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Abstract Background Bromadiolone is a wide-use long-acting anticoagulant rodenticide known to cause severe coagulation dysfunction. At present, there have been no detailed reports of acute kidney injury (AKI) resulting from bromadiolone poisoning. Case presentation A 27-year-old woman was admitted to the hospital due to severe coagulopathy and severe AKI. Coagulation test revealed a prothrombin time exceeding 120 s and an international normalized ratio (INR) greater than 10. Further examination for coagulation factors showed significantly reduced level of factors II, VII, IX and X, indicating a vitamin K deficiency. The AKI was non-oliguric and characterized by gross dysmorphic hematuria. Following the onset of the disease, the patient’s serum creatinine rose from 0.86 to 6.96 mg/dL. Suspecting anticoagulant rodenticide poisoning, plasma bromadiolone was identified at a concentration of 117 ng/mL via gas chromatography/mass spectrometry. All other potential causes of AKI were excluded, except for the presence of a horseshoe kidney. The patient’s kidney function fully recovered after the coagulopathy was corrected with high doses of vitamin K and plasma transfusion. At a follow-up 160 days post-discharge, the coagulation function had normalized, and the serum creatinine had returned to 0.51 mg/dL. Conclusion Bromadiolone can induce AKI through a severe and prolonged coagulation disorder. Kidney function can be restored within days following treatment with high-dose vitamin K1.

Background: Bromadiolone is a wide-use long-acting anticoagulant rodenticide known to cause severe coagulation dysfunction. At present, there have been no detailed reports of acute kidney injury (AKI) resulting from bromadiolone poisoning. Case presentation: A 27-year-old woman was admitted to the hospital due to severe coagulopathy and severe AKI. Coagulation test revealed a prothrombin time exceeding 120 s and an international normalized ratio (INR) greater than 10. Further examination for coagulation factors showed significantly reduced level of factors II, VII, IX and X, indicating a vitamin K deficiency. The AKI was non-oliguric and characterized by gross dysmorphic hematuria. Following the onset of the disease, the patient's serum creatinine rose from 0.86 to 6.96 mg/dL. Suspecting anticoagulant rodenticide poisoning, plasma bromadiolone was identified at a concentration of 117 ng/mL via gas chromatography/mass spectrometry. All other potential causes of AKI were excluded, except for the presence of a horseshoe kidney. The patient's kidney function fully recovered after the coagulopathy was corrected with high doses of vitamin K and plasma transfusion. At a follow-up 160 days post-discharge, the coagulation function had normalized, and the serum creatinine had returned to 0.51 mg/dL. Conclusion: Bromadiolone can induce AKI through a severe and prolonged coagulation disorder. Kidney function can be restored within days following treatment with high-dose vitamin K1. [ABSTRACT FROM AUTHOR]

Treatment of long-acting, anticoagulant rodenticides (LAAR)-poisoned patients with high-dose oral vitamin K1 (VK1) is expensive and requires several months. The long duration can result in non-adherence leading to recurrent severe coagulopathy, bleeding, and hospitalizations. Cholestyramine (CSA) is an inexpensive, safe, and effective gut-restricted resin used to treat primary hypercholesterolemia or pruritus, and to accelerate clearance of teriflunomide. We propose using inexpensive CSA therapy in LAAR-poisoned patients while administering daily high-dose oral VK1 and periodically monitoring plasma LAAR concentrations until declining to a safe concentration. We suggest that this regimen should be available to public health clinics responding to outbreaks of LAAR poisoning. CSA treatment could improve patient adherence, shorten duration of high dose oral VK1 therapy, and reduce healthcare expenditures.

Abstract Background Field rodents cause significant damage to standing crops in agroecosystems at vulnerable stages. Of all the methods available, chemical rodent control is the most practical and economically feasible. Laboratory studies demonstrate the potential of synergistic bait formulations containing bromadiolone and cholecalciferol. This study is the first multi-site multi-crop trial to assess the efficacy of cereal bait formulations containing lower than standard doses of bromadiolone (0.0025 and 0.001%) and cholecalciferol (0.02 and 0.04%) compared to presently recommended bait formulations of zinc phosphide (2.0%) and bromadiolone (0.005%) to protect wheat, rice and sugarcane crop fields against rodent attack. Results Rodent control success was highest (74.21–88.80%) in fields treated with a combination bait formulation containing bromadiolone (0.0025%) and cholecalciferol (0.04%), which led to a significant reduction in crop damage (from 6.82 to 26.56% cut tillers/canes and 251.75–1448.00 kg/ha yield loss (in reference block) to 1.18–6.18% cut tillers/canes and 46.67–745.00 kg/ha yield loss (in treated blocks). Conclusions This study therefore found that cereal bait formulation containing bromadiolone (0.0025%) and cholecalciferol (0.04%) can be effectively used to manage rodent population in agricultural crop fields and it is suggested that consideration be given to registering this combination rodenticide formulation to improve global food security.

The extensive use of rodenticides poses a severe threat to non-target species, particularly birds of prey and scavengers. In this study, a GC-MS/MS-based method was used to unlock the cause of bird deaths in Poland. Organs (liver, heart, kidney, and lungs) collected during autopsies of two rooks (Corvus frugilegus) and one carrion crow (Corvus corone corone), as well as fecal samples, were analyzed for the presence of anticoagulant coumarin derivatives, i.e., warfarin and bromadiolone. As for warfarin, the highest concentration was found in crow samples overall, with concentrations in the feces and lungs at 5.812 ± 0.368 µg/g and 4.840 ± 0.256 µg/g, respectively. The heart showed the lowest concentration of this compound (0.128 ± 0.01 µg/g). In the case of bromadiolone, the highest concentration was recorded in the liver of a rook (16.659 ± 1.499 µg/g) and this concentration significantly exceeded the levels in the other samples. By revealing the reality of the threat, these discoveries emphasize the need to regulate and monitor the trade in rodenticides. [ABSTRACT FROM AUTHOR]

