State Enterprise “L. I. Medved’s Research Center of Preventive Toxicology, Food and Chemical Safety of the Ministry of Health of Ukraine”, Kyiv, Ukraine
ABSTRACT. Introduction. Pyrethroids are analogues of natural pyrethrins, primarily isolated from plants of the genus Pymthrum, a family of Asteraceae known for their insecticidal properties.
Objective. To study literature data on the history of synthesis, peculiarities of the chemical structure of pyrethrins, pyrethroids and their most common isomers, a combination of synthetic pyrethroids (SPs) with other chemical substances and insecticidal activity of SPs. Also, to perform an experimental assessment of SP mutagenicity.
Materials and Мethods. For the literature review, data of international organizations, electronic databases and articles of the authors from different countries were used. To study SP mutagenicity, in vivo test for micronucleus (MN) induction in polychromatophilic erythrocytes (PCE) in mice bone marrow was used. Five active substances of SPs were studied: Cypermethrin 94.0 % at the doses of 46.0, 9.2,1.84 mg/kg body weight, 2 samples of Alpha-cypermethrin — 94.0 and 94.7 % at the doses of 20.0,2.0, 0.2 mg/kg, and 2 samples of Lambda-cyhalothrin — 95.2 and 97.1 % at the doses of 5.0,1.0, 0.2 mg/kg.
Results and Discussion. The history of SP synthesis dates back about 70 years. Currently, a significant number of SPs were synthesised that differ in chemical structure, have different strength of insecticidal action, as well as may be used in combination with other compounds. Results of experimental studies suggest that Cypermethrin at the doses from 46.0 to 1.84 mg/kg body weight, 2 samples of Alpha-cypermethrin at the doses from 20.0 to 0.2 mg/kg body weight, as well as 2 samples of Lambda-cyhalothrin at the doses 1.0 and 0.2 mg/kg did not show significant increase in MNPCE level in PCs. However, both samples of Lambda-cyhalothrin at the doses: 5.0 mg/kg body weight induced statistically significant exceeding of the spontaneous rate of MNPCE (р < 0.05).
Conclusion. Cypermethrin at the doses from 46.0 to 1.84 mg/kg body weight did not show a significant increase in MNPCE level. Samples of Alpha-cypermethrin at the doses from 20.0 to 0.2 mg/kg body weight did not show a significant increase in MN level. Samples of Lambda-cyhalothrin at the doses from 1.0 to 0.2 mg/kg did not show a significant increase in MN level. Samples of Lambda-cyhalothrin at the doses: 5.0 mg/kg body weight induced statistically significant exceeding of the spontaneous rate of MNPCE in comparison with the data of negative and historical controls.
Key Words: synthetic pyrethroids, pyrethrins, pyrethroid synergists, mutagenicity, micronucleus test.
Introduction. For thousands of years, people used different means of protection of agricultural crops, domestic animals, housing and warehouses against pests. Pests destroy about 14 % of yield, plant pathogens — 13 %, weeds — 13 % [1,2]. Such methods as sideration, melioration or drying of soils, weeding, pest and insect destroyers and snares have been using by these days. This problem, however, is much commonly resolved using chemical substances. As per investigators’ assessments, about one-third of agricultural products is produced using pesticides [1,3]. In the US, they are used for 80 % of fruit and vegetable crops [4]. This results in the reduction of yield loss due to pests by 35–42 % [5]. If pesticides are not used, losses of fruit may extend back about 78 %, vegetables — 54 % and cereals — 32 %, exportation of cotton, wheat and soybean would be reduced by 27 % [2,6,7]. In a ten-year study of Okayama Institute (Japan), it has been established that careful manual plant treatment without pesticides reduces the yield of agricultural crops by about 10 % [8]. Study of the Texas A&M University showed that prohibition on pesticides may lead to the increase in food cost, job losses, and an increase in the number of undernourished in the world [9,10]. However, careless use of pesticides may result in irreversible consequences for the environment and human health [12-20].
World market for pesticides is rapidly developed. The annual increase in the number of plant protection agents is on average 5 % [10,11]. Currently, about 2.4 mln tonnes of pesticides annually with a total cost of almost USD 56 billion is used all over the world, and of them 45 % are used in Europe, up to 25 % in the US and 25 % in other regions of the world [2, 21, 22].
Ukraine ranks 8th place in the top 10 exporters of food products to the EU and forms part of the top 20 exporters of agricultural products in the world [23]. Ukrainian market of plant protection agents outruns worldwide parameters: from 2009 till 2013, the average annual increase in the use of pesticides was 11 %. According to the State Registry of Pesticides and Agrochemicals Approved for Use in Ukraine [24], 8,037 positions have been registered from 2008 till 2017 (Fig. 1). Pesticides compose more than 16 % from registered pesticides and agrochemicals, 39.4 % of them are synthetic pyrethroids (SPs).
