Toxicology and development (AB_1026)
Lecture 1: Kickoff
Dose reponse curves: the dose makes the poison. Everything can be toxic, but it depends on
the dose; low doses may cause no effect, while higher doses can cause stronger effects.
LD50: the dose at which 50% of the population dies
Duration of exposure:
1. Acute: <24 hours
2. Sub- acute: up to 28 days
3. Sub- chronic: 1-3 months
4. Chronic: >3 months
Frequency of exposure:
1. Peak exposure: one short high dose
2. Constant exposure
3. Repeated (pulse) exposure: multiple separate doses over time
Toxicokinetic: what does the organism do with the chemical?
ADME: absorption, distribution, metabolism and elimination
Toxicodynamic: what does the chemical do to the organism?
Lecture 2: Introduction to toxicology part 1
Minamata disease: release of methylmercury into industrial wastewater -> chemical
bioaccumulated in shellfish/ fish -> eaten by the local population -> ataxia, muscle weakness,
microcephaly and cognitive disabilities.
Diethylstilbestrol (DES) syndrome: exposure to DES during pregnancy to prevent
miscarriages -> malformation syndrome in children and grandchildren of women who were
exposed (reproductive tract malformation, decreased fertility and increased risk of cervical
cancer).
Thalidomide/ softenon: drug to prevent morning sickness, but teratogenic -> amelia (absence
of limbs) or phocomelia (shortened limbs).
Toxic effects:
1. Systemic toxicity: substance is absorbed and distributed throughout the whole body,
but mainly affects one or two organs, called the target organs of toxicity.
2. Organ specific toxicity: specific target organs are affected
, Toxicology and development (AB_1026)
Distribution: accumulation (result: more than average distribution) + barriers (result: less than
average distribution, examples: brain + placenta)
1. Brain: blood- brain barrier, a protective barrier which limits what can move from the
blood into the brain.
Made of tightly joined endothelial cells,
surrounded by astrocytes and ATP-
dependent transporters.
- Not a complete barrier: small
molecules and lipid- soluble
substances can pass!
2. The placenta: not a real ‘barrier’, but
prevents many harmful substances from
passing from mother to child
- Not a complete barrier: many lipid-
soluble substances can pass!
Biotransformation: an enzymatic change to the structure of a molecule that alters its activity
Goal: make it less toxic (detoxification), but sometimes it becomes more toxic
(bioactivation)!
Excretion: most common (urine and faeces), alternative (exhalation and sweat)
Reproductive toxicity: damage to the male or female reproductive organs
Hepatoxicity: toxicity to the liver, bile duct and gall bladder
Nephrotoxicity: toxicity to the kidney
Neurotoxicity: damage to the cells of the central nervous system, as well as the peripheral
nervous system
1. Neuronopathy: primary damage to the neuron cell body
- Aluminum: degeneration in brain cortex
- Arsenic: axonal degeneration in peripheral nervous system
- Methanol: ganglion cell degeneration
2. Axonopathy: primary damage to the axon
- Acrylamide: progressive axonal degeneration
3. Myelopathy: primary damage to the myelin sheath or supporting glial cells
4. Synaptic signaling damage: interference with neurotransmission
Immunotoxicity: toxicity of the immune system
Hypersensitivity: immune system becomes too active = allergies
Immunodeficiency: immune system becomes weakened = infections
Uncontrolled proliferation: immune cells grow uncontrollably = leukemia
Respiratory toxicity: any effect on the upper respiratory system and lower respiratory system
Blood and cardiac toxicity: toxicity directly on cells in the circulating blood, bone marrow and
heart
, Toxicology and development (AB_1026)
Lecture 3: Introduction to toxicology part 2
Concentration- response relationships:
1. Concentration increases -> response of the endpoint decreases
- Survival: higher concentration -> less survival
- Enzyme activity: higher concentration -> less enzyme activity
2. Concentration increases -> response of the endpoint increases
- Mortality: higher concentration -> more mortality
- Enzyme inhibition: higher concentration -> more enzyme inhibition
LD50/ LC50: the dose/ concentration at which 50% of the population dies
ED50/ EC50: the dose/ concentration which causes 50% of the maximum effect
ED10/ EC10: the dose/ concentration which causes 10% of the maximum effect
NOEC (no observed effect concentration): highest dose where no effect is seen
LOEC (lowest observed effect concentration): lowest dose where an effect first appears
= The lower the endpoint value, the more toxic the chemical!