Background: Field rodents cause significant damage to standing crops in agroecosystems at vulnerable stages. Of all the methods available, chemical rodent control is the most practical and economically feasible. Laboratory studies demonstrate the potential of synergistic bait formulations containing bromadiolone and cholecalciferol. This study is the first multi-site multi-crop trial to assess the efficacy of cereal bait formulations containing lower than standard doses of bromadiolone (0.0025 and 0.001%) and cholecalciferol (0.02 and 0.04%) compared to presently recommended bait formulations of zinc phosphide (2.0%) and bromadiolone (0.005%) to protect wheat, rice and sugarcane crop fields against rodent attack. Results: Rodent control success was highest (74.21–88.80%) in fields treated with a combination bait formulation containing bromadiolone (0.0025%) and cholecalciferol (0.04%), which led to a significant reduction in crop damage (from 6.82 to 26.56% cut tillers/canes and 251.75–1448.00 kg/ha yield loss (in reference block) to 1.18–6.18% cut tillers/canes and 46.67–745.00 kg/ha yield loss (in treated blocks). Conclusions: This study therefore found that cereal bait formulation containing bromadiolone (0.0025%) and cholecalciferol (0.04%) can be effectively used to manage rodent population in agricultural crop fields and it is suggested that consideration be given to registering this combination rodenticide formulation to improve global food security. [ABSTRACT FROM AUTHOR]

To investigate the potential ecological toxicity of the second generation anticoagulant rodenticide bromadiolone, the developmental toxicity of bromadiolone on zebrafish embryos / larvae and its effect on the antioxidant system were studied. The results showed that the exposure to bromadiolone could lead to developmental toxicity such as death and deformity in zebrafish embryos / larvae. When the bromadiolone concentration was higher than 0.39 mg·L–1, the mortality and deformity rate of zebrafish embryos / larvae increased significantly. Exposure to bromadiolone also had a significant effect on the antioxidant system of zebrafish embryos / larvae. The activities of SOD and CAT and the contents of GSH and MDA increased significantly with the increase of bromadiolone exposure concentration, indicating that bromadiolone caused oxidative damage to zebrafish embryos / larvae, which led to the attenuation of other body functions and even death. In this paper, the developmental toxicity and oxidative damage of embryos / larvae caused by bromadiolone exposure were investigated and discussed, which provided a basis for further study on the developmental toxicity mechanism of bromadiolone on animals and its potential ecological hazards. [ABSTRACT FROM AUTHOR]

Rodent pests not only cause severe agricultural loss but also spread zoonotic pathogens to human beings. Anticoagulant rodenticides are widely used to decrease the population densities of rodents but often lead to the spillover of ectoparasites because fleas and ticks may gather on surviving rodents. Therefore, it is necessary to kill fleas and ticks before culling rodents to minimize the risk of pathogen transmission. In this study, we used a mixture of ivermectin (an antiparasitic drug) and bromadiolone (an anticoagulant rodenticide) to control both rodent and flea/tick abundances. We found that in a laboratory test, 0.01% ivermectin bait was not lethal for greater long‐tailed hamsters after 7 days of treatment, while 0.1% ivermectin bait was lethal for approximately 33% of treated rodents. In a field test, bait containing 0.001%, 0.005%, 0.01%, and 0.05% ivermectin decreased the number of fleas per vole of Brandt's voles to 0.42, 0.22, 0.12, and 0.2, respectively, compared with 0.77 in the control group, indicating that 0.01% ivermectin bait performed best in removing fleas. In another laboratory test, bait containing a 0.01% ivermectin and 0.005% bromadiolone mixture caused the death of all voles within 6–14 days after the intake of the bait. In the field test, the bait containing 0.01% ivermectin and 0.005% bromadiolone reduced the average number of fleas per vole to 0.35, which was significantly lower than the 0.77 of the control group. Our results indicate that a 0.01% ivermectin and 0.005% bromadiolone mixture could be used to control both rodents and fleas to minimize the spillover risk of disease transmission when using traditional rodenticides. [ABSTRACT FROM AUTHOR]

It is well known that rodenticides are widely used, and there are multiple routes by which they can reach non-target wildlife species. Specifically, in the Canary Islands, a high and concerning incidence of these compounds has been reported. However, in this scenario, reptiles remain one of the least studied taxa, despite their potential suitability as indicators of the food chain and environmental pollution has been noted on several occasions. In this context, the California Kingsnake (Lampropeltis Californiae), widely distributed on the island of Gran Canaria, occupies a medium trophic level and exhibits feeding habits that expose it to these pollutants, could be studied as a potential sentinel of exposure to these compounds. For this reason, 360 snake livers were analyzed by LC-MS/MS. Similarly, 110 livers of birds of prey were sampled. Thus, we present the analysis of 10 anticoagulant rodenticides (warfarin, diphacinone, chlorophacinone, coumachlor, coumatetralyl, brodifacoum, bromadiolone, difethialone, difenacoum and flocoumafen) in both data series; snakes, and raptors. Furthermore, this dataset includes biological data (weight, length, sex, colour, and design pattern), geographic data (distribution area and municipalities) and necropsy findings that could be of interest for a better understanding of this snake species and for future studies.

