Module 3: Toxicology - Section 2: General Principles of Toxicology
TOX2.3: Toxicokinetics

TOXICOKINETICS:

The concentration of a toxin and its effects depend on the following:

  1. Fraction and rate of absorption of the chemical
  2. Distribution in the body compartments
  3. Rate of biotransformation (and toxicity of metabolites)
  4. Rate of excretion

Mechanisms of Transfer Across Tissues:

  1. Passive Diffusion especially of lipophillic or hydrophobic substances. In passive diffusion, rate is determined by the lipid solubility, molecular size, degree of ionization and concentration gradient of a substance and there is no energy expense.
  2. Facilitated transport also follows a concentration gradient and occurs without energy expenditure but requires a carrier protein.
  3. Active transport is a selective transport mechanism requiring a carrier molecule with motion against an electrochemical or concentration gradient with energy expenditure in the form of ATP usage. Active transport is a saturatable system with a transport maximum defined in part by saturation of the carrier protein.
  4. Endocytosis, Phagocytosis and Pinocytosis are energy dependent processes which may or may not involve a rector for specific substance. In this process the membranes of cells invaginate a foreign substance forming vesicles which surround, engulf and introduce the substance into the inside of the cell.

Kidney, Liver and CNS:

Each have specialized active transport mechanism for nutrient supply and for excretion of organic acids and bases.

The passage of chemicals through the body is a dynamic process and is can be described using compartmental models.

One Compartment Model:

The chemical is distributed through out the body and the concentration in plasma represents the concentration in the compartment.

Two Compartment Model:

The central compartment represents the vascular space and the rapidly perfused tissues while the peripheral compartment represents the rest of the body.

We denote Kab as the constant rate of absorption of the chemical, and,
Kel as the constant rate of elimination from the central compartment.

The volume in which a chemical is dispersed depends on its solubility in water and if it binds to plasma proteins or intracellular sites.

The volume of distribution (Vd) relates the amount of chemical in the body to the concentration of chemical in the blood. Chemicals bound to plasma proteins are in the plasma and thus the Vd is small.

The body burden of a chemical = plasma concentration of a chemical x Vd

The clearance, (Clt) is a measure of the overall efficiency of the removal of a chemical from the body.

Clt = Vd x Kel

If chemical elimination occurs by a first order process in which the chemical removed per unit time remains constant it will occur exponentially. The plasma half life is inversely proportional to the Kel.

T½ = 0.693/Kel

If elimination is through a saturable process then the rate of elimination follows zero-order kinetics (a constant rate is eliminated).

With repeated exposure, assuming first order elimination, the amount of chemical eliminated will equal the amount absorbed. As a result, a steady state will be reached, and is reflected by the formula:



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Postgraduate Diploma in Occupational Health (DOH) - Modules 3: Occupational Medicine & Toxicology (Basic) by Profs Mohamed Jeebhay and Rodney Ehrlich, Health Sciences UCT is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 2.5 South Africa License. Major contributors: Mohamed Jeebhay, Rodney Ehrlich, Jonny Myers, Leslie London, Sophie Kisting, Rajen Naidoo, Saloshni Naidoo. Source available from here. For any updates to the material, or more permissions beyond the scope of this license, please email healthoer@uct.ac.za or visit www.healthedu.uct.ac.za. Last updated Jan 2007.
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