Applicators and Pesticide Toxicity Moire Creek Manager, Toxicology Valent USA Corporation
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
Pesticide Examples
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 both FIFRA 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)
FIFRA The consequences are real **** The label is the LAW!
Requirements for a Modern Agrochemical Efficacy: High degree of biological efficacy Broad spectrum of efficacy Good plant compatibility Low risk for development of resistance User Friendly: Low acute and chronic toxicity Good formulation qualities Easy to handle Low application rate Good storage stability The innovative Product Environmental Profile: Low toxicity to non-target organisms Sufficient degradation in soil Low leaching No significant residues in food and animal feed Economy: Favourable cost / benefit ratio Competitiveness Broad spectrum of uses Patentability
New Product Development Process Discovery Screening Candidate Pre-project Project EPA Review Commercial Early Development Project Management Product Manager / Marketing Early hazard assessment Commercial Development Registrations Formulations Toxicology EcoTox Env. Research Exposure estimates Risk Assessment
The Challenge for Agrochemical Research Cost of New Product R&D In a Regulated Industry $m 200 180 160 140 120 100 80 60 40 20 0 Total $152 m. 13 13 18 18 18 10 30 32 11 16 18 Development 79 25 67 Research 72 Total $184 m. 20 9 44 41 1995 2000 Development Research 94 Today s Costs Nearing $250 m.! Registration Environmental Chemistry Toxicology Field Trials Chemistry Tox / Env Chemistry Biology Chemistry Source : Phillips McDougall study for ECPA and Crop Life America
EPA Data Requirements Product 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 Requirements Environmental 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 Requirements ACUTE (Short Term Exposure) Acute Oral Toxicity Acute Dermal Toxicity Acute Inhalation Toxicity Dermal Irritation Eye Irritation Skin Sensitization Acute Neurotoxicity SUBCHRONIC (Intermediate Term Exposure) CHRONIC (Long Term/Lifetime Exposure) Chronic Toxicity (2 species) Oncogenicity (2 species) 2-Generation Reproduction OTHER STUDIES 21-Day Dermal 90-Day Feeding Studies (2 species) Developmental Toxicity (2 speces) 90-Day Neurotoxicity (rat) 90-Day Inhalation (conditional) Developmental Neurotoxicity (conditional) Genetic Toxicity (Ames, MN, CA) Metabolism Dermal Penetration Immunotoxicology Endocrine Disruptor Screening&Testing
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 Rats Children Adults
Toxicology Testing Requirements Acute Toxicity Testing Acute Oral LD 50 Acute Dermal LD 50 Acute Inhalation LD 50 Eye Irritation Skin Irritation Skin Sensitization Required for all active ingredients and end use (formulated) products
Acute Toxicity: LD 50 Acute toxicity tests measure mortality following a single exposure The LD 50 is the dose of toxin that produces 50% mortality in a test population LD 50 is usually expressed in milligrams of toxin per kilogram of test animal body weight (mg/kg) HIGH TOXICITY = LOW LD 50
Dose Response Function 100 % Response 75 50 25 No Effect: NOAEL Half Effected: LD 50 All Effected LD 100 0 0 10 20 30 40 50 60 70 80 90 100 Dose (mg/kg body weight) Increasing dose
Agent Oral LD 50 (mg/kg) Ethyl alcohol 10,000 Salt (sodium chloride) 3,000 Iron (Ferrous sulfate) 1,500 Morphine 900 Aspirin 250 DDT 250 Cyanide 10 Nicotine 1 Tetrodotoxin (from fish) 0.01 Botulinum Toxin 0.00001 }Most pesticides fall in this region Least Toxic Most Toxic
Relative Toxicity of Familiar Active Ingredients (not formulated) Pesticide AI Oral LD 50 (mg/kg) Endothall 50 >2000 Diquat Dibromide 700 300 Hydrogen 1000 >2000 Peroxide(35%) Glyphosate >5000 >2000 Flumioxazin >5000 >2000 Dermal LD 50 (mg/kg)
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 Acute Dermal Acute Inhalation 1 Eye Irritation < 50 mg/kg < 200 mg/kg <0.05 mg/liter Corrosive or corneal damage or irritation persisting for more than 21 days > 50 thru 500 mg/kg > 200 thru 2000 mg/kg > 0.05 thru 0.5 mg/liter Corneal involvement or irritation clearing in 8-21 days > 500 thru 5000 mg/kg > 2000 thru 5000 mg/kg > 0.5 thru 2 mg/liter Corneal involvement or irritation clearing in 7 days or less > 5000 mg/kg > 5000 mg/kg > 2 mg/liter Minimal effects clearing in less than 24 hours Skin Irritation 1 4 hr exposure Corrosive Severe irritation Moderate irritation Mild or slight irritation
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 - DANGER Toxicity Category II - WARNING Toxicity 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 III IV III III II Inhalation 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 PPE Toxicity Category by Route of Exposure of End Use Product Route of I II III IV Exposure Danger Warning Caution Caution Dermal Toxicity or Skin Irritation Potential Coveralls worn over long sleeved shirt and long pants Socks Chemical- Resistant Footwear Gloves Coveralls worn over long sleeved shirt and long pants Socks Chemical- Resistant Footwear Gloves 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
The LD 50 Determines: Signal Word Precautionary Statements First Aid Statements
Category I Irritant Restricted Use Strong Signal Word Extensive PPE
Toxicology Studies of Longer Duration General (Systemic) Toxicity Neurotoxicity Reproductive/Developmental Toxicity Immunotoxicity Carcinogenicity Mutagenicity
REPRODUCTION STUDY 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
Dose Response Function 100 % Response 75 50 25 0 No Effect Level: NOAEL 0 10 20 30 40 50 60 70 80 90 100 Dose (ppm in the diet) Increasing dose Low Effect Level: LOAEL Maximum Tolerated Dose: MTD
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 10-Fold Reductions Below NOAEL 1 10 100 0 No Effect: NOAEL 1000 Theoretical Human Exposure MOE 100 MOE 1000 PASS!
Margin of Exposure (MOE) Determination 10-Fold Reductions Below NOAEL 1 10 100 1000 No Effect: NOAEL Theoretical Human Exposure MOE 100 MOE 1000 0 FAIL!
Mitigation Strategies Label Instructions More PPE Worker Risk 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 Strategies Dietary 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
Examples: Aquatic Herbicide Label Mitigation 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.
THANK YOU! Questions?