In this article we will discuss about:- 1. Definition of Selective Toxicity 2. Need of Selective Toxicity 3. Convincing Demonstration of Selective Toxicity in Man 4. Scientific Basis of Selective Toxicity 5. Advantages of Selective Toxicity.
Definition of Selective Toxicity:
Albert (1965) coined the term selective toxicity. Selective toxicity means that a chemical produces injury to one kind of living matter without harming another form of life even though the two may exist in intimate contact. The living matter that is injured is termed the uneconomic form (or undesirable), and the matter protected is called the economic form (or desirable). They may be related to each other as parasite and host or may be two tissues in one organism.
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In agriculture, for example, there are fungi, insects, and even competitive plant life that injure the crop, and thus selective pesticides are needed. Similarly, animal husbandry and human medicine require agent such as antibiotics, that are selectively toxic to the undesirable form but do not produce damage to the desirable form.
From the above discussion, it becomes evident that selective toxicity is the injury of one species of living matter without harming another species with which the first is in intimate contact. The species which is to be eliminated is the uneconomic species and the species which is to be preserved is the economic species. Often these are related to one another as parasite and host, but in other cases they are symbiotic.
Need of Selective Toxicity:
The need of selective toxicity is multi-disciplinary in life sciences. In agriculture, the need for selective toxicity arose in ancient period. Man learnt to grow crops of plants in order to obtain food and clothing.
The seeds of these plants themselves became infected with all sorts of fungi, weeds and insect pests which threatened actually the economic success of the crops. Obviously, it is an achievement of the prime importance to have those selectively toxic agents which are applied in agriculture to remove many of the uneconomic species without deleterious effect or injury to the economic ones.
In animal husbandry a similar situation is clearly recognizable. Man’s domestic as well as economic animals are afflicted by both ectoparasites as well as endoparasites. Application of potent selective toxic agent to get rid of the parasites clearly gives an explanation of selective toxicity needed for these animals.
Man himself is no less subject to various parasites than his domestic and economical animals. Chemotherapy is the name assigned to that branch of selective toxicity which is concerned with the removal of parasites from man and his tended animals. So far more has been investigated of the scientific principles underlying the practice of chemotherapy than of any other branch of selective toxicity.
Convincing Demonstration of Selective Toxicity in Man:
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General anesthetics admirably illustrate the selective use of toxicity. The more toxic the anesthetic, the more valuable it is but only if the toxicity is selective for the central nervous system and completely reversible with time.
Morton’s success with ether as a general anesthetics in 1846 was an early and convincing demonstration of selective toxicity. The accepted general anesthetics combine a high toxicity for the central nervous system with negligible toxicity to other tissues, all toxicity rapidly and completely disappears when administration is halted.
The same mechanism is followed with local anaesthetics, muscle relaxants, and (but less rapidly the antagonists of histamine and neurotransmitters). Antiparasitic agents, on the other hand, although they must be selective against the parasite and sparing to the host, are preferably irreversible.
Scientific Basis of Selective Toxicity:
There are three main principles by which an agent can exert a favourable selective effect. Either it can be equitoxic to all species, but accumulated principally by uneconomic species, or it may react with a cyto- or biochemical feature which plays a more important part in the uneconomic than in the economic species.
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The scientific basis of selective toxicity:
1. Selectivity through accumulation
2. Selectivity through comparative biochemistry
3. Selectivity through comparative cytology.
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1. Selectivity through Accumulation:
Selectivity through accumulation is sometimes only a matter of gross morphology. Thus the comparatively large surface area (per unit weight) of an insect resting on a mammal, brings about a greater retention of sprayed material by the uneconomic species. In other cases, selective accumulation is achieved in a more positive way, for example, orally administered phenothiazine is much toxic to the intestinal worms in a sheep than to the sheep itself.
Accumulation implies some or all of the following:
(a) Efficient transport to the outside of the cell,
(b) A favourable permeability mechanism, and
(c) A satisfactory storage mechanism.
2. Selectivity through Comparative:
It is thought that all living matter — whether plant, or animal or microbes — had a common biochemistry, which, if universal, would offer no biochemical basis for selective toxicity. This thought is not true. It is a well-known fact that one species functions differently from another, which clearly indicates that there is actually marked biochemical difference. Strong species-differences are shown by homologous proteins, that is, those serving similar functions in related species.
