**2. A new situation**

consequences. Despite the fierce opposition by chemical companies, the book's impact on the American public was a seminal event for the environmental movement, spurring a reversal in national pesticide policy. Still the issue has great actuality, considering the recent debate [2–

In 1972, DDT was banned on the agricultural uses in the US, and soon after in EU. Before DDT was banned, more than 600,000 tonnes were applied in the US. The environmental movement led to the creation of the US EPA (Environmental Protection Agency). The first resistance episode concerned DDT in 1914 [6]. In May 2015, US President Obama, considering the final report of the Commission, stated the primary importance of antibiotic multiresistance, leading to the ban of the use of antibiotics in agriculture and farm practices. However, deep divide exists between American and European regulation of pesticides and other chemicals, many

Accordingly to the current definitions, resistance can be defined as "a heritable change in the sensitivity of a pest population that is reflected in the repeated failure of a product to achieve the expected level of control when used according to the label recommendation for that pest species" [7]. In this chapter, we will consider resistance as "the inherited ability of an organism to become tolerant to a dosage of the chemical that would be lethal to a definite species." Evidence for pesticide resistance in arthropods of agricultural and medical importance is an emerging threat. It is possible that in the next 20–30 years, all the synthetic pesticides now employed for pest control will lose their efficacy. Research on newer and safer control tools may be helpful in future scenarios for mankind, dramatically involving feed and food.

Synthetic insecticides are usually utilized to reduce damages caused by insects that destroy crops or transmit diseases. To be effective, an insecticide should be lethal to the majority of the individuals in a normal wild population. However, the insecticide can lose its efficacy, thus many pest populations developed resistance to the toxic effects [8]. This key point is only a further example of the consequences of human tendency to amplify the natural resources beyond any limit in order to obtain the maximum of the effects and not considering the consequences. The problem is inherent: the resistance is related to a massive and persistent use of pesticides, exactly like for antibiotics in microorganisms. Many species have resistant populations, which can resist to one or many treatments [9]. In the moment of the insecticide use, some individuals result resistant. Sensitive insects exposed to the insecticide will die, except the few resistant ones, which can continue to develop and proliferate. Continuing the use, they will be favored. More use of pesticide fuels the dominance of resistant populations. The consequence of the mechanism is that, in the right time, insecticides, once effective, are not sufficient in controlling insects [10]. Nowadays, the above definitions risk to be insufficient to describe the complex system that generates the resistance phenomenon to insecticides or the absence of any real efficacy in control of insect pests. The solution can be considered simply as "find the best weapon to kill the bacterium and solve the problem," as so far mainly considered. As in the general medicine, where the "chemical magic bullet" was considered the central solution for any disease, this approach is nowadays in crisis because the physiologic aspects are more complex and complicated by interactions at several levels. Resistance is the

chemicals that are banned or strictly regulated in EU are permitted in the US.

4] about effects of neonicotinoids on honey bees and birds [5].

220 Insecticides Resistance

consequence of a series of events.

So far, much attention of research and public concern was focused on vector-borne human diseases in order to eradicate their presence and to save as many lives as possible [11]. However, if the resistance will affect our life supports, the surviving struggle will be in balance due to two key factors: resistance to many pesticides and/or the impossibility of using current effective substances because of the consequences of the effects on environment. Even pyreth‐ roids are now considered dangerous for nontarget animals since they can impair memory and movement [12]. Currently, we have to face new epidemic emergencies due to several factors (including climate change) concerning crops and livestock. Insects are vectors of important diseases involving nonhuman targets, causing important effects on plants and animals of strategic economic relevance. Recently, some of such diseases are of increasing concern to the general population, attracting a level of attention never experimented before and generating great alarms for the consequences of their rapid diffusion. The economic negative effects are enormous, and the damages on the local economic system are dramatic. Agricultural produc‐ tion must increases in relation to the needs of world population. However, losses due to arthropod pests account now for around 20–30% of the production [13]. Insect damages are important in the field and in the stored products. Agricultural production resorts to the use of a large quantity of insecticides to raise production and preservation of foodstuff. According to the increasing needs, the use of insecticides has increased even more than necessary, although it was demonstrated that the excessive and inappropriate use of synthetic pesticides is frequently even counterproductive. Effects are not limited to the treated field, involving undesirable consequences on public health and environment. Current pesticide pollution of Adige valley in Northern Italy, due to the continuous heavy treatments of apple monoculture, is a clear example. The introduction of OGM did not afford solutions, inducing additional problems to farmers.

Most of insecticides are usually employed to reduce the damages caused by insects that destroy crops or transmit diseases. Up to now, agricultural pests account for 59% of the resistant insect species, while veterinary pests account for 41%. Antibiotics in the US and the UK mainly utilized to treat livestock are considered immunostimulants, similarly, most insecticides are used in agricultural practice to improve the production and preservation of foodstuff. In both cases, the use is now widespread, excessive, and inappropriate.

