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Vulture declines in South Asia were caused by accidental poisoning by the veterinary non-steroidal anti-inflammatory drug (NSAID) diclofenac. Although veterinary use of diclofenac has been banned, other vulture-toxic NSAIDs are legally available, including aceclofenac, which has been shown to metabolise into diclofenac in domestic cattle. We gave nine domestic water buffalo the recommended dose of aceclofenac (2 mg kg -1 body weight), collected blood at intervals up to 48 h, and carried out a pharmacokinetic analysis of aceclofenac and its metabolite diclofenac in plasma. Aceclofenac was rapidly converted to diclofenac, and was barely detectable in plasma at any sampling time. Diclofenac was present within 20 min, and peaked 4-8 h after dosing. Aceclofenac is a prodrug of diclofenac, and behaves similarly in domestic water buffalo as it did in domestic cattle, posing the same risk to vultures. We recommend an immediate ban on the veterinary use of aceclofenac across vulture-range countries., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Veterinary use of the non-steroidal anti-inflammatory drug diclofenac on domesticated ungulates caused populations of resident Gyps vultures in the Indian sub-continent to collapse. The birds died when they fed on carrion from treated animals. Veterinary diclofenac was banned in 2006 and meloxicam was advocated as a 'vulture-safe' alternative. We examine the effectiveness of the 2006 ban, whether meloxicam has replaced diclofenac, and the impact of these changes on vultures. Drug residue data from liver samples collected from ungulate carcasses in India since 2004 demonstrate that the prevalence of diclofenac in carcasses in 2009 was half of that before the ban and meloxicam prevalence increased by 44%. The expected vulture death rate from diclofenac per meal in 2009 was one-third of that before the ban. Surveys at veterinary clinics show that diclofenac use in India began in 1994, coinciding with the onset of rapid Gyps declines ascertained from measured rates of declines. Our study shows that one pharmaceutical product has had a devastating impact on Asia's vultures. Large-scale research and survey were needed to detect, diagnose and quantify the problem and measure the response to remedial actions. Given these difficulties, other effects of pharmaceuticals in the environment may remain undetected., (© 2014 The Author(s) Published by the Royal Society. All rights reserved.)

Populations of oriental white-backed vulture (Gyps bengalensis), long-billed vulture (Gyps indicus) and slender-billed vulture (Gyps tenuirostris) crashed during the mid-1990s throughout the Indian subcontinent. Surveys in India, initially conducted in 1991-1993 and repeated in 2000, 2002, 2003 and 2007, revealed that the population of Gyps bengalensis had fallen by 2007 to 0.1% of its numbers in the early 1990s, with the population of Gyps indicus and G. tenuirostris combined having fallen to 3.2% of its earlier level. A survey of G. bengalensis in western Nepal indicated that the size of the population in 2009 was 25% of that in 2002. In this paper, repeat surveys conducted in 2011 were analysed to estimate recent population trends. Populations of all three species of vulture remained at a low level, but the decline had slowed and may even have reversed for G. bengalensis, both in India and Nepal. However, estimates of the most recent population trends are imprecise, so it is possible that declines may be continuing, though at a significantly slower rate. The degree to which the decline of G. bengalensis in India has slowed is consistent with the expected effects on population trend of a measured change in the level of contamination of ungulate carcasses with the drug diclofenac, which is toxic to vultures, following a ban on its veterinary use in 2006. The most recent available information indicates that the elimination of diclofenac from the vultures' food supply is incomplete, so further efforts are required to fully implement the ban.

