applicators and pesticide toxicity - uf/ifas oci · · 2011-05-16toxicology: the science of...
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Toxicology: The Science of Poison
“All substances are poisons;
there is none which is not a poison.
The right dose differentiates a poison from a
remedy.”
Paracelsus (1493-1541)
What Is A Pesticide?
• Any substance or mixture of substances intended for preventing, destroying, repelling or mitigating any pest.
• Also includes plant regulators, defoliants, desiccants and nitrogen stabilizers.– Conventional– Antimicrobial– Bio-pesticide/microbial pesticide
Federal Pesticide Law and Regulations
• Federal Insecticide, Fungicide and Rodenticide Act (FIFRA): regulates the sale and use of pesticides
• Federal Food, Drug and Cosmetic Act (FFDCA): controls pesticide residues in food
Food, Drug and Cosmetic Act Enforcement
• EPA establishes tolerances for pesticide residues on raw and processed food
• FDA enforces tolerances on most domestic and imported food
• USDA enforces tolerances on meat, milk, poultry and eggs
Food Quality Protection Act of 1996
• Very significant amendment to bothFIFRA and FFDCA
• Emphasis on safety for infants and children (NAS report, Pesticides in the Diet of Infants and Children, 1993)
– Enables EPA to add a 10X safety factor to tolerance setting decisions for protection of sensitive populations (infants and children)
• Emphasis on endocrine disruption (Theo Coburn, Our Stolen Future, 1996)
Efficacy:• High degree of biologicalefficacy
• Broad spectrum of efficacy• Good plant compatibility• Low risk for development ofresistance
User Friendly:• Low acute and chronic toxicity• Good formulation qualities• Easy to handle• Low application rate• Good storage stability
Environmental Profile:• Low toxicity to non-target organisms
• Sufficient degradation in soil• Low leaching• No significant residues in foodand animal feed
Economy:• Favourable cost / benefit ratio• Competitiveness• Broad spectrum of uses• Patentability
TheinnovativeProduct
Requirements for a Modern Agrochemical
New Product Development Process
Discovery Screening Candidate Pre-project Project CommercialEPA Review
Early Development
Toxicology
EcoTox
Env. Research
Risk Assessment
Formulations
Registrations
Commercial Development
Project Management
Product Manager / Marketing
Early hazard assessment
Exposure estimates
Source : Phillips McDougall study for ECPA and Crop Life America
3241
30
44
918
2018
2518
18
13
16
13
11
10
0
20
40
60
80
100
120
140
160
180
200
1995 2000
Registration
Environmental Chemistry
Toxicology
Field Trials
Chemistry
Tox / Env Chemistry
Biology
Chemistry
$m
ResearchResearch
Development
Development 79
94
67
72
Total $152 m.
Total $184 m.
Cost of New Product R&D In a Regulated Industry
The Challenge for Agrochemical Research
Today’s Costs Nearing $250 m.!
EPA Data RequirementsProduct Chemistry• physical and chemical characteristics, e.g. pH, solubility, flammability
General Toxicology• more next!
Wildlife and Aquatic Toxicity• avian -- aquatic and terrestrial species• aquatic species -- freshwater and estuarine -- invertebrates, fish, and
mollusks
Nontarget Plant Toxicity• seed germination/seedling emergence, vegetative vigor and aquatic
plant growth
Nontarget Insect Toxicity – honey bees
EPA Data RequirementsEnvironmental Fate• Hydrolysis, metabolism, photolysis, leaching, field/aquatic dissipation…
Residue Chemistry• Metabolism in plants and animals• Magnitude of Residue in crops, processed foods, meat/milk/eggs…
Spray Drift
Worker Exposure and Re-entry• Foliar and soil dissipation• Dermal and inhalation exposure• Mixer/Loader and Applicator• Re-entry personnel
Toxicology Testing RequirementsACUTE (Short Term Exposure) CHRONIC (Long Term/Lifetime
Exposure) Acute Oral Toxicity Chronic Toxicity (2 species) Acute Dermal Toxicity Oncogenicity (2 species) Acute Inhalation Toxicity 2-Generation Reproduction Dermal Irritation Eye Irritation Skin Sensitization Acute Neurotoxicity SUBCHRONIC (Intermediate OTHER STUDIES Term Exposure) 21-Day Dermal Genetic Toxicity (Ames, MN, CA) 90-Day Feeding Studies (2 species) Metabolism Developmental Toxicity (2 speces) Dermal Penetration 90-Day Neurotoxicity (rat) Immunotoxicology 90-Day Inhalation (conditional) Endocrine Disruptor
Screening&Testing Developmental Neurotoxicity (conditional)
Characterization of Toxicity
• Lethality• Organ System Dysfunction
– Cancer– Birth Defects– Immune system– Endocrine, Neurological, etc.
