Water vole management - Could anticoagulant rodenticides stereochemistry mitigate the ecotoxicity issues associated to their use?
Introduction
Upsurges in the numbers of water voles (i.e., Arvicola terrestris) occur periodically in certain mountainous areas in Europe. Voles population explosions cause great damage to fields and affect fodder production quantitatively and qualitatively. They also impact their own ecosystem by altering the flora of their environment and pose a threat to animals and humans by spreading Echinococcus multilocularis, a zoonotic cestode causing alveolar echinococcosis (Beerli et al., 2017).
Since the early 1950s, anticoagulant rodenticides (AR) have been used to control rodents worldwide. These molecules act as vitamin K antagonists, as they inhibit the vitamin K epoxide reductase enzyme (VKORC1) and therefore block the formation of necessary blood clotting factors, thus causing death from hemorrhage (Buckle and Smith, 2015). AR molecules are divided into 2 generations, the first-generation AR (FGAR), includes agents such as chlorophacinone, and the second-generation AR (SGAR), comprises bromadiolone and difenacoum. SGAR molecules are more potent than FGAR and toxic in a single ingestion. In Europe, AR can be used as biocides to control commensal rodents or as plant protection products (PPP) for field applications to control agricultural pests. In France, only bromadiolone is currently approved to control water voles, whilst chlorophacinone was withdrawn in 2010. Bromadiolone is also used as PPP in the Netherlands and Romania; chlorophacinone can be exceptionally used in Hungary and Romania by means of derogation.
Unfortunately, wildlife poisonings have often been reported after campaigns of AR bait release in agricultural areas and ARs are therefore considered exceedingly harmful to wildlife (i.e. birds and mammals). Evidence of exposure of non-target wildlife to AR has been reported worldwide (e.g. Denmark (Elmeros et al., 2011); France (Fournier-Chambrillon et al., 2004) (Berny et al., 1997); Great Britain (Shore et al., 2003); Italy (Bertero et al., 2019) and also Canada (Albert et al., 2010)). During normal field control operations, predators such as kites (Milvus milvus, Milvus migrans), foxes (Vulpes vulpes) and buzzards (Buteo buteo), feeding on rodents are potentially exposed to AR and can receive a daily dose of AR that exceeds the LD50 values (Giraudoux et al., 2006). Moreover, the long persistence of SGARs in tissues of rodents and non-target species (for example, the half-life of bromadiolone has been reported to be 170–300 days in rat (Erickson, 2004)) makes these molecules more dangerous than FGARs to non-target fauna. This tissue persistence may cause death of the exposed species following repeated exposure to sublethal doses (Berny, 2007).
In 2010, to limit the ecotoxicity issue of bromadiolone as a PPP in France, its application was forbidden where population density was high. In addition, the quantities legally applicable per hectare for low to intermediate densities were reduced. Moreover, an integrated pest management has been developed and proposed to farmers in order to encourage the implementation of alternative methods (e.g., trapping, mechanical destruction of vole tunnels, mole control, and predator fostering). These measures clearly diminished the poisoning risk for non-target species. Nevertheless, because AR do not fulfill the environmental and public health safety criteria required by the European Union, they have been identified as “Candidates for Substitution” by European Union, which led to periodic renewals of approval of these active substances. In 2021, bromadiolone as a PPP will no longer be approved, leaving farmers without an effective solution to control water voles. Thus, exploring new ways to improve AR to reduce their tissue-persistence can be an alternative solution, and this can be done by changing bait compositions based on stereoisomeric properties in order to obtain safer products for the environment. Indeed, SGAR molecules are a mixture of two diastereoisomeric pairs and it has been shown in rats that tissue persistence of diastereoisomeric pairs is different (Damin-Pernik et al., 2017). For example, commercial bromadiolone formulations currently contain more than 70 % of trans-bromadiolone, the rest being cis-bromadiolone that is less persistent in rats. Similar differences in properties in water voles would result in a safer AR for wildlife. In this study, we aimed to explore this hypothesis. To do so, we tested the pharmacokinetic and pharmacodynamic properties of bromadiolone diastereoisomers in water voles compared to the properties of current bromadiolone, but also to those of chlorophacinone, as mentioned earlier, an agent no longer used in France but is still deployed elsewhere to control these rodents.
