The use of toxicokinetics and exposure studies to show that carprofen in cattle tissue could lead to secondary toxicity and death in wild vultures

Abstract

Veterinary medicines can be extremely damaging to the environment, as seen with the catastrophic declines in Gyps vulture in South Asia due to their secondary exposure to diclofenac in their primary food source. Not surprisingly, concern has been raised over other similar drugs. In this study, we evaluate the toxicity of carprofen to the Gyps vulture clade through plasma pharmacokinetics evaluations in Bos taurus cattle (their food source) and Gyps africanus (a validated model species); tissue residues in cattle; and the effect of carprofen as a secondary toxicant as both tissue-bound residue or pure drug at levels expected in cattle tissues. Carprofen residues were highest in cattle kidney (7.72 ± 2.38 mg/kg) and injection site muscle (289.05 ± 98.96 mg/kg of dimension of 5 × 5 × 5 cm). Vultures exposed to carprofen as residues in the kidney tissue or pure drug equivalents showed no toxic signs. When exposed to average injection site concentrations (64 mg/kg) one of two birds died with evidence of severe renal and liver damage. Toxicokinetic analysis revealed a prolonged drug half-life of 37.75 h in the dead bird as opposed to 13.99 ± 5.61 h from healthy birds dosed intravenously at 5 mg/kg. While carprofen may generally be harmless to Gyps vultures, its high levels at the injection site in treated cattle can result in lethal exposure in foraging vultures, due to relative small area of tissue it is found therein. We thus suggest that carprofen not be used in domesticated ungulates in areas where carcasses are accessible or provided to vultures at supplementary feeding sites.

The complete mitochondrial genome of Gyps coprotheres (Aves, Accipitridae, Accipitriformes): phylogenetic analysis of mitogenome among raptors

“…This incidence raises concern on the vulnerability of the Accipitriformes and other raptors to diclofenac toxicity. Complications due to the toxic consequences of diclofenac have also been reported in the Cape vulture ( Swan et al, 2006b ; Naidoo et al, 2009 ; Naidoo et al, 2010 ; Naidoo et al, 2018 ; Adawaren et al, 2018 ).…”

“…Raptors are valuable indicators of habitat quality based on their ecological sensitivity as predators and scavengers ( Lerner & Mindell, 2005 ). However, vultures belonging to the Accipitriformes order are currently facing devastating drops in their population numbers from an array of problems ranging from loss of their natural habitat, collision with high-tension electric cables and wind turbines, intentional poisoning of animal carcasses by poachers of endangered wildlife species and accidental ingestion of carcasses contaminated with pharmaceuticals ( Ogada et al, 2016 ; Naidoo et al, 2018 ; Adawaren et al, 2018 ). One notable incident was the near complete extinction of three Gyps vulture species the white-rumped vulture ( Gyps bengalenesis ), the Indian vulture ( G. indicus ) and the slender-billed vulture ( G. tenuirostris ) in India, Nepal and Pakistan from the consumption of carcasses of animals dosed with diclofenac ( Oaks et al, 2004 ; Swan et al, 2006b ; Naidoo et al, 2009 ; Adawaren et al, 2018 ).…”

“…One notable incident was the near complete extinction of three Gyps vulture species the white-rumped vulture ( Gyps bengalenesis ), the Indian vulture ( G. indicus ) and the slender-billed vulture ( G. tenuirostris ) in India, Nepal and Pakistan from the consumption of carcasses of animals dosed with diclofenac ( Oaks et al, 2004 ; Swan et al, 2006b ; Naidoo et al, 2009 ; Adawaren et al, 2018 ). At present, it is estimated that the drug caused the deaths of over 10 million vultures in the region ( Naidoo et al, 2018 ). Furthermore, diclofenac has been implicated as the cause of death of a steppe eagle ( Aquila nipalensis ), a member of the Accipitridae family with classical sign of toxicity seen in vultures ( Sharma et al, 2014 ).…”

Development and Validation of a High-Throughput Method for the Determination of Eight Non-Steroidal Anti-Inflammatory Drugs and Chloramphenicol in Milk, using Liquid Chromatography-Tandem Mass Spectroscopy

“…In the European Union (EU) a few NSAIDs are au-thorized for dairy cows with established maximum residues limits (MRLs) in milk: Tolfenamic acid (TLF) -50 µg/kg; flunixin (FLU) (marker residue 5-hydroxyflunixin) -40 µg/kg; meloxicam (MLX) -15 µg/ kg; metamizole (marker residue 4-methylaminoantipyrine (4MMA)) -50 µg/kg; and diclofenac (DCL) with very low MRL of 0.1 µg/kg [5]. Carprofen (CPF) is licensed for use in dairy cattle and has no required MRL in bovine milk; the target value for the analytical method was set at 500 µg/kg for our in-house monitoring of the substance, due to occurrence of vultures' death from consuming livestock carcasses [6]. Ibuprofen (IBU) and phenylbutazone (PBZ) are non-authorized for veterinary use in food-producing animals and have no established MRLs in milk; IBU and PBZ should be analyzed (as defined in CRL Guidance Paper of 2007 [7]) at the recommended concentrations (RC) of: 10 µg/kg and 5 µg/kg, respectively.…”

Population-level impacts of chemical contaminants on apex avian species

“…Since then, safety trials have now confirmed nephrotoxicity at plausible field exposure levels in Gyps due to ketoprofen [33], carprofen [34] and aceclofenac [35] -whilst very worryingly, both nimesulide (in South Asia; [36] and flunixin (in Europe; [37]) have now been clearly linked to wild Gyps mortalities on two continents. Further, concern now also exists regarding potential impacts on what some may consider to be more enigmatic species such as eagles, following the death of two steppe eagles (Aquila nipalensis) in India in association…”