**1. Introduction**

A pesticide has been described as an agent applied to kill, repel, or mitigate industry-, public health- and/or agriculture-related pests. They can also be used as plant growth

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

regulator or nitrogen stabilizer. We use them to reduce the risk of decreased agricultural and industrial yield and prevent public health concerns such as vector-borne diseases, asthma and allergies, and microbial contamination (for more information: https://www. epa.gov/pesticides). Pesticides have entered into our lives more than 3000 years ago [1] and dried, ground Dalmatian pyrethrum flowers (contain natural pyrethrins) have been used against insect pests since ancient China. It has also been used in Europe more than 200 years ago against cockroaches, bedbugs, flies, and mosquitoes [2]. A pyrethrin-derived synthetic pyrethroid allethrin has been synthesized in 1949 and entered the market in 1952 to use against household pests [3]. To date, there are over 3500 pyrethroid-containing products registered [4].

the pyrethroid insecticides are less persistent in the environment compared to organochlorines, they are highly lipophilic with their high octanol/water partition coefficient (Kow) [13]. Therefore, dietary exposure to these compounds trigger the safety concerns [14]. Indoor

Significant pyrethroid residues have been found in drinking water, human breast milk, and cow milk in a sample location of South Africa where indoor residual spraying was applied for malaria control compared to a mountain population [15]. Malaria control or agricultural applications have caused pyrethroid accumulation such as cypermethrin, lambda-cyhalothrin, esfenvalerate/fenvalerate, and permethrin in breast milk from Brazil, Colombia, and Spain mothers [16]. However, the residues never exceeded the maximum daily intake levels. Babina et al. reported that more than one chemical and simultaneous exposure to organophosphate and pyrethroids was common in South Australian preschool children [17]. Barr et al. surveyed the U.S. population with 5046 samples between the period of 1999 and 2002 to detect pyrethroid residues in urine samples, and they concluded that pyrethroid exposure is widespread in the U.S. population and children probably have higher exposure risk compared to adolescents and adults [18]. Exposure to pyrethroids in the levels common in Canadian children's urine has been associated with parent-reported behavioral anomalies [19]. A sex-dependent attention-deficit/hyperactivity disorder has been found in U.S.

CAS No: 584-79-2

CAS No: 240494-70-6

CAS No: 52645-53-1

IUPAC name: (3-phenoxyphenyl) methyl

IUPAC name: (2-methyl-4-oxo-3-prop-2-enylcyclopent-2-en-1-yl) 2,2-dimethyl-3-(2-methylprop-1-enyl) cyclopropane-1-carboxylate

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IUPAC name: [2,3,5,6-tetrafluoro-4-(methoxymethyl) phenyl] methyl 2,2-dimethyl-3-[(E)-prop-1-enyl] cyclopropane-1-carboxylate

3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane-1-carboxylate

application to control household pests is also another path for human exposure.

Allethrin1 (Type I)

Metofluthrin<sup>2</sup> (Type I)

Permethrin3 (Type I)

The primary toxic effect of pyrethroids is on the voltage-gated sodium channels (VGSCs) like organochlorines such as DDT. The opening of these channels is extended by pyrethroid action and this causes the altered nerve function. According to their effect and chemical structure, pyrethroids divided into two types. Type I chemicals (allethrin, bifenthrin, bioresmethrin, permethrin, phenothrin, resmethrin, tefluthrin, and tetramethrin) do not contain a cyano group and they cause slowing in the closure of VGSCs. Therefore, the observed symptoms are tremors and seizures. On the contrary, Type II chemicals (cyfluthrin, cyhalothrin, cypermethrin, cyphenothrin, deltamethrin, fenpropathrin, fenvalerate, flucythrinate, flumethrin, fluvalinate, and tralomethrin) are the ones that are predominantly alpha-cyano-3-phenoxybenzyl alcohol esters and they cause a longer duration in the sodium current. The observed symptom is choreoathetosis accompanied by profuse salivation [5, 6]. Permethrin, a Type I pyrethroid, has not a disordering effect on polar head groups of phospholipids while it localizes within the hydrocarbon core [7]. Because of its cyano group, cypermethrin, a Type II, localizes preferentially in the hydrophilic/hydrophobic region of the lipid plasma membrane, shows greater permanence and more fluidic effect on the membrane compared to permethrin [8]. Therefore, the permanence of cypermethrin can be connected to the prolonged opening of sodium channels. This interaction could also be related to the more reduction of lipid-lipid interactions compared to Type Is; therefore, it decreases plasma membrane fluidity that is linked to the affected Na<sup>+</sup> -K+ ATPase activity to become the plasma membrane more permeable to the Na+ cations [8]. Type I pyrethroids have a higher binding affinity to the protein of VGSCs [9] while they penetrate more easily into the cell. Although this is another issue for a review, the mutations observed on the VGSCs' protein produce more resistant individuals against pyrethroid intoxication (for more information, see Silva et al. [10]). There is also a discrimination between these types according to their effects on calcium and chloride channels [11]. **Table 1** shows the chemical structures of pyrethroids that are mostly discussed in the current chapter.

