Toxicology 410 (2018) 125–131

Contents lists available at ScienceDirect

Toxicology
journal homepage: www.elsevier.com/locate/toxicol

Neurotoxic effects of organophosphorus pesticides and possible association T

with neurodegenerative diseases in man: A review
Milan Jokanović
Experta Consulting, Belgrade, Serbia

A R T I C LE I N FO A B S T R A C T

Keywords: In this article the neurotoxic disorders appearing in patients exposed to organophosphorus pesticides and known
Organophosphorus compounds mechanisms involved are reviewed. Organophosphorus compounds cause four main neurotoxic effects in hu-
Neurotoxicity mans: the cholinergic syndrome, the intermediate syndrome, organophosphate-induced delayed polyneuropathy
Acetylcholinesterase and chronic organophosphate-induced neuropsychiatric disorder. Compared to the cholinergic syndrome, that
Neurodegenerative diseases
causes millions of cases of poisoning with fatality of more than 15% each year, other disorders involve much
Toxicity
smaller number of patients. Possible link of exposure to organophosphorus pesticides with neurodegenerative
diseases, dementia, attention deficit hyperactivity disorder and Parkinson's disease in man is also approached.
This article is focused on neurotoxic disorders appearing after acute and chronic exposure to organophosphates
with emphasis on molecular mechanisms, clinical presentation, pathogenesis, and possibilities for prevention/
medical treatment.

1. Introduction 2. The cholinergic syndrome

Organophosphorus compounds (OP) have been used as pesticides
and developed as warfare nerve agents such as soman, sarin, tabun, VX
and others. Pesticide poisoning results from occupational, accidental,
and intentional exposure (Clark, 2002). The epidemiological pattern of
poisoning shows significant variation in number of deaths and form of
poisoning between developing and industrial countries (Jeyaratnam,
1990; Van der Hoek et al., 1998; Eddleston, 2000; Eddleston and
Phillips, 2004). According to the World Health Organization, about 1
million accidental and 2 million suicidal poisonings with organopho-
sphorus insecticides are reported per year, with more than 300,000
fatalities (Jeyaratnam, 1990). Medical management is difficult, with
case fatality generally more than 15% (Eddleston et al., 2008;
Jokanović et al., 2010).
OP cause four main neurotoxic disorders in humans: the cholinergic
syndrome, the intermediate syndrome, organophosphate-induced de-
layed polyneuropathy (OPIDP) and chronic organophosphate-induced
neuropsychiatric disorder (COPIND). Most of the cases of poisoning can
be prevented by better administrative control, restricted access to OP
pesticides, effective measures of personal protection and education of
OP pesticide applicators and medical personnel.
Signs and symptoms of cholinergic syndrome occurring in acute
poisoning with OP pesticides are predictable from their biochemical
mechanism of action and are directly related to the levels of acet-
ylcholinesterase (AChE) activity. In cases of human poisoning, general
acute symptoms of peripheral nicotinic and muscarinic intoxication are
clearly apparent (World Health Organization, 1986). These symptoms
include miosis; sweating, rhinorrhea, lacrimation, and salivation; ab-
dominal cramps and other gastrointestinal symptoms; respiratory dif-
ficulties and cough; dyspnea, constriction sensation in the chest,
wheezing; twitching of facial muscles and tongue, tremors, and fasci-
culations; bradycardia and electrocardiogram (ECG) changes, pallor,
and cyanosis; anorexia, nausea, vomiting, diarrhea, and involuntary
urination and defecation. These signs and symptoms are accompanied
by central effects such as dizziness, tremulousness, and confusion;
ataxia; headache, fatigue, and paresthesia. Finally, seizures, convul-
sions, twitching, coma, and respiratory failure may occur. If the poi-
soned patient survives the first day of poisoning, there are personality
changes, mood swings, aggressive events and psychotic episodes in-
cluding schizoid reactions, paranoid delusions, and exacerbations of
preexisting psychiatric problems. Sleep is poor due to nightmares and
hallucinations; disturbances or deficits in memory and attention, and
additional delayed effects also occur. Death usually occurs due to re-
spiratory failure resulting from a combination of central and peripheral

E-mail address: milan.jokanovic@gmail.com.

https://doi.org/10.1016/j.tox.2018.09.009
Received 23 March 2018; Received in revised form 4 September 2018; Accepted 6 September 2018
Available online 25 September 2018
0300-483X/ © 2018 Elsevier B.V. All rights reserved.

Descargado para LUIS HERRERA GUTIERREZ (l.herrera1406@gmail.com) en Antenor Orrego Private University de ClinicalKey.es por Elsevier en mayo 17, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
M. Jokanović
effects, paralysis of the respiratory muscles, and depression of the brain
respiratory center (Karchmar, 2007; World Health Organization, 1986;
IPCS, 1998; Clark, 2002; Eyer, 2003; Marrs and Vale, 2006; Jokanović
et al., 2011).
The first four to six hours are the most critical in acute poisoning
with OP pesticides. If there is improvement in symptoms after initial
treatment then the patient is very likely to survive if adequate treat-
ment is continued (IPCS, 1998).
The mechanism of cholinergic syndrome involves inhibition of
AChE at synapses and neuromuscular junctions in cholinergic pathways
leading to accumulation of acetylcholine and overstimulation of post-
synaptic muscarinic and nicotinic receptors. Inhibition of AChE occurs
after phosphorylation of hydroxyl group at serine at the active site of
the enzyme. Following inhibition, AChE can be spontaneously re-
activated at the rate that depends on chemical structure of OP. For OP
having dimethyl radicals the AChE reactivation is relatively rapid with
a half-time of about 1–2 h, while that for OP having diethyl functional
groups is 31–57 h. For OP belonging to the group of warfare nerve
agents (soman, sarin, tabun, VX) having branched radicals spontaneous
AChE reactivation does not occur at all. For certain OP, an additional
step can occur on phosphorylated AChE known as aging reaction that
represents non-enzymatic time-dependent loss of one alkyl group (R)
bound to the phosphorus. The aging reaction depends on the chemical
structure of the inhibitor and leads to a stable non-reactivatable form of
phosphorylated AChE (Reiner and Pleština, 1979; Worek et al., 1999;
Jokanović and Stojiljković, 2006; Jokanović and Prostran, 2009;
Jokanović, 2012a).
The duration of effects is determined mainly by the properties of the
compound: its liposolubility, the stability of the OP-AChE complex and
whether it is reactivatable after the use of cholinesterase reactivators
(such as oximes). It is important to note that only OP containing P]O
bond (known as direct inhibitors) are potent AChE inhibitors; those
having a P]S group (indirect inhibitors) must be metabolically acti-
vated to P]O group (Jokanović, 2001). The signs and symptoms of
poisoning with direct inhibitors appear quickly during or after ex-
posure, while those with indirect inhibitors appear slowly and last
longer, even up to several days after cessation of exposure.
Clinical diagnosis of acute poisoning with OP compounds is rela-
tively simple and is based on medical history, circumstances of ex-
posure, clinical presentation, and laboratory tests. Confirmation of di-
agnosis can be made by measurement of erythrocyte AChE or plasma
cholinesterase (ChE). Activities of these enzymes have been accepted as
biomarkers of exposure and/or toxicity of OP. Erythrocyte AChE is
identical to the enzyme present in the target synapses and its levels are
assumed to reflect the effects in target organs. For that reason, ery-
throcyte AChE is regarded as biomarker of toxicity of these compounds.
