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Ecobichon, Donald J. : Tocic Effects of Pesticides, in Klaassen, Curtis (Ed) Casarett
& Doull’s Toxicology: The Basic Science of Poisons 6th Edition, Chapter 22,
McGraw-Hill, 2001
A pesticide is any substance or mixture of substances intending for preventing,
destroying, mitigating repelling, or killing any pest. The term pesticide is generic for a
variety of agents that are usually more specifically classified on the basis of the pattern of
use and organism killed (insecticides, herbicides, rodenticides, fungicides, etc.). The
insecticide is the largest and most prominent class.
All of the chemical insecticides in use today are neuro-toxicants and act by
poisoning the nervous system of the insect. The central nervous system (CNS) of insects
is highly developed and not unlike that of mammals. The peripheral nervous system
(PNS) is similar to mammals but not as complex. Given the fact that insecticides are very
selective and affect nontarget species as readily as target organisms, it is not surprising
that an insecticide that acts on the insect nervous system will have similar effects on
higher forms of life. The target site and mechanism(s) of action may be similar for all
species; only the dosage will dictate the intensity of biological effects.
Neurotoxicity. Certain toxicants are specific for neurons, resulting in their injury
or death. The loss of neurons (neuronopathy) is irreversible and includes degeneration of
all its cytoplasmic extensions, dendrites and axons, and the myelin sheath ensheathing the
axon. Because many neurotoxic compounds act at the site of the cell body, when massive
loss of axons and myelin are discovered in the peripheral or central nervous system, the
first question is whether the neuronal cell bodies themselves have been destroyed.
The neurotoxic disorders termed “axonopathies” are those in which the primary
site of toxicity is the axon itself. The axon degenerates (“dying back”), and with it, the
myelin surrounding the axon; however, the cell body remains intact. The distal axon
degenerates progressively from the synapse, back toward the cell body with increasing
injury. The toxicant causes chemical transection of the axon at some point along its
length, and the axon distal to the transection, biologically separated from the cell body,
degenerates. Longer axons have more targets for damage than shorter ones, therefore the
longer ones are affected more. The long axons of the CNS along with the long sensory
and motor axons of the PNS are the most affected. Peripheral axons can regenerate,
whereas central axons cannot. Thus partial recovery can occur after axonal degeneration
in the PNS, whereas the same event in the CNS is irreversible. The number of axonal
toxicants is staggering. Axonal transport appears to be the likely target. As the axons
degenerate, the result is often the clinical condition of peripheral neuropathy, in which
the sensations and motor strength are first impaired in the most distal axonal processes,
the feet and hands. The deficit progresses to involve more proximal areas of the body and
the long axons of the spinal cord. The potential for regeneration is greater when the insult
is limited to the peripheral nerves and may even be complete if the initiating event can be
determined and removed quickly.
A. Effects:
DDT has been one of the best known, cheapest and probably one of the most
effective of the synthetic insecticides. DDT was used extensively during World War II in
control of lice and other insects by application directly to humans. There is no evidence
that harm to these people resulted from this direct application. There seems to be no
undocumented, unequivocal report of fatal human poisoning from DDT in spite of its
widespread use and availability. Acute nonfatal human poisonings have occurred as a
result of accidents or suicide attempts. Although the functional injury produced by high
doses of DDT is usually related to its effects on the central nervous system, i.e.
instability, dizziness, disturbed equilibrium, tremor and convulsions, there is little
pathologic change in the cells and tissues of the central nervous system in acute
poisonings. The locus of primary toxic action of DDT is believed to be sensory and
motor nerve fibers and motor cortex. Humans and animals exposed to high oral (little
toxicity is seen after dermal exposures, it was once applied directly to the heads of
children to control lice) doses of DDT show signs and symptoms of perithecia (burning,
pricking, tickling sensation) of the tongue, lips, and face; apprehension,
hypersusceptibility to external (light, touch, sound) stimuli; irritability; dizziness; vertigo;
tremor; and tonic and chronic convulsions. Liver and reproductive organs (testes) are
sites injured by DDT. There is no documented case of human cancer.
B. Mechanism:
Essential to the action of organochlorine insecticides is an intact reflex arc
consisting of afferent (sensory) peripheral neurons impinging on interneurons in the
spinal cord, with accompanying ramifications and interconnections up and down the CNS
and interconnections with efferent, motor neurons. The most striking observation in a
poisoned person is the display of periodic sequences of persistent tremor and/or
convulsive seizures suggestive of repetitive discharges in neurons. The second most
striking observation is that these repetitive tremors or seizures, tremors, and electrical
activity can be initiated by tactile and auditory stimuli, suggesting that the sensory
nervous system is much more responsive to stimuli.
A prolongation of the falling phase in the action potential (the negative
afterpotential) occurs. The nerve membrane remains in a partially depolarized and
partially polarized state and is extremely sensitive to depolarization again by very small
stimuli. Thus, following exposure to DDT, the repetitive stimulation of the peripheral
sensory nerves by DDT by touch and sound is magnified in the CNS, causing generalized
tremor throughout the body.