Long-term health effects of pesticides such as their developmental and reproductory, endocrine disruption, neurobehavioral, carcinogenic, and immunological ones besides their acute impact have been considered by many scientists and regulatory services such as WHO, FAO, USEPA, and ECHA for many years. Currently, we experience the pesticides via drinking water, soil, food, and air. Directly ingesting of pesticide products can be assessed as a suicide action, but millions of acute poisoning cases occur in every year worldwide [12]. Although the pyrethroid insecticides are less persistent in the environment compared to organochlorines, they are highly lipophilic with their high octanol/water partition coefficient (Kow) [13]. Therefore, dietary exposure to these compounds trigger the safety concerns [14]. Indoor application to control household pests is also another path for human exposure.

regulator or nitrogen stabilizer. We use them to reduce the risk of decreased agricultural and industrial yield and prevent public health concerns such as vector-borne diseases, asthma and allergies, and microbial contamination (for more information: https://www. epa.gov/pesticides). Pesticides have entered into our lives more than 3000 years ago [1] and dried, ground Dalmatian pyrethrum flowers (contain natural pyrethrins) have been used against insect pests since ancient China. It has also been used in Europe more than 200 years ago against cockroaches, bedbugs, flies, and mosquitoes [2]. A pyrethrin-derived synthetic pyrethroid allethrin has been synthesized in 1949 and entered the market in 1952 to use against household pests [3]. To date, there are over 3500 pyrethroid-containing prod-

The primary toxic effect of pyrethroids is on the voltage-gated sodium channels (VGSCs) like organochlorines such as DDT. The opening of these channels is extended by pyrethroid action and this causes the altered nerve function. According to their effect and chemical structure, pyrethroids divided into two types. Type I chemicals (allethrin, bifenthrin, bioresmethrin, permethrin, phenothrin, resmethrin, tefluthrin, and tetramethrin) do not contain a cyano group and they cause slowing in the closure of VGSCs. Therefore, the observed symptoms are tremors and seizures. On the contrary, Type II chemicals (cyfluthrin, cyhalothrin, cypermethrin, cyphenothrin, deltamethrin, fenpropathrin, fenvalerate, flucythrinate, flumethrin, fluvalinate, and tralomethrin) are the ones that are predominantly alpha-cyano-3-phenoxybenzyl alcohol esters and they cause a longer duration in the sodium current. The observed symptom is choreoathetosis accompanied by profuse salivation [5, 6]. Permethrin, a Type I pyrethroid, has not a disordering effect on polar head groups of phospholipids while it localizes within the hydrocarbon core [7]. Because of its cyano group, cypermethrin, a Type II, localizes preferentially in the hydrophilic/hydrophobic region of the lipid plasma membrane, shows greater permanence and more fluidic effect on the membrane compared to permethrin [8]. Therefore, the permanence of cypermethrin can be connected to the prolonged opening of sodium channels. This interaction could also be related to the more reduction of lipid-lipid interactions compared to Type Is; therefore, it decreases plasma membrane fluid-

ucts registered [4].

294 Mitochondrial Diseases

ity that is linked to the affected Na<sup>+</sup>

permeable to the Na+

in the current chapter.


protein of VGSCs [9] while they penetrate more easily into the cell. Although this is another issue for a review, the mutations observed on the VGSCs' protein produce more resistant individuals against pyrethroid intoxication (for more information, see Silva et al. [10]). There is also a discrimination between these types according to their effects on calcium and chloride channels [11]. **Table 1** shows the chemical structures of pyrethroids that are mostly discussed

Long-term health effects of pesticides such as their developmental and reproductory, endocrine disruption, neurobehavioral, carcinogenic, and immunological ones besides their acute impact have been considered by many scientists and regulatory services such as WHO, FAO, USEPA, and ECHA for many years. Currently, we experience the pesticides via drinking water, soil, food, and air. Directly ingesting of pesticide products can be assessed as a suicide action, but millions of acute poisoning cases occur in every year worldwide [12]. Although

ATPase activity to become the plasma membrane more

cations [8]. Type I pyrethroids have a higher binding affinity to the

Significant pyrethroid residues have been found in drinking water, human breast milk, and cow milk in a sample location of South Africa where indoor residual spraying was applied for malaria control compared to a mountain population [15]. Malaria control or agricultural applications have caused pyrethroid accumulation such as cypermethrin, lambda-cyhalothrin, esfenvalerate/fenvalerate, and permethrin in breast milk from Brazil, Colombia, and Spain mothers [16]. However, the residues never exceeded the maximum daily intake levels. Babina et al. reported that more than one chemical and simultaneous exposure to organophosphate and pyrethroids was common in South Australian preschool children [17]. Barr et al. surveyed the U.S. population with 5046 samples between the period of 1999 and 2002 to detect pyrethroid residues in urine samples, and they concluded that pyrethroid exposure is widespread in the U.S. population and children probably have higher exposure risk compared to adolescents and adults [18]. Exposure to pyrethroids in the levels common in Canadian children's urine has been associated with parent-reported behavioral anomalies [19]. A sex-dependent attention-deficit/hyperactivity disorder has been found in U.S.

