Pesticides

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Pesticides

• Principles of Toxicology

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Pesticides

• EPA definition substances or mixtures of
  substances intended for preventing, destroying,
  repelling or mitigating any pest

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A bit of history

• Sulfur

• Chinese - 1000BC
• Europe - 1800s
• CA - today !

• Arsenic-containing
• Strychnine
• Nicotine (tobacco leaves extracts - 1690)
• Pyrethrum (chrysanthemum extract)
• Bordeaux mix copper, lime (Ca(OH)2), water

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Later

• 1930s - modern era chemistry
• Alkylthiocyanate
• Dithiocarbamate
• Bromide compounds
• WWII -
• DDT
• Dinitrocresol
• 2,4 D
• Since then, synthesis with goal improved
  specificity, reduced toxicity
• No such a thing as safe pesticide

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Integral part of crop and health
protection Poisonings are anticipated 3mil
acute cases annually (ww) 220,000 deaths CA -
25,000 pesticide related illnesses, annually USA
- 80,000
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Efficacy of crop protection
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Pesticide poisonings by occupational activity
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Medical successes

• DDT
• Typhus in Naples, Italy
• River blindness, West Africa
• Malaria - Africa, Asia, Middle East
• There are still many parasitic and vector-borne
  diseases

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Regulations

• 1906 - First Federal Food and Drugs Act
• 1938 - Federal Food, Drugs and Cosmetics Act
• 1958 amend. - Delaney clause no additive shall
  be deemed safe if found to induce cancer
• 1947 - FIFRA Federal Insecticide, Fungicide and
  Rodenticide Act all pest control products under
  one law - by USDA
• 1972 - FIFRA reorganized and passed to EPA
• FIFRA Amendments - 1975, 78, 80, 84
• 1996 - Food Quality protection Act (children)
• Developing countries adapt or lack regulations

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Nervous System
Central
Peripheral
Afferent
Efferent
Somatic
Autonomic
Para-Sympathetic
Sympathetic
ENS
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Anatomic Classification
CNS ? Skull and Spinal cord PNS ? 12 pairs of
cranial nerves 31 pairs of spinal
nerves
afferent
CNS PNS
efferent
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Sympathetic ANS
Fight or flight
Parasympathetic ANS
Rest and digest
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Parasympathetic Cholinergic
cranio-sacral
Sympathetic Adrenergic
thoraco-lumbar
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Sympathetic nerves
T1 . . . . T12
L1 L2 L3
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Afferent Nerves Efferent Mixed
Neurons
Spinal nerves are mixed for major length
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Structure of a typical neuron
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Pre-ganglionic neuron
organ
Post-ganglionic neuron
Ganglion
Multi-neuron synapse
Neuroeffector junction
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Somatic
Ach
Parasympathetic -cholinergic
Ach
Ach
Sympathetic - adrenergic
Ach
Adr/NA
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Feature Sympathetic Parasympathetic Start
point thoraco-lumbar cranio-sacral Ganglion
near spine on organ (terminal) Ganglion
synapse Ach Ach Pregangl. neuron short long Po
stgangl. neuron long short Effector
synapse Adr Ach Effector organs throughout
body limited
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Typical Synapse
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Cholinergic Transmission
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O
Acetylcholine Synthesis

• CH3C-O- HO-CH2-CH2-N(CH3)3

Acetate
Choline
Choline Acetylase
Coenzyme A
O
CH3C-O-CH2-CH2-N(CH3)3
Acetylcholine
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O
Acetylcholine Catabolism
CH3C-O-CH2-CH2-N(CH3)3
Acetylcholine
Cholinesterase
O

• CH3C-O- HO-CH2-CH2-N(CH3)3

Acetate
Choline
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Cholinergic Receptors
Muscarinic M1 CNS, sympathetic (exceptions),
presynaptic M2 Smooth muscle, heart,
presynaptic M3 Exocrine glands, blood vessels
Nicotinic NM skeletal muscle NN ganglia
(post-), presynaptic
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• Acetylcholine Nicotinic Receptor

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Nicotinic Receptor structure
a
b
d
a
g
Ion Channel
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Na
d
g
a
a
b
Na
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Muscarinic receptor
Agonist
G protein
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Muscarinic receptor
G- proteins
Excitatory action
Inhibitory action
Phosholipase C
Adenylic cyclase
K channels
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Muscarinic receptor stimulation
Gi
Signal transduction cascade involving Adenylic
cyclase
Protein Kinase A
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Muscarinic receptor stimulation
Gq
Signal transduction cascade involving
Phospholipase C
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Cholinergic agonists
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Adrenergic Transmission
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Sympathetic Nerve Terminal
Tyrosine
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1
mitochondria contains MAO, oxidizes amines
transport
exocytosis
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2
DA, Nepi stored with ATP in granules
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a , b Receptors
re-uptake
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Adr (NA) synthesis
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Adrenergic Receptors
Alpha a a1 most effector cells a2 presynaptic
, lipocytes, platelets, some smooth muscle
Beta b b1 effector cells (heart), brain,
lipocytes, presynaptic b2 smooth muscle and
myocardium b3 lipocytes
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Adrenergic receptors a2 and b
Adenylyl cyclase
b receptor
a2 receptor
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Adrenergic receptors a1
Phospholipase C
a1 receptor
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Pesticides

• Organochlorines
• ChE inhibitors
• Organophosphates
• Carbamates
• Phenoxyherbicides
• Pyrethroids
• Bromine-based
• Phenol- derivatives
• Dipyridyl derivatives

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Organochlorine insecticides
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Organochlorine insecticides

• DDT
• first commercially produced insecticide (1940s)
• banned in the US in the 1970s but is still
  manufactured and exported (1 ton/day)
• Cyclodienes
• Most toxic (CNS) and persistent pesticides known
• HCH and Cl-benzene
• Mixtures of isomers
• Medicinal use (lice shampoo) (lindane)