Recently, some of such diseases have rapidly gained media's attention, generating great alarm for the consequences of their diffusion. The economic negative effects are enormous, and the damages on the local living system are dramatic. Several epidemic emergencies are in act, and the emergency is going to be converted into a normal trend, as a consequence of the perma‐ nence of several factors, including in first place the climate changes [14].

On the basis of novel knowledge, some new approaches are emerging, changing the aspect of insect control. Integrated pest management is an important approach, developed in the last years to control disease vectors and limit economic agricultural damages, improving crop yield with minimum cost. Main goals are (a) to increase basic knowledge of biology of the insect pest and its relationship with other organisms sharing the same ecological niche [15]; (b) to reduce pesticide application and quantity developing biological controls, farming practices, farmers collaboration, and mechanical and physical controls; and (c) to build new models of integrated managements on the basis of laboratory and field experiments, including the research of new active compounds. Novel pesticides to be suitable must be low cost, ecofriendly, from renewable raw material, nontoxic to nontarget organisms, of rapid degradation, and no accumulation in the environment.

However, resistance is only the last consequence of a series of events. Most of this paper will be dedicated to the deep knowledge of this sequence, being considered the key to struggle resistance. Insect-borne diseases are the result of complex multiorganism interactions. The network of several different collaborating organisms is on the basis of diffusion, effectiveness, and metabolism of insect vectors, including the resistance phenomenon. The integrated network acts like a "superorganism," integrating functions of all the different types of involved organisms. Disease is the result of a brave and useful collaboration between organisms totally different, from bacteria to insect, giving rise to an integrated system that is the key to survive and proliferate. It is the example that we must learn, asking for several levels of eco-friendly interactions. The consequences that we consider as negative are only the collateral effects of the competitive struggle.

In these years, the Mediterranean Sea was an incubation sap of several massive migrations of organisms, mainly due to climate changes and commercial routes, which radically modified previous equilibrium. Migrations start from distant sites but are able to spread in a large area until they find the right conditions to set up and rapidly become dominant.

Therefore, insects, like microorganisms, are particularly able to change their genome. It is a problem of survival. In some cases, the change generates an organism more aggressive and virulent. Previous treatments are usually not useful, in particular when they are the cause of the genetic change, like the exaggerated use of pesticides and/or climate changes.

In Italy, at least three cases are focusing on scientific, social, and policy attention, causing strong alert for the consequences of their anomalous increasing speed of spreading. The first one concerned *Aedes albopictus* (Skuse), commonly known as the Asian tiger mosquito [16–18]. This species is currently retained the most invasive mosquito species in the world since it is able to rapidly adapt to different anthropogenic environments, thanks to its ecological and physio‐ logical plasticity [19]. Recently, the Asian tiger mosquito has invaded many countries, spreading rapidly to Europe, North and South America, the Caribbean, Africa, and the Middle East [20,21]. *A. albopictus* is both a nuisance and a disease vector. Its medical importance is mainly due to the aggressive daytime human-biting behavior and to its ability to transmit many diseases. It works as a vector for many viruses, including dengue, yellow fever, West Nile, Japanese encephalitis, St. Louis, encephalitis virus (Flaviridae, genus *Flavivirus*); chikun‐ gunya, Eastern equine encephalitis, Venezuelan equine encephalitis, Western equine ence‐ phalitis, Ross River, Sindbis, Mayaro, Getah (Togaviridae, genus *Alphavirus*); Potosi, San Angelo, La Crosse, Jamestown Canyon (Bunyaviridae, genus *Bunyavirus*); Rift Valley fever (Bunyaviridae, genus Phlebovirus), and Orungo virus (Reoviridae, genus *Orbivirus*). *A. albopictus* is also the vector of different filariasis, such as *Dirofilaria immitis* Leidy, *Dirofilaria repens* Railliet and Henry, and *Setaria labiatopapillosa* Perroncito [19]. Although the introduction of Tiger mosquito was casual, probably due to the commerce of old tires, the permanence is clearly due to the climate change with the rising of temperature.

Two recent exceptional cases of overflowing insect-borne diseases not directly involving human health are reported to evidence of the difficulties of fighting new insect emergencies. Both emergencies are the results of a complex multiorganism interaction. The network of several different organisms is on the basis of the mechanism of survival and diffusion, conditioning effectiveness and metabolism of insect vectors, including the resistance phenom‐ enon. The network acts like a "superorganism," integrating functions of all the different types of involved organisms, asking for several levels of eco-friendly actions. Integrated methods are urgently needed for control of these pests. On the basis of novel knowledge, some new approaches are emerging, changing the aspect of insect control.

Both cases present several, not casual, similarities and therefore can be considered as para‐ digms of next future or actual situations. The first case is the expanding relevance of bluetongue disease, vectored by *Culicoides* sp., so far concerning Southern Europe (Sardinia in particular) and going to be present in other countries. The second case is the alarm concerning the olive trees epidemic disease, probably due to *Xylella fastidiosa*, which may lead to the disappearance of extensive areas cultivated with olive trees in Southern Italy. Actually, no useful control tools have been reported.
