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Learned lessons from wildlife toxicology to improve the risk assessment of pharmaceuticals

This study examines the effects of pharmaceuticals on wildlife and explores how ecotoxicology and ecology can be bridged to improve risk assessment. It focuses on the environmental impact of veterinary drugs in both intensive and extensive livestock production scenarios. The study also investigates the risks faced by avian scavengers, such as vultures, associated with exposure to veterinary pharmaceuticals. Specifically, it looks at the crisis of the Asian vultures caused by diclofenac and other nonsteroidal anti-inflammatory drugs (NSAIDs). Furthermore, the study explores the exposure of bearded vultures to external antiparasitics. Overall, the research aims to identify safe alternatives to harmful pharmaceuticals and emphasizes the importance of protecting wildlife populations.

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Learned lessons from wildlife toxicology to improve the risk assessment of pharmaceuticals

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  1. Learned lessons from wildlife toxicology to improve the risk assessment of pharmaceuticals Rafael Mateo Instituto de Investigación en Recursos Cinegéticos, IREC CSIC-UCLM-JCCM Ronda de Toledo 12, 13005 Ciudad Real Effects of pharmaceuticals on wildlife – Bridging the gap between ecotoxicology and ecology

  2. Environmentalimpact of veterinarydrugs Preventive and therapeutic use of pharmaceuticals Intensive production Different scenarios according to the type of livestock production Extensive production

  3. Environmental impact of veterinary drugs Intensive poduction Extensive production Lixiviates, effluents… Residues in carrion Residues in feces Aquatic organisms Avian scavengers Coprophagous insects

  4. Ecosystem services • Carcass disposal service • Carcass collection: €20/animal • Industrial destruction: €66-96/ton • Spain: Vultures eat 10,000 tons/year • Reduction of emission of greenhouse gases derived from transport and incineration • Disease prevention Free! Margalida et al. (2012) Science

  5. Griffon vulture population in Spain 2008: 24,609 breeding pairs 76,288-79,177 birds 0.62 0.69 0.65 Fledged chicks/pair Del Moral, J. C. (Ed.). 2009. El buitreleonado en España. Poblaciónreproductora en 2008 y método de censo. SEO/BirdLife. Madrid.

  6. Scavengerseatlikehumans…but Vultures can eatonanimalsdeadduringmedication Security period 15 daysfor manu drugs

  7. Risks in avian scavengers associated with veterinary pharmaceuticals • The crisis of the Asian vultures: diclofenac and other nonsteroidal anti-imflammatory drugs (NSAIDs) • Exposure to external antiparasitics in bearded vulture • Chronic exposure to antibiotics in Spanish vultures

  8. 1. The crisis of the Asian vultures: diclofenac and other nonsteroidal anti-imflammatory drugs (NSAIDs)

  9. 1. The crisis of the Asian vultures: Forensic ecotoxicology Warning:Important mortalities of vultures in India and Pakistan in the 90s. ¿Pathogens? ¿Toxic substances? Decline of >90% of the vulture populations of genus Gyps in India y Pakistan by the end of the 90s – early 2000s Decline of 44% by year between 2000 and 2007 in Gyps bengalensisin India >60.000.000 of individuals in the 1980s

  10. The forensic investigation Ecological studies Adult mortality with consequent breeding failure Diagnostic studies Pathology Epidemiology and and some clues Gout Toxic or infectious disease? Acute necrosis of renal tubules 2002: Mortality in captivity Without inflammatory infiltrate New pharmaceutical with oral absorption and nephrotoxic Diclofenac: early 1990s in India, 1998 in Pakistan Oaks and Watson 2011

  11. Identification of the etiology Vultures dead with visceral gout: 0.05-0.64 µg/g of diclofenac in kidney LD50: 0.098 mg/kg bw Oaks et al. (2004) Nature; Swan et al. (2006) Biol. Lett.

  12. Ecologicalmodelling 0.13-0.76% of carrion withdiclofenac can produce a decline of 30% per year Mortality >10% of vulturesscavengingonan animal treatedwithdiclofenac 1-2 daysbeforedeath 0.098 mg/kg BW as LD50 x 8.95 kg BW = 0.585 mg/kg of carrion to reachthe LD50 1.5 kg/meal Green et al. (2006) J. Appl. Ecol.

