Insecticide Mode of Action
Insecticide Mode of Action
Insecticide Mode of Action
1 Introduction
contents
Inside this pocket is the complete
Insecticide Resistance Action Committee
(IRAC) Classification chart in poster
format as a companion to this book.
Introduction
Insecticides are essential tools for preventing or minimizing insect
damage to, and significantly increasing the quality and quantity of
crops, as well as for improving the quality of life for humans, domestic
animals and livestock. There are currently more than 20 different
mechanisms, or modes of action, by which various commercial
insecticides control insects by disrupting specific vital biological
processes, but not all of these can be used against any particular pest
insect. Despite the best efforts of the entire crop protection industry,
a new insecticide mode of action comes to market only every 5 or
10 years, the last being in 2007.
Nevertheless, mode of action diversity is the most important tool we have for ensuring
our sustained ability to control insect pests. Repeated application of insecticides with the
same mode of action contributes to resistance by killing the susceptible insects and leaving
those with resistance to that entire class of insecticides. By rotating pest control chemicals
that work through different modes of action, insecticide resistance can be forestalled
or avoided altogether.
Insects are animals, with similarities to and differences from other animals. Indeed, all living
things share a common set of biological processes that make life possible, and the more
closely related two organisms are, the more vital processes they have in common. Ideally,
insecticides would specifically target vital processes unique to pest species, but that is
seldom possible. While insects are close relatives of mites and ticks which are also often
pests, they are also kin to lobsters, crabs and shrimp, which are not. These relationships
have led, on the one hand, to important acaricides for controlling mites and ticks, but
on the other, to collateral toxicity of insecticides to non-target soil-dwelling and aquatic
arthropods, as well as to bees and other beneficial insects. While some insecticides target
processes unique to insects and closely-related arthropods, such as the biosynthesis
of chitin, a tough, semitransparent polysaccharide that is the main component of the
insects exoskeleton, most gain species selectivity by other means. Key insecticide target
groups include: neuromuscular poisons, respiratory poisons, gut disruptors and insect
growth regulators.
Since the 1940s, mineral and botanical insecticides have been largely replaced by
successive generations of synthetic organic insecticides and microbially-derived products
with improved properties. There are now approximately 275 insecticide active ingredients
registered globally, and the value gained from their proper use is significant. A 2009 study
estimated that U.S. farmers gained a net value of approximately $21.7 billion each year
from the use of insecticides, a return of $19 for every $1 spent. Without insecticides,
it is estimated that yields of most crops would decline by 40% to 50%. As the worlds
population is estimated to increase by over 1 billion people by 2020, the capacity of
producers to meet the increasing need for quality food and fiber will be stretched to the
limit. (Source: Crop Life Foundation.) Many factors will affect producers ability to meet this
increased demand, including weather variability, climate change, government policy and
shifting dietary demands. The adoption of new technologies by developing countries,
the availability of and efficient use of land, water and crop production tools, as well as the
continued availability of and sustainability of effective pest control technologies, may
enable producers to meet the growing near-term needs of a growing population.
In 2011, the global insecticide/acaricide/nematicide market was $14 billion, with
$11.6 billion in crop uses (foliar, soil and seed treatments) and $2.4 billion in non-crop
applications. (Source: Phillips McDougall-AgriService.) The crop segment (e.g., maize,
cotton, fruit, vegetables, rice, soybeans, etc.) is divided into the following pest subsegments: chewing insects, piercing & sucking insects, mites and nematodes. These
four classes of pests can cause significant crop damage and often occur concurrently
on the same crop and in the same season.
With the high demand for cost-effective technologies comes the responsibility of product
stewardship regarding environmental awareness, insect resistance management, nontarget impacts, dietary residues and consumer and applicator exposure. With increasing
pressure on crop production and quality, growers will rely more heavily on multiple
insecticide treatments to control an increasingly complex diversity of pests.
from top to bottom:
chemical messenger acetylcholine (ACh) in the insect nervous system, and has the same
action in humans. Nicotine, though natural, is much more toxic to humans than any
messenger acetylcholine in
the nervous systems of both
Insecticide target protein molecules are many times larger than the insecticides that act on
them, and can have more than one site where small molecules like insecticides can bind.
While nicotine and many other toxicants and drugs exert their effects on the body by
of developing insecticides
that affect harmful insects
but not beneficial ones.
heritable changes that hamper action at the target site can confer resistance to entire
classes of insecticides. The Insecticide Resistance Action Committee (IRAC) is a specialist
technical group of the industry association CropLife, organized to provide a coordinated
industry response to prevent or delay the development of resistance in insect and mite
pests. IRAC classifies insecticides into groups with a common mode of action and then into
chemical subgroups within those groups.
While consolidating the 50 or so chemical insecticide classes into mode of action groups is
very useful, further grouping the 26 recognized mode of action groups into four categories
provides a broader understanding of this relationship. The four categories are: neuromuscular
toxins, which attack the nervous system or muscles; insect growth regulators (IGRs), which
affect growth and development; respiratory poisons, also called metabolic poisons, which
affect energy metabolism; and gut disruptors, which destroy the integrity of the gut lining.
In addition to these four categories, there is a group of compounds that are thought to
be non-specific multi-site inhibitors, which interact with one or more specific target sites,
as well as a group of compounds that are thought to act specifically, but whose targets
are currently unknown. The insert in the front pocket of this manual illustrates the complete
IRAC classification grouped into the four categories mentioned above.
immature insects. They inhibit an enzyme involved in the biosynthesis of fatty acids,
which are essential components of cell membranes.
On the other hand, most respiratory poisons are enzyme inhibitors except for uncouplers,
which are ionophores (in red), which means that there is no protein target, and the
insecticide molecules themselves carry ions across membranes.
Some insecticide target proteins are very complex, containing more than one target site
where agents bind to disrupt function. Among the most complex of these are the ion
channels, which are also the most important insecticide targets. Inorganic ions and the ion
channels that facilitate their movement across membranes, are the basis of bioelectricity,
which drives many vital processes. Electrical current requires the flow of charged particles,
which, in the body, are sodium (Na+), potassium (K+), calcium (Ca 2+) and chloride (Cl-) ions.
Positive ions are atoms with a deficit of electrons, whereas negative ions have an excess of
electrons, making them negatively charged. Being charged, like ions repel each other and
easily permeate polar media like water, but they cannot enter nonpolar areas like cell
membranes, except via polar channels traversing those membranes that are formed by ion
channel proteins. These transmembrane proteins occur in many varieties that are
specific for particular ions, and literally form channels or pores through which ions can
tunnel across the membrane.
A simple ion channel could be formed from a relatively small and simple molecule, but the
complexity and much of the sensitivity comes from the mechanisms that open and close
the channel to allow ion flow only under certain conditions. Opening and closing of the
pore, known as gating, depends on a signal such as a neurotransmitter substance,
or a physical stimulus such as heat, pressure or electrical potential. Flux of the ions across
the membrane can generate an electrical signal, and, in the case of Ca 2+, the ion itself
also can interact with intracellular proteins to cause many effects.
Insecticides can affect ion channels in various ways. Channel blockers enter and become
trapped in the pore, blocking ion flow through the channel. Agonists bind to and mimic the
action of the neurotransmitter at the neurotransmitter binding site, while antagonists also
bind to the neurotransmitter site but hinder activation of the ion channel. Lastly, modulators
are compounds that bind to a modulatory site and modify the normal function of the
channel. Some modulators activate the channel, others keep it open much longer than
normal and still others prevent it from opening at all.
All three of these binding sites are present within the cys-loop ligand-gated ion channels,
which are target proteins of five of the eleven groups of insecticides that act on the
neuromuscular system. These channels are composed of five subunits, which are similar if
not completely identical, and fit together like staves to form a barrel around the pore.
About half of each subunit is embedded in the membrane and half protrudes from the surface
of the cell. In the resting state, the staves form a tight barrel and the pore is too small to pass
ions, so the channel is closed. Channel blocker insecticides can bind in the pore either when
it is open, closed, or both, depending on the compound. Ions cannot pass through the pore
when a blocker is bound. The neurotransmitter binds to the agonist sites, which are situated
between adjacent subunits in the extracellular region. Since there are five subunits, there can
be up to five agonist sites per channel. Like the agonist sites, the modulator sites of cys-loop
channels are also situated between subunits, but within the membrane, far removed from the
extracellular agonist site. One can imagine that binding of the agonist or modulator, or both,
moves the staves of the barrel apart and opens the channel. Antagonists that bind to the
agonist site while the channel pore is closed are called competitive antagonists because they
compete with agonists for the binding sites and prohibit opening of the channel. Compounds
that bind to the modulatory site in the closed state are called allosteric antagonists, and
they can prevent opening of the channel by agonists. The modulatory site on the cys-loop
ligand-gated ion channels is known as the macrocyclic lactone binding site and is the target
site of avermectins on glutamate-gated chloride channels, and spinosyns on nicotinic
below, left:
acetylcholine receptors. A macrocyclic lactone binding site also exists on GABA receptors
and is the target of some novel experimental insecticides that may soon be commercialized.
( A)
O U TS I D E O F C EL L
AG O N I S T S I T E
( N e u ro t ran smit t e r
m im ics)
( B)
BL O C K ER S I T E
( Blo c k e rs)
PLAS MA ME MB R A N E
M O D U L AT O R S I T E
( M o d u la t o rs)
(M)
= Ions
I N S ID E O F C EL L
= Neurotransmitters
( c l os e d)
IO N C H A N N E L S
( o p en )
O PEN I O N C HA NNEL
C R O S S -S ECTION
above:
In order for an insecticide to act at its target site, it must enter the insect through one or
more absorption routes, including absorption through the cuticle, orally through the
consumption of treated foliage or sap, or inhalation through the spiracles as a vapor. Once
absorbed into the body, the active ingredient then distributes throughout the body to reach
the target sites, which may only occur deep within certain tissues. At the same time, natural
defense mechanisms of the insect are acting to break down and excrete the insecticide
molecules. These processes, which together with mode of action determine the biological
effect of the insecticide, are absorption, distribution, metabolism and excretion, respectively.
CE NT R AL NE R V OUS
SYS T E M G ANG L I ON
Axodendritic
Synapse
AXON
DENDRITE
Sensory Neuron
Cell Body
Neuromuscular
Synapse
Motor Neuron
Cell Body
DE NDR I T E
PR E S YNAPT I C
T E R MI NAL
POS T SYNAPT I C
T E R MI NAL
AXON
MUS CLE
CE L L
right:
While the neuromuscular system is complex, composed of many circuits that control
different body parts and behaviors, it is assembled from a much smaller variety of well-
understand the functions of these components and the effects of insecticides on them.
To illustrate the essential components of the nervous system involved in insecticide mode
of action, we consider the simplest type of neural circuit, the monosynaptic reflex arc
shown above, as would be involved, for example, in the well-known knee-jerk reflex. Insects
have analogous reflexes. Starting on the left side of the diagram, a sensory neuron receives
an external stimulus, such as the tap of the physicians hammer on a patients knee or the
bending of a sensory hair on an insects leg, which generates an electrical signal that travels
down the dendrite or input side of the cell, past the sensory neuron cell body and then along
the axon to its terminus in the synapse: the junction with the next cell. At the synapse, the
electrical signal is converted into a chemical signal that is transmitted across the synaptic
space to the postsynaptic cell, by a neurotransmitter substance that is emitted from the
presynaptic terminal to activate receptors on the postsynaptic cell, which in the case of a
monosynaptic reflex arc is a motor neuron. The signal in the motor neuron travels to the
below:
Dendrites and axons conduct signals electrically, but by different mechanisms. Like
wires, both of these structures are tubular, constructed of a conductor the cytoplasm,
ensheathed by an insulator the cell membrane. Wires are passive conductors: charged
particles are forced into one end and flow out the other, minus a few that have escaped
through the insulation. Cytoplasm, however, is a poor conductor and membranes are poor
insulators, making dendrites and axons poor passive conductors. Fortunately, dendrites are
short enough that passive conduction suffices, but passive conduction is inadequate in
axons, which must carry signals over much longer distances. Instead, the axon conducts
conduction.
