1. Passage of Toxic Agent from Out-side to the Inside of a Cell:

To cause toxicity a toxic agent has to be absorbed into the biological system and translocated to the site of action in active state. An elaborate membrane system exists within the body of a living organism. A toxic agent has to pass through these membraneous barriers to reach its site of action.

If the toxic agent is taken in via respiratory track or gastrointestinal track, it has to pass through the outermost mucosal lining into the extra-cellular interstitial fluid followed by its entry into the blood circulation through walls of the capillaries. Materials which cannot enter blood circulation may be transported by the system of lymphatic vessels which ultimately drain their contents into the blood stream. Once the toxic agent is in the blood stream it is distributed to various parts of the body along with blood circulation.

Larger vessels act as a conduit for transport of chemical agents from one parts of the body to another while it is only through the capillaries that actual passage of materials from the blood stream to extra-cellular fluid occurs. Walls of capillaries consist of a single layer of flat epithelial cells which are held together by an intercellular cementing material. It is through this intercellular cementing material that passive transfer of water and solutes probably occur.

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This passive transfer or filtration is a function of differences in osmotic pressure and hydrostatic pressures on the two sides of the capillary walls. At the site or action or deposition, the toxic agent has to pass out through the walls of capillaries to extracellular interstitial fluid. It is finally from this fluid that the toxic agent enters the cells through the cell membrane.

2. Membrane Barriers:

Plasma-membrane is an efficient and selective barrier for most of the toxic agents. Inside the body of a living being a toxic agent has to cross this membranous barrier to enter intracellular compartments of the biological system. However, other more specialised membranous barriers occur within the body of higher organism.

A very efficient barrier, known as blood-brain barrier exists between the blood and the brain many toxic agents fail to reach this vital organ. However, this barrier is not absolute. It represents, as a matter of fact a location which is less permeable to toxicants. Reduced permeability of capillaries, very small extra-cellular spaces, presence of a layer of glial cells closely surrounding the capillaries and myelin sheath etc. are the probable factors which contribute to the lot permeability of the blood-brain barrier. This barrier is highly selective for non-polar, lipid soluble substances which enter the brain rapidly. Highly polar water soluble substances cross this barrier with difficulty.

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Another specialised barrier exists in pregnant females between the foetal blood and mother’s blood circulation. This barrier is known as placental barrier. The maternal blood is in contact with foetal blood across the trophoblastic layer, mesenchymal tissues and capillary endothelium. Placenta behaves as a selective barrier and the transfer mechanisms which operate there are passive diffusion, active transport (amino-acid and glucose) and pinocytosis (foetal red cells and maternal immunoglobulins). This barrier is also more permeable to the lipid soluble substances whereas highly polar water soluble substances pass through it with difficulty.

3. Passage of Toxic Agents through Cell Membrane:

There are four possible ways by which various foreign substances pass across the cell membrane or the plasmalemma.

(a) Filteration through spaces or pores in the membrane.

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(b) Passive diffusion by dissolution in the lipoid material of the membrane.

(c) Specialised transport system employing lipid soluble carrier molecules which effectively from complexes with water soluble chemical agents to be transported.

(d) Other specialised modes of transfer such as pinocytosis, phagocytosis etc.

The cell membrane which separates cell contents from the outside environment is made up of thin layer of lipids or lipid like material covered on both sides by a layer of proteins. This membrane contains a number of pores and perforations. In mammals this membrane is approximately 100 A in thicknesses while the small pores in it vary from 2-4 A in diameter.

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Transfer of water soluble toxic agents from extracellular interstitial fluid must either involve process of diffusion along a concentration gradient or employ a transport mechanism which would affect the transfer of chemicals through the lipoid membrane. Organic solutes of low molecular weight such as urea, creatin, organic acids etc. are carried across the membrane by the process of diffusion.

The transfer of water probably takes place through the small water filled pores in the membrane and so also is the case of many molecules which are small enough to pass through the pores in the membrane. Ions like sodium art potassium are selectively taken up by active transport mechanism which involves expenditure of energy to maintain an electrochemical gradient on the two sides of the membrane.

Lipoid insoluble substances which are soluble in water may be carried across the cell membrane by active transport system involving carrier-mechanism. Foreign chemicals which are insoluble in lipid as well as in water pass through the cell membrane with difficulty. Biological membranes are capable of engulfing particulate material by the process known as pinocytosis or phagocytosis in which temporary discontinuity appears in the cell membrane through which particles are engulfed and drawn in.

The process although common in lower animals and some plants is of little consequences in mammals. However, it has been reported to occur in mucosal lining of lungs of higher animals where it is of great utility in clearing particulate matter from the alveoli of lungs.