Toxicology
TOX01 – Introduction to toxicology (open textbook 1.3)
Toxicology = science of poisons
Paracelsus, “Luther of medicine”: “All things are poisonous and nothing is not poisonous. Only the
dose makes something not being a poison.”
Phases in toxic response:
1. Exposure
- External exposure
- Dose
- Internal exposure
Human exposure routes are oral, dermal, respiratory, “special routes” (injection etc.)
2. Toxicokinetics what does the body do to the compound
- Absorption
- Distribution
- Metabolism (biotransformation)
- Elimination (excretion)
3. Toxicodynamics what does the compound do to the body
- Irritation, inflammation, etc.
Classification of toxic effects:
Rate
- Acute effect (inhibition of cellular respiration)
- Chronic effect (carcinogenesis)
Possibility for repair
- Reversible (DNA damage)
- Irreversible (tumor progression)
Site of action
- Local effect at site of first contact (epithelium lesion)
- Systemic effect (target organs)
Dose-response curve:
LD50: Median Lethal Dose (mg/kg)
ED50: Median Effect Dose (mg/kg)
LOAEL: Lowest Observed Adverse Effect Level (dose)
NOAEL: No Observed Adverse Effect Level (dose)
LC50: median Lethal Concentration in water/air/soil (mg/kg)
EC50: median Effect Concentration
LOEC: Lowest Observed Effect Concentration
NOEC: No Observed Effect Concentration
, TOX02 – Absorption Distribution (open textbook 4.1.2)
Absorption = uptake
Intake ≠ uptake
Total absorption = ∑(fi x Ii) with f being the absorption efficiency
Absorption after oral intake (+ passing the gastro-intestinal track without absorption):
Entherohepatic circulation (repeat of ADME)
Presystemic elimination (elimination before systemic distribution can take place)
Portal vein
Absorption after intake by inhalation (+ exhaling of non-absorbed gasses):
Gasses get absorbed very quickly; this is due to the Henry coefficient = p air / Cwater. Transport via
osmosis takes places, and there is a continuous bloodstream, which causes further osmosis to take
place.
Distribution depends on the volume of body water.
Concentration = Dose / Volume
Lipophilic compunds (high Kow) in fat tissue:
- Released during fat mobilization
- Risk in case of small fat deposits
Accumulation:
Selective binding or uptake into specific tissues
In most cases not biologically available, i.e. not toxic
Can be mobilized from deposit
Dynamic equilibrium with concentration in blood
Barriers in distribution:
Blood-Brain Barrier (BBB)
- Endothelial cells tight junctions, efflux by transporter proteins, no pinocytosis,
biotransformation capacity
- Astrocytes (gliacells) physicial support, (efflux by transporter proteins,
biotransformation capacity)
Placenta
- Not a true “barrier” many lipophilic compounds diffuse through the placenta
- Defense active transport, biotransformation capacity
TOX01 – Introduction to toxicology (open textbook 1.3)
Toxicology = science of poisons
Paracelsus, “Luther of medicine”: “All things are poisonous and nothing is not poisonous. Only the
dose makes something not being a poison.”
Phases in toxic response:
1. Exposure
- External exposure
- Dose
- Internal exposure
Human exposure routes are oral, dermal, respiratory, “special routes” (injection etc.)
2. Toxicokinetics what does the body do to the compound
- Absorption
- Distribution
- Metabolism (biotransformation)
- Elimination (excretion)
3. Toxicodynamics what does the compound do to the body
- Irritation, inflammation, etc.
Classification of toxic effects:
Rate
- Acute effect (inhibition of cellular respiration)
- Chronic effect (carcinogenesis)
Possibility for repair
- Reversible (DNA damage)
- Irreversible (tumor progression)
Site of action
- Local effect at site of first contact (epithelium lesion)
- Systemic effect (target organs)
Dose-response curve:
LD50: Median Lethal Dose (mg/kg)
ED50: Median Effect Dose (mg/kg)
LOAEL: Lowest Observed Adverse Effect Level (dose)
NOAEL: No Observed Adverse Effect Level (dose)
LC50: median Lethal Concentration in water/air/soil (mg/kg)
EC50: median Effect Concentration
LOEC: Lowest Observed Effect Concentration
NOEC: No Observed Effect Concentration
, TOX02 – Absorption Distribution (open textbook 4.1.2)
Absorption = uptake
Intake ≠ uptake
Total absorption = ∑(fi x Ii) with f being the absorption efficiency
Absorption after oral intake (+ passing the gastro-intestinal track without absorption):
Entherohepatic circulation (repeat of ADME)
Presystemic elimination (elimination before systemic distribution can take place)
Portal vein
Absorption after intake by inhalation (+ exhaling of non-absorbed gasses):
Gasses get absorbed very quickly; this is due to the Henry coefficient = p air / Cwater. Transport via
osmosis takes places, and there is a continuous bloodstream, which causes further osmosis to take
place.
Distribution depends on the volume of body water.
Concentration = Dose / Volume
Lipophilic compunds (high Kow) in fat tissue:
- Released during fat mobilization
- Risk in case of small fat deposits
Accumulation:
Selective binding or uptake into specific tissues
In most cases not biologically available, i.e. not toxic
Can be mobilized from deposit
Dynamic equilibrium with concentration in blood
Barriers in distribution:
Blood-Brain Barrier (BBB)
- Endothelial cells tight junctions, efflux by transporter proteins, no pinocytosis,
biotransformation capacity
- Astrocytes (gliacells) physicial support, (efflux by transporter proteins,
biotransformation capacity)
Placenta
- Not a true “barrier” many lipophilic compounds diffuse through the placenta
- Defense active transport, biotransformation capacity
