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Pesticide Resistance: Strategies and Tactics for Management. 1986. National Academy Press, Washington, D.C. Managing Resistance to Rodenticides J. H. GREAVES To manage rodenticide resistance, rodenticide susceptibility must be conserved and the frequency of resistant phenotypes must be reduced to an acceptable level and kept there. Several attempts to manage resistance to anticoagulant rodenticides in the Norway rat, Rattus norvegicus, are reviewed, and the responses of users, sup- pliers of rodenticides, and official agencies to the problem of resis- tance are discussed. Although improvements in rodent-control techniques and further analysis of genetical-ecological aspects of the problem would be useful, the technical means for making long-term progress already exist. Certain short-term factors, however, seem to predispose the interested parties to act in ways that facilitate rather than retard or reverse the continued development of resistance. INTRODUCTION Resistance to warfarin and some other anticoagulant rodenticides was re- corded first in the Norway rat, Rattus norvegicus, in Scotland in 1958 (Boyle, 1960) and has since been found in other countries and species. The subject has been reviewed most recently by Lund (1984) and Greaves (1985~. Briefly, anticoagulant resistance in the Norway rat is generally due to a single major gene, of which there seem to be more than two alleles whose effects are subject to the action of modifiers and whose phenotypic expression is usually dominant. (For a detailed discussion on biochemistry of resistance, see the paper by MacNicoll in this volume.) 236

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MANAGING RESISTANCE TO RODENTICIDES RESISTANCE MANAGEMENT 237 Resistance to a rodenticide becomes a problem when the proportion of resistant phenotypes in the targeted rodent population increases to where the rodenticide cannot effectively control infestation. To manage resistance we must conserve rodenticide susceptibility or reduce the phenotypic frequency of resistance to, and keep it at, an acceptable level, preferably close to the underlying mutation frequency. The only way to reach this objective is to place resistant individuals at a selective disadvantage. In theory this may be accomplished either by selecting against resistant individuals; within popu- lations or by selecting against populations containing resistant individuals; doing so in practice is more complex. This general approach is usually reinforced by natural selection, since resistance alleles are usually deleterious in the absence of artificial selection with the pesticide. The concept of resistance management involves (1) setting practical man- agement objectives, (2) determining how to reach the objectives, (3) assigning resources commensurate with the size and nature of the task, and (4) iden- tifying managers who will be accountable for reaching the objectives. That such resistance managers rarely, or more probably never, exist reflects the fact that the problem of resistance crosses the boundaries within which man- agement functions normally are confined. This is why few, if any, of the theoretical approaches to resistance management (Georghiou, 1983) have been implemented successfully. Managing resistance requires a management structure comparable perhaps with those that have been successfully devel- oped to control communicable diseases. PRACTICAL ATTEMPTS TO MANAGE RESISTANCE IN BRITAIN Nipping Resistance in the Bud For several years Britain maintained official vigilance for new outbreaks of resistance using the procedures described by Drummond and Rennison (1973) and tried to exterminate the resistant rats with acute rodenticides. These operations normally involved joint action by the research and field advisory services of the Ministry of Agriculture and staff of the local mu- nicipal health departments, as well as official teams of pest-control opera- tives. The method was used 11 times (Drummond, 1971~. In seven cases no subsequent evidence of resistance was found. Thus, nipping resistance in the bud seems to have worked. The significance of these apparent successes, however, is difficult to assess since insufficient evidence is available on the genetic nature of the resistance. Therefore, it is not known whether the successes were due to the promptness and efficiency of the countermeasures

