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Wilks MF 1 , Brown RA 1 , Bentley KS 2 , Cordova D 2

On the horizon - new pesticides, new applications, predicting future risks from today’s experiments. Wilks MF 1 , Brown RA 1 , Bentley KS 2 , Cordova D 2 1. Syngenta Crop Protection AG, Basel, Switzerland. 2. DuPont Crop Protection, Wilmington DE, USA. Importance of Pesticide Regulation.

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Wilks MF 1 , Brown RA 1 , Bentley KS 2 , Cordova D 2

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  1. On the horizon - new pesticides, new applications, predicting future risks from today’s experiments Wilks MF1, Brown RA1, Bentley KS2, Cordova D2 1. Syngenta Crop Protection AG, Basel, Switzerland. 2. DuPont Crop Protection, Wilmington DE, USA

  2. Importance of Pesticide Regulation PESTICIDEREGULATION is designed to protect the health of those who apply pesticides, those who are exposed as bystanders, and those who are exposed to residues in food and water.

  3. Stages of Risk Assessment Toxicological Hazard Assessment Identification of intrinsic toxicological properties and assessment of their relevance to humans

  4. World Health Organization (WHO)Classification of Pesticides by Hazard LD for the rat (mg/kg body weight) 50 Class Oral Dermal Solids Liquids Solids Liquids Ia Extremely 5 or less 20 or less 10 or less 40 or less hazardous Ib Highly 5 - 50 20 - 200 10 - 100 40 - 400 hazardous II Moderately 50 - 500 200 - 2000 100 - 1000 400 - 4000 hazardous III Slightly Over 500 Over 2000 Over 1000 Over 4000 hazardous

  5. Key Toxicological Studies Used in Risk Assessment for Pesticide Operators • 90 day, sub-acute oral dosing study • 21/28 day dermal dosing study • Reproductive toxicity studies • 1 year oral dosing study (depending on use pattern)

  6. Stages of Risk Assessment Toxicological Hazard Assessment Dose-Response Evaluation Determination of quantitative relationships between internal dose and effects for the endpoints of concern

  7. The Dose Response Curve

  8. Stages of Risk Assessment Toxicological Hazard Assessment Dose-Response Evaluation Human Exposure Assessment Assessment of intensity, frequency, duration and routes of human exposure for the purpose of quanti-fication of internal dose

  9. Stages of Risk Assessment Toxicological Hazard Assessment Dose-Response Evaluation Human Exposure Assessment Risk Characterisation Integration of available information to produce conclusions on the probability of adverse effects

  10. Crop protection compounds: the long road to market 30 Support 100’000 compounds 1 - 2 Evaluate Profile 5000 compounds Discover Time

  11. Development of a New Crop Protection Product Researchoptimization Earlydevelopment Late development 1 2 3 4 5 6 7 8 9 10 Years • Chemistry • Synthesis • Formulation of product • Biology • Research • Trials • Field development Toxicology Environmental safety

  12. Toxicology Information in the Development Process Early Late • Physico-chemical properties • Acute oral toxicity, mutagenicity • Dermal absorption, inhalation toxicity • Subacute & subchronic toxicity • Reproductive & developmental toxicity • Chronic toxicity, carcinogenicity

  13. Evolution of Crop Protection Product Formulations Soluble Liquid Soluble and stable in water WP in WSB Wettable Powder Solid or unstable in water WG SC (suitable only if hygroscopically stable) Liquids in WSB Emulsifiable Concentrate Oil in water emulsion Soluble in organic solvent Improved EC Micro-emulsion Capsule Suspension 1960 1970 1980 1990 2000

  14. Example: Anthranilic Diamides

  15. Modes of action of the top-selling insecticides/acaricides and their world market share (Nauen, 2002)

  16. Ryanodine receptor channels (RyRs) • Class of intracellular calcium channels in excitable animal tissues (heart, muscle, neurons) • Major cellular mediator of calcium-induced calcium release (CICR) in animal cells • Multiple mammalian isoforms: RyR1 (skeletal muscle), RyR2 (myocardium), RyR3 (heterogenous, brain) • Antagonists include ryanodine and dantrolene; agonists are suramin and xanthines • Insects express a single form of RyR, sharing 47% homology with mammalian RyRs (Takeshima et al., 1994)

  17. DuPont Rynaxypyr (chlorantraniliprole) • Targeted against a broad range of biting insects in fruits, vegetables, grapes and field crops • Low acute mammalian toxicity (Rat LD50 > 5,000 mg/kg) • Little to no toxicity in 90-day studies (up to 1,500 mg/kg/d) • No evidence for mutagenicity, carcinogenicity, neurotoxicity, immunotoxicity, developmental and reproductive toxicity

  18. Differential RyR selectivity of DuPont Rynaxypyr™ in insect and mammalian cell lines C2C12 = mouse myoblast cell line expressing RyR1 PC12 = rat cell line expressing RyR2 IMR32 = human cell line expressing functional RyRs (isoforms unknown)

  19. Example: Pyrethroid-Treated Bednets

  20. Major mosquito-borne diseases

  21. Personal protection Clothing Screens Repellents Nets Coils Aerosols Emitters .............. Vector control Indoor residual spraying Insecticide treated nets Space spraying Larviciding Mosquito Control: Personal Protection and Vector Control

  22. Insecticide Treated Nets Ready-to-use long-lasting insecticide-treated net >20 washes DIY Long-lasting insecticide net treatment>20 washes Conventional DIY insecticide net treatments 3-5 washes

  23. Long lasting net treatment • Icon CS formulation + polymer binding agent • More durable coating for treating mosquito nets • Potential for treating new, or re-treating existing nets • Protection from mosquitoes for at least 20 washes • Easy to use, water-based formulation • WHOPES interim recommendation in 2007

  24. A generic risk assessment model for insecticide treatment of mosquito nets and their subsequent use (WHO 2004) • Generic model for risk assessment of exposure to insecticides during production and use of insecticide-treated bednets • Covers the assessment of risks to those treating bednets in a domestic setting (operators) and to those sleeping under insecticide-treated bednets (users) • Does not include the special situation of commercial production of nets in a factory environment

  25. The Risk Assessment Model • Hazard identification & evaluation • Data sources • Range of toxicity tests • Evaluation of toxicity information • Exposure assessment • Treating bednets with insecticides • Washing of treated nets • Sleeping under treated nets • Accidental swallowing of concentrated formulations • Risk characterisation • Acceptable exposure level (AEL) • Acute reference dose (ARfD) • Margin of safety (MOS)

  26. Conclusions • Risk assessment is an important activity in the development of new pesticides and new applications of existing products and is integral to every stage of the process • The challenge is to design products which provide maximum efficacy in their chosen applications while minimising human health and environmental risks

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