Translator Disclaimer
1 June 2016 Potential Toxicity of Fenbendazole to Gyps Vultures on the Indian Subcontinent: A Review
Author Affiliations +

Fenbendazole is an antihelminthic compound belonging to the benzimidazole class that is commonly used both for treatment and prophylaxis of various species of nematode, trematode, cestode, and a few protozoan endoparasites in livestock (Bowman 1995). Fenbendazole is one of the most widespread and common antiparasitic agents used in veterinary medicine due to its efficacy, broad spectrum, and ease of oral administration. Fenbendazole is a tasteless compound and does not affect palatability of feed, and is therefore suited to oral administration.

Fenbendazole acts by binding to β-tubulins of nematode cells, thereby interfering in dimerization of β-tubulins to α-tubulins. This consequently inhibits polymerization of tubulins into microtubules, which are required for protein synthesis and various metabolic processes (Martin 1997) including cell division. Interruption of these processes arrests normal biochemical and physiological functioning of cells of parasites, resulting in death. The drug is considered safe in livestock and other mammalian species because of its selective inhibition of β-tubulins of nematode cells over mammalian β-tubulins (Friedman and Platzer 1980, Reinemeyer and Courtney 2001). However, marked bone marrow suppression and adverse effects on gut mucosa were also reported in some mammalian species (Gary et al. 2004, Weber et al. 2006).

The Long-billed Vulture (Gyps indicus), White-rumped Vulture (G. bengalensis) and Slender-billed Vulture (G. tenuirostris) are endemic to the Indian subcontinent, and are critically endangered due to toxicity caused by residual diclofenac in carcasses of various species of livestock, which were treated by diclofenac prior to their death (Oaks et al. 2004, Swan et al. 2006). Remaining populations are extremely small and fragmented and these vultures remain vulnerable to diclofenac-induced mortalities (Taggart et al. 2007). A survey of the literature revealed fenbendazole toxicity in many species of domesticated, as well as wild, birds. Residue of fenbendazole in carcasses of livestock could be ingested by Gyps vultures, as diclofenac was. Considering the dwindling population of Gyps vultures and the proven toxicity of diclofenac through livestock carcasses, I here provide a brief review of potential toxicity of fenbendazole to Gyps vultures.

Toxicity in Birds

Fenbendazole was initially found to be safe with respect to effects on various avian species (Kirsch 1983, Santiago et al. 1985). More recently, however, studies have documented fenbendazole toxicity episodes causing mortalities in different domestic as well as wild species (Taylor et al. 1983, Pedersoli et al. 1989, Latimer 1994, Rivera et al. 2000, Wiley et al. 2009). No empirical data are available in the literature on the extent of selective binding of fenbendazole to parasitic β-tubulin over avian β-tubulin, which raises concerns about the safety of fenbendazole use in avian species (Howard et al. 2002). Results of multiple studies have suggested that metabolism of fenbendazole varied across avian species and differed relative to fenbendazole metabolism in mammals (Short et al. 1988, Howard et al. 2002). Consequently, there is uncertainty about the safety profile of fenbendazole, as it appears that some avian speciesare more susceptible to fenbendazole toxicity than others.

In terms of pathological findings, leukopenia resulting from bone-marrow hypoplasia and intestinal crypt cell necrosis was common in the multiple toxicity episodes caused by fenbendazole in phylogenetically distinct species of birds. These species included pigeons and doves (Howard et al. 2002, Gozalo et al. 2006), Painted Storks (Mycteria leucocephala; Weber et al. 2002), and more specifically African White-backed Vultures (G. africanus), Lappet-faced Vultures (Torgos tracheliotus), and Marabous (Leptoptilos crumenifer; Bonar et al. 2003). The similarity of pathological lesions in different avian species suggests the underlying mechanisms of fenbendazole toxicity in some birds could be similar in that it involves bone marrow and intestinal crypts, both of which have cells that undergo rapid multiplication by cell division (mitosis), indicating that the toxic effects could be associated with the pronounced inhibitory effect of fenbendazole, or its metabolites, on avian β-tubulins.

