# Behavioral consequences of organophosphorus poisoning: insights from human exposures and rodent models

Rosalie Bel, Alexandre Champault, Frédéric Dorandeu, Karine Thibault, Gregory Dal Bo

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Rosalie Bel, Alexandre Champault, Frédéric Dorandeu, Karine Thibault, Gregory Dal Bo. Behavioral consequences of organophosphorus poisoning: insights from human exposures and rodent models. Neuroscience and Biobehavioral Reviews, 2026, pp.106617. 10.1016/j.neubiorev.2026.106617. hal-05525428

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# Behavioral consequences of organophosphorus poisoning: Insights from human exposures and rodent models

Rosalie Bel<sup>a, 1</sup>, Alexandre Champault<sup>a, b, 1</sup>, Frédéric Dorandeu<sup>c</sup>, Karine Thibault<sup>a, b, 2, *</sup>, Gregory Dal Bo<sup>a, b, 2, *</sup>

## ARTICLE INFO

### Keywords:

Organophosphorus compound

Behavior

Cognition

Anxiety

Locomotion

Therapy

## ABSTRACT

The risks of exposure to organophosphorus (OP) chemicals, predominantly used as pesticides as well as chemical warfare agents (NA, nerve agents), remain a present concern. Human studies have revealed severe neurological and psychiatric consequences of acute or chronic exposures. In order to improve the medical management of exposed patients, it is crucial to develop preclinical models that can investigate transient and persistent neurofunctional impairments. However, most research has focused on treatments that reduce mortality and seizures and restore cholinesterase activity in the short term. Few studies have evaluated the long-term benefits of these therapies. In this review, we summarize behavioral studies that assess the impact of OP exposure on affective, cognitive, and sensorimotor functions in humans and rodent models. To distinguish the specific neurobehavioral alterations induced by different OP compounds, we differentiate between lethal, single or repeated (chronic or subchronic) low-dose exposures to NA or pesticides. The review provides critical insights into the methodologies used to assess these alterations. Additionally, the study focuses on behavioral parameters used to evaluate treatment efficacy. Novel strategies aim to address the multifactorial consequences of OP exposure beyond seizure control, including neuroinflammation, excitotoxicity, and/or oxidative stress. Our research indicates the need for rigorous, long-term behavioral studies that incorporate multimodal analyses and longitudinal follow-up to detect delayed deficits and validate therapeutic benefits.

## 1. Introduction

The synthesis of the first organophosphorus (OP) compound in the 19th century, tetraethylpyrophosphate (TEPP), paved the way for numerous pesticides like parathion and chlorpyrifos (Hrvat and Kovarik, 2020; O'Brien, 1963; Soltaninejad and Shadnia, 2014). In the 1930s, the neurotoxic properties of OP interested the Nazi military, leading to the synthesis of new chemical warfare agents (CWA): the nerve agents (NA). This gave rise to the 'G' class ('German') agents, including tabun (GA, 1936), sarin (GB, 1938), and soman (GD, 1944) (Hrvat and Kovarik, 2020; Voros et al., 2024). Although not used during World War II, possibly due to fear of important retaliation (Black, 2016), new categories, the 'V' and 'A' (Novichok) agents, emerged during the Cold War (Gupta, 2020; Hrvat and Kovarik, 2020; Nepovimova and Kuca,

2018; Voros et al., 2024). The first documented use of OP compounds in armed conflict occurred during the Iraq-Iran War (1980–1988), when the Iraqi government used NA, initially deploying tabun with sulfur mustard (another chemical warfare agent), and subsequently incorporating sarin in later stages. These agents were employed both against Iranian forces and Kurdish civilians, notably during the 1988 Halabja massacre, which resulted in the death of approximately 4000 individuals (Ghanei et al., 2010). In response to these attacks the Chemical Weapons Convention (CWC) was signed in 1993 and entered into force in 1997 to prohibit the use of CWA. However, despite the existence of these international regulations, non-state actors showed interest for these agents. From 1993–1995, the *Aum Shinrikyo* cult in Japan perpetrated a series of terrorist attacks using VX and sarin, most notably during the Tokyo subway attack (Chai et al., 2017; Okumura et al., 1996).

<footnote><sup>a</sup> Department of Toxicology and Chemical Risks, French Armed Forces Biomedical Research Institute, Brétigny-sur-Orge, France</footnote>

<footnote><sup>b</sup> Laboratoire d'Imagerie Biomédicale Multimodale (BioMaps), CEA, CNRS, Inserm, Service Hospitalier Frédéric Joliot, Université Paris-Saclay, Orsay, France</footnote>

<footnote><sup>c</sup> Ecole du Val-de-Grâce, 1 place Alphonse Laveran, Paris, France</footnote>

<footnote>* Correspondence to: Institut de Recherche Biomédicale des Armées, Département de Toxicologie et Risques Chimiques, 1 place du Général Valérie AndréBP73, Brétigny-sur-Orge 91223, France</footnote>

<footnote>E-mail addresses: karine.thibault@def.gouv.fr (K. Thibault), gregory.dal-bo@def.gouv.fr (G. Dal Bo).</footnote>

<footnote n="1">¹ These authors contributed equally to this work.</footnote>

<footnote n="2">² These authors contributed equally to this work.</footnote>
More recently, NA had been used during the Syrian civil war ( Brooks et al., 2018; John et al., 2018). In addition, OP have been implicated to significant targeted political attacks, including the assassination of Kim Jong-Nam in Malaysia with VX in 2017 and the attempted assassinations of Sergei and Yulia Skripal in Salisbury (United Kingdom) in 2018 and Alexei Navalny in Tomsk (Russia) in 2020 both involving Novichok agents (Nakagawa and Tu, 2018; Pampalakis and Kostoudi, 2023; Vale et al., 2018).

