On the horizon new pesticides, new applications, predicting future risks from todays experiments

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On the horizon - new pesticides, new
applications, predicting future risks from
todays 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
for the rat (mg/kg body weight)
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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
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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-Response Evaluation
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 Exposure Assessment
Dose-Response Evaluation
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 Exposure Assessment
Dose-Response Evaluation
Risk Characterisation
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
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Support
100000 compounds
1 - 2
Evaluate
Profile
5000 compounds
Discover
Time
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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
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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

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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
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Example Anthranilic Diamides
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Modes of action of the top-selling
insecticides/acaricides and their world market
share (Nauen, 2002)
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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 gt 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)
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Example Pyrethroid-Treated Bednets
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Major mosquito-borne diseases
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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 gt20 washes
DIY Long-lasting insecticide net treatmentgt20
washes
Conventional DIY insecticide net treatments 3-5
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