Abstract

Insect control agents remain an important part of most insect pest management (IPM) programs. Over the past decade, a variety of new insect and mite control agents have been developed, or are being developed, that may fit a variety of IPM needs, and many of these have novel modes of action. Several new acaricides acting at complex I of the mitochondrial transport system and chlorfenapyr, a proinsecticidal uncoupler, are representative of new compounds targeting insect respiration. Several diacylhydrazines (e.g. methoxyfenozide, an ecdysone agonist), along with pyriproxyfen, a juvenoid, are relatively new insect control agents that act on the insect endocrine system. Several new acaricides/insecticides (etoxazole, spirodiclofen) also disrupt mite and insect developmental processes. Among the new neurally active insect control agents, ethiprole (a phenylpyrazole) and emamectin benzoate both act on GABA gated chloride channel, although in very different ways, while indoxacarb acts at a novel site in the voltage gated sodium channel. Pymetrozine and IKI-220 act on the (aphid) insect nervous system in novel ways to disrupt feeding. There are several new neo-nicotinoids including thiacloprid, thiamethoxam and clothianidin that, like imidacloprid, are potent agonists for insect nicotinic acetylcholine receptors. The novel macrolide, spinosad, appears to alter the function of the nicotinic as well as GABA gated chloride channels in a novel manner. These recent new insect control agents demonstrate a variety of new and under-utilized modes of action. In many cases these new insect control agents also couple field efficacy with improved selectivity (compared to older chemistries) towards beneficial insects, especially predators. The preservation of a beneficial insect component in any IPM program is an important non-chemical source of selection pressure against a pest population, resulting in not only in an overall enhancement in pest control, but a reduced likelihood of resistance development.

Keywords

Insecticide mode of action, mammalian toxicity, beneficial insects

Introduction

The goal of any crop protection program is to provide the grower with effective, reliable and, most importantly, a cost effective means to address pest problems. The grower’s tool-box of insect control options includes a variety of approaches such as biological control, cultural practices, transgenic crops, host plant resistance, as well as insect control agents. However, there are no “silver bullets” when it comes to pest insect control, since no one technology is appropriate or suitable to every pest problem. Because insect control agents provide a predictable, effective and timely means to address pest problems, they are likely to remain a key component of integrated pest management (IPM) programs for the diamondback moth and most other important insect pest species. As such, the availability of effective, affordable and safe synthetic organic insect control agents is thus critical. The last decade has seen a far wider variety of new chemistries with new modes of action and enhanced selectivity become available than at any other time since the advent of DDT. Compared with organophosphates, carbamates and pyrethroids, many of these new insect control agents provide improved environmental/mammalian toxicology profiles along with greater opportunities to integrate multiple control tactics. In light of the diamondback moth’s (Plutella xylostella, DBM) long history of resistance development, a true integration of control tactics is essential to the long-term availability of control options for DBM. This enhanced selectivity not only encompasses mammalian safety, but also a trend towards improved safety to beneficial insects. As such, preserving beneficial insects provides a valuable adjunct for insect control agents, increasing options for pest control and providing an important alternative selection pressure on the pest to reduce the chances for resistance development. The following is a very brief overview of selected examples of these newer insect control agents and their respective modes of action.

Inhibitors of respiration

The disruption of mitochondrial respiration can, like the nervous system, be an effective target for insect control agents. If mitochondrial electron transport (MET) is blocked or if oxidative phosphorylation is uncoupled, the production of ATP is stopped, ultimately leading to death.

MET inhibitors - MET involves the re-oxidation of NADH by transferring electrons through a chain of carriers to oxygen (Fukami 1985). A chemically diverse group of acaricides including fenazaquin, fenpyroximate, pyridaben, tebufenpyrad (Figure 1) and pyrimidifen, all appear to act at the same site (complex I) as rotenone of the MET system (Hollingworth & Ahammadsahib 1995, Hollingworth 2001). Although these compounds are primarily acaricides, studies have shown that the spectrum can be altered and expanded (Hackler et al. 1998) to include Lepidoptera (e.g. tolfenpyrad, Figure 1). In addition to site I inhibitors, many patents point to methoxyacrylate chemistry as potential insecticides. NA-83 (fluacrypyrin) is an example of a methoxyacrylate site III-based acaricide currently under development (Smith 2001).

