College aantekeningen Toxicology And Development (AB_1026)

Lectures Toxicology and Development

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

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, 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


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,  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

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, 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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