• t1/2 7-30y
• Bioaccumulates
• Persistent
• Lipophilic

• Non-selective
• Endocrine disrupter
• Reproductive toxins
• Neurotoxins (Lindane)

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Observed effects

• DDT
• Enzyme induction
• Competes with estradiol for receptor
• Cyclodienes
• Reproductive toxicity (reduced fertility, loss of
  pups, teratogenic)
• CNS toxicity
• HCH and Cl-benzene
• CNS toxicity
• Increased hepatocellular tumors (mice)

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Mechanisms of action

• DDT
• Peripheral sensory neurons
• prolonged negative afterpotential in neurons
• K transport, inactivate Na channel closure,
  inhibit Na /K and Ca2 /Mg2 ATPases, inhibit
  calmodulin-transport of Ca2 (fig. 22-4)
• Cyclodienes
• CNS localized
• GABAA receptor/channel antagonists, inhibit
  Cl--uptake and Na /K and Ca2 /Mg2 ATPases
• HCH and Cl-benzene
• Suggested similar to cyclodienes but unknown

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Cholinesterase inhibitors

• Organophosphates (OP) and Carbamates
• Strong Acute neurotoxicity - AChE inhibition
  (cholinergic effects)
• Nervous system toxins - nerve gas (sarin)

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1st OP TEPP (tetraethylpyrophosphate), followed
by parathion 1st carbamic 1930
WWII chemical warfare 1988 Iraq- against
Kurds 1994 Japan 1995 Tokyo subway
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O
Cholinesterase

CH3 C - O - CH2 - CH2 - N(CH3)3
Esteratic
Anionic

• CH3C-O- HO-CH2-CH2-N(CH3)3

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O
Organophosphates
R1
Parathion Malathion Soman Ecothiophate
P
R2
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O
Organophosphates
Strong Covalent Bond, Inactivates Enzyme (stable
gt100h)
R1
X
P
R2
Aging of complex
Anionic
Esteratic
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Organophosphates are slower to release from AchE
- also aging effect Carbamates are faster
reversible Phase I metabolic activation
Multiple metabolic reactions
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Neurobehavioral, muscular and cognitive
effects Delayed Neuropathy (OPIDN) - ginger jake
WHO has a battery of neuropsychological tests
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OPs causing OPIDN
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Phase I and II biotransformation
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Antidote pralidoxime, removing OP from enzyme site
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Pyrethroids
Newer (1980) but were 30 of all use by 1982
Extensive agricultural use Indoor use Pet flee
control Household plants Modify Na channel
kinetics Abnormal repetitive discharges Type A
shorter action than type B
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Avermectins
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New generation pesticides
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Herbicides

• 1.9 increase/year between 1980-1985 (x2 of
  insecticides) due to
• Monoculture
• Mechanization of agricultural processes
• Categories by application
• Pre-planting
• Pre-emergent
• Post-emergent
• Low mammal toxicity
• Suspected mutagens, carcinogens, teratogens
• Skin irritants

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Phenoxyherbicides

• Introduced in 1946
• 2,4Dichloro- and 2,4,5Trichloro phenoxy acetic
  acids
• Defoliants (Vietnam war) - Forestry
• Nerve toxicity, peripheral neuropathy
• Controversy about NHL and HL
• Contaminants may be responsible for toxicity

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Dipyridyl derivatives
startling human toxicity Banned in many
countries but still in use in 130 others Lung is
the most susceptible target organ Highly polar-
poor GI absorption (5-10)
LD5022-262mg/kg
LD50100-400mg/kg
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Chloroacetanilides
Only slight acute toxicity but Carcinogens of
category 2B Metabolic activation to mutagenic
metabolite (DEBQ1) 1985 Canada incident (well
water contamination)
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Phosphomonomethyl aminoacids

• Non-selective systemic herbicides
• Free acids or salts -
• ocular and mucus membrane irritants
• Class E carcinogens (EPA)
• Solvent may be the toxic compound (POEA)

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Fungicides

• Lipophilic, accumulate
• 90 are carcinogenic in animals --gt 75 mil pounds
  produced annually
• 10 acreage but 60 of total dietary carcinogenic
  risk
• Contaminants are dioxins and furans
• Hexachlorobenzene (banned)
• Pentachlorophenol (banned)
• Phthalimides
• Dithiocarbamates

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Fungicides

• Dithiocarbamates
• Ferbam, ziram, maneb, zineb, nabam (metal-based
  names)
• Some reported as teratogenic
• Degradation to ethylene thiourea (ETU) a known
  mutagen, carcinogen, teratogen and antithyroid
  compound.
• Some neurotoxicity at high doses
• May cross into CNS if bound to divalent metals

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Fumigants

• Very volatile - inhalation exposure
• Non-selective, highly reactive and cytotoxic
• acrylonitrile
• carbon disulfide
• carbon tetrachloride
• ethylene dibromide (gastric carcinomas,
  sterility)
• ethylene oxide (carcinogen, developmental tox.)
• phosphine (PH3) released from aluminum phosphide
  (AlP) in moist conditions (grain storage)

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Rodenticides

• Rodents vectors of disease
• Zinc phosphide - PH3 (cell toxicity, necrosis,
  GI, liver, kidneys)
• Fluoroacetic acid and derivatives
  (Fluoroacetyl-CoA --gt fluorocitrate Krebs cycle
  collapse)
• ?-naphthyl thiourea (ANTU)
• must be metabolically activated --gt resistance
• Anticoagulants (coumadin, warfarin) - antagonist
  of vit. K in synthesis of clotting factors
  requires multiple doses resistance

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