Pesticide Interactions: Mechanisms, Benefits, and Risks - Journal of

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Pesticide Interactions: Mechanisms, Benefits, and Risks John E. Casida* Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy, and Management, University of California, Berkeley, California 94720, United States ABSTRACT: Interactions between pesticides at common molecular targets and detoxification systems often determine their effectiveness and safety. Compounds with the same mode of action or target are candidates for cross resistance and restrictions in their recommended uses. Discovery research is therefore focused on new mechanisms and modes of action. Interactions in detoxification systems also provide cross resistance and synergist and safener mechanisms illustrated with serine hydrolases and inhibitors, cytochrome P450 and insecticide synergists, and glutathione S-transferases and herbicide safeners. Secondary targets are also considered for inhibitors of serine hydrolases, aldehyde dehydrogenases, and transporters. Emphasis is given to the mechanistic aspects of interactions, not the incidence, which depends on potency, exposure, ratios, and timing. The benefits of pesticide interactions are the additional levels of chemical control to achieve desired organismal effects. The risks are the unpredictable interactions of complex interconnected biological systems. However, with care, two can be better than one. KEYWORDS: molecular target, detoxification, resistance, synergist, safener, cytochrome P450, glutathione S-transferase

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INTRODUCTION Over 800 pesticides are used in producing our food and protecting our health.1 They are often intentionally applied as combinations for maximum effectiveness. What do we know about pesticide interaction mechanisms and their benefits and risks? The scope of the subject is dauntingly large, so the examples presented emphasize research in the author’s laboratory.

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TARGET SITE CROSS RESISTANCE A principal limiting factor in the use of chemicals in pest management is the selection of resistant strains often involving reduced target site sensitivity.2,3 This first became important with DDT and pyrethroids acting at the insect voltagedependent sodium channel and the organophosphates (OPs) and methylcarbamates (MCs) at acetylcholinesterase (AChE). The selection process has continued with each new class of pesticides and reached a level of concern leading to “Pesticide Resistance Action Committees” to classify compounds as to common mode of action and likely cross resistance (Figure 1). The impact of this type of interaction is evident from recent market value data7 for the top three to five insecticide, herbicide, and fungicide common targets with likely cross resistance that account for 61, 47, and 45% of market value, respectively; that is, these are overused targets with major risks of control failures because of resistance (Table 1). The solution to this dilemma is to introduce new chemicals acting on novel targets. This has been possible so far with focused search programs. The Pesticide Resistance Action Committees have made an outstanding contribution in achieving this goal.

Figure 1. Target site interactions and cross resistance evaluated by the Insecticide Resistance Action Committee (IRAC),4 Herbicide Resistance Action Committee (HRAC),5 and Fungicide Resistance Action Committee (FRAC).6

The enzymes involved are normally serine hydrolases (SHs), cytochrome P450s (CYPs), and glutathione S-transferase (GSTs) of many types, varying with species and strains and difficult to predict in their sites of metabolic attack and contribution to resistance. In each people, insects, plants, and fungi (Homo sapiens, Drosophila melanogaster, Arabidopsis thaliana, and Neurospora crassa), there are a few to more than 200 SHs (including serine proteases and metabolic SHs), CYPs, and GSTs, only a portion of which are known to contribute to pesticide detoxification. Extensive reviews are available on pesticide metabolism and properties of the principal detoxifying SHs,8−10 CYPs,2,11−13 and GSTs.14−17 All of these enzymes are involved in the metabolism of chlorpyriphos (Figure 2), illustrating the need to focus on the most relevant systems.

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METABOLIC CROSS RESISTANCE Many of the most critical resistance problems are from selection for detoxifying enzymes rather than for less sensitive targets. Although this type of resistance is totally independent of their mode of action, each pesticide chemotype usually has similar substituents that facilitate metabolic cross resistance. © 2017 American Chemical Society

Received: Revised: Accepted: Published: 4553

April 19, 2017 May 18, 2017 May 24, 2017 May 24, 2017 DOI: 10.1021/acs.jafc.7b01813 J. Agric. Food Chem. 2017, 65, 4553−4561

