Insecticides Prior to the Chemical

To our knowledge, the first documented compendium of insecticide substances is the Egyptian Ebers Papyrus (ca. 1600 BC).6 Another example of historical reports concerning the control of insect pests can be found in ancient Chinese civilizations, where fire was used to destroy plagues of migratory locust (Locusta migratoria manilensis).7 Pre-Roman civilizations already reported the burning of brimstone (sulfur)6 as an insecticide and purifying agent. Such an application was also described by Homer in The Odyssey (ca. 1000 BC). Currently, sulfur (applied as dust, granulated or as a colloidal formulation) is not only used as an insecticide in crops and in indoors applications against mites and some caterpillars, but also as a fungicide and fertilizer.8 Sulfur was not found to cause adverse effects in the environment, and also lacked any remarkable damage against humans.9

Pliny the Elder recorded in his Natural History various types of insecticides from the preceding 300 years coming from folk culture,10 comprising pepper, turpentine or fish oil among others. He mentioned the repellent activity towards insects of both, fresh and burning leaves from Mentha pulegium (from Latin "pulex", meaning flea).11

Inorganic chemicals, known to be agents for struggling insect pests since antiquity, were used extensively from the 19th century until the first third of the 20th century.12 The use of arsenic sulfides in China against garden pests was already reported by the year 900 AD, although the employment of such inorganic chemicals in the Western civilization did not take place until the 17th century.13 Copper acetoarsenite (Cu(CH3COO)2 • 3Cu(AsO2)2, Paris Green pigment) is considered to be the first broad spectrum insecticide, first used in 1865 to protect potato plants against the Colorado potato beetles.14 Lead and calcium arsenates were introduced in 1892 and 1907, respectively, for improving insect control in ornamentals, fruits, tobacco or cotton.15 Lead arsenate was particularly effective against the gypsy moth, and soon replaced Paris Green because of its strong phytotoxicity when used in large amounts.16 White arsenic (arsenious oxide) was used in large quantities against grasshoppers as poisoned baits and against cattle ticks; the basic character of arsenious oxide precluded its direct use on foliage.17 Arsenicals were quite efficient for controlling chewing insects. Unfortunately, both arsenic and arsenic-containing compounds were found to be highly toxic.18 Arsenic induces skin and bladder cancer, and also affects vascular, neurological and cognitive functions.19 The US Environmental Protection Agency (US EPA) banned the use of most arsenic-based pesticides in the 1990s, and only allowed those organo-arsenicals that were not suspected carcino-gens.20 Nevertheless, the lack of data on the stability and transformations of these compounds in soil does not guarantee that they can be considered as completely harmless.21

Due to the environmental concerns of arsenic salts, cryolite (sodium fluoro-aluminate, Na3AlF6) surged as an alternative in the beginning of the 20th century for the preservation of fruits and vegetables. Although the use of such mineral insecticide decreased upon the introduction of synthetic insecticides, it is still allowed due to its environmental safety, low toxicity and limited capacity to be dispersed by water.22 Cryolite, unlike other mineral salts containing fluorine, does not release the fluoride ion upon decomposition,22 which ensures a low toxicity against mammals. As a consequence, cryolite is currently considered as a suitable insecticide for organic crop culture.23

Another popular mineral insecticide was the Bordeaux mixture, a combination of copper (ii) sulfate and hydrated lime (calcium hydroxide) introduced by French viticulturists as a fungicide, and still used as insecticide and fungicide.24

Boron-containing insecticides, comprising boric acid and its salts (e.g. borax and disodium octaborate), are also in current use. Their formulations were registered as pesticides in the USA in 1948.25 Borate insecticides have been used successfully against fleas, beetles, ants, cockroaches and some species of termites,25 thus acting as a wood-preserving agent. Besides being inexpensive chemicals, they are relatively non-toxic compounds, lacking mutagenic and carcinogenic properties.26 Boric acid is frequently used as a bait formulation containing an insect attractant within IPM (Integrated Pest Management) programs27 (see Chapter 9), and it is usually formulated as tablets and as powder.

Traditional insecticide preparations often included some other heavy and toxic elements as well (such as antimony, thallium, selenium or mercury) or hazardous substances (like hydrogen cyanide),1,17 thus strongly contributing to environmental pollution and increasing the risk of human poisoning.

