**4. Vector control as a key strategical approach for malaria eradication**

The historical successful elimination of malaria in various parts of the world has been ach‐ ieved mainly by vector control (Harrison, 1978). Since early nineteenth century (Breman, 2001), vector control has remained the most generally effective measure to prevent malaria transmission and therefore is one of the four basic technical elements of the Global Malaria Control Strategy. The principal objective of vector control is the reduction of malaria mor‐ bidity and mortality by reducing the levels of transmission. Vector control methods vary considerably in their applicability, cost and sustainability of their results.

#### **4.1. Classification of insecticides used for vector control**

rapidly after gametogenesis. The fertilization event produces a zygote that remains inactive for some time and then elongates into a worm-like ookinete. The ookinete is one of the most important stages of *Plasmodium* development in the mosquito. It is morphologically and bio‐ chemically distinct from the earlier sexual stages (gametocytes and zygote), and from the later stages (oocyst and sporozoites). Development to ookinete allows the parasite to escape from the tightly packed blood bolus, to cross the sturdy peritrophic matrix, to be protected from the digestive environment of the midgut lumen, and to invade the gut epithelium. The success of each of these activities may depend on the degree of the biochemical and physical barriers in the mosquito (such as density of blood bolus, thickness of peritrophic matrix, proteolytic activities in the gut lumen etc.) and the ability of the ookinete to overcome these barriers. Ookinete motility, resistance to the digestive enzymes, and recognition/invasion of the midgut epithelium may play crucial roles in the transformation to oocyst. At the end of the process oocysts produce sporozoites, which can navigate successfully to the salivary glands, where they will be ready for further infection of human beings, and continuation of

The transmission of the parasite to humans starts when the mosquito injects a small amount of saliva containing 5-200 sporozoites (resident in the salivary gland of the vector) into the skin of the human vector (Menard, 2005). Once in the bloodstream, sporozoites reach the liv‐ er and infect the hepatocytes (Trieu et al., 2006). In the liver district, sporozoites grow and change into a new structure of parasite called schizont, a large round cell. The schizont di‐ vides through an asexual reproduction (schizogony) resulting in the formation of a thou‐ sand small cells called merozoites. After a developmental period in liver, during which patients do not show any clinical symptoms of disease, merozoites are released from liver schizonts into the blood, entering host erythrocytes and starting the intraerythrocytic stage

This occurs inside a parasitophorous vacuole, the membrane of which separates the cytosol of the erythrocyte from the plasma membrane of the parasite. In the erythrocyte young 'ring' forms of the parasite grow to become trophozoites. lntraerythrocytic development is completed by the formation of new plasma membranes after multiple nuclear divisions (schizogony). Infectious merozoites are then released from the erythrocyte and a new cycle restart (Cowman & Crabb, 2006). One erythrocytic cycle is completed in 48 hours. The toxins are liberated into the blood along with merozoites. The toxins are then deposits in the liver, spleen and under the skin. The accumulated toxins cause malaria fever that lasts for 6 to 10 hours and then it comes again after every 48 hours with the liberation of new generated merozoites. During the erythrocytic stage, some merozoites increase in size to form two types of gametocytes, the macrogametocytes (female) and microgametocytes (male). This process is called gametocytogenesis. The specific causes underlying this sexual differentia‐ tion are largely unknown. These gametocytes take roughly 8–10 days to reach full maturity. The gametocytes develop only in the appropriate species of mosquito. If this does not hap‐

their life cycle (Beier, 1998).

**3.2.** *Plasmodium* **life cycle in humans**

334 Insecticides - Development of Safer and More Effective Technologies

of parasite development (Banting et al., 1995).

pen, they degenerate and die (Rogier & Hommel, 2011).

The most prominent classes of insecticides act by poisoning the nervous system of insects, which is very similar to that of mammals. They are often subclassified by chemical type as organochlorines (OCs), organophosphates (OPs), carbamates (Cs) and pyrethroids (PYs) (Prato et al., 2012).

OCs belong to a larger class of compounds called chlorinated hydrocarbons, containing chlorine and including DDT. They have various chemical structures, and are cheap and effective against target species. OCs can alter and disrupt the movement of ions (calcium, chloride, sodium and potassium) into and out of nerve cells, but they may also affect the nervous system in other ways depending on their structure. OCs are very stable, slow to degrade in the environment and soluble in fats: unfortunately, due to persistence and fat solubility, OCs can bioaccumulate in the fat of large animals and humans by passing up the food chain.

OPs were developed in the 1940s as highly toxic biological warfare agents (nerve gases). On the other hand, Cs feature the carbamate ester functional group. OPs and Cs are very different at a chemical level; however, they have a similar mechanism of action. OPs and Cs block a specific enzyme, the acetylcholinesterase, which is able to remove an impor‐ tant neurotransmitter, the acetylcholine, from the area around the nerve cells stopping their communication. Hence, these insecticides are called acetylcholinesterase inhibitors. Structural differences between the various OPs and Cs affect the efficiency and degree of acetylcholinesterase blockage, highly efficient and permanent for nerve gases, temporary for commonly used pesticides. Many different OPs have been developed in order to re‐ place DDT and find compounds that would be less toxic to mammals. Unfortunately, OP Parathion acute toxicity is greater than DDT, and this characteristic causes a significant number of human deaths.

