Download - Pesticides
Pesticides
Principles of Toxicology
Pesticides
• EPA definition: “substances or mixtures of substances intended for preventing, destroying, repelling or mitigating any pest…”
A bit of history…
– Chinese - 1000BC– Europe - 1800s– CA - today !
•Sulfur
•Arsenic-containing•Strychnine•Nicotine (tobacco leaves extracts - 1690)•Pyrethrum (chrysanthemum extract)•Bordeaux mix: copper, lime (Ca(OH)2), water
Later…• 1930’s - 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”
Integral part of crop and health Integral part of crop and health protectionprotectionPoisonings are anticipated…Poisonings are anticipated…
3mil acute cases annually (ww)3mil acute cases annually (ww)220,000 deaths220,000 deaths
CA - 25,000 pesticide related CA - 25,000 pesticide related illnesses, annuallyillnesses, annually
USA - 80,000 USA - 80,000
Efficacy of crop protection
Pesticide poisonings by occupational
activity
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…
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
Nervous System
Central Peripheral
EfferentAfferent
Somatic Autonomic
Para-Sympathetic Sympathetic
ENS
Anatomic Classification
CNS Skull and Spinal cord
PNS 12 pairs of cranial nerves 31 pairs of spinal nerves
CNS PNSafferent
efferent
Sympathetic ANS
Fight or flight
Parasympathetic ANS
Rest and digest
Sympathetic: Adrenergic
Parasympathetic: Cholinergic
thoraco-lumbar
cranio-sacral
Parasympathetic nerves
4 CranialIII oculomotor
VII facialIX glossopharyngial
X vagus
SacralS2S3S4
L1L2L3
T1....
T12
Sympathetic nerves
AfferentNerves Efferent
Mixed
Spinal nerves are mixed for major length
Afferent dorsal root
Efferent ventral root
– then divide
Neurons
Structure of a typical neuron
Pre-ganglionic neuron
Post-ganglionic neuron
GanglionMulti-neuron synapse
organ
Neuroeffector junction
Somatic
AchParasympathetic -cholinergic
Ach Ach
Sympathetic - adrenergic
Ach Adr/NA
Feature Sympathetic Parasympathetic
Start point thoraco-lumbar cranio-sacralGanglion near spine on organ (terminal)Ganglion synapse Ach AchPregangl. neuron short longPostgangl. neuron long shortEffector synapse Adr AchEffector organs throughout body limited
Typical Synapse
Cholinergic Transmission
Acetate Choline
CH3C-O- + HO-CH2-CH2-N+(CH3)3
CH3C-O-CH2-CH2-N+(CH3)3
O
O
Acetylcholine
Acetylcholine Synthesis
Choline Acetylase
Coenzyme A
Acetate Choline
CH3C-O- + HO-CH2-CH2-N+(CH3)3
CH3C-O-CH2-CH2-N+(CH3)3
O
O
Acetylcholine
CholinesteraseCholinesterase
Acetylcholine Catabolism
Cholinergic Receptors
Nicotinic: NM skeletal muscleNN ganglia (post-), presynaptic
Muscarinic:M1 CNS, sympathetic (exceptions), presynapticM2 Smooth muscle, heart, presynapticM3 Exocrine glands, blood vessels
Acetylcholine Nicotinic Receptor
Nicotinic Receptor structure
Ion Channel
Na+
Na+
Muscarinic receptor
G protein
Outside
Inside
Agonist
Muscarinic receptor
G- proteins
Excitatory action Inhibitory action
Phosholipase C Adenylic cyclase
K+ channels
Signal transduction cascade involving Adenylic cyclase
Muscarinic receptor stimulation
Gi
-
Protein Kinase A
-
-
-
Signal transduction cascade involving Phospholipase C
Muscarinic receptor stimulation
Gq
Cholinergic agonists
Adrenergic Transmission
Sympathetic
Nerve
Terminal
1
Tyrosine
mitochondria contains
MAO, oxidizes amines
2
DA, Nepi
stored with ATP
in granules
3
4 exocytosis
Receptors
5
re-uptake
transport
Adr (NA) synthesis
Adrenergic Receptors
Alpha most effector cells
presynaptic, lipocytes, platelets, some smooth muscle
Betaeffector cells (*heart), brain, lipocytes, presynaptic
smooth muscle and myocardium
lipocytes
Adrenergic receptors: 2 and
receptor receptor+ -
Adenylylcyclase
receptor+
Phospholipase C
Adrenergic receptors: 1
Pesticides
•Organochlorines•ChE inhibitors
•Organophosphates•Carbamates
•Phenoxyherbicides•Pyrethroids•Bromine-based•Phenol- derivatives•Dipyridyl derivatives
Organochlorine insecticides
Organochlorine insecticides• DDT
– first commercially produced insecticide (1940’s)