The ionic nature of inorganic insecticides allows a better absorption through the insect gut wall than through the integument,28 a major difference with the highly lipophilic organic insecticides covered in the next section. Inorganic insecticides are therefore considered as stomach poisons, which act by ingestion.28 These chemicals are quite stable in the environment, easily dispersed, so they can easily contribute to soil and water pollution. In many cases they also affect non-targeted species, such as beneficial insect families, aquatic organisms and mammals.28

Among the organic substances used in insect control, whale-oil soap (1842) and petroleum components, such as kerosene (1865) are remarkable.29 Insec-ticidal soaps are considered to be selective insecticides, as they are almost innocuous for humans, because they mainly affect soft-bodied insects, such as mites and sucking insects.30 The amphiphilic nature of these compounds allows cuticle penetration by contact and disruption of the cell integrity, which leads to dehydration and death of the insect.30 Potassium salts of fatty acids can be used either alone or in combination with other insecticides.31

As indicated previously, another source of organic chemicals that has been historically used as insecticides are botanical extracts. As an example, pyrethrum (Chrysanthemum cinerariaefolium) is a plant commercially grown for the extraction of pyrethrins from the flowers.32 Such extracts were already used by Chinese civilizations around the year 1000 BC. Nevertheless, the strong photolability of these compounds has limited them to indoor use.1

In the 17th century, it was observed that nicotine present in water extracts from tobacco leaves killed plum beetles. However, it was never used as a marketed insecticide, due to its low potency and high toxicity to mammals.33 Other botanicals are rotenone34 (from cube resin), ryanodine and related compounds35 (from Ryania speciosa), veratridine36 (from sabadilla), d-limonene (from the citrus extract), or the triterpenoid azadirachtin37 (from neem tree, Azadirachta indica A. Juss). A more detailed compilation of botanical insecticides can be found in Chapter 7.

2.3 Classical Chemical Insecticides 2.3.1 Organochlorine Insecticides

Although the first commercially available synthetic insecticide was potassium 3, 5-dinitro-o-cresylate38 (sprayed for the control of insects affecting fruit trees), it is generally accepted that the chemical era of insecticides started with the development of organochlorine insecticides, in particular with 1,1,1-trichoro-2,2-bis (4-chlorophenyl)ethane, more commonly known as DDT 1 (from its trivial name: DichloroDiphenylTrichloroethane). DDT and its derivatives, together with many other chlorinated organic hydrocarbons, comprise the so-called ''organochlorine insecticides'', the first groups of agrochemicals of synthetic interest as pest control agents.

Organochlorine insecticides can be classified according to their chemical structure (see Figure 2.1), and they fall into three major groups: diphenylethanes

Chlorinated Derivatives Tree
Figure 2.1 Main families of organochlorine insecticides.

(e.g. 1-5), whose more noticeable example is DDT 1, cyclodienes (e.g. 6-15) and cyclohexanes (e.g. 16), as well as two less numerous families: chlorinated benzenes (e.g. 17-19) and norbornane derivatives (e.g. 20). Diphenylethanes

The development of DDT marked a milestone in the history of agrochemicals, as it inaugurated a new era where insects started to be efficiently and more selectively controlled by synthetic chemicals. It was also DDT that led to a time where humanity started to be increasingly conscious of the need for safer agrochemicals.

The discovery of DDT proved to be rather haphazard. The first synthesis was reported by Othmar Zeidler in 1874, a PhD student working under the supervision of Adolf von Baeyer at Strasbourg University.39 The insecticidal properties of DDT were not discovered until 1939, however, when the Swiss chemist, Paul Hermann Müller, in his search for contact poisons, proved DDT's remarkable effectiveness against flies, mosquitoes and beetles.39 Large production of DDT began in 1948.40 The first uses of DDT involved soldier protection against several diseases during World War II, using a relatively low amount of insecticide.41 In 1944, for the first time in history, people dusting with DDT managed to rapidly eradicate a typhus epidemic in Naples, Italy.2 Müller was awarded the Nobel Prize for Physiology and Medicine in 1948 for his important contribution to pest control.39

DDT was originally prepared by Baeyer condensation of chloral with chloro-benzene in the presence of sulfuric acid (H2SO4) as catalyst (see Scheme 2.1). Oleum and chlorosulfonic acid were also proposed as catalysts.42 Although the major product of the reaction was the p,p0-isomer 1 (up to 80%), the commercial formulation also included some other isomers (21-23) obtained as side-products.43 Furthermore, traces of bis(4-chlorophenyl)sulfone 24 were also detected. The marketed formulations (Anofex®, Cearex®, Genitox®, Zerdane® and some others trademarks) were comprised of solutions (xylene, petroleum ether), emulsions, water-wettable powders, or aerosols, among others.41

Scheme 2.1 Industrial preparation of DDT.