• ADME– Adsorption, Distribution, Metabolism, Elimination
Routes of Exposure
• Oral – Dietary– Drinking Water– Hand to Mouth
• Dermal– Occupational– Residential– Recreational
• Inhalation• Eyes
Critical Considerations
• Critical Sensitive Populations– infants/children
• Activities– Golf– Swimming
• Extrapolation of Data– Uncertainty
Humans ≠ RatsChildren ≠ Adults
Toxicology Testing Requirements
• Acute Toxicity Testing– Acute Oral LD50
– Acute Dermal LD50
– Acute Inhalation LD50
– Eye Irritation– Skin Irritation– Skin Sensitization
•Required for all active ingredients and end use (formulated) products
• Acute toxicity tests measure mortality following a single exposure
• The LD50 is the dose of toxin that produces 50% mortality in a test population
• LD50 is usually expressed in milligrams of toxin per kilogram of test animal body weight (mg/kg)
HIGH TOXICITY = LOW LD50
Acute Toxicity: LD50
Dose Response Function
Dose (mg/kg body weight)Increasing dose
0
25
50
75
100
0 10 20 30 40 50 60 70 80 90 100
% R
esp
on
se
No Effect:NOAEL
All EffectedLD100
Half Effected:LD50
Agent Oral LD50 (mg/kg)
Ethyl alcohol 10,000Salt (sodium chloride) 3,000Iron (Ferrous sulfate) 1,500Morphine 900Aspirin 250DDT 250Cyanide 10Nicotine 1Tetrodotoxin (from fish) 0.01Botulinum Toxin 0.00001
} Most pesticides fall in this region
Least Toxic
Most Toxic
Relative Toxicity of Familiar Active Ingredients (not formulated)
Pesticide AI
Oral LD50(mg/kg)
Dermal LD50(mg/kg)
Endothall 50 >2000
DiquatDibromide
700 300
Hydrogen Peroxide(35%)
1000 >2000
Glyphosate >5000 >2000
Flumioxazin >5000 >2000
Acute Toxicity Results Dictate Label Language
• Signal Words• Precautionary Statements• First Aid Statements • Personal Protective Equipment• Application Methods• Re-Entry Intervals
Toxicity Category Designations
Study Category I Category II Category III
Category IV
Acute Oral < 50 mg/kg > 50 thru 500 mg/kg
> 500 thru 5000 mg/kg > 5000 mg/kg
Acute Dermal < 200 mg/kg > 200 thru 2000
mg/kg > 2000 thru 5000 mg/kg > 5000 mg/kg
Acute Inhalation1 <0.05 mg/liter > 0.05 thru 0.5
mg/liter > 0.5 thru 2
mg/liter > 2 mg/liter
Eye Irritation
Corrosive or corneal damage
or irritation persisting for more than 21
days
Corneal involvement or
irritation clearing in 8-21
days
Corneal involvement or
irritation clearing in 7 days or less
Minimal effects
clearing in less than 24
hours
Skin
Irritation Corrosive Severe irritation Moderate
irritation Mild or slight
irritation 1 4 hr exposure
Signal Word Designation
• Correct Signal Word: The signal word is determined by the most severe toxicity category assigned to the five acute toxicity studies or by the presence of special inerts (methanol in concentrations of 4% or more).