BackgroundBromadiolone is the second-generation anticoagulant rodenticide widely used all over the world. Exposure to bromadiolone in early life stage can lead to neurodevelopmental toxicity, but its toxic mechanism of neurodevelopment is not clear so far. ObjectiveTo investigate the developmental neurotoxicity and mechanism of bromadiolone to zebrafish embryos. MethodsZebrafish embryos were randomly divided into four groups: a solvent control group (dimethylsulphoxide) and three bromadiolone exposure groups (0.39, 0.78, and 1.18 mg·L−1). The exposure period was from 4 h to 120 h post-fertilization. The number of spontaneous movement per minute was recorded at 24 h post-treatment. The locomotor ability of zebrafish larvae and the activity of acetylcholinesterase (AChE) were tested at 120 h post-treatment. The relative expression levels of neurodevelopment-related genes (elavl3, gap43, mbp, and syn2a) were measured by fluorescence quantitative PCR. ResultsCompared with the control group, the number of spontaneous movement per minute at 24 h decreased significantly in the 1.18 mg·L−1 bromadiolone exposure group (P

Treatment of long-acting, anticoagulant rodenticides (LAAR)-poisoned patients with high-dose oral vitamin K1 (VK1) is expensive and requires several months. The long duration can result in non-adherence leading to recurrent severe coagulopathy, bleeding, and hospitalizations. Cholestyramine (CSA) is an inexpensive, safe, and effective gut-restricted resin used to treat primary hypercholesterolemia or pruritus, and to accelerate clearance of teriflunomide. We propose using inexpensive CSA therapy in LAAR-poisoned patients while administering daily high-dose oral VK1 and periodically monitoring plasma LAAR concentrations until declining to a safe concentration. We suggest that this regimen should be available to public health clinics responding to outbreaks of LAAR poisoning. CSA treatment could improve patient adherence, shorten duration of high dose oral VK1 therapy, and reduce healthcare expenditures. [ABSTRACT FROM AUTHOR]

Bromadiolone, a potent, long-acting anticoagulant rodenticide is frequently tinted to a red or pink color and mixed with cereals as rat bait. Six peoples working in a small factory suffered from a severe bleeding tendency several weeks after consuming a rice meal that was tainted with bromadiolone mistaken to be healthy food. High serum levels of bromadiolone and excessive bleeding were found in these individuals, and they needed vitamin K1 therapy for weeks. These cases indicated that long-acting anticoagulant rodenticide might induce cumulative toxicity in repeated, low-dose exposure, and the blood levels of bromadiolone might be an indicator for antidote therapy if available. [ABSTRACT FROM AUTHOR]

Abstract Background Clinically, bromadiolone poisoning is characterized by severe bleeding complications in various organs and tissues. Bromadiolone-induced toxic encephalopathy is extremely rare. Here, we report a special case of bromadiolone-induced reversible toxic encephalopathy in a patient who had symmetrical lesions in the deep white matter. Case presentation A 23-year-old woman mainly presented with dizziness, fatigue, alalia and unsteady gait after the ingestion of bromadiolone. The laboratory examinations showed normal coagulation levels. Brain magnetic resonance imaging (MRI) showed apparent diffusion restriction in the bilateral deep white matter. The clinical manifestations and MRI alterations were reversible within one month of treatment with vitamin K. The neuropsychological assessment showed no neurodegenerative changes at the 2-year follow-up. Conclusion With the increased use of bromadiolone as a rodenticide, more cases of ingestion have been reported annually over the past several years. Bromadiolone-induced toxic encephalopathy has no special clinical manifestations and is potentially reversible with timely treatment. Because of the reversible restricted diffusion on diffusion-weighted images (DWI) and low apparent diffusion coefficient (ADC) values, transient intramyelinic cytotoxic oedema is thought to be the cause rather than persistent ischaemia. The underlying pathophysiological mechanism is still unknown and may be coagulant-independent. This clinical case extends the current knowledge about neurotoxicity in cases of bromadiolone poisoning and indicates that MRI is useful for the early detection of bromadiolone-induced toxic encephalopathy.

Anticoagulant rodenticides (ARs) are used globally to control rodent pest infestations in both urban and agricultural settings. It is well documented that non-target wildlife, including predatory birds, are at risk for secondary anticoagulant exposure and toxicosis through the prey they consume. However, there have been no large-scale studies of AR exposure in raptors in Ontario, Canada since new Health Canada legislation was implemented in 2013 in an attempt to limit exposure in non-target wildlife. Our objective was to measure levels of ARs in wild raptors in southern Ontario to assess their exposure. We collected liver samples from 133 raptors representing 17 species submitted to the Canadian Wildlife Health Cooperative (CWHC) in Ontario, Canada, between 2017 and 2019. Liquid chromatography-tandem mass spectrometry (LC–MS/MS) was used to quantitatively assess the level of exposure to 14 first- and second-generation ARs. Detectable levels of one or more ARs were found in 82 of 133 (62%) tested raptors, representing 12 species. The most commonly detected ARs were bromadiolone (54/133), difethialone (40/133), and brodifacoum (33/133). Of AR-positive birds, 34/82 (42%) contained residues of multiple (> 1) anticoagulant compounds. Our results indicate that AR exposure is common in raptors living in southern Ontario, Canada. Our finding that brodifacoum, difethialone, and bromadiolone were observed alone or in combination with one another in the majority of our sampled raptors indicates that legislative changes in Canada may not be protecting non-target wildlife as intended. [ABSTRACT FROM AUTHOR]