Contamination of their carrion food supply with the non-steroidal anti-inflammatory drug diclofenac has caused rapid population declines across the Indian subcontinent of three species of Gyps vultures endemic to South Asia. The governments of India, Pakistan and Nepal took action in 2006 to prevent the veterinary use of diclofenac on domesticated livestock, the route by which contamination occurs. We analyse data from three surveys of the prevalence and concentration of diclofenac residues in carcasses of domesticated ungulates in India, carried out before and after the implementation of a ban on veterinary use. There was little change in the prevalence and concentration of diclofenac between a survey before the ban and one conducted soon after its implementation, with the percentage of carcasses containing diclofenac in these surveys estimated at 10.8 and 10.7%, respectively. However, both the prevalence and concentration of diclofenac had fallen markedly 7-31 months after the implementation of the ban, with the true prevalence in this third survey estimated at 6.5%. Modelling of the impact of this reduction in diclofenac on the expected rate of decline of the oriental white-backed vulture (Gyps bengalensis) in India indicates that the decline rate has decreased to 40% of the rate before the ban, but is still likely to be rapid (about 18% year(-1)). Hence, further efforts to remove diclofenac from vulture food are still needed if the future recovery or successful reintroduction of vultures is to be feasible.

The non-steroidal anti-inflammatory drug diclofenac is a major cause of the rapid declines in the Indian subcontinent of three species of vultures endemic to South Asia. The drug causes kidney failure and death in vultures. Exposure probably arises through vultures feeding on carcasses of domesticated ungulates treated with the drug. However, before the study reported here, it had not been established from field surveys of ungulate carcasses that a sufficient proportion was contaminated to cause the observed declines. We surveyed diclofenac concentrations in samples of liver from carcasses of domesticated ungulates in India in 2004-2005. We estimated the concentration of diclofenac in tissues available to vultures, relative to that in liver, and the proportion of vultures killed after feeding on a carcass with a known level of contamination. We assessed the impact of this mortality on vulture population trend with a population model. We expected levels of diclofenac found in ungulate carcasses in 2004-2005 to cause oriental white-backed vulture population declines of 80-99% per year, depending upon the assumptions used in the model. This compares with an observed rate of decline, from road transect counts, of 48% per year in 2000-2003. The precision of the estimate based upon carcass surveys is low and the two types of estimate were not significantly different. Our analyses indicate that the level of diclofenac contamination found in carcasses of domesticated ungulates in 2004-2005 was sufficient to account for the observed rapid decline of the oriental white-backed vulture in India. The methods we describe could be used again to assess changes in the effect on vulture population trend of diclofenac and similar drugs. In this way, the effectiveness of the recent ban in India on the manufacture and importation of diclofenac for veterinary use could be monitored.

Three endemic vulture species Gyps bengalensis, Gyps indicus and Gyps tenuirostris are critically endangered following dramatic declines in South Asia resulting from exposure to diclofenac, a veterinary drug present in the livestock carcasses that they scavenge. Diclofenac is widely used globally and could present a risk to Gyps species from other regions. In this study, we test the toxicity of diclofenac to a Eurasian (Gyps fulvus) and an African (Gyps africanus) species, neither of which is threatened. A dose of 0.8 mg kg(-1) of diclofenac was highly toxic to both species, indicating that they are at least as sensitive to diclofenac as G. bengalensis, for which we estimate an LD50 of 0.1-0.2 mg kg(-1). We suggest that diclofenac is likely to be toxic to all eight Gyps species, and that G. africanus, which is phylogenetically close to G. bengalensis, would be a suitable surrogate for the safety testing of alternative drugs to diclofenac.