A common feature among all NA is their high lipophilicity, which enables them to cross biological barriers such as the skin and inside the body the blood-brain barrier (BBB). The volatile G-series agents represent primarily an inhalational hazard (Figueiredo et al., 2018) while the more persistent V and A-series agents are predominantly absorbed through skin exposure (Nepovimova and Kuca, 2018; Noga and Jurowski, 2023; Pampalakis and Kostoudi, 2023).

The toxicity of these substances is attributed to their capacity to promptly inhibit acetylcholinesterase (AChE), an enzyme that is indispensable for the hydrolysis of acetylcholine (ACh). Butyrylcholinesterase (BChE) inhibition is also observed with difference between agents and unclear consequences (Franjesevic et al., 2019; Shih et al., 2005). The resulting accumulation of ACh in the synaptic cleft and the neuromuscular junction, leads to the overstimulation of nicotinic (ionotropic) and muscarinic (metabotropic) receptors, causing an acute cholinergic syndrome. Symptoms include muscle weakness, tachycardia, hypertension, fasciculations, and flaccid paralysis driven by nicotinic receptors and miosis, hypersecretion, bronchoconstriction, and gastrointestinal disturbance issues from muscarinic receptor activation (Alsaleh et al., 2022; Ciottone, 2018; Gupta, 2020; Hulse et al., 2014; Pulkrabkova et al., 2023). The acute effects of NA exposure have been the subject of extensive research, whereas the delayed consequences are less documented. This review describes the short- and long-term behavioral consequences of exposure to NA in humans, while highlighting the importance of animal models in elucidating and con-textualizing these effects.

## 2. Follow-up on the effects of humans exposed to NA

The European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC) describes the acute effects of NA exposure as lasting several hours to 48 h. Subsequently, the 'intermediate syndrome' emerges within 2-4 days post-exposure, characterized by weakness of the muscles of respiration and of the proximal limb muscles (Das et al., 2013; Karalliedde et al., 2006). Over time, the intermediate syndrome dissipates, resulting in clinical improvement and eventual discharge from the hospital (Karalliedde et al., 2006). However, chronic exposure to low doses, or acute poisoning, as experienced by individuals exposed to pesticides or by survivors of NA attacks, can result in permanent neurological and emotional disturbances (Figueiredo et al., 2018; Kori et al., 2018; Loh et al., 2010; Muñoz-Quezada et al., 2016; Ross et al., 2013; Talabani et al., 2018). As previously reported, the most frequent symptoms following OP exposure are: impaired vigilance and reduced concentration; reduced information processing and psychomotor speed; memory deficit; linguistic disturbances and depression, anxiety and irritability (Eyer, 1995). In the present study, the focus was directed towards the cognitive, mood and sensorimotor impacts of OP on human conditions. Tables present summaries of the behavioral tests performed in human for the evaluation of cognitive affections (Table 1), mental health disorders (Table 2) and sensorimotor impairments (Table 3) subsequent to OP exposure. Each table meticulously documents the test employed and the exposure condition (when available): the nature of OP, the approximate duration of exposure, the route of exposure, and the assessment period after the last exposure.

### 2.1. Effects of OP on cognitive processes

Cognition is a broad term encompassing functions such as memory, learning, language, and attention, all of which are commonly affected after OP poisoning. Indeed, OP-exposed victims reported impaired cognitive function, including mental confusion, and attention deficits (Dassanayake et al., 2009, 2008, 2022; Grob and Harvey, 1958; Levin and Rodnitzky, 1976; Loh et al., 2010; Rosenstock, 1991; Sánchez Lizardi et al., 2008; Sidell, 1974). One of the most used tools for evaluating cognitive consequences after both acute and chronic intoxication is event-related potentials (ERP). ERP is a neurophysiological technique based on electroencephalography that records brain responses to specific sensory, cognitive, or motor events (Reinvang, 1999). A particularly informative component is the P300, a positive wave that appears approximately 300 ms after the presentation of a stimulus requiring attention or decision-making. The P300 is characterized by two factors: amplitude, which reflects the allocation of attentional resources, and latency, which is indicative of the speed of cognitive processing. Increased P300 latency has been observed in suicide attempt survivors (Dassanayake et al., 2008, 2022) and in Japanese terrorist attack victims (Murata et al., 1997), and is indicative of impaired cognitive functioning following neurotoxic exposure. Furthermore, the P300 disturbances are not limited to acute exposure, as farmers using regularly OP also exhibit similar attention deficits and information processing impairment (Dassanayake et al., 2009). This finding highlights the possibility of developing long-lasting cognitive impairments following chronic or acute exposure to different OP compounds and varying doses. Furthermore, some reports indicate that the neurophysiological mechanisms underlying working memory are compromised following OP exposure. Indeed, sarin-exposed Gulf war (GW) soldiers, as well as victims of the Tokyo subway attack, have reported memory difficulties and impaired performance on attention assessments tests (Bowers et al., 1964; Hatta et al., 1996; Loh et al., 2010; Miyaki et al., 2005; Nishiwaki et al., 2001; Ohtani et al., 2004). A similar trend was observed in individuals chronically exposed to OP, including farmers and scientists. Among patients, many developed problems with different components of memory (verbal, prospective, etc.) or deficits in selective and/or divided memory (Gershon and Shaw, 1961; Malekirad et al., 2013). Moreover, transient chronic exposure has been demonstrated to result in significant cognitive decline, as evidenced by studies ranging from 2 months (Chittrakul et al., 2022) up to 6.5 years (Paul et al., 2018). However, OP exposure may need to reach a threshold to trigger cognitive deterioration (Salvi, 2003).