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Journal of Agricultural and Food Chemistry Table 1. Common Pesticide Target Sites Resulting in Likely Interactions and Cross Resistance Based on Resistance Action Committee Classifications compounds top five target sites, classifications and chemotypesa

major

Insecticides (IRAC Classifications) nAChR (4A), neonicotinoids imidacloprid Na+ channel (3A), pyrethroids λ-cyhalothrin ryanodine receptor (28), diamide chlorantraniliprole glutamate CI− channel (6), abamectin avermectin AChE (lB), OP, MC chlorpyriphos sum Herbicides (HRAC Classifications) EPSPS (G), glycine derivative glyphosate HPPD (F2), triketone mesotrione VLCFA (K3), chloroacetanilide S-metolachlor superoxide (D), bipyridylium paraquat glutamine synthetase (H), glufosinate phosphonic acid sum Fungicides (FRAC Classifications) Qo 1 (11, C3), strobilurin azoxystrobin 14a-demethylase (3, Gl) prothioconazole multisite (M3, M), mancozeb bis(dithiocarbamate) SDHI (7, C2), boscalid pyridinecarboxamide multisite (M5, M), chloronitrile chlorothalonil sum

other

market valueb (%)

4c 7d le lf

25 13 10 8

lg

5 61

lh 2i 2j 0 0

22 21 4 3 2 52 (47%)

k

5 4l 0

27 13 6

2m

5

0

Figure 3. Negatively correlated cross resistance involving (A) specificity of carbofuran and n-propyl carbofuran at AChE binding site of S- and R-green rice leafhopper and (B) CYP detoxification of DDT and activation of phenylthiourea (PTU) in fruit flies (oxidation site known for DDT and proposed for PTU shown by arrows).

4 55 (45)

This might mean one could alternate the chemicals to maintain control. The first major example was DDT and phenylthiourea in fruit flies.21,22 Another was N-methylcarbamates and Npropylcarbamates or the corresponding oxadiazolones for green rice leafhoppers23 and Colorado potato beetles.24 Many examples are described for negatively correlated cross resistance in fungicides.25 Although these and other studies contribute to understanding resistance mechanisms, they have not resulted in altered pest management practices.

a

Top 30 for each of insecticides, herbicides, and fungicides in 2015 world market value. Data provided by Thomas C. Sparks of Dow AgroSciences. Abbreviations are given at the end of the text. bSum of top 30 insecticides as 100% and also for herbicides and fungicides. There are five common targets for the insecticides but only three for the herbicides and fungicides with their total market value shown in parentheses. cThiamethoxam, clothianidin, acetamiprid, and thiacloprid. dDeltamethrin, permethrin, bifenthrin, λ-cypermethrin, cypermethrin, tefluthrin, and etofenprox. eFlubendiamide. fEmamectin benzoate. gCarbofuran. hGlyphosate-trimesium. iTembotrione and isoxaflutole. jAcetochlor and dimethenamid-P. kPyraclostrobin, trifloxystrobin, fluoxastrobin, kresoxim-methyl and picoxystrobin. l Tebuconazole, epoxiconazole, difenoconazole and propiconazole. m Isopyrazam and bixafen.

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SERINE HYDROLASES AND INHIBITORS Many pesticides are carboxylic esters and amides hydrolyzed by carboxylesterases or carboxylamidases, sometimes named after their substrates, for example, propanil acylamidase, pyrethroid esterase, and indoxacarb hydrolase (Figure 4). They each have multiple potential interactions with other pesticides or substrates or inhibitors.26 The propionanilide herbicide propanil, once extensively used on rice, is detoxified by an acyl amidase more active in the crop than in the weeds but inhibited by OP and MC insecticides, thereby destroying the mechanism of crop safety.27,28 “Pyrethroid esterases” detoxifying pyrethroids with trans- and cis-cyclopropanecarboxylate substituents are inhibited by OP pesticides such as tribufos and profenfos1 to greatly increase their insecticidal activity and mammalian toxicity.29−34 These esterases provide natural pyrethroid tolerance to green lacewing larvae in integrated control programs.35 Several of the pyrethroid hydrolases of human, rat, and mouse liver have been characterized including human carboxylesterases hCE-1 and hCE-2.33,34 The oxadiazine insecticide indoxacarb is bioactivated by hydrolases in lepidopterous larval fat body and midgut.36 This bioactivation is selective for insect versus mammals and makes it possible to use a potent insecticidally active sodium channel blocker as a new class of insecticides to circumvent cross resistance.