Abstract Background Exposure to anticoagulant rodenticides (ARs) in dogs is among the most common causes of poisoning in small animal practice, but information about toxicokinetic of these rodenticides in dogs is lacking. We analysed blood and faeces from five accidentally exposed dogs and 110 healthy dogs by reversed phase ultra-high performance liquid chromatography-tandem mass spectrometry. The aim of the study was to estimate elimination of brodifacoum, bromadiolone and difenacoum after acute exposure, calculate the half-lives of these rodenticides in dogs, estimate faecal elimination in a litter of puppies born, and further to identify the extent of AR exposure in a healthy dog population. Results Three dogs were included after single ingestions of brodifacoum; two dogs ingested bromadiolone and one dog ingested difenacoum. Maximum concentrations in faeces were found after day 2–3 for all ARs. The distribution half-lives were 1–10 days for brodifacoum, 1–2 days for bromadiolone and 10 days for difenacoum. Brodifacoum and difenacoum had estimated terminal half-lives of 200–330 days and 190 days, respectively. In contrast, bromadiolone had an estimated terminal half-life of 30 days. No clinical signs of poisoning or coagulopathy were observed in terminal elimination period. In blood, the terminal half-life of brodifacoum was estimated to 8 days. Faeces from a litter of puppies born from one of the poisoned dogs were examined, and measurable concentrations of brodifacoum were detected in all samples for at least 28 days after parturition. A cross-sectional study of 110 healthy domestic dogs was performed to estimate ARs exposure in a dog population. Difenacoum was detected in faeces of one dog. Blood and faecal samples from the remaining dogs were negative for all ARs. Conclusions Based on the limited pharmacokinetic data from these dogs, our results suggest that ARs have a biphasic elimination in faeces using a two-compartment elimination kinetics model. We have shown that faecal analysis is suitable and reliable for the assessment of ARs exposure in dogs and a tool for estimating the AR half-lives. Half-lives of ARs could be a valuable indicator in the exposed dogs and provides important information for veterinarians monitoring AR exposure and assessment of treatment length in dogs.

Prolonged persistence of second-generation anticoagulant rodenticides (SGARs) in animal tissues facilitates trophic transfer of residues, with exposure of predatory and scavenging non-target wildlife now widely reported. In many instances, antico-agulant residue levels measured in wildlife are apparently sublethal, although longer-term effects of such exposures are currently not well understood. Conversely, prolonged metabolic persistence is of practical utility when compounds are used as biological markers to determine food uptake by animals. We required two effective and distinct marker compounds to progress field-based research on optimal baiting strategies to manage introduced brushtail possums in New Zealand. Two SGARs (flocoumafen and bromadiolone) were evaluated, as neither are currently registered for application as rodenticides in areas typically subject to possum management. All captive possums ingesting small, sublethal (2-6 g) quantities of food containing 0.0005% (by weight) of either SGAR were reliably marked by the presence of residual concentrations in liver as measured by HPLC analysis. This marking persisted for at least six weeks, and liver concentrations in marked possums did not decline between three and six weeks after the marker was ingested. Marking was also quantitative for both SGARs with a correlation between liver residue concentration and the amount of marker ingested. Using such marker baits would provide at least a six-week period in which to recover possums in field research. By recording bodyweight and testing liver samples from such possums for both markers, regression equations generated from the work reported here will enable back-estimation, with confidence intervals, of the amounts of marker bait eaten by each possum.

The aim of this study was to investigate the beneficial effects of vitamin K relate to protection against detrimental effects of bromadiolone. Wistar rats (n = 30) were divided in three groups (n = 10): control group and two groups treated with bromadiolone (0.12 mg/kg) and bromadiolone + vitamin K (0.12 mg/kg + 100 mg/kg) over the period of four days. The main findings in the bromadiolone-exposed rats, such as damaged hepatocytes, high levels of globulin, total proteins and lymphocytes, and altered albumin/globulin ratio, collectively indicate an acute inflammatory process. Morphological changes in erythrocytes include microcytosis, hypochromia, hyperchromia, hemolysis, stomatocytosis, and spherocytosis. Significantly low values of RBC, Hct, and hemoglobin concentrations indicate impairments of the hematopoietic pathway causing combined anemia. The selected dose of bromadiolone caused a non-significant increase of catalase activity and a significant increase of the total protein content in brain tissue homogenates. Vitamin K supplementation reduced many of the harmful effects of bromadiolone. The cytoprotective role of vitamin K was proved to be of great importance for the preservation of structural changes on the membranes of hepatocytes and erythrocytes, in addition to the known role in the treatment of coagulopathies. The results of the study suggest valuable properties of vitamin K in the prevention and treatment of various types of anemia caused by bromadiolone toxicity. Future research is necessary to determine the adequate dose and treatment duration with vitamin K in disorders caused by the cumulative action of bromadiolone and possibly other pesticides. [ABSTRACT FROM AUTHOR]

Bromadiolone, a potent, long-acting anticoagulant rodenticide is frequently tinted to a red or pink color and mixed with cereals as rat bait. Six peoples working in a small factory suffered from a severe bleeding tendency several weeks after consuming a rice meal that was tainted with bromadiolone mistaken to be healthy food. High serum levels of bromadiolone and excessive bleeding were found in these individuals, and they needed vitamin K1 therapy for weeks. These cases indicated that long-acting anticoagulant rodenticide might induce cumulative toxicity in repeated, low-dose exposure, and the blood levels of bromadiolone might be an indicator for antidote therapy if available.

Five horses originating from 4 different California race tracks were submitted to the California Animal Health and Food Safety Laboratory for necropsy and diagnostic workup. The 5 horses had a history of sudden collapse and death during exercise. In all of them, massive hemoperitoneum and hemorrhages in other cavities or organs were observed. The liver from these 5 animals and from 27 horses that had been euthanized due to catastrophic leg injuries (controls) were subjected to a rodenticide anticoagulant screen. Traces of brodifacoum, diphacinone, or bromadiolone were detected in the 5 horses with massive bleeding (5/5), and no traces of rodenticides were detected in control horses (0/27). Other frequent causes of massive hemorrhages in horses were ruled out in 4 of the cases; one of the horses had a pelvic fracture. Although only traces of anticoagulants were found in the livers of these horses and the role of these substances in the massive bleeding remains uncertain, it is speculated that exercise-related increases in blood pressure may have reduced the threshold for toxicity of these anticoagulants.

