Samenvatting Toxicologie
College 1: Introduction History and Scope of Toxicology
Toxicology:
- Study of the adverse toxic effects of chemicals on living organisms
o This knowledge is essential for safe use of chemicals including drugs, additives,
novel food ingredients, etc.
What is toxic?
- Amanita muscaria - Neurotoxic
- Taxus baccata - taxins inhibit Ca2+ currents heart
Toxicology is part of daily life
- January 2011: 500 ton toxic compounds stored at chemical company Chemiepack in
Moerdijk on fire. “Some 400,000 litres of carcinogenic material are stored at the Chemie-
Pack plant ”De Telegraaf newspaper says. “Some reports said toxic fumes had been
released, but others said they were not dangerous”.
- May 2013: Train crash: Toxic chemicals(acrylonitrile) on fire near Ghent Belgium: Two
people died and 14 were injured The burning material releases fumes of hydrogen cyanide
and oxides of nitrogen.
Acrylonitrile: Used for synthesis of pe rubbers and plastics.
o Acute effects: irritation, nausea, anemia, leukocytosis, renal effects, damage to the
skin, lethal at high dose levels
o Chronic effects: cancer: Class 2B carcinogen (possibly carcinogenic) (IARC)
- Food company hit by chicken chemical food scare. Drop in profits after animals excessively
pumped with antibiotics (February 2013)
- 2013: salmon with too high levels of dioxins. EU banned export Baltic salmon from Sweden
back in 2002 due to the fact that they were found to be heavily contaminated with dioxins
History of toxicology
- Greek and Romans
o Hippocrates (400 BC): Description of poisons and clinical toxicology principles like
bioavailability
o Socrates: Drinking Hemlock (Dolle Kervel) -> Greek state poison
- Middle Ages
o Atropa belladonna (wolfskers)
Antropos: Greek goddess of death
Bella-donna: use atropine to widen eye pupils
Contains atropine/scopolamine (10-20 berries are fatal) -> linked to witches
o Mycotoxicoses from ergot alkaloids -> produced by Claviceps Purpurea (ergot)
fungus on rey (rogge)
Cause St Anthony’s fire: Black limbs (=Gangrene) due to vasoconstriction and
extremes, madness
- Ancient Europe/Asia: Aconitum sp. Contains Aconitin (3-6 mg. is fatal)
used to poison hunting spears and enemy water supplies during war
Cardiac arrhythmias (slowing heart rate) and hypotension (lowering blood pressure)
- Important people:
o Paracelsus: notion of dose: “alle Ding sind Gift, und Nichts ohn Gift; allein die Dosis
macht dass eind Ding kein Gift ist”
Example: Botox injections are not fatal but higher dose will be
o Percival Pott: Chimney sweepers had high incidence of scrotal cancer -> constant
exposure to soot
o Orfila: Introduction of the target organ
, o Van Hasselt: First Dutch Toxicologist
- Modern toxicology
o 20th century
Industrial revolution & WWII: many new drugs, pesticides, munitions,
synthetic fibers and industrial chemicals:
chlorinated hydrocarbon insecticides: DDT
war gasses, munition: sarin, soman, uranium, agent orange (dioxins)
drugs: softenon (thalidomide), diethylstilbestrol (DES)
DDT: dichlorodiphenyltrichloroethane
Late 1920’s
Still used as insecticide to fight malaria
Highly persistent
Search for alternatives
Dioxins: TCDD
Agent Orange (Vietnam 1960’s)
Softenon: thalidomide
introduced 1956 (sleeping aid)
1960/1961: recognized as cause of malformations
thalidomide inhibits angiogenesis (formation of blood vessels)
only one of the stereoisomers toxic
o New emerging problems:
natural = safe ? (botanicals)
functional foods & supplements
EINECS list chemicals (REACH)
organic farming
low dose risks carcinogens
o new emerging strategies
-omics technology
alternatives for animal testing
in vitro and in silico testing
epigenetics
o Major aims:
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
4.
College 2: Principles of toxicology
- Major aims:
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
Hazard Risk
Gevaar Risico
Potential danger of a compound of Probability that an adverse effect
process will occur
No exposure -> no risk Hazard + exposure = risk
Risk assessment: the process by which hazard, exposure and risk are determined
Process of risk evaluation as defined by the FAO and WHO
, Risk management
- Is not only based on risk assessments but also on other aspects.
- Based on risk assessment and social, economic and political aspects
o Example: Politics: also for gaining votes, even if there is no real risk (protecting your
good name)
Risk assessment
- Major steps:
o Hazard identification -> hazard characterization
Hazard identification
Qualitative principles
o Receptor = the molecular structure affected by the toxic agent
(DNA, protein like enzyme, ion channel)
o Primary lesion = type of primary molecular damage
o Target organ (orfilla) = most sensitive organ
Reversible versus irreversible toxicity
Local (1st site of contact) versus systemic toxicity (taken up
and toxic elsewhere)
Quantitative principles
o Dose response relationship
o LD50 =lethal dose 50%
o NOAEL: No Observed Adverse Effect Level (IMPORTANT!)
o LOAEL: Lowest Observed adverse effect level (not so much used
as noael)
College 1: Introduction History and Scope of Toxicology
Toxicology:
- Study of the adverse toxic effects of chemicals on living organisms
o This knowledge is essential for safe use of chemicals including drugs, additives,
novel food ingredients, etc.