Figure 2. SH, CYP450, and GST metabolism of chlorpyriphos and its oxon by human liver microsomes ± NADPH or GSH or CYP3A4 ± NADPH.18 Several esterases and SHs hydrolyze the chlorpyriphos oxon.19 CYP isoform specificity for desulfuration is 2B6 > 3A4 and for dearylation is 2C19 > 3A4.20

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NEGATIVELY CORRELATED CROSS RESISTANCE An intriguing and challenging aspect of pesticide interactions is the observation that resistance to one chemical is sometimes associated with increased susceptibility to a second pesticide; that is, there is negatively correlated cross resistance (Figure 3). 4554

DOI: 10.1021/acs.jafc.7b01813 J. Agric. Food Chem. 2017, 65, 4553−4561

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Journal of Agricultural and Food Chemistry

Figure 4. OP-sensitive serine hydrolases detoxify propanil (A) in rice and phthalthrin (B) in insects and mammals, activate indoxacarb (C) in insects, and govern the toxicity of malathion (D) and acephate (E) in insects and mammals.

Figure 5. Insecticides are CYP substrates and inducers, and synergists are CYP inhibitors. Arrows designate sites of oxidation.

of malathion is less effectively oxidized than hydrolyzed. A similar relationship holds for acephate, which undergoes OPsensitive amidase activation to methamidophos, which in turn is probably oxidized by CYP to methamidophos sulfoxide that in turn inhibits the amidase activation, thereby making acephate nearer the toxicity of methamidophos on a chronic than an acute basis.38 Other OPs inhibiting malathionase or acephate amidase would have much the same effect.

Some OP pesticides such as malathion and acephate (Figure 4) are metabolized by multiple pathways, which may not be independent of each other such that the product of one reaction inhibits another pathway. Malathion is a carboxylic acid ester detoxified by the carboxylesterase malathionase and bioactivated on CYP-mediated oxidation to malaoxon, a likely malathionase inhibitor.37 Multiple low doses may favor malaoxon formation and toxicity, whereas a single high dose 4555


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Figure 6. Herbicide safeners enhance crop safety by inducing GSH/GST detoxification.

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CYPs AND INSECTICIDE SYNERGISTS Pyrethrum has been used since the middle ages as the principal botanical insecticide, providing outstanding control of many major pests.39 The active ingredients are pyrethrin I (Figure 5) and five related esters, which are short residual and metabolically labile. They are stabilized or synergized by addition of the synthetic methylenedioxyphenyl (MDP) synergist piperonyl butoxide (PBO).40 Other MDP synergists are the earlier botanicals sesame oil,41 and the synthetic sesamex, and the more recent myristicin42 from parsley and dillapiol43 from dill. Although PBO increases the potency of many insecticides, it is used primarily with chrysanthemate pyrethroids40 and is sometimes supplemented with the synergistic dicarboximide MGK-264.44 There are also many other types of insecticide synergists including the very effective O-(2-propynyl) O-n-propyl phenylphosphonate (PPP), which have not been developed commercially.45−47 PPP is bioactivated by alkene epoxidation and rearrangement to the ketene as the reactive inhibitor.48 Imidacloprid is detoxified by CYP-mediated imidazole methylene hydroxylation reactions and increased in toxicity to houseflies by >100-fold by PPP.49 The imidazole-fungicide triflumizole,1 an ergosterol biosynthesis inhibitor, and dietholate, which prolongs herbicide persistence in soil, are also CYP inhibitors and synergists. CYPs are the primary enzymes for metabolism of many insecticides and interactions with synergists (Figure 5). Abass et al.50 noted that 12 human recombinant CYP isoforms (IA1, IA2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, 3A5, and 3A7) are involved in the metabolism of 36 insecticides, 10 herbicides, and 14 fungicides. Human CYP450 isozymes differ in selectivity for imidacloprid imidazolidine oxidation (3A4 > 2C19 or 2A6 > 2C9) versus nitroimine reduction (1A2, 2B6, 2D6, and 2E1)51 (Figure 5). The broad scope combined with selectivity of the CYP450 reactions illustrates the potential complexities of

substrate and inhibitor interactions. The synergists known to date are selective for some CYP isozymes but not between insect and mammalian CYPs. Insecticides are not only CYP substrates but also serve as CYP inducers enhancing xenobiotic detoxification.12,52,53