The lobular distribution of 9 different anticoagulant rodenticide (AR) residues in the liver of a sentinel predator/scavenger i.e. the red fox (Vulpes vulpes) was determined following multi-residue analysis using Ultra (High) Performance Liquid Chromatography tandem Mass Spectrometry (UHPLC-MS/MS). The aim of the study was to address concerns that if distribution of AR residues in the liver was significantly heterogeneous, analysis of random sub-samples or finite remnants of liver could result in false negatives or lead to incorrect toxicological diagnoses. Intact livers excised from animals shot as part of routine legal pest control activities in Scotland during 2018 and 2019 were sub-sectioned and the lobular concentration of AR residues was investigated. Analysis of individual lobes from 10 different fox livers revealed that AR residues initially detected in a randomly selected small portion of liver tissue were present throughout the liver. Also, in cases where AR residues were not found in the initial randomly selected portion, they were not found in the subsequent more detailed examination. The limit of quantitation was 3 μg kg‐1 and AR residue concentrations ranged from 3 to 885 μg kg−1. Statistical analysis of variance (ANOVA) was performed on the eight and six out of ten livers that tested positive for bromadiolone and brodifacoum, respectively. No statistical evidence was found of differences in mean residue levels of bromadiolone throughout the liver i.e. within and between liver lobes. However, brodifacoum showed a statistically significant difference (p < .001) in mean residue concentration between the lobes but there was no statistical evidence of mean differences within the lobes.

Treatments efficacy assessed for rodent incidence and tiller damage revealed that all the treatments caused significant reduction of rat live burrows and rat tiller damage over control. Integration of rodent management techniques in Module-1 (trapping-bromadiolone poison baiting - burrow smoking) and Module-2 (Zinc Phosphide poison baitingbromadiolone poison baiting-Aluminium Phosphide burrow application) found promising with significantly lowered rodent incidence and crop damage. % reduction in live burrows was 68.6 and 71.1 during 2017-18 and 61.8 and 65.8 during 2018-19 in Module-1 and 2, respectively. Tiller damage protection % was 65.9 and 68.9 in 2017-18 and 67.2 and 69.9 during 2018-19 for these treatments. Continuous application of rodenticides solo in M-5 (ALP) and M-4 (bromadiolone) also showed superior performance in containing the rodent damage and they are at par with the integrated treatments at certain crop stages. All the treatments recorded significant yield advantage over the control, but the benefit cost ratio were found relatively higher in the rodenticide treatments, highest (8:1) in the Module-2. [ABSTRACT FROM AUTHOR]

Background: Clinically, bromadiolone poisoning is characterized by severe bleeding complications in various organs and tissues. Bromadiolone-induced toxic encephalopathy is extremely rare. Here, we report a special case of bromadiolone-induced reversible toxic encephalopathy in a patient who had symmetrical lesions in the deep white matter.Case Presentation: A 23-year-old woman mainly presented with dizziness, fatigue, alalia and unsteady gait after the ingestion of bromadiolone. The laboratory examinations showed normal coagulation levels. Brain magnetic resonance imaging (MRI) showed apparent diffusion restriction in the bilateral deep white matter. The clinical manifestations and MRI alterations were reversible within one month of treatment with vitamin K. The neuropsychological assessment showed no neurodegenerative changes at the 2-year follow-up.Conclusion: With the increased use of bromadiolone as a rodenticide, more cases of ingestion have been reported annually over the past several years. Bromadiolone-induced toxic encephalopathy has no special clinical manifestations and is potentially reversible with timely treatment. Because of the reversible restricted diffusion on diffusion-weighted images (DWI) and low apparent diffusion coefficient (ADC) values, transient intramyelinic cytotoxic oedema is thought to be the cause rather than persistent ischaemia. The underlying pathophysiological mechanism is still unknown and may be coagulant-independent. This clinical case extends the current knowledge about neurotoxicity in cases of bromadiolone poisoning and indicates that MRI is useful for the early detection of bromadiolone-induced toxic encephalopathy. [ABSTRACT FROM AUTHOR]

Anticoagulant rodenticides (AR), principally difethialone, brodifacoum, and bromadiolone, were detected in the livers of 89% of 72 Red-tailed Hawks (Buteo jamaicensis) from New York City, New York, US examined for cause of death over a 7-yr period (January 2012–December 2018). Fatal hemorrhage likely attributable to AR exposure was diagnosed in 41% (30/74) of cases, and 46% (18/39) of the cases analyzed with no gross evidence of AR-mediated hemorrhage had liver concentrations of AR that overlapped those with an AR-poisoning diagnosis. Although urban areas like New York City can support surprisingly dense populations of Red-tailed Hawks, the threat posed by extensive use of AR can be large. [ABSTRACT FROM AUTHOR]

• Bromadiolone, an antivitamin K rodenticide does not exhibit the teratogenic effect of warfarin, an antivitamin K drug. • Warfarin is highly transferred from the dam to the fetus during gestation. • There is little or no transfer of bromadiolone from the dam to the fetus during gestation. • This difference appears to be due to almost complete uptake of bromadiolone by the dam's liver resulting in its low bioavailability in dam's plasma. All vitamin K antagonist active substances used as rodenticides were reclassified in 2016 by the European authorities as active substances "toxic for reproduction", using a "read-across" alternative method based on warfarin, a human vitamin K antagonist drug. Recent study suggested that all vitamin K antagonist active substances are not all teratogenic. Using a neonatal exposure protocol, warfarin evokes skeletal deformities in rats, while bromadiolone, a widely used second-generation anticoagulant rodenticide, failed to cause such effects. Herein, using a rat model we investigated the mechanisms that may explain teratogenicity differences between warfarin and bromadiolone, despite their similar vitamin K antagonist mechanism of action. This study also included coumatetralyl, a first-generation active substance rodenticide. Pharmacokinetic studies were conducted in rats to evaluate a potential difference in the transfer of vitamin K antagonists from mother to fetus. The data clearly demonstrate that warfarin is highly transferred from the mother to the fetus during gestation or lactation. In contrast, bromadiolone transfer from dam to the fetus is modest (5% compared to warfarin). This difference appears to be associated to almost complete uptake of bromadiolone by mother's liver, resulting in very low exposure in plasma and eventually in other peripheric tissues. This study suggests that the pharmacokinetic properties of vitamin K antagonists are not identical and could challenge the classification of such active substances as "toxic for reproduction". [ABSTRACT FROM AUTHOR]