Figure 1. Structures of selected insect control agents

Pyrroles – Unlike the MET acaricides, the insecticidal pyrroles function by the uncoupling of oxidative phosphorylation from the MET chain. Chlorfenapyr is a pro-insecticide requiring biological activation before it can function (Hunt & Treacy 1998). The pro-insecticidal nature of chlorfenapyr contributes to a favourable mammalian toxicity profile (Kuhn et al. 1993, Table 1).

Insect growth regulators

Juvenoids - Juvenoids are compounds that mimic the action of juvenile hormone, thereby disrupting metamorphosis leading to a variety of deleterious effects (Sparks 1990, Dhadialla et al. 1998). While juvenoids have had limited impact on IPM programs, the introduction of new, more active and more photostable juvenoids such as pyriproxyfen (Figure 1, Miyamoto et al. 1993, Dhadialla et al. 1998) may yet change this trend, especially for the control of pests such as whiteflies and aphids. As exemplified by pyriproxyfen, the juvenoids tend to have highly favourable mammalian toxicity profiles (Table 1).

Diacylhydrazines - The diacylhydrazines are a novel class of IGRs (Hsu 1991) which in the Lepidoptera function as ecdysone agonists, disrupting the moulting process by mimicking the action of 20-hydroxyecdysone (Wing & Aller 1990). Tebufenozide is effective in the control of a variety of lepidopterous insect pests (Hsu 1991, Heller et al. 1992), as is methoxyfenozide. Two other additions to this class of chemistry include halofenozide (Dhadialla et al. 1998) and chromafenozide (Yanagi et al. 2000, Smith 2001, Figure 1). In part, due to their novel mode of action, the diacylhydrazines display a very favourable mammalian and environmental toxicity profile (Table 1) as well as good selectivity towards beneficial insects (Table 2).

Chitin synthesis inhibitors and other developmental inhibitors - In addition to the now classical acylureas such as diflubenzuron and hexaflumuron, other types of compounds that inhibit chitin synthesis or other related processes are making their way to the marketplace. One example is etoxazole (Suzuki et al. 2001, Figure 1), a highly effective acaricide with a very favourable mammalian and avian toxicity profile (Table 1). Another developmental inhibitor that is also an acaricide that is effective on a variety of resistant mite species is spirodiclofin (Wachendorff et al. 2000, Figure 1).

Compounds acting on the insect nervous system

Due to the many sites available for disruption, the insect nervous system continues to be the favoured target for most insect control agents. A majority of the insect control agents in use today, including organophosphate, carbamate and pyrethroid insecticides. All act via disruption of nervous transmission.

Avermectins - Abamectin is a fermentation derived insecticide that acts on the insect nervous system functioning to open chloride channels, acting as a gamma-aminobutyric acid (GABA) agonist at binding sites, and/or enhancing the action of GABA at the receptor site or stimulating the presynaptic release of GABA (Fisher 1993, Miller & Chambers 1987, Lasota & Dybas 1991, Turner & Schaeffer 1989). Extensive structure activity studies identified the semi-synthetic derivative, emamectin benzoate (Figure 1), as a very effective insecticide for Lepidoptera (Fisher 1993). Given the novel mode of action and high degree of efficacy, emamectin benzoate should be a very useful tool in IPM programs for DBM and other lepidopterous pests.

Phenylpyrazoles - The phenylpyrazole, fipronil (Figure 1), is the first of a new class of broad-spectrum insect control agents that act to block the GABA gated chloride channel in the insect nervous system (Gant et al. 1998). This mode of action is similar to the cyclodienes, however, the exact binding site for fipronil in the GABA gated chloride channel may be distinct from that of the cyclodienes and picrotoxinin (Gant et al. 1998). Ethiprole (Smith 2001), another phenylpyrazole in development, is structurally very similar to fipronil, but has improved mammalian safety (Table 2).

