the definition, various

pesticides and the mechanism

TIK:
to mention the definition, various
pesticides and the mechanism

Pesticides
Physical, chemical or biological agent intended to kill an
undesirable plant/animal pest
Major classes: insecticides, fungicides, herbicides
Most pesticides are synthetic agents new to humans and
the environment
Developed since 1940s
891 pesticidal active ingredients licensed by US EPA*
523 used on food or feed

Inherent toxicity
140 pesticides currently considered neurotoxic by EPA

Acute, High Dose Toxicity

US Poison Control (2000)
11,000 unintentional organophosphate (OP)
exposures; 3000 treated in health care facility
includes 4000 children < 6 yr

World Health Organization

3 million acute, severe poisonings/yr
220,000 deaths/yr

Acute Toxicity:
Tip of the Iceberg?
Limits of acute poisoning data
Incomplete coverage of U.S. population
Unreported incidents
Long term impacts of acute/high level exposures
Limits of pesticide toxicity data
Few studies of impact of chronic/low-dose exposures
Few developmental/neurodevelopment studies
State of evidence: Analagous, perhaps, to what was
known about lead toxicity in early 1900s?

Background Pesticide
Exposures Widespread
Reported use: 98% of families, 80% during pregnancy
In Humans - detectable chlorpyrifos metabolites in
92% of childrens, 82% of adults urine samples
In Food - detectable residues of at least one pesticide on
72% fruits/vegetables
In Homes 3 to 9 pesticide residues in typical
home
with 70% infant exposure from dust
In Air - indoor air levels 10-100X higher than outdoor air
In Water - >90% stream samples, 50% of wells

Rural Exposures:
Agricultural Health Study
Exposures to farmers and families of farmer
pesticide applicators:
27% of applicators store pesticides in their home
94% of clothing worn for pesticide work is washed in
the same machine as other laundry
40% of wives of applicators also mixed or applied
pesticides
Over 50% of children aged 11 or more do farm chores

Prenatal Exposures:
The Urban Environment
Meconium assays in 20 newborns (Whyatt 2001):
diethylphosphate (DEP); diethylthio-phosphate
(DETP)
Metabolites of chlorpyrifos, diazinon, parathion,
organophosphate (OP) insecticides
Detections:
DEP in 19/20 (95%) of samples (range 0.8-3.2 ug/g)
DETP in 20/20 (range 2.0-5.6 ug/g)
In animal toxicity tests, chlorpyrifos, diazinon linked to
adverse neurodevelopmental effects.

Minnesota Children's Pesticide

Exposure Study
Urinary metabolites in 90 urban and non-urban Minnesota children, 313 yrs old (Adgate 2001):
Metabolite
Parent Pesticides
3,5,6-trichloro-2-pyrifinol (TCPy)
chlorpyrifos & related
cmpds
1-naphthol (NAP)
carbaryl or napthalene
malathion dicarboxylic acid (MDA) malathion
Detections in first-morning-void samples
TCPy
93%
1-NAP
45%
MDA 37%

Insecticide Sites of Action

Organochlorines
Pyrethroids

Enzymes
Axonal Membranes
Ions (Na+, K+, Ca++, Cl-)

Organophosphorus
and
Carbamate Esters

Enzymes
Neurotransmitters

Figure 22-4. Potential sites of action of classes of insecticides

on the axon and the terminal portions of the nerve.
Casarett and Doulls Toxicology: The Basic Science of Poisons, 5th Edition, Ed: Klaassen, CD.
McGraw-Hill, New York, 1996. P. 649

Example of Pesticide Mechanism:

Organophosphate (OP)
Blocks function of cholinesterase
Increases levels of acetylcholine,
an important neurotransmitter

Effecting:
*Nerve impulse transmission
*Brain growth and development

Normal Functions of Acetylcholine &

Acetylcholinesterase
ACh
AChE

Choline
+

Acetate
Transmits nerve impulse
across synapse
Morphogen in developing
brain affecting:

cell division
differentiation
Neurite growth
synaptogenesis
apoptosis

Organophosphate Pesticides (OP)

Mechanisms of Toxicity
1. Normal:

ACh

AChE

Choline + Acetate

2. With OP pesticide:

ACh

OP - AChE

Choline + Acetate

Disruption of ACh & AChE

Function by Dursban

ACh

Dursban-AChE

Transmission of nerve impulses

Altered morphogenesis
Cell division
Differentiation
Synaptogenesis
Apoptosis

Choline + Acetate

Neurite growth

Noncholinergic Dursban effects:

DNA synthesis, interfering with cell signaling cascades
(cholinergic and noncholinergic cells)

Organophosphate Pesticide (OP)

Effects in Laboratory Animals
OP

Cellular effect

Behavior

DFP
muscarinic cholinergic
hyperactivity
receptors in brain
at 4 mos. of age
Dursban
muscarinic cholinergic
receptors in brain
righting
cliff avoidance
brain weight
Diazinon

auditory startle

delayed reflexes
contact placing
All low dose (<7 mg/kg/day)
coordination
Early developmental exposure
endurance

altered reflexes

New Risk Assessments Raise

Concerns
Concerns raised by EPA risk assessments of
individual OPs, resulting in:
Dursban over the counter sales banned
Diazinon banned indoors, phase out 4 yrs

EPA assessment of cumulative OP risks:

Only cumulative impact on cholinesterase inhibition
considered
No developmental neurotoxicity testing available for
most of the 35 registered OPs

Emerging Themes

Conclusions

With increasing scientific understanding, as

neurodevelopmental effects emerge, estimates of toxic
thresholds tend to fall.
Animal testing for neurodevelopmental toxicity has
underpredicted human vulnerability by a factor of 10010,000 (HG, lead, PCBs).
Subtle effects in individuals may carry profound impacts
when expressed over a population.
Adverse effects of some developmental neurotoxicants
are synergistic or additive.