On the other hand, ChE is also an esterase that can react with OP in the
same was as AChE. While the effects of inhibition of AChE can be fatal
(depending on the dose taken), inhibition of ChE does not have any
known consequences on the normal body functions (Jokanović and
Maksimović, 1997). ChE is a circulating plasma glycoprotein synthe-
sised in the liver, which does not serve any known physiological
function. Since ChE (EC 3.1.1.8) is classified as different enzyme from
AChE (EC 3.1.1.7), not being involved in cholinergic transmission in the
nervous system, it does not provide accurate information regarding the
severity of the OP poisoning (Jokanović, 2009, 2012b). Many OP in-
secticides (e.g. chlorpyrifos, demethon, malathion) appear to be more
potent inhibitors of ChE than they are of erythrocyte AChE and, as the
consequence, ChE inhibition might occur to a greater extent than AChE
inhibition (Jokanović, 2009, 2012b).
3. The intermediate syndrome
Clinical manifestations of the intermediate syndrome (IMS) occur
within 24 to 96 h after exposure to OP when the symptoms of the
cholinergic syndrome (e.g. muscle fasciculations, muscarinic signs) are
126
Descargado para LUIS HERRERA GUTIERREZ (l.herrera1406@gmail.com) en Antenor Orrego Private University de ClinicalKey.es por Elsevier en mayo 17, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
Toxicology 410 (2018) 125–131
no longer apparent (Senanayake and Karalliedde, 1987) and before the
onset of organophosphate-induced delayed polyneuropathy (OPIDP,
discussed in the following section). Following exposure to various OP
pesticides, clinical manifestations of IMS typically occur within 24 to
96 h, and affect patients without fasciculation or other cholinergic
signs. The incidence of IMS is between 7.7% and 84% cases with OP
poisoning (John et al., 2003). Jayawardane et al. (2009) defined IMS as
a spectrum disorder affecting the neuromuscular junction with two
main forms: a forme fruste variety associated with mild weakness and
the classical IMS with weakness of 3/5 or less than 3/5 on the Medical
Research Council grading where the patients from the latter category
are at risk of developing late onset respiratory failure. Although IMS is
well recognized as a disorder of neuromuscular junctions, its exact
etiology, incidence, and risk factors are not clearly understood. IMS
generally occurred among patients with prolonged and severe inhibi-
tion of AChE and consequent persistent excess of ACh in the neuro-
muscular junctions, but not in every patient (Yang and Deng, 2007).
Other risk factors of IMS involve delayed metabolism of OP pesticides,
impaired organ function, severity of poisoning, elevated muscle en-
zymes, and inadequate or delayed therapy with atropine and pyr-
idinium oximes. IMS has been linked with exposure to specific OP
pesticides having dimethyl phosphate structure (e.g. fenthion, di-
methoate, monocrotophos, dichlorvos, methylparathion), but also de-
veloped after exposure to parathion (ethyl phosphate) and methami-
dophos (phosphoramidate) (De Bleecker et al., 1993; Yang and Deng,
2007; Balali-Mood and Balali-Mood, 2008; Bird et al., 2016). Two ty-
pical cases of IMS caused by fenthion and diazinon were discussed by
Jokanović et al. (2010). So far, the IMS has not been reported after
poisoning with warfare nerve agents (Balali-Mood and Saber, 2012).
A case of carbofuran-induced IMS, possibly indicating the same
mechanisms of OP- and carbamate-induced IMS, was reported by Paul
and Mannathukkaran (2005).
Marked weakness of neck flexion and varying degree of proximal
limb muscle weakness, manifesting as weakness of shoulder abduction
and hip flexion, are the regular clinical features. Respiratory in-
sufficiency is also common and frequently draws medical attention to
the onset of the syndrome. Other possible manifestations are involve-
ment of muscles innervated by motor cranial nerves and decreased deep
tendon reflexes. Studies conducted in nineties have shown that IMS
goes along with excretion of cholinesterase inhibitor metabolites in the
urine and by severe depression in cholinesterase levels. It was suggested
that the condition might reflect the recirculation of lipid soluble cho-
linesterase inhibitors from body fat compartments or gastric fluids (De
Bleecker, 2006).
John et al. (2003) demonstrated an association between the devel-
opment of IMS and increased activity of enzymes creatine phosphoki-
nase and lactate dehydrogenase, the markers of muscle function, in 25
patients with acute organophosphate poisoning. Muscle injury was seen
in all patients beginning at admission, peaking over the first 5 days and
then declining over the next 5 days. Khan et al. (2001) and Dhandapani
et al. (2003) demonstrated that oxidative cellular damage of muscle
membranes could be associated with muscle necrosis. In a prospective
study conducted by De Bleecker (1995) muscle biopsy performed in 19
patients with OP poisoning showed only minimal number of necrotic
fibers. IMS might involve the reduction in number of functioning cho-
linergic receptors at the postjunctional membrane, or a failure of
acetylcholine release. All these abnormal findings on electromyography
suggested a combined presynaptic and postsynaptic defect, without
sensory impairment (Baker and Sedgwick, 1996). Abdollahi and
Karami-Mohajeri (2012) suggested additional mechanisms of IMS in-
cluding prolonged AChE inhibition, muscle necrosis, down regulation
or desensitization of postsynaptic ACh receptors and oxidative stress-
related myopathy.
Management resembles that of rapidly developing respiratory dis-
tress and failure. Delays in instituting respiratory support may result in
death. The respiratory support is required during 7–21 days. In patients
M. Jokanović
with IMS continuous and careful monitoring of respiratory function
(partial pressure of O2 and CO2 in arterial blood, arterial O2 saturation)
and blood pH are necessary (Karalliedde et al., 2006). The recovery
among patients who survived IMS starts with the improvement of
muscular power in cranial nerve-innervated muscles, followed by re-
spiratory muscles, proximal muscles, and neck flexors. As IMS generally
takes place at the same time with severe OP toxicity and persistent
inhibition of AChE, early gastrointestinal decontamination, followed by
appropriate treatment with atropine and oximes, and prompt initiation
of respiratory support, should be helpful in ameliorating the severity of
IMS. Yilmaz et al. (2013) reported clinical improvement in 13 out of 17
patients with IMS treated with therapeutic plasma exchange performed
with fresh frozen plasma. The prognosis of IMS appears to be favorable
if respiratory failure can be promptly recognized and treated accord-
ingly (De Bleecker et al., 1993; De Bleecker, 2006; Karalliedde et al.,
2006; Yang and Deng, 2007).
4. Organophosphate induced delayed polyneuropathy
OPIDP is a unique toxicological phenomenon caused by a single
exposure to certain OP with effects usually appearing after 10 to 20
days or later. OPIDP is toxicologically different from the cholinergic
syndrome in that it is based on different mechanisms not involving
AChE and appearing a few weeks after cholinergic syndrome has been
medically solved with standard therapeutic measures and patient
usually dismissed from hospital. OPIDP is also a different syndrome
from IMS.
There were two major outbreaks of OP poisoning in which OPIDP
appeared in thousands cases of poisoning with triorthocresyl phosphate
(TOCP) that occurred mainly due to beverage and food contamination
in USA in 1930 and Morocco in 1959 (Johnson, 1982; Morgan, 1982;
Lotti, 1992; Jokanović et al., 2004). Many cases of OPIDP due to TOCP
poisoning were reported in Romania, Sri Lanka, former Yugoslavia and
China. In addition to TOCP, several other OP pesticides have been re-
ported to cause OPIDP in man (Jokanović et al., 2002; Lotti and
Moretto, 2005; Jokanović and Kosanović, 2010; Jokanović et al., 2011;
Satoh and Jokanović, 2014; Jokanović, 2017). Cases of OPIDP caused
by pesticides were discussed in more details by Lotti and Moretto
(2005).