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GSTs AND HERBICIDE SAFENERS Herbicides must control major weeds in important crops without injuring the crop itself. Alternatives are to change the herbicides by structural alterations or the crop by genetic modification or induced biochemical changes.54−58 The major thiocarbamate and chloroacetanilide herbicides are very effective in weed control in maize, sorghum. and rice. but many are not adequately selective (Figure 6). The serendipitous discovery that 2,4-dichlorophenoxyacetic acid (2,4-D) action on tomato was blocked by the 2,4,6-trichloro analogue54 led to the search for herbicide antidotes or safeners to decrease crop damage without lowering potency on weeds. A multiple crop−multiple herbicide screen revealed 1,8-naphthalic anhydride (NA) as a broad-spectrum seed treatment antidote.54 The first commercialized herbicide−safener combination was the thiocarbamate S-ethyl dipropylthiocarbamate (EPTC) with NA, but it was soon replaced by the more effective dichloroacetamide dichlormid. The mechanism of safener action was established with EPTC and dichlormid. 59,60 EPTC is bioactivated to the sulfoxide and sulfone, and dichlormid induces the synthesis of GSH and GST in maize. The induced GSH/GST system detoxifies EPTC sulfoxide. This GST is not one normally expressed in maize. Comparable systems were found for chloroacetanilides such as metolachlor and acetochlor and set the pattern for GSTs and herbicide safeners.56−62 Major safeners are dichloroacetamides (dichlormid and benoxacor for maize) but other types are preferred for sorghum (fluxofenim), rice (fenchlorim) and small grain cereals (cloquintocet-mexyl). The common feature is increased crop detoxification of the 4556


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Figure 7. Sulfonylurea herbicide crop safety (A) increased by safener-enhancing detoxification in cereals and (B) decreased by insecticide-inhibiting detoxification in maize.

Figure 8. Pesticide interactions with aldehyde dehydrogenases: (A) ethanol sensitivity from acetaldehyde accumulation; (B) Parkinson’s disease associated with DOPAL accumulation.

mechanism are increasingly revealed relative to their specificity and relevance. There are also other types of herbicide−safener action. The sulfonylurea herbicides have remarkable potency as acetohydroxyacid synthase inhibitors, but problems with selectivity necessitate a critical balance of substituents. Mesosulfuron-

herbicide from the safener-induced elevated GSH level and GST activity. Dichlormid in maize roots increased sulfate metabolism and ATP sulfurylase activity.63 A safener binding protein64 and the relevant gene65 have been recognized for dichlormid action in maize. Oxidative stress and oxylipid signaling appear to be involved66 as the pieces of the 4557


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and lost to agriculture and public health. This requires introducing one new compound and mode of action after the other. This is the same problem for chemicals and genetically modified organisms (GMOs). A synergist can be added to inhibit detoxification and increase potency. A safener may be useful to enhance detoxification in the crop without effect on weed sensitivity. In contrast to GMOs, these additives can be used only when necessary on a temporary basis. The toxic effects of pesticides on wildlife and human health are generally evaluated on compounds individually rather than on the interactions of mixtures.90−92 Interactions can only be tested in a limited number of combinations, and therefore knowledge of the target site and detoxification mechanisms is essential in the safe and effective use of pesticides in pest management.

methyl is a major herbicide safened with mefenpyr-diethyl, which induces increased herbicide detoxification in cereals67 (Figure 7). The nicosulfuron analogue is safe on maize due to pyrimidine 5-hydroxylation, but this favorable selectivity is blocked by terbufos sulfone, such that the systemic insecticide destroys the herbicide selectivity.68,69

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SECONDARY TARGETS OF SERINE HYDROLASES AND ALDEHYDE DEHYDROGENASE INHIBITORS Several fungicides such as thiram, ziram, and benomyl interact at aldehyde dehydrogenase (ALDH) targets contributing to their toxicological effect in mammals (Figure 8). Thiram, ziram, and related dithiocarbamate pesticides via thiocarbamate sulfoxide metabolites formed in multistep reactions inhibit ALDH, thereby blocking acetaldehyde detoxification important in ethanol poisoning.70 Even more potent is the fungicide benomyl acting via its n-butylisocyanate and S-methyl nbutylthiocarbamate sulfoxide metabolites.71,72 These findings are relevant to Parkinson’s disease (PD), in which 3,4dihydroxyphenylacetaldehyde (DOPAL) plays a role.73−75 Thus, interactions occurring at ALDH are of potential toxicological concern. Other pesticides proposed to contribute to PD are rotenone, which decreases ALDH activity,76 and paraquat via mechanisms other than DOPAL accumulation.77 The large number of OP SH inhibitors used now or earlier as pesticides and the enormous variety of OP-sensitive SHs has resulted in many possible interactions including synergism, potentiation, and delayed neurotoxicity considered in earlier reviews78−81 but not here.

