Applicators and Pesticide Toxicity

Moire CreekManager, 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 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)

FIFRA

The consequences are real

****

The label is the LAW!

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

The LD50 Determines:

• Signal Word

• PrecautionaryStatements

• First AidStatements

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

•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.

THANK YOU!

Questions?