Page 626 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Anticoagulant Chapter | 46 591

VetBooks.ir intestinal elimination of flocoumafen has been reported in resistance mechanisms continue to be considered. An
absolute requirement for vitamin K 1 in Danish Norway
rats (Huckle et al., 1989a,b), and metabolic and toxicolog-
rats (Rattus norvegicus)(Markussen et al., 2003),
ical studies have been reported (Veenstra et al., 1991).
Accumulation of flocoumafen in rats after repeated increased expression of P450 (CYP) (Ishizuha et al.,
exposure has been examined (Huckle et al., 1988). 2008), and the potential for differential absorption or
Flupropadine: Flupropadine is nearly as effective accumulation of chlorophacinone (Vein et al., 2013) have
as calciferol/warfarin in control of the house mouse recently been reported.
(M. musculus)(Rowe et al., 1985a,b).
Warfarin: The efficacy of warfarin has been evaluated Pest Management Approaches
against squirrels (Chambers and Chambers, 1983) and a
host of other species. Newly integrated pest management approaches are being
Fenacoum has recently been reported to be effectively proposed for the use of anticoagulant rodenticides, in part
reduced in rats that serve as a reservoir of Leishmania in because those that retain utility for Norway rat control at
Saudi Arabia. an operational level may be impossible to actually use
because of restrictions (Buckle, 2013). One proposal for
water vole (Arvicola terrestris) control includes use of
Resistance
trapping or limited chemical treatment when pests are at
Resistance to anticoagulant rodenticides has been recog- low densities, with consideration of mechanical destruc-
nized for decades. Initial investigators postulated that a tion of vole tunnels, mole control, landscape management,
genetic mutation in the resistant rodents produced an and predator fostering (Coeurdassier et al., 2014).
epoxide reductase with reduced binding affinity for An innovative use of PVC hoops (“Hula Hoops”) was
warfarin and similar anticoagulants, resulting in resistance used to examine bait densities in aerially applied brodifa-
to warfarin (Bell and Caldwell, 1973; Zimmerman and coum in a biodiversity center’s efforts to eradicate inva-
Matschiner, 1974; Hadler and Shadbolt, 1975; sive black rats (Engeman et al., 2013). Successful
Misenheimer et al., 1994); a number of such mutations eradication of alien-invasive rabbits and mice occurred in
have been reported. 1 and 6 months, respectively, in the Natural Park of
Eight different mutations in the vitamin K reductase Madeira, using about 17,000 individual brodifacoum bait-
reaction have been identified in laboratory strains of ing points. Mitigated adverse impacts of the eradication
brown rats and house mice, and in wild-caught brown program on nontarget species was balanced with adverse
rats. Mutations at Leu128Gln, Tyr139Ser, Tyr139Cys, effects of these invasive species on the island’s
Tyr139Phe, and Leu120Gln have been reported to impact ecosystem.
the efficacy of anticoagulant rodenticides in the United
Kingdom (Pelz et al., 2005; Buckle, 2013), and substitu-
tions at Leu128Ser, Tyr139Cys, and a linked sequence NONTARGET EXPOSURES
change Arg12Trp/Ala26Ser/Ala48Thr/Arg61Leu are
reported in Germany (Pelz et al., 2012). The genomic Recently, the United States Environmental Protection
assignment of the warfarin-resistant locus (Kohn and Agency provided notice of intent to cancel registration of,
Pelz, 1999) and a gene-anchored map of the rat warfarin- and notice of denial of, applications for certain rodenti-
resistant locus (Kohn and Pelz, 2000) have been reported. cide products. The affected products are anticoagulant
These followed on reports of the biochemical basis of rodenticide pesticides containing warfarin, brodifacoum,
warfarin and bromadiolone resistance in house mice or difethialone (Federal Register Volume 78, No 24,
(Misenheimer et al., 1994). Tuesday, February 5, 2013).
Literature often refers to these mutations generally as Unfortunately, nontarget species may also be exposed
VKOR activity or coding (Endepols et al., 2013; to anticoagulant rodenticides because they are a potential
Endepols et al., 2012; Jacob et al., 2012; Pelz et al., hazard to all species of mammals and birds. The preva-
2012). Rodents with these mutations are reported as being lence of exposure to nontarget species in the environment,
resistant to effective control with warfarin, bromadiolone insects, birds, and mammals are briefly summarized.
(Endepols et al., 2012), difethialone (Lefevre et al., 2016) Prevalence: In the United States, anticoagulant roden-
and, perhaps, difenacoum (Buckle et al., 2013); however, ticides are the most common rodenticide exposure of dogs
control with brodifacoum may be achieved (Buckle et al., (Murphy and Hornfeldt), and the most common toxin
2012). seen in many US veterinary practices (Murphy et al.,
Control problems not associated with Vkore1 coding 2006; Beasley and Trammel, 1989). A recent retrospec-
have been recently encountered (Endepols et al., 2013) tive study of 123 dogs tested for anticoagulant rodenti-
and previously postulated (Bell et al., 1976), so other cides reported that 75 (60.9%) dogs tested positive and 48