  13. Safealternatives to diclofenac Taggart et al. (2016) Issues in Environmental Science and Technology

  14. Prevalence of diclofenac in carrion Ban of diclofenac 2006 6.5% (2007-2008) 10.1% (2004-2005) 2007-08 2006 2004-05 Taggart et al. (2007) Environment International Cuthbert et al. (2011) PLoSOne

  15. Change of populationtrendaftertheban Gypsbengalensis G. indicusand tenuirostris Prakash et al. (2012) PLoSOne

  16. And afterthat… Aproval of diclofenacforlivestock in Europeby 2013! WHAT???

  17. Fourspecies of vultures in Spain and Europe 1,300 pairs 2008: 24,609 pairs 95% 95% Cinereousvulture (Aegypiusmonachus) Griffonvulture (Gypsfulvus) 100 pairs 1,400 pairs 30% 50% Beardedvulture (Gypaetusbarbatus) Egyptianvulture (Neophronpercnopterus)

  18. Residues in carrion 4 carrionswithNSAIDs (3.2%) N=125 Estimatedmortalityfrom 70-125 carrion Green et al.: 715-6,389deadvultures/year AEMPS: 15-39deadvultures/year Decline of 0.9-7.7% per year Green et al. (2016) J. Appl. Ecol.; AEMPS (2014). Mateo et al. (2017) Informe inédito

  19. 2. Exposure to external antiparasitics in bearded vulture

  20. 2. Exposure to externalantiparasitics in beardedvultureGypaetusbarbatus • Global: Least concern • Europe-Spain: Priority-Endangered • 186 reproductive units (including couples and trios) • 118 of them are located in the Pyrenees between France and Spain. Historic Current Reintroduction Quebrantahuesos “Bone-breaker”

  21. Threats Casos • Especies Intoxicadas • Familias por especies • Familias totales • Tóxicos totales • llegal use of poison against predators • Lead poisoning • Electrocution and collisions2 • Human disturbance • Decline of livestock in mountains • Restrictions on carrion disposal after “mad cow” disease1 • Phylopatry of the species3: Saturation of the Pyrenees and formation of polyandrous trios4 1Margalida et al. 2012 El Voltors de Catalunya; 2Margalida et al. (2008) Bird Conservation International. 3López-López et al. (2013). Bird Study; 4 Bertran and Margalida (2004) Ethology, Ecology and Evolution

  22. Poisoningsof scavengersfromthePyrenees 2004-2013

  23. Chemical families involved in poisonings

  24. Case study of 24 beardedvultures 1TFD: estimated time from death to collection; 2Captive bird.

  25. Summary of findings • Visceral congestion in four birds • Relatively low activity of brain AChE (↓30%) in two of these four birds • Presence of diazinon in the gastric content of two of these four birds • Presence of diazinon in a pellet found in a failed nest. • Diazinon used as an external antiparasitic in sheep. • Lamb feet supplied in artificial feeders for bearded vultures

  26. Positives Negatives Lambfeetwithantiparasiticresidues Lamb: 71.4% with AP Pork: 0% 1 P y r e n e e s 2 6 Feeders 1.- Hecho (n=5) 2.- Sta Cilia (n=8) 3.- Luesia (n=6) 4.- Tauste (n=1) 5.- Monegrillo (n=4) Slaughterhouses 6.- Broto (n=13) 7.- Sabiñanigo (n=20) 8.- Huesca (n=40) 9.- Baells (n=10) 10.- Monzón (n=20) 7 3 Huesca 8 9 4 10 Ebro river 5 Zaragoza Diazinon (64.3%), cypermethrin (27.8%), pirimiphos-methyl (25.4%), chlorpyrifos (7.1%), fenthion (1.6%), permethrin (0.8%).

  27. Washinglambfeet to reduce antiparasiticlevels

  28. Riskassessment of theexposure of beardedvultures to antiparasitics Food intake (FI): 0.492 kg/day Body mass (BM): 5.79 kg1 Food intake rate (FIR): 0.08 kg FI/kg BM Estimated theoretical exposure (ETE): [AP] x FIR1,2 (Assuming 100% feet with AP in some areas. Antiparasitic treatments are common in sheep farms and we have been working only with lambs sampled at the slaughterhouse) 1Shore et al. (2005). Ecotoxicology; 3EFSA (2009). Risk Assessment for Birds and Mammals .

