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- Wageningen University (WUR)
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[Meer zien]Voorbeeld 4 van de 46 pagina's
Voorbeeld 4 van de 46 pagina's
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VolgenVoorbeeld van de inhoud
C1 – Introduction, history and principlesToxicology = study of the adverse (toxic) effects of exogenous chemicals on living organisms
Bv. DDT = dichlorodiphenyltrichloroethane and other organohalides → birds: fragile egg
shells, reproduction problems
Risk assessment → the systematic scientific characterisation of potential adverse health
effects resulting from human exposures to hazardous
agents or situations (bv. the consequences of exposure
to pesticide residues in food)
Hazard → potential danger of a compound or process;
LET OP! Is not necessarily also a risk, because a risk is
the probability that the adverse effect will occur.
Risk → the probability of an adverse outcome
Risk assessment consist of 2 steps:
- Hazard characterisation → qualitative (measure) and quantitative (describing)
characterisation of the effects
- Exposure assessment → define the route and site of exposure and also the duration
and frequency of exposure
Risk management → select type of actions to be taken (based on risk assessment and social,
economic and political aspects)
Exposure of animals to chemicals in four categories:
• Acute exposure = exposure to a chemical for less than 24 hours
• Subacute exposure = repeated exposure to a chemical for 1 month or less
• Subchronic exposure = exposure for 1 to 3 months
• Chronic exposure = exposure for more than 3 months up to 80-90% of the life span
Estimated daily intake (EDI) = concentration x consumption
Duration and frequency → Haber’s rule:
Cxt=k
- C = concentration or dose
- T = time of exposure needed to produce a given toxic effect
- K = a constant (depending on chemical and effect)
ADI = acceptable daily intake (for avoidable contaminants additives, pesticides)
TDI = tolerable daily intake (for unavoidable contaminants dioxins, mycotoxins, heavy
metals)
1
,C2 – Mechanisms
Different types of interactions and molecular mechanisms of action:
1) Non covalent binding
Covalent binding due to interactions like the formation of hydrogen and ionic
bonds
Could be reversible.
Interacting with structural similarity with natural ligand
- Agonist → stimulates signal-transduction
- Antagonist → blocks signal-transduction (CO binds 220 times stronger to
heme Fe2+ of haemoglobin than O2)
Interacting with no structural similarity with natural ligand → large group of
chemicals interacting with the ion channels for K+, Na+ or Ca2+ cations.
- Blocker → reduced permeability activity (Puffer fish produces tetrodotoxin;
blocks Na+ channels)
- Modulator → increased permeability activity
2) Covalent binding
Electrophilic toxicants react with nucleophilic atoms that are
abundant in biological macromolecules (bv. proteins)
Bv. Enzyme acetylcholinesterase (AChE) irreversible
inhibition by variety of chemicals
- AChE hydrolysis: acetylcholine → choline + acetate
- Prevents overstimulation of postsynaptic receptors
- 2 binding sites: esterase site & anionic site
3) Hydrogen abstraction
Neutral free radicals can readily abstract H atoms from endogenous compounds,
converting those compounds into radicals → in this way macromolecules can be
damaged, including unsaturated fatty acids membrane lipids in the process of lipid
peroxidation
Example: hydroxyl radicals .OH
Damage to proteins (inactivation), DNA (mutation) and lipids
(lipid peroxidation: disturbs membrane structure!)
4) Electron transfer
The toxic action of some chemicals can be based on their oxidising potential
Methemoglobinemia iron in haemoglobin → unable to carry oxygen caused by
nitrate (LET OP! No oxygen binding)
2
,There are 2 kinds of repair:
✓ Molecular repair
▪ Reverse (methylation of DNA)
▪ Replace (peroxidized lipids)
✓ Cellular repair
▪ Apoptosis = programmed cell death → when the cell is exposed to so much toxic
elements that it cannot survive
▪ Necrosis = happens to cells that are so damaged that they are out of control.
There is loss of membrane, which causes the immune system to react. It does not
require any energy
Apoptosis Necrosis
Membrane intact Loss membrane integrity
Shrinking cytoplasm Swelling cytoplasm
Cell fragmentation Cell lysis
ATP dependent No energy requirement
No inflammatory response Inflammatory response
Physiological stimuli Non physiological stimuli
Proliferation → damage is reversed by deletion of the injured cells and regeneration of the
tissue
LET OP! Failure of repair when uncontrolled proliferation: carcinogenicity & fibrosis
(accumulation of collagen).
APOPTOSIS
NECROSIS
3
, Qualitative aspects of toxicity
Primary lesion = primary molecular damage
Local toxicity = refers to those that occur at the site of first contact between the biological
system and the toxicant, and are produced by the ingestion of caustic substances or the
inhalation of irritant chemicals
Systemic toxicity = requires absorption and distribution of a toxicant from its entry point to
a distant site where deleterious effects are produced
Dose response relations → establishes causality
that the chemical has in fact induced the observed
effects; determines the rate at which injury builds
up
❖ Can be illustrated through a dose response
curve
o X-axis → dose / concentration
o Y-axis → degree of effectiveness
❖ GOAL: derive a concentration that does not
cause and adverse effect
C3 – Absorption, distribution and excretion
The degree of interaction between a toxic substance and receptors depends on a number of
factors, which can be subdivided into three phases:
1) Exposure phase
- External exposure = amount or concentration of a substance present in the
organism’s environment
- External load = amount of substance available for uptake by the organism
2) Kinetic phase (toxicokinetics) → ADME
- Absorption → Distribution → Metabolism → Excretion
3) Dynamic phase (toxicodynamics) → phase in which interaction occurs between a
toxic substance and the corresponding receptors
4
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