Pharmacokinetics of Fenbendazole in Bovines and Vultures

Fenbendazole is used orally as an antiparasitic agent in animals with internal helminthic infestations and, more importantly, in prophylaxis as well, which extends its use to healthy animals. Use of antiparasitic agents, such as fenbendazole, is fairly common in modern dairy, meat, and poultry farming. The use of fenbendazole in veterinary institutions, and its availability in pharmacies without a prescription contribute to its widespread use. Furthermore, febantel, another antihelmintic of the benzimidazole class, is biotransformed into fenbendazole inside the body by metabolic processes (McKellar and Scott 1990).

Vultures mostly feed on carcasses of domestic animals on the Indian subcontinent (Pain et al. 2008). Residual availability of fenbendazole in carcasses of cattle and buffalo depends on pharmacokinetic parameters of fenbendazole in these species. Tmax is defined as time taken by a drug to achieve maximum concentration in blood serum after administration. Mean Tmax values of fenbendazole and its metabolites were in the range of 30–36 hr in cattle and 18–38 hr in buffalo after a single standard dosing of 7.5 mg/kg body weight, and fenbendazole and its metabolites could be detected up to 120 hr post-dosing (Sanyal 2011); residues of diclofenac in cattle were detectable up to 71 hr post-dosing (Taggart et al. 2007). Comparison of pharmacokinetics of fenbendazole and diclofenac reveals relatively higher temporal persistence of fenbendazole and its metabolites in livestock after administration, increasing the probability of ingestion by vultures, compared to diclofenac, which has been proven to be toxic to Gyps vultures. It is evident based on these factors that vultures are likely to ingest varying amounts of residual fenbendazole in livestock carcasses on a regular basis. Dosing of fenbendazole in a range of 47–60 mg/kg resulted in toxicity in Lappet-faced Vultures and White-backed Vultures (Bonar et al. 2003). Because of the absence of quantitative information on the lethal dose (LD50) of fenbendazole for Gyps vultures, I urge investigation of the concentration of residual fenbendazole in livestock carcasses lethal to Gyps vultures.

Potential Toxicity in Gyps Vultures

White-backed Vultures are phylogenetically similar to White-rumped Vultures, and this similarity suggests that other or perhaps all Gyps vultures could be similarly susceptible to diclofenac toxicity based on their phylogenetic relationships and previously observed toxicity in four species of Gyps vultures (Johnson et al. 2006, Naidoo et al. 2009b). Toxicity testing in vivo of diclofenac in White-backed Vultures and White-rumped Vultures resulted in similar increased and lethal levels of uric acid in blood of the two species; increased uric acid led to visceral gout and subsequent death in affected vultures post-diclofenac dosing (Swan et al. 2006). Further, in vivo diclofenac toxicity trials in Cape Griffons (G. coprotheres) revealed that toxicity was similar to that observed in three species of Gyps vultures from the Indian subcontinent (Oaks et al. 2004). Also, ketoprofen had toxic effects in White-backed Vultures and Cape Griffons (Naidoo et al. 2009a), highlighting the metabolic similarities and possible susceptibility to certain compounds within the Gyps genus. Moreover, similar toxicity of fenbendazole in White-backed Vultures and Lappet-faced Vultures (Torgos tracheliotus; Bonar et al. 2003), which belong to different genera, suggests that other vultures, apart from the Gyps genus, may be susceptible to fenbendazole toxicity. Metabolic processes and pathological lesions involved in fenbendazole toxicity are different from those of diclofenac, yet metabolic similarities and phylogenetic relationships among species in the Gyps genus suggest that fenbendazole toxicity observed in White-backed Vultures may be of concern across the Gyps genus.

Vultures are obligate scavengers, and they have a robust immune system, which facilitates carcass-feeding by providing protection from various infective and pathological microbes. Fenbendazole induces intestinal cell necrosis, which can facilitate entry of intestinal bacteria into systematic circulation (Howard et al. 2002). Concomitant immuno-suppression due to leukopenia significantly reduces the defense mechanisms of the body, and lesions mutually supplement and predispose septicaemia, which increases the probability of mortality. Prolonged ingestion of residual fenbendazole in livestock carcasses below a toxic level may also adversely affect Gyps vultures in unknown ways. Furthermore, as three species of Gyps vultures are critically endangered, any pharmacological agent with potential toxicity to these vultures should be evaluated comprehensively to minimize risk to critically endangered White-rumped Vulture, Long-billed Vulture, and Slender-billed Vulture and possibly other vultures on the Indian subcontinent.