DDT affects the permeability of potassium ions, reducing transport across the
membrane. DDT altars the porus channels through which sodium ions pass - these
channels activate (open) normally but once open are inactivated (closed) slowly, thereby
interfering with the active transport of sodium out of the nerve axon during
DDT inhibits neuronal adenosine triphosphatase (ATPase) especially the Na+, K+
- ATPase and Ca2+ -ATPase that play a vital role in neuronal repolarization.
DDT inhibits the ability of calmodulin, a calcium mediator in nerves, to transport
calcium essential for the intraneuronal release of neurotransmitters.
C. Treatment:
In case of ingestion, emesis is indicated unless the patient is comatose or
convulsing. Emesis should be followed by administration of activated charcoal and saline
cathartics. Oil based cathartics should be avoided since these substances enhance the
absorption of the chlorinated hydrocarbon from the gastrointestinal tract. Epinephrine is
contraindicated since it may induce ventricular fibrillation due to the sensitization of the
myocardium by the chlorinated hydrocarbon. Convulsions may be treated with diazepam
(0.1 mg/kg iv).
A. Acute Poisoning.
1. Effects:
The signs and symptoms caused by anticholinesterases are similar and are
explained by the inhibition of acetylcholinesterase, which constitutes the biochemical
lesion. Inhibition of the enzyme permits an abnormal accumulation of acetylcholine;
minimal excess causes (1) excessive activity of the parasympathetic system (miosis,
sweating, profuse secretions in the upper respiratory tract, abdominal cramps and
discomfort in chest from overactivity of smooth muscle, and nausea, vomiting, and
diarrhea); (b) central nervous system effects (headache, giddiness, and nervousness); and
(c) overactivity of the voluntary muscles (fasciculation). A further accumulation of
acetylcholine tends to increase the parasympathetic and central nervous system signs, but
causes profound weakness of the muscles.
2. Mechanisms:
The function of acetylcholinesterase is to hydrolyze and terminate the action of
acetylcholine. Inhibition of the enzyme causes accumulation of acetylcholine and
excessive transmission (overstimulation) in cholinergic nerve endings. Overstimulation
of muscarinic receptors causes hyperactivity of many parasympathetic responses, such as
gastrointestinal manifestations, increased salivation and respiratory secretions, and
miosis. Overstimulation of nicotinic receptors results in depolarization of neurons within
the autonomic (both parasympathetic and sympathetic) ganglia, as well as depolarization
of neuromuscular endplates. The CNS contains both muscarinic and nicotinc receptors.
3. Treatment:
Organophosphate poisoning can be confirmed in the laboratory by documenting a
significant reduction in red blood cell or plasma cholinesterase. Red blood cell
cholinesterase test are preferable because they more accurately reflect nervous tissue
cholinesterase activities. The cholinesterase activities vary considerably among
individuals therefore a reduction more than 50% for plasma cholinesterase or more than
30% for Red Blood Cell cholinesterase is needed in order to confirm the diagnosis.
Laboratory test for cholinesterase activities can take a long time. In an emergency
situation, the clinician may need to start treatment before the tests are completed in order
to prevent tragic results. In this case the physician can make a preliminary clinical test.
Atropine antagonizes many of the central cholinergic effects as well as the peripheral
muscarinic effects (such as miosis) that are consequences of ACh accumulation. A test
dose of atropine (0.05 mg/kg, given intravenously) may be given to confirm that the
problem indeed is due to Ach accumulation. The physician looks for the constricted
pupils to dilate, a sign that confirms the suspected etiology.
Atropine is a competitive antagonist of Ach at muscarinic receptors and should
be used to counter the toxic muscarinic effects. After the initial test dose is given,
atropine (0.05 mg/kg) should be administered intravenously every 10-15 minutes until the
increased salivation and respiratory secretions are reversed and stable. Repeated doses or
a steady atropine drip may be necessary for several days in severe cases.
Although atropine counters the muscarinic effects (including some of the CNS
effects, it is not effective treatment for the nicotinc effects (outside the CNS).
Pralidoxime (2-PAM, 25-50 mg/kg) is administered as soon as the patient receives
atropine. Pralidoxime reacts with the enzyme-inhibitor complex to break the covalent
bond between the OP-AChE complex, thus reactivating the acetylcholinesterase. If the
muscular weakness is not reversed in 1 to 2 hours, the dose is repeated. Atropine + 2Pralidoxime (2-PAM) act synergistically to provide effective therapeutic relief. More
than what would be predicted by the sum of the two individual agents. In the meantime
mechanical ventilation may be required. Note that the pralidoxime does not penetrate the
CNS to a significant degree.
Appropriate therapy also includes nonpharmacologic measures. An adequate
airway must be established and respiration maintained, perhaps by mechanical
ventilation. Respiratory secretions may be copious, and thus suction may be required to
clear the airway. If exposure involves ingestion, either activated charcoal administration
or removal by gastric lavage is indicated. If the exposure is external, the contaminated
clothing should be removed and the skin should be washed.