DDT was cheap to produce, exerted reduced acute toxicity against mammals (oral median lethal dose (LD50) of 100-800 mgkg-1 in rats),44 had a high toxicity against a broad spectrum of insects and showed prolonged stability in the environment as a result of a very low biodegradation, which allowed for a more prolonged action.45 However, this last property also proved to be one of the main disadvantages of DDT. DDT soon became the most important chemical in insect control, and was considered a panacea for public health, reducing vector-borne diseases (see Chapter 1), mainly malaria and typhus,46 and for controlling agricultural pests affecting cotton, fruits, potatoes and corn.47 DDT was also used against head lice without observed human toxicity.48 It is estimated that around 400 000 tons of DDT were used annually in the 1960s, and roughly 80% comprised agricultural use.40

The mode of action of DDT has been debated for a long time and was found to be similar45 to that of natural pyrethrins and synthetic pyrethroids type I (see Chapter 3). It is generally accepted that DDT acts as a contact axionic nerve poison,49 by binding the insect voltage-gated sodium channel proteins and affecting their peripheral nerves and brain; a high lipophilicity is required for the contact poison to penetrate the insect cuticle and reach the nerves.50 Binding of DDT inhibits the closure of the sodium channel, which remains in its open-state, and as a result the inwards conductance of Na1 is prolonged in time,51 provoking a membrane depolarization and appearance of a residual slow-acting current, called "tail current''.52,53 The effects in the insect are hyperexcitation, tremors, paralysis ("knockdown") and death.45 Despite the similarities between insect and vertebrate sodium channels, DDT binds selectively to the insect sodium channels. This is due not only to a higher affinity, but also to the body temperature difference between insects (15-20 °C) and vertebrates (37 °C for humans).53 It has been demonstrated that the insecticidal potency of DDT decreased with temperature; the lower temperature of insects in comparison with that of vertebrates allows for a faster action. Furthermore, the lower temperature and reduced size of insects' bodies reduce the chance of deactivation by metabolization.52 Furthermore, DDT penetrates the insect cuticle, but not the mammal's skin. Latter studies also suggested that DDT provoked disruption of some other cellular functions connected to membranes, such as oxidative phosphorylation and the Hill reaction.54

DDT was particularly effective in controlling the populations of Anopheles mosquitoes, the vectors transmitting malaria from the protozoal parasites of the genus Plasmodium,55 especially in tropical countries comprising sub-Saharan Africa, Southeast Asia, the Pacific Islands and South America, where malaria was an endemic disease.55 DDT was sprayed both indoors and outdoors as part of the Global Malaria Eradication Campaign, and by the end of the 1960s, malaria was eradicated in developed countries and in most of subtropical Asian and Latin American regions.47 For instance, it was estimated that in 1947, 75 million malaria cases existed in India (roughly 23% of the population), whereas in 1964 only 100 000 cases were detected.56 Conversely, the disease re-emerged again in subsequent years, reaching 1.1 million reported cases in 2000.57

A major environmental concern of DDT is its long persistence in the environment, and the first adverse effects started to be studied in the 1950s. The intrinsic low reactivity of DDT provokes a bioaccumulation via the food chain in adipose tissues, due to it pronounced lipophilicity.40 As a result, a biomagnification takes place,46 where those living organisms located on the high trophic levels of the ecological pyramid show DDT concentrations above the amount originally used, even when located quite far away from the initial application point. One of the most important observed effects of the bioaccumulation was the thinning of avian eggshells, probably by hormonal changes or disruption of the calcium metabo-lism.46 The low water solubility led to accumulation as deposits in the water currents. In contrast, methoxychlor 4 is eliminated much faster than DDT, mainly by oxidation and dechlorination processes.58

The toxicological effects of DDT and its analogues have been extensively reviewed,40,41,46,47 covering a vast number of epidemiological studies. Many of these studies are not easily carried out, however, and in some cases no definite conclusions can be reached. High concentrations of DDT were found in workers handling the chemical, and in the rest of the population, DDT was found to accumulate mainly through food.47 In people having a strong occupational exposure, decline of the neurobehavioral function46 was a clear symptom of DDT-induced neurological damage, probably by affecting human sodium channels.41