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CONCLUDING COMMENTS The pesticide interactions considered in this review are examples rather than an encyclopedic list and are meant to illustrate the nature rather than the full scope of the topic. Some interactions involving intentional pesticide combinations are predictable and can be made with full consideration of the effects. However, other interactions may be overlooked due to the complex nature of “real-world” field systems involving multiple pesticides,93 crops, weeds, fungi, insects, nontarget organisms, soil, air, and waterways. Unexpected interactions provide new challenges to define the mechanisms, establish their relevance, and alter the pest management system when necessary.

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TRANSPORTERS AND INHIBITORS P-Glycoprotein (P-gp) and other ATP-binding cassette (ABC) proteins are involved in the action of and resistance to diverse pesticides and some bacteria and bacterial toxins82−86 (Figure 9). P-gp substrates include diazinon, rotenone, and the 1-

AUTHOR INFORMATION

Corresponding Author

*Phone: (510) 642-5424. E-mail: [email protected]. ORCID

John E. Casida: 0000-0002-3181-7561 Notes

The author declares no competing financial interest.

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ACKNOWLEDGMENTS I give special thanks to Minhchau (MC) Le Nguyen (B.S. 2017, Department of Nutritional Sciences and Toxicology: Physiology and Metabolism at the University of California, Berkeley) and Ilsa Zhang (B.S. 2017, Department of Nutritional Sciences and Toxicology: Molecular Toxicology at the University of California, Berkeley), who assisted with devotion and distinction in searching, compiling, and presenting the information in this review.

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Figure 9. ATP-binding cassette proteins inhibited by (A) ivermectin for P-gp and (B) abamectin and spinetoram for Helicoverpa armigara ABC proteins.

ABBREVIATIONS USED 2,4-D, dichlorophenoxyacetic acid; ABC, ATP-binding cassette; AChE, acetylcholinesterase; AChR, ACh receptor; ALDH, aldehyde dehydrogenase; CYP, cytochrome P450; DOPAL, 3,4-dihydroxyphenylacetaldehyde; EPSPS, EPSP synthase; EPTC, S-ethyl dipropylthiocarbamate; FRAC, Fungicide Resistance Action Committee; GMO, genetically modified organism; GST, glutathione S-transferase; hCE-1, human carboxylesterase 1; hCE-2, human carboxylesterase 2; HPPD, 4-hydroxyphenylpyruvate dioxygenase; HRAC, Herbicide Resistance Action Committee; IRAC, Insecticide Resistance Action Committee; MC, methylcarbamates; MDP, methylenedioxyphenyl; MPP+, 1-methyl-4-phenylpyridinium ion; NA, 1,8-naphthalic anhydride; nAChR, nicotinic AChR; OP, organophosphates; PBO, piperonyl butoxide; PD, Parkinson’s

methyl-4-phenylpyridinium ion (MPP+), whereas ivermectin is a potent P-gp inhibitor.87 A mutation disrupting the ABC transporter of the lepidopterous pest Helicoverpa armigara selected for resistance to Bt toxin Cry1A is increased in susceptibility to abamectin and spinetoram88,89 (Figure 9).

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BENEFITS AND RISKS Each pesticide is structurally optimized to control pests under a variety of circumstances. The biggest problem of multiple pesticide exposure involves compounds of common mode of action and selection of resistant pest strains. The dose must be increased and classes of effective pesticides become ineffective 4558