Na+
G R ADI E NT
action potential, but rather in establishing the transmembrane potential and ion gradients
that drive the action potential as well as many cellular processes. This protein resides in the
Pump
K+
G RA D I E N T
cell membrane and uses energy from adenosine triphosphate (ATP) to pump sodium ions
out of the cell and potassium ions into the cell.
ATP is the energy currency of cells: energy obtained from foodstuffs is harnessed by
subcellular organelles called mitochondria to form a high energy phosphate bond in the
ATP
ATP molecule, and most cellular processes are driven by the stored energy released when
that bond is broken. Insecticides that disrupt the production of ATP will be discussed in
another section.
MI T OCHONDR I O N
For each ATP molecule it consumes, the sodium-potassium pump expels three sodium ions
from the cell but brings in only two potassium ions, leading to a net expulsion from the cell
CE L L
ME MB R ANE
of one positive charge for each pump cycle, eventually making the interior of the cell
negative by 50 to 100 mV. Another consequence of pump activity is that the potassium ion
concentration becomes 10 or more times higher inside of the cell than out, and the sodium
ion concentration becomes much higher on the outside.
The sodium-potassium pump is one of the most important proteins in the body, consuming
about one third of all energy expended by an animal and about two-thirds of all energy
ENERGY
FROM FOOD
expended in the nervous system. It is easy to see how building up an electrical potential
can be useful as a form of energy storage, but the real repository of the energy expended
by the pump is the transmembrane gradients of sodium and potassium ions.
Ion concentration gradients have the capacity to do work because ions have a strong
tendency to move from areas of high concentration to areas of low concentration, even
against electrical potential. The reason for this is the simple, yet extremely subtle second
law of thermodynamics: systems tend to move from a state of order to a state of disorder.
The pump has established highly-ordered, high-energy gradients for sodium and potassium
ions by separating those ions across the cell membrane. All that is needed to harness this
order are transmembrane ion channels specific for sodium and potassium ions.
Both the sodium and potassium channels have gates that sense and respond to the
transmembrane electrical potential. These ion channels are shown in green in the
illustrations on the facing page. The Na+ and K+ concentration gradients are depicted by
the number of ions on either side of the membrane. At the negative resting potential
established by the Na+, K+ pump, the sodium channel is closed but poised to open in
response to positive signals. The flow of positively-charged sodium ions into the cell
through the open channel drives the interior of the cell positive. The sodium channels that
are still closed sense this and they also open, so there is positive feedback, which takes
over and soon all of the sodium channels are open and the cell interior becomes highly
positive, as shown in the central part of the illustration at right, labeled Active. The
transmembrane potential is shown in the corresponding line chart below the illustrations.
This depolarization can occur in less than one millisecond. At the peak of positivity,
two processes kick in to terminate the action potential: the sodium channels become
temporarily inactivated, halting the sodium influx, and voltage-dependent potassium
channels open, allowing K+ ions to flow out of the cell and restore the negativity.
After the action potential is over, the sodium channels remain inactivated and the potassium
channels remain open, making the conduction of another action potential impossible.
This refractory period, which lasts about one hundredth of a second, ensures that the
action potential travels only forward, self-propagating along the axon membrane. The open
K+ channels driving repolarization are shown in the right side of illustration A, labeled
Refractory, on the next page.
To understand how the action potential moves, it helps to think of these diagrams as a
snapshot in time, depicting three regions of the membrane in different stages of the
sequence, as an action potential travels from right to left. In the resting area on the left,
where the action potential is approaching, the inside of the axon is negative and the
potential is -75 mV. In the active region just to the right (orange), the Na+ permeability is
high, which has resulted in Na+ influx and charge reversal. This has driven the membrane
potential positive. The action potential keeps moving toward the left because the excess
positive charge on the inside flows into the adjacent resting section, causing depolarization
and activation of the sodium permeability in this area.
10
To the right of the orange active section is the blue refractory section, from where the action
potential has just come.
Here, two processes are occurring to restore the membrane to its resting state. First, the
Na+ channels that generated the action potential have become inactivated so that no more
Na+ flows in, and second, K+ channels have opened to allow K+ ions to flow out of the cell
and restore the internal negativity. In addition to restoring the resting conditions, these
processes also ensure that the action potential does not travel backward. The region of
membrane on the far right has fully recovered and is ready for the next action potential.
Of the three proteins involved in action potential conduction the sodium-potassium pump,
the sodium channel and the potassium channel only the sodium channel is a target
of insecticides.
Pyrethroids and DDT slow the closing of sodium channels after an action potential, causing
the cell to become re-excited. Indoxacarb and metaflumizone block the sodium channels,
which prevents action potential generation.
A. Intracellular Action Potential States
11
neurotransmitters are known, but only four are widely used in the insect neuromuscular
system. Acetylcholine (ACh) is the major, if not the only, fast excitatory neurotransmitter in
the insect central nervous system (CNS), and synapses that use it, known as cholinergic
synapses, can transmit an excitatory signal from the presynaptic cell to the postsynaptic
cell. The chemical structure of acetylcholine is shown below.
OH
O-
HO
GLUTAMATE (Glu)
NH2
NH3+
HO
ACETYLCHOLINE (ACh)
NH2
HO
GAMMA-AMINOBUTYRIC
ACID (GABA)
OCTOPAMINE (OA)
With at least four distinct target sites, cholinergic synapses are by far the most important
in terms of insecticide action, but GABA, glutamate and octopamine synapses are
Neurotransmission at
also important.
a cholinergic synapse:
1) A nerve signal (action
Cholinergic Synapse
P R ESYNAPTIC
MEMBR ANE
VESICLE
M IT OCHONDR ION
A CT ION
POT ENT IA L
12
PRESY NAPTIC
T ERMINAL
P OSTSYNAPTIC
TER MINAL
P OSTS Y NA P TIC
MEMB R A NE
The presynaptic terminal is loaded with membrane-bound vesicles packed with ACh. When
an action potential arrives down the axon, the resulting depolarization triggers the fusion of
some of these vesicles with the presynaptic membrane, resulting in the release of their
contents into the synaptic cleft.
Once free in the cleft, the individual molecules of ACh diffuse across to the postsynaptic
membrane, which is studded with ACh receptors, so called because their purpose is to
receive the ACh signal transmitted by the presynaptic terminal. There are several different
types of ACh receptors, but those on the postsynaptic membranes in insects are thought
to be all of the nicotinic type, so called because they are sensitive to the ACh-mimicking
action of nicotine. Activation of the nicotinic receptor by the binding of two ACh molecules
gates a hydrophilic channel in its center that permits the passage of Na+ ions into the
postsynaptic cell, driving the intracellular potential positive. If enough receptors are activated,
an action potential can be generated in the postsynaptic cell.
It is important that ACh be quickly removed from the synaptic cleft after signal transmission,
so that the signal has a finite duration, and this is accomplished by a high concentration of
the acetylcholinesterase enzyme (AChE) in the cleft. AChE cleaves ACh into its acetic acid
and choline components, which no longer stimulate the receptors and are transported back
into the presynaptic cell where they are recombined into ACh and repackaged into vesicles.
In general, synapses using any other neurotransmitter function by the same principles
described for nicotinic synapses, but have transmitter-specific synthesis, reception,
degradation and reuptake mechanisms. ACh is the only neurotransmitter that is
degraded by an enzyme in the synaptic cleft; all others are taken back up intact into the
presynaptic terminal by specific transporters. In addition to the nicotinic receptor, the
acetylcholinesterase enzyme is also an important insecticide target site.
Excitatory, Inhibitory and Modulatory Neurotransmission
ACh is the major fast excitatory neurotransmitter in the insect CNS, but glutamate is the
fast excitatory neurotransmitter that insect motor neurons release onto muscle cells to elicit
contractions. Not all neurotransmission is excitatory, however. Inhibition is also extremely
important in the nervous system. It is well established in insects that gamma-aminobutyric
acid (GABA) is a major inhibitory neurotransmitter in the CNS as well as at neuromuscular
synapses. GABA activates receptors that gate chloride channels, and the influx of
negatively charged chloride ions has an inhibitory effect on the postsynaptic cell, which
counteracts the effect of excitatory input. Inhibitory glutamate-gated chloride channels
(GluCls) are also widespread on insect muscle and nerve cells, and while they have
not yet been demonstrated to participate in inhibitory neurotransmission, that is
considered probable.
13
right:
Octopamine receptors:
G-Protein
Trimer
OAR
b g ; 4) GTP-a binds to
adenylate cyclase; and 5)
cAMP is produced from ATP.
GTP
= Octopamine
GDP
GTP
AC
ATP
cAMP
14
left:
Ryanodine receptors in
muscle excitation-contraction
coupling: 1) glutamate
released from the motor
nerve terminal activates
M O T O R N E R VE
TERMINAL
ION
CHANNEL
in the SR membrane; 4)
released Ca 2+ ions activate
MUSCLE
FILAMENTS
3
4
extracellular spaces.
SARCOPLASMIC
RETICULUM
15
Acetylcholinesterase (AChE), a critical enzyme in the function of the insect central nervous
system, is the target of inhibition by organophosphate (OP) and carbamate insecticides.
Many competing products in these groups, from various companies, dominated the
insecticide market from the 1950s to the 1980s. Although their use has been in slow
decline, due largely to regulatory action but also to resistance, OPs and carbamates still
accounted for 18.1 and 8.3 %, respectively, of the global agricultural insecticide market in
2010, allowing AChE to keep its place as the most important insecticide target site.
Organophosphates and carbamates are broad-spectrum insecticides with a large variety of
crop and non-crop uses. The group includes several of the most important soil-applied and
foliar insecticides for row crops and vegetables. Some members of these classes also
control nematodes and mites.
IRAC Group 1A: Carbamates
Scottish missionaries to the kingdom of Calabar in Southern Nigeria in the 1840s regularly
observed poisonings by seeds of the local plant Physostigma venenosum, which were fed
to suspected witches as a trial by ordeal. If the accused vomited after chewing and
swallowing 20 to 30 Calabar beans, he survived and was exonerated. The carbamate
physostigmine (eserine), isolated from the Calabar bean in 1864, soon found use as a drug
that is still in use today to treat myasthenia gravis, glaucoma, Alzheimers disease and
delayed gastric emptying.
The insecticidal activity of carbamates was first discovered in 1947 at the Geigy Company
in Switzerland, but it wasnt until 1956 that carbaryl, the first successful carbamate
insecticide, was introduced by Union Carbide. Since then, BASF, DuPont, FMC
Corporation, Syngenta, Dow AgroSciences, Bayer and other companies have developed
and commercialized their own proprietary carbamate insecticides, and this group still
accounts for 8.3% of the insecticide market, although use is declining as older products
are phased out.
Carbamates are mostly broad spectrum insecticides used on cotton, fruit, vegetables,
row and fodder crops. Carbaryl, with a broad spectrum and low mammalian toxicity, is sold
under the trade name Sevin. Some carbamates are systemic and can be applied by soil
application or seed treatment.
Examples of Carbamate Insecticides
16
n
Common
n
Common
n
Common
n
Common
n
Common
n
n
Common
nCommon
Organophosphates were discovered in the early 1930s at the Bayer division of the German
chemical conglomerate I.G. Farben, and are still one of the largest families of insecticides.
Though their use is declining due to regulatory action, organophosphates are still widely
used for their broad spectrum of activity, flexibility in use, and good residual characteristics.
Notable members of the group include Perfekthion insecticide (dimethoate) and Abate
mosquito larvicide (temephos), by BASF. Perfekthion insecticide is used for the control of
aphids and certain other pests in wheat, rye, triticale, sugar beet and other beet crops,
seed crops and ornamental plant production. Abate mosquito larvicide, important in the
war against malaria, controls mosquitoes that vector human diseases. When applied to
standing water where mosquitoes breed, Abate mosquito larvicide kills the larvae, interrupting
the life-cycle of the protozoal malaria parasites.
Integrated campaigns including the use of Abate mosquito larvicide are responsible for
significantly reducing the occurrence of guinea worm disease (dracunculiasis) worldwide.
When the World Health Organization began its effort to eradicate this parasite in 1986, there
were 3.5 million new cases each year across 21 countries in Africa and Asia. From January
to September 2013, there were only 129 new cases in four African countries, down 75%
from the same period in 2012, and dracunculiasis is on track to be the first parasitic disease
and only the second disease, after smallpox, to be completely eradicated worldwide.