Neo-nicotinoids - In the insect nervous system, nicotinic acetylcholine receptors appear to predominate while in mammalian systems, muscarinic receptors predominate (Eldefrawi & Eldefrawi 1990, Eto 1992) providing a potential source of selectivity. The neo-nicotinoid, imidacloprid (Figure1) acts as an acetylcholine agonist on the nicotinic receptor (Mullins 1992). In addition to imidacloprid, several other neo-nicotinoids (Figure 1) including acetamiprid, thiamethoxam, thiocloprid, TI-435 (clothianidin) and MTI-0446 have been or are being developed, some possessing an expanded spectrum (Nakayama & Sukekawa 1998, Elbert et al. 2000, Smith 2001). The development of two neo-nicotinoids (nitenpyram and AKD-1022) has been dropped for agricultural use (Smith 2001). The neo-nicotinoids exhibit generally favourable environmental and toxicological profiles (Table 1) coupled to reasonable selectivity towards beneficial insects (Table 2) all contribute to the expanding use of this chemistry in vegetable and other crop IPM programs.

Oxadiazines - Indoxacarb (Figure 1), an oxadiazine, is bioactivated through the action of an esterase/amidase to a highly potent blocker of voltage gated sodium channels at a site distinct from that of the pyrethroids (Wing et al. 1998). Indoxacarb is effective against a variety of insect pests, especially lepidopterous larvae and appears to possess an excellent environmental profile (Harder et al. 1996, Table 1). Indoxacarb is also selective towards beneficial insects (Table 2) providing a very good fit for DBM IPM programs.

Table 1. Toxicity values (technical material) for selected insect control agents

	Rat /Mouse LD50 (mg/kg)		LD50 (mg/kg)	LC50 (ppm)
Compound	Oral	Dermal	Avian	Fish	Daphnia
Standards
DDT	87-500	1931	611	0.08	0.0047
Dieldrin	40-100	52-117	37	0.0012	0.00024
Aldicarb	0.9	2.5 – 5	594	0.61	0.061
Carbofuran	8	2550	190	0.38	--
Methyl parathion	9-42	63-72	90	3.7	0.00014
Chlorpyrifos	82-245	202-2000	940	0.0071	0.0017
Profenofos	400	472-1610	--	0.024	0.0014
Cypermethrin	247	>2000	>10000	0.025	0.0013
Respiratory
Fenazaquin	130-140	>5000	1747->2000	0.004-0.034	0.004
Pyridaben	820-1350	--	>2250	0.001-0.008	0.0006
Tebufenpyrad	100-600	>2000	>2000	0.073	1.2
Tolfenpyrad	>100	--	--	--	--
Chlorfenapyr	>626	>2000	10 – 34	7.4-11.6	--
Developmental
Pyriproxyfen	>5000	>2000	>2000	0.45-2.7	0.40
Tebufenozide	>5000	--	>2150	3.0-5.7	3.8
Methoxyfenozide	>5000	>2000	>5620	>4.3	3.7
Chromafenozide	>5000	>2000	>5000	>18.9 - >47	>94.5
Etoxazole	>5000	>2000	>2000	7.8	>40
Spirodiclofin	>2500	>2000	>2000	--	--
Neural Actives
Imidacloprid	450	>5000	31-5000	211	32-85
Thiacloprid	444-836	>2000	2716	30.5	>85
Thiamethoxam	1563	>2000	576-1552	>114-125	--
Acetamiprid	146-217	>2000	--	>100	>100
MTI-0446	>2000	>2000	1000->2000	>40->1000	--
Fipronil	100	>2000	31-2150	0.25-0.43	0.19
Ethiprole	>2000	>2000	--	--	--
Emamectin benzoate	70	--	--	--	--
Indoxacarb	>5000	>2000	>2250	0.5	--
Spinosad	>3683	>5000	>1333	6-30	14
Pymetrozine	5820	--	--	--	--
IKI-220	884-1768	>5000	--	>92 ->100	>100

Data adapted from Larson et al. 1985, Hollingworth 2001, Smith 2001, Ware 1982, Elbert et al. 2000, Yanagi et al. 2000

Dihalopropenoxy aryl ethers – S-1812 (pyridanil, Figure 1, Smith 2001) is a recent novel class of chemistry. It is a broad spectrum lepidopteran material that also shows a high degree of safety towards beneficial insects (Table 2).

