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Pesticide Resistance: Strategies and Tactics for Management. 1986. National Academy Press, Washington, D.C. Case Histones of Anticoagulant Resistance WILLIAM B. JACKSON and A. DANIEL ASHTON Genetic resistance to anticoagulant rodenticides by commensal rodents (Rattus norvegicus, R. rattus, Mus musculusJ is widespread. Where it occurs rats and mice are not readily controlled with first- generation compounds. Second-generation anticoagulants, however, are effective in most situations. The first evidence of resistance to these compounds is now available. Management of rodent popula- tions is importantfor aesthetic, economic, and public health reasons. INTRODUCTION Anticoagulant rodenticides introduced in the 1950s selected for resistance within a decade, first in Norway rats (Rattus norvegicus) from Scotland (Boyle, 1960) then elsewhere in the United Kingdom (Rowe and Redfern, 1966; Bentley, 1969; Greaves et al., 1973~; from many areas of Europe, including the roof rat (R. rattus) and house mouse (Mus musculus) (Lund, 1964, 19724; and eventually the United States (Jackson et al., 19714. More recently resistance has been confirmed in commensal rats in Japan (Naganuma et al., 1981) and Australia (Saunders, 19781. In Malaysia the Malay wood rat (R. tiomanicus) (C. H. Lee, Malaysian Agriculture Research and Development Institute, personal communication, 1982) and R. r. diardii (Lam et al., 1982; Lam, 1984) are involved. The World Health Organization (WHO, 1970) initially defined a resistant Norway rat as one that survived a 6-day, no-choice feeding test with 50 ppm warfarin bait. (Appropriate criteria were also specified for the roof rat and house mouse.) These criteria were verified by breeding tests (Greaves 355
356 TACTICS FOR PREVENTION AND MANAGEMENT me 1' : ~ !~- ~ , 1 ~ ~ Y \ \ OWL , , ~ , .. 1 1 1 o 1 1 1 1 ~ ~r~ J · Cities with resistant populations of Norway rats a Cities without resistant Norway rat populations Identified , ~a ~° ; ~~ ~-- · ~ ~ ·~ N.e a/ -~ (~ ma FIGURE 1 Distribution of warfar~n-resistant Norway rat populations in the United States. and Ayres, 19761; and additional collection criteria and minimum consump- tion levels were added in the United States (Frantz, 19771. Field-test criteria have also been developed (Drummond and Rennison, 1973; Bishop et al., 19771. In Europe resistant populations frequently were identified from rural sites. The first United States finding was in a rural area, but most of the identified sites in the United States have been urban (Jackson et al., 19751. A nationwide survey in the United States to determine the extent of anticoagulant resistance in rodents was facilitated under the U.S. Public Health Service Urban Rat Control Program (Jackson et al., 1973, 1975; Jackson and Kaukeinen, 1976; Jackson and Ashton, 1980; Jackson et al., 1985~. Forty-five of the 98 sites sampled had resistant Norway rat populations (Figure 11. That most of the sites were urban may well be a function of the rodenticide use patterns, but more likely this results from congressional funding of urban rat-control pro- grams. The problem of mouse resistance is believed to be far greater than the rat problem, partly from differences in mouse population dynamics and feeding
ANTICOAGULANT RESISTANCE 357 behavior. House mouse populations had such a high level of resistance in Europe a decade ago that conventional anticoagulants were no longer rec- ommended for mouse control. Our knowledge of this species in the United States is meager. Ashton and Jackson ~ 1984) reported anticoagulant resistance in mice in several areas, both urban and rural, but no comprehensive (na- tionwide) examination of mouse resistance has been conducted (Table 11. Canada also has reported mouse resistance (Cronin, 1979; Siddiqi and Blaine, 19821. The following case histories illustrate the problems inherent in controlling rat and mouse populations in both rural and urban settings. They will also show how and why control programs, if done improperly, can create greater problems. CHICAGO The Chicago Rat Control Program began in June 1952, although rodent control efforts had begun years earlier. Developed as a tripartite program (the Departments of Health, Streets and Sanitation, and Buildings), initial treatments covered six of the city's 50 wards during the first six months of operation. Early rodenticides were cyanide gas, red squill, and 0.025 percent warfarin (1: 191. The warfarin toxicant-to-bait ratio was later reduced to 1:49 (0.01 percent), when a mixer for the warfarin bait became available locally. (This level was probably insufficient to produce consistent mortality and enhanced resistance selection.) The operational pattern was to move system- atically, ward by ward, block by block, through the city. During March 1953 the effectiveness of the poisoning program was ana- lyzed. In one block eight of nine premises that had active colonies (27 total burrows) before the poisoning operations still had colonies with evidence of activity afterward (Jackson and Evans, 19531. Operational efforts varied over the years. Our next analysis was in 1972 as part of the U.S. Public Health Service Urban Rat Control Program. Rats collected from the Lawndale target area during 1972 to 1974 were subjected to the WHO (1970) protocol for determining rodent resistance. Of the 87 rats tested, 50 (57 percent) survived (Environmental Studies Center, 1974~. By 1978 rats had been tested from four wards; 75 percent resistance to warfarin was found in three of the four wards. The trend continued at least through 1982. The Englewood area (Table 2) in 1978 had a 43 percent incidence of rat resistance, a figure similar to the Lawndale resistance pattern of 1972 to 1974. It is likely that the proportion of resistant rats in the Englewood population has since increased, but no subsequent collections have been made. The problems of resistance in Chicago were both socioeconomic and man- agerial. Rodent infestations were most abundant in the lower socioeconomic