Examples of Organophosphate Insecticides
n
n
Common
n
Common
n
Common
n
Common
n
Common
n
Common
Mode of Action and Resistance: Acetylcholinesterase inhibitors bind to and inhibit the
enzyme thats normally responsible for breaking down ACh after it has carried its message
across the synapse. This allows the ACh to continue stimulating the postsynaptic neuron,
leading to overstimulation of the nervous system and eventual death of the insect.
17
AChE is one of the fastest enzymes known each molecule being able to degrade 25,000
ACh molecules per second. AChE is a type of hydrolytic enzyme known as a serine
esterase, so called because of the presence of the amino acid serine (Ser 200 ) in the active
site, whose hydroxyl side chain becomes esterified (ester group added to molecule) by the
substrate during catalysis. The acetyl enzyme intermediate forms rapidly, and releases the
acetate group with a half-life of microseconds. Carbamates and organophospates are
suicide inhibitors of AChE. They enter the active site of the enzyme and react with the
catalytic serine residue, but the carbamoylated and phosphorylated enzymes are much more
stable than the acetylated form, so the enzyme is inhibited. Resistance to AChE inhibitors is
often due to enhanced metabolism, but modified AChE also often plays a role in many cases.
Mode of Action of AChE Inhibitors
right:
A. ACh + AChE
B. Carbamate + AChE
C. Organophosphate + AChE
Mode of Action
of AChE Inhibitors:
A) Acetylation of the catalytic
CH3
seconds.
H
N
Ser 200
CH3
O
O
B) Carbamoylation of
Ser 200
Ser 200
slow
OH
Native AChE
C) Phosphorylation of the
serine residue by an OP
insecticide leads to longer-
have varying levels of toxicity to non-target organisms, including humans. As a group, these
of hours or days.
are among the most toxic insecticides to man. Some are toxic to birds and fish and their
uses have accordingly been restricted by regulatory agencies.
Symptoms of acute poisoning by organophosphates and carbamates can develop within
minutes to hours, depending on the route of exposure. Early symptoms include headache,
nausea, dizziness, pupillary constriction and hypersecretion (sweating, salivation, watery
eyes, and runny nose). The primary cause of death in organophosphate poisoning is
respiratory failure.
18
Many early symptoms can be easily confused with other illnesses like heat stress, overfatigue and lack of sleep. Although similar in the symptoms they elicit, the treatment for
carbamate versus organophosphate acute overexposure can vary. Always seek medical
attention if the above symptoms are exhibited after exposure, as a life-threatening condition
may exist.
Carbamates and organophosphates break down readily in the environment and are not
considered persistent; nor do they biomagnify (increase in animal tissues through the food
chain). Some have very high water solubility and have the potential to leach into groundwater.
IRAC Group 2: GABA-Gated Chloride Channel Antagonists
IRAC Group 2A: Cyclodiene Organochlorines
Cyclodienes were introduced in the 1940s. Their stability in soil and the environment, broad
spectrum of activity, high level of performance and relatively low cost gained the group
extensive use globally. However, due to widespread insect resistance, persistence, longrange transport and bio-magnification in wildlife food chains, the use of cyclodienes - once a
mainstay of the insecticide market has seen a period of rapid decline. Endosulfan, the sole
member of this class in wide use until recently, is banned in over 80 countries but still used
extensively in India, China and a few other countries. Under a global ban that went into
effect in mid-2012, cyclodienes should be phased out over five years.
Agricultural uses of lindane were banned under the Stockholm Convention in 2009, and it is
now only allowed as a topical treatment for lice and scabies.
Examples of Cyclodiene Organochlorides
n
Common
of the world
n
Common
19
Mode of Action and Resistance: As mentioned in the section Excitatory, Inhibitory and
Modulatory Neurotransmission, gamma-aminobutyric acid (GABA) is an inhibitory
neurotransmitter used to transmit signals that inhibit the activity of postsynaptic cells.
A certain amount of inhibition in the nervous system is essential for normal function,
and blocking of the GABA-gated chloride channels by cyclodienes and phenylpyrazoles
leads to overstimulation and convulsions.
Blockers interfere with inhibitory neurotransmission by occluding the
A G O N IS T S IT E
( N e uro tra ns mitte r
mimic s )
B LO C K E R S IT E
( B lo c k e rs )
M O D U LA T O R S IT E
( M o d ula to rs )
O PE N I O N C H A N N E L
C RO SS- SE C T IO N
20
Pyrethrum is the powdered dried flower head of the pyrethrum daisy, a species of
chrysanthemum that has been used as an insecticide since the 1st century CE in China and
still enjoys worldwide sales of Euro 350 million. Pyrethrins are the insecticidal compounds
that occur naturally in this material. Synthetic analogs of pyrethrins, called pyrethroids,
were pioneered by chemist Michael Elliot at Rothamsted Experimental Station in the United
Kingdom, culminating in the discovery of deltamethrin and cypermethrin in 1977.
Pyrethroids have been specifically designed to be more environmentally stable than
Pyrethrins, whose activity is measured in hours. They provide long-lasting control and
improved mammalian safety relative to other products in use at the time they were
developed. These compounds are generally effective against caterpillars, beetles, certain
aphids and mites in crops, and are used for mosquito, termite and cockroach control in
non-crop segments. In addition, certain members of the class are used to control
ecto-parasites on pets and humans. Key applications include foliar sprays in vegetable
crops, oilseed rape and cotton, as well as soil and foliar uses in maize.
Alpha-cypermethrin, a third generation pyrethroid, was introduced to the market in 1983,
and is now one of the top-selling insecticides globally. Alpha-cypermethrin formulations
developed by BASF are registered in 40 countries around the world and used on more
than 90 crops, controlling a broad spectrum of crop pests. BASFs alpha-cypermethrin
formulations incorporated into Interceptor mosquito long-lasting insecticidal nets also play
a key role in preventative applications against vectors of tropical diseases like malaria
and dengue fever.
Examples of Pyrethroid and Pyrethrin Insecticides
n
Common
n
Common
n
Common
n
Common
n
n
Common
n
Common
nCommon
21
First synthesized by an Austrian student in 1873, DDT, one of the best known insecticides,
was rediscovered as a toxicant in 1940 by chemist Paul Mueller at the Geigy Chemical
Company in Basel. Introduced in 1942, DDT was the most widely used insecticide for 20
years. Its enormous value in combating malaria and typhus in World War II and thereafter,
earned Mueller the 1948 Nobel Prize for Physiology or Medicine.
DDT was used on a large scale as a crop insecticide because of its low mammalian toxicity.
It proved to be highly persistent, however, and more than one billion pounds accumulated
in the environment by 1968, disrupting ecological food chains. Environmental concerns led
the EPA to ban DDT in 1972, and have virtually eliminated all uses globally, although it has
recently been reintroduced in Africa for the control of mosquito disease vectors by interior
wall and ceiling treatments in dwellings. Another member of this group, methoxychlor,
was introduced as a replacement for DDT, but has been banned in the United States and
Europe since 2003 due to its potential for bioaccumulation and endocrine disruption.
Examples of DDT and Methoxychlor
n
Mode of Action and Resistance: Sodium channel modulators are neurotoxins that act on
the action potential sodium channel. They slow the closing and inactivation of the channel,
causing it to remain open longer than normal, which has the effect of prolonging the action
potential, as shown by the dashed trace in the lower part of the figure on page 11. When
the action potential is not promptly terminated, it can re-excite the same area of membrane,
leading to repetitive firing.
Because nerve axons occur throughout the insects body, even near the surface of the
cuticle in sensory organs and motor nerve terminals, pyrethroids and DDT cause symptoms
as soon as they enter the body and are considered extremely fast-acting, causing immediate
knockdown.
Pyrethroid and DDT resistance is widespread and can be metabolic or target-site-based.
A number of cytochrome P450s that are overexpressed in pyrethroid-resistant insects have
been identified. Metabolic resistance confers resistance to certain pyrethroids, whereas
target-based resistance extends to all pyrethroids and DDT, and is known as knockdown
resistance (kdr). In contrast to the cys-loop ligand-gated ion channels, in which the
channel is formed from five similar or identical subunits, the voltage-dependent sodium
channel is formed from four similar domains of a single polypeptide chain. These domains
act like pseudosubunits, each forming a stave of the channel barrel. Interestingly, mutations
in at least three of the domains have been found to confer kdr resistance, but domain II is
22
the most common location. Five different amino acid residues in domain II are mutated in
various kdr insects, defining a binding pocket for pyrethroid and DDT molecules. There may
also be corresponding binding pockets in other domains.
Environmental and Toxicological Considerations: Pyrethroids have low mammalian
toxicity, and although highly toxic to fish and aquatic organisms, they have a low
bioaccumulation potential. Skin sensitization affects some people using both pyrethrins and
synthetic pyrethroids. The sensitization is caused by the modulatory effect on sodium
channels of sensory nerve endings in the skin. It affects sensitive areas of the body, such as
the face, causing a tingling, burning or numbing feeling that usually lasts less than 24 hours.
Applicators who have an allergic reaction to these insecticides must either increase the
amount of personal protective equipment worn during handling, or stop working with this
class of insecticides. Pyrethroid exposure can also cause nausea and paralysis. There is no
antidote to acute pyrethroid poisoning, so symptoms are treated individually as they occur.
Pyrethroids and DDT are unusual among biologically active compounds in having a strong
negative temperature dependence of activity at their target site, which increases their
activity at low temperature. This contributes to their high mammalian safety.
In the environment, synthetic pyrethroids are rapidly degraded in soil and plants. The major
degradation mechanisms are catalyzed by UV light, water and oxygen. Pyrethroids do not
biomagnify they have low water solubility and are strongly adsorbed to soil particles,
which results in low soil mobility and minimizes the potential for leaching. (Note: adsorption
is the adhesion of molecules to a surface, unlike absorption, which happens when a fluid
permeates or is dissolved by a liquid or solid).
DDT is extremely persistent in the environment and can accumulate through the food chain.
While the toxicity of DDT to non-target invertebrates probably stems from sodium channel
effects, effects on vertebrates may be due to endocrine disruption. DDE, a metabolite of
DDT is notorious for causing eggshell thinning in birds that led to severe declines in bird
populations in the 50s and 60s, especially of large predatory species such as the bald
eagle and California condor. Like DDT, methoxychlor is also an endocrine disruptor.
IRAC Group 4: Nicotinic Acetylcholine Receptor (nAChR) Agonists
IRAC Group 4A: Neonicotinoids
Neonicotinoids provide excellent acute and residual control of sucking insects, including
aphids, leafhoppers, planthoppers and whiteflies, as well as certain chewing insects
including Colorado potato beetle, rice water weevil and codling moth. In addition, two
neonicotinoids, thiacloprid and acetamiprid, have proven to be effective in the control of
many Lepidoptera pests. Imidacloprid, commercialized in 1991, is the most widely used
crop insecticide worldwide and is also registered for many non-crop uses, particularly as
23
a spot-on flea treatment, turf treatment for white grubs and as a termiticide. The extremely
potent aphid antifeedant effect of the group reduces the insect-vectored transmission
of certain viruses. + neonicotinoid insecticides have been commercialized.
Possessing high water solubility and robust plant systemicity, neonicotinoids can be applied
by foliar spray, soil treatment, seed treatment, trunk injection or painting onto plant tissue.
The application rates for neonicotinoids are low compared to most insecticide groups.
Examples of Neonicotinoids
nCommon
n
Common
n
Common
n
Common
Nicotine is a natural insecticide, made by plants (e.g., tobacco) for defense against insects.
Nicotine-based insecticides have been banned by the EPA since 2001 because of their high
acute toxicity.
IRAC Group 4C: Sulfoxaflor
Sulfoxaflor, introduced by Dow AgroSciences in 2011, is a novel sulfoximine nAChR agonist
offering excellent broad spectrum activity against key sap-feeding pests, excellent residual
activity and control of many imidacloprid-resistant insects.