Pymetrozine and IKI-220 - Aphids treated with pymetrozine (Figure 1) simply cease feeding, usually within a short time of treatment, with the ultimate effect being the insects starve to death (Kristinsson 1994, Harrewijn & Kayser 1997). This feeding disruption appears to be the result of a direct, novel effect on the insect nervous system (Harrewijn & Kayser 1997). IKI-220 (Figure 1) has a different structure than pymetrozine, but has similar effects on aphids, in that it acts on the nervous system to shut down feeding (Morita et al. 2000).

Spinosyns – Spinosad (a mixture of spinosyns A and D, Figure 1) represents a new class of fermentation-derived tetracyclic macrolides (Kirst et al. 1992, Sparks et al. 1999). The spinosyns, which act via the insect nervous system, are especially active against a variety of lepidopterous pests (DeAmicis et al. 1997, Sparks et al.1999) and possess very favourable mammalian toxicity and environmental profiles (Sparks et al. 1999, Crouse & Sparks 1998, Table 1). The mode of action appears to involve alteration of nicotinic receptor function as well as the function of GABA gated chloride channels (Salgado et al. 1997, Watson 2001). Additionally, spinosad also exhibits a great deal of selectivity towards beneficial insects, especially predators (Table 2) enabling a great deal of utility in DBM and other IPM programs.

Table 2. Relative selectivity of selected compounds towards beneficial insects

Compound				Predators					Parasitoids
	Orius	Geocoris	Chrysopa		Hippodamia convergens		Coccinella		Cotesia marginiventis	Trichogramma
Tebufenozide	* * * *	* * * *					* * * *
Methoxyfenozide	* * *	* * * *
Spinosad	* * *	* * * *	* * * *		* * * *		* * * *		*	*
Indoxacarb	* * * *	* * * *	* * * *				* * * *		* * * *	* * * *
S-1812	* * *	* * * *	* * * *		* * * *				* * * *	* * *
Imidacloprid	* * *	* * *			* *
Emamectin benzoate	*
Abamectin	*
Fipronil	*	*			* * * *
Chlorfenapyr	**	*			* * * *
Cyhalothrin	*	*	* * * *		* * *		* * * *		* *	* * *
Cyfluthrin	**	* * * *			*
Cypermethrin										* * *
Profenofos	*	* * * *			* * *					* *
Malathion	*	*			* *
Endosulfan		* * * *			* * *

Rating is a relative scale with * being not very selective, while **** indicates a relatively selective material.
Data adapted from Tillman et al. 1998; Ruberson & Tillman 1999; Tillman & Mulrooney 2000; Elzen 2000, 2001; Studebaker & Kring 2001.

Summary

Insect control agents remain a critical component of most IPM programs. The availability of insect control agents that act on new or under-exploited target sites reduces the potential for target site-based (but perhaps not metabolism-based) cross-resistance to existing products and provides growers with new, and in many cases safer and/or more selective, insect control choices. The modes of action demonstrated by some of these new insect control agents represent new chemistry on known, but generally under-utilised, target sites (MET acaricides, pyrroles, phenylpyrazoles, neo-nicotinoids, juvenoids), while others represent new target sites within known systems (diacylhydrazines, oxadiazines). In some cases, it is clear that the insect nervous system is the target, but the actions of these new insect control agents are incompletely understood (pymetrozine, spinosyns). Regardless, all of the above insect control agents certainly possess modes of action outside of the mainstream (inhibition of acetylcholinesterase - organophosphates and carbamates; and opening of voltage-gated sodium channels - pyrethroids) and thus present new opportunities for IPM and insect resistance management programs.

In addition to new modes of action, and in some cases directly attributable to a novel mode of action, many of the new insect control agents also possess very favourable mammalian and environmental profiles (Table 1), as well as high levels of selectivity towards a variety of beneficial insects (Table 2). Thus, many of these new chemistries present growers and the scientific community with new opportunities to address many of the IPM and resistance management needs of critical insect pests such as the diamondback moth. However, at the same time, there is a real need/responsibility to make the best use of these new tools as is possible. For a variety of reasons, including the continuing rapid consolidation of the agrochemical industry worldwide, the future replacement of any of these new tools is increasingly problematic. Thus the loss of any of these new chemistries potentially represents an increasingly irreplaceable resource that may be difficult or even impossible to replace in the not too distant future.

Acknowledgement

Thanks are due to Dow AgroSciences for support of the conference and this review.

References