Interest of the faecal and plasma matrix for monitoring the exposure of wildlife or domestic animals to anticoagulant rodenticides.

Anticoagulant rodenticides (ARs), particularly second-generation compounds (SGAR), are known to be a potential threat to unintended species due to their tissue persistence. The liver is the storage tissue of ARs and is a matrix of choice in diagnosing exposure and intoxication of non-target fauna. However, it is only available on dead animals. Blood and faeces can be used on living animals. These two biological matrices were compared in terms of their relevance to exposure to ARs. In addressing this question, we compared the faecal, plasma and liver concentrations of bromadiolone, one of the SGAR frequently implicated in wildlife exposure. We studied this comparison at the individual level and at the population level, considering three influencing factors: dose, sex and time. Our findings demonstrate that faecal analyses are more valuable than plasma analyses for monitoring AR exposure of domestic and wild animals, even if faecal concentrations cannot be correlated with liver concentrations.

Comparative pharmacokinetics of difethialone stereoisomers in male and female rats and mice: development of an intra- and inter-species model to predict the suitable formulation mix.

The ecotoxicity of anticoagulants used for rodent pests' management is a major concern, particularly with second generation anticoagulants, which are more persistent in the body of rodents and therefore more likely to cause secondary exposure in their predators. One of the solutions envisaged to mitigate this risk is to use stereoisomers of these anticoagulants, each of which has particular pharmacokinetics. However, the few studies published to date have considered only one species and one sex. Here, we study the pharmacokinetics of the 4 stereoisomers of 3.4 mg/kg of difethialone in rats (Rattus norvegicus) and 3 mg/kg in mice (Mus musculus) in both sexes and propose a model to choose the optimal stereoisomer efficacy/ecotoxicity mixture for the management of all these animals. Our results show that while the most persistent stereoisomer (E3-cis) is common to both species and sexes, the pharmacokinetics of the other stereoisomers show marked differences between sexes and species. Thus, the area under curve (AUC) of E4-trans in male rats is four times lower than in females or mice, making it a priori unusable in male rats. Conversely, our modeling seems to show that the E1-trans stereoisomer seems to offer the best compromise AUC persistence. In conclusion, we highlight that studies on anticoagulants must necessarily integrate research on the effect of gender and species both on efficacy and with regard to the ecotoxicity of these molecules.

Seasonal diet-based resistance to anticoagulant rodenticides in the fossorial water vole (Arvicola amphibius).

Anticoagulant rodenticides (AR) resistance has been defined as "a major loss of efficacy due to the presence of a strain of rodent with a heritable and commensurately reduced sensitivity to the anticoagulant". The mechanism that supports this resistance has been identified as based on mutations in the Vkorc1 gene leading to severe resistance in rats and mice. This study evaluates the validity of this definition in the fossorial water vole and explores the possibility of a non-genetic diet-based resistance in a strict herbivorous rodent species. Genetic support was explored by sequencing the Vkorc1 gene and the diet-based resistance was explored by the dosing of vitamins K in liver of voles according to seasons. From a sample of 300 voles, only 2 coding mutations, G71R and S149I, were detected in the Vkorc1 gene in the heterozygous state with low allele frequencies (0.5-1%). These mutations did not modify the sensitivity to AR, suggesting an absence of genetic Vkorc1-based resistance in the water vole. On the contrary, vitamin K1 was shown to be 5 times more abundant in the liver of the water vole compared to rats. This liver concentration was shown to seasonally vary, with a trough in late winter and a peak in late spring/early summer related to the growth profile of grass. This increase in concentration might be responsible for the increased resistance of water voles to AR. This study highlights a non-genetic, diet-related resistance mechanism in rodents to AR. This diet-based resistance might explain the different evolution of the Vkorc1 gene in the fossorial water vole compared to rats and mice.