Example of Sulfoxaflor
nCommon
The popular view is that neonicotinoids and indeed nicotine itself, continually stimulate
the receptors and in so doing cause nerve overstimulation, but it is becoming clear that the
action is more complicated. Most receptors do not remain activated indefinitely when an
agonist is bound, but instead become desensitized. Desensitization involves a
conformational transition of the nicotinic acetylcholine
receptor (nAChR)-insecticide complex to a very stable
desensitized state that binds the insecticide 500-fold more
ACh
H
NICOTINE
IMIDACLOPRID
degradation. The first case of field-evolved target site resistance has recently arisen in populations of the green
peach aphid, Myzus persicae, in Spain and France,
resulting from a point mutation in the ACh binding site of
one of its six nAChR subunit genes. This same resis-
SULFOXAFLOR
CATIONIC
SITE
25
26
A point mutation in the macrocyclic lactone binding site (page 7) of the a6 nAChR subunit
of Western flower thrips has recently helped localize the action of spinosyns to this site.
Environmental and Toxicological Considerations: This group is considered integrated
pest management (IPM) friendly, with no known significant adverse effects on beneficial
arthropods such as ladybird beetles, lacewings and spiders. Although there is high intrinsic
toxicity when applied to or ingested by worker honeybees, there is low acute toxicity after
residues have dried on plant foliage. Extremely high doses of spinosyns are required to elicit
a response in mammals and non-target organisms. Spinosyn labels carry the lowest human
hazard rating assigned by the EPA.
Spinosyns are non-volatile materials that bind moderately to strongly to soils. On plant
surfaces, spinosyns readily degrade and have a half-life of a few days. Spinosyns are
stable in water, but their use in crops poses minimal risk to aquatic organisms when label
directions are followed. Always refer to and follow local label guidelines.
IRAC Group 6: Chloride Channel Activators Avermectins and Milbemycins
Avermectins and milbemycins are closely related, naturally occurring macrocyclic lactones
generated by soil-dwelling actinobacteria. All are insecticidal, acaricidal and nematicidal,
but different products within this group have various advantages in terms of spectrum and
animal safety.
Abamectin, the leading product in this group, was introduced in 1985. Derived from the
fermentation of Streptomyces avermitilis, abamectin controls pests like leaf miners and
mites and is used mainly in vegetable and fruit crops. Major markets include the U.S.,
Brazil, Mexico, Italy, Egypt, France, Spain, Indonesia and Argentina. Emamectin benzoate
was introduced in 1998 for use on vegetable crops and was later expanded to cotton for
bollworm control. The main markets are Japan, Australia, South Korea, USA, Taiwan and
Mexico. Milbemectin, a mixture of natural endotoxins, acts as a contact miticide on all mite
life stages and significantly reduces the fecundity of adult females.
Examples of Chloride Channel Activators
n
Common
n
Common
n
Common
27
O P E N I O N CH ANNEL
C R O S S -S E C T ION
These compounds are rapidly absorbed by plants. Remaining surface residues are
rapidly degraded by UV light, which reduces their bioavailability to bees. There is no
bioaccumulation potential, since chloride channel activators bind tightly to the soil and
do not leach.
IRAC Group 9 : Selective Homopteran Feeding Blockers
Selective homopteran feeding blockers control homopterous insects, a group that includes
aphids, cicadas, whiteflies and leafhoppers. These insecticides are used on a variety of
crops, including vegetables, potatoes, rice, stone fruits and ornamentals, causing rapid
cessation of feeding in homopterans and some other insects. Considered a major rotation
partner for neonicotinoids, selective homopteran feeding blockers work through direct
contact with the pest, systemically within the plant, or locally systemic: penetrating leaf
tissues and forming a reservoir of active ingredient within the leaf. Because they are
considered of low toxicity to beneficial insects, selective homopteran feeding blockers fit
well into integrated pest management systems.
IRAC Group 9B: Pymetrozine
28
Flonicamid was developed and introduced on a global basis in the late 1990s by ISK
Biosciences Corporation and its parent company, Ishihara Sangyo Kaisha but is distributed
in the Americas and Europe by FMC.
Example of Flonicamid
n
29
Mode of Action and Resistance: Octopamine receptor agonists mimic the action of the
neurotransmitter octopamine in insects. Octopamine is the insect adrenaline, modulating
the function of the central nervous system and enhancing the level of excitability of many
tissues in the body. Activation of octopamine receptors is coupled by a GTP-binding protein
to the production of the intracellular messenger cyclic-AMP (page 14), elevation of which
triggers many excitatory effects related to fight-or-flight, and too much of which results
in tremors and convulsions, as well as suppression of feeding and reproduction at lower
doses. Amitraz is the only octopamine receptor agonist in current use.
Resistance to Amitraz appears to be mainly metabolic. No target site resistance is known.
Environmental and Toxicological Considerations: Amitraz has low toxicity to mammals,
but is suspected to be a carcinogen. It is practically non-toxic to bees, but may adversely
affect avian reproduction. It is highly toxic to many aquatic vertebrates and invertebrates,
but poses a low risk because of its rapid environmental dissipation.
30
Metaflumizone, a new class of chemistry co-developed by BASF and Nihon Nohyaku Co.,
does not require bioactivation. It controls most Lepidoptera, as well as certain members
of other insect orders, including Coleoptera, Hemiptera, Diptera, Orthoptera and
Hymenoptera. Metaflumizone effectively controls pests in a variety of crop markets,
including cotton, potatoes, fruits and leafy vegetables. It is also used for the control of
ants and other nuisance pests.
Example of Metaflumizone
n
Common name metaflumizone trade names Alverde insecticide, Siesta fire ant bait
Mode of Action and Resistance: Sodium channel blocking insecticides bind in and
obstruct the sodium channel pore, blocking nerve action potentials and paralyzing insects.
Paralysis by sodium channel blockers has been called relaxed paralysis, to distinguish it
from the tetanic paralysis caused by many other insecticides.
Many cases of resistance to indoxacarb have been reported, all of which appear to be due
to enhanced metabolism. So far, resistance to metaflumizone has not been reported, and
metaflumizone controls most indoxacarb-resistant insects.
Environmental and Toxicological Considerations: Indoxacarb was classified by the EPA
as a reduced-risk pesticide. It is practically non-toxic to bees and poses little risk to
humans and other non-target organisms when used according to the label. Metaflumizone
is generally considered non-toxic to mammals and birds, and slightly toxic to fish and
bees. It has low impact on key beneficial insects. Although highly toxic to some aquatic
invertebrates, it is strongly adsorbed to soil, is rapidly degraded in the environment, and is
not expected to leach.
31
The insecticides in IRAC Group 28 represent a relatively new mode of action. Flubendiamide
was co-developed by Nihon Nohyaku Company and Bayer CropScience and introduced
in 2007, while chlorantraniliprole was launched by DuPont in 2008. Both products have
broad-spectrum larvidical activity on Lepidoptera pests and can be used on a wide range of
crops. They provide effective control of pest populations resistant to other insecticidal
products. Cyantraniliprole was introduced by DuPont in 2012 as a second generation
ryanodine receptor modulator offering cross-spectrum foliar and systemic activity against
chewing and sucking insects.
Examples of Diamide Insecticides
n
Common
n
Common
n
Common
32
left:
E XOCUT I CL E
CUT I CL E
E NDOCUT I CL E
non-chitinous epicuticle;
procuticle consisting of
exocuticle and endocuticle,
E PI DE R MI S
Insect growth progresses through stages: eggs hatch into an immature stage, and the
insect may pass through several more immature stages before emerging as an adult.
As the exoskeleton cannot expand, it must be shed and replaced with a larger one at each
molt to the next stage.
33
1. INTERMOLT STA GE
3. S E CR E T I ON OF F LU I D
G R OW T H OF E PI D E R M I S
CUTICLE
EP I DERMIS
A molt can involve a change not only in size, but also of form, to a more mature life stage.
A molt to a more mature form is called a metamorphosis, while a molt to a new immature
stage is called an immature molt. Insects may go through more than one immature molt
and even more than one metamorphosis, such as larva to pupa and pupa to adult, but the
molt to the adult stage is the final one.
The major developmental hormone in insects, the steroid hormone ecdysone, plays a
central role in all molting and metamorphosis. Ecdysone is produced and released by the
prothoracic gland in the thorax, under control of the nervous system. When the brain
has determined that the time is right, two pairs of neurosecretory neurons secrete a
neuropeptide into the hemolymph that acts on the prothoracic gland to stimulate release of
ecdysone. The hormone enters cells of the epidermis and other tissues where it binds to
the ecdysone receptor, EcR. This hormone-receptor complex moves into the nucleus where
it complexes with another DNA-binding protein called USP, forming a tertiary complex that
binds to specific short DNA sequences, activating genes required for molting.
34
While a pulse of ecdysone induces molting, the nature of the molt depends on juvenile
hormone (JH), so named because its presence during the ecdysone peak prevents
metamorphosis to a more mature stage. Juvenile hormone is produced by a pair of glands
behind the brain called the corpora allata, under the control of two neurohormones
released by the brain. JH production stops during metamorphosis and circulating JH is
degraded by a pair of enzymes. It reappears in the adult, where it regulates female
reproductive maturation.
Juvenile hormone enters the nucleus and binds to its receptor called Met, a DNA binding
protein that pairs with itself and other DNA binding proteins to form dimers (a molecule
below:
A cicada molting.
4 . SEC R ET I ON OF N EW CUTICLE
composed of two simpler molecules). The dimers bind to short DNA segments, called
juvenile hormone response elements, in order to switch on genes. The juvenile hormone
receptor is called Met because it was identified in methoprene resistance. The antimetamorphic effect of juvenile hormone is due to the switching on of a single gene that
represses the expression of the genes needed for adult development.
There are seven groups of insect growth regulators in the IRAC classification. Both the
juvenile hormone and ecdysone mimics bind to and activate the receptors for these
hormones, while four groups of chitin synthesis inhibitors hinder the formation of new
cuticle during the molt by unknown mechanisms. The newest group of insect growth
regulators does not affect molting and metamorphosis directly, but affects development
by inhibiting the biosynthesis of fats, which are required for growth.
35
n
Common
n
Common
Mode of Action and Resistance: The figure on page 37 shows the chemical structure
of the most common form of JH, JH III, along with examples of the three classes of
insecticides that mimic it. Clearly, methoprene is a very close chemical analog, and in fact
all of the JH mimics work by binding to and mimicking the action of JH at its receptor.
Activation of JH receptors during molting inhibits the expression of genes needed to form
larval or adult structures. In immature molts this has little or no effect, but it can severely
disrupt metamorphosis, leading to incomplete molting, or in some cases, a successful molt
to a supernumerary immature stage.
Although target site resistance to JH mimics was generated in the laboratory in fruit flies,
resistance in the field appears to be largely metabolic, due to enhanced metabolism by
P450 monooxygenases and glutathione S-transferases (GSTs).
Environmental and Toxicological Considerations: JH mimics are relatively non-toxic to
mammals and most other organisms, but have moderate to high acute toxicity to estuarine
invertebrates. These insecticides vary in their environmental persistence, but most have
extremely low water solubility and are not considered to have a potential to leach.
36
JH III
METHOPRENE
FENOXYCARB
PYRIPROXYFEN
37
n
Common
Etoxazole controls spider mites in a variety of crops, including citrus, strawberries, nuts,
vegetables, ornamentals, cotton and pome fruits. It kills mite eggs and nymphs and
prevents adults from laying viable eggs. Etoxazole controls mites resistant to hexythiazox
and clofentezine.
Example of Etoxazole
n
Common
Mode of Action and Resistance: Clofentezine and Diflovidazin are close analogs and are
grouped with Hexythiazox because they commonly exhibit cross-resistance, despite being
structurally distinct. The target site of these compounds is considered unknown, but recent
investigations of resistance mechanisms indicate that these compounds may be chitin
synthase inhibitors.
Etoxazole has been shown to inhibit chitin biosynthesis in whole larvae and isolated
integuments of Spodoptera frugiperda and to cause similar symptoms to triflumuron.
Furthermore, a mutation in the chitin synthase gene confers resistance to etoxazole,
clofentezine and hexythiazox.
Environmental and Toxicological Considerations: Both clofentezine and hexythiazox
exhibit low acute mammalian toxicity, have low solubility, degrade rapidly and have very low
soil mobility once applied. They have low toxicity to terrestrial arthropods, including predatory
mites, making them useful in integrated pest management programs. Both products are toxic
to certain aquatic organisms. Hexythiazox is highly toxic to Daphnia on a chronic basis.