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ANTICOAGULANT RESISTANCE TABLE 2 Summary of Norway Rats from Chicago, Illinois, Subjected to WHO Test for Warfann Resistance Number ofNumber of Percent District Rats TestedRats Surviving Resistant Austin 6244 71 Englewood 6930 43 Garf~eld 118 73 Lawndale 212152 72 SOURCE: Jackson and Ashton (1980). 359 areas, which were characterized by large transient populations, absentee landlords, abundant garbage, and vacant lots and vandalized buildings. These general conditions throughout several wards of the city provided abundant food and harborage, which supported large rat infestations. In contrast nearby areas with block clubs had overall cleaner alleys, neater back yards, and fewer rats. Managerial problems also helped increase resistance. Warfarin baits were manufactured by city personnel and distributed throughout the neighbor- hoods. The quality of the bait was generally poor and inconsistent. Battings were usually insufficient to control rodents, since warfarin baits require multiple feedings over several days, and blocks were often baited only once a month. Large dogs were present in many yards so only areas along the alleys were baited, while burrows adjacent to buildings and inside locked fences were left untouched. Inside-building infestations generally were not treated. The systematic control program often gave way to political pressure, and rodent battings were handled on a complaint rather than systematic basis. Thus, particular premises would be baited, but the entire block or even the adjacent premises would be left untouched. Red squill treatments, which would have killed resistant rats, were only partially effective because of induced bait shyness. Therefore, rodent control was never really achieved. Cyanide gas operations provided visible (political) evidence of rodent control but offered little overall reduction in rats, because gassings were confined to burrows in alleyways or away from structures and domestic animals. Gassing operations were also labor-intensive, requiring more manpower per unit area than baiting. Other rodenticides, including Vacor and norbormide, were used in the city, but with limited success; both compounds are no longer registered for use in rodent control in the United States. Also in 1978 the Centers for Disease Control (CDC, U.S. Public Health Service in Atlanta) restricted the use of conventional anticoagulants in federal target areas, thus leaving the city with only zinc phosphide as a toxicant tool. Coincident with the federal program a major clean-up campaign was ini
360 TACTICS FOR PREVENTION AND MANAGEMENT tiated in 1978. Vacant lots were cleared of old cars, garbage, and rubbish; lids were provided for all of the SS-gallon drums that were used as garbage cans. The program aimed at educating the public was left understaffed, however, resulting in insufficient follow-up and emphasis on long-term en- vironmental improvement. These practices all fostered the increasing frequency of resistant rats. The ineffective applications of anticoagulant baits meant that rats with the resistant allele survived, and enough target-area rats remained to facilitate rapid breed- ing. Populations quickly rebuilt, and when warfarin baits were distributed again, resistant genotypes tended to be selected. After several years of such operations, most rats in these areas were anticoagulant-resistant. Rat Bites The number of reported and confirmed rat bites hit a low of 90 in 1968, reflecting a major clean-up campaign initiated in 1966 with the onset of support from the federal rat-control program (Table 3~. Cases of rat bite increased during the 1970s, however. They peaked in 1979, a result of heavy snows hampering garbage pickup and facilitating an increase in the rodent populations, combined with ineffective rat-control efforts due to an increase in the incidence of resistance. Second-Generation Anticoagulants Brodifacoum, a second-generation anticoagulant, was registered for urban use in 1979. By 1984 rodent activity had decreased 75 percent in much of the area (Terry Howard, Chicago Sun Times, personal communication, 19841. Better bait materials and better placement of baits contributed to the reduction, as did the single-feeding characteristic of this rodenticide. Many of the underlying problems that permitted the establishment of pop- ulations resistant to warfarin, however, are still present. Since no rats were collected in recent years for testing, the current incidence of resistance is not known. The potential for development of resistance to the new second- generation anticoagulants exists, and Chicago might well be the premier site in the United States for identifying this phenomenon. DECATUR There have been few investigations of rural rodent resistance in the United States, and most have been of mouse infestations. Although the number of iRat bites usually are not uniformly reported, and any statistics concerning them should be used cautiously. In Chicago, however, records are carefully maintained, and reported cases are investi- gated. Consequently, these data are indicative of trends in rat populations.