### 2.2. Impact of OP on mental health conditions

The correlation between OP pesticides exposure and the subsequent development of neuropsychiatric disorders has been well-documented. According to the review conducted by Levin and Rodnitzky in 1976, various cognitive components were identified as being impacted, including mental health disorders. Indeed, schizophrenic syndrome has been observed in some individuals who have been in contact with OP pesticides. However, it is important to note that this syndrome does not manifest in every instance of intoxication, and its presence is not always searched for. Mood disorders, which include anxiety and depression, manifest more frequently following chronic OP poisoning, even at low doses (Levin and Rodnitzky, 1976). The prevalence of such disorders is significantly higher among farmers chronically exposed to OP pesticides. Indeed, between 40 % and 50 % of the evaluated farm workers had received psychiatric diagnoses ranging from generalized anxiety disorder to major depression (Harrison and Mackenzie Ross, 2016; Salvi, 2003). Furthermore, the prevalence of suicidal ideation was found to be significantly higher among farm workers compared to the control group (~22 % vs. ~6 %, respectively) (Wesseling et al., 2010). This increase may be attributable to an elevated level of impulsivity
<caption>**Table 1**</caption>

Impacts of organophosphorus compounds on human cognitive performances, with particular regard to the health parameters evaluated, the tests used, the exposure conditions (type of OP, approximate duration of exposure, route of exposure, and period of assessment after the last exposure). In instances where information is unavailable, table boxes are left empty.

<table><thead><tr><th>Health parameters</th><th>Tests</th><th>Conditions (OP and approximate duration of exposition)</th><th>Route</th><th>Assessment period (after the last administration)</th><th>Articles</th></tr></thead><tbody><tr><td rowspan="10">Attention</td><td rowspan="4">Auditory consonant trigrams ERP<br>(Event-Related Potentials)</td><td>Sarin (acute)</td><td rowspan="4">Ingestion</td><td>8 months</td><td>Loh et al., (2010)</td></tr><tr><td>Chlorpyrifos, dimethoate, phenthoate, fenthion, malathion, coumaphos, oxydemeton methyl or profenofos (acute)</td><td>6 months</td><td>Dassanayake et al., (2008)</td></tr><tr><td>Dimethoate, chlorpyrifos, quinalphos, profenophos, phenthoate, fenitrothion, or fenthion (chronic)</td><td></td><td>Dassanayake et al., (2009)</td></tr><tr><td>Pesticides (acute)</td><td></td><td></td></tr><tr><td>Sarin (acute)</td><td></td><td></td></tr><tr><td>Paper-and-pencil test</td><td>EA-1701 (acute)</td><td>Percutaneous</td><td>On the first 24 h</td><td>Murata et al., (1997)</td></tr><tr><td>seashore rhythm test</td><td>Sarin (acute)</td><td></td><td>8 months</td><td>Bowers et al., (1964)</td></tr><tr><td rowspan="2">Simple reaction time</td><td>Sarin (acute)</td><td></td><td>2 years 10 months to 3 years 9 months</td><td>Loh et al., (2010)</td></tr><tr><td></td><td></td><td>2 years</td><td>Nishiwaki et al., (2001)</td></tr><tr><td>Trail making test and its derivative</td><td>Pesticides<br>Sarin (acute)</td><td></td><td>8 months</td><td>Rosenstock, 1991</td></tr><tr><td>Wisconsin card sort categories</td><td>Pesticides</td><td></td><td></td><td>Sánchez Lizardi et al., 2008</td></tr><tr><td rowspan="10">Executive function General cognition</td><td>CVLT<br>(California Verbal Learning Test)</td><td>Sarin (acute)</td><td></td><td>8 months</td><td>Loh et al., (2010)</td></tr><tr><td>MSE<br>(Mental state examination) and its derivatives</td><td>Pesticides</td><td></td><td>1-2 months</td><td>Chittrakul et al., (2022)</td></tr><tr><td></td><td>Pesticides</td><td></td><td>6.5 years</td><td>Paul et al., (2018)</td></tr><tr><td></td><td>Combination of OP (chlorpyrifos and acephate), herbicides, plant growth regulators, fungicides, and insecticides, 3 months</td><td></td><td>Immediately after + 3 months</td><td>Salvi, 2003</td></tr><tr><td>Mini-cognition test</td><td>Pesticides</td><td></td><td>1-2 months</td><td>Chittrakul et al., (2022)</td></tr><tr><td>MoCA<br>(Montreal Cognitive assessment)</td><td>Pesticides</td><td></td><td>1-2 months</td><td>Chittrakul et al., (2022)</td></tr><tr><td>Spanish English Neuropsychological Assessment Scales</td><td>Pesticides</td><td></td><td>6.5 years</td><td>Paul et al., (2018)</td></tr><tr><td>Subjective Neurocognition Inventory</td><td>Pesticides (chronic)</td><td></td><td></td><td>Malekirad et al., (2013)</td></tr><tr><td>WISC<br>(Wechsler Intelligence Scale for Children)</td><td>Pesticides</td><td></td><td></td><td>Sánchez Lizardi et al., 2008</td></tr><tr><td>Children's memory test</td><td>Pesticides</td><td></td><td></td><td>Sánchez Lizardi et al., 2008</td></tr><tr><td rowspan="3">Memory (general)</td><td rowspan="3">WMS<br>(Wechsler memory scale) and its derivative</td><td>Sarin (acute)</td><td></td><td>6 months</td><td>Hatta et al., (1996)</td></tr><tr><td>Sarin (acute)</td><td></td><td>8 months</td><td>Loh et al., (2010)</td></tr><tr><td>Sarin (acute)</td><td></td><td>5 years</td><td>Ohtani et al., (2004)</td></tr><tr><td>Memory (episodic)</td><td>CVLT<br>(California Verbal Learning Test)</td><td>Sarin (acute)</td><td></td><td>8 months</td><td>Loh et al., (2010)</td></tr><tr><td rowspan="2">Memory (verbal)</td><td>Rey Auditory verbal learning test</td><td>Pesticides</td><td></td><td>2 years</td><td>Rosenstock, 1991</td></tr><tr><td>SEVLT<br>(Spanish and English Verbal Learning Test)</td><td>Pesticides</td><td></td><td>6.5 years</td><td>Paul et al., (2018)</td></tr><tr><td rowspan="4">Memory (visual)</td><td>Word memory test</td><td>Sarin (acute)</td><td></td><td>8 months</td><td>Loh et al., (2010)</td></tr><tr><td>Benton visual retention test</td><td>Sarin (acute)</td><td></td><td>7 years</td><td>Miyaki et al., (2005)</td></tr><tr><td></td><td>Sarin (acute)</td><td></td><td>2 years 10 months to 3 years 9 months</td><td>Nishiwaki et al., (2001)</td></tr><tr><td></td><td>Pesticides</td><td></td><td>2 years</td><td>Rosenstock, 1991</td></tr><tr><td></td><td>Visual retention task</td><td>Soman (25 % (V/V) and the total volume was less than 1 mL)</td><td>oral and skin contamination (soman)</td><td>3 days to 6 months (soman)</td><td>Sidell, 1974</td></tr></tbody></table>

