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Samenvatting Toxicology and Development (AB_1026) - Minor Biomedical Topics in Healthcare

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Dit document bevat een samenvatting van de stof van het vak Toxicology and Development, onderdeel van de minor Biomedical Topics in Healthcare.

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  • 15 februari 2024
  • 57
  • 2023/2024
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Toxicology & Development
Lecture 1: Introduction to Toxicology
- Toxicology -> study of adverse effects of chemicals on living organisms.
o Toxicologists examines nature of these effects and assesses probability of their occurrence.
o Toxicology testing conducted to determine degree by which substance damages organisms.
o Paracelsus: “All substances are poisons; there is none which is not a poison. The proper dose
separates a poison from a remedy.”
o Areas of toxicology
 Mechanistic toxicology identifies cellular, biochemical, and molecular mechanisms by
which chemicals exert their toxic effects.
 Descriptive toxicology focuses on toxicity testing to provide information on safety
evaluation and regulatory requirements.
 Regulatory toxicology decides if a drug or another chemical is of sufficiently low risk to
be marketed for a stated purpose.
o Types of toxic effects
 Systemic toxicity are toxic effects caused as result of absorption and distribution of
substance that affects the whole body rather than a specific (local) area.
 Organ-specific toxicity can be reproductive toxicity, hepatotoxicity, nephrotoxicity,
neurotoxicity, immunotoxicity, respiratory toxicity, and blood/cardiac toxicity.
- Concentration-response relationships
o Paracelsus principle -> establishment of dose-
effect relationships with graph that shows
performance of tested organism (growth/survival)
plotted as the function of the concentration of a
toxicant in water, soil, or air.
o LD50 = median lethal dose; LC50 = median lethal
concentration → dose in mg/kg body weight,
often oral or topical dosing.
o EC/ED50 = concentration/dose causing 50%
effect ; EC/ED10 = concentration/dose causing
10% effect; NOEC = no observed effect concentration; LOEC = lowest observed effect
concentration → concentration in air (mg/m3) water (mg/L), soil, sediment, or food (mg/kg).
o NEL = no effect level.
o Endpoints provide a measure of toxicity and enable comparison of toxic potency of chemicals.

Lecture 2: Toxicology
- Dose-response curves
o Endpoint decreases with increasing concentration (e.g., % survival) & response of endpoint
increases with increasing exposure concentration (e.g., % mortality).
 Generic endpoints → survival, growth/metabolism, reproduction, and behaviour.
 Specific endpoints → gene expression, enzyme activity, histology, neurotransmission.
o LC50, EC50, and EC10 determined by fitting dose-response
models (no point on the line) and LOEC/NOEC by statistical
test of the chemical.
o The more points in the curve, the more accurate it is;
minimum of 5 points in curve.
o Logarithmic dose-response curves are generally sigmoidal
(S-shaped) and monophasic (have a single phase).
o NOEC is highest test concentration that does not cause a
significant adverse effect compared to corresponding control. LOEC is lowest test
concentration that causes a significant adverse effect compared to corresponding control.
o Forward use -> predicting effect (response) caused by specific toxicant concentration (know
x-axis and determine y-axis for example to predict effect size).

, o Backward use -> estimate exposure concentration that triggers certain response; derive
chemical properties and trigger values (know y-axis and determine x-axis for example to derive
substance characteristics).
o Dose-response curves characterised by location (EC 50/potency), maximum response
(effectiveness), and steepness of the curve (slope).
 Relative potency (REP) =
EC 50 of a standard
EC 50 of a sample -> only valid when
dose-response curves for sample and
standard are parallel and reach the same
maximum response (efficacy).
 Increasing potency means a lower EC50.
 Compounds could all have the same EC50, but
a different maximal response.
 The steepness of the curve predicts how quickly an effect will happen.
- Therapeutic index -> measure of safety of a drug relating to blood
concentration at which a drug is toxic compared to concentration at
LD 50 toxic effect
which drug is effective = =
ED 50 therapeutic effect
o Hight TI → safe window & not very toxic (paracetamol).
o Low TI → very small window & toxic (lithium).
- Window of causality
o Optimal balance of essential metallic elements important for
sustaining normal functions in organism -> too little of it results in deficiency and poor quality of
life & too much can be toxic.




o Deficiencies associated with adverse pregnancy outcomes, including neural tube defects
(NTDs), congenital heart defects, preterm birth, miscarriage, and stillbirth.
o Non-essential metallic element exposure plays a role in the aetiology of NTDs.
- Toxicity tests in practice




o Organisation of Economic Co-operation and Development (OECD) prepares guidelines for
chemical regulation and toxicity testing (internationally agreed).

,o The OECD Guidelines for Testing of Chemicals is a collection of 150 testing methods used to
identify and characterise potential hazards of chemicals.

, - OECD – acute & sub-acute testing
o Testing effect of single dose on particular animal species: does it die or survive -> change dose
accordingly -> identify LC50, ED50, EC50, etc.
o Duration is from several days to weeks after single dose.
o Endpoints in acute studies are mortality, clinical pathology, gross necropsy, weight change,
and signs of toxicity.
o Endpoint of sub-acute studies are mortality, weight change, signs of toxicity, clinical pathology,
pathology, and histopathology.
- OECD – chronic & sub-chronic testing
o Establish NOEL and characterise dose-response relationships following repeated doses to
identify/ determine affected organs.
o Prediction of reasonable and appropriate dosing for chronic exposure studies -> evaluation of
cumulative toxicity of chemicals and assessing carcinogenic potential.
o Duration is from 28 days, through 90 days (sub-chronic) up to 6/12/24 months (chronic).
o Endpoints are mortality, weight change, signs of toxicity, clinical pathology, pathology, and
histopathology.
- OECD – reproduction & development testing
o Reproductive studies determine potential adverse effects of test item on fertility and
reproductive performance / sexual function, as well as developmental toxicity in offspring.
o Development studies (teratology) relate to adverse toxic effects to developing embryo or
foetus, respectively adverse effects induced during pregnancy.
o Duration varies depending upon endpoint.
o Endpoints are according to OECD guidelines.
- Acute to chronic ratio (ACR) -> toxicity increases with increasing exposure time.
o Uses acute toxicity data to measure the chronic toxicity of a chemical.
 High ACR means that compounds bioaccumulate (not acute, so toxicity rises slowly
and there is a long exposure time).
 Low ACR means a strong direct lethal effect (very acute, so already a high toxicity with
short exposure time).
- Multigenerational toxicity -> populations that do not go extinct and persist, may have developed
resistance / adaptation to substance(s).
o Remains unclear whether this lower sensitivity is due to genetic adaptation, epigenetics, or
phenotypic plasticity.

Lecture 3: ADME
- Toxicokinetics -> how the body handles a chemical, as a function of dose and time.
o The rate of chemical absorption from the site of application into the bloodstream (ADME).
- Absorption (A) -> process of taking toxins into the system (site of entry).
o Different absorption routes:
 Oral intake -> absorption through passive (transcellular/paracellular) and active
(transcellular) carrier-mediated transport, or endocytosis (specialised).
 Ingestion -> substance first absorbed in intestines and then moved to blood and lymph
through portal vein. In small
intestine, water and digested
nutrients are absorbed in blood
and lymph vessels & in large
intestine, absorption of water
occurs by osmosis.
 Inhalation -> chemical exchange
with blood happens in alveoli &
different sizes of particles can
arrive in different part of the lungs.

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