Thus, the N-terminal amino acids in the fibrinogen of seven mammals was found to be:
i. Man – Alanine and tyrosine
ii. Pig – Alanine (twice) and tyrosine
iii. Ox – Glutamic acid and tyrosine
iv. Dog and Horse – Threonine and tyrosine
v. Sheep and Goat – Glycine, alanine, and tyrosine
The most striking-biochemical difference between species are present not in degradative processes, but in the choice and biosynthesis of enzymes and smaller substances used in growth and division.
3. Selectivity through Comparative Cytology:
It is an established fact that plants and animals have outstanding cytological differences. For example, the cell wall and chloroplast are found in plants, but not in animals, likewise muscle cells and nerve cells are found only in animals but not in plants.
In the last two decades, with the help of the electron microscope, it has been proved that the cell itself is full of organelles-and that each kind of these components display strong species difference; and so much so that there are differences between cells from different tissues in the same species. It may, therefore, be conjectured that these differences certainly may assist selectivity in toxic agents.
Advantages of Selective Toxicity:
It is a great achievement of human beings that they have found selectively toxic agents for ills and also for use in animal husbandry, fields and forests. The continuance and even expansion of these advantages require uninterrupted investigations to improve upon the already known selectively toxic agents. One can feel it most unfortunate that the search for biological controls proves very expensive and has not often yielded practical results. Selective toxicity, on the other hand, may solve a high proportion of the problems of disease in plants, domestic animals and human beings.
At present the most successful examples of biological control are those effected with selectively toxic agents. Thus trypanosomiasis, a protozoan disease of man and cattle, is controlled by chemical defoliation of those areas of African forests where tse-tse flies breed and then spraying organophosphorus insecticides on the exposed breeding sites. In this way, by attacking the insect vectors, which transfer trypanosomes to their mammalian hosts with every bite, the biological life cycle of these parasites is broken.
For the same reason, houses in malarial areas and swampy grounds, which harbour anopheles mosquitoes, are regularly sprayed with insecticides to kill these insect vectors of plasmodium. The plasmodium is a protozoan which is transmitted to humans by the mosquitoe’s bite, and produces malaria.
Another useful example of the use of selectively toxic agents is molluscides to kill snails that are the intermediate host to the worm that causes bilharziasis in man.
Besides aforementioned advantages of selective toxicity few more practical advantages are:
1. Use of selectively toxic agents in controlling weeds.
2. Use of selectively toxic agents in controlling insect pests.
3. Use of selectively toxic agents in seed protection.
4. Use of selectively toxic agents in veterinary practice.
5. Use of selectively toxic agents in cure of diseases of economical animals.
6. Use of selectively toxic agents in controlling infectious diseases of human.
1. Use of Selectively Toxic Agents in Controlling Weeds:
Bonnet for the first time showed, in France, that yellow charlock could be killed in a field of oats, without injury to the crop, by spraying a solution of copper sulphate over the entire field. Further, in 1911, another Frenchman, Rabate, showed that solution of H2SO4 could be safely used on crops to destroy the weeds. Nowadays, the most versatile of the weed-killers are dinitro-o-cresol and 2,4-D.
The introduction of organic weed killers has brought about tremendous economic gain. They are non-toxic to man and animals, and non- corrosive to equipment. They have resulted in an overall increase of 20% in grain crops. These substances have been successfully used on crops of flax and grasses, and also in removing weeds from lawns.
Somewhat akin to weed killing is defoliation (leaf-removal). In East Africa, trees are defoliated with the n-butyl ester of 2, 4, 5 – trichloro- phonxyacetic acid, which is sprayed in the air. The purpose is to eliminate tse-tse flies which carry trypanosomes.
2. Use of Selectively Toxic Agents in Controlling Insect Pests:
Although the chemical removal of weeds from crops is of fairly recent origin, the removal of insect pests is being practiced since long. Previously inorganic substances like lead arsenate were principally applied and later such vegetable products as tobacco dust and powdered pyrethrum were introduced. A striking advance was made by using DDT which was highly toxic for insects. Since it proved to be toxic to human its use has now been abandoned and also cannot be included under selective toxicity.
Further, certain organo-phosphorus insecticides viz. tetraethyl phosphate (TEP), parathion, and thiophos, when sprayed on crops, showed non-toxicity by virtue of the lack of cholinesterase.