Etoxazole is relatively non-toxic to mammals, birds and honeybees, moderately toxic to fish,
and extremely toxic to oysters and freshwater invertebrates. Terrestrial degradation studies
indicate that etoxazole breaks down readily in soil and does not accumulate.
IRAC Group 15: Inhibitors of Chitin Biosynthesis, Type 0,
Lepidopteran (Benzoylureas)
Chitin is an essential structural component of insect cuticle. Group 15 insecticides interfere
with the biosynthesis of chitin in Lepidoptera and some other orders. When an insect
cannot make chitin, it dies during the molt.
38
Insecticides in this group are used to control certain major pests in a variety of crops,
including boll weevils and Lepidoptera (moths and butterflies) in cotton and Lepidoptera
and Coleoptera (beetles) in citrus, rice, tea, soybeans, vegetables and ornamentals.
These insecticides generally enter the insect orally through the consumption of treated
foliage or insecticide baits.
BASFs Cascade insecticide and Tenopa insecticide, members of IRAC Group 15, contain
the active ingredient flufenoxuron, available in Asia for use in fruit and vegetable crops.
BASFs Nomolt insecticide with the active ingredient teflubenzuron is sold in South
America and Europe for use in soybean, maize, cotton, fruits and vegetables. Nomax
insecticide containing the same a.i., is used solely in Brazil for soybean pest control.
Examples of Inhibitors of Type 0, Lepidopteran
n
Common
n
Common
n
Common
name flucycloxuron
n
Common
n
Common
n
Common
n
Common
n
Common
n
Common
n
Common
Mode of Action and Resistance: Chitin biosynthesis inhibitors interfere with the formation
of chitin during molting, resulting in a weak, soft exoskeleton and deformed appendages
and sexual organs. The molecular target of the chitin biosynthesis inhibitors is not known.
Environmental and Toxicological Considerations: Chitin biosynthesis inhibitors have low
toxicity to mammals, but in the environment, particularly aquatic ecosystems, they can be
very toxic to non-target insects and other arthropods. Most have extremely low water
solubility and are not considered to have potential to leach through the soil. Some chitin
synthesis inhibitors can persist in the environment and are active at very low levels.
39
Mode of Action and Resistance: Chitin biosynthesis inhibitors interfere with the formation
of chitin during molting, resulting in a weak, soft exoskeleton and deformed appendages
and sexual organs. The molecular target of the chitin biosynthesis inhibitors is not known.
Environmental and Toxicological Considerations: Chitin biosynthesis inhibitors have low
toxicity to mammals, but in the environment, particularly the aquatic environment, they can
be very toxic to insects and other arthropods. Most have extremely low water solubility and
are not considered to have a potential to leach through the soil. Some chitin synthesis
inhibitors can persist in the environment and are active at very low levels.
IRAC Group 17: Molting Disruptor, Dipteran
The only member of IRAC Group 17 is cyromazine, which disrupts the growth and
development of larval life stages of the order Diptera, including mosquitoes, gnats, onion
maggots, fruit flies and midges, all of which have a single pair of wings and are classified as
true flies. Cyromazine is used as a foliar spray to control leaf miners and other fly larvae in
vegetables, mushrooms, ornamentals and as a feed-through product in animal health. It is
broadly systemic and moves within plants by translaminar and acropetal action.
Example of Molting Disruptor, Dipteran
n
Common
Mode of Action and Resistance: Cyromazine disrupts growth and development of dipteran
larvae by an unknown mechanism. It appears to affect the hormonal control of molting, but
the mechanism of action is unknown. While resistance to cyromazine has been reported in
house flies, leafminers and blow flies, it does not appear to be target site-based.
40
Mode of Action and Resistance: Diacylhydrazine insecticides bind in the ecdysone binding
site of the ecdysone receptor-usp dimer, causing it to activate ecdysone-responsive
genes that are normally activated during molting and metamorphosis. One of the earliest
symptoms, occurring within 3 to 14 hours, is feeding cessation, a normal effect of ecdysone
that allows insects to clear food from the gut in preparation for molting. Separation of the
old cuticle from the epidermis and synthesis of the new cuticle begins during this time
also. The continued activation of ecdysone receptors, in contrast to the brief activation by
the pulse of ecdysone in a normal molt, does not allow the proper timing of gene activation.
This results in an improperly formed cuticle and mouth parts that are soft and mushy and
unable to break the insect out of the old cuticle. The selectivity of diacylhydrazines for
Lepidoptera is due in large part to the high selectivity for lepidopteran ecdysone receptors.
41
n
Common
n
Common
42
43
Typical Cell
NUCLEUS
compartment from the outer compartment known as the intermembrane space. Certain
intermediates derived from the metabolism of nutrient molecules in the cell penetrate into
the mitochondrial matrix, with the help of specific transport proteins. In the matrix, these
intermediates are fully oxidized by a biochemical pathway known as the Krebs cycle to
produce energy in the form of ATP and two other energy-rich molecules, nicotinamide
adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2).
Electrons in molecules exist at specific energy levels, and their transfer between
GOLGI
BODIES
molecules transfers this energy as well. Four giant protein complexes embedded in the
ENDOPLASMIC
RETICULUM
MITOCHONDRIA
inner mitochondrial membrane, together with the small molecules coenzyme Q (CoQ) and
cytochrome C (CytC), form the electron transport chain, as shown in the figure below.
High-energy electrons from NADH enter the electron transport chain via complex I while
those from FADH2 enter via Complex II. After passing through this chain, they are accepted
by oxygen to form water in a reaction catalyzed by complex IV.
OUTER
MEMBRANE
INNER
MEMBRANE
I N T E R M E M B R A N E S PA C E
COMPLEX III
UNCOUPLER
COMPLEX IV
COMPLEX I
COMPLEX II
CoQ
UNC H
Cyt C
UNC -
FAD H 2
Typical Mitochondrion
O2
SUCCINATE
H 2O
NADH
NAD +
KREBS
CYCLE
FUMARATE
ADP
ATP
AT P S Y N T H A S E
Electrons
Protons
M I T O C H O N D R I A L M AT R I X
Excess energy derived from the electron transfers carried out by complexes I, III and IV
is used to pump ions across the inner mitochondrial membrane, creating an ion gradient.
As discussed earlier in connection with the Na+, K+ pump, an ion gradient has potential
energy, or the capacity to do work, because of the entropy-driven tendency of the ions
to move from an ordered (high concentration) to a disordered (low concentration) state.
The ions that are pumped by the electron transport complexes are protons, the nuclei
of hydrogen atoms, which are always present in aqueous solutions as a result of the
dissociation of water molecules. Protons give water its acidity. In fact, the widely known
measure of acidity, pH, is actually a measure of proton concentration.
44
ATP synthase, also known as F0 F1-ATPase, is the enzyme in the inner mitochondrial
membrane that uses the energy of the proton gradient across it to power the
phosphorylation of ADP to form ATP. It is a rotary enzyme composed of two motors that are
connected by a common shaft to exchange rotational energy with one another. During ATP
synthesis, the movement of protons from the intermembrane space to the matrix, through
the membrane-embedded F0 motor, generates torque, causing the F0 motor to rotate.
Rotation is transmitted by the shaft to the F1 motor in the matrix, where it drives the
phosphorylation of ADP to form ATP.
The entire process described in the preceding three paragraphs is known as oxidative
phosphorylation. The energy released by oxidation of nutrients in the electron transport chain
is coupled by a proton gradient to the phosphorylation carried out by ATP synthase. All six
groups of respiration disruptor insecticides act on the inner mitochondrial membrane of
mitochondria, either by inhibiting ATP synthase or one of the electron transport complexes,
or by uncoupling oxidation from phosphorylation by making the membrane leaky to protons
so that it cannot support a proton gradient. While all six of these groups starve cells of
energy by preventing ATP synthesis, they do so in different ways, offering a richness of
insecticide target sites.
45
A broad spectrum acaricide and insecticide, diafenthiuron is registered for use on cotton,
soybeans, vegetables, fruit and ornamentals. It controls all post-hatch stages of mites,
whiteflies and aphids. Its ability to control all sucking pests of cotton as well as mites, with
no known toxicity to beneficial insects, is unique and very valuable in cotton integrated pest
management (IPM) programs.
Example of Diafenthiuron
n Common name diafenthiuron trade name Polo
Mode of Action and Resistance: Diafenthiuron is a proinsecticide, which means that it
must be converted to another compound the drug in order to be toxic. Activation of
diafenthiuron to its carbodiimide drug occurs on the leaf surface, catalyzed by light, or in
the insect, catalyzed by P450 monooxygenases. Diafenthiuron carbodiimide binds to the
glutamate residue in the transmembrane F0 subunit of ATP synthase where protons from
the intermembrane space dock to begin their journey across the inner mitochondrial
membrane. Binding of diafenthiuron carbodiimide to this site blocks proton transport and ATP
synthesis. Diafenthiuron was launched in 1991 and resistance has not yet been reported.
Environmental and Toxicological Considerations: Diafenthiuron has low toxicity to birds,
mammals and beneficial insects, and is only slightly toxic to predatory mites. It is toxic to
fish, but presents little hazard because it is rapidly degraded.
IRAC Group 12B: Organotins
n
Common
Mode of Action and Resistance: Organotins inhibit ATP synthase. Like diafenthiuron,
they act at the proton binding site in the F0 subunit. Cases of resistance to fenbutatinoxide, cyhexatin and azocyclotin have all been reported, but target site resistance has
not been found.
46
Propargite is a contact acaricide that controls motile stages of phytophagous (or plant
feeding) mites on almonds, beans, carrot seeds, Christmas trees, conifers, clover seeds,
maize, cotton, fruit, hops, mint, ornamentals, potatoes, peanuts, sorghum, sugar beets and
walnuts. Its also effective for postharvest use in sweet cherries and citrus.
Example of Propargite
n
Common
Mode of Action and Resistance: Propargite inhibits ATP synthase. While resistance has
been reported, target site resistance has not been found.
Environmental and Toxicological Considerations: Propargite is not shown to have toxicity
to birds and beneficial arthropods when used as directed, but is highly toxic to fish and
some aquatic invertebrates. It causes eye and skin irritation in humans.
IRAC Group 12D: Tetradifon
Tetradifon is an acaricide that gives long residual control of eggs and immature stages
of phytophagous mites on top-fruit, vegetables, ornamentals, hops, cotton, nuts, tea,
sugarcane and forestry. It is a non-systemic compound with activity on eggs (ovidical)
and immature life stages.
Example of Tetradifon
n
Common
Mode of Action and Resistance: Tetradifon inhibits ATP synthase in the F0 subunit.
While resistance is known, target site resistance has not been described.
Environmental and Toxicological Considerations: Tetradifon is not phytotoxic to most
crops and is considered non-toxic to non-target organisms, including beneficial arthropods.
IRAC Group 13: Uncouplers of Oxidative Phosphorylation via Disruption
47
It is also excellent for use in urban pest control against ants, cockroaches, bed bugs and
termites in soil and wood.
Chlorfenapyr is active against larvae and adults of many insect and mite pests, and is used
in a wide range of crops, including vegetables, tree fruits, vines and ornamentals. Its
contact activity and lack of repellency make it an excellent product against many non-crop
pests, including termites, ants, cockroaches and bed bugs.
Chlorfenapyr is a pro-insecticide, requiring bioactivation by oxidative metabolism within the
insect. Target pests acquire the compound primarily through consumption of treated
residues or contact with treated surfaces. Chlorfenapyr has excellent translaminar
movement, which means that when applied to the top of a leaf, it will cross to the bottom
surface where many pests feed.
DNOC (4,6-dinitro-o-cresol, also known as 2-methyl-4,6-dinitrophenol) is an insecticide/
acaricide used as a dormant spray for the control of insects, mites and disease on top fruit.
It is also used as a herbicide.The compound is highly toxic and its registrations and uses are
extremely limited. DNOC was banned in the U.S. in 1991 and in the E.U. in 1999.
Sulfluramid is a pro-insecticide that is bioactivated by oxidative metabolism in the insect.
It is used in bait stations for ants, termites, cockroaches and wasps, but its uses are being
phased out in the U.S. by 2016 because of human toxicity.