  29. Potentialeffects of antiparasiticsonbeardedvultures • A single AntiChE exposure of 5% of the LD50can reduce body temperature in homoiothermic animals1: • 2 ºC in moderate environment (25-30 ºC). • 3-6 ºC in cold environment (<6 ºC). Laying: December Hatching: February • Young birds are not fully homoiothermus until 1-3 weeks of age1. • Oral LD50 of diazinon2: • Adult goose 14.7 mg/kg • Gosling: 2.8 mg/kg 1Hill 1995. Handbook of Ecotoxicology (Hoffman et al., eds.), 2Toxnet-HSDB

  30. Riskassessment of theexposure of beardedvultures to antiparasitics 1TOXNET-HSDB: amallard, bbobwhite quail, cpheasant, d5% LD-LC50; 2Shore et al. (2005). Ecotoxicology; 3EFSA (2009). Risk Assessment for Birds and Mammals .

  31. 3. Chronicexposure to antibiotics in Spanishvultures

  32. 3. Exposure of griffon vulture to antibiotics Eurasian griffon vultures Gyps fulvus(n=500) were captured at 19 feeding sites in Aragón (NE Spain) between 2008 and 2011. Huesca Zaragoza Teruel Spain Aragón

  33. Vultures were measured, weighted and their age was determined. Blood samples were taken from brachial vein in heparinisedtubes and plasma was separated by centrifugation. • Measurement of antibiotics in plasma • Measurement of lead in whole blood (Mateo-Tomás et al. 2016 Proceedings of the Royal Society B)

  34. Antibioticanalysis Enrofloxacin 100 µl plasma 20 µl HCL 10% 280 µl metanol Ciprofloxacin Vortex-cooling-centrifuge LC-ESI/APCI-MS, C18 column, acetonitrile: 0.1% formic acid LOD: 1 ng/ml

  35. Occurrencebyprovinces Fluoroquinolones were detected in 15.2% of the plasma samples and this percentage differed significantly among provinces (χ22=19.8, p<0.001). Huesca N=175 Zaragoza Teruel N=155 N=162 Otherstudies: 13.1% in Catalunya1 24.4% in Navarra1 92% in Segovia-Ávila2 1Casas-Díaz et al. (2016) Sci. Total Environ.; 2Blanco et al. (2016) Chemosphere

  36. Occurrence by feeders Fluoroquinolonesoccurrence differed among feeding sites (χ218=176, p<0.001). Positive samples detected in half of the “vulture restaurants” Pyrenees Ebro Valley Iberian System Mountains The percentage of samples with enrofloxacin/ciprofloxacin was as high as 73.5%.

  37. Plasma levels Mean ± SE: 12.9 ± 1.7 ng/ml Comparison with therapeutic levels: Cmax oral dose: 2800 ng/ml Cmax IV dose: 4520 ng/ml

  38. Residues in carrion Pigcarcasses: n=33, 15.2% withantibiotics IREC (unpublished data) 6.1% 9.1% Liver Muscle Liver Muscle

  39. Pharmacokinetics Griffonvulture (n=1) Oral dose: 15 mg/kg Red-tailedhawks (n=8) Dose: 15 mg/kg >60 ng/ml at 144 h Half-life: 18.5 h Half-life: 8.9-19.4 h Harrestein et al. (2000) J. AvianMed. Sur. IREC (unpublished data)

  40. Effects of antibiotics Several papers by Lemus et al. from Spain described: Antibiotic in plasma of free-rangingvultures RETRACTED Changes in gut microbiota Bacterial antibiotic resistance Immundepression Chondraldamage in embryo Lemus et al. (2009) Environ. Pollut.

  41. Riskassessment Food Intake: 472-627 g/day Body mass: 8.9 kg bw Maximum concentration 2088 ng/g Maximum exposure: 0.11-0.15 mg/kg bw Therapeutic dose: 5-15 mg/kg bw Chondral damage: ≥50 mg/kg 5 days poultry 3-7 µg/ml of egg ? Lemus et al. (2009) Environ. Pollut. Hendosed 5 d with 10 mg/kg bw: Max. 32 ng/g of egg Gajda et al. (2012) FoodChem. Maślanka et al. (2009) Pol J. Vet. Sci.

  42. Benefit and Riskof vulture restaurants • Food safety: • Lower risk of intentional poisoning • Potential exposure to pharmaceuticals • Facilitates carcass management • Food security: • Minimized the carcass disposal regulation after “Mad Cow” disease. • Counteracts livestock intensification • Alters the foraging ecology of vultures Carcassmanagement and selection Beardedvulture Margalida et al. (2014) Ecol. Appl. Mateo et al. (in prep.)

  43. Messages - Needs of specificriskassessmentsaccording to the use and fate of pharmaceuticals in theenvironment. - Give more importance to theexperienceacquired in othergeographicareas. Thankyouforyourattention!

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