However, these phosphorus insecticidal compounds are more deleterious than DDT, because they do not discriminate between different forms of animal life. For example, parathion, which is an important organophosphate insecticide, kills not only spiders and mites, but also the birds, which keep these pests in check. Additionally, its toxicity to man has caused fatalities among farm workers who had not adopted requisite protective measures.
Keeping in view the principle of selective toxicity, organo-phosphorus insecticides require certain modifications:
(a) So that the chemical changes needed for activation can be accomplished by pests but not by birds, mammals, or else.
(b) So that total hydrolysis occurs slowly in pests but rapidly in birds and mammals. A promising substance of this kind is tetram. Actually it is systemic (i.e., rises with the plants sap) and protects the plant from infection by red spiders, mites etc. Apparently birds are not affected. Thus it can be regarded as an important selectively toxic agent.
3. Use of Selectively Toxic Agents in Seed Protection:
There is another section of agriculture in which selectively toxic agents have been put to work. Seed — particularly grain seeds — are commonly dusted with phenol mercuric nitrate during storage to prevent infection by fungi. This treatment does not affect germination of the seeds. The phenol group increases the lipophilic properties of the mercury, and, hence, aids penetration into the fungus.
4. Use of Selectively Toxic Agents in Veterinary Practices:
There have been many economically valuable uses of selectively toxic agents in veterinary practices in spite of the fact that the remedies devised for human illness cannot always be used in veterinary because of their high cost.
Bovine mastitis, which greatly reduces the yield of milk, is now cured with sulphanilamide.
5. Use of Selectively Toxic Agents in Cure of Diseases of Economical Animals:
Worm infections in sheep, which lead to severe economic loss of wool and meat, are controlled with CCl4 (carbon tetrachloride) and phenothiazine. The cheap and simple remedy piperazine is much used as selectively toxic agent in pigs, horses, dogs, cats and poultry.
6. Use of Selectively Toxic Agents in Controlling Infectious Diseases of Human:
Fungal diseases of man, even when superficial, are being treated more successfully by certain antifungal compounds as selectively toxic agent than before by internal medication. There is, however, still great scope for improved remedies.
Also selectively toxic drugs viz., suramin (Bayer 205) or pentamidine for treatment of schistosomiasis are now available although better prophylactic drugs are needed.
Amebic dysentery is treated successfully with few selectively toxic drugs like emetine and synthetic drugs such as camoquine. Sulphonamides are used to control tropical bacillary dysentery.
Virus diseases like poliomyelitis, small pox, yellow fever, rabies and influenza have been controlled through chemotherapy. Vaccines exist to prevent these five viral diseases, but actually there is no perfect curative treatment.
Conclusion:
Selective toxicity of any drug/chemical means the injury of one kind of living matter without harming another kind with which the first is in intimate contact. The living matter which is injured is conveniently referred to as the uneconomic species, and the unaffected is the economic species.
It is an achievement of prime importance for man that selectively toxic agents have been found not only for many of his ills, but also for use in his animal husbandry, fields and forests.
Drugs and other chemical agents used for selective toxic purposes are selective mainly for one of two reasons. Either (1) the chemical is equitoxic to both economic and uneconomic cells but is accumulated mainly by uneconomic cells, or (2) it reacts fairly specifically with a cytological or a biochemical feature that is absent from or does not play an important role in the economic form.
Selectivity resulting from differences in distribution usually is caused by differences in the absorption, biotransformation, or excretion of the toxicant. The selective toxicity of an insecticide spray- may be partly due to a larger surface area per unit weight that causes the insect to absorb a proportionally larger dose than does the mammal being sprayed. The effectiveness of radioactive iodine in the treatment of hyperthyroidism (as well as its thyroid carcinogenicity) is due to the selective ability of the thyroid gland to accumulate iodine.
A major reason why chemicals are toxic to one but not to another type of tissue is that there are differences in accumulation of the ultimate toxic compound in various tissues. This, in turn, may be due to differences in the ability of various tissues to biotransform the chemical into the ultimate toxic product.
Selective toxicity caused by differences in comparative cytology is exemplified by a comparison of plant and animal cells. Plants differ from animals in many ways; for example, absence of a nervous system, an efficient circulatory system, and muscles and the presence of a photosynthetic mechanism and cell walls.
The fact that bacteria contain cell walls and humans do not has been utilised in developing selective toxic chemotherapeutic agents — such as penicillin and cephalosporins — that kill bacteria but are relatively non-toxic to mammalian cells.
Selective toxicity also can be a result of a difference in biochemistry in the two types of cells.