Acknowledgments

I thank K.S. Gopisundar and A.M. Goswami for their assistance with the literature. Two anonymous reviewers provided comments that improved an earlier version of this report.

Literature Cited

1.

C. Bonar A. Lewandowskiand J. Schaul 2003. Suspected fenbendazole toxicosis in 2 vulture species (Gyps africanus, Torgos tracheliotus) and Marabou Storks (Leptoptilos crumeniferus). Journal of Avian Medicine and Surgery 17:16–19. Google Scholar

2.

D. Bowman 1995. Helminths. Pages 228–229 in J. Georgi [Ed.], Parasitology for veterinarians. WB Saunders, Philadelphia, PA U.S.A. Google Scholar

3.

P.A. Friedmanand E.G. Platzer 1980. Interaction of anthelmintic benzimidazoles with Ascaris suum embryonic tubulin. Biochimica et Biophysica Acta 630:271–278. Google Scholar

4.

A.T. Gary M.E. Kerl C.E. Wiedmeyer S.E. Turnquistand L.A. Cohn 2004. Bone marrow hypoplasia associated with fenbendazole administration in a dog. Journal of American Animal Hospital Association 40:224–229. Google Scholar

5.

A. Gozalo R. Schwiebertand G. Lawson 2006. Mortality associated with fenbendazole administration in pigeons (Columba livia). Journal of the American Association for Laboratory Animal Science 45:63–66. Google Scholar

6.

L.L. Howard R. Papendick I.H. Stalis J.L. Allen M. Sutherland-Smith J.R. Zuba D.L. Wardand B.A. Rideout 2002. Fenbendazole and albendazole toxicity in pigeons and doves. Journal of Avian Medicine and Surgery 16:203–210. Google Scholar

7.

J. Johnson H. Lerner P. Rasmussenand D. Mindell 2006. Systematics within Gyps vultures: a clade at risk. BMC Evolutionary Biology 6:65. doi: 10.1186/1471-2148-6-65. Google Scholar

8.

R. Kirsch 1983. Treatment of nematodiasis in poultry and game birds with fenbendazole. Avian Diseases 28:311–318. Google Scholar

9.

K. Latimer 1994. Oncology. Pages 640–672 in B. Ritchie G. Harrisonand L. Harrison [Eds.], Avian medicine: principles and application. Wingers Publishing Inc., Lake Worth, FL U.S.A. Google Scholar

10.

R.J. Martin 1997. Modes of action of anthelmintic drugs. Veterinary Journal 154:11–34. Google Scholar

11.

Q.A. McKellarand E.W. Scott 1990. The benzimidazole anthelmintic agents—a review. Journal of Veterinary Pharmacology and Therapeutics 13:223–247. Google Scholar

12.

V. Naidoo K. Wolter D. Cromarty M. Diekmann N. Duncan A.A. Meharg M.A. Taggart L. Venter and R. Cuthbert 2009a. Toxicity of non-steroidal anti-inflammatory drugs to Gyps vultures: a new threat from ketoprofen. Biology Letters 6:339–341. Google Scholar

13.

V. Naidoo V. Naidoo V. Naidoo R. Cuthbertand N. Duncan 2009b. Veterinary diclofenac threatens Africa’s endangered vulture species. Regulatory Toxicology and Pharmacology 53:205–208. Google Scholar

14.

J.L. Oaks M. Gilbert M.Z. Virani R.T. Watson C.U. Meteyer B.A. Rideout H.L. Shivaprasad S. Ahmed M. Jamshed I. Chaudhry M. Arshad S. Mahmood A. Aliand A.A. Khan 2004. Diclofenac residues as the cause of vulture population decline in Pakistan. Nature 427:630–633. Google Scholar

15.

