Sept 2008 - My elected 3rd Year Prestation; reviews paraquat toxicity in dogs

1. ParaquatToxicity Katie Krimetz Western University of Health Sciences CVM DVM 2010 September 8, 2008

2. Headlines July 2003 – Laurelhurst Park, Portland, OR(11) August 2004 – Willamette Park, Portland, OR(11) Images: http://www.aspca.org/site/DocServer/vetm0904_755-762.pdf?docID=5581&AddInterest=1101

3. Why can’t we fix this?How do I recognize/Differentiate clinical signs?

4. 1,1’-dimethyl-4,4’-bipyridylium Uses Non-selective contact herbicide Allowed no-till farming Sources Restricted Use Pesticide Commercial Applicator License(13) Today products have <0.44% paraquat(4) Older products with 50% paraquat can be found(4) Protective Measures Emetics, Bitters, Odor, Color Image: http://agri.astate.edu/weeds/select_images.html

5. Toxicity Exposure(4,5) Ingestion Absorption at brush border Primarily absorbed in the jejunum Skin – blisters, burns, nail damage Eyes – stinging sensation, inflammation, corneal ulcer Inhalation – nausea, headache, epistaxis Toxic Levels(4) Oral LD50 – dogs: unknown cats: 30-50 mg/kg I.V. LD50 – dogs: 7.48 mg/kg cats: ?? Image: http://www.broyhill.com/images/interior/safety.gif

6. Mechanism of Toxicity Paraquat is taken up actively and selectively Polyamine transporter(4,15) Required for maintenance of high metabolic activity levels Cells depend on them for growth, renewal and metabolism Type I and II Alveolar cells most commonly affected by toxicity(4) Damage mostly confined to areas with high accumulations of paraquat

7. Mechanism of Toxicity Absorbed portion accumulates in tissues Cyclic oxidation-reduction rxns free radicals Oxygen and hydroxyl Free radicals overwhelm cellular defense Cause damage to tissues, esp membrane lipids Image: http://www.syngenta.com/pqmedguide/downloads/paraquat_booklet.pdf

8. Clinical Signs & Pathophysiology GI upset and vomiting present at all levels of toxicity Remember: emetics added to formulation “Early” Signs: Compromised renal function Mild hypertension Pulmonary alveolar damage Edema Hemorrhage Inevitable: Death by respiratory failure Image: 2007 MS ClipArt

9. Clinical Signs & Pathophysiology “Moderate” dose (>20-30mg/kg but <40-50mg/kg)(5) Immediately: vomiting Hours: diarrhea, abd pain, throat/mouth ulcerations 1-4 d: renal failure, hepatic fxn impaired, tachycardia 1-2 wk: cough, hemoptysis, pleural effusion, pulmonary fibrosis “High” dose (>40-50 mg/kg) (Systemic poisoning)(5) Immediately: vomiting Hours-days: Acute pulmonary edema, renal failure, hepatocellular damage, intra/extrahepatic bile duct and gall bladder necrosis, adrenal failure

10. Diagnosis Histologic examination of tissues (lungs!)(4,5,6) Spectrophotometry, gas/liquid chromatography(4,5) HPLC Fluorescense(5) Radioimmunoassay(4) Dithionite reaction/ dithionite spot test(4,5) Solid Phase Extraction(5) Elevated Serum Lipase(4) Radiographs?(4) Image: http://picasaweb.google.com/aluapa/PathGallery/photo#5102345173274680146

11. [Realistic] Diagnosis Histologic examination of tissues Dithionite reaction/dithionite spot test Elevated Serum Lipase Radiographs CAUTION – Misdiagnoses/Complications Ingestion of unknown food Vomiting may be only clinical sign Serum lipase – ddx: pancreatitis Radiographs – usually appreciate abnormalities in late stage of toxicity Images: http://www.achilles-online.com