OPIDP is a rare neurodegenerative disorder in humans character-
ized by loss of function and ataxia of distal parts of sensory and motor
axons in peripheral nerves and ascending and descending tracts of
spinal cord. The early neurological symptoms usually are sharp, cramp-
like pains in the calves, tingling in the feet and hands followed by distal
numbness and parenthesis. Pain and weakness in muscles spread and
patients rapidly become unable to keep their balance. Progressive leg
weakness occurs with depression of tendon reflexes. Symptoms also
appear in the arms and forearms. Sensory loss may be mild. Muscle
tonus of the limbs gradually increase and spasticity appears in the lower
limbs. Physical examination reveals distal symmetrical mostly motor
polyneuropathy, with flaccid weakness of distal limb muscles in the
lower limbs. In severe OPIDP quadriplegia with foot and wrist drop
were observed as well as mild pyramidal signs (Lotti, 1992). Some
functional recovery may be seen in less severe cases with more distal
involvement and sparing of spinal cord axons, but pyramidal and other
signs of central neurological involvement appear with time. It appears
that clinical signs of OPIDP in children are considerably milder than in
adults. The recovery was observed only sensory nerves, while motor
neurons may permanently lose its function as confirmed by Morgan
(1982) who described the lack of improvement during 47 years in 11
patients poisoned with TOCP. Similar findings were also reported by
Tosi et al. (1994) who found still persistent symptoms of OPIDP in 7
patients poisoned with TOCP 50 years ago. However, the study pre-
sented by Wang et al. [12] conducted 13 years after TOCP poisoning of
74 patients revealed that out of 61 survivors, 35 patients almost re-
gained normal function of limbs and work outside; 23 patients walked
127
Descargado para LUIS HERRERA GUTIERREZ (l.herrera1406@gmail.com) en Antenor Orrego Private University de ClinicalKey.es por Elsevier en mayo 17, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
Toxicology 410 (2018) 125–131
with bilateral support and could perform housework; and 3 patients
could not self-care. Neurophysiological investigations showed normal
electroencephalogram and visual, brainstem auditory and somatosen-
sory evoked potentials. Motor evoked potential obtained from the upper
limbs had normal central motor conduction time, but it was delayed or
absent in bilateral lower limbs. Motor and sensory nerve conduction
velocity and electromyography studies were normal except for two
severely affected patients. The prognosis for functional recovery de-
pends on the degree of pyramidal involvement with ataxia and paralysis
representing a permanent outcome of severe OPIDP (Jokanović, 2017).
Several mechanisms of OPIDP have been proposed. OPIDP is in-
itiated by phosphorylation and subsequent aging of > 70% the enzyme
originally known as neurotoxic esterase, but later renamed to neuro-
pathy target esterase (NTE) in peripheral nerves (Johnson, 1982; Lotti,
1992). NTE was discovered by Martin Johnson, who described its most
important toxicological and biochemical features (Johnson, 1982). NTE
is an integral membrane protein in vertebrate neurons present in all
neurons, but not in glia (Glynn, 1999; Li et al., 2003). It is codified by
gene PNPLA6 (Sogorb et al., 2016). The active site of NTE contains
Ser966 and two aspartates Asp960 and Asp1086 that appear essential for
enzymatic activity. The physiological substrate for NTE is considered to
be lysolecithin (Quistad et al., 2003). NTE regulates phospholipid me-
tabolism and is known to be a phospholipase B (Read et al., 2009;
Chang and Wu, 2010. Inactivation of NTE may reduce the degradation
of phosphatidylcholine to glycerophosphocholine. The deficiency of the
NTE activity may lead to abnormal accumulation of phosphatidylcho-
line-containing membranes in cells, which may interfere with normal
membrane lipid homeostasis and fluidity affecting the initiation of
neurites. Since NTE hydrolyzes lysolecithin (Vose et al., 2008; Greiner
et al., 2010), the delay in initiation of neurites may also be caused by an
abnormal accumulation of lysolecithin in NTE-deficient cells (Li et al.,
2005).
Sogorb et al. (2016) suggested that gene PNPLA6 and/or the NTE
protein might play a role in early neurodifferentiation stages. NTE is
involved in intracellular membrane trafficking and cell-signaling
pathway between neurons and glial cells (Glynn, 2006). There is a re-
lationship between NTE activity and the axonal maintenance since it
facilitates the transport of macromolecules from the neuron to the distal
ends of long axons (Read et al., 2009).
It was also suggested that NTE may be involved in the regulation of
calcium entrance into cells being responsible for the maintenance of
normal function of calcium channels, and that increasing calcium ac-
tivated neutral protease activity is responsible for triggering OPIDP
(Emerick et al., 2010). Song and Xie (2012) proposed that the activa-
tion of calpains (calcium-dependent cysteine proteases) plays a critical
role in OPIDN. The molecular mechanisms involved is still unclear.
Medical treatment of OPIDP in humans is symptomatic. Standard
treatment of OP poisoned patients comprising atropine, oxime and
diazepam was not effective in treatment of OPIDP. However, there were
several reports in the literature describing attempts of treatment of
OPIDP in animals and these studies were reviewed by Lotti (1992) and
Jokanović et al. (2004), but none of these treatments have been tested
in patients so far.
5. Chronic organophosphate-induced neuropsychiatric disorder
Chronic exposure to OP has been associated with impaired neuro-
behavioral performance in some, but not all, epidemiological studies
(Ray and Richards, 2001). Chronic organophosphate-induced neu-
ropsychiatric disorders (COPIND) occur without cholinergic symptoms
and apparently are not dependent on AChE inhibition (Ray and
Richards, 2001; Singh and Sharma, 2000). COPIND usually appears
with a delay and persists for a long period possibly suggesting the
permanent damage of the central nervous system (Savage et al., 1988;
De Silva et al., 2006; Tan et al., 2009). The most common symptoms of
COPIND include cognitive deficit (impairment in memory,
M. Jokanović
concentration and learning, problems with attention, information pro-
cessing, eye-hand coordination and reaction time), mood change (an-
xiety, depression, psychotic symptoms, emotional lability), chronic fa-
tigue, autonomic dysfunction, peripheral neuropathy and
extrapyramidal symptoms such as dystonia, resting tremor, bradiky-
nesia, postural instability and rigidity of face muscles (Jokanović et al.,
2011; Ray and Richards, 2001; Singh and Sharma, 2000; Ahmed and
Davies, 1997; Davies et al., 2000a; Salvi et al., 2003; Kamel and
Hoppin, 2004; London et al., 2005; Roldan-Tapia et al., 2005; Ross
et al., 2013; Venkategowda et al., 2015; Jamal et al., 2016; Taghavian
et al., 2016). Suicidality and alcohol intolerance have also been re-
ported (Davies et al., 2000a).
In children exposed to OPs impairment of memory, attention, verbal
learning, behavioral and motor coordination were observed (Ruckart
et al., 2004). Some of the findings in these studies were apparently too
subtle to be detected by a general neurological examination (Pope,
2006).
Similar clinical features have also been reported by soldiers suf-
fering from the Gulf-War Syndrome, which led to the hypothesis that
the illness was caused by chronic exposure to chemical warfare agents
with similar effects to OP pesticides (Gronseth, 2005). However, as
there was no correlation between the cause and the effect, it was con-
sidered unlikely that Gulf War veterans were suffering chronic effects
from illnesses caused by chemical warfare agent exposure (Riddle et al.,
2003; Lotti, 2002).
Kawana et al. (2001) investigated psychological and physiological
symptoms in 582 sarin poisoned patients after the Tokyo subway
system terrorist attack on March 20, 1995. The patients were given
emergency care at St. Luke’s International Hospital on the day of the
attack. It was demonstrated that victims of the Tokyo sarin attack
continued to suffer from physical and physiological symptoms 5 years
after. The most common physical symptoms reported were eye symp-
toms (tiredness of eyes, dim vision, difficulty with eye accomodation
and distance vision, focus), tiredness, fatigue, muscle stiffness and
headache. Psychological symptoms did not decrease over the 5 years of
the study except for depressed mood. Ten years after the Matsumoto
and Tokyo accidents long-lasting psychological problems (such as for-
getfulness, chronic lack of concentration, depressive mood) were still
evident (Yanagisawa et al., 2006).