Veterinary use of the nonsteroidal anti-inflammatory (NSAID) drug diclofenac in South Asia has resulted in the collapse of populations of three vulture species of the genus Gyps to the most severe category of global extinction risk. Vultures are exposed to diclofenac when scavenging on livestock treated with the drug shortly before death. Diclofenac causes kidney damage, increased serum uric acid concentrations, visceral gout, and death. Concern about this issue led the Indian Government to announce its intention to ban the veterinary use of diclofenac by September 2005. Implementation of a ban is still in progress late in 2005, and to facilitate this we sought potential alternative NSAIDs by obtaining information from captive bird collections worldwide. We found that the NSAID meloxicam had been administered to 35 captive Gyps vultures with no apparent ill effects. We then undertook a phased programme of safety testing of meloxicam on the African white-backed vulture Gyps africanus, which we had previously established to be as susceptible to diclofenac poisoning as the endangered Asian Gyps vultures. We estimated the likely maximum level of exposure (MLE) of wild vultures and dosed birds by gavage (oral administration) with increasing quantities of the drug until the likely MLE was exceeded in a sample of 40 G. africanus. Subsequently, six G. africanus were fed tissues from cattle which had been treated with a higher than standard veterinary course of meloxicam prior to death. In the final phase, ten Asian vultures of two of the endangered species (Gyps bengalensis, Gyps indicus) were dosed with meloxicam by gavage; five of them at more than the likely MLE dosage. All meloxicam-treated birds survived all treatments, and none suffered any obvious clinical effects. Serum uric acid concentrations remained within the normal limits throughout, and were significantly lower than those from birds treated with diclofenac in other studies. We conclude that meloxicam is of low toxicity to Gyps vultures and that its use in place of diclofenac would reduce vulture mortality substantially in the Indian subcontinent. Meloxicam is already available for veterinary use in India.

Recent declines in the populations of three species of vultures in the Indian subcontinent are among the most rapid ever recorded in any bird species. Evidence from a previous study of one of these species, Gyps bengalensis, in the Punjab province of Pakistan, strongly implicates mortality caused by ingestion of residues of the veterinary non-steroidal anti-inflammatory drug diclofenac as the major cause of the decline. We show that a high proportion of Gyps bengalensis and G. indicus found dead or dying in a much larger area of India and Nepal also have residues of diclofenac and visceral gout, a post-mortem finding that is strongly associated with diclofenac contamination in both species. Hence, veterinary use of diclofenac is likely to have been the major cause of the rapid vulture population declines across the subcontinent.

1. Spain holds > 95% of the European breeding population of the Eurasian griffon vulture Gyps fulvus. Vultures provide important ecosystem services in carcass removal and influence emissions of greenhouse gases. Despite the known toxicity of the non-steroidal anti-inflammatory drug diclofenac to this species and other Gyps vultures, in March 2013 the Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) approved the use of two medicines containing diclofenac for veterinary use in horses, pigs and cattle in Spain. 2. To assess the potential impact of medicated ungulate carcasses on Eurasian griffon vulture populations in Spain, we first used information on the metabolism and elimination of diclofenac from medicated cattle and pigs to calculate residue levels in relation to time elapsed between dosing and death. Secondly, probabilities of the death of a vulture per meal were calculated based upon experimental studies of diclofenac toxicity. Finally, annual numbers of vulture deaths expected to be caused by diclofenac were obtained by multiplying the death rates per meal by the estimated numbers of vulture meals taken from expected numbers of medicated carcasses suggested by AEMPS. 3. Assuming that vultures feed on carcasses that were treated with diclofenac 8 h before the animal's death, the annual number of vulture deaths caused by diclofenac was estimated at 715-6389, depending upon the estimate of numbers of medicated carcasses assumed and the version of the dose–response model used. Using a density-independent simulation model of a vulture population, the expected rate of decline of the Spanish population of Eurasian griffon vultures caused by these deaths is 0·9-7·7% per year. A density-dependent simulation model also indicated substantial population-level effects. Formal estimates of precision and sensitivity analyses of effects of unmeasured variables highlight the uncertainty of estimates using currently available data. 4. Synthesis and applications. Due to the possibility of causing an important impact on vulture populations, our findings justify a precautionary ban on the veterinary use of diclofenac in Spain and encourage the use of meloxicam, a vulture-safe alternative drug. A programme of monitoring of non-steroidal anti-inflammatory drug contamination of ungulate carcasses available to vultures and of moribund and dead obligate and facultative avian scavengers would be needed to be confident that a damaging level of contamination is not present. [ABSTRACT FROM AUTHOR]