• Toxicity Category I - DANGERToxicity Category II - WARNINGToxicity Categories III & IV - CAUTION
Acute Toxicity Category Determination For Sample Products
Type of Study Product A Product B Product C Product D Product E
(contains MeOH)
Acute Oral III IV I III II Acute Dermal IV III III IV II Acute Inhalation
III IV III III II
Primary Eye III II I I II Primary Skin IV IV II IV II Special Inert No No No No Yes Correct Signal Word
CAUTION
WARNING
DANGER*
DANGER
DANGER*
*Product C and Product E must also show
Skull & Crossbones symbol near the word “POISON”
Acute Toxicity Determines PPEToxicity Category by Route of Exposure of End Use Product
Route of Exposure
IDanger
IIWarning
IIICaution
IVCaution
Dermal Toxicity or Skin Irritation Potential
Coveralls worn over long sleeved shirt and long pantsSocksChemical-Resistant FootwearGloves
Coveralls worn over long sleeved shirt and long pantsSocksChemical-Resistant FootwearGloves
Long sleeved shirt and long pants
Socks
Shoes Gloves
Long sleeved shirt and long pants
Socks
Shoes
No minimum
Inhalation Toxicity
Respiratory protection device
Respiratory protection device
No minimum No minimum
Eye Irritation Potential
Protective eyewear
Protective eyewear
No minimum No minimum
Toxicology Studies of Longer Duration
• General (Systemic) Toxicity• Neurotoxicity• Reproductive/Developmental Toxicity• Immunotoxicity• Carcinogenicity• Mutagenicity
•Dietary Dosing for 2 Generations
•Multiple Generations
•Comprehensive Examination Items
•Time Consuming (~1.5 years)
•Expensive
•Animal Intensive
http://www.ppp.purdue.edu/Pubs/PPP-40.pdf
REPRODUCTION STUDY
Dose Response Function
Dose (ppm in the diet)Increasing dose
0
25
50
75
100
0 10 20 30 40 50 60 70 80 90 100
% R
esp
on
se
No Effect Level:NOAEL
Maximum ToleratedDose: MTD
Low Effect Level: LOAEL
Human Health Risk Characterization
Risk = f(Exposure, Toxicity)
http://www.ppp.purdue.edu/Pubs/PPP-48.pdf
How Do We Assess Risk?Four broad categories:
– Food– Aggregate
• Food• Water• Residential
– Cumulative– Occupational
…each of which can be evaluated over multiple time frames:
• Acute• Short or Intermediate Term• Chronic/Lifetime
Risk Characterization (general)
Hazard assessment– Acute toxicity classification (label signal word)– Toxicity endpoints
• Short-term, intermediate, chronic• Route – dermal, oral, inhalation
Exposure assessment– Residue of concern (food, foliage, water, air etc.)– Populations, subpopulations exposed– Route, magnitude, duration & frequency of exposure
• many assumptions
Determination of “Acceptable” level– Safety/uncertainty factors (100x, “special” factors)– MOE (margin of exposure) compared to LOC (level of
concern)– <1 x 10-6 excess cancer for carcinogens
Margin of Exposure (MOE) Determination
0
100
10
1
10-F
old
R
edu
ctio
ns
Bel
ow
NO
AE
L No Effect:NOAEL
1000 Theoretical Human Exposure
MOE 100
MOE 1000
PASS!
Margin of Exposure (MOE) Determination
0
100
10
1
10-F
old
R
edu
ctio
ns
Bel
ow
NO
AE
L No Effect:NOAEL
1000
TheoreticalHuman Exposure
MOE 100
MOE 1000
FAIL!
Mitigation StrategiesWorker Risk
• Label Instructions– More PPE – Engineering controls
• For example, closed system or water soluble packaging
– Lowered use rates or limited use pattern • Limit number of acres or lb applied per day
– Increased re-entry intervals
Mitigation StrategiesDietary Risk
• For Consumers (dietary concerns)– Limit the number of crops treated
• Reduces residues consumed
– Reduce residues in food/water• Lower quantity of material applied• Reduce number of applications• Increase harvest interval
Aquatic Herbicide Label Mitigation
• Examples:– Do not swim/drink from treated water for 5
days• Toxicology
– Do not eat fish from treated water for 10 days• Toxicology or No Established Tolerances
– Do not use water for irrigation of food crops• Phytotoxicity or No Established Tolerances
Summary
• Risk = f(Toxicity & Exposure)• Safety is a Primary Concern• FOLLOW THE LABEL!• Use PPE
– Lower Exposure = Lower Risk
• Don’t get complacent! – Familiarity does not Reduce Risk.