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ES/RP 532Applied Environmental Toxicology

Lecture 9Pesticides:

Regulations, Chemistry, & Toxicology

Regulatory Definition ofPesticide

• FIFRA (1947)• Any substance or mixture of substances

intended for preventing, destroying, repelling,or mitigating any pest

• Pest: insect, rodent, plant, or animal life orviruses, bacteria, or other microorganisms,except viruses, bacteria, or othermicroorganisms on or in living man or otheranimals

• Pesticide includes plant regulators, defoliants,or desiccants

• Pesticide includes disinfectants

Natural EcosystemsSelf-sustaining as aresult of biological(genetic) diversity– Diverse in

species andfunction

Responsive to systemperturbations– System can quickly

recover afterdisruptions

Energy flow balanced–Nutrients recycled–Soil stores plant

nutrients

Why Use PesticidesNatural vs. Agricultural Ecosystem Characteristics

Agroecosystems

Limited biological diversity bydesign– monocultures & bicultures

System cannot adapt– One organism can become dominant

to detriment of othersEnergy flow unbalanced– nutrients constantly removed with

crop harvesting

Yield(bushels/acre)

Year

Acres

Harvested

0

20000

40000

60000

80000

100000

120000

0

20

40

60

80

100

120

140

1890 1910 1930 1950 1970 1990 2010

Corn Production--USA

A

A. Hybrids

B

B. Mineralized Fertilizers

C

C. Soil Insecticides

D

D. Transgenic Crops

Impact of Technology Advantages of Pesticides

Many times they are the only practicalor available technologyRapid action– can be used in an emergency– biodegradable (modern pesticides)

Wide range of properties, uses, andmethods of application– broad spectrum to selective

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Economic return-cost ratio favorable– $4 - $29 returned per $1 spent– However,

• Ratio goes down when– price of crop decreases but pesticide cost is

fixed;– a product is used and pest populations are not

at a level that will cause economic damage– development costs for a new product are high

Advantages of Pesticides

1989 2000

Insecticide Use in WA StateApple Orchards Has Decreased

PoundsUsed

Per Year

The Down Side ofPesticides

Worker exposure & poisoningPest resistanceReduction of natural enemiesPotential for adverse environmentalhealth effectsPotential for human health effects

Historically Parallel Regulations

Pure Food & Drug Act(1906)

Insecticide Act(1910)

Pure Food & Drug Insecticide Act

Health Protection

Prohibit Misbranding and Adulteration

Ensure Efficacious Product

Adulteration Standard Placed the Laws in Conflict

Historically Parallel Regulations

Pure Food & Drug Act(1906)

Insecticide Act(1910)

Federal Food, Drug &Cosmetic Act (FFDCA,1938) Federal Insecticide,

Fungicide & RodenticideAct (FIFRA,1947)

registrationlabeling

residue tolerances

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Historically Parallel Regulations

Pure Food & Drug Act(1906)

Insecticide Act(1910)

Federal Food, Drug &Cosmetic Act (FFDCA,1938)

Federal Insecticide,Fungicide & RodenticideAct (FIFRA,1947)

Miller Amendment(1954)

Food Additives Amendment(Delaney Clause) 1958

FFDCA Amended(Food & Drug Admin.-FDA)

FIFRA(USDA)

EPA(1970)

Federal Environmental Pesticide Control Act (FEPCA, 1972)

FDA (food residues)

Shared Responsibilities

U.S. Pesticide Law 101

FIFRA(1947)

FFDCA(1938)

Tolerance (“MRL”)

FEPCA(1972)

Labelling Registration

Risk Assessment

FQPA(1996)

Miller (1954)Delaney (1958)

Mandate of the FQPA

• Tolerances will be “safe,” i.e., “areasonable certainty that no harm willresult from aggregate exposure”

• All tolerances will be reassessed by2006

What Is a Safe Tolerance?