D.J. Pain C.G.R. Bowden A.A. Cunnningham R. Cuthbert D. Das M. Gilbert R.D. Jakati Y. Jhala A.A. Khan V. Naidoo J.L. Oaks J. Parry-Jones V. Prakash A. Rahmani S.P. Ranade H.S. Baral K.R. Senacha S. Saravanan N. Shah G. Swan D. Swarup M.A. Taggart R.T. Watson M.Z. Virani K. Wolterand R.E. Green 2008. The race to prevent the extinction of south Asian vultures. Bird Conservation International 18:S30–S48. Google Scholar

16.

W. Pedersoli J. Spano L. Krista J. Whitesides W. Ravis R. Kemppainenand D. Young 1989. Effects of fenbendazole administration on hematology, clinical chemistries and selected hormones in the white Pekin Duck. Journal of Veterinary Pharmacology and Therapeutics 12:200–208. Google Scholar

17.

C. Reinemeyerand C.H. Courtney 2001. Chemotherapy of parasitic diseases. Pages 947–979 in R. Adams [Ed.], Veterinary pharmacology and therapeutics. Iowa State Univ. Press, Ames, IA U.S.A. Google Scholar

18.

S. Rivera J. McClearenand D. Reavill 2000. Suspected fenbendazole toxicity in pigeons (Columba livia). Proceedings of the Association of Avian Veterinarians 21:207–209. Google Scholar

19.

C. Santiago P. Millsand C. Kirkpatrick 1985. Oral capillariasis in a Red-tailed Hawk: treatment with fenbendazole. Journal of American Veterinary Medical Association 187:1205–1206. Google Scholar

20.

P.K. Sanyal 2011. Plasma levels of fenbendazole metabolites in buffalo and cattle after long-term intraruminal administration. Veterinary Quarterly 15:157–159. Google Scholar

21.

C.R. Short S.A. Barker L.C. Hsieh W.M. Pedersoli L.M. Kristaand J.S. Spano 1988. The elimination of fenbendazole and its metabolites in the chicken, turkey and duck. Journal of Veterinary Pharmacology and Therapeutics 11:204–209. Google Scholar

22.

G.E. Swan R. Cuthbert M. Quevedo R.E. Green D.J. Pain P. Bartels A.A. Cunningham N. Duncan A.A. Meharg J.L. Oaks J. Parry-Jones S. Shultz M.A. Taggart G. Verdoornand K. Wolter 2006. Toxicity of diclofenac to Gyps vultures. Biology Letters 2:279–282. Google Scholar

23.

M.A. Taggart R. Cuthbert D. Das C. Sashikumar D.J. Pain R.E. Green Y. Feltrer S. Shultz A.A. Cunninghamand A.A. Meharg 2007. Diclofenac disposition in Indian cow and goat with reference to Gyps vulture population declines. Environmental Pollution 147:60–65. Google Scholar

24.

S. Taylor A. Kenny S. Houstonand S. Hewitt 1983. Efficacy, pharmacokinetics and effects on egg-laying and hatchability of two dose rates of in-feed fenbendazole for the treatment of Capillaria species infections in chickens. Veterinary Record 133:519–521. Google Scholar

25.

M. Weber M. Miller D. Neifferand D.S. Terrel 2006. Presumptive fenbendazole toxicosis in North American porcupines. Journal of American Veterinary Medical Association 228:1240–1242. Google Scholar

26.

M. Weber S. Terrell D. Neiffer M. Millerand B. Mangold 2002. Bone marrow hypoplasia and intestinal crypt cell necrosis associated with fenbendazole administration in five Painted Storks. Journal of American Veterinary Medical Association 221:417–419. Google Scholar

27.

J. Wiley J. Whittington C. Wilmesand B. Messick 2009. Chronic myelogenous leukemia in a Great Horned Owl (Bubo virginianus). Journal of Avian Medicine and Surgery 23:36–43. Google Scholar
© 2016 The Raptor Research Foundation, Inc.
Pradeep Sharma "Potential Toxicity of Fenbendazole to Gyps Vultures on the Indian Subcontinent: A Review," Journal of Raptor Research 50(2), 207-210, (1 June 2016). https://doi.org/10.3356/rapt-50-02-207-210.1
Received: 14 June 2015; Accepted: 1 December 2015; Published: 1 June 2016
JOURNAL ARTICLE
4 PAGES


SHARE
ARTICLE IMPACT
Back to Top