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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…. Sulfur. Chinese - 1000BC Europe - 1800s CA - today !. Arsenic-containing Strychnine

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pesticides

Pesticides

Principles of Toxicology

pesticides2
Pesticides
  • EPA definition: “substances or mixtures of substances intended for preventing, destroying, repelling or mitigating any pest…”
a bit of history
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
later
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”
slide5

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

medical successes
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
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
slide11

Nervous System

Central

Peripheral

Afferent

Efferent

Autonomic

Somatic

Para-Sympathetic

Sympathetic

ENS

anatomic classification
Anatomic Classification

CNS Skull and Spinal cord

PNS 12 pairs of cranial nerves

31 pairs of spinal nerves

afferent

CNS PNS

efferent

slide14

Sympathetic ANS

Fight or flight

Parasympathetic ANS

Rest and digest

slide15

Parasympathetic: Cholinergic

cranio-sacral

Sympathetic: Adrenergic

thoraco-lumbar

slide16

Parasympathetic nerves

4 Cranial

III oculomotor

VII facial

IX glossopharyngial

X vagus

Sacral

S2

S3

S4

slide17

Sympathetic nerves

T1

.

.

.

.

T12

L1

L2

L3

slide18

Afferent  dorsal root

– then divide

Efferent  ventral root

Afferent

Nerves Efferent

Mixed

Neurons

Spinal nerves are mixed for major length

slide20

Pre-ganglionic neuron

organ

Post-ganglionic neuron

Ganglion

Multi-neuron synapse

Neuroeffector junction

slide21

Somatic

Ach

Parasympathetic -cholinergic

Ach

Ach

Sympathetic - adrenergic

Ach

Adr/NA

slide22

Feature SympatheticParasympathetic

Start point thoraco-lumbar cranio-sacral

Ganglion near spine on organ (terminal)

Ganglion synapse Ach Ach

Pregangl. neuron short long

Postgangl. neuron long short

Effector synapse Adr Ach

Effector organs throughout body limited

slide25

Acetylcholine Synthesis

O

CH3C-O-+ HO-CH2-CH2-N+(CH3)3

Acetate

Choline

Choline Acetylase

Coenzyme A

O

CH3C-O-CH2-CH2-N+(CH3)3

Acetylcholine

slide26

Acetylcholine Catabolism

O

CH3C-O-CH2-CH2-N+(CH3)3

CH3C-O- + HO-CH2-CH2-N+(CH3)3

Acetylcholine

Cholinesterase

O

Acetate

Choline

cholinergic receptors
Cholinergic Receptors

Muscarinic:

M1 CNS, sympathetic (exceptions), presynaptic

M2Smooth muscle, heart, presynaptic

M3 Exocrine glands, blood vessels

Nicotinic:

NMskeletal muscle

NN ganglia (post-), presynaptic

slide30

Na+

d

g

a

a

b

Na+

slide31

Outside

Inside

Muscarinic receptor

Agonist

G

protein

slide32

Muscarinic receptor

G- proteins

Excitatory action

Inhibitory action

Phosholipase C

Adenylic cyclase

K+ channels

slide33

Muscarinic receptor stimulation

-

-

-

-

Gi

Signal transduction cascade

involving Adenylic cyclase

Protein Kinase A

slide34

Muscarinic receptor stimulation

Gq

Signal transduction cascade

involving Phospholipase C

slide37

Sympathetic Nerve Terminal

Tyrosine

3

1

mitochondria contains

MAO, oxidizes amines

transport

exocytosis

4

2

DA, Nepi

stored with ATP

in granules

5

a , b

Receptors

re-uptake

slide38

Adr (NA)

synthesis

adrenergic receptors
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

slide40

Adrenergic receptors: a2 and b

-

+

Adenylyl

cyclase

b receptor

a2 receptor

slide41

+

Adrenergic receptors: a1

Phospholipase C

a1 receptor

pesticides42
Pesticides
  • Organochlorines
  • ChE inhibitors
    • Organophosphates
    • Carbamates
  • Phenoxyherbicides
  • Pyrethroids
  • Bromine-based
  • Phenol- derivatives
  • Dipyridyl derivatives
organochlorine insecticides44
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)
  • 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
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
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
Cholinesterase inhibitors
  • Organophosphates (OP) and Carbamates
    • Strong Acute neurotoxicity - AChE inhibition (cholinergic effects)
    • Nervous system toxins - nerve gas (sarin)
slide48

1st OP: TEPP (tetraethylpyrophosphate), followed by parathion

1st carbamic: 1930

WWII chemical warfare

1988 Iraq- against Kurds

1994 Japan

1995 Tokyo subway

slide49

Cholinesterase

O

O

+

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

CH3C-O- + HO-CH2-CH2-N(CH3)3

Esteratic

Anionic

+

slide50

X

X

R1-2

= e- withdrawing

= aliphatic

Organophosphates

O

R1

Parathion

Malathion

Soman

Ecothiophate

P

R2

slide51

Organophosphates

O

Strong Covalent Bond,

Inactivates Enzyme (stable >100h)

R1

X

P

R2

Aging of complex

Anionic

Esteratic

slide52

Organophosphates are slower to release from AchE - “also aging effect”

Carbamates are faster: reversible

Phase I metabolic activation

Multiple metabolic reactions

slide53

Neurobehavioral, muscular and cognitive effects

Delayed Neuropathy (OPIDN) - ginger jake

WHO has a battery of neuropsychological tests

slide57

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

herbicides
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
slide61

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
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%)

LD50=22-262mg/kg

LD50=100-400mg/kg

chloroacetanilides
Chloroacetanilides

Only slight acute toxicity but Carcinogens of category 2B

Metabolic activation to mutagenic metabolite (DEBQ1)

1985 Canada incident (well water contamination)

phosphomonomethyl aminoacids
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)
slide65

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
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
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
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