Pesticide resistance in wild mammals - Mechanisms of anticoagulant resistance in wild rodents

Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo.
The Journal of Toxicological Sciences (Impact Factor: 1.29). 09/2008; 33(3):283-91. DOI: 10.2131/jts.33.283
Source: PubMed


Warfarin is commonly used worldwide as a rodenticide. It inhibits coagulation of blood by inhibiting vitamin K 2,3-epoxide reductase (VKOR) activity. An inadequate supply of vitamin K blocks the production of prothrombin and causes hemorrhage. It has been reported that repeated or long-term treatments with this drug cause resistance in wild rodents. However, the mechanism of warfarin resistance in rodents is still not known precisely. Recent studies reported and identified the function of the molecule, vitamin K epoxide reductase complex subunit 1 (VKORC1), which is the main unit of VKOR. An amino acid substitution in VKORC1 is one of the supposed mechanisms of warfarin resistance. An accelerated detoxification system involving cytochrome P450 (CYP) could also cause the rodenticide resistance. Administration of SKF-525A, a potent inhibitor for P450, increased the mortality due to reduction of warfarin metabolism in warfarin-resistant rats. Meanwhile, the appearance of warfarin-resistant rodents has led to the development of the more effective and toxic rodenticide superwarfarin, which is widely used in Europe and the USA. However, animals resistant to this second-generation rodenticide have already been reported in Europe. In this review, we focus on the mechanism and the pleiotropic effects of pesticide resistance in wild rodents.

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    • "Monitoring studies of ARs in wildlife show differences in the use patterns in various geographic areas, and may reveal differences in sensitivity and bioaccumulation among species. The development of the resistance by rodents to the first generation ARs (FGARs) led to the development of second generation ARs (SGARs) of very low LD 50 and high persistence in the hepatic tissue of rodents and their predators (Watt et al., 2005; Ishizuka et al., 2008). Some of these SGARs, such as brodifacoum, have similar acute LD 50 in mammals (0.16–25 mg/kg) and birds (0.2–4.6 mg/kg); but in other cases, such as for bromadiolone, mammals seem to be more sensitive (0.49–25 mg/kg) than birds (81– 261 mg/kg) (EPA, 2004). "
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    ABSTRACT: We studied the prevalence of anticoagulant rodenticides (ARs) in the liver of 344 individuals representing 11 species of predatory wildlife that were found dead in the Mediterranean region of Spain (Catalonia and Majorca Island). Six different ARs (brodifacoum, bromadiolone, difenacoum, flocoumafen, difethialone, warfarin) were found in the liver of 216 (62.8%) animals and >1 AR co-occurred in 119 individuals (34.6%). The occurrence of ARs was positively correlated with the human population density. Catalonia and Majorca showed similar prevalence of AR detection (64.4 and 60.4%, respectively), but a higher prevalence was found in the resident population of Eurasian scops owl (Otus scops) from Majorca (57.7%) compared to the migratory population from Catalonia (14.3%). Birds of prey had lower levels of bromadiolone than hedgehogs, whereas no difference was found for other ARs. The risk of SGAR poisoning in wild predators in NE Spain is believed to be elevated, because 23.3% of the individuals exhibited hepatic concentration of ARs exceeding 200ng/g. Copyright © 2014 Elsevier B.V. All rights reserved.
    Full-text · Article · Dec 2014 · Science of The Total Environment
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    • "The development of resistance in rodents to the compounds that were used initially (first generation anticoagulant rodenticides—FGARs) (Ishizuka et al., 2008) led to the introduction in the 1970s of more toxic and bioaccumulative second generation anticoagulant rodenticides (SGARs) (Thomas et al., 2011). Nevertheless, rodents have already developed resistance against some SGARs (Ishizuka et al., 2008; Vein et al., 2011). The mean rat lethal dose (LD 50 ) from an acute oral exposure to warfarin (the most common FGAR) is 50–100 mg/kg (Stone et al., 1999), but repeated exposures can reduce LD 50 by two orders of magnitude (1 mg/kg × 5 days; Eason et al., 2002). "
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    ABSTRACT: Anticoagulant rodenticide (AR) levels were studied in liver of 401 wild and domestic animals found dead in Spain with evidences of AR poisoning, including 2 species of reptiles (n=2), 42 species of birds (n=271) and 18 species of mammals (n=128). Baits (n=32) were also analyzed to detect the potential use of ARs in their intentional preparation to kill predators. AR residues were detected in 155 (38.7%) of the studied animals and 140 (34.9%) may have died by AR poisoning according to the clinical information, necropsy findings, residue levels and results of other toxicological analysis. Animals considered with sublethal AR exposure had total AR residues (geometric mean with 95% CI) in liver of 0.005 (0.003-0.007)μg/g wet weight (w.w.) and animals diagnosed as dead by AR poisoning had 0.706 (0.473-1.054)μg/g w.w. ARs were detected in 19% of baits illegally prepared to kill predators. In terms of the total incidents studied in our laboratory between 2005 and 2010 (n=1792 animals), confirmed poisonings represented 40.9% of the cases, and 21.1% of these were due to ARs (8.6% of the total sample). Nocturnal raptors (62%) and carnivorous mammals (38%) were amongst the secondary consumers with highest prevalence of AR exposure, especially to second generation ARs (SGARs). On the other hand, granivorous birds showed the highest prevalence of AR exposure (51%), especially to chlorophacinone in a region treated against a vole population peak in 2007. The presence of hemorrhages was significantly associated with AR levels in liver, but some animals (7.2%) with elevated residue levels (>0.2μg/g w.w.) showed no evidence of macroscopic bleeding. The use of accumulative SGARs and the application of baits on surface (i.e. treated grain by spreader machines) should be discontinued in future EU regulations on the use of rodenticides to prevent the poisoning of non-target wildlife species.
    Full-text · Article · Mar 2012 · Science of The Total Environment
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    • "Finally, in 2004, the gene encoding one of the subunit of the VKOR enzymatic complex (vkorc1) has been cloned and sequenced in human and rat (Rost et al. 2004; Li et al. 2004). Nevertheless, other mechanisms probably metabolism based resistance are described or suspected (Ishizuka et al. 2008; Markussen et al. 2008). The study of Lasseur et al. (2005) on a strain of resistant Norway rat has shown that AVKs remain non competitive inhibitors of the VKOR but with a highly increased K i (inhibitory constant) and that this resistant strain has a reduced VKOR activity in comparison to a wild-type strain. "
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    ABSTRACT: In this study, osprey (Pandion haliaetus) tissues collected in France were used for contaminants analyses by a non-invasive approach. 53 pesticides (organochlorine, organophosphate, carbamate, pyrethroids, herbicides, anticoagulant rodenticides), 13 PCBs, and 5 metals (mercury, lead, cadmium, copper and arsenic) were quantified in liver of 14 individual samples. PCBs and mercury were frequent (mean 0.5 mg/kg, range < d.l.-2.6 mg/kg and mean 3.4 mg/kg, range < d.l.-16.3 mg/kg wet weight, respectively). Inter-individual variations in contaminant diversity and amounts were noticed. Immediate conservation of the species in the country does not seem to be threatened by global contamination.
    Full-text · Article · Nov 2011 · Bulletin of Environmental Contamination and Toxicology
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