(continued on next page)
<table><caption>Table 1 (continued)</caption><thead><tr><th>Health parameters</th><th>Tests</th><th>Conditions (OP and approximate duration of exposition)</th><th>Route</th><th>Assessment period (after the last administration)</th><th>Articles</th></tr></thead><tbody><tr><td rowspan="6">Memory (working)</td><td rowspan="2">Rey-Osterrieth complex figure</td><td>Sarin (acute)</td><td></td><td>6 months</td><td>Hatta et al., (1996)</td></tr><tr><td>Sarin (acute)</td><td></td><td>8 months</td><td>Loh et al., (2010)</td></tr><tr><td rowspan="2">Global or partial WAIS (Wechsler Adult Intelligence Scale)</td><td>Sarin (acute)</td><td></td><td>8 months</td><td>Loh et al., (2010)</td></tr><tr><td>Sarin (acute)</td><td></td><td>7 years</td><td>Miyaki et al., (2005)</td></tr><tr><td rowspan="2">Word span test</td><td>Sarin (acute)</td><td></td><td>2 years 10 months to 3 years 9 months</td><td>Nishiwaki et al., (2001)</td></tr><tr><td>Pesticides</td><td></td><td>2 years</td><td>Rosenstock, 1991</td></tr><tr><td></td><td></td><td>Combination of OP (chlorpyrphos and acephate), herbicides, plant growth regulators, fungicides, and insecticides, 3 months</td><td></td><td>Immediately after + 3 months</td><td>Salvi, 2003</td></tr></tbody></table>

(London et al., 2005). These symptoms can be triggered not only by chronic exposure to low doses of pesticides, but also by acute exposure to NA. As case studies have demonstrated, accidental exposure to sarin or soman in high doses results in the rapid onset of psychological disorders that persist for several weeks. Nevertheless, a marked improvement in the psychiatric condition of the victims was observed in the long-term follow-up period (more than six months) (Sidell, 1974). Following the administration of scopolamine, a cholinergic blocking compound with a high affinity for the CNS, the improvement in the patient's mental state during the acute episode demonstrated the direct CNS effect of NA on psychological state (Sidell, 1974). In addition, most cases of mental disorder documented are from the sarin terrorist attacks that occurred in Japan in 1994 and 1995. In the aftermath of these attacks, a considerable number of individuals have reported the onset of symptoms indicative of anxiety and post-traumatic stress disorder (PTSD), even though not all of them were exposed to sarin. A variety of diagnostic tools were used to evaluate the development of PTSD, including: the PTSD Checklist (Kawana et al., 2005; Murata et al., 1997), the Clinician-Administered PTSD Scale (CAPS) (Hoffman et al., 2007), the self-reported measures such as the Impact of Event Scale-Revised (IES-R) (Hoffman et al., 2007; Nishiwaki et al., 2001), the General Health Questionnaire (GHQ) (Hoffman et al., 2007; Yokoyama et al., 1998), and the Profile of Mood States (POMS) (Yokoyama et al., 1998). PTSD has been observed to manifest early on (within a month of the attack) and persist for over 14 years (Sugiyama et al., 2020). Two years after the attack, 60 % of the victims who completed a survey developed PTSD, exhibiting symptoms such as a fear of the subway (32 %) and sleep disturbances (29 %) (Ohbu et al., 1997). A correlation was identified between the level of blood ChE and PTSD: individuals who developed PTSD exhibited a lower ChE activity 5 years later after the attack (Murata et al., 1997; Ohtani et al., 2004; Tochigi et al., 2002). Anxiety has been identified as the most prominent symptom of PTSD in individuals exposed to sarin in Japan, particularly when the sarin is evoked (Ohtani et al., 2004; Tochigi et al., 2002; Yokoyama et al., 1998). The others psychological and somatic effects of PTSD may also include headaches, fatigue, palpitations, abdominal pain, difficulty focusing, nightmares, insomnia, and a loss of interest and appetite. Approximately 50 % of sarin-exposed victims also developed agoraphobia and panic disorder (Ohtani et al., 2004; Tochigi et al., 2002).

## 2.3. Influence of OP exposure on the sensorimotor system

Several weeks after poisoning some individuals may experience an OP-induced delayed neuropathy (OPIDN) (Das et al., 2013; Kobayashi et al., 2017) or chronic OP-induced neuropsychiatric disorders (COPIND) after the intermediate syndrome (Jokanović, 2018). OPIDN is characterized by progressive muscle weakness, abnormal gait (ataxia due to peripheral nerve degeneration) (Viswanath et al., 2023), numbness and tingling in the extremities (Boostani et al., 2014; Jayasinghe et al., 2012) and loss of deep tendon reflexes (Lotti and Moretto, 2005; Panggabean et al., 2023; Porey et al., 2023). It is widely accepted that

OPIDN predominantly occurs with certain OP, whose chemical structure allows them to inhibit Neuropathy Target Esterase (NTE) and to induce aging of the complex (Lotti and Moretto, 2005; Richardson et al., 2013). The inhibition of NTE by OP has the potential to result in the development of axonopathy.