Background: Exposure to anticoagulant rodenticides (ARs) in dogs is among the most common causes of poisoning in small animal practice, but information about toxicokinetic of these rodenticides in dogs is lacking. We analysed blood and faeces from five accidentally exposed dogs and 110 healthy dogs by reversed phase ultra-high performance liquid chromatography-tandem mass spectrometry. The aim of the study was to estimate elimination of brodifacoum, bromadiolone and difenacoum after acute exposure, calculate the half-lives of these rodenticides in dogs, estimate faecal elimination in a litter of puppies born, and further to identify the extent of AR exposure in a healthy dog population. Results: Three dogs were included after single ingestions of brodifacoum; two dogs ingested bromadiolone and one dog ingested difenacoum. Maximum concentrations in faeces were found after day 2–3 for all ARs. The distribution half-lives were 1–10 days for brodifacoum, 1–2 days for bromadiolone and 10 days for difenacoum. Brodifacoum and difenacoum had estimated terminal half-lives of 200–330 days and 190 days, respectively. In contrast, bromadiolone had an estimated terminal half-life of 30 days. No clinical signs of poisoning or coagulopathy were observed in terminal elimination period. In blood, the terminal half-life of brodifacoum was estimated to 8 days. Faeces from a litter of puppies born from one of the poisoned dogs were examined, and measurable concentrations of brodifacoum were detected in all samples for at least 28 days after parturition. A cross-sectional study of 110 healthy domestic dogs was performed to estimate ARs exposure in a dog population. Difenacoum was detected in faeces of one dog. Blood and faecal samples from the remaining dogs were negative for all ARs. Conclusions: Based on the limited pharmacokinetic data from these dogs, our results suggest that ARs have a biphasic elimination in faeces using a two-compartment elimination kinetics model. We have shown that faecal analysis is suitable and reliable for the assessment of ARs exposure in dogs and a tool for estimating the AR half-lives. Half-lives of ARs could be a valuable indicator in the exposed dogs and provides important information for veterinarians monitoring AR exposure and assessment of treatment length in dogs. [ABSTRACT FROM AUTHOR]

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• The Fetal warfarin syndrome is a congenital abnormality due to maternal ingestion of warfarin during pregnancy. • In a rodent model, teratogenic effect of warfarin at therapeutic dose is demonstrated. • In the same conditions, bromadiolone, a vitamin K antagonist used as rodenticide, does not induce teratogenic effect. • These results challenge the classification of all the vitamin K antagonists as reprotoxic agents. Vitamin K antagonists (VKA) are not recommended during pregnancy because warfarin (a first-generation VKA) is associated with a malformation syndrome "the fetal warfarin syndrome" (FWS). VKA are also used for rodent management worldwide. Recently, the Committee for Risk Assessment responsible for the European chemical legislation for advances on the safe use of chemicals had classed 8 anticoagulant used as rodenticides in the reprotoxic category 1A or 1B. This classification emerges from a read-across prediction of toxicity considering the warfarin malformation syndrome. Herein, our study explores the teratogenicity of warfarin at the human therapeutic dose and that of bromadiolone, a second-generation anticoagulant rodenticide. Using a rat model, our study demonstrates that warfarin used at the therapeutic dose is able to induce teratogenicity, while in the same conditions bromadiolone does not induce any teratogenic effect, challenging the classification of all VKA as reprotoxic molecules. [ABSTRACT FROM AUTHOR]

Concerned that San Joaquin kit foxes from urban areas may be exposed to commensal anticoagulants, the California Department of Fish and Game, Pesticide Investigations Unit, in conjunction with the Endangered Species Recovery Program’s Urban Kit Fox Project, began monitoring San Joaquin kit foxes from the Bakersfield, CA population. Necropsies were performed and liver tissue samples collected from kit fox carcasses. Livers from archived kit foxes dating back to 1977 were also analyzed. A non-urban population of San Joaquin kit foxes from Lokern was used as a control. Other predators in the area, including coyotes and red foxes, were also analyzed for comparison. Between 1999 and 2007, tissue samples from 45 animals have been analyzed for residues of anticoagulant rodenticides. Anticoagulant compounds identified included brodifacoum, bromadiolone, pival, and chlorophacinone. Twenty-six of the 30 San Joaquin kit foxes from Bakersfield contained at least one anticoagulant, and the most commonly detected anticoagulant was brodifacoum. None of the 12 Lokern San Joaquin kit foxes contained anticoagulants. Other predators followed the same pattern: both red foxes from Bakersfield contained anticoagulant residues, but the coyote taken from Lokern did not.

The development of second-generation anticoagulant rodenticides for commensal rodent control arose from the need to overcome genetic resistance to earlier anticoagulants, to improve efficacy, and to reduce hazard over older acute rodenticide materials. Over the past three decades, the second-generation anticoagulant products have become the principal commensal rodenticides used in the U.S. and elsewhere. During this long usage, individual cases of human and nontarget wildlife exposure have been documented, and the significance has been debated. Following a lengthy re-registration and review process, the U.S. Environmental Protection Agency in January 2007 proposed restrictions on the use of second-generation anticoagulant rodenticides for commensal rodent control. The proposed restrictions would shift emphasis to other rodenticides, including those with inherent problems that were the basis for developing second-generation anticoagulants. Reduced efficacy, prolonged public exposure to rodents, limitations in bait formulations and placements, increased genetic resistance, and greater application rates (exposure) are anticipated if these restrictions are adopted. Various nontarget concerns will remain with alternative products and use patterns by professional users and consumers, including use of products without specific antidotes. These impacts would occur amidst increasing rodent problems in many U.S. municipalities with declining management resources and aging infrastructure. Alternative measures should include use of human taste deterrents in baits and revised label statements to limit the use of all commensal rodenticide from sensitive areas, including placement along fence lines, and bordering natural habitats.

