Transcript Document 7422717

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
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
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Oral
Dermal
Solids
Liquids
Solids
Liquids
Ia Extremely
hazardous
5 or less
20 or less
10 or less
40 or less
Ib Highly
hazardous
5 - 50
20 - 200
10 - 100
40 - 400
II Moderately
hazardous
50 - 500
200 - 2000
100 - 1000
400 - 4000
III Slightly
hazardous
Over 500
Over 2000
Over 1000
Over 4000
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
Dose-Response
Evaluation
Human Exposure
Assessment
Assessment of intensity,
frequency, duration and
routes of human exposure
for the purpose of quantification of internal dose
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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
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Crop protection compounds: the long road to market
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Support
100’000
1-2
compounds
Evaluate
Profile
5000
Discover
compounds
Time
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Development of a New Crop Protection Product
Research
optimization
Years
Chemistry
 Synthesis
 Formulation of
product
Biology
 Research
 Trials
 Field development
Toxicology
Environmental safety
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1
2
Early
development
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4
5
Late
development
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8
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Toxicology Information in the Development Process
Early
● Physico-chemical properties
● Acute oral toxicity, mutagenicity
● Dermal absorption, inhalation toxicity
● Subacute & subchronic toxicity
● Reproductive & developmental toxicity
● Chronic toxicity, carcinogenicity
Late
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Evolution of Crop Protection Product Formulations
Soluble and
stable in water
Soluble Liquid
WP in WSB
Solid or
unstable in
water
Wettable Powder
SC (suitable only if hygroscopically stable)
Emulsifiable
Concentrate
Soluble in
organic solvent
1960
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WG
1970
Liquids in WSB
Oil in water emulsion
Improved EC
Micro-emulsion
Capsule Suspension
1980
1990
2000
Example: Anthranilic Diamides
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
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18
+1.4
Nicotinic receptor
1.5
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+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)
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Example: Pyrethroid-Treated Bednets
Major mosquito-borne diseases
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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
Mosquito Control: Personal Protection and Vector
Control
Personal protection
Vector control
● Clothing
● Indoor residual spraying
● Screens
● Insecticide treated nets
● Repellents
● Space spraying
● Nets
● Larviciding
● Coils
● Aerosols
● Emitters
● ..............
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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
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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 retreating 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 insecticidetreated 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
Exposure assessment
• Data sources
• Treating bednets with insecticides
• Range of toxicity tests
• Washing of treated nets
• Evaluation of toxicity information
• 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
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