Section snippets
Chemicals
Bromadiolone (3-[3-[4-(4-bromophenyl)phenyl]-3-hydroxy-1-phenylpropyl]-4-hydroxychromen-2-one) and chlorophacinone (2-[2−4-chlorophenyl)-1 oxo-2-phenylethyl]indane-1,3-dione) were supplied by Liphatech (Agen, France). The (1R,3R)(1S,3S)-isomers (called cis-isomers) of bromadiolone were purified in a silica gel column and contained 96 % of (1R,3R)(1S,3S)-isomers and 4 % of (1R,3S)(1S,3R)-isomers (called trans-isomers). The trans-isomers of bromadiolone were also separated and purified in a
Results
Inhibiting effects of cis- and trans-bromadiolone diastereoisomeric pairs compared to current bromadiolone and chlorophacinone
The inhibition constants towards VKOR activity (Ki) of cis- and trans-diastereoisomers of bromadiolone were evaluated in vitro on water vole liver microsomes. Inhibition constants were 69.7 ± 17.3 nM for the current mixture of bromadiolone (i.e., composed of 85 % trans-isomers and 15 % cis-isomers), 58.3 ± 3.1 and 42.0 ± 2.2 nM for the trans- and cis-isomers of
Discussion
Pharmacokinetic studies on AR are rare and have all been conducted on mice or rats (Damin-Pernik et al., 2016; Kamil, 1987; Nagashima and Levy, 1969; Vandenbroucke et al., 2008). No pharmacokinetic study is available concerning prairie rodents even though their use as PPP is known to cause secondary poisoning of non-target species. Before 2010, 2 anticoagulant molecules were available in France to manage water vole populations, i.e. bromadiolone and chlorophacinone, today only bromadiolone is
Funding
This work was partly funded by the Auvergne-Rhônes-Alpes region.
CRediT authorship contribution statement
Rami Abi Khalil: Conceptualization, Methodology, Formal analysis, Investigation, Resources, Writing - original draft, Writing - review & editing, Visualization. Brigitte Barbier: Investigation. Antoine Rached: Investigation. Etienne Benoit: Conceptualization, Resources, Writing - review & editing, Funding acquisition. Adrien Pinot: Resources, Writing - review & editing. Virginie Lattard: Conceptualization, Methodology, Formal analysis, Investigation, Resources, Writing - original draft, Writing
Declaration of Competing Interest
The authors declare that they have no known competingfinancialinterestsor personal relationships that could have appeared to influence the work reported in this paper.
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Weasel exposure to the anticoagulant rodenticide bromadiolone in agrarian landscapes of southwestern Europe
2022, Science of the Total EnvironmentCitation Excerpt :One diastereomer form may have a shorter half-life than the other, and hence the risk of secondary intoxication in predators from each diastereomer may be different. In the case of bromadiolone, the trans-bromadiolone diastereomer is more bioaccumulative than cis-bromadiolone and thereby predators could be much more frequently exposed to trans-bromadiolone (Abi Khalil et al., 2021; Fourel et al., 2017a; Lefebvre et al., 2017). Currently, rodent management with rodenticides is advancing towards the third generation of anticoagulant rodenticides, with lower bioaccumulation capacity and lower exposure of predators and scavengers (Damin-Pernik et al., 2017); however, it is still poorly known which diastereomers can bioaccumulate to a larger extent in different species of predators in the wild, and such information in small mustelids would be helpful (Fourel et al., 2017a).
Seasonal diet-based resistance to anticoagulant rodenticides in the fossorial water vole (Arvicola amphibius)
2021, Environmental ResearchCitation Excerpt :Consistent with this distribution, enzymatic characterization revealed that the presence of this mutation does not lead to resistance to bromadiolone, a second-generation anticoagulant, nor to cis-bromadiolone. This latter can be assimilated by its short persistence to a first generation anticoagulant and may constitute an eco-compatible alternative to the current use of bromadiolone (Damin-Pernik et al., 2017; Fourel et al. 2017, 2018, Abi Khalil et al., 2021). The S149I mutation was found at a lower allelic frequency (0.5%) and systematically in the heterozygous state.