12. Treatment EARLY! Within hours in order to be effective Adsorbent(4) Fullers Earth, Activated Charcoal (rodent - add Mg citrate!)(4) ER? Kitty litter Caution with esophageal tubes Remove it(4) Emesis – but then control Gastric lavage Fluids/Forced Diuresis(4,5) Analgesics – opiates best(5) NO OXYGEN!(4,5) Nitrous Oxide improves gas exchange

13. Treatment in Research Taurine @CRI, followed by hemodialysis(8) Antioxidants(4,5) N-acetyl cysteine(5) Desferriozamine(5) Propanolol(5) Collagen synthesis inhibitor(4) Radiotherapy(5) Lung Transplant(5)

14. Prognosis Prognosis – Grave  Depends on circumstance of poisoning: Good circumstances: inhalation, skin exposure, dilute formula Bad circumstances: ingestion Image: http://www.syngenta.com/pqmedguide/downloads/paraquat_booklet.pdf

16. Recent Last meal/size

17. Accidental Ingestion

18. Lack of lesions

19. Lack of:Renal, hepatic, pancreatic, or respiratory failure Image: http://farm1.static.flickr.com/66/187783004_db3362fd81.jpg?v=0

20. But there IS hope!! Image: www.syngentacropprotection-us.com Different Formulation Alginate Additive  GramoxoneInteon(7,14) First used in human medicine for acid reflux Gelling action extends paraquat retention in stomach 0.79% absorbed/hour Other Possibilities… A higher concentration (10g/L) would be better(7) Require mixing prior to use?(2,17) Image: 2007 MS ClipArt

21. Resources AG PICoboSCP. Paraquat: Get the Facts at the Paraquat Information Center. 2008; http://www.paraquat.com/, 2008. Betman ND. New Formulation of Paraquat: A Step in the Wrong Direction? Public Library of Science. 2008. Broyhill I. Personal Safety Procedures. 2006; http://www.broyhill.com/images/interior/safety.gif. Cope RB, BCs, BVSc, PhD. Helping animals exposed to the herbicide paraquat. Veterinary Medicine. 2004;September 2004:755-762. http://www.aspca.org/site/DocServer/vetm0904_755-762.pdf?docID=5581&AddInterest=1101. CTL S. Paraquat Poisoning a practical guide to diagnosis, first aid and hospital treatment2008. Hampson EC, Pond SM. Ultrastructure of canine lung during the proliferative phase of paraquat toxicity. Br J Exp Pathol. Feb 1988;69(1):57-68. Heylings JR, Farnworth MJ, Swain CM, Clapp MJ, Elliott BM. Identification of an alginate-based formulation of paraquat to reduce the exposure of the herbicide following oral ingestion. Toxicology. Nov 20 2007;241(1-2):1-10. Izumi K, Nagata R, Motoya T, et al. Preventive effect of taurine against acute paraquat intoxication in beagles. Jpn J Pharmacol. Jun 1989;50(2):229-233. Paula. Path Gallery. In: Paraquat Toxicity l, dog, 20x, ed. Picasa Web Albums.Vol 2007. Prevention CfDCa. Facts about Paraquat. 2006; http://www.bt.cdc.gov/agent/paraquat/basics/facts.asp, 2008. Robben J. Test on dead dog points to paraquat. Portland Tribune. 7/25/2003, 2003. Spradley P. Pesticide Commercial Applicator License for Applying Restricted Use Pesticides. 2006; http://www.aragriculture.org/pesticides/training/commlicense.htm. Syngenta. GramoxoneInteon Label2008. Wallace HM, Fraser AV, and Hughes A. A Perspective of Polyamine Metabolism. Biochemical Journal. 2003(376):1-14. Wiesbrook M. Recent Happenings with Paraquat. May 2006 Newsletter. 2006. http://web.extension.uiuc.edu/ipr/i4147_829.html#2. Wilks MS, al e. Improvement in Survival After Paraquat Ingestion Following Introduction of a New Formulation in Sri Lanka. PLoS Medicine. 2008;5(2).

22. Questions&Discussion