Toxicology
Terminology in dose response
LD50: median lethal dose (mg per kg bodyweight)
- ED50: median effect dose (mg per kg bodyweight)
- LOAEL: lowest observed adverse effect level (dose)
- NOAEL: no observed adverse effect level (dose)
- LC50: median lethal concentration in water, air, soil (μg/L, μg/m3, mg/kg)
- EC50: median effect concentration
- LOEC: lowest observed effect concentration
- NOEC: no observed effect concentration
- CES: critical effect size
- BMDL: benchmark dose lower confidence bound
Lecture 02
Toxicology in science
Alkaloids from hemlock (Coniine) block the acetylcholine-receptor in neurons of the autonomous
nervous system.
Paracelsus is the luther of medicine. He took the compound (toxicon) as starting point and not the
mixture. Points of departure:
- Experimenting is essential
- Distinguish between poisonous and therapeutic properties
- These cannot always be distinguished
- Compounds may have specific effect
All things are poisonous and nothing is not poisonous only the dose makes something not being a
poison.
General principles
Phases in toxic response:
- Exposure
o External exposure (ug/l water, ug/m3 air)
o Dose (ug/kg bodyweight)
o Internal exposure (ug/l blood, ug/kg fat)
- Toxicokinetics: what does body do to the compound (ADME)
o Absorption, Distribution, Metabolism (biotransformation), Elimination (excretion)
- Toxicodynamics: what does compound do to body
o Irritation, inflammation, corrosion, narcosis, carcinogenesis etc.
o Will be dealt with for different group of compounds
Human exposure routes:
- Oral
- Dermal
- Respiratory
- Special routes (injection, intravenous therapy)
,Classification of toxic effects
- Rate
o Acute effect
o Chronic effect (carcinogenesis)
- Possibility for repair
o Reversible (DNA damage)
o Irreversible (tumor progression)
- Site of action
o Local effect at site of first contact
o Systemic effect
Target organs, CNS, circulatory system, skin
Unborn embryo
Example of systemic toxicity
- Developmental toxicity
- Softenon-baby, very serious structural birth defects related to use of thalidomide during
pregnancy.
- Thalidomide is teratogenic causing:
o Amelia: absence of limbs
o Phocomelia: reduction of long bones of limbs
Acute vs chronic toxicity:
- Acute toxicity occurs soon after a short exposure to a compound
- Chronic toxicity occurs after repeated, longterm exposure to a compound.
Toxicity test – endpoints:
- Specific endpoints
o Gene expression
o Enzyme activity
o Neurotransmission
o Histological tissue examination
- General endpoints (important for population)
o Survival
o Growth/metabolism
o Reproduction
o Behavior
Toxicity test – how:
- In vivo testing
o Model species applicable to humans (mouse, rat, pig, zebrafish)
o Model species representing ecological food chain (algae, fish, macrophytes)
o Alternative models (nematode worms, zebrafish embryos)
- In vitro testing
o Protein-based, cell-based systems
- Human epidemiological studies
o Not testing
o Studying the human population
- In silico testing:
, o Quantitative structure activity relationships (QSAR), Read Across, in vitro-in vivo
extrapolation (IVIVE)
Toxicity test in practice:
- Negative control (C0)
- Series of increasing test concentrations or doses (C1-Cn)
- Positive control (Cp)
Dose-response curves
Dose response curve:
- Forward use
o From X-as to Y-as, so what doses gives what response
o To predict effect size and risk
- Backward use
o From Y-as to X-as,
o To express the measure of effect caused by a mixture with unknown composition in
terms of a dose of a single reference compound causing exactly the same response
level (“equivalent dose”)
o To derive compound characteristics
o Threshold values
o Risk assessment
CES: Critical effect size
CED: Critical effect dose
BMD: Benchmark dose
CI: Confidence interval
BMDL: Benchmark dose lower confidence bound
LD50: Median lethal dose
- If it is high, it is not toxic
- If the dose is low, it is very toxic
Potency and efficacy:
- In a curve. Most left.
o High effect with low dose. Low EC50
- Most right:
o Needs higher dose to have an effect. High EC50.
