Relationship between resistance ratios and treatment efficacy

The different resistance SNPs confer on the animals that carry them different degrees of resistance to anticoagulants. Generally, possession of a resistance SNP in both rats and mice confers resistance to all first-generation anticoagulants, although the actual degree of resistance may vary. Some SNPs in both rats and mice also confer resistance to the second-generation compounds bromadiolone and difenacoum. A number of SNPs have been found which have no effect on anticoagulant susceptibility.

The RRAC has carried out a series of studies, in collaboration with leading resistance experts, to determine the degree of resistance conferred by some of the most important resistance SNPs using the BCR technology it has developed (see Technical Monograph at www.rrac.info). The following tables provide data on the degree of resistance, respectively, in known resistant strains of the Norway rat and the house mouse. Resistance factors given are the multiples in the dose of the respective compound, which is required to cause a certain level of disturbed blood clotting in animals of the homozygous resistant strain in comparison to the baseline susceptible strain (see Table 2 and Table 3 and Table 4 and Table 5). RF below 1.0 means that the tested strain responded a little bit more to the experimental treatment with the anticoagulant than the baseline strain. RF = 1.0 means that there is no difference between the tested strain and the baseline susceptible strain. RF between 1 and below 2 means that there is only a minor difference, which will not noticeably influence the product performance. Higher resistance factors may be indicators of practical control problems, depending on the compound concerned.

When considering the resistance factor as a measure of resistance, particular consideration must be given to further statistical analysis. Resistance factors usually are calculated only as a factor of the acute (i.e. single dose) ED50 values. Taking into account individual deviations expressed in statistical calculations like confidence limits, larger differences in the susceptibility of individuals of different strains may occur. Also given is information where such strains already have been identified (see Figure 2), and recommended anticoagulant rodenticides to control them (see Table 4 and Table 5). Recommendations for mouse control are based on experiments and experiences provided by RRAC-members.

Some VKOR polymorphisms were found, which do not alter the susceptibility of the enzyme to the anticoagulants, and therefore are no marker for resistance. These polymorphisms are not contained in this review.

Relationship between resistance ratios and treatment efficacyFigure 2. Distribution of anticoagulant-resistant strains of the Norway rat in Europe. The shaded areas are intended to show the approximate locations of the different resistance mutations in Europe and not their exact extent. Data from a number of published sources. For more information on the distribution of resistance in some countries see chapter 15.


Table 2: Three of the most important polymorphisms of the VKOR proven to induce resistance to anticoagulants in Norway rats (Rattus norvegicus), and resistance factors in male and female resistant rats, based on BCR data. Also given are the ED50 values for males and females in mg/kg bodyweight of the susceptible baseline strain. The data in this table are the result of work funded by RRAC and conducted by Dr C Prescott and Mr D Rymer (the University of Reading, UK) and Dr A Esther, (Julius Kuehn Institute, Germany).


VKORResistance factors in male/female homozygous rats
Susceptible strain ED50: (males/females)BromadioloneDifenacoumBrodifacoumFlocoumafenDifethialone
0.47 / 0.620.65 / 0.790.22 / 0.230.29 / 0.340.43 / 0.49
L120Q10 / 144.8 / 122.8 / 6.72.5 / 3.22.2 / 2.3
Y139C17 / 151.6 / 2.91.2 / 1.80.8 / 1.00.5 / 0.8
Y139F7 / 91.4 / 1.91.3 / 1.31.0 / 1.00.9 / 0.8

Table 3a: One of the most important polymorphisms of the VKOR proven to induce resistance to anticoagulants in the house mouse (Mus musculus), and resistance factors in male and female resistant mice, based on BCR data. Also given are the ED50 values for males and females in mg/kg bodyweight of the susceptible baseline strain. The data in this table are the result of work funded by RRAC and conducted by Dr C Prescott and Ms Mhairi Stevens (the University of Reading, UK).


VKORResistance Factors in male/female homozygous house mice
Susceptible strain ED50: (males/females)BromadioloneDifenacoumBrodifacoumFlocoumafenDifethialone
1.96 / 1.680.85 / 0.560.39 / 0.350.51 / 0.440.83 / 0.83
Y139C17 / 211.2 / 2.71.7 / 1.90.9 / 1.21.5 / 1.5

Table 3b: Resistance Factors to first generation anticoagulant rodenticides in the Y139C homozygous mouse strain.  Data were provided by Prescott, Baxter, Coan, Jonses, Rymer and Buckle (University of Reading).


VKORResistance Factors in male/female homozygous mice
Susceptible strain ED50: (males/females)ChlorphacinoneCoumatetralylDiphacinoneWarfarin Sodium
0.86 / 0.861.95 / 5.020.91 / 0.911.50 / 1.50
Y139C628 / 62832 / 21539 / 539275 / 534

Table 4: Polymorphisms of the VKOR, and compounds recommended (+) to control these strains of the Norway rat (Rattus norvegicus), based on BCR data and field trials. Products containing rodenticides marked with (-) shall not be used to control respective strains.


VKORCompounds recommended (+) and not recommended (-) for control
StrainFirst-generation anticoagulantsBromadioloneDifenacoumBrodifacoumFlocoumafenDifethialone
L120Q---+++
L128Q--++++
Y139C---+++
Y139F--++++
Y139S-+++++

Table 5: Polymorphisms of the VKOR proven to induce resistance to warfarin in the house mouse (Mus musculus), and compounds recommended to control them (+). Mouse strains resist those compounds are marked with (-).


VKOR PolymorphismCompounds recommended (+) and not recommended (-) for control
StrainFirst-generation anticoagulantsBromadioloneDifenacoumBrodifacoumFlocoumafenDifethialone
L120Qno data available+++
L128S--++++
Y139C--++++
Y139Sno data available+++
R12W/A26S/ A48T/R61L (spretus-Introgression strain)---+++