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238 POPULATION BIOLOGY OF PESTICIDE RESISTANCE or because the resistance was of a kind inherently unlikely to survive and spread. In the four unsuccessful cases the resistance was of the monogenic, dominant type. In principle it should be possible to eradicate local populations of rats showing monogenic resistance by these means, except that a resistant infes- tation develops 12 to 18 months before it is discovered (Drummond, 1970, 1971), during which time it might spread a radial distance of 5 to 10 kilo- meters (km). Thus, prompt and sustained countermeasures probably should be conducted within a radius of 20 km to eliminate any new outbreak of monogenic resistance. Eradicating Widely Established Resistant Populations A pilot scheme to eradicate warfarin-resistant rats was conducted in a rural area of five square miles in Wales, using the acute rodenticides zinc phosphide, arsenious oxide, antu, and norbormide (Bentley and Drum- mond, 19651. It failed because of the limited efficacy of the available rodenticides and also probably because such a small experimental area is vulnerable to invasion by rats from the surrounding countryside. Further, the objective may have been defined inappropriately as the total eradication of rats, both resistant and susceptible, rather than eliminating primarily the resistant individuals. Resistance monitoring might have shown that switching from warfarin to other, nonselective rodenticides had brought the resistance under control. The failure of this particular scheme, however, does not vitiate the concept of selective targeting of relatively large areas for managing resistance. Today a similar scheme would have a greatly increased chance of success, owing to improvements both in rodent control-technology and in our understanding of the problem. Containment of Resistant Populations A third approach adopted in Britain as a short-term expedient was to throw a kind of guarded perimeter strip S km wide around a resistance area that was about 60 km in diameter. A rat-control program was instituted on the perimeter "containment zone." All sites were inspected regularly and, if infested, treated with acute rodenticides (Drummond, 19661. Resistant rats, however, were found 8 km outside the perimeter within two years (Pam- philon, 1969), casting doubt on the efficacy of the scheme and indeed on whether the entire resistant population had been enclosed within the perim- eter.-Such considerations further emphasize the importance of resistance monitoring in any management scheme.

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MANAGING RESISTANCE TO RODENTICIDES TABLE 1 Relative Fitness of Genotypes in Norway Rat Populations in the Presence and Absence of Anticoagulant Treatment 239 Genotypes Conditions RR RS SS Anticoagulants Presenta 0.37 1.00 0.68 Anticoagulants Absentb 0.46 0.77 1.00 SOURCE: aGreaves et al (1977); Partridge (1979). Natural Selection Resistance to anticoagulants in Norway rats seems to be a pleiotropic effect of a defect in vitamin K metabolism such that the dietary requirement for the vitamin is increased (Hermodson et al., 19691. Two independent studies in Britain suggest that this physiological defect alone may eliminate resistance from natural populations when artificial selection with anticoagulant roden- ticides is withheld. In the first study, when acute rodenticides were substituted for anticoag- ulants in a sizable experimental area, the frequency of phenotypic resistance decreased steadily from 57 to 39 percent in two years. Simultaneously, in a control area where approximately one-half of the farmers were using anti- coagulants, the resistance frequency remained stable at about 44 percent (Greaves et al., 19771. Analysis of the genotypic frequencies indicated that the stability of the resistance in the control area represented a balanced polymorphism in which selection favored heterozygotes (Table 11. The second study concerned a single, somewhat isolated rat infestation on a farm. During the 18 months when no treatment was applied to the infes- tation, the frequency of phenotypic resistance decreased from approximately 80 to 33 percent. Evaluation of the phenotypic frequencies by an optimization procedure suggested that in the absence of selection with anticoagulants, heterozygotes as well as resistant homozygotes were at a substantial disad- vantage compared with susceptibles (Table 1) (Partridge, 1979~. No detailed analysis, however, has yet been made of the ecological-genetical processes that control the level of anticoagulant resistance in wild rodent populations. NEW RODENTICIDES Although the previous experiences suggest that substantial progress could be made in managing resistance (even with blunt instruments), the increasing prevalence of resistance to anticoagulants has given considerable impetus to research on new rodenticides. The most outstanding new products are three highly toxic, broad-spectrum anticoagulants: brodifacoum, bromadiolone, and difenacoum. Warfarin-resistant strains may show various, usually minor,

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240 POPULATION BIOLOGY OF PESTICIDE RESISTANCE degrees of cross-resistance to the new compounds, but they can usually eliminate resistant rats. These compounds are potentially extremely valuable tools for managing resistance. Inadequate application methods, however, allow some rodents to survive treatment. Populations then tend to increase both the degree and the frequency of resistance. Thus, resistance to all three compounds is increasing (Lund, 19841. For example, difenacoum has suffered a very marked loss of efficacy against Norway rats in one area of England,~where continual selection with the new anticoagulants seems to have raised the frequency of phenotypic resistance to warfarin to around 85 percent (Greaves et al., 1982a,b). The introduction of new products to control resistant rodents, therefore, probably has accelerated rather than retarded the evolution of resistance in this area. Simply substituting new rodenticides for old ones to cope with resistance rests on one of two assumptions, which if not palpably false may be insecure: (1) resistance to new rodenticides will not evolve, or (2) the process of developing new rodenticides to counter new forms of resistance can be re- peated indefinitely. The essential question to ask about any technique in the context of resistance management is not whether it can control resistant rats but whether it can control resistant rats selectively, because only then will it be possible to reverse the evolution of resistance or prevent it from pro- ceeding at its natural pace. THE CAUSE OF RESISTANCE The origin of resistance may be a random event such as a mutation, but its development into a practical problem results solely from human activities. We must examine the behavior and attitudes of groups that are affected by rodenticide resistance to help us decide how to manage the problem. Users The main users of rodenticides farmers, environmental health workers, and professional pest-control operators often are unaware of the possibility of resistance until a control method fails. Alternatively, if the resistance has had any notoriety, they often blame all failures on resistance, although the failures may be due to faults in formulation or method of application. Such factors produce a confused picture of resistance. Users, therefore, should report control problems promptly and accept expert advice on how to deal with them. If resistance is the problem an alternative rodenticide often gives acceptable results. The alternative rodenticide, however, may be more expensive, more hazardous, more difficult to use, or less effective than the original compound. Consequently, users often revert to the original product, taking advantage