After having been exposed to sarin, Tokyo subway workers demonstrated delayed neuropathy 3-7 years later. This condition is characterized by a progressive decline in response to sensory stimuli and/or the onset of motor disorders (Miyaki et al., 2005). Nonetheless, a decline in psychomotor function evidenced by impaired nerve conduction can be observed after acute or chronic exposure to pesticide (Albers et al., 2007; Bharali et al., 2023; Das et al., 2013; Jayasinghe et al., 2012; Kobayashi et al., 2017; Porey et al., 2023). Nerve conduction abnormalities could be observed 1 month after poisoning and may indicate sensorimotor axonal polyneuropathy (Kobayashi et al., 2017). Eight months after sarin exposure, certain difficulties were observed in the execution of rapid alternative finger-tapping, which is indicative of motor coordination impairment, and may reveal peripheral damage or a cognitive deficit (Loh et al., 2010). Additionally, muscle weakness may appear within the first few days after poisoning, although it can also develop several years after OP exposure (Das et al., 2013; Gajurel et al., 2023; Malla et al., 2013).

The effects of OP—whether acute, prolonged, or chronic—highlight their profound and multifaceted impact on human health. However, human studies face significant challenges, including subjectivity in reported symptoms, uncertainty in dose assessment, confounding biases, and the difficulty of conducting long-term follow-up studies on victims of OP exposure (Eyer, 1995). To overcome these limitations, preclinical studies involving animal models are crucial.

## 3. Preclinical models to assess behavioral changes induced by OP exposure

A multitude of behavioral assays using rodents have been developed to assess cognitive performance, affective states, and motor function. The selection of tests is determined by the specific hypothesis, the timing of post-exposure assessments, and whether the objective of the study focused on transient or persistent dysfunctions. In this section, we have included studies that investigated the effects of OP, whether derived from pesticides or CWA, in rodents exposed from postnatal day 21 onward. The investigation involved the consideration of both male and female subjects. Studies involving therapeutic interventions were excluded, except in cases of high-dose exposures where pre-treatment (pyridostigmine) and/or emergency treatment was necessary to prevent animal death (atropine and/or oximes). Tables present summaries of the behavioral tests utilized for evaluation of memory (Table 4), mood disorders (Table 5), locomotion and sensorimotor (Table 6) changes after OP exposure. Each table documents the test employed, the model (nature of OP, dose, route of exposure, and species), the presence or absence of emergency treatment, and the assessment period calculated after the last exposure. For clarification, in this review, the term
<caption>**Table 2**</caption>

Impacts of organophosphorus compounds on mental health conditions, with particular regard to the mood disorders evaluated, the tests used, the exposure conditions (type of OP, approximate duration of exposure, route of exposure, and period of assessment after the last exposure). In instances where information is unavailable, table boxes are left empty.

<table><thead><tr><th>Health parameters</th><th>Tests</th><th>Conditions (OP and approximate duration of exposition)</th><th>Route</th><th>Assessment period (after the last administration)</th><th>Articles</th></tr></thead><tbody><tr><td rowspan="3">Overall health rating</td><td>POMS (Profile of Mood States)</td><td>Sarin (acute)</td><td></td><td>6-8 months</td><td>Yokoyama et al., (1998)</td></tr><tr><td>GHQ (General Health Questionnaires)</td><td>Sarin (acute)</td><td></td><td>1 year, 3 years and &gt; 3 years</td><td>Hoffman et al., (2007)</td></tr><tr><td></td><td>Sarin (acute)</td><td></td><td>6-8 months</td><td>Yokoyama et al., (1998)</td></tr><tr><td>Anxiety</td><td>BAI (Beck Anxiety Inventory)</td><td>Pesticides (chronic exposure 80.78 days per years)</td><td></td><td>mean of 10.31 years</td><td>Harrison and Mackenzie Ross, (2016)</td></tr><tr><td></td><td>HADS-A (Hospital Anxiety and Depression Scale)</td><td>Pesticides (chronic exposure 80.78 days per years)</td><td></td><td>mean of 10.31 years</td><td>Harrison and Mackenzie Ross, (2016)</td></tr><tr><td></td><td>Self-grading questionnaire STAI (State-Trait Anxiety Inventory)</td><td>Sarin (acute)</td><td></td><td>5 years</td><td>Ohtani et al., 2004</td></tr><tr><td></td><td>SCL-90-R (Symptom Checklist-90-Revised - Brief Symptoms Inventory)</td><td>Sarin (acute)</td><td></td><td>5 years</td><td>Tochigi et al., (2002)</td></tr><tr><td></td><td>HADS-D (Hospital Anxiety and Depression Scale)</td><td>Pesticides (chronic exposure 80.78 days per years)</td><td></td><td>mean of 10.31 years</td><td>Harrison and Mackenzie Ross, (2016)</td></tr><tr><td></td><td>BDI (Beck Depression Inventory)</td><td>Pesticides (chronic exposure 80.78 days per years)</td><td></td><td>mean of 10.31 years</td><td>Harrison and Mackenzie Ross, (2016)</td></tr><tr><td></td><td>DSM-IV - Axis 1</td><td>combination of OP (chlorpyrphos and acephate), herbicides (glyphosate and clomazone), plant growth regulators (flumetralin), fungicides (iprodione), and insecticides (imidacloprid), mean of 17.8 years working hours per day 5.4 in contact of OP pesticides organophosphate (terbufos, fenamiphos, ethoprophos or cadusafos) or carbamate (carbofuran or oxamyl) compounds, once or twice a life</td><td>Inhalation or skin contamination</td><td>at least 1 year</td><td>Wesseling et al., 2010</td></tr><tr><td rowspan="5">PTSD</td><td>SCL-90-R (Symptom Checklist-90-Revised - Brief Symptoms Inventory)</td><td>Sarin (acute)</td><td></td><td></td><td></td></tr><tr><td>PTSD questionnaires</td><td>Sarin (acute)</td><td></td><td></td><td></td></tr><tr><td></td><td>Sarin (acute)</td><td></td><td></td><td></td></tr><tr><td></td><td>Sarin (acute)</td><td></td><td></td><td></td></tr><tr><td></td><td>Sarin (acute)</td><td></td><td></td><td></td></tr><tr><td></td><td>Self-grading questionnaire STAI (State-Trait Anxiety Inventory)</td><td>Sarin (acute)</td><td></td><td></td><td></td></tr><tr><td></td><td>Self-grading questionnaire, IES and its derivative (Impact of Event Scale)</td><td>Sarin (acute)</td><td></td><td></td><td></td></tr><tr><td></td><td></td><td>Sarin (acute)</td><td></td><td></td><td></td></tr><tr><td></td><td></td><td>Sarin (acute)</td><td></td><td></td><td></td></tr><tr><td></td><td>CAPS (Clinician-Administered PTSD Scale)</td><td>Sarin (acute)</td><td></td><td></td><td></td></tr><tr><td></td><td></td><td>Sarin (acute)</td><td></td><td></td><td></td></tr><tr><td></td><td></td><td>Sarin (acute)</td><td></td><td></td><td></td></tr><tr><td>Psychiatric disorders</td><td>MINI (Mini-International Neuropsychiatric Interview)</td><td>Sarin (acute)</td><td></td><td></td><td></td></tr></tbody></table>

