2. Distribution
Accumulation: higher concentration in some organs.
Barriers reduce toxicant distribution. Like placenta or
BBB. in less than average distribution
3. Metabolisme/ ‘biotransformation’
Enzymatic changes to the structure. Occur in the liver, kidneys, or where the appropriate
enzymes are found. Goal: Detoxify substances for elimination, but sometimes activate toxic
metabolites.
4. Elimination
Routes: Urine, feces, sweat, exhalation. Efficient elimination crucial to avoid toxicity buildup.
Barriers
BBB protects the CNS by restricting ion, molecule and cell movement. Done by tightly joined
endothelial cells and atrocytes. Permeable for: small molecules, lipophilic substances, drugs
and alcohol can pass through. ATP-dependent transporters move chemicals into the brain.
BBB is also vulnerable to damage, lead weakens BBB, causing neurobehavioral issues.
Reduced bBB integrity, altered myelination and synaptigenesis, increased iron deposition
and shifts brain metabolic content. Key determinant in neurobehavioral consequences. Also
oxidative stress, mitochondrial dysfunction and increased permeability can lead to brain
changes. The developing brain is very sensitive to toxin> fetal exposure> profound influence.
The placenta is a partial barrier, relying on active transport and biotransformation. Prevents
many harmful substances from passing from mother to child. Lipophilic compounds can
diffuse through, affecting the fetus. Developing fetal brain is highly sensitive to toxicants. The
toxicokinetics (body to compound) of the maternal-fetal unit are poorly understood.
Types of toxic effects
1. Systemic toxicity: affects the entire body, not limited to one area. Do not cause a
similar toxicity in all organs (usually one or two). Example: Mercury affecting CNS.
2. Organ specific toxicity: specific organs (CNS, skin, unborn embryo) are affected.
- Neurotoxicity: CNS damage form lead
- Hepatotoxicity: liver damage
- Reproductive toxicity: infertility or birth defects
- Nephorotoxicity: kidney due to high volume of blood flow
- Respiratory toxicity: upper and lower respiratory system
- Blood and cardiac toxicity: xenobiotics acting directly on heart/ bone marrow
, College 2 - toxicology part 2
● Concentration-response curves and how to read them
● Relationshipos between dose-response curves and outputs
● Generate a concentration-response curve in practise
● Potency and therapeutic index can be determined from concentration-response curves
Paracelsus
“All substances are poisions: there is none which is not a poison. The proper doses
seperates a poison from a remedy.” / It's the dose that makes the poison.” Distinguish
between poisonous and therapeutic doses > important for activity of toxicologists, the
establishment of dise-effect relationships.
Concentration-response curves
Concentration-response curves represent the relationship between the concentration of a
toxicant and the biological response it elicits. allows us to quentify the toxicity of a substance
and predict its effects at various concentrations.
Concentration-response relationships
1. Response of the endpoint decreases with increasing concentration
% Enzyme activity = Graded (continuous) response
% Survival = dichotomous/quantal response, “a yes-no response”
2. Response of the endpoint increases with increasing exposure
% Enzyme inhibition = Graded (continuous) response
% mortality = dichotomous/quantal response
Steepness = sensitivity (more steeper, more potent > more powerful).
Location on x-as shows potency (the lower the value, the more toxic)
- LC50, EC50, EC10 determined by fitting dose-response models
(not a tested concentration but a point on the line)
- NOEC and LOEC are determined by statistical testing (tested)
NOEC (No Observed Effect Concentration) = highest test
concentration with no significant adverse effect (compared to
corresponding control).
LOEC (Lowest Observed Effect Concentration) = lowest test
concentration showing significant adverse effects (compared to
the corresponding control).