Examples of Uncouplers of Oxidative Phosphorylation
n
Mode of Action and Resistance: Uncouplers are the only insecticides that do not act
on a protein target. Most are weak acids that can accept a proton in the proton-rich
intermembrane space, transport it across the inner mitochondrial membrane, deposit it
in the matrix and return across the membrane to pick up another proton and repeat the
cycle. The result of this proton shuttling is that the energy stored in the proton gradient is
dissipated as heat, without being used for ATP synthesis. In the absence of a proton
gradient, ATP synthase runs in reverse, quickly hydrolyzing the available ATP to futilely pump
protons back into the intermembrane space. ATP is quickly depleted, leading to rapid
paralysis and death.
Any lipophilic weak acid could pick up protons in the intermembrane space and transport
them into the matrix, but in order to act as an uncoupler, the deprotonated form of the
molecule, which has a negative charge, must diffuse back across the inner mitochondrial
48
membrane to pick up another proton in the intermembrane space, thus sustaining a cycle
of proton transport. Most charged molecules cannot traverse the nonpolar interior of the
membrane. In a polar medium, such as water, a charged atom in a molecule attracts polar
water molecules that shield its charge, thus reducing repulsive forces between like-charged
molecules. This shielding would not occur inside the non-polar lipid membrane, so there
would be strong repulsion between charged molecules. Uncoupler molecules are able to
shield the charge internally within the molecule, by delocalizing it over many atoms. This
greatly reduces the electrostatic repulsion between like molecules in a nonpolar medium.
The active form of chlorfenapyr is very good at delocalizing the negative charge over a
system of double bonds, and is one of the most potent uncouplers known.
Without a target site, uncouplers are not subject to target site resistance. Laboratory tests
have shown no indication of cross-resistance with other insecticides.
Environmental and Toxicological Considerations: Chlorfenapyr is highly toxic to birds, but
the results of extensive avian field studies and a probabilistic risk analysis indicate that the
use of chlorfenapyr in agriculture presents a low risk to avian species. Greenhouse and
non-agricultural uses of chlorfenapyr do not pose significant risk to birds, due to its low
water solubility and immobility in soils, which precludes it from leaching into water supplies.
Chlorfenapyr is strongly adsorbed by various soil types and degrades in the soil gradually
over time.
IRAC Group 20: Mitochondrial Complex III Electron Transport Inhibitors
The three insecticides that act as mitochondrial complex III electron transport inhibitors
represent three different chemical families.
IRAC Group 20A - Hydramethylnon
Common name hydramethylnon trade names Amdro Pro, Siege cockroach gel bait
Acequinocyl is used for control of all stages, including eggs, of phytophagous mites in
fruit crops, including apple, cherry, citrus, melon, peach and pear, as well as ornamentals
and vegetables.
Example of Acequinocyl
n
49
Fluacrypyrim is a strobilurin acaricide introduced in 2002 for use on fruit crops. Its route
of exposure is through ingestion of treated residues or by contact with treated surfaces.
It exhibits rapid activity on all mite life stages, with residual control lasting up to one month.
Example of Fluacrypyrim
n
Tebufenpyrad, one of the compounds in this group, is the active ingredient in Masai
insecticide/acaricide, developed by BASF. Effective as an acaricide, this product
controls spider mites and citrus red mites on cotton, citrus, fruit and vegetable crops
and ornamentals.
Other Group 21A insecticide/acaricides are used to control leafhoppers, mites and
whiteflies in fruit crops, vegetables, ornamentals, nuts and cotton. They are generally
fast-acting and offer long-lasting control of all life stages of susceptible insects and mites.
Examples of Mitochondrial Complex I Electron Transport Inhibitors
n
n
Common
50
Rotenone (Group 21B) is effective on aphids, beetles, moths, spider mites and thrips in
fruit and vegetable crops, as well as on fire ants and mosquito larvae in pond water. It is
also used to control fish populations in the field of water management and to eliminate
invasive fish species.
Example of Rotenone
n
Common name rotenone trade name Prentox
Mode of Action and Resistance: Group 21 insecticide/acaricides inhibit mitochondrial
electron transport complex I, leading to rapid paralysis and death. Resistance to METI
acaricides has developed in several mite species, but surprisingly has not yet been found to
be target-site-based. Resistance is metabolic, but often extends to other members of this
group, because of chemical similarities.
Environmental and Toxicological Considerations: Group 21 insecticides are generally
non-toxic to slightly toxic to mammals and birds, but tend to be highly toxic to fish and
aquatic invertebrates. Some, such as fenazaquin, are also toxic to predatory mites.
IRAC Group 24: Mitochondrial Complex IV Electron Transport Inhibitors.
IRAC Group 24A: Phosphine
Phosphine is a colorless, odorless, flammable toxic gas with the chemical formula PH3.
Pellets of aluminum phosphide, calcium phosphide or zinc phosphide release phosphine
gas upon contact with atmospheric moisture or rodents stomach acid. These pellets also
contain agents to reduce the potential for ignition or explosion of the released phosphine.
Phosphines are fumigants used as rodenticides and to control a broad spectrum of insect
pests of grains and non-food/non-feed plant and animal products, such as animal hides,
leather products, feathers, wood chips, bamboo, paper and dried plants and flowers in
sealed containers or structures. There are no homeowner or agricultural row crop uses
for these products.
Because the previously popular fumigant methyl bromide has been phased out in some
countries under the Montreal Protocol, phosphine is the only widely used, cost-effective,
rapidly acting fumigant that does not leave residues on the stored product.
Examples of Phosphine
n Common name phosphine trade name - Profume
n
Common
name phosphides
Cyanide is produced by certain bacteria, fungi and algae, and is found in a number of
plants. Cyanide is also found in small amounts in certain seeds and fruit stones. In plants,
cyanide is usually bound to sugar molecules in the form of cyanogenic glycosides that
defend the plant against herbivores. Highly toxic to humans and animals, cyanide has been
banned for use as a pesticide.
51
Mode of Action and Resistance: Phosphine gas and cyanide are considered to inhibit
mitochondrial electron transport complex IV, the last complex in the electron transport
chain, which uses electrons from cytochrome C to reduce molecular oxygen to water.
Pests developing high levels of resistance toward phosphine have become common in
Asia, Australia and Brazil. High level resistance is also likely to occur in other regions, but
may not have been as closely monitored. Phosphine resistance has recently been found
to be due to any of several mutations that cluster around the catalytic center in the enzyme
dihydrolipoamide dehydrogenase, which is a component of four major multienzyme
complexes in mitochondria, not including complex IV, suggesting that Electron Transfer
Complex IV might not be the target of phosphine.
Environmental and Toxicological Considerations: Phosphines are Restricted Use
Pesticides RUP; Category I, due to high acute oral toxicity of the pellets and inhalation
toxicity of phosphine gas.
IRAC Group 25: Mitochondrial Complex II Electron Transport Inhibitors
This group includes the selective acaricides cyenopyrafen, which controls mites on
ornamentals, top fruits, tea, vegetables, and non-bearing fruit trees, as well as cyflumetofen,
a new acaricide developed by Otsuka and offered by BASF in certain areas of the world.
Expected to launch in 2014, cyflumetofen will be used to protect a variety of crops,
including tree nuts, pome fruits, grapes, vegetables and citrus.
Examples of Mitochondrial Complex II Electron Transport Inhibitors
n
n
Common
Sultan miticide
Mode of Action and Resistance: Cyenopyrafen and cyflumetofen are pro-insecticides that
are metabolized to corresponding enol products that inhibit mitochondrial electron transport
complex II, leading to rapid paralysis and death due to cellular energy starvation. Resistance
has not yet been reported.
Environmental and Toxicological Considerations: Cyenopyrafen and cyflumetofen have
been shown to have very low toxicity to mammals, birds, bees and beneficial insects,
including predatory mites. They have some toxicity to fish and aquatic invertebrates, but
pose minimal risk because they are rapidly degraded in water and soil.
52
53
Common name B.t. tenebrionis trade names M-Trak , Novodor (both discontinued)
Mode of Action and Resistance: When Bt crystals are ingested by an insect, they dissolve
under the alkaline conditions of the gut to liberate one or more protein toxins. Of those, only
the crystal, or Cry toxins, have been engineered into crops. More than 500 Cry proteins in
67 classes were identified in the various known Bt strains. Cry toxins liberated from Bt
crystals are actually protoxins, requiring two successive transformations in the host before
they become active. The first step is the cleavage by gut protein-digesting enzymes to yield
an activated toxin monomer. The activated monomer passes through the peritrophic
membrane and binds to a specific cadherin on the brush border membrane of epithelial
cells. Cadherins are proteins on the surface of cells that serve a variety of functions,
including binding cells together into tissue. Binding to a cadherin triggers removal of the
toxin fragments N-terminal end, known as helix -1. With helix -1 gone, toxin monomers
are able to self-assemble into tetramers, which bind to secondary receptors on the epithelial
surface. These receptors can be either aminopeptidase N or alkaline phosphatase, both of
which are abundant. After binding, the toxin tetramer partially inserts into the membrane to
make pores that lyse the cells and destroy the integrity of the gut. This gut destruction by
the action of the toxin is sufficient to kill the insect by fluid loss and septicemia. In bacterially
infected hosts, the actively replicating bacteria can also invade and replicate in the host
tissues. Although a few days may elapse before the insect dies, it stops feeding soon after
ingesting Bt.
From the beginning, it was realized that widespread use of Bt crops would speed
resistance development in target pests if countermeasures were not taken, and the best
practical strategy was the high dose refuge strategy. In this strategy, a high dose of Bt is
expressed, so that survivors are rare. Furthermore, a significant number of non-Bt trait
plants are required in the vicinity of fields sown with Bt trait varieties. These must not be
treated with insecticides, in order to ensure the availability of an excess of susceptible
insects to mate with the rare Bt survivors. Bt resistance genes are recessive, so offspring
of a union between susceptible and resistant individuals would be susceptible and unable
54
C R Y S TA L
PROTIEN
PROTOXIN
A C T I V AT E D
TOXIN
MONOMER
TETRAMER
ALP or APN
PROTEIN
P O R E F O R M AT I O N
3
HELIX -1
CADHERIN
to survive on the Bt crop. This strategy has been recommended for all Bt crops, and when
left:
implemented has proven effective in delaying resistance. Where it has not been used,
Several different resistance mechanisms affecting the various steps of toxin action have
been observed in the lab, but only modified cadherins no longer recognized by the toxin
active fragments have been observed as a resistance mechanism in the field. Resistance
due to modified cadherins has occurred in several lepidopteran species, but is unstable
55
In contrast to the insecticides previously discussed, most of which interact selectively with
only one specific protein, Group 8 insecticides are reactive compounds that chemically
modify proteins in a specific way that can affect multiple targets. This makes them less
selective, but also makes them almost immune to target site-based resistance, compared
to more specific compounds.
IRAC Group 8A: Alkyl Halides
Methyl bromide, which represents alkyl halide compounds, has been used as a structural
fumigant as well as a pre-plant soil fumigant to control pests across a wide range of
agricultural and commercial sectors. Methyl bromide is an odorless, colorless gas that can
be produced either in the laboratory or biologically by bacteria, fungi and seaweed.
Example of Alkyl Halides
n
Common
Mode of Action and Resistance: Methyl bromide is a reactive chemical that reacts and
donates its methyl group to sulfur-containing amino acids in proteins, thereby disrupting
the function of many proteins. Because there is no single target site, target site resistance
is unlikely.
Environmental and Toxicological Considerations: Brief exposure to high concentrations
and prolonged inhalation of lower concentrations can be toxic to humans. It can cause
respiratory distress, cardiac arrest and central nervous system effects. Signs of exposure
include nausea, abdominal pain, weakness, confusion, pulmonary edema and seizures.
Persistent neurological deficits are frequently present after moderate to severe poisoning.
Because methyl bromide was determined to be a significant ozone-depleting substance, its
general use was phased out under the Montreal Protocol in 2005 in industrialized countries,
and will be eliminated in developing countries by 2015. Selected uses, including quarantine
applications, will remain and are exempt from the phase-out regulation as long as effective
alternatives are not available.
IRAC Group 8B: Chloropicrin
Chloropicrin was first synthesized in 1848 and was patented as an insecticide in 1908.