ANTICOAGULANT RESISTANCE TABLE 3 Summary of Number of Confirmed Rat Bite Cases in Chicago, Illinois, from 1959 to 1982 Calendar Year Number/Year 214 219 191 193 116 127 155 144 140 90 131 189 148 87 cat 200 323 240 177 156 1959 1960 1961 1962 1963 1964 1965 1966 1967 1968 1969 1970 1971 1972 (to Sept. 29) 1973-1978 (incl.) 1979 1980 1981 1982 SOURCE: Chicago Department of Health. 361 sites and sample sizes have been small, half of the mouse infestations have had resistant mice. House mouse populations generally are confined to a single building (or a single house in a city), and treatment patterns may vary greatly. In agricultural sites such as poultry or hog farms, however, the mouse infestations may be extensive. Usually when a problem is identified the mouse population is well estab- lished. Mouse movements tend to be vertical as well as horizontal; therefore, large groups of mice can live in a relatively small area. Mouse population dynamics can thus compound control efforts. When anticoagulants are used mice from the "visible" population only are likely to encounter the bait. Generally, the quantities of anticoagulant baits placed are insufficient to control the infestation. Even if baits are maintained continuously for the recommended 21 days, most mice will not encounter them. In field tests mouse "waves" occur at approximately three-week intervals, and in large populations in complex environments, several waves may occur as mice are removed by poisoning (Ashton et al., 19831. Therefore, control of such populations may take months. If bait is available for only three weeks, the new immigrants may encounter only remnants of the bait, resulting in sublethal doses and enhanced selection of the resistant gene. Such was the case on a chicken farm near Decatur, Indiana.
362 TACTICS FOR PREVENTION AND MANAGEMENT The farm was composed of three older, deep-litter grower houses. Main- tenance in the buildings was minimal, and the feeding operation was semiautomatic. Some grain was stored within the buildings. Mice had infested the building for several years, and the farmer had treated with locally pro- duced, low-quality warfarin bait. Considering the size of the mouse popu- lation, the ample harborage and food to support a continuously breeding population, and a poor-quality bait, the selection of resistant mice was only a matter of time. During one six-week period, 250 pounds of the poor-quality bait were consumed without any apparent reduction in the mouse infestation. Labo- ratory studies (conducted at the Bowling Green State University Rodent Research Laboratory) of mice collected at the site revealed that 76 percent were resistant to warfarin. Another site (Monroe, Indiana) had been treated with the same bait for several years: 70 percent of the mice tested were resistant to warfarin. UNITED KINGDOM Although the initial identification of warfarin resistance was in Scotland (Boyle, 1960), most resistance sites were found in England and Wales (Greaves and Rennison, 19731. Most were rural, although resistant rats apparently spread from the initial site into nearby Glasgow, and Folkestone in south- eastern England had a well-identified resistant urban population. The best-studied resistant population was at a site on the Welsh-English border near Welshpool. Initial efforts went into encircling and containing the infested area using zinc phosphide as a toxicant. As the infested area expanded 5 km/yr, however, defending the perimeter became increasingly difficult and eventually was abandoned (Drummond, 1970~. Resistance (involving all three species of commensal rodents) was docu- mented in so many areas of the United Kingdom that field collections and studies were discontinued. Use of anticoagulants in these resistant areas was discouraged. Zinc phosphide was the prime alternative, and calciferol was recommended for house mice; later, second-generation anticoagulants be- came available. Some considered the resistant phenotypes to be at a repro- ductive disadvantage once the selective pressure of anticoagulant use was lifted (Bishop et al., 19771. In the absence of the rodenticide selection pres- sure, the frequency of resistance decreased from 57 to 39 percent over several years (Greaves et al., 19771. Difenacoum (the first second-generation anticoagulant) use was initiated in 1975. By the end of the decade resistance was widespread in Hampshire in southern England: 14 percent of the rats tested (40 percent of the sites) were resistant to the compound; 85 percent were resistant to warfarin. Prob
ANTICOAGUL4NT RESISTANCE 363 ably the distribution of difenacoum-resistant rats is more widespread than the survey indicated (Greaves et al., 19821. DATA BASE Warfarin is a vitamin K antagonist; it inhibits the reduction of vitamin K 2,3-epoxide to vitamin K (Bell and Matschiner, 1972; Bell et al., 1972), eventually blocking the vitamin K-regeneration enzyme system. This block- ing inhibits the post-translational modification of prothrombin (carboxylation of glutamic acid to ~y-carboxyglutamic acid) and eventual completion of the bloodclotting sequence. Ultimately the animal dies from internal hemor- rhaging. Although the exact mechanism of warfarin resistance is still under inves- tigation, a mutation probably occurs in warfarin-resistant animals at the active site of the vitamin K-epoxide reductase, such that warfarin cannot compete as effectively with vitamin K-epoxide. The cycle continues with y-carboxy- glutamic acid being continuously supplied and subsequently producing nor- mal prothrombin (Suttie, 1980; MacNicoll, 19811. MacNicoll (this volume) has suggested some alternatives to the vitamin K-epoxide reductase mech- anism. Most investigators have determined resistance to be related to an autosomal dominant allele (Greaves and Ayres, 19671. At one time resistance in the house mouse was thought to be polygenic, but more recently, rat and mouse resistance have been considered very similar (Wallace and MacSwiney, 19761. In the United Kingdom, hypotheses of incomplete penetrance and modifier genes have been expressed. Strains (based on geographic origin) have been identified, and multiple allelism has been advanced to explain such variations (Greaves and Ayres, 19821. In the laboratory, maintenance of resistant an- imals requires diet supplementation with vitamin K. In natural populations the heterozygote is considered to have survival advantage over the resistant homozygote (Bishop and Hartley, 1976; Greaves et al., 19771. Because North American resistant animals do not seem to require this vitamin K supple- mentation, there may be several (or more) resistance genotypes. Research and tests to identify these genetic variations, however, have not been carried out. Data Base United States In the combined efforts at Bowling Green State University and the New York State Department of Health, more than 10,000 Norway and roof rats collected from over 100 locations have been examined (Jackson et al., 19851. Nearly 50 Norway rat resistance sites have been identified, and the incidence of resistance in most samples was less than 20 percent.