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propylcarbamate or oxadiazolone for green rice leafhopper. Arch. Insect Biochem. Physiol. 1993, 22, 277−288. (24) Kim, H. J.; Dunn, J. B.; Yoon, K. S.; Clark, J. M. Target site insensitivity and mutational analysis of acetylcholinesterase from a carbofuran-resistant population of Colorado potato beetle, Leptinotarsa decemlineata (Say). Pestic. Biochem. Physiol. 2006, 84, 165−179. (25) Pittendrigh, B. R.; Huesing, J.; Walters, K. R., Jr.; Olds, B. P.; Steele, L. D.; Sun, L.; Gaffney, P.; Gassmann, A. J. Negative crossresistance: history, present status, and emerging opportunities. In Insect Resistance Management: Biology, Economics and Predictions, 2nd ed.; Onstad, D. Ed.; Academic Publishers Elsevier: Oxford, UK, 2004; pp 373−402. (26) Wheelock, C. E.; Shan, G.; Ottea, J. Overview of carboxylesterases and their role in the metabolism of insecticides. J. Pestic. Sci. 2005, 30, 75−83. (27) Matsunaka, S. Propanil hydrolysis: inhibition in rice plants by insecticides. Science 1968, 160, 1360−1361. (28) Khodayari, K.; Smith, R. J., Jr.; Tugwell, N. P. Interaction of propanil and selected insecticides on rice (Oryza sativa). Weed Sci. 1986, 34, 800−803. (29) Abernathy, C. O.; Casida, J. E. Pyrethroid insecticides: esterase cleavage in relation to selective toxicity. Science 1973, 179, 1235−1236. (30) Jao, L. T.; Casida, J. E. Insect pyrethroid-hydrolyzing esterases. Pestic. Biochem. Physiol. 1974, 4, 465−472. (31) Casida, J. E.; Ueda, K.; Gaughan, L. C.; Jao, L. T.; Soderlund, D. M. Structure-biodegradability relationships in pyrethroid insecticides. Arch. Environ. Contam. Toxicol. 1975, 3, 491−500. (32) Ishaaya, I. Insect detoxifying enzymes: their importance in pesticide synergism and resistance. Arch. Insect Biochem. Physiol. 1993, 22, 263−276. (33) Nishi, K.; Huang, H.; Kamita, S. G.; Kim, I.-H.; Morisseau, C.; Hammock, B. D. Characterization of pyrethroid hydrolysis by the human liver carboxylesterases hCE-1 and hCE-2. Arch. Biochem. Biophys. 2006, 445, 115−123. (34) Crow, J. A.; Borazjani, A.; Potter, P. M.; Ross, M. K. Hydrolysis of pyrethroids by human and rat tissues: examination of intestinal, liver and serum carboxylesterases. Toxicol. Appl. Pharmacol. 2007, 221, 1− 12. (35) Ishaaya, I.; Casida, J. E. Pyrethroid esterase(s) may contribute to natural pyrethroid tolerance of larvae of the common green lacewing. Environ. Entomol. 1981, 10, 681−684. (36) Wing, K. D.; Sacher, M.; Kagaya, Y.; Tsurubuchi, Y.; Mulderig, L.; Connair, M.; Schnee, M. Bioactivation and mode of action of the oxadiazine indoxacarb in insects. Crop Prot. 2000, 19, 537−545. (37) Main, A. R.; Dauterman, W. C. Kinetics for the inhibition of carboxylesterase by malaoxon. Can. J. Biochem. 1967, 45, 757−771. (38) Mahajna, M.; Quistad, G. B.; Casida, J. E. Acephate insecticide toxicity: safety conferred by inhibition of the bioactivating carboxyamidase by the metabolite methamidophos. Chem. Res. Toxicol. 1997, 10, 64−69. (39) Quistad, G. B.; Casida, J. E. Pyrethrum Flowers: Production, Chemistry, Toxicology and Uses; Oxford University Press: New York, 1995; pp 384. (40) Glynne-Jones, D. Piperonyl Butoxide: The Insecticide Synergist; Academic Press: New York, 2008; pp 323. (41) Beroza, M. Pyrethrum synergists in sesame oil. Sesamolin, a potent synergist. J. Am. Oil Chem. Soc. 1954, 31, 302−305. (42) Lichtenstein, E. P.; Casida, J. E. Naturally occurring insecticides. Myristicin, an insecticide and synergist occurring naturally in the edible parts of parsnips. J. Agric. Food Chem. 1963, 11, 410−415. (43) Liu, S. Q.; Scott, I. M.; Pelletier, Y.; Kramp, K.; Durst, T.; Sims, S. R.; Arnason, J. T. Dillapiol: a pyrethrum synergist for control of the Colorado potato beetle. J. Econ. Entomol. 2014, 107, 797−805. (44) Hallman, A.; Bond, C.; Buhl, K.; Stone, D. 2016 MGK-264 General Fact Sheet; National Pesticide Information Center, Oregon State University Extension Services; http://npic.orst.edu/factsheets/ mgk264gen.html (accessed March 27, 2017).

disease; P-gp, P-glycoprotein; PPP, O-(2-propynyl) O-n-propyl phenylphosphonate; Qo, ubiquinol oxidizing site; SDHI, succinate dehydrogenase inhibitor; SH, serine hydrolases; VLCFA, very long chain fatty acid

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