**3.** *Plasmodium* **life cycle**

Malaria parasites have evolved a complicated life cycle alternating between human and *Anopheles* mosquito hosts, as represented in Figure 1. Five *Plasmodium* strains (*P. falciparum*, *P. vivax*, *P. ovale*, *P. malariae*, and *P. knowlesi*) can affect humans in more than 90 countries, inhabited by 40% of the global population. In some of these areas, over 70% of residents are continuously infected by the most deadly form of the parasite, *P. falciparum*. Surviving chil‐ dren develop various levels of natural immunity; however, it does not protect them from re‐ peated infections and illness throughout life.

#### **3.1.** *Plasmodium* **life cycle in** *Anopheles* **mosquitoes**

*Plasmodium* is transmitted to humans by female mosquitoes of *Anopheles* species. There are approximately 484 recognised species, and over 100 can transmit human malaria; however, only 30–40 commonly transmit *Plasmodium* parasites in endemic areas. *Anopheles gambiae* is one of the best known malaria vectors that lives in areas near human habitation (Rogier & Hommel, 2011). The intensity of malaria parasite transmission varies geographically accord‐ ing to vector species of *Anopheles* mosquitoes. Risk is measured in terms of exposure to in‐ fective mosquitoes, with the heaviest annual transmission intensity ranging from 200 to >1000 infective bites per person. Interruption of transmission is technically difficult in many parts of the world because of limitations in approaches and tools for malaria control. In ad‐ dition to ecological and behavioral parameters affecting vectorial capacity, *Anopheles* species also vary in their innate ability to support malaria parasite development. Environmental conditions such as temperature in mosquito microhabitats serve to regulate both the proba‐ bility and timing of sporogonic development (Rogier & Hommel, 2011).

**Figure 1.** *Plasmodium* parasite life cycle.

The chapter will open on a short illustration of the *Plasmodium* life cycle, which occurs either in mosquito vector (sexual reproduction) or in human host (asexual replication). Since anti‐ vector control measures are directed to mosquito killing, *Plasmodium* sexual cycle will be pri‐ oritized. Therefore, the insecticides currently allowed for malaria vector control, including organochlorines (OCs), organophosphates (OPs), carbamates (Cs), and pyrethroids (PYs), will be briefly described. After such a brief introduction, a special attention will be paid to DDT. Formulation, cost-effectiveness, mechanisms of action, resistance and environmental issues will be discussed. The big debate among pro-DDT, DDT-centrist, or anti-DDT scien‐ tists will be examined. In this context, the state-of-the-art of knowledge on DDT toxicity will

Taken altogether, these notions should help the reader to arise his own opinion on such a hot topic, in order to feed the ongoing debate. In areas endemic for malaria, is DDT dangerous as the bull in a China shop? Or perhaps is it worth using DDT, since its advantages related to malaria prevention are self-evident as the elephant in the room? Any answers aimed at finding the most

All data were obtained from literature searches, by using the search engines Scopus and Pubmed. Because of the complexity of the subject, only the most relevant studies were se‐ lected, and reviews were prioritized. Old literature was accessed electronically, or hard cop‐ ies were obtained from libraries. Information on human exposure and health effects was based on reviews published over the past ten years and supplemented with recent studies

Malaria parasites have evolved a complicated life cycle alternating between human and *Anopheles* mosquito hosts, as represented in Figure 1. Five *Plasmodium* strains (*P. falciparum*, *P. vivax*, *P. ovale*, *P. malariae*, and *P. knowlesi*) can affect humans in more than 90 countries, inhabited by 40% of the global population. In some of these areas, over 70% of residents are continuously infected by the most deadly form of the parasite, *P. falciparum*. Surviving chil‐ dren develop various levels of natural immunity; however, it does not protect them from re‐

*Plasmodium* is transmitted to humans by female mosquitoes of *Anopheles* species. There are approximately 484 recognised species, and over 100 can transmit human malaria; however, only 30–40 commonly transmit *Plasmodium* parasites in endemic areas. *Anopheles gambiae* is one of the best known malaria vectors that lives in areas near human habitation (Rogier &

be analyzed, and few tips on possible alternatives to DDT will be given.

332 Insecticides - Development of Safer and More Effective Technologies

practicable way to fight malaria through vector control are urgently required.

on exposure due to indoor spraying and treated bednets.

**2. Materials and methods**

**3.** *Plasmodium* **life cycle**

peated infections and illness throughout life.

**3.1.** *Plasmodium* **life cycle in** *Anopheles* **mosquitoes**

In the mosquito, three phases of life of the parasite involve developmental transitions be‐ tween gametocyte and ookinete stages, between ookinetes and mature oocysts, and between oocysts and sporozoites. When a female Anopheles sucks the blood of a malaria patient, the gametocytes also enter along with blood. They reach the stomach, and gamete formation takes place (Aly et al., 2009). Two types of gametes are formed: the microgametocytes (male) originate active microgametes, and the megagametocyte (female) undergoes some reorgani‐ zation forming megagametes. Fertilization of the female gamete by the male gamete occurs 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 their life cycle (Beier, 1998).

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

considerably in their applicability, cost and sustainability of their results.

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

(Prato et al., 2012).

the food chain.

number of human deaths.

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

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

http://dx.doi.org/10.5772/53241

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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)

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

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

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.

)

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

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

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