It was used as a toxic tear gas in World War I for its severely irritating, lachrymatory and
toxic effects. It moves rapidly in soil and is used as a soil fumigant for the control of insects,
nematodes and fungi in a wide range of agricultural and non-agricultural crops, including
fruits, vegetables and ornamental plants. It is often used in combination with other fumigants
(1,3-Dichloropropene; Iodomethane; Methyl Bromide) for greater potency and spectrum of
activity, and as a warning agent for these otherwise odorless fumigants.
56
Example of Chloropicrin
n
Common
Mode of Action and Resistance: Chloropicrin is highly reactive and reacts with
sulfur-containing amino acids in multiple proteins and other biomolecules.
Environmental and Toxicological Considerations: Chloropicrin is a strong lachrymator
(tear gas) and is severely irritating to eyes, skin and mucosal membranes of the respiratory
and gastrointestinal tracts, causing nausea, vomiting, difficulty breathing and respiratory
tract inflammation. Because of its high volatility, the main route of human exposure to
chloropicrin is inhalation. Damage to the respiratory tract can lead to pulmonary edema and
death. Chloropicrin can be absorbed systemically through inhalation, ingestion and the skin.
It is severely irritating to the lungs, eyes and skin, causing potentially fatal tissue damage
and edema at higher levels. In the atmosphere, it is rapidly degraded and does not deplete
the ozone layer.
IRAC Group 8C: Sulfuryl Fluoride
With methyl bromide being phased out in both developed and non-industrial nations, the
use of sulfuryl fluoride as a replacement has increased rapidly. This odorless, colorless gas
is used as a fumigant to kill insects post-harvest on products like grains, fruit and nuts, and
to control drywood termites in structures. It is also being evaluated as a soil fumigant
Example of Sulfuryl Fluoride
n
Common
Mode of Action and Resistance: As a fumigant, sulfuryl fluoride penetrates materials and
insect bodies rapidly. Containment is important, to ensure that it is present in the insects
body long enough to be broken down to release toxic fluoride ions, which are known to
inhibit several enzymes. The insecticidal mechanism of fluoride ions is not well understood,
but is thought to involve inhibition of one or more key enzymes. Its protective action against
dental caries is due to the formation of a complex with magnesium and phosphate that
inhibits the enzyme enolase, which is important for sugar utilization by bacteria. Resistance
to sulfuryl fluoride has not yet been reported.
Environmental and Toxicological Considerations: Sulfuryl fluoride is a colorless odorless
gas that is highly toxic to humans if inhaled. Symptoms may include weakness, nausea,
vomiting, hypotension, metabolic acidosis, hypocalcemia, cardiac dysrhythmia and
pulmonary edema, which can be fatal if not treated. Fumigation of food with sulfuryl fluoride
leaves a significant residue of fluoride ions behind. In January 2011, the US EPA proposed
significant restrictions on the use of this compound in the food industry on the grounds of
fluorides negative effects on children, but a final decision is still pending. Sulfuryl fluoride
has been classified as a greenhouse gas, but it is not ozone-depleting.
57
Boric acid and borate salts have been registered since 1948 as nonselective herbicides,
fungicides and insecticides. Many formulations are available, including liquids, soluble and
emulsifiable concentrates, granules, powders, dusts, pellets, tablets, solids, pastes, baits
and crystalline rods, The major insecticide uses are as a wood preservative and for control
of cockroaches and other crawling pests, where it is safe for household and kitchen use.
Examples of Borates
n
n
Common
Mode of Action and Resistance: All borate salts dissolve in the body to yield boric
acid. There is no information available on the mode of action of boric acid and borates.
The symptomology in insects includes reduced appetite, weight loss, desiccation and
mortality. Boric acid powder is said to abrade the exoskeleton of crawling insects, leading
to desiccation, but this appears to be supposition and is probably an oversimplification.
Resistance to boric acid and borates has not been reported.
Environmental and Toxicological Considerations: Boric acid and borates occur naturally
and are re-released into the environment by many human activities including the use of
borate salt laundry products, coal burning, power generation, chemical manufacturing,
copper smelters, rockets, mining operations and industries using boron compounds in the
manufacture of glass, fiberglass, porcelain enamel, ceramic glazes, metal alloys and fire
retardants. These products are non-mutagenic, non-carcinogenic, and relatively non-toxic
to mammals, but have been fatal to humans and livestock when accidentally consumed in
large amounts.
IRAC Group 8E: Tartar Emetic
Tartar emetic, antimonyl potassium tartrate, is used as the toxic agent in ant poisons and
for the control of thrips. It is only used today in South Africa and Zimbabwe.
Example of Tartar Emetic
n
Common name tartar emetic trade names Tartox, Brennotox
Mode of Action and Resistance: The mode of action is unknown. Resistance in thrips has
been reported, but the mechanism has not been determined.
Environmental and Toxicological Considerations: Tartar emetic is highly irritating to skin,
eyes and mucus membranes.
58
The compounds in this group have an unknown or uncertain mode of action because the
target protein responsible for the biological activity is unknown or uncharacterized.
Azadirachtin
Azadirachtin is the principal insecticidal component of extracts of seeds of the neem tree,
a large, fast-growing mahogany of tropical and subtropical regions of India, Pakistan,
Bangladesh and Southeast Asia. Neem seeds were traditionally ground to a powder and
mixed with water to control insects on crops. Azadirachtin is used to kill locusts, aphids,
beetles, borers, bugs, caterpillars, flies, leafhoppers, leafminers, mealybugs, mole crickets,
nematodes, psyllids, sawflies, scales, thrips, weevils, whiteflies and fruit flies.
Example of Azadirachtin
n
Common
Mode of Action and Resistance: The mode of action of bifenazate has recently been
determined to be inhibition of mitochondrial electron transport complex III by binding in the
Q 0 center (ubiquinol oxidation site) in the cytochrome b subunit. Mutations of two different
amino acids in the binding site confer resistance to bifenazate and also to the group 20
miticide acequinocyl. Bifenazate will be reclassified in IRAC group 20D.
Environmental and Toxicological Considerations: Bifenazate is practically non-toxic to
mammals, moderately toxic to birds and highly toxic to fish and aquatic invertebrates.
It is moderately toxic to bees, but non-toxic to predatory mites and beneficial insects.
59
Benzoximate
Benzoximate is an acaricide used to control all stages of spider mites on pome fruit, stone
fruit, citrus fruit, vines and ornamentals. It was commercialized in Japan in 1971 but
discontinued there in 1998 and is currently registered only in Italy, South Korea, South
Africa and Switzerland.
Example of Benzoximate
n
Common
name benzoximate
Mode of Action and Resistance: The mode of action of benzoximate is not known.
Resistance has been reported in citrus red mite, European red mite and twospotted
spider mite.
Environmental and Toxicological Considerations: Benzoximate is relatively non-toxic
to mammals and fish, but is moderately toxic to predatory mites.
Cryolite
Cryolite is an uncommon mineral salt of sodium, fluoride and aluminum that was first
discovered on the west coast of Greenland. The supply was depleted by 1987, and
synthetic cryolite is now produced from the common mineral fluorite. Cryolite is used at
very high application rates of 5-30 kg/ha to control Lepidoptera and Coleoptera on certain
fruits, vegetables and citrus. 92% of total cryolite applied in the U.S. is used on grapes
in California.
Example of Cryolite
n
Mode of Action and Resistance: Cryolite is thought to act through the release of fluoride
ions. The insecticidal mechanism of fluoride ions is not well understood, but is thought to
involve inhibition of one or more key enzymes. Its protective action against dental caries is
due to the formation of a complex with magnesium and phosphate that inhibits the enzyme
enolase, which is important for sugar utilization by bacteria. The only known case of
resistance to cryolite was in walnut husk fly, reported in 1943.
Environmental and Toxicological Considerations: Cryolite does not contaminate ground or
surface water and is considered low risk to non-target organisms. However, like sulfuryl
fluoride, it is currently under review by the US EPA because of the possibility of negative
effects of fluoride on the neurodevelopment of children.
Chinomethionat
Chinomethionat is a quinoxaline fungicide and acaricide introduced in 1968 to control
powdery mildew and spider mites on fruits, ornamentals, cucurbits, cotton, coffee, tea,
tobacco, walnuts, vegetables and glasshouse crops. It is nonsystemic, with contact
activity only.
60
Example of Chinomethionat
n
Common
Mode of Action and Resistance: Chinomethionat reacts with sulfur-containing amino acids
in proteins, thereby disrupting the function of many enzymes and other proteins. Because
there is no single target site, target site resistance is unlikely. Chinomethionat resistance has
not been reported.
Environmental and Toxicological Considerations: Chinomethionat has been shown
to have low toxicity to mammals, birds and bees, but is highly toxic to fish and some
aquatic invertebrates.
Dicofol
Dicofol is a selective miticide in use since 1957 for control of many phytophagous mites on
a wide range of crops, including fruits, vines, ornamentals and field crops. It is nonsystemic,
with contact action.
Example of Dicofol
n
Common
Mode of Action and Resistance: Although dicofol is a close structural analog of DDT, and
is even produced in some insects as a metabolite of DDT, its effects on sodium channels
are weak, and the mode of action is considered to be undetermined. Mites with target site
resistance to pyrethroids are not cross-resistant to dicofol, and dicofol resistance has so far
been found to be due to enhanced metabolism.
Environmental and Toxicological Considerations: Dicofol has moderate toxicity to mammals
and birds, but is highly toxic to aquatic organisms, including fish and invertebrates. Dicofol
is moderately persistent, and has moderate bioaccumulation potential in fish, with a half-life
of several weeks. Labeling and other risk mitigation measures must be followed to avoid
contamination of surface water from spray drift and runoff.
Pyridalyl
Pyridalyl was introduced by Sumitomo in 2004 for the control of Lepidoptera and thrips. It is
highly selective for these orders, a preferred characteristic in integrated pest management
programs. It appears to have a new mode of action and is active against insects resistant
to other compounds.
Example of Pyridalyl
n
Mode of Action and Resistance: Pyridalyl is selectively cytotoxic to cells of target species,
by an unknown mechanism.
61
Mode of Action and Resistance: Pyrifluquinazon modifies insect behavior, rapidly stopping
feeding such that insects starve to death. It may have the same mode of action as
pymetrozine, but this has not yet been determined. Resistance to pyrifluquinazon has not
yet been reported.
Environmental and Toxicological Considerations: U.S. registration of pyrifluquinazon
restricts it to greenhouse use on ornamentals because of its persistence and high toxicity
to freshwater invertebrates.
62
Product Safety
Today and in the future, farmers need to produce more food and fiber from less cultivated
land. This requires a careful and thoughtful balance of agricultural technologies, including
crop protection, plant biotechnology and other more traditional farming practices, to sustain
yields. Crop protection products protect against pests, weeds, and diseases, not only
during cultivation, but also during storage, where crops are highly susceptible to damage.
Without crop protection products, food losses would be significant. The challenge is to do
all this while minimizing the impact on the environment the ultimate resource for future
generations of farmers and consumers.
BASF is committed to protect human health and the environment through the development
of innovative products, technologies and services, to promote and support the safe and
responsible use of our crop protection technologies, and to support the inclusion of crop
protection products in sustainable agriculture worldwide.
As we work to bring new products to market, we place a huge emphasis on consumer
safety, conforming to rigorous internal and external guidelines. Pesticides are some of the
most researched and regulated products on earth. Each product takes eight to ten years
to develop. Before registration is granted, more than 800 specific tests of a products
environment and health impact must be conducted. During the registration process, a label
is created. The label contains directions for proper use of the material in addition to safety
restrictions. This allows new products to be introduced in a safe, predictable manner, while
providing consistent and clear guidance to national and international food safety authorities,
farmers, distributors, and retailers.
It goes without saying that we meet all relevant laws, regulations and international
agreements by acting in accordance with the principles of Responsible Care , the FAO
(United Nations Food and Agriculture Organization) international code of conduct on the
distribution and use of pesticides and our own high internal standards. However, as a good
corporate citizen, we want to go the extra mile to help farmers use our products in a
responsible way, with due care for both human health and the environment.
BASF works closely with customers and suppliers to help them adopt and further develop
consistent global standards, and to promote best practice. By ensuring the appropriate use
of crop protections products, we train farmers to grow more food and avoid crop losses.