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MANAGING RESISTANCE TO RODENTICIDES 241 of any recession in resistance, until further control failures occur. This be- havior maintains resistance, causes persistent control problems, and promotes the spread of the resistant strain. It also may promote readaptation, the process by which a resistance gene may be integrated into the gene pool of the population. One of the main objectives, therefore, in managing resistance must be to prevent the use of compounds to which resistance has developed or in circumstances that make the further development of resistance likely. Industry For many years industry has joined with others in voicing concern about the strategic threat to crop protection posed by pesticide resistance, bearing in mind the high cost of introducing new products and that every new com- pound seems to be vulnerable to the development of resistance. When re- sistance is first encountered, however, firms tend to respond with caution, which is engendered by (1) confidence in the excellence of their products; (2) an awareness that many reports of resistance turn out to be spurious; (3) the knowledge that for a while the resistance, if real, is likely to be highly localized; and (4) trepidation that publicity about the resistance may adversely affect their competitive position in the market. This caution may militate against early action to control the resistance. A practical and indispensable response by industry is to develop new rodenticides to control the resistant strains. The timing of this response tends to be governed by economics. Thus, it tends to occur late, when markets are being eroded significantly by the increasing prevalence of resistance, or when the expiry of exclusive commercial rights make an existing product less viable, or when a new concept for a competitive new product is invented. Because rodenticides are specialized, minor-use compounds, investment in research on new compounds frequently is regarded as unprofitable. Con- sequently, little effective investment has been made in this area except when a special commercial interest has been at stake, or when there has been some form of official sponsorship or interest. Despite these difficulties several new rodenticides have reached the market, thus lessening the resistance problem. When new rodenticides with a useful degree of toxicity to resistant strains are registered, normal marketing strategy dictates that they be promoted for their "anti-resistant" and other favorable properties. Such action may be counterproductive, in that the indiscriminate introduction of a new product may speed up the evolution of resistance. This dilemma, although it may not be perceived as such, is heightened when the first indications of resistance to a new product are recognized. The problem of how rodenticides may best be deployed to manage resis- tance is complex, requiring some research and analysis. Since selective action (increased deployment of certain compounds and restraint on the use of others

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242 POPULATION BIOLOGY OF PESTICIDE RESISTANCE in particular localities) is required, effective regulation of the sale and use of certain compounds is essential. Industry may not be able to do this alone, chiefly because companies cannot control the use of their products once they are sold. It cannot be accomplished, however, without the consent and co- operation of industry. Official Agencies The primary role of many official agencies is to provide a source of impartial, expert advice to individual users of rodenticides and to undertake or sponsor the investigational work necessary for sound advice. Sometimes they may organize or conduct practical rodent-control operations. Official agencies are usually responsible for administering legislation concerned with the control of infestations and the use of rodenticides. They are in a powerful position to influence whatever action is taken to manage resistance in rodent populations. Information on the extent to which such influence is actually exercised is limited. What has been done ranges (in different countries) from almost no action to fairly direct intervention. In Britain, for example, action by the Ministry of Agriculture has included field investigations of new outbreaks of resistance, development of diagnostic tests for resistance, research into its formal genetics, local programs to control or eliminate resistant popula- tions, and collaboration with industry in research on new rodenticides. These efforts, in part, have prevented the situation from getting out of hand. Indeed many countries are benefiting from the work done in Britain, most notably from the introduction of new rodenticides to control resistant strains. Nevertheless, the prevalence of resistance to rodenticides is not decreasing, and in some countries it is getting worse. In this sense the success of official intervention in resistance management has been limited. To the extent that they have continued to advocate the use of rodenticides that could be expected to further the development of resistance, the activities of these agencies, like those of users and suppliers, are counterproductive. CONCLUSION The foregoing outline of how the rodenticide resistance problem has been addressed points toward two general conclusions. First, the logical structure of the problem seems to be clear in its technical aspects: rodenticide resistance can be controlled by eliminating resistant populations faster than new ones can develop. Such control requires information about the location and char- acteristics of the resistant populations, prevents the use of rodenticides that accelerate the development and spread of resistance, and increases the use of nonselective or counter-selective control techniques against the populations

