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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