Cis-bromadiolone diastereoisomer is not involved in bromadiolone Red Kite ( Milvus milvus) poisoning

Abstract

Anticoagulant rodenticides (ARs) are widely used pesticides to control rodent populations. Bromadiolone, a second generation anticoagulant rodenticide (SGARs), is authorized in France to control the population of water voles (Arvicola scherman). The persistence of SGARs in rodents is responsible for secondary exposure or poisoning of predators and scavengers, and is of ecological concern for the conservation of endangered species. Commercial formulations are a mixture of two diastereoisomers of bromadiolone: 70-90% is trans-bromadiolone and 10-30% is cis-bromadiolone. Both diastereoisomers have been shown to inhibit coagulation function with the same potency. On the other hand, cis-bromadiolone has been shown to be less tissue-persistent than transbromadiolone in rats. This difference led to residue levels in rats with substantially weakened proportion in cis-bromadiolone compared to the composition of baits. In this study, a multi-residue LC-MS/MS method for the quantification of the diastereoisomers of SGARs was used to investigate their proportions in field samples of predators. In 2011, 28 red kites (Milvus milvus) were found dead within a few months of bromadiolone application in grassland to control water vole outbreaks. In this study, we report the concentrations of the two diastereoisomers of bromadiolone measured in the livers of thirteen red kites. Exposure to bromadiolone was apparent in all the kites with hepatic concentrations of trans-bromadiolone ranging from 390 to 870 ng/g (89 to 99% of summed SGARs). However, cisbromadiolone was not detected in 5 of 13 red kites and was present at very low concentrations (below 2.2ng/g) in 8 of 13 kites, demonstrating that cis-bromadiolone is not involved in this red kite poisoning event.The results suggest that a change of the proportions of bromadiolone diastereoisomers in baits could reduce the risk of secondary poisoning of predators, but retain primary toxicity for control rodent outbreaks.Response to Reviewers: May 31, 2017 Dear Daniel A. Wunderlin Thank you for your remarks on our manuscript entitled « Cis-bromadiolone diastereoisomer is not involved in bromadiolone Red Kite (Milvus milvus) poisoning» by Fourel et al. We carefully re-revised the manuscript to address the reviewers' concerns. Specific responses to each question are given below. Reviewers/Editor comments:Reviewer #2: This is a re-review of a paper that I reviewed previously. The manuscript that has been resubmitted is much improved and I believe the authors have satisfactorily addressed or rebutted the reviewers' comments. The paper presents important novel data on how isomer composition may alter the risk of secondary poisoning from SGARs.Although the grammar and language are much improved on the original ms, there is still some improvement that is necessary. I have split my comments on this into two parts on the attached pdf, the first that covers small scale questions re meaning where language has been ambiguous to some extent and needs clarification, the second are simply sug...

The stereoisomerism of second generation anticoagulant rodenticides: a way to improve this class of molecules to meet the requirements of society?

“…The development of such a method has already allowed us to evaluate the proportions between diastereoisomeric pairs of SGAR in different species such as wild Norway rat ( Rattus norvegicus ), red kite (Milvus milvus ) and red fox ( Vulpes vulpes ). Only trans ‐isomers of bromadiolone were detected in liver of red kites or red foxes poisoned or exposed to bromadiolone, confirming elimination of cis ‐isomers by the double filter composed of the target and the non‐target species. This monitoring in wildlife will enable a contribution to the identification of the least ecotoxic stereoisomer of SGARs and thus to enrich SGAR molecules with this stereoisomer to reduce ecotoxicity associated to ARs.…”

First evidence of anticoagulant rodenticides in fish and suspended particulate matter: spatial and temporal distribution in German freshwater aquatic systems

“…An important aspect of rodenticides was recently identified to be the metabolism by Fourel et al ( 2017b ). They found a high abundance of trans-bromadiolone in red kite, indicating individual metabolic rates for the two bromadiolone enantiomers.…”

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

“…However, as if significant differences are observed in our study performed on two laboratory strains belonging to the same phylogenetic super-family, one must question the need to avoid extrapolation from one species to the other, at least until the underlying mechanisms of SGAR stereoisomers metabolism and distribution, which are still in question, have been elucidated. Furthermore, as it is not possible to perform pharmacokinetic studies on all non-target species that may be exposed to anticoagulants, it is essential to characterize which stereoisomers are found in wildlife and which are not in order to assess the ecotoxic potential of each stereoisomer, as it is performed today with diastereoisomers [29][30][31] and ultimately improve pest management by limiting effects on non-target fauna.…”