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Resistance and Its Management

Changes in technology are easy to see. What may not be as obvious is that the pests themselves keep changing. Perhaps the most important change is the development of resistance. In many agricultural systems, resistance has been the most important factor causing the decline of a pest management strategy.

Resistance is a genetic change in response to selection by toxicants that may impair control in the field. Pesticides are one type of toxin. Pests can withstand toxins to some degree, often in relation to the dose they are subjected to. There is variation in this ability to detoxify - that is, some individuals can detoxify more easily than can others. When applying a pesticide, individuals in a population are killed. If individuals exist which have improved ways to detoxify, selection for those individuals will inadvertently occur. Those individuals will survive and reproduce more easily in an environment which includes the pesticide. This is selection for resistant individuals by the toxicant. Continued selection will result in a resistant population. This process is evolution in action, and it is the same process resulting in strains of human pathogens which become resistant to antibiotics.

Evolution of resistant pest populations is a common fact of agriculture today. Over 500 pest insect species have evolved resistance to at least one pesticide during the last 40 years, and the increase in numbers of resistant species has been exponential (J-shaped curve) for these last 40 years. More recently, the increase in resistant populations of pathogens and weeds are beginning to follow the same curve. It should come as no surprise, therefore, that resistance in vegetable pests is now well documented. Insect examples include Colorado potato beetle, western corn rootworm, whiteflies, some aphid species, diamondback moth, cabbage looper, fall armyworm, and corn earworm in the southern US.

Resistance must be evaluated with respect to the natural variation among individuals and populations in their abilities to detoxify a pesticide. It can be a matter of opinion as to when to label a population as resistant, and when it is just displaying natural variation. The World Health Organization has set a standard of 10 - that is, when a population requires 10 times the amount of pesticide to kill 50% of a test population compared to a reference susceptible population, it is classified as resistant. Also, it is very common for populations to exhibit different abilities to withstand pesticides in different geographic areas. Thus, a pest may be resistant in only certain geographic areas.

Resistance management The realistic potential for resistance is a predictable, evolutionary consequence of use of pesticides (and other management tactics as well). Therefore, resistance management is now considered and must be a part of integrated pest management. As a new management tactic is deployed, such as a new chemical, it should be utilized in a manner that is designed to prevent or slow the development of resistance. This is becoming especially important as we move to use of newer, selective materials. The goals of resistance management are to avoid resistance, slow the rate of resistance development, and cause resistant populations to revert to more susceptible populations.

To understand resistance management, it is helpful to understand the evolutionary process that results in resistance. When measuring something about an individual, such as its ability to withstand a pesticide, you are describing its phenotype. When measuring phenotypes for a population of individuals, the phenotype of that population can be described (for example, you may observe that 20% of a population withstands a specific dose of a specific pesticide). With resistance, we observe reduced rates of mortality (lower efficacy) when a pesticide is applied. Lower efficacy can be due to many causes. In agricultural cases, lower efficacy is due to application, timing, or something that is not due to resistance. However, when lower efficacy is due to a change in the proportion of the pest population that carries a heritable genetic component (i.e., gene, which is a piece of DNA), then lower efficacy is due to resistance.

Mutations cause the variation of DNA among individuals. Mutations are rare (perhaps one in a million at a given site), but they are present. For example, if mutations occur at a rate of one in a million at a given site on a long strand of DNA, and there are 100 million such sites in the DNA of a human, then there are about 100 mutations occurring in each human. In DNA which codes for protein, mutations result in different versions of the same protein. Most mutations have either no effect, or are harmful; however, some mutations produce beneficial results: some proteins provide individuals with improved abilities to survive and/or reproduce.

Principles of Resistance Management When a pesticide with a new mode of action is introduced into commercial use and gains acceptance, it can be assumed that it is effective. At that point, it kills the target pest, and resistance is not a problem. What has been learned from many experiences with pests that have evolved resistance is that alleles (segments of DNA that code for protein) that confer resistance are either not present, or are present at very low frequencies, when the new material first is used. These low frequencies are often lower than can be measured economically. For the purposes of this exercise, assume that resistant alleles are present in less than one in 100,000 individuals.

When this same pesticide is observed by a grower to be not as effective as it used to be, and assuming that everything else is the same, then resistance is probably occurring. By that time, enough individuals are carrying resistant alleles to make it visible to a grower. To be visible to a grower, the resistant individuals would have to occur reasonably frequently, for example, one in 1,000 individuals would now be surviving the pesticide treatment. That represents a 100 fold increase in the frequency of resistant individuals! The key to effective resistance management is to start a resistant management program early. Do not wait until field failures become obvious - by that time, a dramatic increase in the frequency of resistant alleles already has occurred. The best time to design a resistant management program is before a new product is ever used.

Crop protection companies are anticipating the evolution of resistance to their new materials and are providing resistance management programs as part of initial introduction of a new material. In some cases, companies are monitoring for resistant alleles at the time of introduction, with sensitivity that would detect the very low levels expected in the early stages of resistance development. Pesticide Resistance Management (PRM) is becoming a part of IPM.