THE TOXIC ICEBERG

PROVEN HARM

PARTIALLY
PROVEN

NOT YET RECOGNIZED

FOREVER UNRECOGNIZED

Organochlorine Pesticides
Background Information
7 Common Characteristics
5 Major Groups of OCs

Background
DDTs success stimulated the production
of several OC pesticides
Successful eradicators
Severe toxic effects
Currently in the U.S. and Europe OCs are
not a major pesticide, but they are in
developing countries and tropical regions
Cost-benefit

7 Common Characteristics
1.
2.
3.
4.
5.
6.
7.

Atomic structure
Lipid solubility
Persistence
Bioaccumulation
Toxicity
Physiological Response
Interactions

1. Atomic Structure
Characterized by the presence of carbon,
chlorine, and hydrogen (sometimes
oxygen)
Cyclic carbon chains (benzene ring)

Atomic Structure

2. Lipid Solubility
High lipid solubility (non-polar)
High log Kow
Stored in lipids/fat
Fasting can cause reentry into circulation

The concentration in biota has decreased

since the banning of several OCs

3. Persistence
Persistence is based on the half lives in
the organism and in the environment
Stable compounds
Physical and biological influences
Environmental
Organism

Persistence Cont.
Dependent on the compound
Aldrin is rapidly metabolized
Endrin and dicofol have short half lives in an
organism and in the environment
DDT, its metabolites and dieldrin are
extremely persistent

4. Bioaccumulation
Accumulation of pesticides through
absorption through skin, gills, or food
Bioconcentration and biomagnification
Aquatic organisms vs. terrestrial
organisms

5. Toxicity
Biochemical lesions
Neuroactive agents
Ingestion, inhalation and dermal
absorption
Mortality
Lethal brain and liver residues indicate
biochemical lesions

Influences on toxicity

Toxicity Cont.
DDT
Acts on CNS by interfering with ion movement
through neuronal membranes
4 mechanisms
Na2+ and K+
ATP
Ca 2+ inhibition
Ca2+Mg2+
Maintain depolarization, which leads to hypersensitive
neurons
Persistent tremoring, seizures or convulsions

Toxicity Cont.
Cyclodienes
Alter the neurotransmitter gammaaminobutyric acid (GABA)
Inhibit Na2+, K+, and Ca2+Mg2+ channels

HCH
Block chloride ion
Alter Ca2+ levels

6. Physiological Response
Induced enzyme activity
Species variations

Persistence and excretion

Endocrine disruptors

7. Interactions
Synergism, potentiation, antagonism, or
additive toxic effects
Antagonistic: Japanese quail were treated
with chlordane and later with parathion
Synergism: Aldrin increases the storage of
DDT
Additive effects are most common for
industrial chemicals and pesticides

5 major groups of OCs

1. Dichlorodiphenylethane
DDT, dicofol, and methoxychlor

2. Cyclohexane
Hexachlorocyclohexane (HCH)

3. Chlorinated cyclodiene
Aldrin, dieldrin, and endrin

4. Toxaphene
5. Mirex and chlordecone

DDT, DDD, and DDE

(Dichlorodiphenylethane)
Paul Muller (1939)
Subsequent discovery of large-scale
mortality of birds, insects, and
invertebrates
Determination lethal brain residues
DDE

DDT, DDD, and DDE Cont.

Adverse affects on wildlife
Avian populations
Brown pelicans
Peregrine falcons
Osprey and bald eagles
Fish and bats

DDT, DDD, and DDE Cont.

DDD sprayed 3 times on Clear Lake,
which lead to bioaccumulation data
Resistance to DDT
DDT was banned in 1972
DDT has estrogenic activity

Aldrin/Dieldrin

(cyclodiene)

Very toxic
Aldrin is quickly transformed into Dieldrin
Adverse affects on wildlife
Aldrin/Dieldrin spraying in 1960 and 1961 for
Japanese beetles
Whistling ducks, snow geese, and others
Gray bats in Missouri

The combined effects of DDE and Dieldrin

Aldrin/Dieldrin were banned in 1974

Endrin

(cyclodiene)

Short half life, but very acutely toxic

Adverse affects on wildlife
Brown pelican
Voles, birds, and quail

Metabolic pathways
12-Ketoendrin is more toxic than endrin

Endrin was banned in 1979

Hexachlorocyclohexane (HCH)
(Cyclohexane)

Lindane (gamma isomer)

Persistent or easily eliminated?
Veterinary and human medicine
Some isomers were voluntarily canceled
by the primary manufacturer in 1978;
lindane is still in use

Dicofol

(dichlorodiphenylethane)

Produced from DDT

Persistence or Elimination?
Adverse affects on wildlife
Ecotoxicological studies

Dicofol products that contain >1% of DDT

ceased in 1989, products with <1% are
still in use

Methoxychlor

(dichlorodiphenylethane)
Replaced DDT in treating Dutch elm
disease
Rapidly broken down
Estrogenic activity
Still in use

Thank you