Fig. 1. Number of pesticides and agrochemicals authorised in Ukraine during 2008–2017. * – the line of consistency of change in the number of authorised positions [24].
SPs are widely used against pests or unwanted flying and crawling insects, in particular, flies, horse flies, mosquitoes, black flies, wasps, cockroaches, flies, fleas, spiders, beetles, scorpions, and others. [13,20,27,41]. SPs are needed for protection of agricultural crops and gardens, for control of ectoparasites of domestic animals and domestic insects, carriers of dangerous diseases, for processing of the places of storing clothes, ready-made clothing, packaging materials, food warehouses. Such measures result in the complete elimination of insects, and protective effect may persist 6 to 12 months, since domestic premises, medical premises and even food processing enterprises are processed, and they are used as well as pharmaceutical product for the treatment of lice infestation and scabies [20]. Currently, SPs belong to the most widespread anti-insecticidal agents of the wide spectrum of action, and they are an alternative for organophosphorus and organochlorine pesticides [25,26].
Manufacture of SPs is constantly enlarging: their proportion at the world market in 1976 was 1 %, and in 1987 — 22 %. According to the UK Poison Information Documents (UKPID) and International Program on Chemical Safety (IPCS), in 1989–1990 the following amount of SPs has been produced in the world: about 1,000 tonnes of fenvalerate, 600 tonnes of permethrin, several hundred tonnes of allethrin and its isomers, 340 tonnes of cypermethrin, about 250 tonnes of deltamethrin, several tones of tetramethrin, 70–80 tonnes of d-Phenothrin, and 20-30 tonnes of resmethrin [27-29]. In domestic premises, SPs are used in about 70 % of cases [30]. Since 1990, production of cyhalothrin and lambda-cyhalothrin has been started. Currently, SPs compose 81 % among all insecticides, their world manufacture is now exceeding 3,000 tonnes annually and amounted to more than 3,500 authorised products [32,33].
Along with the benefits of the use of pesticides, mishandling may result in the risk of environmental pollution and food products. The ability of chemical substances to cause mutations has been discovered in 1932 by V. V. Sakharov [50]. Therefore, mutagenicity studies are essential for the justification of toxicological assessment for safe use of pesticides in Ukraine. It is known that SP mutagenic properties vary depending on the chemical structure [13].
Objective. Study literature data on the history of synthesis, peculiarities of the chemical structure of pyrethrins, pyrethroids and their most common isomers, a combination of synthetic pyrethroids (SPs) with other chemical substances and insecticidal activity of SPs, as well as perform an experimental assessment of SP mutagenicity.
Materials and methods. For the literature review, data of international organizations, electronic databases and articles of the authors from different countries were used.
One of the methods used in the Laboratory of Experimental Toxicology and Mutagenesis of the Scientific Centre is the mutagenicity study in the in vitro test for micronucleus (MN) induction in polychromatophilic erythrocytes (PCE) of mice bone marrow. The laboratory has accreditation for study conduct according to the GLP principles. All handling with animals was agreed with the Ethics Committee on Medical and Biological Studies. Following OECD 474 (Guideline for Testing of Chemicals “Mammalian Erythrocyte Micronucleus Test”) [49] recommendations, we have modified SOP for rapid screening of mutagenicity of known pesticides.
The objective of this test is to identify the ability of the test substance to induce cytogenetic (aneugenic and/or clastogenic) lesions leading to the MN formation that contain either whole chromosome or its fragments that were delayed in the process of cell division.
In the in vivo test for MN induction in erythrocytes of mice bone marrow, 5 active substances of pyrethroid insecticides from different manufacturers and with different percentage content of impurities: Cypermethrin 94 % was studied at the doses of 46.0, 9.2, 1.84 mg/kg body weight, 2 samples of Alpha-cypermethrin — 94.0 and 94.7 % at the doses of 20.0, 2.0, 0.2 mg/kg, and 2 samples of Lambda-cyhalothrin — 95.2 and 97.1 % at the doses of 5.0, 1.0, 0.2 mg/kg.