– banned in the US in the 1970’s but is still manufactured and exported (1 ton/day)banned in the US in the 1970’s 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)
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)
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
Cholinesterase inhibitors
• Organophosphates (OP) and Carbamates– Strong Acute neurotoxicity - AChE inhibition
(cholinergic effects)
– Nervous system toxins - nerve gas (sarin)
WWII chemical warfareWWII chemical warfare1988 Iraq- against Kurds1988 Iraq- against Kurds1994 Japan 1994 Japan 1995 Tokyo subway1995 Tokyo subway
1st OP: TEPP 1st OP: TEPP (tetraethylpyrophosphate), (tetraethylpyrophosphate), followed by parathionfollowed by parathion1st carbamic: 19301st carbamic: 1930
Cholinesterase
CH3C-O- + HO-CH2-CH2-N(CH3)3
CH3 C - O - CH2 - CH2 - N(CH3)3
O
O
+
+
Esteratic Anionic
O
P X
R1R1
R2R2
= aliphaticR1-2R1-2
ParathionMalathionSomanEcothiophate
Organophosphates
= e- withdrawingX
X
Strong Covalent Bond, Inactivates Enzyme
(stable >100h)
Organophosphates
P
R1
R2
Esteratic Anionic
O
Aging of complex
Organophosphates are Organophosphates are slower to release from slower to release from AchE - “also aging effect”AchE - “also aging effect”
Carbamates are faster: Carbamates are faster: reversiblereversible
Phase I metabolic Phase I metabolic activation activation Multiple metabolic Multiple metabolic reactionsreactions
Neurobehavioral, Neurobehavioral, muscular and cognitive muscular and cognitive effectseffectsDelayed Neuropathy Delayed Neuropathy (OPIDN) - ginger jake(OPIDN) - ginger jake
WHO has a battery of WHO has a battery of neuropsychological testsneuropsychological tests
OPs causing OPIDN
Phase I and II biotransformation
Antidote pralidoxime, removing OP from enzyme site
PyrethroidsNewer (1980) but were 30% of all use by 1982Newer (1980) but were 30% of all use by 1982
Extensive agricultural useExtensive agricultural useIndoor useIndoor usePet flee controlPet flee controlHousehold plantsHousehold plants
Modify NaModify Na++ channel kinetics channel kineticsAbnormal repetitive dischargesAbnormal repetitive dischargesType A shorter action than type BType A shorter action than type B
Avermectins
New generation pesticides
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
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
Dipyridyl derivatives““startling human toxicity”startling human toxicity”Banned in many countries but still in use in 130 othersBanned in many countries but still in use in 130 othersLung is the most susceptible target organLung is the most susceptible target organHighly polar- poor GI absorption (5-10%)Highly polar- poor GI absorption (5-10%)
LD50=22-262mg/kgLD50=22-262mg/kg
LD50=100-400mg/kgLD50=100-400mg/kg
ChloroacetanilidesOnly slight acute toxicity but Only slight acute toxicity but Carcinogens of category 2BCarcinogens of category 2B
Metabolic activation to Metabolic activation to mutagenic metabolite (DEBQ1) mutagenic metabolite (DEBQ1)
1985 Canada incident (well 1985 Canada incident (well water contamination)water contamination)
Phosphomonomethyl aminoacids
•Non-selective systemic Non-selective systemic herbicidesherbicides•Free acids or salts - Free acids or salts - ocular and mucus ocular and mucus membrane irritantsmembrane irritants•Class E carcinogens Class E carcinogens (EPA)(EPA)•Solvent may be the Solvent may be the toxic compound (POEA)toxic compound (POEA)
Fungicides• Lipophilic, accumulate• 90% are carcinogenic in animals
--> 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
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
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)
Rodenticides• Rodents: vectors of disease
– Zinc phosphide - PH3 (cell toxicity,
necrosis, GI, liver, kidneys)
– Fluoroacetic acid and derivatives (Fluoroacetyl-CoA --> fluorocitrate: Krebs cycle collapse)
-naphthyl thiourea (ANTU) must be metabolically activated --> resistance
– Anticoagulants (coumadin, warfarin) - antagonist of vit. K in synthesis of clotting factors; requires multiple doses; resistance