364 TACTICS FOR PREVENTION AND MANAGEMENT Warfarin-resistant house mice have been detected at 21 sites throughout the country, but samples generally have been small. (Federal Rat project funds could not be used for studies on mouse populations.) About half the animals tested were resistant to warfarin, and 10 out of 11 urban samples contained resistant mice. Thus, the mouse problem seems to be widespread and critical in the United States. Cross-Resistance Norway rats and house mice have been tested against other first-generation anticoagulant rodenticides. With Norway rats (from 16 locations in 13 cities and 1 rural site) 165 out of 176 individuals (94 percent) resistant to warfarin were also resistant to pival. Samples of warfarin-resistant house mice and roof rats resistant to pival are small but definitive (five of five and two of two, respectively). Tests for warfarin resistance on laboratory strain, pival- resistant rats, however, produced mortality in 44 of 46 animals (Fukui, 19851. Greaves and Ayres (1976) found a similar relationship between Welsh and Scottish strains resistant to coumatetralyl, with the Welsh strain showing a high resistance to warfarin and diphacinone. Different alleles probably are responsible for this action (Greaves and Ayres, 19821. Following this logic the pival-resistant strain should represent another allele, although this has not been confirmed. In general an animal resistant to warfarin is likely to survive (i.e., be resistant to) feeding tests with any of the other hydroxycoumarin or indan- dione compounds. Consequently, alternating first-generation rodenticides for rodent control when resistance is suspected is not likely to be efficacious, but rather may enhance selection of resistant populations. MANAGEMENT Second-Generation Anticoagulants The new group of anticoagulants characterized as single-feeding (but with delayed death) is a suitable tool for managing rodents. Brodifacoum and bromadiolone have been marketed in the United States and elsewhere; di- fenacoum, only outside the United States. These rodenticides kill rats and mice resistant to first-generation compounds. Resistance to these second- generation compounds has been found, however: in Canada, house mice resistant to bromadiolone (Siddiqi and Blaine, 1982~; in England, Norway rats resistant to difenacoum (Greaves et al., 19821; and in Denmark, bro- madiolone resistance in rats (Lund, 1984~. Resistance to either second-gen- eration compound in the United States has not been confirmed. There are no published data as yet indicating brodifacoum resistance in natural popu
ANTICOAGULANT RESISTANCE 365 rations anywhere in the world, although an occasional laboratory rat has been observed to survive a test with brodifacoum; similar observations have been made in England with difenacoum-resistant strains (Lund, 1984; Cornwell, 1984; P. B. Cornwell, Rentokil, Ltd., East Grinstead, Great Britain, personal communication, 19841. Nonanticoagulant Alternatives Alternative rodenticides (or other control tools) must be found when re- sistance occurs. Acute (single-dose) rodenticides are not wholly acceptable. Red squill is currently not available. Zinc phosphide is relatively hazardous when not properly placed and quickly produces bait shyness. A new chemical, bromethalin, was introduced commercially in December 1985 under the trade names "Vengeance" and "Assault." This rodenticide is not an anticoagulant and acts after a single feeding. Although no further feeding occurs, death is delayed several days. The compound kills antico- agulant-resistant rodents (Jackson, 19851. Another new compound, Quintox, was introduced in 1985; a form of vitamin D (cholecalciferol), it disrupts calcium metabolism, producing hy- percalcemia. It is effective against anticoagulant-resistant rodents and is sim- ilar to the calciferol formulations long-used in Europe to control resistant mice. Field-test efficacy data have not been published. Alpha-chlorohydrin (Epibloc), a male sterilant, is toxic to resistant rats of both sexes (Andrews and Belknap, 1983; Kassa and Jackson, 19841. It was introduced as a restricted-use rodenticide, but has not been widely accepted by pest control operators (PCOs). Other compounds, still in testing and development modes by various companies, also have the potential for being effective against resistant populations. The high costs of testing and data acquisition now required for U. S. Environmental Protection Agency (EPA) registration, however, may discriminate against their development for the U. S. market. Improving sanitation and repairing/proofing structures are long-term so- lutions that have long been recognized as fundamental to managing pest populations (Davis, 1953, 1972; NRC, 19801. Without them the effectiveness of toxicants is reduced, and the selection pressure for resistance is increased. With increased numbers of resistant rodents in our environment, the potential for transmission of rodent-borne diseases is also increased. Concern for resistance is important because of the public health significance, as well as the depredations of these rodents to crops and stored products. Especially when these rats and mice share our environment, the potential for transmission to humans of many rodent-borne diseases is greatly increased. The clinical forms of some of these diseases are just now being recognized (e.g., hem- orrhagic fever with renal syndrome).