• Infants & Children• Threshold vs. Non-threshold Effect• Endocrine Disruption• Aggregate Exposure Assessment• Cumulative Exposure Assessment

Factors To Consider

Determination of aSafe Tolerance

• All exposures must be less than theReference Dose (RfD)– RfD = NOEL/100

• Applicable to Consumers

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Food Quality Protection ActThe Non-Mandate

• Does not cover worker exposure• Does not cover ecological hazards

But some of the most contentiousissues in meeting the mandates of theFQPA have been worker exposure!!!!!

EPA was sued by EarthJustice forfailing to implement the EndangeredSpecies Act in its re-registration ofpesticides.

So How Did Worker & Eco ConcernsBecome Entangled in the FQPA?

• FIFRA already had mandated periodic re-registration of pesticides

• Important earlier mandates– FEPCA (Federal Environmental Pesticide

Control Act)• Reasonable certainty of no harm to the

environment standard• Restricted and general use classification• System of pesticide applicator training

– Worker Protection Standard (~1994)

Registration Eligibility DecisionDocuments (REDs)

• EPA’s analyses leading to a determination ofeligibility for registration

• Input from– HED (Health Effects Division)– EFED (Ecological Fate & Effects Division)

• Chapters are typical risk assessment process– Hazard & Dose-Response Assessment– Dietary, Drinking Water, Residential & Worker

Exposure– Nontarget Organism Exposure– Risk Characterization

Caveats of Pesticide RiskAssessment

• The assessment of risk to consumers isnow guided by the mandates of theFQPA– No benefits consideration (with one

exception)• The assessment of risk to workers and

the environment is pretty much thesame as before the FQPA– But, benefits of pesticide use can be

considered

Consent Decrees Drive RA• In late 1999, the NRDC (Natural Resources

Defense Council) and several otherenvironmental advocacy groups sued EPAclaiming failure to properly implement theFQPA– The main issue was failure to consider cumulative

exposure• Consent Decree signed Spring, 2001

– Provisions to ensure cumulative exposureassessment and publication of determinations

– Provisions to include worker exposureand ecological effects

Testing Required• Product chemistry• Residue chemistry• Environmental fate• Human/Domestic

animal hazards• Field Re-entry

protection studies

• Pesticide spray driftevaluation

• Hazards tonontarget organisms

• Productperformance

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Naming Pesticides

• Common chemical name– Endosulfan

• Formulation name– Thiodan

• IUPAC approved chemical nomenclature– 6,7,8,9,10,10-hexachloro-1,5,5a,6,9,9a-

hexahydro-6,9-methano-2,4,3-benzodioxathiepin-3-oxide

O

OS O

Cl

Cl

Cl

ClClCl

endosulfan

Chlorinated Hydrocarbons &Chlorinated Cyclodienes

• Almost all (except) endosulfan, banned• Persistent Organic Pollutants (POPs)

classification

CCCl3

H

Cl Cl

p,p'-DDT

Cl

CCCl3

H

Cl

o,p'-DDT

DDE

C

Cl

CCl2

Cl

DDD

CH

Cl

CHCl2

Cl

Cl

CCCl3

Cl

HO

Dicofol

CCCl3

H

H3CO OCH3methoxychlor

aldrin dieldrin

Cl

Cl

Cl

ClCl Cl

Cl

Cl

Cl

Cl O

ClCl

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ClCl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

alpha HCH beta HCH

gamma hexachlorocyclohexane (lindane)

Cl

Cl

Cl

ClCl

Cl

P-O-XR-OO

R-O

may be S

may be S

R is an alkyl group usually of 1 or 2 C;both R groups usually the same

LeavingGroup

Basic Structure of Organophosphorus Insecticides

NN

N

O

SP

CH3O

CH3O S

azinphos-methyl (Guthion) CH3O

CH3OP O C CHCOCH3

OCH3O

mevinphos (Phosdrin)

CH3CH2O

CH3CH2OP

S

NO2

parathion

NO2

S

PCH3CH2O

CH3CH2O CH3

fenitrothion

Oral LD50=3 mg/kgDermal LD50 = 7 mg/kg

Oral LD50 = 250 mg/kgDermal LD50 = 1300 mg/kg

Selectivity: Influence of structure

usually CH3 or (CH3)2

usually a ring structure or oxime group

R1-O-C-N-R

O

2

Methyl Carbamate Insecticides

carbaryl (Sevin)