The use of warfarin in commensal rodenticides has been avoided by the pest control industry for many years because of concerns with low palatability, resistance, and its chronic toxicity requirements. It has been all but forgotten by the industry. Genesis Laboratories, Inc. evaluated warfarin in a currently-marketed commensal rodenticide, Kaput Rat and Mouse Bait (0.025% warfarin), in comparison to Maki pellets (0.005% bromadiolone) and Talon G pellets (0.005% brodifacoum) in a simulated field study design using warfarin-resistant wild Norway rats. Approximately 20 wild rats of varying ages and weights were randomly added to each of 3 study rooms, one for each product. After a 7-day acclimation period, the respective rodenticide baits were presented to the rats along with the EPA field rodent challenge diet or another alternate diet. The first death in each study room was recorded on Day 3 for Kaput, Day 13 for Maki, and Day 5 for Talon. Kaput acceptance was high, causing 9 deaths in the first 14 days. Again, because of poor acceptance of the Maki and Talon baits, the alternate diet was changed to milo on Day 22 and again to a no-choice regime on Day 28. At this point (Day 28), efficacy of the Kaput, Maki, and Talon rooms were at 85%, 20%, and 10%, respectively. 100% efficacy was achieved on Day 36 by Kaput, Day 38 by Maki, and Day 42 by Talon during the no-choice phase of the study. To investigate the warfarin toxicology profile further, we initiated another study with laboratory Norway rats and house mice in a no-choice regime with varying exposure periods (1, 2, 3, 4, and 5 days). At least two days of exposure was required to produce 100% mortality with the rats and 5 days of exposure was necessary for 100% mortality of house mice.

Abstract Background Accidental poisoning with anticoagulant rodenticides is not uncommon in dogs, but few reports of the elimination kinetics and half-lives in this species have been published. Our objectives were to develop and validate a new method for the quantification of anticoagulant rodenticides in canine blood and faeces using reversed phase ultra-high performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS) and apply the method on a case of anticoagulant rodenticide intoxication. Results Sample preparation was liquid–liquid extraction. Six anticoagulant rodenticides were separated using a UPLC® BEH C18-column with a mobile phase consisting of 5 mM ammonium formate buffer pH 10.2 and methanol. MS/MS detection was performed with positive electrospray ionization and two multiple reaction monitoring transitions. The limits of quantification were set at the levels of the lowest calibrator (1.5–2.7 ng/mL or ng/g). The method was successfully applied to a case from a dog accidentally poisoned with anticoagulant rodenticide. Coumatetralyl and brodifacoum concentrations were determined from serial blood and faecal samples. A terminal half-life of at least 81 days for coumatetralyl in blood was estimated, which is longer than previous reported in other species. A slow elimination of brodifacoum from the faeces was found, with traces still detectable in the faeces at day 513. Conclusions This study offers a new method of detection and quantification of six frequently used anticoagulant rodenticides in canine faeces. Such drugs might cause serious health effects and it is important to be able to detect these drugs, to initiate proper treatment. The very long elimination half-lives detected in our study is important to be aware of in assessment of anticoagulant rodenticide burden to the environment.

The common vole, Microtus arvalis, which is prone to cyclic overpopulation, poses a significant threat to sustainable alfalfa production by either chewing shoots periodically or gnawing and damaging roots permanently. In areas with established vole colonies, the density of alfalfa plants was shown to decrease 55.3–63.4%. Simultaneously, the number of alfalfa shoots decreased by 60.9–71.7%. These experiments were conducted in compliance with an EPPO standard method in alfalfa fields at three geographically remote sites. The experiment tested the efficacy of the most widely used acute rodenticide zinc phosphide (2%), and anticoagulants applied at significantly reduced doses of active ingredients, i.e., bromadiolone (25 ppm) and brodifacoum (25 ppm), as well as a combination of these active ingredients at a low concentration (10 + 10 ppm). Three weeks after treatment, zinc phosphide and brodifacoum achieved the highest average efficacy, at 98.5% and 92.05%, respectively, while the average efficacy of the anticoagulant combination and bromadiolone was 87.2% and 75.5%, respectively. The achieved efficacy of baits based on brodifacoum and the combination of brodifacoum and bromadiolone in controlling common voles indicates their possible utilization in the field. Baits with 25 ppm of brodifacoum and the combination of bromadiolone and brodifacoum (10 + 10 ppm) showed satisfactory results and their introduction could significantly improve pest management programs for rodent control. At the same time, the use of anticoagulant rodenticides with reduced contents of active ingredients would significantly reduce their exposure to non-target animals, especially predators and vultures. By further improving the palatability of tested baits for target rodent species, their efficacy and safety of application would be significantly improved.

Meiling Wang,1 Yanfeng Yang,2 Yiwei Hou,1 Wenbin Ma,1 Rui Jia,1 Jinbo Chen1 1Neurology Department, Binzhou Medical University Hospital, Binzhou Medical University, 2Binzhou Blood Center, Binzhou, China Abstract: Cases of rodenticide poisoning (second-generation long-acting dicoumarin rodenticide, superwarfarin) have occasionally been reported. The main symptoms of bromadiolone poisoning are skin mucosa hemorrhage, digestive tract hemorrhage, and hematuresis. However, the symptoms of central nervous system toxicity have rarely been reported. Our case reports on a 41-year-old male who had no contact with bromadiolone. His main symptoms were dizziness, unsteady gait, and abnormal behavior. Laboratory test results revealed the presence of bromadiolone in his blood and urine, a longer prothrombin time, activated partial thromboplastin time, and a high international normalized ratio. Magnetic resonance imaging of the brain showed that the bilateral posterior limb of the internal capsule, splenium of corporis callosum, and bilateral centrum semiovale formed symmetrical patch distribution. The patient gradually recovered after treated with vitamin K1 and plasma transfusion. Our clinical study could pave the way to improve the detection of bromadiolone poisoning and avoid misdiagnosis. Keywords: bromadiolone, poisoning, central nervous system, superwarfarin