The collapse of South Asia's Gyps vulture populations is attributable to the veterinary use of the non-steroidal anti-inflammatory drug (NSAID) diclofenac. Vultures died after feeding on carcasses of recently-medicated animals. The governments of India, Nepal and Pakistan banned the veterinary use of diclofenac in 2006. We analysed results of 62 necropsies and 48 NSAID assays of liver and/or kidney for vultures of five species found dead in India between 2000 and 2012. Visceral gout and diclofenac were detected in vultures from nine states and three species: Gyps bengalensis, Gyps indicus and Gyps himalayensis. Visceral gout was found in every vulture carcass in which a measurable level of diclofenac was detected. Meloxicam, an NSAID of low toxicity to vultures, was found in two vultures and nimesulide in five vultures. Nimesulide at elevated tissue concentrations was associated with visceral gout in four of these cases, always without diclofenac, suggesting that nimesulide may have similar toxic effects to those of diclofenac. Residues of meloxicam on its own were never associated with visceral gout. The proportion of Gyps vultures found dead in the wild in India with measurable levels of diclofenac in their tissues showed a modest and non-significant decline since the ban on the veterinary use of diclofenac. The prevalence of visceral gout declined less, probably because some cases of visceral gout from 2008 onwards were associated with nimesulide rather than diclofenac. Veterinary use of nimesulide is a potential threat to the recovery of vulture populations. [ABSTRACT FROM PUBLISHER]

1. The populations of three species of South Asian vultures ( Gyps bengalensis, Gyps indicus and Gyps tenuirostris) have declined rapidly within the last decade and all are now critically endangered. Veterinary use of the non-steroidal anti-inflammatory drug diclofenac appears to be a major cause of the declines. Vultures are likely to be exposed to the drug when they feed on carcasses of livestock that were treated with diclofenac before death. 2. We measured the concentration of diclofenac in the tissues of treated Indian humped and European cattle ( Bos indicus and Bos taurus) in relation to the interval between dosing and death. We used a dose–response model to assess the risk posed to wild vultures if they feed on carcasses of treated livestock. 3. Diclofenac concentrations in fat, intestine, kidney and liver were considerably higher than those in muscle, but concentrations in the first four tissues initially depleted more rapidly (half-life 6–8 h) with time since the last injection of the drug, compared with muscle (half-life 15 h). Depletion rates became much slower in all tissues 25–98 h after the last injection. 4. Diclofenac concentration, averaged across the carcass, was enough to cause appreciable mortality (> 10% of birds per meal) if oriental white-backed vultures G. bengalensis were to take a large meal from the carcass of an animal that was given its last dose of the drug within a day or two before death. Vultures that feed selectively on tissues with high concentrations of the drug, such as kidney, liver and intestine, would be exposed to a higher risk and for longer after dosing. 5. Synthesis and applications. The tissues of cattle treated with diclofenac are a hazard to wild vultures that feed on an animal that dies within a few days after treatment. Intestine, kidney and liver have the highest diclofenac concentrations, but the concentration averaged across all the edible tissues of the carcass is also hazardous. Withdrawal of diclofenac from veterinary use on animals whose carcasses may become available to scavenging vultures is recommended. In ex situ and in situ conservation projects, vultures should be fed on carcasses of animals that are known not to have been treated with diclofenac in the week before death. [ABSTRACT FROM AUTHOR]