O CO

NH CH3

CH3-S-C-CH=N-O-C-NH-CH3

CH3

CH3

aldicarb (Temik)

O

O

CH3

CH3

O CO

NHCH3

carbofuran (Furadan)

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1R trans permethrin

H

H

CH3H3C

CCl

ClC

OC-OO C

1S trans permethrin

CH3H3C

C-OC O

O

H

HCCl

ClC

Stereoisomerism

Pyrethroid Insecticides

1S trans permethrin

CH3H3C

C-OC O

O

H

HCCl

ClC

CCl

ClC

H3C CH3H H

OC-OO

C

1S cis permethrin

atrazine (Aatrex)

CH3CH2

NN

N

Cl

NHNHCH3CHCH3

NN

N

(CH3)3

O

SCH3

NH2

metribuzin

Triazine Herbicides

Symmetrical triazine

Asymmetrical triazine

C2H5

C2H5

CH2-O-CH3C-CH2-Cl

N

O

alachlor

metolachlor

CH3

C2H5

CH-CH2-O-CH3C-CH2-Cl

N

O

CH3

Chloroacetamides(chloroacylanilines)

O-CH2-C-OH

O

Cl

Cl Cl

Cl

O

O-CH2-C-O-

+ H+

pKa ~ 4.3

2,4-D

Phenoxyacetates

dimethyl amine salt of 2,4-D

OCH C OH

O

Cl

Cl

CH3

CH3NH

2,4-D

OCH C OH

O

Cl

Cl

Weed & Feed2,4-D

DicambaMecoprop

COHO

OCH3

Cl

Cl

dicamba

Cl

CH3

OOH

OCCHH3C

mecoprop (MCPP)

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N

CH2CH2CH3CH3CH2CH2

NO2O2N

CF3

trifluralin

N+ N+ CH3CH3 2 Cl-

paraquat (Gramaxone) --dichloride salt

Dinitroanilines

Bipyridiliniums

Getting to Know Glyphosate

NHCH2P

OHO

HO

CH2 C OH

O

methyl phosphonate glycine

N-phosphonomethyl glycine

CHCH3

CH3

NH2 isopropyl amine

NN

N

CH3

OCH3

NHOCNH

O

OS

Cl

chlorsulfuron (Glean)

N

C OHO

HN

N

O

CH3C

CH3

CH3H

imazapyr

Sulfonylureas

Imidazolinones

Comparative Toxicity• Rule of Thumb (Acute Toxicity)

– OPs more toxic than carbamates;– Both OPs and carbamates more toxic than DDT

and chlorinated cyclodienes– Herbicides less toxic than insecticides

• Rule of Thumb (Chronic Toxicity)– Compounds of low acute toxicity tend to be found

tumorigenic in rodents more often thancompounds of high acute toxicity

• Example: malathion(LD50 885 mg/kg) is one of the fewOP insecticides in which EPA is uncertain over whether itis a rodent carcinogen

For Risk Characterization, Acute Toxicity Is LessImportant than the NOAEL for the Most Sensitive Effect

Pesticide

Acute orSubchronic

NOAEL

Acute orSubchronic

LOAELChronicNOAEL

ChronicLOAEL

ChronicRfD

ChronicPAD

azinphosmethyl 0.3 1 0.149 0.688 0.00149 0.00149chlorpyrifos 0.5 1 0.03 0.22 0.0003 0.00003atrazine 10 70 1.8 3.65 0.018 0.00182,4-D 67 227 1 5 0.01 0.01glyphosate <63 63 175 350 2 2

NOAEL Data from EPA REDs(Registration Eligibility Decision Documents

Doses in mg/kg/day

Dermal Absorption

• Many pesticides are inefficientlyabsorbed through the skin– Azinphos-methyl: 42% in 24 h– Chlorpyrifos: 3%– Atrazine: 5.6%– 2,4-D: 6%