The study was performed in young sexually mature male mice (Mus Musculus l. – CD1 albino) with a body weight from 18 to 20 g received from SPF breeding nursery of small laboratory animals with the appropriate certificate of quality on animal health. Animals were examined by the veterinary physician on a daily basis during acclimatisation and experiment for compliance with the requirements to the biological models in the toxicological experiment and eligibility for this study. Acclimatisation of the animals under conditions of vivarium was performed for at least 5 days at the study initiation. Test substances were administered as a single oral dose. The experiment included a negative and positive control. Negative control (solvent) — animals received purified, UV sterilised, deionised water with the addition of emulsifier in the same amount and in the same way as test animals. Positive control — animals received 0.1 mL of cyclophosphamide solution as a single intraperitoneal dose of 40 mg/kg body weight. Five animals were included in each test and control group. In 24 hours, animals were humanely sacrificed, samples of the bone marrow were prepared and analysed using microscopy.
Results and discussion. Insecticidal properties of plants of the genus Pyréthrum, a family of Asteraceas, were used even in ancient Macedonia, China, in medieval Persia, and in Europe, it got out more than 200 years ago [13]. Dried and milled blossom clusters of Dalmatian pyrethrum containing 0.15–0.5 % of pyrethrins kill cockroaches, bugs, flies and mosquitoes, and other pests. Therefore, these plants were also introduced in the culture of Japan, Brasilia, and the US. At the end of 19th century in Japan, production of mosquito sticks and spirals was initiated from 2—10 % solution of the extract of this flowers or from fine grinding of dried flowers, and they have been continuously burning and scared insects. At the beginning of the 20th century, about 20 thous tonnes of dried flowers were manufactured annually, and 70 % of them were manufactured in Japan [30, 34, 35]. At the same time, pyrethrins were for the first time extracted from chamomile flowers using organic solvents, and the US produced products containing up to 90 % of pyrethrins, they are obtained by distillation of solvent from extracts under low temperatures [36].
Natural pyrethrin is a mixture of 6 components which are esters of chrisanthemic or pyrethrin acid and alkyl-cyclical keto-alcohol of pyrethrolone, jasmolon, and cynerolone, their structural formulas and percentage ratio in the natural pyrethrin are shown in Table 1 [30, 37-40]. Pyrethrin-I has the highest insecticidal activity compared with other components [38, 39]. The molecular formula of Pyrethrin-I - C21H 28O3, the relative molecular weight is 328.452 g/mol.
Table 1
Content of ethers in the natural Pyrethrin and their percentage ratio [29,36-39]
First of SPs, allethrin, was synthesised in 1949 in the US [30]. The following products were produced based on the first generation pyrethroids (similar in chemical structure to the natural pyrethrins): furethrin, cyclethrin, barthrin, dimethrin, neopinamine, resmethrin. These compounds have high insecticidal activity, however, they are easily oxidised under ultraviolet, and therefore, they were used mainly in closed premises [41].
In 1960–70, new photostable pyrethroid insecticides of the wide spectrum of action were authorised, and they are effective under the low consumption rate (scores or hundreds of grams per hectare of treated area). For example, deltamethrin has 900-fold better insecticidal activity that natural pyrethrin-I [29, 38, 42], and permethrin acts on insects 50–100-fold potently than well-known insecticide DDT [36]. These are the second generation SPs (chrisanthemic acid derivatives) that are more toxic for insects and more stable in the environment: tetramethrin, bioallethrin, phenothrin, permethrin, cypermethrin, and also deltamethrin. Disadvantages of the second generation pesticides include high toxicity for bees, as well as for birds and aquatic organisms. Many of these SPs have no acaricidal properties, and there is also the relatively rapid development of resistance in insects (therefore, they are commonly used in a mixture with organophosphorus insecticides) [43].
Third generation SPs (ethers of permethrin, cyclopropane carboxylic, isovaleric acid) include cyhalothrin, tralomethrin, cyfluthrin, phenpropathrin, bifenthrin, and cycloprothrin. Despite the absence of cyclopropane ring, similar insecticidal activity was found in the group of phenyl acetic 3-phenoxybenzolic ethers, such as fenvalerate and other related compounds such as etofenprox, flucythrinate, and fluvalinate. Some of these substances have high acaricidal activity, less toxic for bees, birds, and fish. Cyhalothrin is the most commonly used among these SPs, and it is 2.5-fold more active than deltamethrin [29,38,42].
Currently, SPs virtually drive natural pyrethrins out of the market of insecticides, since SPs have significantly higher insecticidal activity and better photostability in the environment compared with pyrethrin [37]. At present, thousands of different SPs and their derivatives were synthesised, however, only scores of them are used [13,30]. Upon synthesis of the majority of SPs, 4 or 8 stereoisomers are formed with different positions of substituting groups in cyclopropane ring or equivalent part of phenyl acetate, however, 1 or 2 isomers, in general, have high insecticidal activity [13]. Different isomers of one SPs may have a common name by different biological activity. Commonly SP manufacturers produce substances under in-house names. The most common synonyms of pyrethroids are provided in Table 2 [44].