oxygen species (ROS) and lipid peroxidation levels and decrease in superoxide dismutase (SOD) and catalase (CAT) activities in rat pheochromocytoma cells (PC12); but this effect is

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Pyrethroid biotransformation in mammals including human consists oxidation, ester hydrolysis (both are called as Phase I reactions), and conjugation with endogenous molecules (Phase II reactions) [3, 25, 26]. Oxidation reactions are catalyzed by isoforms of cytochrome

The produced metabolites can be more potent endocrine disruptors than parent compound for humans [27]. Romero et al. found that CYP450-mediated oxidation products of deltamethrin (2'-OH and 4'-OH deltamethrin) are more toxic than the parent compound measured with cell viability, lipid peroxidation, and nitric oxide formation on human dopaminergic neuroblastoma SH-SY5Y cells [28]. Moreover, abnormal locomotor activity observed in prenatal deltamethrin exposure has been associated with increased expression of CYP450 enzymes in the offsprings of rats [29]. However, the pyrethroids are commonly used as a replacement of organophosphate and organochlorine insecticides because of their low mammalian toxicity at the first time of their popularity. The low toxicity has been attributed to their rapid metabolism in mammals [18]. For this reason, their metabolism considered as a detoxification because of rapid clearance from the body [25, 30]. Most of the metabolites are highly hydrophilic, and then rapidly excreted via urine and feces. Some of the metabolites from *R*-cyano-3-phenoxybenzyl alcohol derivative pyrethroids, however, shows incomplete excretion and have longer bioretention in skin and stomach [25, 26]. Moreover, some of the conjugation metabolites are lipophilic and participate in toxicity reactions [25]. The biotransformation to hydrophilic compounds may also be a source of their toxicity in mammals as described below.

A single dose of cypermethrin and/or fenvalerate has caused the increase in SOD and CAT activities and in lipid peroxidation levels in the erythrocytes of rats [31]. As specified, noncyano (Type I)—cyano (Type II) discrimination can also be observed in oxidative stress-inducing potential of these chemicals. For example, permethrin (a Type I) disturbed the antioxidant defense more than cypermethrin (a Type II) in the erythrocytes of treated rats [8]. Because of its cyano group, cypermethrin shows longer permanence in the membrane, while permethrin can pass easily from this lipid bilayer with its lipophilic nature to reach more readily to cellular subcompartments such as endoplasmic reticulum (ER) membranes that contain CYP450s. Although the presence of α-cyano group decreases the hydrolysis rate of ester bond [32], this group decomposes to cyanides and aldehydes to produce free radicals [33]. Endogenously

O2

and/or glutathione peroxidases (GPx) in the cytosol, mitochondria, nucleus, and also in per-

hydroxyl radical formation via a metal (it is mostly iron) catalyzed reaction if it cannot convert to water efficiently. Hydroxyl radical is the strongest radical capable of oxidizing DNA, cellular membrane lipids, and proteins, and there is no effective agent to escape them in the cell [35]. The most important intracellular iron source is the active site of CYP450s because of

O2

is degraded to water via CAT in peroxisomes

is not assessed as a ROS, it can act as a substrate for

) spontaneously

formed superoxide anion radical is dismutated to hydrogen peroxide (H2

O2

or a SOD-catalyzed reaction. The formed H2

their iron content in the catalytically active center [36–40].

oxisomes [34, 35]. Although the H2

enantioselective, and the most effective stereoisomer is 1*R*-*trans*-permethrin [24].

P450s (CYP450s), and ester bonds are hydrolyzed by carboxylesterase(s) [26].

1 National Center for Biotechnology Information. PubChem Compound Database; CID = 11,442, https://pubchem.ncbi. nlm.nih.gov/compound/11442 (accessed June 18, 2018).

2 National Center for Biotechnology Information. PubChem Compound Database; CID = 5,282,227, https://pubchem.ncbi. nlm.nih.gov/compound/5282227 (accessed June 18, 2018).

3 National Center for Biotechnology Information. PubChem Compound Database; CID = 40,326, https://pubchem.ncbi. nlm.nih.gov/compound/40326 (accessed June 18, 2018).

4 National Center for Biotechnology Information. PubChem Compound Database; CID = 2912, https://pubchem.ncbi.nlm. nih.gov/compound/2912 (accessed June 18, 2018).

5 National Center for Biotechnology Information. PubChem Compound Database; CID = 40,585, https://pubchem.ncbi. nlm.nih.gov/compound/40585 (accessed June 18, 2018).

**Table 1.** Chemical structures of the pyrethroids that are mostly discussed in the current chapter.

children associated with detectable levels of pyrethroid metabolites in the urine; therefore, abnormalities in the dopamine system that is more threatening for boys may be a result of growing use of pesticides, especially pyrethroids [20]. Urinary pyrethroid residues have been correlated with increased chronic heart disease in nonoccupational exposed Chinese people [21]. Occupational exposure to pyrethroids, for example, in the textile industry, is also an important issue throughout the world [22].