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MANAGING RESISTANCE TO RODENTICIDES 243 concerned. Although further improvements in techniques for controlling re- sistant populations would be welcome, the existing technical means may be adequate. For practical implementation we need to understand more precisely the genetical-ecological processes that control the level of resistance in natural populations and, thus, how the available rodent-control techniques could be deployed advantageously. Adequate resistance monitoring also is necessary to steer and verify the progress of any practical scheme. The human factors affecting the management of resistance are less easy to assess since they concern subjective judgments of value, most notably of how the certainty of short-term costs should be balanced against less-certain long-term gains. Since resistance is responsive to selection, the actions of users and suppliers of rodenticides and of advisory and regulatory agencies play a crucial role in its management. The exigencies of rodent control in the real world create pressures, however, that predispose the various partic- ipants to cooperate involuntarily in the continued evolution of resistance rather than to reverse or retard it. Progress has been made in areas of technique, but rodenticide resistance continues to develop, probably because resistance, like communicable dis- ease, cuts across the boundaries of most ordinary management structures. We need to improve coordination and above all to redirect the efforts of the interested parties. Such coordination may be possible through consensus and through vigorous promotion. The alternatives are either to increase official regulation in the field of rodent control or to allow resistance to continue to evolve at its own unregulated pace. REFERENCES Bentley, E. W., and D. C. Drummond. 1965. The resistance of rodents to warfarin in England and Wales. Pp. 58-76 in Report of the International Conference on Rodents and Rodenticides. Paris: European and Mediterranean Plant Protection Organization. Boyle, C. M. 1960. Case of apparent resistance of Rattus norvegicus Berkenhout to anticoagulant poisons. Nature (London) 188:517. Drummond, D. C. 1966. Rats resistant to warfarin. New Sci. 30:771-772. Drummond, D. C. 1970. Variation in rodent populations in response to control measures. Symp. Zool. Soc. London 26:351-367. Drummond, D. C 1971. Warfarin-resistant rats some practical aspects. Pestic. Abstr. News Sum. 17:5-8. Drummond, D. C., and B. D. Rennison. 1973. The detection of rodent resistance to anticoagulants. Bull. W.H.O. 48:239-242. Georghiou, G. P. 1983. Management of resistance in arthropods. Pp. 769-792 in Pest Resistance to Pesticides, G. P. Georghiou and T. Saito, eds. New York: Plenum. Greaves, J. H. 1985. The present status of resistance to anticoagulants. Acta Zool. Penn. 173:159- 162. Greaves, J. H., R. Redfern, P. B. Ayres, and J. E. Gill. 1977. Warfarin resistance: A balanced polymorphism in the Norway rat. Genet. Res. 30:257-263.

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244 POPULATION BIOLOGY OF PESTICIDE RESISTANCE Greaves, J. H., D. S. Shepherd, and J. H. Gill. 1982a. An investigation of difenacoum resistance in Norway rat populations in Hampshire. Ann. Appl. Biol. 100:581-587. Greaves, J. H., D. S. Shepherd, and R. Quy. 1982b. Field trials of second-generation anticoagulants against difenacoum-resistant Norway rat populations. J. Hyg. 89:295-301. Hermodson, M. A., J. W. Suttie, and K. P. Link. 1969. Warfarin metabolism and vitamin K requirement in the warfarin resistant rat. Am. J. Physiol. 217:1316-1319. Lund, M. 1984. Resistance to the second-generation anticoagulant rodenticides. Pp. 89-94 in Proc. 11th Vertebr. Pest Conf., D. O. Clarke, ed. Davis: University of California. Pamphilon, D. A. 1969. Keeping the super-rats down. Munic. Eng. (London) 146:1327-1328. Partridge, G. G. 1979. Relative fitness of genotypes in a population of Rattus norvegicus polymorphic for warfarin resistance. Heredity 43:239-246.