Three characteristics of curve
- Location of x-as (ED50, potency)
- Maximum response on y-as (effectiveness)
- Steepness of curve
Critisicim on NOAEL and LOAEL:
- NOAEL: No Observed Adverse Effect Level.
o Depends on:
Replicates
Variation in replicates
Dose interval
Statistical test and p-value
Terminology in dose response
LD50: median lethal dose (mg per kg bodyweight)
- ED50: median effect dose (mg per kg bodyweight)
- LOAEL: lowest observed adverse effect level (dose)
- NOAEL: no observed adverse effect level (dose)
- LC50: median lethal concentration in water, air, soil (μg/L, μg/m3, mg/kg)
- EC50: median effect concentration
- LOEC: lowest observed effect concentration
- NOEC: no observed effect concentration
- CES: critical effect size
- BMDL: benchmark dose lower confidence bound
Lecture 02
Toxicology in science
Alkaloids from hemlock (Coniine) block the acetylcholine-receptor in neurons of the autonomous
nervous system.
Paracelsus is the luther of medicine. He took the compound (toxicon) as starting point and not the
mixture. Points of departure:
- Experimenting is essential
- Distinguish between poisonous and therapeutic properties
- These cannot always be distinguished
- Compounds may have specific effect
All things are poisonous and nothing is not poisonous only the dose makes something not being a
poison.
General principles
Phases in toxic response:
- Exposure
o External exposure (ug/l water, ug/m3 air)
o Dose (ug/kg bodyweight)
o Internal exposure (ug/l blood, ug/kg fat)
- Toxicokinetics: what does body do to the compound (ADME)
o Absorption, Distribution, Metabolism (biotransformation), Elimination (excretion)
- Toxicodynamics: what does compound do to body
o Irritation, inflammation, corrosion, narcosis, carcinogenesis etc.
o Will be dealt with for different group of compounds
Human exposure routes:
- Oral
- Dermal
- Respiratory
- Special routes (injection, intravenous therapy)
,Classification of toxic effects
- Rate
o Acute effect
o Chronic effect (carcinogenesis)
- Possibility for repair
o Reversible (DNA damage)
o Irreversible (tumor progression)
- Site of action
o Local effect at site of first contact
o Systemic effect
Target organs, CNS, circulatory system, skin
Unborn embryo
Example of systemic toxicity
- Developmental toxicity
- Softenon-baby, very serious structural birth defects related to use of thalidomide during
pregnancy.
- Thalidomide is teratogenic causing:
o Amelia: absence of limbs
o Phocomelia: reduction of long bones of limbs
Acute vs chronic toxicity:
- Acute toxicity occurs soon after a short exposure to a compound
- Chronic toxicity occurs after repeated, longterm exposure to a compound.
Toxicity test – endpoints:
- Specific endpoints
o Gene expression
o Enzyme activity
o Neurotransmission
o Histological tissue examination
- General endpoints (important for population)
o Survival
o Growth/metabolism
o Reproduction
o Behavior
Toxicity test – how:
- In vivo testing
o Model species applicable to humans (mouse, rat, pig, zebrafish)
o Model species representing ecological food chain (algae, fish, macrophytes)
o Alternative models (nematode worms, zebrafish embryos)
- In vitro testing
o Protein-based, cell-based systems
- Human epidemiological studies
o Not testing
o Studying the human population
- In silico testing:
, o Quantitative structure activity relationships (QSAR), Read Across, in vitro-in vivo
extrapolation (IVIVE)
Toxicity test in practice:
- Negative control (C0)
- Series of increasing test concentrations or doses (C1-Cn)
- Positive control (Cp)
Dose-response curves
Dose response curve:
- Forward use
o From X-as to Y-as, so what doses gives what response
o To predict effect size and risk
- Backward use
o From Y-as to X-as,
o To express the measure of effect caused by a mixture with unknown composition in
terms of a dose of a single reference compound causing exactly the same response
level (“equivalent dose”)
o To derive compound characteristics
o Threshold values
o Risk assessment
CES: Critical effect size
CED: Critical effect dose
BMD: Benchmark dose
CI: Confidence interval
BMDL: Benchmark dose lower confidence bound
LD50: Median lethal dose
- If it is high, it is not toxic
- If the dose is low, it is very toxic
Potency and efficacy:
- In a curve. Most left.
o High effect with low dose. Low EC50
- Most right:
o Needs higher dose to have an effect. High EC50.
Three characteristics of curve
- Location of x-as (ED50, potency)
- Maximum response on y-as (effectiveness)
- Steepness of curve
Critisicim on NOAEL and LOAEL:
- NOAEL: No Observed Adverse Effect Level.
o Depends on:
Replicates
Variation in replicates
Dose interval
Statistical test and p-value