What is toxic?
- Amanita muscaria - Neurotoxic
- Taxus baccata - taxins inhibit Ca2+ currents heart
Toxicology is part of daily life
- January 2011: 500 ton toxic compounds stored at chemical company Chemiepack in
Moerdijk on fire. “Some 400,000 litres of carcinogenic material are stored at the Chemie-
Pack plant ”De Telegraaf newspaper says. “Some reports said toxic fumes had been
released, but others said they were not dangerous”.
- May 2013: Train crash: Toxic chemicals(acrylonitrile) on fire near Ghent Belgium: Two
people died and 14 were injured The burning material releases fumes of hydrogen cyanide
and oxides of nitrogen.
Acrylonitrile: Used for synthesis of pe rubbers and plastics.
o Acute effects: irritation, nausea, anemia, leukocytosis, renal effects, damage to the
skin, lethal at high dose levels
o Chronic effects: cancer: Class 2B carcinogen (possibly carcinogenic) (IARC)
- Food company hit by chicken chemical food scare. Drop in profits after animals excessively
pumped with antibiotics (February 2013)
- 2013: salmon with too high levels of dioxins. EU banned export Baltic salmon from Sweden
back in 2002 due to the fact that they were found to be heavily contaminated with dioxins
History of toxicology
- Greek and Romans
o Hippocrates (400 BC): Description of poisons and clinical toxicology principles like
bioavailability
o Socrates: Drinking Hemlock (Dolle Kervel) -> Greek state poison
- Middle Ages
o Atropa belladonna (wolfskers)
Antropos: Greek goddess of death
Bella-donna: use atropine to widen eye pupils
Contains atropine/scopolamine (10-20 berries are fatal) -> linked to witches
o Mycotoxicoses from ergot alkaloids -> produced by Claviceps Purpurea (ergot)
fungus on rey (rogge)
Cause St Anthony’s fire: Black limbs (=Gangrene) due to vasoconstriction and
extremes, madness
- Ancient Europe/Asia: Aconitum sp. Contains Aconitin (3-6 mg. is fatal)
used to poison hunting spears and enemy water supplies during war
Cardiac arrhythmias (slowing heart rate) and hypotension (lowering blood pressure)
- Important people:
o Paracelsus: notion of dose: “alle Ding sind Gift, und Nichts ohn Gift; allein die Dosis
macht dass eind Ding kein Gift ist”
Example: Botox injections are not fatal but higher dose will be
o Percival Pott: Chimney sweepers had high incidence of scrotal cancer -> constant
exposure to soot
o Orfila: Introduction of the target organ
, o Van Hasselt: First Dutch Toxicologist
- Modern toxicology
o 20th century
Industrial revolution & WWII: many new drugs, pesticides, munitions,
synthetic fibers and industrial chemicals:
chlorinated hydrocarbon insecticides: DDT
war gasses, munition: sarin, soman, uranium, agent orange (dioxins)
drugs: softenon (thalidomide), diethylstilbestrol (DES)
DDT: dichlorodiphenyltrichloroethane
Late 1920’s
Still used as insecticide to fight malaria
Highly persistent
Search for alternatives
Dioxins: TCDD
Agent Orange (Vietnam 1960’s)
Softenon: thalidomide
introduced 1956 (sleeping aid)
1960/1961: recognized as cause of malformations
thalidomide inhibits angiogenesis (formation of blood vessels)
only one of the stereoisomers toxic
o New emerging problems:
natural = safe ? (botanicals)
functional foods & supplements
EINECS list chemicals (REACH)
organic farming
low dose risks carcinogens
o new emerging strategies
-omics technology
alternatives for animal testing
in vitro and in silico testing
epigenetics
o Major aims:
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
4.
College 2: Principles of toxicology
- Major aims:
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
Hazard Risk
Gevaar Risico
Potential danger of a compound of Probability that an adverse effect
process will occur
No exposure -> no risk Hazard + exposure = risk
Risk assessment: the process by which hazard, exposure and risk are determined
Process of risk evaluation as defined by the FAO and WHO
, Risk management
- Is not only based on risk assessments but also on other aspects.
- Based on risk assessment and social, economic and political aspects
o Example: Politics: also for gaining votes, even if there is no real risk (protecting your
good name)
Risk assessment
- Major steps:
o Hazard identification -> hazard characterization
Hazard identification
Qualitative principles
o Receptor = the molecular structure affected by the toxic agent
(DNA, protein like enzyme, ion channel)
o Primary lesion = type of primary molecular damage
o Target organ (orfilla) = most sensitive organ
Reversible versus irreversible toxicity
Local (1st site of contact) versus systemic toxicity (taken up
and toxic elsewhere)
Quantitative principles
o Dose response relationship
o LD50 =lethal dose 50%
o NOAEL: No Observed Adverse Effect Level (IMPORTANT!)
o LOAEL: Lowest Observed adverse effect level (not so much used
as noael)
