1. South Asian Clinical Toxicology Research Collaboration Relative toxicity of pesticides in the developing world A Dawson, M Fahim, I Gawarammana, N Buckley, M Eddleston, G Manuweera South Asian Clinical Toxicology Research Collaboration, Faculty of Medicine, University of Peradeniya 1

2. South Asian Clinical Toxicology Research Collaboration Pesticide Poisoning Problem  Asia 300,000 deaths /year –Underestimate  Sri Lanka –17000 admissions –35% ICU –10% Die –(20% if symptomatic)

3. South Asian Clinical Toxicology Research Collaboration SACTRC: Overview  Observational Cohort of 19,000 patients –Nested clinical trials  Community studies  15 postgraduate students  International Partners: –UK, USA, Denmark, Germany, Portugal Chilaw.

4. South Asian Clinical Toxicology Research Collaboration Anuradhapura District 2006 Peripheral Hospitals 1942 admissions Peripheral Hospitals 1942 admissions 1107 Anuradhapura General Hospital 1908 admissions Anuradhapura General Hospital 1908 admissions

5. South Asian Clinical Toxicology Research Collaboration Background  Clinical impact of pesticide poisoning is a function of both: –the intrinsic toxicity of the pesticide –and availabilty of treatment resources  Effective pesticide regulation –can be threatened by illegal importation –considers agricultural and economic outcomes.  Effective regulation in Sri Lanka with targeted pesticide restrictions –reduced pesticide deaths –maintained agricultural production. l Do targeted bans of insecticides to prevent deaths from self- poisoning result in reduced agricultural output? (Manuweera G ) 5

6. South Asian Clinical Toxicology Research Collaboration Pesticide Restriction Gunnell D, Fernando R, Heganawathna N et al Journal of Epidemiology 2007;1–8

7. South Asian Clinical Toxicology Research Collaboration Aim  To provide information about the relative toxicity of pesticides that: –could inform regulatory policy –and may assist in the development of a minimum pesticide list l Eddleston,M. et al. Pesticide poisoning in the developing world--a minimum pesticides list. Lancet 360[9340], 1163-1167. 2002. 7

8. South Asian Clinical Toxicology Research Collaboration Methods  Data was prospectively collected from a cohort of consecutive patients from April 2002 to April 2007.  Identification of pesticides was based on –history or positive identification of the container –and plasma assays in some cases.  Case fatality calculated. 8

9. South Asian Clinical Toxicology Research Collaboration Results  6449 patients who ingested a pesticide and were analysed.  Plasma assayed for pesticides –60% of all patients –90% of organophosphate admissions –Confirmed the history in over 90% patients..  Overall mortality 11.2% 9

10. The case fatality for commonly ingested pesticides 10

11. South Asian Clinical Toxicology Research Collaboration Dying is too easy for death to be a “Hard Outcome” in the developing world. South Asian Clinical Toxicology Research Collaboration

12. Primary Rural Hospitals Lalith Senarathna: Master’s Thesis 2007 www.sactrc.org  Poor antidote stocking  Poor antidote utilisation  A gap between actual practice and perceived practice “We are like frogs in a well”  Clustered RCT Antidote Stocking & Academic Detailing

13. South Asian Clinical Toxicology Research Collaboration 3 compounds: 60% of mortality South Asian Clinical Toxicology Research Collaboration

14. Results: Pesticide Withdrawal  Assuming paraquat and dimethoate were removed from the market –and that people substituted the next most toxic compound in that class  Paraquat removal could lead to a 30% reduction in deaths  Dimethoate removal could lead to a 12% reduction.  Extrapolation of this data to the national figures of 3000 deaths per year from pesticides suggests a reduction in deaths of about 1200 per year. 14

15. South Asian Clinical Toxicology Research Collaboration Pesticide Restriction in Sri Lanka Gunnell D, Fernando R, Heganawathna N et al Journal of Epidemiology 2007;1–8 Bans 2008 Paraquat Dimethoate Fenthion

16. South Asian Clinical Toxicology Research Collaboration Results (2)  Pesticide Withdrawal November 2007 –Paraquat 6.5% Concentration l Model a 10 % reduction –Dimethoate & Fenthion to be withdrawn over 3 years from 2008 –Paraquat withdrawn from 2009  Modeled Substitutions –Worst CFR within the class –Median CFR within the class 16

17. South Asian Clinical Toxicology Research Collaboration Projected CFR 95% CI 17

18. South Asian Clinical Toxicology Research Collaboration Discussion  Benefit of dimethoate restriction may be an underestimation –clinical research units has been shown to reduce mortality  Mortality from paraquat is likely to be a robust estimate as there is no treatment which clearly alters outcome. 18

19. South Asian Clinical Toxicology Research Collaboration When can we decide ? South Asian Clinical Toxicology Research Collaboration

20. Discussion  within a pesticide class there is a significant range of mortality.  The usefulness of point estimates of zero fatalities which have wide confidence intervals could be enhanced by –including other more sensitive clinical markers of toxicity –based on animal toxicity data –and known mechanisms of action. 20

21. South Asian Clinical Toxicology Research Collaboration Discussion (2)  This data can inform a restricted pesticide policy that operates within the constraints of local health systems.  A cost-minimization approach could be explored, using models similar to those developed for drug regulation and subsidy. 21

22. South Asian Clinical Toxicology Research Collaboration Conclusion  There is sufficient information to iteratively develop a minimum pesticide list.  Such implementation will require continuous sentinel monitoring of usage and clinical presentations. 22