Use of the concentration response curve:
1. Forward use: from dose to response -> to predict an effect size and to predict a risk
2. Backward use: from response to dose -> to define the toxicity of the chemical
Lecture 1: Kickoff
Dose reponse curves: the dose makes the poison. Everything can be toxic, but it depends on
the dose; low doses may cause no effect, while higher doses can cause stronger effects.
LD50: the dose at which 50% of the population dies
Duration of exposure:
1. Acute: <24 hours
2. Sub- acute: up to 28 days
3. Sub- chronic: 1-3 months
4. Chronic: >3 months
Frequency of exposure:
1. Peak exposure: one short high dose
2. Constant exposure
3. Repeated (pulse) exposure: multiple separate doses over time
Toxicokinetic: what does the organism do with the chemical?
ADME: absorption, distribution, metabolism and elimination
Toxicodynamic: what does the chemical do to the organism?
Lecture 2: Introduction to toxicology part 1
Minamata disease: release of methylmercury into industrial wastewater -> chemical
bioaccumulated in shellfish/ fish -> eaten by the local population -> ataxia, muscle weakness,
microcephaly and cognitive disabilities.
Diethylstilbestrol (DES) syndrome: exposure to DES during pregnancy to prevent
miscarriages -> malformation syndrome in children and grandchildren of women who were
exposed (reproductive tract malformation, decreased fertility and increased risk of cervical
cancer).
Thalidomide/ softenon: drug to prevent morning sickness, but teratogenic -> amelia (absence
of limbs) or phocomelia (shortened limbs).
Toxic effects:
1. Systemic toxicity: substance is absorbed and distributed throughout the whole body,
but mainly affects one or two organs, called the target organs of toxicity.
2. Organ specific toxicity: specific target organs are affected
, Toxicology and development (AB_1026)
Distribution: accumulation (result: more than average distribution) + barriers (result: less than
average distribution, examples: brain + placenta)
1. Brain: blood- brain barrier, a protective barrier which limits what can move from the
blood into the brain.
Made of tightly joined endothelial cells,
surrounded by astrocytes and ATP-
dependent transporters.
- Not a complete barrier: small
molecules and lipid- soluble
substances can pass!
2. The placenta: not a real ‘barrier’, but
prevents many harmful substances from
passing from mother to child
- Not a complete barrier: many lipid-
soluble substances can pass!
Biotransformation: an enzymatic change to the structure of a molecule that alters its activity
Goal: make it less toxic (detoxification), but sometimes it becomes more toxic
(bioactivation)!
Excretion: most common (urine and faeces), alternative (exhalation and sweat)
Reproductive toxicity: damage to the male or female reproductive organs
Hepatoxicity: toxicity to the liver, bile duct and gall bladder
Nephrotoxicity: toxicity to the kidney
Neurotoxicity: damage to the cells of the central nervous system, as well as the peripheral
nervous system
1. Neuronopathy: primary damage to the neuron cell body
- Aluminum: degeneration in brain cortex
- Arsenic: axonal degeneration in peripheral nervous system
- Methanol: ganglion cell degeneration
2. Axonopathy: primary damage to the axon
- Acrylamide: progressive axonal degeneration
3. Myelopathy: primary damage to the myelin sheath or supporting glial cells
4. Synaptic signaling damage: interference with neurotransmission
Immunotoxicity: toxicity of the immune system
Hypersensitivity: immune system becomes too active = allergies
Immunodeficiency: immune system becomes weakened = infections
Uncontrolled proliferation: immune cells grow uncontrollably = leukemia
Respiratory toxicity: any effect on the upper respiratory system and lower respiratory system
Blood and cardiac toxicity: toxicity directly on cells in the circulating blood, bone marrow and
heart
, Toxicology and development (AB_1026)
Lecture 3: Introduction to toxicology part 2
Concentration- response relationships:
1. Concentration increases -> response of the endpoint decreases
- Survival: higher concentration -> less survival
- Enzyme activity: higher concentration -> less enzyme activity
2. Concentration increases -> response of the endpoint increases
- Mortality: higher concentration -> more mortality
- Enzyme inhibition: higher concentration -> more enzyme inhibition
LD50/ LC50: the dose/ concentration at which 50% of the population dies
ED50/ EC50: the dose/ concentration which causes 50% of the maximum effect
ED10/ EC10: the dose/ concentration which causes 10% of the maximum effect
NOEC (no observed effect concentration): highest dose where no effect is seen
LOEC (lowest observed effect concentration): lowest dose where an effect first appears
= The lower the endpoint value, the more toxic the chemical!
Use of the concentration response curve:
1. Forward use: from dose to response -> to predict an effect size and to predict a risk
2. Backward use: from response to dose -> to define the toxicity of the chemical