Diagnostic criteria for COPIND include (Davies et al., 2000b):
1 Repeated exposure to OP;
2 At least four of the following: a) personality change and destabili-
zation of mood, b) impairment of concentration, c) impaired ex-
ercise tolerance, d) reduced tolerance to alcohol, e) increased sen-
sitivity to OP;
3 At least three of the following: a) exacerbation of “dippers flu”, b)
impulsive suicidal thinking, c) language disorder, d) improved sense
of smell, e) deterioration of handwriting.
In several epidemiological studies conducted among farm workers
and pesticide applicators, neuropsychological damage accompanied
with damage of peripheral nervous system, anxiety and depression
were predominant among the exposed group (Steenland et al., 1994;
London et al., 1998; Bessler and Stallones, 2008; Bayrami et al., 2012).
Agricultural workers tested about two years after a pesticide exposure
episode showed significantly lower performance in verbal and visual
attention, visual memory, sequencing and problem solving (Rosenstock
et al., 1991). Savage et al. (1988) showed abnormalities in psycho-
metric testing and motor reflexes. Farm workers with symptoms of mild
OP pesticides intoxication requiring no hospitalization performed
worse on tests of cognitive and psychomotor function than non-exposed
workers tested 2 years later. During the process of dipping sheep into
the basin with insecticide, workers exposed to OPs developed greater
vulnerability to psychiatric disorders such as significant anxiety and
depression (Jamal, 1997; Kamel and Hoppin, 2004). A literature review
128
Descargado para LUIS HERRERA GUTIERREZ (l.herrera1406@gmail.com) en Antenor Orrego Private University de ClinicalKey.es por Elsevier en mayo 17, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
Toxicology 410 (2018) 125–131
of mortality and morbidity studies related to suicide among pesticide-
exposed populations, revealed high suicide rates in farming populations
(Parron et al., 1996).
The underlying mechanism of COPIND has not been established.
Tan et al. (2009) hypothesized that COPIND could be derived from
withdrawal of OP pesticide after chronic low-level exposure or acute
exposure. Other scientists have suggested that mechanisms other than
inhibition of AChE might also be involved. These alternative mechan-
isms may involve other protein targets (such as serine hydrolases, acyl
peptide hydrolase) present in the nervous system, interacting with some
OPs, that may be changed even after low level exposure leading to
cognitive damage (Ray, 1998; Ray and Richards, 2001; Pancetti et al.,
2007). Several animal studies have shown that cognitive enhancing
action of low doses of certain OPs, such as dichlorvos, in rats were
unrelated to AChE inhibition. It was suggested that OPs may affect
neuropeptide metabolism through the release of endogenous opiates
and/or through interactions with yet unidentified receptors (Kohen
et al., 1980; Kubek et al., 1997; Desi and Nagymajtenyi, 1999). It has
also been observed that administration of different OPs has different
behavioral presentation, suggesting that observed effects are not en-
tirely a result of AChE inhibition (Pope et al., 1992; van Dongen and
Wolthuis, 1989v). London et al. (2005) reported that exposure to OPs
may cause serotonin disturbances in the central nervous system, which
are implicated in depression and suicidal behavior in humans. Rohlman
et al. (2011) suggested that oxidative stress and inflammation being
mechanistically linked to chronic OP neurotoxicity correlate well with
neurobehavioral deficits observed consequent to neurodegenerative
diseases (Rohlman et al., 2011).
6. The link between exposure to OP pesticides and neurotoxic and
neurodegenerative diseases in man
Most epidemiological studies of occupational exposure to pesticides
are apparently of limited value due to the lack an adequate tox-
icological evaluation. Most of them did not have a correlation between
the specific cause and the effect. In many cases the pesticides were not
even identified and the information about the exposure is obtained only
through certain undefined questionnaires and interviews whose re-
levance is unclear. The most important problems with these studies are:
1) not making any difference between chemical structure and me-
chanisms of toxicity of the pesticides involved; 2) not considering the
presence and effects of chronic exposure to organic solvents and/or
diluents that are present in much higher quantities in technical pesti-
cide formulation than active substance; 3) the possible presence of
toxicologically relevant impurities and/or isomers was not considered;
4) exposure to pesticides was not clearly described in terms of dose
level and duration of exposure, detection of pesticides and/or their
metabolites in blood/urine or human tissues, whether safety equipment
was applied; 5) there was no indication whether different types of
pesticides were used during the spraying season in the same area and
the possibility of exposure to different pesticides at the same time; 6) in
case of OP insecticides the levels of AChE and ChE activity as well as
interaction with the enzymes involved in metabolism of OP compounds
(carboxylesterases, paraoxonases, CYP450's) were not considered.
Given the above limitations, in this study only the results of the
studies where exposure to OP pesticides was confirmed will be sum-
marized.
6.1. OP and Alzheimer’s dementia (AD)
The analysis of exposures associated with incidence of AD revealed
that in workers occupationally exposed to OP the risk is increased by
1.5 times (Hayden et al., 2010).
Rothlein et al. (2006) compared the neurobehavioral performance
of 92 Hispanic immigrant farmworkers with 45 non-agricultural con-
trols matched by age and educational level. They found that
M. Jokanović
farmworkers performed worse than controls but more importantly there
was a positive correlation between urinary OP metabolite levels and
poorer performance on some neurobehavioral tests, thus confirming
that low level long term occupational exposure to organophosphates
could adversely affect cognitive performance.
It has been observed that individuals exposed to OP display memory
and learning impairment, especially after acute poisoning. Patients
seriously poisoned with OP can be subject to nonspecific brain injury
(such as anoxia) possibly indicating direct neurotoxic effects of OP.
However, current biomarkers of organophosphate exposure (such as
blood cholinesterase activity and urinary levels of OP metabolites) do
not correlate consistently with neurobehavioral performance (Rohlman
et al., 2011).
Another association of OP to AD comes from a number of studies
reporting that certain polymorphisms on the PON1 gene for
Paraoxonase 1, in accordance with similar results obtained in PD stu-
dies (Manthripragada et al., 2010), correlated to increased risk for AD
(Zaganas et al., 2013).
6.2. OP and attention deficit hyperactivity disorder (ADHD)
Elevated odds ratio of 1.5 and 5.1 for ADHD have been linked with
OPs by two studies examining the exposure via urine and blood samples
(Bouchard et al., 2010; Suarez-Lopez et al., 2013). Comparing the cases
of ADHD with control regarding exposure to OPs indicated that the
biomarkers of OPs were 2–3 times more detectable in the urine sample
of the cases than that of controls (Yu et al., 2016).
A cohort study measuring the OP biomarkers in the urine samples of
the mothers revealed an odds ratio of 1.3 for the risk of ADHD in as-
sociation with maternal exposure to OPs (Marks et al., 2010). Another
study measuring the urine concentration of OPs indicated that maternal
exposure to chlorpyrifos increased the risk of ADHD in boys and at-
tention deficit in girls with respective odds ratio 5.5 and 5.8
(Fortenberry et al., 2014). The link between prenatal exposure to
chlorpyrifos and higher incidence of ADHD with a risk estimate of 6.5
was resulted from a cohort study examining the exposure via blood
level measurement of the pesticides (Rauh et al., 2011; Mostafalou and
Abdollahi, 2017).
Epidemiological studies connecting exposure to OP pesticides and
neurodevelopment have focused on populations with high exposure
relative to the general population. Prenatal exposure to OP pesticides
was associated with increased risk of developmental disorders, delays in
cognitive development, and attentional deficits (Eskenazi et al., 2007;
Bouchard et al., 2011; Marks et al., 2010; Engel et al., 2007; Rauh et al.,
2011). Postnatal OP exposure has been associated with behavioral
problems, poorer short-term memory and motor skills, and longer re-
action time in children (London et al., 2012).