Slow environmental degradation of DDT furnishes, among other derivatives, 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene 22 (DDE), which is even more persistent than DDT itself. DDE is also one of the metabolites resulting from DDT biotransformation upon ingestion.41 Exposure to DDT and DDE has been found to induce an increase in liver weight and hepatic necrosis.47 Although there are some reports on DDT and DDE being carcinogenetic in mice, rats and non-human primates, DDT is only considered as a possible carcinogen in humans, as no definite data are available.47 DDE was reported as an androgen receptor antagonist, whereas DDT showed estrogenic effects in rats.40

Another problem associated with DDT is that insects can develop resistance, so its effectiveness decreases.45,51 It is for this reason that an increase is observed in the malaria cases in DDT-mediated Anopheles mosquito control in India. Resistance can be provoked either by mutations affecting the voltage-gated sodium channel, making it less sensitive to DDT binding (knockdown resistance, kdr) or by detoxification mechanisms that speed up metabolization. Insect resistance has been reported in important pests, usually accompanied by what is called super-kdr, a stronger resistance to pyrethroids,45 which as indicated above shares the same insect target with DDT. Moreover, DDT possesses an irritant and repellent nature, so it is possible that mosquitoes may leave before ingesting the lethal dose.47

A large number of DDT derivatives were synthesized, as an attempt to obtain agrochemicals with enhanced activity, and improved environmental behavior.59,60 SAR54,61 and QSAR62 studies were carried out to address the steric and electronic factors61 that are important in active DDT analogues. Such studies revealed that p-disubstituted phenyl rings are essential for the derivatives to show insecticidal activity. Furthermore, the substituents on the ring must be relatively non-polar and no larger than a butoxy group (e.g. -alkyl, -OR, -SR or -X).54

DDT analogues bearing alkyl or alkoxy substituents (e.g. ethyl-DDT 3 or methoxychlor 4) turned out to undergo biodegradation by enzymatic-mediated processes involving side-chain oxidation or O-dealkylation, respectively,63 the former being the more effective process. The presence of alkylthio groups also allows side-chain oxidation.64 Substitution in the phenyl rings, however, decreases the ratio of biodegradation by hydroxylation of the aromatic rings.

Methoxychlor 4 (oral LD50 of 5000-6000 mg kg-1 in rats)41 is one of the most important commercially-available DDT analogues. It is less effective as an insecticide than DDT, however, and much more expensive to produce industrially (as anisole is more costly than chlorobenzene as starting material).48 The substituent on the methyl residue has also some restrictions concerning size and polarity. Optimal substituents are the trichloromethyl moiety, -CH(NO2)CH3 or -CH(NO2)CH2CH3, and some DDT analogues of this type have been marketed.41 Some other groups, such as hydroxyl or amino groups, were found to be too polar to confer insecticidal activity.50

Metcalf's group accomplished63 the preparation of a series of symmetrical and asymmetrical a-trichloromethylbenzylanilines as DDT analogues, significantly more biodegradable than DDT starting by condensation of substituted aldehydes and anilines in refluxing ethanol to give Schiffs bases, followed by treatment with trichloroacetic acid.63 a-(Trichloromethyl)benzyl phenyl ethers were also prepared by acid-promoted condensation reaction between a-(trichloromethyl)benzyl alcohols and phenol derivatives. Besides nitrogen, sulfur and oxygen have also been used in numerous derivatives as bridging atoms39,63 between the two phenyl rings, and some of the corresponding derivatives also showed insecticidal activity close to that of DDT.

Fukuto and co-workers reported59 the preparation of 2,2-bis(p-ethoxyphenyl)-1,1-dichloropropane as a DDT analogue with a higher toxicity against house flies. Such a derivative possesses two key structural aspects: the p-ethoxy substituent in the phenyl rings (which allows a biodegradable scaffold in the molecule), and the replacement of the benzylic proton by a methyl group.59 Although it might confer more steric hindrance because of the larger size of the methyl compared to hydrogen, the trichloromethyl moiety of DDT was also replaced by a dichloromethyl group, thus compensating for the steric hindrance.59

Replacement of the methylene bridge or of the trichloromethyl group by silicon led to no insecticidal activity.65 Hybrid structures of DDT-pyrethroids with insecticidal activity have also been reported.66

Due to ecological concerns, DDT was firstly banned in Sweden in 1970, followed by the former USSR (1970) and in most countries worldwide in 1972.40 Nevertheless, in 1985, 300 tons of DDT were still exported from the USA. Underdeveloped countries nowadays claim for a controlled use of DDT against insect vectors transmitting malaria, still a major disease in many tropical underdeveloped countries. DDT is being produced in three countries: India, China and North Korea, and is currently used in 14 countries, although some others are still debating about its re-introduction.67

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