Factors affecting resistance management The development and rate of resistance are affected by genetic factors, by biological and ecological factors, and by what is referred to as operational factors, or what activities are performed within, and surrounding, a production facility.

Genetic factors refer to the genetics of the pest itself. Does the capacity exist? Do some individuals in the population process alleles that code for proteins that confer resistance? Do some detoxification proteins of some individuals work faster? Do some have thicker cuticles that slow the rate of pesticide entry? Genetic factors are varied, pests do have mutations, and it is possible, although rare, that a new mutation will confer resistance. For purposes of long-term resistance management, it should be assumed that, at some level, resistant alleles are present. Resistant alleles, pieces of DNA that code for proteins that confer resistance, will be labeled with capital R for the purpose of illustration. Susceptible alleles will be labeled with capital S. Most insect pests have two copies of each allele, so they may be labeled as RR, RS, or SS.

So what is the frequency of resistant alleles - what is the percent of the population that displays resistance? The higher the frequency, the higher the rate of development of resistance. The R allele is mixing every time an insect mates, every time a pest has sexual reproduction. If RR individuals mate with SS individuals, offspring will be RS, helping to dilute the R allele. Possible combinations include:

- RR with RR to give RR - RR with RS to give RR and RS - RR with SS to give RS - RS with RS to give RR, RS, and SS - SS with RS to give SS and RS, and - SS with SS to give SS.

When a pesticide is introduced into effective commercial use, present individuals are almost entirely of the SS type. As resistance develops, some RS become present (from one in 100 to one in 10,000), and there are many, many fewer RR (from one in 10,000 to one in 100,000,000). Even if R alleles are present, it is desirable to keep many SS individuals nearby and mating, slowing resistance development. So if the population can be swamped with susceptible individuals, resistance can be slowed. This is important, because most of the population (say, from outside the mushroom house) consists of susceptible individuals (SS) during early stages of resistance. In the early stages of resistance, the very rare RR individual might have a greater chance of drowning or desiccating - or dying from any number of causes - than mating. After a pesticide application, some individuals with R alleles may survive, but some with S alleles might also (they may have been in a protected growth stage, like the egg stage, and may not have been affected). As long as we can keep the frequency of R low, we have an effective resistance management program.

With few important exceptions, the R allele probably is mildly deleterious. It mildly reduces fecundity, at least initially, in the absence of the pesticide. The initial R frequency is held in check by a balance between mutation and selection, although exceptions are important because they lead to stable resistance. However, in the presence of the pesticide, the R allele confers an advantage to individuals which contain it. Over time, the R allele is balanced with other alleles so that it may no longer be deleterious.

Biological and ecological factors refer to the biology and ecology of the pest. Reviews of the many pest species that have evolved resistance have shown some clear patterns. This is of primary importance in generation time. Pests that quickly speed through one generation after another have a much greater potential of evolving resistance in response to selection by pesticides than pests with slower generation times. Similarly, pests that have a high reproductive potential, each female generating many offspring that survive long enough to reproduce, evolve resistance quicker. Immigration traits are also important, but tend to work in the opposite direction. Pest species that have higher rates of immigration tend to have slower rates of resistance, because the constant flow of S alleles into the population serves as a resistance management tool. Those species with low rates of immigration have greater chances of RS or RR individuals mating with each other, which rapidly increase resistance.

The host range of the pest also has shown a trend. Pests that have populations spread out among many hosts (polyphagy) tend towards lower rates of resistance than those that specialize on one host. This is because there is a tendency for patches of pest populations to exist on untreated areas, or refuges, and susceptible individuals existing in untreated refuges serve to maintain S alleles. Pests that have many matings also tend toward lower rates of resistance, because there is less chance for RR individuals to occur.

Operational factors are what you can control. These include the timing and dose of a pesticide, choice of materials, decisions about tank-mixing, and decisions about alternating products. Dosage, or application rate, often determines if an individual is susceptible or resistant. At some very high dose level, every individual will be killed, and at some low dose level all individuals will survive, regardless of whether they carry R or S alleles. Controlling dose, and considerations about how dose changes over time, is part of resistance management. The result is that population dynamics and population genetics interact. With resistant management, the population of alleles (R and S) and the population of individuals (the density of individuals of each type) must be considered. For example, there can be an unstable equilibrium, where R is selected for, but not maintained at high levels. This can occur within a large population, where RR exists at a low level. A discriminating dose selects for the RR individuals, but there are few of them. If high rates of immigration and mating of SS individuals follow, most of the offspring will be SS and RS, although some RR will occur. Population density, population genetics, and resistance are fluctuating over time, and resistance management, as stated earlier, is striving to avoid resistance, slow the rate of resistance, or cause resistant populations to revert to susceptible populations.

Strategies and Tactics of Pesticide Resistance Management Applying the aforementioned theory to different strategies can help manage resistance. These strategies have been classified as saturation, multiple attack, or moderation, and have been tested with simulation models and limited field experiments in various agricultural systems.