The later study examined the cross-sectional association between
urinary dialkyl phosphate metabolite concentrations and ADHD pre-
valence in children of ages 8–15 years. The urinary dialkyl phosphate
metabolites measured in this study were 3-dimethyl alkylphosphate
molecules and 3-diethyl alkylphosphate molecules. The study was
conducted in 1139 children aged 8–15 years. The metabolite di-
methylthiophosphate was the most commonly detected 3-dimethyl al-
kylphosphate (in 64.3% of children). Children with creatinine adjusted
dimethylthiophosphate concentrations above the median of detectable
values had double the odds of ADHD compared to those with con-
centrations below the detection (London et al., 2012).
The odds of meeting the diagnostic criteria for hyperactive im-
pulsive subtype increased significantly with higher 3-diethyl alkyl-
phosphate, 3-dimethyl alkylphosphate, and total dialkyl phosphate
(adjusted odds ratio for a 10-fold increase in concentration 2.2 and 1.9
respectively). The odds of inattentive subtype increased with higher
concentrations of 3-dimethyl alkylphosphate metabolites although this
did not reach significance level (adjusted odds ratio 1.5). The study
indicated an association between urinary 3-dimethyl alkylphosphate
129
Descargado para LUIS HERRERA GUTIERREZ (l.herrera1406@gmail.com) en Antenor Orrego Private University de ClinicalKey.es por Elsevier en mayo 17, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
Toxicology 410 (2018) 125–131
metabolite concentrations (indicators of exposure to dimethyl OPs) and
increased odds of ADHD in children 8–15 years. There was a 55–72%
increase in the odds of ADHD for a 10-fold increase in 3-dimethyl al-
kylphosphate concentration. The authors concluded that the results
support the hypothesis that current levels of OP pesticides exposure
may contribute to ADHD prevalence (London et al., 2012).
6.3. OP and Parkinson's disease (PD)
Environmental exposure to chlorpyrifos has been compared be-
tween cases of PD and the matched controls by an analysis of ground-
water. It was found that elevated risk of PD after using well water
contaminated with chlorpyrifos was 1.87-fold (Gatto et al., 2009). In
another similar study it was reported that residential exposure to
chlorpyrifos and diazinon increased the risk of PD by more than two
times (Manthripragada et al., 2010). Increased risk of PD after exposure
to OP insectides (mainly chlorpyrifos) was shown as odd ratio of 1.7
(Mostafalou and Abdollahi, 2017; Narayan et al., 2013).
A more than 2-fold increase in the risk of PD incidence was asso-
ciated with chlorpyrifos use in Texan agricultural workers (Dhillon
et al., 2008), and with potential exposure to high chlorpyrifos levels
through well-water consumption in residents of rural California (Gatto
et al., 2009). When PON1 was taken into consideration it was found
that the association between potential exposure to chlorpyrifos and PD
risk was strengthened (by around 3-fold) in carriers of the PON1 55 MM
variant, which encodes for possible functional variants of xenobiotic
metabolizing enzymes (Manthripragada et al., 2010; Freire and
Koifman, 2012).
In conclusion, in this article the neurotoxic disorders appearing in
patients poisoned with OP pesticides and known mechanisms involved
are reviewed. OP cause four main neurotoxic effects in humans: the
cholinergic syndrome, the intermediate syndrome, organophosphate-
induced delayed polyneuropathy and chronic organophosphate-in-
duced neuropsychiatric disorder. Compared to the cholinergic syn-
drome, that causes millions of cases of poisoning with fatality of more
than 15% each year, other disorders involve much smaller number of
patients. Possible link of exposure to organophosphorus pesticides with
neurodegenerative diseases, dementia, attention deficit hyperactivity
disorder and Parkinson's disease in man is also approached. This article
is focused of neurotoxic disorders appearing after acute and chronic
exposure to OP with emphasis on molecular mechanisms, clinical pre-
sentation, pathogenesis, and possibilities for prevention/medical
treatment.
Conflict of interest
None.
Acknowledgement
This study was supported in part by the Ministry of Education,
Science and Technological Development of the Republic of Serbia
(Project 175045).
References
Abdollahi, M., Karami-Mohajeri, S., 2012. A comprehensive review on experimental and
clinical findings in intermediate syndrome caused by organophosphate poisoning.
Toxicol. Appl. Pharmacol. 258, 309–314.
Ahmed, G.M., Davies, D.R., 1997. Chronic organophosphate exposure: toward the defi-
nition of a neuropsychiatric syndrome. J. Nutr. Environ. Med. 7, 169–176.
Baker, D.J., Sedgwick, F.M., 1996. Single fiber electromyographic changes in man after
organophosphate exposure. Hum. Exp. Toxicol. 15, 369–375.
Balali-Mood, M., Balali-Mood, K., 2008. Neurotoxic disorders of organophosphorous
compounds and their managements. Arch. Ir. Med. 11, 65–89.
Balali-Mood, M., Saber, H., 2012. Recent advances in the treatment of organopho-
sphorous poisonings. Iran. J. Med. Sci. 37, 74–91.
Bayrami, M., Hashemi, T., Malekirad, A.A., Ashayeri, H., Faraji, F., Abdollahi, M., 2012.
M. Jokanović
Electroencephalogram, cognitive state, psychological disorders, clinical symptom,
and oxidative stress in horticulture farmers exposed to organophosphate pesticides.
Toxicol. Ind. Health 28, 90–96.
Bessler, C.L., Stallones, L., 2008. A cohort study of pesticide poisoning and depression in
Colorado farm residents. Ann. Epidemiol. 18, 768–774.
Bird, S.B., Krajačić, P., Sawamoto, K., Bunya, N., Loro, E., Khurana, T.S., 2016.
Pharmacotherapy to protect the neuromuscular junction after acute organopho-
sphorus pesticide poisoning. Ann. N.Y. Acad. Sci. 1374 (1), 86–93.
Bouchard, M.F., Bellinger, D.C., Wright, R.O., Weisskopf, M.G., 2010. Attention-deficit/
hyperactivity disorder and urinary metabolites of organophosphate pesticides.
Pediatrics 125, e1270–e1277.
Bouchard, M.F., Chevrier, J., Harley, K.G., Kogut, K., Vedar, M., Calderon, N., Trujillo, C.,
Johnson, C., Bradman, A., Barr, D.B., Eskenazi, B., 2011. Prenatal exposure to or-
ganophosphate pesticides and IQ in 7-year-old children. Environ. Health Perspect.
119, 1189–1195.
Chang, P.A., Wu, Y.J., 2010. Neuropathy target esterase: an essential enzyme for neural
development and axonal maintenance. Int. J. Biochem. Cell Biol. 42, 573–575.
Clark, R.F., 2002. Insecticides: organic phosphorus compounds and carbamates.
Goldfrank’s Toxicological Emergencies, 7 ed. McGraw-Hill Professional, New York,
pp. 1346–1360.
Davies, R., Ghouse, A., Tegwedd, F., 2000a. Chronic exposure to organophosphates:
background and clinical picture. Adv. Psychiatr. Treat. 6, 187–192.
Davies, R., Ghouse, A., Tegwedd, F., 2000b. Psychiatric aspects of chronic exposure to
organophosphates: diagnosis and management. Adv. Psychiatr. Treat. 6, 356–361.
De Bleecker, J., 1995. The intermediate syndrome in organophosphate poisoning: an
overview of experimental and clinical observations. J. Toxicol. Clin. Toxicol. 33,
683–686.
De Bleecker, J.L., 2006. Intermediate syndrome in organophosphate poisoning. In: Gupta,
R.C. (Ed.), Toxicology of Organophosphate and Carbamate Compounds. Elsevier
Academic Press, Amsterdam, pp. 371–380 Chapter 26.
De Bleecker, J., Van Den Neucker, K., Colardyn, F., 1993. Intermediate syndrome in or-
ganophosphorus poisoning: a prospective study. Crit. Care Med. 21, 1706–1711.
De Silva, H.J., Samarawickrema, N.A., Wickremasinghe, A.R., 2006. Toxicity due to or-
ganophosphorus compounds: what about chronic exposure? Trans. Roy. Soc. Trop.