366 TACTICS FOR PREVENTION AND MANAGEMENT PREDICTIONS AND RECOMMENDATIONS · With the continued use of first-generation anticoagulants, resistant pop- ulations will be selected with increasing frequency. · Resistant house mouse populations especially are likely to increase in frequency because of rodenticide use both by professionals and the public. Because of the close association of this species to humans and the high potential for food destruction and contamination, a serious public health, economic, and aesthetic threat exists. · Second-generation anticoagulants will find increasing markets. Resis- tance can be expected in proportion to their market penetration because of excessive placement of baits and failure to implement an integrated pest management (IPM) program. Users should be strongly encouraged (through training) in the prudent use of these rodenticides [e.g., pulsed baiting with Talon (Dubock, 198211. · Nonanticoagulant rodenticides (bromethalin, zinc phosphide, etc.), when not used exclusively, should be alternated with anticoagulants at least an- nually. Such use will mitigate against the selection and buildup of populations resistant to either first- or second-generation anticoagulants. · Resistant populations of the commensal rodent species can be demon- strated readily. As agricultural and noncrop, nonurban uses of anticoagulants expand, resistance in native rodents can be expected following several years of persistent and careless or excessive distribution of baits. RESEARCH NEEDS · Commensal rodents (in the United States, these are Norway and roof rats and house mice), in the absence of effective management tools and efforts, will continue to pose serious public health problems, cause environ- mental destruction and deterioration, and contaminate and consume signif- icant proportions of grains, feeds, and food products. Rodents infesting orchards and croplands can also-be selected for resistance with consequences for serious economic losses. Quantification of such losses to individuals and society are needed to determine cost/benefit patterns for management pro- grams and to provide incentives for developing new tools. · Studies of resistance incidence in the house mouse and native rodent species have been neglected. Monitoring of resistant commensal rat popu- lations should be continued and expanded in both agricultural and urban sites. · The biochemical mechanisms) of resistance need continuing study. Especially needed is support for breeding and maintenance of resistant strains for research and genetic investigations of cross-resistance and the allelic variations among different populations. (Since human anticoagulant resis
ANTICOAGULANT RESISTANCE 367 lance (O' Reilly et al., 1968) is an important consideration in treating vascular problems, potential health benefits accrue as well.) · In the future if anticoagulants are labeled by EPA for use in mainland sugarcane (and other agricultural crops), the potential for selection of resis- tance is present. Evaluation of existing Hawaiian populations, where anti- coagulants have been used peripherally, would be useful. · Strategies for rodent management, based on IPM principles, need to be articulated and used. These will include environmental improvement, effec- tive environmental education, and use (at least annually) of nonanticoagulant rodenticides wherever monitoring indicates anticoagulant resistance exceeds 10 percent. In lieu of monitoring, such alternation of rodenticide types should be part of the scheduled program. · EPA registration procedures for experimental use permits, registration, and reregistration of rodenticides should be made realistic (relative to the characteristics and use patterns of the compounds), to stimulate commercial development of new products. ACKNOWLEDGMENTS We are pleased to acknowledge funding assistance through the Urban Rat Control Program (US PHS-CDC) for some of these studies. City of Chicago personnel greatly facilitated our monitoring studies in Chicago. Staffs at both the New York Health Department Laboratory at Troy and our own Bowling Green State University Rodent Research Laboratory carried out the resistance evaluation tests. Art Beeler was most helpful in allowing our access to his buildings and mouse populations. REFERENCES Andrews, R. V. and R. W. Belknap. 1983. Efficacy of alpha-chlorhydrin in sewer rat control. J. Hyg. (Camb.) 91 :359-366. Ashton, A., and W. B. Jackson. 1984. Anticoagulant resistance in the house mouse in North America. Pp. 181-188 in Proc. Conf. Organ. Pract. Vertebr. Pest Cont., A. C. Dubock, ed. Hampshire, England: ICI Plant Protection Division. Ashton, A., W. B. Jackson, and J. H. McCumber. 1983. An evaluation of methods used in comparative field testing of commensal rodenticides. Pp. 138-154 in Vertebr. Pest Cont. Manage. Mat.: Fourth Symp., ASTM STP 817, D. E. Kaukeinen, ed. Philadelphia, Pa.: American Society for Testing and Materials. Bell, R. G., and J. T. Matschiner. 1972. Warfarin and the inhibition of vitamin K by an oxide metabolite. Nature (London) 237:32-33. Bell, R. G., J. A. Sadowski, and J. T. Matschiner. 1972. Mechanism of action of warfarin. Warfarin and metabolism of vitamin K. Biochem. 11:1959-1961. Bentley, E. W. 1969. The warfarin resistance problem in England and Wales. Schriftenr. Ver. Wasser., Boden, Lufthyg. Berlin-Dahlem 32:19-25. Bishop, J. A., and D. J. Hartley. 1976. The size and age structure of rural populations of Rattus
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