B. Organophosphate Induced Delayed Neuropathy (OPIDN)
1. Effects:
Clinical effects of delayed neurotoxicity are seen 8 to 14 days after exposure to
neurotoxic organophosphorus compounds. Weakness and ataxia develop in the lower
limbs progressing to paralysis. Recovery is slow and seldom complete.
OPIDN usually takes place in three phases.
a) progressive phase
b) Early- first 3 to 6 months
c) Cramping, burning, tightness, tingling pain in calves of legs (also
ankles and feet)
d) Numbness of feet and legs
e) Weakness and atrophy of peroneal muscles (foot drop)
f) Decreased sensitivity to touch, pain, and temperature
g) Steppage fait
h) Stationary phase
i) Months 3 to 12
j) Paralysis becomes stationary
k) Improvement phase
l) Months 6 to 18
m) Recovery begins with hands (reverse order of symptoms)
n) Mild cases - recovery 18 months
o) Moderate severe cases - recovery greater than 2 years
p) Severe cases - hands show improvement but complete paralysis
remains below the knee
q) Complete recovery unlikely
r) Long lasting effects
Later stages of neurologic deficits have been diagnosed as spinal cord lesions.
Central lesions (persistent and long lasting) become unmasked as peripheral neuropathy
is diminished. The long-lasting effect is characterized by spasticity (excessive muscle
tone or rigidity) and exaggerated knee jerk. This (lasting) condition sometimes leads to a
misdiagnosis as multiple sclerosis (MS) of encephalitis.
2. Prognosis
Some functional improvement from regeneration of peripheral nerves will occur
in mild cases. Regeneration of spinal cord is unlikely. Acute reversible changes in the
spinal cord, such as edema, may subside in time.
3. Mechanism:
Histological examinations have led to the mistaken conclusion that the lesions
were essentially due to the loss of the myelin sheath surrounding the nerve axons. Later
work showed that the nerve axon itself was damaged and that demyelination was only
secondary. "Aging" of the phosphoryl group attached to the esterase is a part of the
delayed neurotoxic mechanism. Acetylcholinesterase is not one of the neurotoxic
esterases, and Parathion (paraoxon) does not produce a delayed neurotoxic effect.
4. Treatment:
Attempts to alleviate the metabolic damage, which occurs after inhibition of
“aging” neurotoxic esterase, must be empirical until the mechanism is understood. The
pathological picture provides no clue as to the nature of the effect. Since the delayed
neurotoxic effect develops slowly, there is merit to attempts to modify the initial event or
alleviate the consequences by administration of drugs, which compete for the binding
sites (pralidoxime) during the early stages following exposure. Diazepam is used to treat
A whole family of chemical compounds has inspired fears, argument, and
passionate debate for some years. Animal studies have shown them to be toxic,
carcinogenic, and teratogenic. They persist in soil and accumulate in the food chain.
Yet no one knows what levels of dioxins harm humans. Studies of people exposed
to dioxins show little evidence that the compounds can be linked to cancer or birth
defects (Sci. Am. 254:29, 1986). Whether this is because the exposures were too brief or
too low to cause harm, or because humans are simply less sensitive to dioxin than other
species, no one knows.
Most dioxins are byproducts of chemical reactions used to make the herbicides
2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T);
the wood preservative pentachlorophenol; and the antibacterial agent hexachlorophene.
Dioxins have been found in the fly ash of municipal incinerators, formed in the burning
of wastes containing chlorine. While all dioxins have been found to be toxic in animal
studies, one in particular, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is referred to even in the scientific literature - as “one of the most toxic man-made compounds known”
(Science 232:497, 1986). TCDD is fat soluble and resistant to metabolic breakdown and
Animal studies suggest that TCDD is immensely toxic; Doses on the order of 1
uG/kg kill guinea pigs readily. Still smaller doses cause cancer and birth defects. Yet
animal studies give a bewildering range of results. Hamsters are 5,000 times as resistant
to dioxin as guinea pigs. Although people exposed to TCDD in industrial accidents have
become ill, no one has died from the acute affects.
Where humans have been exposed to dioxin, those who are sensitive have
suffered liver disorders, loss of sex drive, nerve damage, and - most characteristic - a
severe, persistent skin disorder called chloracne.
How various doses of dioxin affect human health or how long the affects linger is
uncertain. Studies of Vietnam veterans exposed to dioxin-contaminated Agent Orange
have turned up no evidence that the exposure caused birth defects in their children.
Workers exposed to dioxin after a plant explosion in Nitro, West Virginia in 1949 show
no difference in mortality or birth defect incidence from anyone else in the population.
But many workers still had chloracne 30 years later. Further they reported sexual
dysfunction, had decreased sensory perception, and abnormal levels of gamma-glutamyl
transpeptidase, an enzyme associated with keratinization.