(continued on next page)
<table><caption>Table 2 (continued)</caption><thead><tr><th>Health parameters</th><th>Tests</th><th>Conditions (OP and approximate duration of exposition)</th><th>Route</th><th>Assessment period (after the last administration)</th><th>Articles</th></tr></thead><tbody><tr><td></td><td></td><td>combination of OP (chlorpyrphos and acephate), herbicides (glyphosate and clomazone), plant growth regulators (flumetralin), fungicides (iprodione), and insecticides (imidacloprid) exposed to OP for 3 months<br><b>Sarin</b> (acute)</td><td></td><td>Immediately after + 3 months</td><td>Salvi, (2003)</td></tr><tr><td></td><td>DSM-IV - Axis 1</td><td>combination of OP (chlorpyrphos and acephate), herbicides (glyphosate and clomazone), plant growth regulators (flumetralin), fungicides (iprodione), and insecticides (imidacloprid), 3 months</td><td></td><td>5 years</td><td>Tochigi et al., (2002)</td></tr><tr><td></td><td>Psychiatrist consultation</td><td><b>Soman</b> (25 % (V/V) and the total volume was less than 1 mL) or<br><b>Sarin</b></td><td>oral and skin contamination (soman) or inhalation (sarin)</td><td>Immediately after + 3 months<br>3 days to 6 months (soman), 4 months (sarin)</td><td>Salvi, (2003)</td></tr><tr><td></td><td>NEO-PI-R<br>Revised NEO Personality Inventory</td><td><b>Sarin</b> (acute)</td><td></td><td>5 years</td><td>Sidell, 1974</td></tr></tbody></table>

"low dose" is defined as all rodent models exposed to an OP at a dose below the median lethal dose (LD₅₀).

## 3.1. Cognitive impairments induced by OP exposure

This chapter reviews the methods for assessing memory deficits induced following OP exposure in animal models and the conclusions reached. Three categories of memory are commonly assessed: spatial memory, working memory, and aversive (fear-associated) memory.

### 3.1.1. Spatial memory

For spatial memory tests, rodents are trained to reach a specific goal or reward in a maze with spatial cues, and their ability to retain and utilize recently acquired information is evaluated.

Few studies have examined spatial memory impairments following acute exposure to a low dose of OP. After an exposure to an asymptomatic dose of sarin, transient memory impairments that do not persist beyond 24 h have been observed in the Y-maze test, which is based on the natural exploratory behavior of rats (Kassa et al., 2001). Conversely, mice exposed to a symptomatic dose of sarin developed memory defaults in Y-maze up to a period of 3 weeks following exposure. This finding is consistent with the outcomes observed 14 days following exposure to diisopropylfluorophosphate (DFP) (Terry et al., 2024). It is noteworthy that this outcome is corroborated by an additional spatial memory assessment: the Morris water maze test (MWM) (Terry et al., 2024). The MWM and the Barnes maze tests are designed to enable rodents to locate a platform or an escape box by utilizing visual cues strategically positioned throughout the test environment. In MWM, single or double sub-lethal chlorpyrifos (CPF) intoxication induced short- and long-term spatial learning impairment in rats up to 23 weeks after injection (Cañadas et al., 2005; López-Granero et al., 2014; Sanchez-Santed, 2004). It is interesting to note that the defects identified in these studies are rather subtle, and demonstrating the long-term consequences of a single injection is more challenging.

The memory consequences of chronic exposures to low doses of OP pesticides or NA, have been more investigated. Indeed, rats exhibited alterations in spatial memory in response to chronic exposure to OP pesticides, including dichlorvos (DDVP) and CPF, over a period of 14–28 days. This finding is supported by results from the MWM (Imam et al., 2018; Yan et al., 2012) and Y-maze (Hussein et al., 2018a) tests. Similarly, malathion exposure in mice resulted in spatial memory alterations, as evidenced by results with the object location test (OLT) (Dos Santos et al., 2016). This test is based on the natural propensity of rodents to explore new objects or objects in a novel location. Finally, a DFP chronic exposure in rats, for 5, 14, or 30 days, may result in an identical default, as evidenced by the results of T-maze (McDonald et al., 1988), the MWM (Prendergast et al., 1998, 1997; Terry et al., 2012)