Med. Hyg. 100, 803–806.
Desi, I., Nagymajtenyi, L., 1999. Electrophysiological biomarkers of an organopho-
sphorous pesticide, dichlorvos. Toxicol. Lett. 107, 55–64.
Dhandapani, M., Zachariah, A., Kavitha, M.R., Jeyaseelan, L., Oommen, A., 2003.
Oxidative damage in intermediate syndrome of acute organophosphorus poisoning.
Ind. J. Med. Res. 117, 253–259.
Dhillon, A.S., Tarbutton, G.L., Levin, J.L., Plotkin, G.M., Lowry, L.K., Nalbone, J.T.,
Shepherd, S., 2008. Pesticide/environmental exposures and parkinson’s disease in
east texas. J. Agromed. 13, 37–48.
Eddleston, M., 2000. Patterns and problems of deliberate self-poisoning in the developing
world. QJM 93, 715–731.
Eddleston, M., Phillips, M.R., 2004. Self-poisoning with pesticides. BMJ 328, 42–44.
Eddleston, M., Juszczak, E., Buckley, N.A., Senarathna, L., Mohamed, F., Dissanayake, W.,
Hittarage, A., Azher, S., Jeganathan, K., Jayamanne, S., Sheriff, M.H.R., Warrell,
D.A., 2008. Multiple-dose activated charcoal in acute self-poisoning: a randomised
controlled trial. Lancet 371, 579–587.
Emerick, G.L., Peccinini, R.G., de Oliveira, G.H., 2010. Organophosphorus -induced de-
layed neuropathy: a simple and efficient therapeutic strategy. Toxicol. Lett. 192,
238–244.
Engel, S.M., Berkowitz, G.S., Barr, D.B., Teitelbaum, S.L., Siskind, J., Meisel, S.J.,
Wetmur, J.G., Wolff, M.S., 2007. Prenatal organophosphate metabolite and organo-
chlorine levels and performance on the Brazelton Neonatal Behavioral Assessment
Scale in a multiethnic pregnancy cohort. Am. J. Epidemiol. 165, 1397–1404.
Eskenazi, B., Marks, A.R., Bradman, A., Harley, K., Barr, D.B., Johnson, C., Morga, N.,
Jewell, N.P., 2007. Organophosphate pesticide exposure and neurodevelopment
health in young Mexican-American children. Environ. Health Perspect. 115,
792–798.
Eyer, P., 2003. The role of oximes in the management of organophosphorus pesticide
poisoning. Toxicol. Rev. 22, 165–190.
Fortenberry, G.Z., Meeker, J.D., Sanchez, B.N., Barr, D.B., Panuwet, P., Bellinger, D.,
Schnaas, L., Solano-Gonzalez, M., Ettinger, A.S., Hernandez-Avila, M., Hu, H., Tellez-
Rojo, M.M., 2014. Urinary 3,5,6-trichloro-2-pyridinol (TCPY) in pregnant women
from Mexico city: distribution, temporal variability, and relationship with child at-
tention and hyperactivity. Int. J. Hyg. Environ. Health 217, 405–412.
Freire, C., Koifman, S., 2012. Pesticide exposure and Parkinson’s disease: epidemiological
evidence of association. NeuroToxicol. 33, 947–971.
Gatto, N.M., Cockburn, M., Bronstein, J., Manthripragada, A.D., Ritz, B., 2009. Well-
water consumption and Parkinson’s disease in rural California. Environ. Health
Perspect. 117, 1912–1918.
Glynn, P., 1999. Neuropathy target esterase. Biochem. J. 344, 625–631.
Glynn, P., 2006. A mechanism for organophosphate-induced delayed neuropathy.
Toxicol. Lett. 162, 94–97.
Greiner, A.J., Richardson, R.J., Worden, R.M., Ofoli, R.Y., 2010. Influence of lysopho-
spholipid hydrolysis by the catalytic domain of neuropathy target esterase on the
fluidity of bilayer lipid membranes. Biochim. Biophys. Acta 1798, 1533–1539.
Gronseth, G.S., 2005. Gulf war syndrome: a toxic exposure? A systematic review. Neurol.
Clin. 23, 523–540.
Hayden, K.M., Norton, M.C., Darcey, D., Ostbye, T., Zandi, P.P., Breitner, J.C., Welsh-
Bohmer, K.A., 2010. Occupational exposure to pesticides increases the risk of in-
cident AD: the Cache County study. Neurol 74, 1524–1530.
IPCS, 1998. Organophosphorus Pesticides. International Programme on Chemical Safety
Poisons Information Monograph G001, World Health Organization, Geneva, 1989;
130
Descargado para LUIS HERRERA GUTIERREZ (l.herrera1406@gmail.com) en Antenor Orrego Private University de ClinicalKey.es por Elsevier en mayo 17, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
Toxicology 410 (2018) 125–131
Updated 1998. Available online at:. http://www.inchem.org/documents/pims/
chemical/pimg001.htm.
Jamal, G.A., 1997. Neurological syndromes of organophosphorus compounds. Adverse
drug reaction. Toxicol. Rev. 16, 133–170.
Jamal, F., Quazi, S., Haque, Q.S., Singh, S., 2016. Interrelation of glycemic status and
neuropsychiatric disturbances in farmers with organophosphorus pesticide toxicity.
Open Biochem. J. 10, 27–34.
Jayawardane, P., Senanayake, N., Dawson, A., 2009. Electrophysiological correlates of
intermediate syndrome following acute organophosphate poisoning. Clin. Toxicol.
47, 193–205.
Jeyaratnam, J., 1990. Pesticide poisoning: a major global health problem. World Health
Stat. Q. 43, 139–144.
John, M., Oommen, A., Zachariah, A., 2003. Muscle injury in organophosphorous poi-
soning and its role in the development of intermediate syndrome. Neuro Toxicol. 24,
43–53.
Johnson, M.K., 1982. The target for initiation of delayed neurotoxicity by organopho-
sphorus esters: biochemical studies and toxicological applications. In: In: Hodgson,
E., Bend, J.R., Philpot, R.M. (Eds.), Revews in Biochemical Toxicology, vol. 4.
Elsevier, New York, pp. 141–212.
Jokanović, M., 2001. Biotransformation of organophosphorus compounds. Toxicology
166, 139–160.
Jokanović, M., 2009. Medical treatment of acute poisoning with organophosphorus and
carbamate pesticides. Toxicol. Lett. 190, 107–115.
Jokanović, M., 2012a. Neurotoxic disorders and medical management of patients poi-
soned with organophosphorus and carbamate pesticides. In: Jokanović, M. (Ed.), The
Impact of Pesticides. Academic Publishers, pp. 39–62.
Jokanović, M., 2012b. Structure-activity relationship and efficacy of pyridinium oximes
in the treatment of poisoning with organophosphorus compounds: a review of recent
data. Curr. Top. Med. Chem. 12, 1775–1789.
Jokanović, M., 2017. Ataxia in patients poisoned with organophosphorus compounds. J.
Neurol. Transl. Neurosci. 5, 1081–1083.
Jokanović, M., Kosanović, M., 2010. Neurotoxic effects in patients poisoned with orga-
nophosphorus pesticides. Environ. Toxicol. Pharmacol. 29, 195–201.
Jokanović, M., Maksimović, M., 1997. Abnormal cholinesterase activity: understanding
and interpretation. Eur. J. Clin. Chem. Clin. Biochem. 35, 11–16.
Jokanović, M., Prostran, M., 2009. Pyridinium oximes as cholinesterase reactivators.
Structure-activity relationship and efficacy in the treatment of poisoning with orga-
nophosphorus compounds. Curr. Med. Chem. 16, 2177–2188.
Jokanović, M., Stojiljković, M.P., 2006. Current understanding of the application of
pyridinium oximes as cholinesterase reactivators in treatment of organophosphate
poisoning. Eur. J. Pharmacol. 553, 10–17.
Jokanović, M., Stukalov, P.V., Kosanović, M., 2002. Organophosphate induced delayed
polyneuropathy. Curr. Drug Targets Cns Neurol. Disord. 1, 591–600.
Jokanović, M., Kosanović, M., Stukalov, P.V., 2004. Organophosphate induced delayed
polyneuropathy. Med. Chem. Rev. Online 1, 123–131.
Jokanović, M., Antonijević, B., Vučinić, S., 2010. Epidemiological studies of antic-
holinesterase pesticide poisoning in Serbia. In: Satoh, T., Gupta, R.C. (Eds.),
Anticholinesterase Pesticides: Metabolism, Neurotoxicity and Epidemiology. John
Wiley & Sons, pp. 481–494 Chapter 35.
Jokanović, M., Kosanović, M., Brkić, D., Vukomanović, P., 2011. Organophosphate in-
duced delayed polyneuropathy in man: an overview. Clin. Neurol. Neurosurg. 113,
7–10.
Kamel, F., Hoppin, J.A., 2004. Association of pesticide exposure with neurologic dys-
function and disease. Environ. Health Perspect. 112, 950–958.
Karalliedde, L., Baker, D., Marrs, T., 2006. Organophosphate-induced intermediate syn-
drome: aetiology and relationships with myopathy. Toxicol. Rev. 25, 1–14.
Karchmar, A.G., 2007. Anticholinesterases and war gases. In: Karchmar, A.G. (Ed.),
Exploring the Vertebrate Central Cholinergic Nervous System. Springer, pp. 237–310
Chapter 7.
Kawana, N., Ishimatsu, S., Kanda, K., 2001. Psycho-physiological effects of the terrorist
sarin attack on the Tokyo subway system. Mil. Med. 166 (Suppl. 2), 23.
Khan, S., Hemalatha, R., Jeyaseelan, L., Oommen, A., Zachariah, A., 2001. Neuroparalysis
and oxime efficacy in organophosphate poisoning; a study of butyrylcholinesterase.
Hum. Exp. Toxicol. 20, 169–174.
Kohen, G.L., Henderson, G., Karczmar, A.G., 1980. Di-isopropyl phosphofluoridate in-
duced antinociception: possible role of endogenous opioids. Eur. J. Pharmacol. 61,
167–173.
Kubek, M.J., Shih, T.M., Meyerhoff, J.L., 1997. Thyrotropin-releasing hormone (TRH) is
markedly increased in the rat brain following soman-induced convulsions. Brain Res.
747, 328–331.
Li, Y., Dinsdale, D., Glynn, P., 2003. Protein domains, catalytic activity and subcellular
distribution of neuropathy target esterase in mammalian cells. J. Biol. Chem. 278,
8820–8825.
Li, Z., Szurek, P.F., Jiang, C., Pao, A., Bundy, B., Le, W.D., Bradley, A., Yu, Y.E., 2005.
Neuronal differentiation of NTE-deficient embryonic stem cells. Biochem. Biophys.
Res. Commun. 330, 1103–1109.
London, L., Nell, V., Thompson, M.L., Myers, J.E., 1998. Effects of long term organo-
phosphate exposures on neurological symptoms, vibration sense and tremor among
South African farm workers. Scand. J. Work Environ. Health 24, 18–29.
London, L., Flisher, A.J., Wesseling, C., Mergler, D., Kromhout, H., 2005. Suicide and
exposure to organophosphate pesticides: cause or effect? Am. J. Ind. Med. 47,
308–321.
London, L., Beseler, C., Bouchard, M.F., Bellinger, D.C., Colosio, C., Grandjean, P., Harari,
R., Kootbodien, T., Kromhout, H., Little, F., Meijster, T., Moretto, A., Rohlman, D.S.,
Stallones, L., 2012. Neurobehavioral and neurodevelopmental effects of pesticide
exposures. Neuro Toxicol. 33, 887–896.
M. Jokanović
Lotti, M., 1992. The pathogenesis of organophosphate delayed polyneuropathy. Crit. Rev.
Toxicol. 21, 465–487.
Lotti, M., 2002. Low-level exposures to organophosphorus esters and peripheral nerve
function. Muscle Nerve 25, 492–504.
Lotti, M., Moretto, A., 2005. Organophosphate-induced delayed polyneuropathy. Toxicol.
Rev. 24, 37–49.
Manthripragada, A.D., Costello, S., Cockburn, M.G., Bronstein, J.M., Ritz, B., 2010.
Paraoxonase 1, agricultural organophosphate exposure, and Parkinson disease.
Epidemiol. 21, 87–94.
Marks, A.R., Harley, K., Bradman, A., Kogut, K., Barr, D.B., Johnson, C., Calderon, N.,
Eskenazi, B., 2010. Organophosphate pesticide exposure and attention in young
Mexican-American children: the CHAMACOS study. Environ. Health Perspect. 118,
1768–1774.
Marrs, T.C., Vale, J.A., 2006. Management of organophosphorus pesticide poisoning. In:
Gupta, R.C. (Ed.), Toxicology of Organophosphorus and Carbamate Compounds.
Elsevier Academic Press, Amsterdam, pp. 715–733 Chapter 49.
Morgan, J.P., 1982. The Jamaica ginger paralysis. J. Am. Med. Assoc. 248, 1864–1867.
Mostafalou, S., Abdollahi, M., 2017. Pesticides: an update of human exposure and toxi-
city. Arch. Toxicol. 91, 549–599.
Narayan, S., Liew, Z., Paul, K., Lee, P.C., Sinsheimer, J.S., Bronstein, J.M., Ritz, B., 2013.
Household organophosphorus pesticide use and Parkinson’s disease. Int. J.
Epidemiol. 42, 1476–1485.
Pancetti, F., Olmos, C., Dagnino-Subiabre, A., Rozas, C., Morales, B., 2007.
Noncholinesterase effects induced by organophosphate pesticides and their re-
lationship to cognitive processes: implication for the action of acylpeptide hydrolase.
J. Toxicol. Environ. Health B 10, 623–630.
Parron, T., Hernandez, A.F., Pla, A., Villanueva, E., 1996. Clinical and biochemical
changes in greenhouse sprayers chronically exposed to pesticides. Hum. Exp. Toxicol.
12, 957–963.
Paul, N., Mannathukkaran, T.J., 2005. Intermediate syndrome following carbamate poi-
soning. Clin. Toxicol. 43, 867–868.
Pope, C.N., 2006. Central nervous system effects and neurotoxicity. In: Gupta, R.C. (Ed.),
Toxicology of Organophosphate and Carbamate Compounds. Elsevier Academic
Press, Amsterdam, pp. 271–291 Chapter 20.
Pope, C.N., Chakraborti, T.K., Chapman, M.L., Farrar, J.D., 1992. Long-term neuro-
chemical and behavioral effects induced by chlorpyrifos treatment. Pharmacol.
Biochem. Behav. 42, 251–256.
Quistad, G.B., Barlow, C., Winrow, C.J., Sparks, S.E., Casida, J.E., 2003. Evidence that
mouse brain neuropathy target esterase is a lysophospholipase. PNAS 100,
7983–7987.
Rauh, V., Arunajadai, S., Horton, M., Perera, F., Hoepner, L., Barr, D.B., Whyattm, R.,
2011. Seven-year neurodevelopmental scores and prenatal exposure to chlorpyrifos, a
common agricultural pesticide. Environ. Health Perspect. 119, 1196–1201.
Ray, D.E., 1998. Chronic effects of low level exposure to anticholinesterases - a me-
chanistic review. Toxicol. Lett. 102–103, 527–533.
Ray, D.E., Richards, P.G., 2001. The potential for toxic effects of chronic, low-dose ex-
posure to organophosphates. Toxicol. Teratol. 120, 343–351.
Ruckart, P.Z., Kakolewski, K., Bove, F.J., Kaye, W.E., 2004. Long-term neurobehavioral
health effects of methyl parathion exposure in children in Mississippi and Ohio.
Environ. Health Perspect. 112, 46–51.
Read, D.J., Li, Y., Chao, M.V., Cavanagh, J.B., Glynn, P., 2009. Neuropathy target esterase
is required for adult vertebrate axon maintenance. J. Neurosci. 29, 11594–11600.
Reiner, E., Pleština, R., 1979. Regeneration of cholinesterase activities in humans and rats
after inhibition by O,O-dimethyl-O-dimethyl-2,2-dichlorvinyl phosphate. Toxicol.
Appl. Pharmacol. 49, 451–454.
Riddle, J.R., Brown, M., Smith, T., Ritchie, E.C., Brix, K.A., Romano, J., 2003. Chemical
warfare and the Gulf war: a review of the impact on Gulf veterans’ health. Mil. Med.
168, 606–613.
Rohlman, D.S., Anger, W.K., Lein, P.J., 2011. Correlating neurobehavioral performance
with biomarkers of organophosphorous pesticide exposure. Neurotoxicology 32,
268–276.
Roldan-Tapia, L., Parron, T., Sanchez-Santed, F., 2005. Neuropsychological effects of
long-term exposure to organophosphate pesticides. Neurotoxicol. Teratol. 27,
259–266.
Rosenstock, L., Keifer, M., Daniell, W., McConnell, R., Claypoole, K., 1991. Chronic
central nervous system effects of acute organophosphate pesticide intoxication.
Lancet 338, 223–227.
Ross, S.M., McManus, I.C., Harrison, V., Mason, O., 2013. Neurobehavioral problems
131
Descargado para LUIS HERRERA GUTIERREZ (l.herrera1406@gmail.com) en Antenor Orrego Private University de ClinicalKey.es por Elsevier en mayo 17, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
Toxicology 410 (2018) 125–131
following low-level exposure to organophosphate pesticides: a systematic and meta-
analytic review. Crit. Rev. Toxicol. 43, 21–44.
Rothlein, J., Rohlman, D., Lasarev, M., Phillips, J., Muniz, J., McCaule, L., 2006.
Organophosphate pesticide exposure and neurobehavioral performance in agri-
cultural and non-agricultural Hispanic workers. Environ. Health Perspect. 114,
691–696.
Salvi, R.M., Lara, D.R., Ghisolfi, E.S., Portela, L.V., Dias, R.D., Souza, D.O., 2003.
Neuropsychiatric evaluation in subjects chronically exposed to organophosphate
pesticides. Toxicol. Sci. 72, 267–271.
Satoh, T., Jokanović, M., 2014. Toxicity and novel biomarkers of OP exposure. In: Balali-
Mood, M., Abdollahi, M. (Eds.), Basic and Clinical Toxicology of Organophosphorous
Compounds. Springer, pp. 119–140.
Savage, E.P., Keefe, T.J., Mounce, L.M., Heaton, R.K., Lewis, J.A., Burcar, P.J., 1988.
Chronic neurological sequelae of organophosphate pesticide poisoning. Arch.
Environ. Health 43, 38–45.
Senanayake, N., Karalliedde, L., 1987. Neurotoxic effects of organophosphorus in-
secticides: an intermediate syndrome. New Engl. J. Med. 316, 761–763.
Singh, S., Sharma, N., 2000. Neurological syndromes following organophosphate poi-
soning. Neurol. India 48, 308–313.
Sogorb, M.A., Pamies, D., Estevan, C., Estevez, J., Vilanova, E., 2016. Roles of NTE
protein and encoding gene in development and neurodevelopmental toxicity. Chem.
Biol. Interact. 259, 352–357.
Song, F., Xie, K., 2012. Calcium-dependent neutral cysteine protease and organopho-
sphate-induced delayed neuropathy. Chem. Biol. Interact. 200, 114–118.
Steenland, K., Jenkins, B., Ames, R.G., O’Maley, M., Chrislip, D., Russo, J., 1994. Chronic
neurological sequelae to organophosphate poisoning. Am. J. Pub. Health 84,
731–736.
Suarez-Lopez, J.R., Himes, J.H., Jacobs Jr., D.R., Alexander, B.H., Gunnar, M.R., 2013.
Acetylcholinesterase activity and neurodevelopment in boys and girls. Pediatrics 132,
e1649–e1658.
Taghavian, F., Vaezi, G., Abdollahi, M., Malekirad, A.A., 2016. A comparative study of the
quality of life, depression, anxiety and stress in farmers exposed to organophosphate
pesticides with those in a control group. J. Chem. Health Risks 6 (2), 143–151.
Tan, D.H., Peng, S.Q., Wub, Y.L., Wang, Y.M., Lu, C.F., Yan, C.H., 2009. Chronic orga-
nophosphate (OP)-induced neuropsychiatric disorder is a withdrawal syndrome.
Med. Hypotheses 72, 405–406.
Tosi, L., Righetti, C., Adami, L., Zanette, G., 1994. October 1942: a strange epidemic
paralysis in Saval, Verona, Italy. Revision and diagnosis 50 years later of tri-ortho-
cresyl phosphate poisoning. J. Neurol. Neurosurg. Psychiatry 57, 810–813.
van der Hoek, W., Konradsen, F., Athukorala, K., Wanigadewa, T., 1998v. Pesticide
poisoning: a major health problem in Sri Lanka. Soc. Sci. Med. 46, 495–504.
van Dongen, C.J., Wolthuis, O.L., 1989v. On the development of behavioral tolerance to
organophosphates. I: behavioral and biochemical aspects. Pharmacol. Biochem.
Behav. 34, 473–481.
Venkategowda, P.M., Harde, Y.R., Rao, M., Mutkule, D.P., Yarramalle, S.P., Mithilesh, K.,
Raut, M.K., 2015. Organophosphate poisoning and its neurological manifestations.
Int. J. Adv. Case Rep. 2 (21), 1303–1305.
Vose, S.C., Fujioka, K., Gulevich, A.G., Lin, A.Y., Holland, N.T., Casida, J.E., 2008.
Cellular function of neuropathy target esterase in lysophosphatidylcholine action.
Toxicol. Appl. Pharmacol. 232, 367–383.
Worek, F., Diepold, C., Eyer, P., 1999. Dimethylphosphoryl-inhibited human cholines-
terases: inhibition, reactivation, and aging kinetics. Arch. Toxicol. 73, 7–14.
World Health Organization, 1986. Organophosphorus Insecticides: A General
Introduction, vol. 63 Environmental Health Criteria, Geneva.
Yanagisawa, N., Morita, H., Nakajima, T., 2006. Sarin experiences in Japan: acute toxicity
and long-term effects. J. Neurol. Sci. 249, 76–85.
Yang, C.C., Deng, J.F., 2007. Intermediate syndrome following organophosphate in-
secticide poisoning. J. Chin. Med. Assoc. 70, 467–472.
Yilmaz, M., Sebe, A., Ay, M.O., Gumusay, U., Topal, M., Atli, M., Icme, F., Satar, S., 2013.
Effectiveness of therapeutic plasma exchange in patients with intermediate syndrome
due to organophosphate intoxication. Am. J. Emerg. Med. 31, 953–957.
Yu, C.J., Du, J.C., Chiou, H.C., Chung, M.Y., Yang, W., Chen, Y.S., Fuh, M.R., Chien, L.C.,
Hwang, B., Chen, M.L., 2016. Increased risk of attention-deficit/hyperactivity dis-
order associated with exposure to organophosphate pesticide in Taiwanese children.
Androl. 4, 695–705.
Zaganas, I., Kapetanaki, S., Mastorodemos, V., Kanavouras, K., Colosio, C., Wilks, M.F.,
Tsatsakis, A.M., 2013. Linking pesticide exposure and dementia: What is the evi-
dence? Toxicology 307, 3–11.