Finally, synthetic PYs, developed in the 1980s, represent one of the newer classes of insecti‐ cides. Although their chemical structure is quite different from that of other insecticides, the target of action is also the nervous system. PYs affect the movement of sodium ions (Na+ ) into and out of nerve cells that become hypersensitive to neurotransmitters.

#### **4.2. Indoor Residual Spraying (IRS) and Insecticide-Treated Nets (ITNs)**

Indoor residual spraying (IRS) with insecticides continues to be the mainstay for malaria control and represents the process of spraying stable formulations of insecticides on the in‐ side walls of certain types of dwellings, those with walls made from porous materials such as mud or wood but not plaster as in city dwellings. Mosquitoes are killed or repelled by the spray, preventing the transmission of the disease. The main purpose of IRS is to reduce ma‐ laria transmission by reducing the survival of malaria vectors, life span of female mosqui‐ toes, thereby reducing density of mosquitoes (WHO, 2006b). Several pesticides have historically been used for IRS, the first and most well-known being DDT.

**5. Dichlorodiphenyltrichloroethane (DDT)**

al arthropods.

**Figure 2.** DDT

(PAN, 2012).

**5.1. Production and use**

DDT is an OC insecticide; it is white, crystalline solid, tasteless, and almost odorless (PAN, 2012). It is a highly hydrophobic molecule, nearly insoluble in water but with good solubili‐ ty in most organic solvents, such as fats and oils. DDT is not present naturally, but is pro‐ duced by the reaction of chloral (CCl3CHO) with chlorobenzene (C6H5Cl) in the presence of sulfuric acid, which acts as a catalyst. DDT was originally synthesised in 1874, but its action as an insecticide was not discovered until 1939. It was the first widely used synthetic pesti‐ cide, employed extensively by allied forces during the Second World War for the protection of military personnel from malaria and typhus, released commercially only in 1945. The Swiss chemist Paul Hermann Müller was awarded the Nobel Prize in Physiology or Medi‐ cine in 1948 for his discovery of the high efficiency of DDT as a contact poison against sever‐

DDT as Anti-Malaria Tool: The Bull in the China Shop or the Elephant in the Room?

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While the post-war period also saw the introduction of most of the other major families of insecticides still in use today, DDT remained the most extensively used insecticide through‐ out the world until the mid 1960s. By this time, it had been credited with a number of signif‐ icant public health successes, including the eradication of malaria from the United States and Europe (Attaran & Maharaj, 2000). DDT is currently being produced in three countries: India, China, and the Democratic People's Republic of Korea (North Korea). By far the larg‐ est amounts are produced in India for the purpose of disease vector control. In China, the average annual production during the period 2000–2004 was 4,500 metric tons of DDT, but 80–90% was used in the production of Dicofol, an acaricide, and around 4% was used as ad‐ ditive in antifouling paints. The remainder was meant for malaria control and was exported

Space spraying, or fogging, relies on the production of a large number of small insecticidal droplets, that resemble smoke or fog by rapidly heating the liquid chemical, intended to be distributed through a volume of air over a given period of time. When these droplets impact on a target insect, they deliver a lethal dose of insecticide. It is primarily reserved for appli‐ cation during emergency situations to rapidly reduce the population of flying insects in a specific area resulting in decrease of transmission (CDC, 2009). It is effective as a contact poi‐ son with no residual effect, thus it must be repeated at intervals of 5-7 days in order to be fully effective. The application must coincide with the peak activity of adult mosquitoes, be‐ cause resting mosquitoes are often found in areas that are out of reach to the applied insecti‐ cides. The best moment to kill adult mosquitoes by fogging is at dusk, when they are most active in forming swarms. The most commonly used products are natural pyrethrum ex‐ tract, synthetic PYs, and Malathion.

Mosquito nets treated with insecticides—known as insecticide treated nets (ITNs) or bed‐ nets—were developed in the 1980s for malaria prevention. Properly used, a mosquito net effectively offers protection against mosquitoes and other insects, and thus against the diseases they may carry. Two categories of ITNs are available: conventionally treated nets and long-lasting ITNs (LLINs). ITNs are estimated to be twice as effective as untreated nets, and offer greater than 70% protection compared with no net. These nets are impreg‐ nated with PYs, which will double the protection over a non-treated net by killing and re‐ pelling mosquitoes, and are proved to be a cost-effective prevention method against malaria (D'Alessandro et al., 1995). Washing and the associated regular retreatment of the nets determine a rapid loss of efficacy of ITNs, thus limiting the operational effectiveness of an ITN program (Lines, 1996).

Biological activity of LLINs, a relatively new technology, generally retains the efficacy for at least 3 years (WHO, 2005), and can reduce human–mosquito contact, which results in lower sporozoite and parasite rates. Different types of long-lasting insecticide impregnated materi‐ als are under field trials in different countries. Treatments of screens, curtains, canvas tents, plastic sheet, tarpaulin, etc., with insecticides may provide a cheap and practical solution for malaria vector control. Particularly, the residual insecticides in insecticide-treated wall lin‐ ing (ITWL) are durable and can maintain control of insects significantly longer than IRS by providing an effective alternative or additional vector control tool (Munga et al., 2009).
