Poisoning by Anticoagulant Rodenticides in Humans and Animals: Causes and Consequences

Anticoagulant rodenticides (ARs) are a keystone of the management of rodent populations in the world. The widespread use of these molecules raises questions on exposure and intoxication risks, which define the safety of these products. Exposures and intoxications can affect humans, domestic animals and wildlife. Consequences are different for each group, from the simple issue of intoxication in humans to public health concern if farm animals are exposed. After a rapid presentation of the mechanism of action and the use of anticoagulant rodenticides, this chapter assesses the prominence of poisoning by anticoagulant rodenticides in humans, domestic animals and wildlife

Exposure of predatory and scavenging birds to anticoagulant rodenticides in France: Exploration of data from French surveillance programs

Wild raptors are widely used to assess exposure to different environmental contaminants, including anticoagulant rodenticides (ARs). ARs are used on a global scale for rodent control, and act by disruption of the vitamin K cycle that results in haemorrhage usually accompanied by death within days. Some ARs are highly persistent and bioaccumulative, which can cause significant exposure of non-target species.We characterized AR exposure in a heterogeneous sample of dead raptors collected over 12 years (2008–2019) in south-eastern France. Residue analysis of 156 liver samples through LC-MS/MS revealed that 50% (78/156) were positive for ARs, with 13.5% (21/156) having summed second-generation AR (SGAR) concentrations\u3e100 ng/gww.While SGARs were commonly detected (97.4% of positive samples), first-generation ARs were rarely found (7.7% of positive samples). ARs were more frequently detected and at greater concentration in predators (prevalence: 82.5%) than in scavengers (38.8%). Exposure to multiple ARs was common (64.1% of positive samples).While chlorophacinone exposure decreased over time, an increasing exposure trend was observed for the SGAR brodifacoum, suggesting that public policies may not be efficient at mitigating risk of exposure for non-target species. Haemorrhage was observed in 88 birds, but AR toxicosis was suspected in only 2 of these individuals, and no difference in frequency of haemorrhage was apparent in birds displaying summed SGAR levels above or below 100 ng/g ww. As for other contaminants, 17.2% of liver samples (11/64) exhibited Pb levels compatible with sub-clinical poisoning (\u3e6 μg/g dw), with 6.3% (4/64) above the threshold for severe/lethal poisoning (\u3e30 μg/g dw). Nine individuals with Pb levels \u3e6 μg/g dw also had AR residues, demonstrating exposure to multiple contaminants. Broad toxicological screening for other contaminants was positive for 18 of 126 individuals, with carbofuran and mevinphos exposure being the suspected cause of death of 17 birds. Our findings demonstrate lower but still substantial AR exposure of scavenging birds compared to predatory birds, and also illustrate the complexity of diagnosing AR toxicosis through forensic investigations

Enantiomeric fraction evaluation of the four stereoisomers of difethialone in biological matrices of rat by two enantioselective liquid chromatography tandem mass spectrometry methods: Chiral stationary phase or derivatization

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Mass spectrometry characterization of anticoagulant rodenticides and hydroxyl metabolites

International audienceRationaleAnticoagulant rodenticides (ARs) are used worldwide for rodent population control to protect human health and biodiversity, and to prevent agricultural and economic losses. Rodents may develop a metabolic resistance to ARs. In order to help understand such metabolic resistance, mass spectrometry was used to position the hydroxylated group of hydroxyl metabolites of second‐generation ARs (SGARs).MethodsMost AR pesticides are derived from the 4‐hydroxycoumarin/thiocoumarin family. We used low‐resolution and high‐resolution mass spectrometry to understand the fragmentation pathways of the ARs and their respective metabolites, and to better define the structure of their tandem mass spectrometry product ions.ResultsSeven specific product ions were evidenced for five ARs, with their respective chemical structures. Those ions were obtained as well from the mass spectra of the hydroxyl metabolites of four SGARs, difenacoum (DFM), brodifacoum (BFM), difethialone (DFTL) and flocoumafen (FLO), with different positions of the hydroxyl group.ConclusionsThe differences in chemical structure between DFM on the one hand and BFM, FLO and DFTL on the other could explain the differences in bioavailability between these two groups of molecules. The defined product ions will be used to investigate the part played by the metabolic issue in the field resistance of SGARs

Stereochemistry: a tool to modify pharmacokinetics properties of anticoagulant rodenticides without modifying their efficiency

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Anticoagulant Rodenticides: Resistance and Residues in Norway Rats in France

In the European Union (EU), anticoagulant rodenticides (AR) represent more than 90% of the commercially available products for use against commensal rodents. The only other active ingredients (CO2, chloralose, corn cob) represent minor alternatives. A major issue in the EU is the resistance level of rat and mice populations, as well as potential non-target species exposure. This study presents results of surveys of anticoagulant resistance in Norway rats based on the sequencing of the VKORC1 gene, the major gene involved in AR and an investigation of the presence of AR residues detected in rodents trapped alive in urban and rural areas in order to investigate the potential risk of secondary poisoning of predators and scavengers. For resistance monitoring, rats were either trapped alive in the city of Lyon or its surroundings, or alternatively rat tails were obtained from pest control operators from France. Specific DNA primers were used for DNA sequencing and mutation identifications. AR residues were monitored by LC-MS-MS (for the 8 ARs marketed in Europe), with a limit of quantification of 1.0 µg/kg in liver samples. AR resistance appears to be extremely common (45-70% of all rats tested, depending on the part of France), with the notable exception of downtown Lyon where all rats are susceptible to AR. AR residues are detected in almost 100% of the rats trapped and tested (>200 individuals in/around Lyon). These results show that resistance is common in France, and evidence from neighboring countries suggests that this is an EU-wide problem. More surprising is the fact that all rodents tested contain detectable residues of AR, which could potentially result in secondary poisoning

Mass spectrometry characterization of anticoagulant rodenticides and hydroxyl metabolites

International audienceRationaleAnticoagulant rodenticides (ARs) are used worldwide for rodent population control to protect human health and biodiversity, and to prevent agricultural and economic losses. Rodents may develop a metabolic resistance to ARs. In order to help understand such metabolic resistance, mass spectrometry was used to position the hydroxylated group of hydroxyl metabolites of second‐generation ARs (SGARs).MethodsMost AR pesticides are derived from the 4‐hydroxycoumarin/thiocoumarin family. We used low‐resolution and high‐resolution mass spectrometry to understand the fragmentation pathways of the ARs and their respective metabolites, and to better define the structure of their tandem mass spectrometry product ions.ResultsSeven specific product ions were evidenced for five ARs, with their respective chemical structures. Those ions were obtained as well from the mass spectra of the hydroxyl metabolites of four SGARs, difenacoum (DFM), brodifacoum (BFM), difethialone (DFTL) and flocoumafen (FLO), with different positions of the hydroxyl group.ConclusionsThe differences in chemical structure between DFM on the one hand and BFM, FLO and DFTL on the other could explain the differences in bioavailability between these two groups of molecules. The defined product ions will be used to investigate the part played by the metabolic issue in the field resistance of SGARs