1. Rapid population declines of the vulturesGyps bengalensis,Gyps indicusandGyps tenuirostrishave recently been observed in India and Pakistan, continuing at least up to 2003. Surveys indicate annual rates of decline of 22–50% forG. bengalensisandG. indicusduring 2000–03. Previous studies in Pakistan have shown that the non-steroidal anti-inflammatory drug diclofenac causes renal failure and is lethal toG. bengalensiswhen it feeds on the carcass of a domestic animal that received a normal veterinary dose shortly before death. In Pakistan, diclofenac poisoning was found to be by far the most frequent cause of death.2. A simulation model of vulture demography, described in this paper, demonstrated that the observed rates of population decline could be caused by contamination with a lethal level of diclofenac in a small proportion (between 1 : 130 and 1 : 760) of ungulate carcasses available to vultures.3. Proportions of adult and subadult vultures found dead or dying in the wild that had signs of diclofenac poisoning were similar to the proportions of deaths expected from the model if the observed population decline was due entirely to diclofenac poisoning. The proportion of the excess mortality required to cause the observed population declines that could be attributable to diclofenac was estimated to be between 71% and 100%, depending on model assumptions. However, across all or most of the plausible range of assumed values for adult survival, the upper 95% confidence limit for the proportion of excess mortality due to diclofenac was 100%. Hence, available data are consistent with diclofenac poisoning being at least the major cause, and possibly the only cause, of rapid population declines ofGypsvultures across the Indian subcontinent.4. Synthesis and applications. We recommend that urgent action is taken in the range states of the three currently threatened vulture species to prevent the exposure of vultures to livestock carcasses contaminated with diclofenac. Research is also needed to identify alternative drugs that are effective in livestock and safe for vultures. Efforts should also be made to raise awareness, among veterinarians, pharmacists, livestock owners and the general public, of the problem of diclofenac contamination and the availability of safe alternatives. Captive holding and breeding of vultures until diclofenac is controlled is recommended as a precaution to ensure the long-term survival of the threatened species and to provide a stock of birds for future reintroduction programmes.Journal of Applied Ecology(2004)41, 793 –800 [ABSTRACT FROM AUTHOR]

In 2006, India, Pakistan, and Nepal banned the manufacture of veterinary formulations of the nonsteroidal anti-inflammatory drug (NSAID) diclofenac. This action was taken to halt the unprecedented decline of three Gyps vulture species that were being poisoned by diclofenac residues commonly present in carcasses of domestic livestock upon which they scavenged. To assess the affect of this ban and evaluate residue prevelances of other NSAIDs, we present a method to detect diclofenac and eight more NSAIDs by liquid chromatography-mass spectrometry and apply this to 1488 liver samples from carcasses of livestock taken across seven Indian states. Diclofenac was present in 11.1% of samples taken between April and December 2006, and meloxicam (4%), ibuprofen (0.6%), and ketoprofen (0.5%) were also detected. Although meloxicam is safe for a range of avian scavengers, including Gypsvultures, data regarding the safety of other NSAIDs is currently limited. If wild Gyps on the Indian subcontinent are to! survive, diclofenac bans must be completely effective, and NSAIDs that replace it within the veterinary drug market must be of low toxicity toward Gyps and other scavenging birds. [ABSTRACT FROM AUTHOR]

The article reflects on the approval of diclofenac, a drug highly toxic to vultures as veterinary treatment in Spain. It mentions that the veterinary use of diclofenac was ban in India, Pakistan and Nepal in 2006 due to near extinction of three vulture species. It notes the proposal of the European Medicines Agency's Committee for Medicinal Products for Veterinary Use that diclofenac should be regulated and assure that the drug do not end up in the food chain of avian scavengers.

Veterinary use of the non-steroidal anti-inflammatory drug, diclofenac is responsible for the population collapse of resident vulture species in India. Conservation efforts, including a ban on veterinary diclofenac and the identification of a vulture-safe alternative (meloxicam), were introduced in 2006 in order to address the threat. Sampling of domesticated ungulate carcasses available to vultures in India was undertaken in three surveys prior to, around the time of, and 1-2 years after the ban in order to quantify the prevalence of diclofenac and meloxicam residues. A total of 1445, 1488 and 1251 liver tissue samples were collected from nine states and analysed with a validated LC-ESI/MS methodology. Overall diclofenac prevalence levels declined by almost a half over the three surveys, and there was an increase in meloxicam prevalence between the second and third surveys, although some states revealed little change. These surveys indicate that two of the key conservation actions to counter the threat faced by vultures - banning veterinary diclofenac and promoting meloxicam as a safe alternative - are beginning to take effect. However, because only a small proportion of diclofenac-contaminated carcasses is sufficient to cause vulture population declines, further efforts are needed to eliminate diclofenac from the food supply of India's vultures. [ABSTRACT FROM AUTHOR]