Table 2
The most common names of synthetic pyrethroids [44]
SPs differ by their chemical structure: type of alcohol component, number and position of substituting groups in acid and alcohol parts of molecules, as well as relative position of certain groups of molecules [26, 34, 35, 37, 38, 42, 45].
Presence of alpha-cyano group divides SPs into two classes. SPs without alpha-cyano group belong to class I, SPs containing this group belong to class II pyrethroids. Summary data on the chemical structure of the most common class I and II pyrethroids, the most insecticidal effective isomers, structural and molecular formulas, relative molecular weight and year of synthesis are provided in Table 3 and Table 4 [13, 27, 29, 34, 35, 39, 41, 44].
Table 3
Class I pyrethroids, their most common isomers, structural and molecular formula, relative molecular weight and year of synthesis [13,26,28,33,34,38,40,43,44]
Table 4
Class II pyrethroids, their most common isomers, structural and molecular formula, relative molecular weight and year of synthesis [13,26,28,33,34,38,40,43,44]
A large number of different methods of SP synthesis, as well as variants of synthesis of certain stereoisomers and schemes to obtain similar structural fragment, is known. Selection of the method depends on the initial compound and possibilities to create conditions for synthesis. The complexity of obtaining certain stereoisomers due to the complex structure of this group of insecticides and the high price of synthesis is common for these methods [38, 45-48].
The most common method of synthesis of 3-dihaloethynyl-2,2-dimethyl cyclopropane carboxylic acid (permethrin) ethers is Farkas method based on the reaction of appropriate unsaturated compounds with diazoacetic ester [37,43]. Advantages of this method include simple organic initial compounds — trichloroacetaldehyde, aminoacetic acid, isobutylene, bromobenzaldehyde, ethyl alcohol and phenol, as well as the course of all stages of reactions takes place with obtaining a large amount of required substance — 70–95 %, and the final mixture contains about 55 % cys- and 45 % trans-isomers [38].
Also it is possible to use the method for obtaining permethrin acid ethers in several stages: first of all, reaction of isobutylene with paraformaldehyde is performed in the presence of disodium phosphate in tert-butanediol, then isomerization is performed on a palladium catalyst to a pure 3-methylbuten-2-ol; then condensation is performed with orthoacetic ether with formation of 3,3-dimethylpentane acid ether that is transformed into permethrin acid ethyl ether [37,43,45].
The method patented by Bayer fundamentally differ replaced butyrolactone upon oxidation of 4-methyl-1,1-dichloro pentadiene with manganese acetate to acetic acid is transformed to permethrin acid ether [37,43,45,46].
Many methods were also developed: for obtaining permethrin and other acids with high content of one of the isomers (1R-cys and 1R- trans with the ration of 85:15 and optical purity of 90 %); reactions without isomerization for obtaining about 95 % of the required substance; obtaining dibromide ethers (more active than deltamethrin), ethers of decamethrinic acid, obtaining other derivatives of cyclopropane acids; synthesis of analogues substances without cyclopropane acid, for example, fenvalerate (residue of arylisovaleric acid instead of cyclopropane acid), etc. [37,38].
A mixture of cys- and trans-isomers may be separated using crystallization with the solvent is solubility of isomers differs. Decys that contains virtually pure cys-isomer is obtained by such a method. However, a mixture of isomers is used more commonly [37,46].
Researches have explored that usually for the manifestation of high insecticidal efficiency structure of atom C-1 is more important than the position of trans- or cys-substituting groups in cyclopropane fragment: 1R-isomers have hundred times higher insecticidal activity compared with 1S-isomer [30,33], and 1R-cys-isomer is almost two-fold less effective than 1R-trans-isomer. Also the most important is atom structure in the alcohol component: isomers with αS-configuration [37]. Also, literature data suggest that the mixtures of stereoisomers of SPs have properties of additivity (synergism) [37,38,43]. 1R-isomers of pyrethroids are a hundred times more effective than 1S-isomers, however, the racemic mixture has two-fold higher insecticidal activity than pure 1R-isomer [34]. However, for some mixtures of pyrethroid isomers presence of antagonism (neutralisation) of isomers is possible — inactive or less active isomer prevents the action of the active component, insecticidal activity of such mixture is much lower compared with pure active stereoisomer [38].
To improve the efficiency of insecticidal action, sometimes SPs of the first and second generation are used in combination with synergic compounds that have no insecticidal action, however, suppress processes of deactivation of pyrethroid insecticides in insects [37,43]. The most common SP synergists may increase toxicity for insects from 100 to 170 fold [20,30]. Piperonyl butoxide (oxidase inhibitor) is commonly used as SP synergist; it increases fenvalerate activity fourfold, and profenofos (esterase inhibitor) increases cypermethrin activity 20-fold. Also, synergists may include N-oxyl bicycloheptene dicarboximide (MGK-264), tropital, bucarpolate, sesamex, piperonyl cyclonel, propyl isome, and other pyrethroids [30,37,40,43]. The most common SP synergists, their structure and molecular formulas, as well as molecular weight, are provided in Table 5 [44]. Sometimes the amount of synergist in the pyrethroid product may several times exceed the amount of pyrethroid, since SPs are characterised with a small consumption rate, and also, in this mixture, pyrethroid is the component that it is more difficult to synthesise. In general, third generation SPs are used without synergists, however, sometimes 1–3 % of the first or second generation SP is added for acceleration of action [37,43]. In order to prevent resistance to SPs in insects, they are commonly used in combination with other insecticides that differ in the mechanism of action [37].
Table 5
The most common synergic pyrethroids [44]
It is known that depending on the chemical structure of pyrethroids, toxicity as well as mutagenicity of SPs for insects, mammals changes [13]. In the experimental study, we assessed the mutagenicity of active substances of SPs from different manufacturers and with different percentage content of impurities.
During the experiment of in vivo MN induction in PCE of mice bone marrow, the behaviour of the test animals did not differ from behaviour in control mice. No clinical symptoms of intoxication or animal death under the action of test substances were observed in all test doses.
Data of positive and negative control obtained during the experiment were compared with historical controls. Number of MN in PCE in the animals of control groups were within the levels of historical controls. Animals of the positive control group (Cyclophosphamide) showed statistically significant (р ≤ 0.05, Student t-test) exceed of the spontaneous rate of MNPCE. This confirms the correctness of this test system to assess mutagenic properties of the chemical substances.
The obtained results are provided in Table 6 suggesting that in the in vivo test for MN induction of PCE in the mice bone marrow Cypermethrin at the doses from 46.0 to 1.84 mg/kg body weight, 2 samples of Alpha-cypermethrin at the doses from 20.0 to 0.2 mg/kg body weight, as well as 2 samples of Lambda-cyhalothrin at the doses 1.0 and 0.2 mg/kg did not show significant increase in MN level. However, two samples of Lambda-cyhalothrin at the doses: 5.0 mg/kg body weight induced statistically significant exceeding of MN rate compared with negative control (р ≤ 0.05).
Table 6
Results of mutagenicity study of SPs in the test for micronucleus induction.
Conclusion
1. Modern synthetic pyrethroids are the result of long-term and difficult work of researchers from many countries. The history of SP development continues for almost 70 years. There is a wide range of pyrethroid compounds with different properties that allows proper choice for each certain case. SPs are used in different forms: moistened powders, concentrate of the emulsion, aerosols, fumigates (pyrotechnic spirals), chalk, granules, in the composition of shampoos, etc. [20, 25, 41]. Currently, the synthesis of new derivatives of cyclopropane carboxylic acid and related compounds by the mechanism of action continues. Simultaneously with the synthesis of new molecules, researchers study mechanisms of action of these substances in insects, physiochemical properties, peculiarities of the analogues, the transformation of substances upon a change in external influences (temperature, humidity, ultraviolet), as well as combinations of SPs with other compounds. Effect of SPs on the mammalian body is also studied, a possible danger for a human is assessed with the development of different mechanisms of SP obtaining [38]. Since not all isomers of SPs have similar insecticidal activity, efforts of chemists are aimed at the development of stereoselective methods of their obtaining [38]. Understanding of the peculiarities of the chemical structure of compounds and mechanisms of action allows establishing the main places of molecule breakdown and acquisition of resistance and gives the possibility to determine the direction for further search of new improved SPs [38,33].
2. In the experimental study, Cypermethrin at the doses from 46.0 to 1.84 mg/kg body weight did not show a significant increase in MNPCE level.
3. Samples of Alpha-cypermethrin at the doses from 20.0 to 0.2 mg/kg body weight did not show a significant increase in MN level.
4. Samples of Lambda-cyhalothrin at the doses from 1.0 to 0.2 mg/kg did not show a significant increase in MN level.
5. Samples of Lambda-cyhalothrin at the doses: 5.0 mg/kg body weight induced statistically significant exceeding of the spontaneous rate of MNPCE compared with the data of negative and historical controls.
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