Saturation is an effort to prevent selection by making sure even resistant individuals are killed, typically with a high dose, and sometimes adding synergists (such as PBO) to block detoxification. To work, it needs to be started while the initial R frequency is very low, and not after some concern about efficacy is occurring. When pests re-invade, the saturation strategy works when the immigrants are susceptible individuals that mate randomly with the resistant ones. Transgenic crops often employ this strategy.

The multiple attack strategy takes aim at different modes-of-action with rotations or tank-mixes of different materials. Rotations involve switching materials for different applications, and requires a good choice of material in the rotation. Ideally, any resistant individuals surviving the first pesticide application are killed with the second material. As in saturation methods, rotation works best when started very early, well before field failures are noted. This is because the few resistant survivors would have less chance of mating and producing offspring that also mate when their population is very low. When populations are very low, lots of natural mortality (drowning, desiccating, disease etc.) can keep them low. Issues about whether the R allele exists, and whether cross-resistance exists, should influence choice of material. Currently, the development of R alleles tends to be fewer for the types of materials that are more ingrained into the developmental biology of the pest. For example, there are fewer examples of resistance to insect growth regulators than to materials that target the transmission of the electrical impulse in the nervous system. However, given enough time and the right conditions, it can be expected that there will be resistance to even insect growth regulators, and this may already have started to happen at a few locations. To work over a long time frame, rotation assumes that the frequency of R to each material declines while it is not being used. This may occur when the next pest immigration is composed mostly of susceptibles (see below). Rotation also assumes no cross resistance.

Tank-mixes also combine materials, but at the same time, and are sometimes used to help ensure efficacy. Tank-mixes with materials of distinctly different modes-of-action may help ensure that the rare individual that is resistant to one material is killed by the second material. However, if a farm starts to tank-mix because a material is not working as well, it may be late - the resistant individual may not be so rare anymore. Tank-mixes also add expense, and if problems arise, they are harder to diagnose. If the different materials do not degrade in the same way, at some time after applications the pests are not really exposed to both materials. In simulation models, tank-mixes work best when started early, while the R frequency for any material involved in the strategy is low, and when the frequency of individuals resistant to both materials is exceedingly rare. The assumptions are that all individuals are susceptible to at least one material, that the materials decay at approximately equal rates, and that there is no cross-resistance.

Cross-resistance refers to resistance that developed against one material also conferring resistance to another material. Cross-resistance has been fairly common for some insects and some classes of modes-of-action. Cross-resistance has occurred from one pyrethroid to another pyrethroid, from the old organocholorines to the newer pyrethroids, and from organophosphates to carbamates. This is because there are some similarities in the modes-of-action of these materials at the molecular level. To avoid cross-resistance, choose materials with distinctly different modes-of-action. Moderation strives to maintain susceptible individuals in the population using all IPM tactics (cultural, exclusion, mechanical, biological, etc.). Moderation attempts to preserve susceptibles in the environment, and allow mating of these SS individuals with those carrying the R allele. The goal is to keep the R allele swamped with S alleles. Try to preserve susceptibles early in the evolution of resistance with timing of application so that not every pest individual is targeted at every moment. Monitoring and timing applications help preserve susceptibles. Creation of refuges - areas that are not sprayed - also preserves susceptibles. Refugia can be in the field itself or in surrounding habitat if they contribute to mating.

The decay rate of pesticides strongly influences the rate of resistance in many studies, and fast-decaying materials are associated with the moderation management strategy. Materials that decay quickly initially have a high (and hopefully not selective) dose, killing all genotypes. Then the fast-decaying materials are gone. There is little time during which the dose is selective. Materials that decay slowly go through a longer time with a selective dose. In general, slow decaying materials - those often credited with "residual activity"- favor the development of resistance. They can exhibit selective activity over longer times, and make it harder for immigrating SS individuals to survive and mate with the rare RR individuals that are surviving. Choosing materials with a fast decay rate has worked as a resistance management tactic for houseflies.

In most field examples to date, pesticide resistance management programs have required preservation and mating with susceptibles. Choice of short-residual materials has worked in models and in practice. Limiting application to specific times of season or generations of the pest, or leaving refuges of untreated areas with immigration of susceptibles from those areas have been useful. The most important factors in simulation models suggest that resistance is most influenced by the reproductive potential of the pest; resistance is best slowed by immigration of susceptibles and reduction of selection pressure by making applications only when needed; careful choice of dosage; and use of shorter-residual materials. One take-home message is that mixtures, rotations, and saturation all require conditions not well met in the field; reducing pesticide use (via IPM) has proven more productive than optimizing pesticide combinations and spatial deployments. Pesticide resistance management has relied on understanding pest biology and ecology, understanding evolution, and the integration of management tactics. Technologies available for pest management constantly are changing to keep up with changing conditions for growing and marketing the crop, and with changes in the pests themselves. A resistant pest population is a change in the pest population. Clearly, pesticide resistance management has a philosophical basis, and is part of IPM.

Warning

Pesticides are poisonous. Read and follow directions and safety precautions on labels. Handle carefully and store in original labeled containers out of the reach of children, pets, and livestock. Dispose of empty containers right away, in a safe manner and place. Do not contaminate forage, streams, or ponds.

Authored by: Shelby Fleischer, Professor

January 2004

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