Toxicokinetics & Toxicodynamics Toxicokinetics (Determines the no. molecules that can reach the receptors) • Uptake • Transport • Metabolism & transformation • Sequestration • Excretion Toxicodynamics (Determines the no. of receptors that can interact with toxicants) • Binding • Interaction • Induction of toxic effects
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Toxicokinetics & Toxicodynamics Toxicokinetics (Determines the no. molecules that can
reach the receptors)• Uptake• Transport• Metabolism & transformation• Sequestration• Excretion
Toxicodynamics (Determines the no. of receptors that can interact with toxicants)
• Binding • Interaction • Induction of toxic effects
Uptake and Elimination
BiologicalSystem
Uptake EliminationK1 K2
K1 > K2 : Accumulation & Toxic effect
Toxicokinetics
1. Uptake
2. Transport
3. Metabolism & Transformation
4. Sequestration
5. Excretion
Uptake routes
1. Ingestion (toxicity may be modified by enzymes, pH and microbes)
2. Respiration (Air borne toxicants)
3. Body surface (Lipid soluble toxicants such as carbon terta chloride and organophosphate)
Uptake Barriers
1. Cell membrane
2. Cell wall/cuticles/stomata
3. Epithelial cells of GI tract
4. Respiratory surface (lung, gill tracheae)
5. Body surface
Uptake of Toxicants
1. Passive diffusion
2. Facilitated transport
3. Active transport
4. Pinocytosis
Uptake by Passive diffusion
Uncharged molecules may diffuse along conc. gradient until equilibrium is reached
Not substrate specific Small molecules of < 0.4 nm (e.g. CO,
N20, HCN) can move through cell pores
Lipophilic chemicals may diffuse through the lipid bilayer
Uptake by Passive diffusion
First order rate process, depends on:– Concentration gradient– Surface area (aveoli = 25 x body surface) – Thickness (fluid mosaic phospholipid bi-layer
ca. 7 nm)– Lipid solubility & ionization(dissolved before
transport, polar chemicals have limited diffusion rate)
– Molecular size (membrane pore size = 4-40 A, allowing MW of 100-70,000 to pass through)
Diffusion governed by Flicks law
D/dt = KA (Co - Ci) / X Where:
– dD/dt = rate of transport accross the membrane – K= constant– A= Cross sectional area of membrane exposed to the
compound– Co = Concentration of the toxicant outside the
membrane– Ci = Concentration of the toxicant inside the membrane– X= Thickness of the membrane
Uptake by Facilitated Transport
Carried by trans-membrane carrier along concentration gradient
Energy independent May enhance transport up to 50,000 folds Example: Calmodulin for facilitated
transport of Ca
Uptake by Active Transport
Independent of or against conc. gradient Require energy Substrate –specific Rate limited by no. of carriers Example: