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

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Importance of Pesticide Regulation

PESTICIDE REGULATION 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.

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Stages of Risk Assessment

Toxicological Hazard Assessment

Identification of intrinsic toxicological properties and assessment of their relevance to humans

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World Health Organization (WHO) Classification of Pesticides by Hazard

LD 50 for the rat (mg/kg body weight)

Class Oral Dermal

Solids Liquids Solids Liquids

Ia Extremelyhazardous

5 or less 20 or less 10 or less 40 or less

Ib Highlyhazardous 5 - 50 20 - 200 10 - 100 40 - 400

hazardous 50 - 500 200 - 2000 100 - 1000 400 - 4000

III Slightlyhazardous Over 500 Over 2000 Over 1000 Over 4000

II Moderately

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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)

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Stages of Risk Assessment

Toxicological Hazard Assessment

Dose-ResponseEvaluation

Determination of quantitative relationships between internal dose and effects for the endpoints of concern

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The Dose Response Curve

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Stages of Risk Assessment

Toxicological Hazard Assessment

Human ExposureAssessment

Dose-ResponseEvaluation

Assessment of intensity, frequency, duration and routes of human exposure for the purpose of quanti-fication of internal dose

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Stages of Risk Assessment

Toxicological Hazard Assessment

Human ExposureAssessment

Risk Characterisation

Dose-ResponseEvaluation

Integration of available information to produce conclusions on the probability of adverse effects

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Crop protection compounds: the long road to market

Profile

Support

Evaluate

Discover

100’000

compounds

5000

compounds

1 - 2

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Time

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1 2 3 4 5 6 7 8 9 10

Development of a New Crop Protection Product

Researchoptimization

Earlydevelopment

Late development

Chemistry Synthesis Formulation of

product

Years

Biology Research Trials Field development

Toxicology

Environmental safety

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Early

Late

● Physico-chemical properties

● Acute oral toxicity, mutagenicity

● Dermal absorption, inhalation toxicity

● Subacute & subchronic toxicity

● Reproductive & developmental toxicity

● Chronic toxicity, carcinogenicity

Toxicology Information in the Development Process

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Evolution of Crop Protection Product Formulations

Soluble and stable in water

Solid or unstable in water

Soluble in organic solvent

1960 1970 1980 1990 2000

Soluble Liquid

Wettable PowderWettable Powder

WP in WSB

WG

SCSC (suitable only if hygroscopically stable)

EmulsifiableEmulsifiableConcentrateConcentrate

Liquids in WSBLiquids in WSB

Improved ECImproved ECOil in water emulsionOil in water emulsion

Micro-emulsionMicro-emulsionCapsule SuspensionCapsule Suspension

Example: Anthranilic Diamides

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

Mode of action 1987 (%) 1999 (%) Change (%)

Acetylcholinesterase 71 51 -20

Voltage-gated Na channel 17 18 +1.4

Nicotinic receptor 1.5 12 +10

GABA-gated Cl channel 5.0 8.3 +3.3

Chitin biosynthesis 2.1 3.0 +0.9

Other 0.5 2.9 +2.4

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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)

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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

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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)

Example: Pyrethroid-Treated Bednets

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Major mosquito-borne diseases

Disease Infected Mortality

Malaria > 500 million > 1 million

Yellow fever 200,000 30,000

Dengue 50 million 24,000

Japanese encephalitis

50,000 10,000

Lymphatic filariasis 120 million

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Mosquito Control: Personal Protection and Vector Control

Personal protection

● Clothing

● Screens

● Repellents

● Nets

● Coils

● Aerosols

● Emitters

● ..............

Vector control

● Indoor residual spraying

● Insecticide treated nets

● Space spraying

● Larviciding

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Insecticide Treated Nets

Ready-to-use long-lasting insecticide-treated net

>20 washes

Conventional DIY insecticide net treatments

3-5 washes

DIY Long-lasting insecticide net treatment>20 washes

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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

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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

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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)

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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