In 1998, the Environmental Protection Agency issued Reregistration Eligibility Decisions for the rodenticides Brodifacoum, Bromethalin, Bromadiolone, Chlorophacinone, Diphacinone, Pival, and Zinc Phosphide. These decisions imposed requirements that bait products containing these ingredients and marketed for control of commensal rodents also contain an "indicator dye" and a "bittering agent." The indicator dye would be used to mark children who come in contact with bait. The bittering agent would be used to render a bait unpalatable to children, possibly reducing the amount of bait eaten. This paper discusses these requirements and other regulatory attempts to limit risks of rodenticide baits to children and nontarget animals. EPA is reconsidering the requirements for the indicator dye and bittering agent. Currently, either type of agent may be added to a bait product voluntarily if the new bait can pass required efficacy tests.

The California Department of Fish and Game collected and analyzed tissue samples from non-target birds and mammals for anticoagulant rodenticides from 1994 through 1999. Many of these animals were collected in recently urbanized areas adjacent to wildlands where they were either found dead or trapped and euthanized as vertebrate pests. The results of the analyses indicate a high frequency of exposure to the anticoagulant rodenticide brodifacoum. Fifty-eight percent of the animals examined had been exposed to brodifacoum, 19% to bromadiolone, 9% to diphacinone, and 8% to chlorophacinone. All of the identified anticoagulants are registered for use to control commensal rodents found in and around structures and are available for sale "over-the-counter" for homeowner use. Brodifacoum and bromadiolone are registered exclusively for commensal rodent control. This paper assesses the frequency of anticoagulant rodenticide residues in tissues of non-target mammalian and avian wildlife and the possible impacts.

After several years of reviewing study data and conducting risk assessments, in September of 1998 the U.S. Environmental Protection Agency (U.S. EPA) issued for comment a Reregistration Eligibility Decision (RED) document for pesticide products in the Rodenticide Cluster. The RED document covered 243 rodenticide products containing the following active ingredients: brodifacoum, bromadiolone, bromethalin, chlorophacinone, diphacinone and its sodium salt, and pival and its sodium salt. The U.S. EPA’s human health risk assessment in the RED document concluded that it was concerned about the risk to children due to accidental exposures to these chemicals through use in and around residences. With regard to ecological effects, the Agency concluded that there is a high risk of secondary poisoning, especially to mammals, from the use of these rodenticides outdoors in rural and suburban areas. In order to address the potential risks to children, the U.S. EPA initially required several mitigation measures designed to minimize exposure (e.g., addition of dye and bittering agent to formulations, labeling changes). The Agency also initiated implementation of a Rodenticide Stakeholder Process through which these and other risk mitigation measures would be discussed and required as needed. To help mitigate potential risks to non-target wildlife, the Agency initially determined that all uses of field-bait rodenticides containing more than 0.005% of chlorophacinone or diphacinone were ineligible for reregistration. The U.S. EPA also decided that all rodenticide products labeled for field use (except those limited to manual underground baiting) should be reclassified as Restricted Use pesticides. This paper reviews the regulatory process for the Rodenticide Cluster RED and discusses the response of the California Department of Food and Agriculture (CDFA) and other registrants to the requirements proposed in the RED document including formation of the Rodenticide Registrants Task Force (RRTF). It also outlines how an on-going dialogue with the Agency, both through the Rodenticide Stakeholder Process and in separate discussions, has diminished the RED requirements from those originally proposed. In addition, the paper discusses the implications and potential impacts of the current RED reregistration requirements for those applicators involved in agricultural and urban rodent control.

Evaluation of the possible impacts of rodenticides on wildlife must be conducted in the context of risk-benefit considerations. Harmful introduced pests (e.g., commensal rats and mice) historically have required management around human habitation for economic and public health reasons. Disparate views of limited data have accumulated concerning the wildlife impacts resulting from commensal rodent control activities. The founding of the Rodenticide Registrants Task Force (RRTF), a trade association that includes all the major manufacturers and importers of anticoagulant rodenticide products (and bromethalin, a non-anticoagulant rodenticide) in the U.S., is described. The potential for anticoagulant dispersion in wildlife via primary and secondary routes is considered. Toxicology and pharmacokinetic studies are analyzed to obtain a better understanding of the biological and toxicological significance of low levels of rodenticide in animal tissue. A framework to address rodenticide impact to wildlife is presented. It is based upon the example of long-term cooperative efforts in England involving government, environmental, and manufacturer groups.

Mus musculus (house mouse) is a serious rodent pest in poultry farms of Argentina. In these habitats, bromadiolone is the most frequently used anticoagulant. In spite of this control, more than 90% of the farms are infested with rodents. The frequent application of anticoagulants and the permanent presence of M. musculus suggest that there are resistant rodent populations. The goal of this study was to assess bromadiolone susceptibility through a blood clotting response (BCR) test in M. musculus populations inhabiting poultry farms of Exaltación de la Cruz, Buenos Aires, Argentina. Results showed that 56.6% of wild M. musculus were responders to the BCR test. We found non-responder individuals in all the poultry farms studied. Non-responder females had at least one non-responder offspring. Since the percentages of resistant animals per poultry farm were high and considering that bromadiolone is extensively used for rodent control in these habitats, there is a potential risk of an increase in the proportion of resistant individuals and a decrease in the effectiveness of bromadiolone through time in the study area. Besides, our results suggest that this resistance has a genetic basis because non-responder mothers had non-responder offspring. [ABSTRACT FROM AUTHOR]