or the OLT (Phillips and Deshpande, 2016) tests. Memory alterations occurred subsequent to chronic exposure to a complex mixture comprising OP and organochlorines. However, the specific contribution of each toxicant remains unclear (Ghasemnejad-Berenji et al., 2021). For an equivalent dosage of CPF administered via the same route, the duration of exposure has been observed to be a critical factor in the persistence of long-term cognitive deficits. Indeed, 2 months after 8 weeks of chronic CPF administration, no cognitive deficits were identified in mice in the MWM test (Basaure et al., 2017). In contrast, rats exposed to CPF for 6 months exhibited persistent cognitive impairments 7 months after the final administration (López-Granero et al., 2016). Nevertheless, the difference in species used between the two studies could also influence resistance to the effects of the pesticide. It is noteworthy that the chronic administration of a low dose VX, or saran, did not result in the occurrence of short- or long-term (lasting up to 2 months) alterations (Bloch-Shilderman et al., 2008; Johnson et al., 2008). Consequently, the nature of the OP compound appears to exert an influence on the development of spatial memory impairments observed with MWM test.

Spatial memory was also tested following administration of lethal dose of soman. A single injection of a high dose of soman has been shown to significantly impair learning ability in rats 2 months after intoxication, as revealed by the MWM test (Joosen et al., 2009). Interestingly, the consequences of intoxication, including weight loss, could be predictive of the time to onset of learning impairments (Filliat et al., 2007). Indeed, B6D2F1 mice that exhibited a significant weight loss demonstrated substantial memory impairment 1 and 3 months following poisoning. Conversely, the mice with only minor weight loss showed no cognitive deficits 1 month after poisoning but displayed a decline in performance in the MWM test 3 months after intoxication (Filliat et al., 2007).

### 3.1.2. Working memory

In the domain of human cognitive science, the term 'working memory' refers to the temporary storage of information that is utilized in the execution of cognitive tasks. In rodents, working memory can be defined as a cognitive faculty that encompasses the ability to represent objects, stimuli, or spatial locations. This representation is generally employed within the context of a testing session, wherein it serves as a guide for behavior. Indeed, the working memory tests utilized in rodents employ either a reward (Delayed Stimulus Discrimination Task (DSDT), the Radial Arm Maze (RAM), an escape (MWM) or a novelty (Novel Object Recognition Test (NORT) or T-maze) as the stimulus.

As with spatial memory, research on the effects of acute low dose-exposure to OP on working memory is limited. Subsequent to the acute administration of the pesticides triazophos or chlorphenvinphos (CVP), no impairment of short-term memory could be detected using the
<caption>**Table 3**</caption>

Impacts of organophosphorus compounds on sensory-motor affections, with particular regard to the health parameters evaluated, the tests used, the exposure conditions (type of OP, approximate duration of exposure, route of exposure, and period of assessment after the last exposure). In instances where information is unavailable, table boxes are left empty.

<table><thead><tr><th>Health parameters</th><th>Tests</th><th>Conditions (OP and approximate time of exposition)</th><th>Route</th><th>Assessment period (after the last administration)</th><th>Articles</th></tr></thead><tbody><tr><td rowspan="21">Nerve conduction</td><td rowspan="11">Clinical exams<br>(Deep tendon reflexes, Medical Research Council scale, Neck holding time)</td><td>Chlorpyrifos (chronic 10 years)</td><td>Inhalation</td><td>T0-1 year (prospective follow-up)</td><td>Albers et al., (2007)</td></tr><tr><td>Monocrotophos (acute, ~20-30 mL)</td><td>Ingestion</td><td>4 days</td><td>Bharali et al., (2023)</td></tr><tr><td>Pesticides mix (Teflubenzuron, Phosalone, Indoxacarb, Diazinon, Azinphosmethyl, Bromopropylate and Oxydemeton-methyl) (chronic 15.7 years (5 time per year))</td><td></td><td>13 years (5 time per year)</td><td>Boostani et al., (2014)</td></tr><tr><td>Malathion (acute)</td><td>Ingestion</td><td>35 days to 4 months</td><td>Das et al., (2013)</td></tr><tr><td>Pesticides (acute)</td><td>Ingestion</td><td>5 weeks</td><td>Gajurel et al., (2023)</td></tr><tr><td>Trichlorfon (acute, 200 mL)</td><td>Ingestion</td><td>1 month</td><td>Kobayashi et al., (2017)</td></tr><tr><td>Sarin (acute)</td><td>Ingestion</td><td>8 months</td><td>Loh et al., (2010)</td></tr><tr><td>Chlorpyriphos (acute)</td><td>i.v</td><td>2 days - 1 month</td><td>Malla et al., (2013)</td></tr><tr><td>Chlorpyrifos and Permethrin</td><td>Ingestion</td><td>3 days to a period of two years</td><td>Porey et al., (2023)</td></tr><tr><td>Pesticides (acute)</td><td>Ingestion</td><td>3-5 weeks</td><td>Viswanath et al., 2023</td></tr><tr><td rowspan="10">NCV<br>(Nerve conduction velocity MNCV or SNCV)</td><td>Chlorpyrifos (chronic 10 years)</td><td>Inhalation</td><td>T0-1 year (prospective follow-up)</td><td>Albers et al., (2007)</td></tr><tr><td>Monocrotophos (acute, ~20-30 mL)</td><td>Ingestion</td><td>4 and 21 days</td><td>Bharali et al., (2023)</td></tr><tr><td>Pesticides mix (Teflubenzuron, Phosalone, Indoxacarb, Diazinon, Azinphosmethyl, Bromopropylate and Oxydemeton-methyl) (chronic 15.7 years (5 time per year))</td><td></td><td>1 day, 5 time per year</td><td>Boostani et al., (2014)</td></tr><tr><td>Malathion (acute)</td><td>Ingestion</td><td>35 days to 4 months</td><td>Das et al., (2013)</td></tr><tr><td>Different pesticide by case report (Chlorpyrifos, Dimethoate, Profenofos, Diazinon, Malathion, Fenthion) (acute)</td><td>Ingestion</td><td>6 days and 6 weeks</td><td>Jayasinghe et al., (2012)</td></tr><tr><td>Trichlorfon (acute, 200 mL)</td><td>Ingestion</td><td>1 month</td><td>Kobayashi et al., (2017)</td></tr><tr><td>Sarin (acute)</td><td>Ingestion</td><td>8 months</td><td>Loh et al., (2010)</td></tr><tr><td>Pesticide 42% OP/carbamates (acute and chronic exposure)</td><td></td><td>at least two weeks</td><td>Panggabean et al., (2023)</td></tr><tr><td>Chlorpyrifos and Permethrin</td><td>Ingestion</td><td>3 days to a period of two years</td><td>Porey et al., (2023)</td></tr><tr><td>Sarin (acute)</td><td>Ingestion</td><td>8 months</td><td>Loh et al., (2010)</td></tr><tr><td>Pesticides (acute)</td><td>Ingestion</td><td>3-5 weeks</td><td>Viswanath et al., 2023</td></tr><tr><td rowspan="10">Peripheral electrophysiology<br>(peripheral nervous system)</td><td rowspan="5">CMAP<br>(compound muscle action potential amplitude)</td><td>Chlorpyrifos (chronic 10 years)</td><td>Inhalation</td><td>T0-1 year (prospective follow-up)</td><td>Albers et al., (2007)</td></tr><tr><td>Pesticides mix (Teflubenzuron, Phosalone, Indoxacarb, Diazinon, Azinphosmethyl, Bromopropylate and Oxydemeton-methyl) (chronic 15.7 years (5 time per year))</td><td></td><td>13 years (5 time per year)</td><td>Boostani et al., (2014)</td></tr><tr><td>Malathion (acute)</td><td>Ingestion</td><td>35 days to 4 months</td><td>Das et al., (2013)</td></tr><tr><td>Trichlorfon (acute, 200 mL)</td><td>Ingestion</td><td>1 month</td><td>Kobayashi et al., (2017)</td></tr><tr><td>Pesticide 42% OP/carbamates (acute and chronic exposure)</td><td></td><td>at least two weeks</td><td>Panggabean et al., (2023)</td></tr><tr><td rowspan="2">SNAP<br>(amplitude of sensory nerve action potential)</td><td>Chlorpyrifos (chronic 10 years)</td><td>Inhalation</td><td>T0-1 year (prospective follow-up)</td><td>Albers et al., (2007)</td></tr><tr><td>Pesticides mix (Teflubenzuron, Phosalone, Indoxacarb, Diazinon, Azinphosmethyl, Bromopropylate and Oxydemeton-methyl) (chronic 15.7 years (5 time per year))</td><td></td><td>13 years (5 time per year)</td><td>Boostani et al., (2014)</td></tr></tbody></table>