Product stewardship is at the very heart of our contribution to sustainable agriculture. This
begins at the research and development phase of a product, continues through distribution
and use, storage, and ultimately, safe disposal of any waste. This lifecycle approach to
product management ensures responsible and ethical management of our crop protection
and biotechnology products, and protects the health of farmers and consumers, as well as
the environment.
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Insecticide Resistance
What is Insecticide Resistance? Resistance is an inherited change in susceptibility of
a pest population to an insecticide, which is generally reflected in the products failure
to achieve the expected level of control or efficacy as defined by the labeled use rate,
frequency of application, length of control or economic threshold. Control or efficacy
can be defined in terms of insect population reduction, yield or quality protection, or
improvement of plant vigor or health, where collectively these benefits result in a financial
return on investment.
Resistance arises because of artificial selection of insect populations with an insecticide.
As a result of continued applications (exposure) over time, initially very rare naturally
occurring traits that confer resistance are favored and thereby selected. The surviving insect
above:
population becomes increasingly difficult to control at the labeled rate and application
interval, as individuals with these traits selectively thrive and proliferate. This in turn leads to
more frequent applications of the insecticide in order to achieve the same level of control.
Both the intensity of the resistance and the frequency of insecticide-resistant individuals in
the population increase as more frequent, less effective treatments are applied. Eventually,
selection has been described as the pesticide treadmill, and the sequence is familiar.
The Arthropod Pesticide Resistance Database (http://www.pesticideresistance.com/) is a
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no control is provided and users switch to another pesticide if one is available. This
Insect
Insecticides Resisted
Diamondback moth
Many insecticides
Many insecticides
House fly
Many insecticides
Maize earworm
Bed bugs
Indianmeal moth
Anopheles mosquitoes
Many insecticides
Tobacco budworm
Many insecticides
Greenhouse whitefly
Many insecticides
site resistance is the second most common type of resistance, and involves
a modification of the target protein structure or abundance, which usually confers some
degree of cross-resistance to all compounds acting at that site. If the mutation involves
a change in the structure of the pocket where the insecticide actually binds, the
level of resistance can depend strongly on chemical structure and the modification
could theoretically even favor the binding of certain analogs, leading to negative
cross-resistance. Negative cross-resistance occurs when the insects ability to develop
resistance to one toxicant results in hypersensitivity to another.
n
Behavioral
resistance occurs when insects evolve the ability to detect and avoid the toxin
resistance is where insects evolve to absorb the toxin through the cuticle
65
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Rotation of Insecticides
A key element of effective resistance management is reducing selection pressure by
rotating or alternating between insecticides with different modes of action in order to avoid
selecting successive generations of insects for the same target site resistance mechanisms.
As many different MoA groups as possible should be included in the rotation, as illustrated
below. It is also important to avoid rotating between compounds that would be metabolized
in the same way, but this is a complicated topic that is not yet codified by IRAC. Local
resources (retailer or agronomic expert) should be consulted.
MoA W
MoA X
MoA Y
MoA Z
MoA W
MoA X
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Refugia
Some programs try to preserve susceptible individuals within the target population by
providing a refuge or haven for susceptible insects, such as unsprayed areas within treated
fields, adjacent refuge fields, or attractive habitats within a treated field that facilitate
immigration. These susceptible individuals may out-compete and interbreed with resistant
individuals, thereby diluting the impact of any resistance that may have developed in the
population. A high-dose with refuge strategy is the only strategy recommended for crops
expressing Bt toxins (pages 53-55).
Conclusion
While insects and mites have always been formidable competitors, global population
growth continues to intensify the share of the earths resources required by humans and the
competition from these arthropod pests. Largely since the 1940s, successive generations
of synthetic insecticides/miticides and microbially derived products have enabled the richness
of low risk and effective pest management technologies available today. Lower toxicity
insecticides/miticides are highly selective and specific in their actions, often taking advantage
of small biochemical differences between pest species and their sometimes beneficial
non-pest cousins that are not targeted. Development of such selective insecticides/
miticides is expensive and increasingly difficult, and small genetic changes in the pests can
lead to resistance and loss of effectiveness of the products - the biggest threat to our
continued ability to control damaging arthropod pests. While resistance cannot be prevented,
it can be significantly delayed with diligent use of resistance management strategies. In
addition to minimizing insecticide/miticide usage by applying economic thresholds for
treatment and integrated control strategies, rotation of compounds with different modes of
action is a major component of resistance management, ensuring that target sites are not
subject to undue selective pressure. Effective insecticide/miticide rotation requires an
accurate classification of insecticides/miticides according to mode of action. This document
explains the known modes of action of all insecticides/miticides on the market today, in the
framework of the industry standard IRAC classification.
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Modulators - Spinosyns 26
IRAC Group 6: Chloride Channel Activators Avermectins and Milbemycins 27
IRAC Group 7: Juvenile Hormone Mimics 36
IRAC Group 8: Miscellaneous Non-Specific (Multi-Site) Inhibitors 56
Acid Derivatives) 42
IRAC Group 24: Mitochondrial Complex IV Electron Transport Inhibitors 51
IRAC Group 25: Mitochondrial Complex II Electron Transport Inhibitors 52
IRAC Group 28: Ryanodine Receptor Modulators - Diamides 32
IRAC Group UN: Unknown 59
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Bibliography
BASF Crop Protection. http://www.agproducts.basf.com/
Chemindustry. http://www.chemindustry.com/
Compendium of Pesticide Common Names http://www.alanwood.net/pesticides/index.html
CropLife Foundation. http://croplifefoundation.org
CropLife International. http://www.croplife.org/
Extoxnet, the extension toxicology network. http://extoxnet.orst.edu/
Farm Chemicals International. http://www.farmchemicalsinternational.com/
Informa Healthcare USA, Inc. http://informahealthcare.com
Insecticide Resistance Action Committee, http://www.irac-online.org/
Pesticide Properties Database, http://sitem.herts.ac.uk/aeru/footprint/index2.htm
Phillips McDougall-AgriService. http://www.phillipsmcdougall.com/agriservice-portal2.asp
U.S. Environmental Protection Agency. http://www.epa.gov/
Trademark Information
Tedion is registered by Applied Agricultural Products. Aztec, Counter, Fortress, Thimet,
Ambush and Ecozin are registered trademarks of Amvac Chemical Corporation. Peropal,
Caligur, Kanemite and Shuttle are registered trademarks of Arysta Lifescience Corporation.
Sultan is a trademark of BASF. Abate, Regent, Standak, Cosmos, Termidor, Impede,
Fastac, Fendona, Mageos, Interceptor, Carifend, Alverde, Siesta, Cascade, Tenopa, Alert,
Perfekthion, Pirate, Phantom, Stealth, Secure, Mythic, Siege, Pyramite, Masai, Nealta,
Cythion, Nomolt and Nomax are registered trademarks of BASF. Thiodan, Sevin, Temik,
Larvin, Monitor, Curbix, Kirappu, Baythroid, Decis, Admire, Gaucho, Merit, Provado, Poncho,
Calypso, Belt, Alsystin, Baycidal, Starycide, Envidor, Oberon, Movento and Morestan are
registered trademarks of Bayer. Solubor, Brennotox and Tartox are registered trademarks of
Brenn-O-Kem. Amdro is a registered trademark of Central Garden and Pet Company.
Javelin and Turex are registered trademarks of Certis USA, LLC. Dimilin, Comite, Omite,
Acramite, Enviromite and Floramite are registered trademarks of Chemtura Corporation.
Torque is a trademark of Cleary Chemicals LLC. Success is a trademark of The Dow
Chemical Company (Dow) or an affiliated company of Dow. Runner and Kelthane are
trademarks of Dow AgroSciences LLC. Applaud, Lorsban, Dursban, Transform, Closer,
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SpinTor, Tracer, Delegate, Radiant, Shatter, Mach 2, Intrepid, Confirm, Mimic, Vikane,
Profume, and Plictran are registered trademarks of Dow AgroSciences LLC. Lannate,
Vydate, Asana XL, Avaunt, Provaunt, Steward, Altacor, Coragen, Exirel, Benevia and Vendex
are registered trademarks of E.I. duPont de Nemours and Company. Mustang Max is a
trademark of FMC Corporation. Brigade, Marshal, Furadan, Pounce, Capture, Fury, Aria,
Firstline and CB Drax are registered trademarks of FMC Corporation. CB Borid is a
registered trademark of FMC Professional Solutions. Onager and Magister are registered
trademarks of Gowan Company, LLC. Metapicrin is a trademark of ICL-IP America, Inc.
Atabron, Beleaf, Carbine, Teppeki, and Ishipron are registered trademarks of Ishihara
Sangyo Kaisha, Ltd. Eatons Answer is a registered trademark of J.T. Eaton & Co., Inc.
Apollo and Diamond are registered trademarks of Makhteshim Agan of North America, Inc.
Rimon is a registered trademark of Makhteshim Chemical Works, Ltd. Nylar is a registered
trademark of McLaughlin Gormley King Company. Miteclean is a registered trademark
of Mitsui Chemicals Agro, Inc. Trebon is a trademark of Mitsui Chemicals America, Inc.
Milbeknock is a trademark of Mitsui Chemicals Agro Japan. M-Trak is a registered
trademark of Mycogen Corporation. Fujimite, Danitron and Hachi-Hachi are registered
trademarks of Nichino America, Inc. Colt and Phoenix are trademarks of Nihon Nohyaku
Company. Evisect and Matric are registered trademarks of Nippon Kayaku Co., Ltd. Assail,
Savey, Titaron and Intruder are registered trademarks of Nippon Soda Co., Ltd. Nexter,
Sanmite and Starmite are registered trademarks of Nissan Chemical Industries, Ltd. Niban
is a registered trademark of Nisus Corporation. Acatak is a registered trademark of
Novartis. Danisaraba is a trademark of Otsuka Kagaku Kabushiki Kaisha. Orthene is a
registered trademark of OMS Investments, Inc. Azatrol is a registered trademark of
PBI-Gordon Corporation. Mitaban is a registered trademark of Pharmacia and Upjohn
Company. Prentox is a registered trademark of Prentiss, LLC. InTice and BorActin are
trademarks of Rockwell Labs, Ltd. Ultiflora is a trademark of Sankyo LLC. Sentry is a
registered trademark of Sergeants Pet Care Products, Inc. Starkle is a trademark of Sotus
International Co., Ltd. Bancol, Padan, Bestguard and Pleo are trademarks of Sumitomo
Chemical. Curacron, Force, Karate, Warrior Insecticide with Zeon Technology, Cruiser,
Actara, Agri-Mek, Zephyr, Proclaim, Chess, Plenum, Fulfill, Insegar, Logic, Trigard and Polo
are trademarks of a Syngenta Group Company. Match is distributed by and registered to
Syngenta Crop Protection Limited. Tim-bor is a registered trademark of U.S. Borax, Inc.,
and is used under license. Kryocide is a registered trademark of United Phosphorus, Inc.
Safari, Venom and Zeal are registered trademarks of Valent U.S.A. Corporation. Gnatrol,
XenTari, DiPel and Novodor are registered trademarks of Valent BioSciences Corporation.
Preventic and Cyclio are registered trademarks of Virbac S.A. in the U.S. and Canada.
Mavrik Aquaflow, Gentrol, Enstar II, Altosid and Precor are registered trademarks of
Wellmark International. MotherEarth and Perma-Dust are registered trademarks of Whitmire
Micro-Gen Research Laboratories, Inc. All other product names not mentioned above are
trademarks or registered trademarks of their respective owners.
71
Legal Disclaimer
Important: While the descriptions, designs, data and information contained herein are
presented in good faith and believed to be accurate, it is provided for your guidance only.
Because many factors may affect processing or application/use, we recommend that you
make tests to determine the suitability of a product for your particular purpose prior to use.
No warranties of any kind, either express or implied, including warranties of merchantability
or fitness for a particular purpose, are made regarding products described or designs, data
or information set forth, or that the products, designs, data or information may be used
without infringing the intellectual property rights of others. In no case shall the descriptions,
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information furnished by BASF hereunder are given gratis and BASF assumes no obligation
or liability for the description, designs, data and information given or results obtained, all
such being given and accepted at your risk.
72
BASF
Crop Protection Division
Global Strategic Marketing,
Insecticides
26 Davis Drive
Research Triangle Park, NC 27709
USA
+1 919-547-2000
www.agro.basf.com
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