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Metabolism

• DDT and chlorinated cyclodiences arerecalcitrant to biodegradation– Degraded very slowly– Bioaccumulate in lipid tissues

• All other pesticides should beconsidered readily biodegradable in anorganism

• DDT is slowly metabolized in rodents• Small changes in structure, however,

can make the basic molecule readilybiodegradable– Methoxychlor: 98% of dose fed to mice

recovered in excreta in 24 h– Dicofol: 50% of dose administered to

rodents is excreted in urine in 24 hours

Metabolism

Metabolism

• Some compounds are excretedunchanged (i.e., as parent compound)– Most of the administered 2,4-D is excreted

unchanged in urine within 24 hours– Ditto for glyphosate

Mode of Action

• The majority of insecticides areneurotoxins with various mechanisms oftoxicity

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Mode of Action

• DDT and pyrethroids– Interact with sodium gate (a protein in the

nerve membrane that controls permeabilityto sodium flux

– Holds the gate open longer, so the nerverecovers to it normal voltage potentialslowly

• GABA (gamma aminobutyric acid)antagonists– Endosulfan; Dieldrin– GABA is an inhibitory neurotransmitter that

dampens the nerve signal– GABA receptors are inhibited by

cyclodienes

Mode of Action

Mode of Action• Organophosphates & Carbamate

Insecticides– Inhibit acetylcholinesterase when in the

oxon form– Many OPs are only slowly hydrolyzed from

AChE, so recovery is slow (a period ofweeks to months!)

– Carbamate are considered completelyreversible inhibitors

P SCH3CH2OCH3CH2O

SCH2 S C CH3

CH3

CH3

terbufos (Counter)

CH3CH3

CH3CCH2 S

CH3CH2OCH3CH2O

SPO

terbufos oxon

Herbicide MOA

• Photosynthesis inhibition (triazines)• Auxin agonists (2,4-D)• Inhibition of amino acid synthesis

(sulfonylureas, imidazolinones,glyphosate)

• Inhibition of mitosis (dinitroanilines-e.g.,trifluralin)

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Physicochemical Properties• General Rule of Thumb

– DDT and chlorinated cyclodienes tend to be ofvery low water solubility

– OPs tend to be lower than carbamates– Herbicides tend to have much higher solubilities

than insecticides, but watch out for exceptions• For example, trifluralin <3 ppm• Paraquat is cationic so it strongly sorbs,

especially to clays

Long Term DDT Experiment(Spencer et al. 1996, JEQ)

• Treat plots in 1971• Measure air and soil residues after

application and in 1994

(based on Spencer et al. 1996) (based on Spencer et al. 1996)

N

ClClHO

ClC2H5O

C2H5O

S

P- OH

N

ClCl

ClC2H5O

C2H5OP-O

S

+

N

ClCl

ClC2H5O

C2H5OP-OO

+C2H5O

C2H5O

O

P- OHN

ClClHO

Cl

Diethoxyphosphorothioate

trichloropyridinol

Diethoxyphosphoroate

NN

N

Cl

NH 2NCH 2CH 3

NN

N

Cl

NH 2H 2N

CH 3

NN

N

Cl

NH

H2N CHCH 3

NN

N

Cl

NH

NCH 2CH 3 CH

H

CH 3

CH 3

atrazine

hydroxy atrazine

CH 3

CH 3

NN

N

OH

NH

NCH 2CH 3 CH

H

de-isopropyl atrazine de-ethyl atrazine

diamino atrazine

Soil transformations of atrazine

Metabolitesfrequentlyfound in water

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Pesticides:A Technology in Transition

Per acre application rate has decreased by10 to 100 foldAcute toxicity has dramatically decreased by100-fold or moreNot stored in bodyPotential for carcinogenic, reproductive,endocrine effects are nil

Although we will focus on historical and recurrentissues or problems with pesticides, the technologyhas changed greatly since DDT and is in a transitionto greatly reduced risk products