Alle hoorcolleges van het vak Toxicology and Development uitgewerkt aan de hand van de leerdoelen. Ik heb het tentamen met een 8.7 gehaald met deze aantekeningen.
Lecture 1: Introduction in toxicology part 1
- Understand disciplines in toxicological sciences
o Multidisciplinary in this course analytical chemistry/toxicology/epidemiology
Biology/chemistry/biochemistry
Physiology
Mathematics/statistics
Medicine
Pharmacology
- Know terms commonly used in toxicology
o Compound
A chemical substance that is composed of a particular set of molecules or ions
o Toxicant/xenobiotic
A type of poison that is made by humans or introduced into the environment by
human activity
o Toxin
Poison produced naturally by an organism
o Contaminant/pollutant
Biological/chemical/physical/radiological substance (normally absent in the
environment), which can adversely affect living organisms
- Know the Paracelsus’ paradigm
o Everything is poisonous, nothing is not poisonous, only concentration determines what is
poisonous
Dose-response curve
- Understand how to make and apply a dose-response curve
o X-axis concentration
o Y-axis response dichotomous/quantal vs continuous
o Characteristics dose-response curves
Location ED50/potency
50% of the response
Potency how toxic it is
Maximum response effectiveness
What can the compound do? not all go to max
Steepness of the curve
o Use of dose-response curves
Forward predict effect size at certain dose
Backward determine compound characteristics (ED50/LOAEL/NOAEL)
o Many different dose-response models
Non-essential compounds (cadmium/pesticides)
Logarithmic dose-response curve sigmoidal & monophasic
From no effect to toxic
Essential compounds (sodium/copper/vitamins)
Homeostasis
o Too few deficiency
o Too much surplus/toxic
Single hit
Linear
No threshold
- Know ins and outs of toxicity testing, including terms as LC50, Benchmark dose etc
o LD50 lethal dose 50%
Concentration where 50% of the treated animals are dead
o ED50 effect dose 50%
Concentration where 50% of the treated animals are affected (malformed/dead)
o NOAEL no observed adverse effect level (dose)
Highest concentration with no effects compared to the control group
1
, o LOAEL lowest observed adverse effect level (dose)
Lowest concentration with effects compared to the control group
o Teratogenicity values
Teratogenic Index (TI) = LC50/EC50 (gap between the curves)
The higher the TI, the more specific teratogenic effect of the chemical can
be expected compared to overall embryotoxicity, as measured by mortality
of organisms
Relative Teratogenic Index = LC1/EC5
o Benchmark Dose
Dose/concentration that produces a predetermined change in the response rate of
an adverse effect benchmark response (BMR)
Normally, the default BMR is 5%/10% change in the response rate of an adverse
effect relative to the control group
Takes uncertainty of data points into consideration
- Be able to explain the different exposure concepts
o Exposure concepts
Environmental
Occupational
Therapeutic
Dietary
Accidental
Deliberate
Lecture 2: Introduction to toxicology part 2
- Distinguish between the four different steps in toxicokinetics
o Absorption
o Distribution
o Metabolism time-dependent
o Excretion
- Understand absorption after oral and inhalatory uptake
o After oral intake
Enterohepatic circulation
Uptake via intestines
Metabolism
Excretion via bile
Intestinal deconjugation
Reuptake
Presystemic elimination
Elimination before systemic distribution
Metabolism = biotransformation
2
, Liver protects body by metabolizing compounds before they enter the
blood circulation
o But liver can also activate compounds bioactivation
o After inhalation (gasses)
Through nose/mouth
Into the lungs smallest particles go the furthest into the lungs
o Dermal absorption via skin
Hair follicle
Sweat gland
Stratum corneum skin
Transcellular though cells
Intercellular around cells
- Understand (barriers in) distribution
o Accumulation (more than the average distribution)
Selective binding or uptake in specific tissues
Sometimes in target organ
Sometimes in depository organ
o Often not biologically available not toxic
o Can be mobilized
o Continuous equilibrium with blood concentration
Lipophilic compounds in fat tissue
Mobilized during fat mobilization
o Losing weight
o Breast feeding
Dangerous in case of little fat deposits (fetus)
Pb++, Sr++, F- in bones
Exchange with Ca++ o OH-
No ( Sr++ & F-) or yes (Pb++) effects on bones
Mobilized during Ca-mobilization
Cadmium in liver and kidneys
Efficient binding to metallothionein
Cd-MT complex itself is also nephrotoxic
o Barriers in distribution (less than average distribution)
Blood-ocular barrier physical barrier between the local blood vessels and most
parts of the eye
Blood-retinal barrier part of the blood-ocular barrier that prevents
certain substances from entering the retina
Blood-air barrier membrane separating alveolar air from blood in lung capillaries
Blood-testis barrier a physical barrier between the blood vessels and the
seminiferous tubules of the animal testes
Blood-thymus barrier a barrier formed by the continuous blood capillaries in the
thymic cortex
Blood-brain barrier semipermeable capillary border that allows selective passage
of blood constituents into the brain
Defense by
o Tight junctions
o Multidrug resistance pump
o Astrocytes (glia cells)
Exceptions eg methylmercury (MeHg+)
Placenta
Not a real barrier
Many lipophilic compounds can diffuse through placenta
Protection is based on
o Active transport mdr & oct proteins
o Biotransformation
- Distinguish the three different phases in biotransformation
3
, o Biotransformation
Any structural change in a molecule may change its activity, caused by enzymatic
conversions
Can occur at any site where appropriate enzymes are (plasma/kidney/lung/gut
wall/liver)
Goal to detoxify chemical and eliminate it
Chemical can be converted to
Less toxic/effective metabolite
More toxic/effective metabolite
o Three phases depends on characteristics of compound
1. Oxidation/reduction to create a “handle” to the compound
-OH/=O/-COOH
Exposing or adding a polar group
Oxidation removal of electrons (eg by oxygenation/dehydrogenation)
Reduction adding of electrons (eg dehalogenation)
Hydrolysis splitting molecule in two via water
Acetylation
2. Conjugation, by attaching a water-soluble molecule to the handle created in phase I
Adding a “big” water soluble molecule
Glutathione coupling (GSTs)
Glucuronic acid coupling (UDPGTs/UGTs)
Methylation (COMT/NMT)
Sulfation (SULT)
Amino acid conjugation
Toxic intermediates can also be formed (bioactivation)
3. Elimination/excretion removal of the conjugated product from the body
Routes
Most important routes
o Urine
o Feces
Alternative routes
o Exhalation
o Sweat
o Hairs
o Lactation
Excretion by active transport
Carrier proteins needed
- Understand enzyme induction important for metabolization
o Enzymes are molecules that catalyze the conversion from one molecule (substrate) into
another one (product), without getting changed themselves
o Only work for specific compounds
o Eg. CYPs/formaldehyde dehydrogenase/alcohol dehydrogenase (phase I)
o Eg. Transferases (phase II)
o Enzyme induction capacity to increase activity and/or synthesis of an enzyme after
exposure to its substrate
Consequences
Increased metabolization (after next exposure)
Habituation (drugs/alcohol)
Many xenobiotics induce their own biotransformation
Lecture 3: Introduction to toxicology part 3
- Know toxic effects and how to classify them
o Classification
Rate
Immediate effect eg inhibition of cellular respiration
Delayed effect eg carcinogenesis
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