(continued on next page)
<table><caption>Table 3 (continued)</caption><thead><tr><th>Health parameters</th><th>Tests</th><th>Conditions (OP and approximate time of exposition)</th><th>Route</th><th>Assessment period (after the last administration)</th><th>Articles</th></tr></thead><tbody><tr><td rowspan="12"></td><td rowspan="12">EMG (electromyography)</td><td>Trichlorfon (acute, 200 mL)</td><td>Ingestion</td><td>1 month</td><td>Kobayashi et al., (2017)</td></tr><tr><td>Pesticide 42% OP/carbamates (acute and chronic exposure)</td><td></td><td>at least two weeks</td><td>Panggabean et al., (2023)</td></tr><tr><td>Chlorpyrifos (chronic 10 years)</td><td>Inhalation</td><td>T0-1 year (prospective follow-up)</td><td>Albers et al., (2007)</td></tr><tr><td>Malathion (acute)</td><td>Ingestion</td><td>4 days and 21 days</td><td>Das et al., (2013)</td></tr><tr><td>Different pesticide by case report (Chlorpyrifos, Dimethoate, Profenofos, Diazinon, Malathion, Fenthion) (acute)</td><td>Ingestion</td><td>6 days and 6 weeks</td><td>Jayasinghe et al., (2012)</td></tr><tr><td>Trichlorfon (acute, 200 mL)</td><td>Ingestion</td><td>1 month</td><td>Kobayashi et al., (2017)</td></tr><tr><td>Sarin (acute)</td><td></td><td>8 months</td><td>Loh et al., (2010)</td></tr><tr><td>Chlorpyrifos and Permethrin</td><td>Ingestion</td><td>3 days to a period of two years</td><td>Porey et al., (2023)</td></tr><tr><td>Sarin (acute)</td><td>Ingestion</td><td>3 days to a period of two years</td><td>Porey et al., (2023)</td></tr><tr><td>Pesticides (acute)</td><td>Ingestion</td><td>3-5 weeks</td><td>Viswanath et al., 2023</td></tr><tr><td>Chlorpyrifos and Permethrin</td><td>Ingestion</td><td>3 days to a period of two years</td><td>Porey et al., (2023)</td></tr><tr><td>Chlorpyrifos and Permethrin</td><td>Ingestion</td><td>3 days to a period of two years</td><td>Porey et al., (2023)</td></tr><tr><td>Sarin (acute)</td><td></td><td>8 months</td><td>Loh et al., (2010)</td></tr><tr><td>Sarin (acute)</td><td></td><td>7 years</td><td>Miyaki et al., (2005)</td></tr><tr><td>Stabilometry</td><td>Sarin (acute)</td><td></td><td>7 years</td><td>Miyaki et al., (2005)</td></tr><tr><td>Sural nerve biopsy</td><td>Malathion (acute)</td><td>Ingestion</td><td>35 days</td><td>Das et al., (2013)</td></tr></tbody></table>

NORT or T-Maze (Rodrigues et al., 2020; Sočko et al., 1989). Similarly, single inhalation exposure to VX at doses that induce mild clinical symptoms of toxicity slowed down learning in the RAM test without affecting long-term cognitive performance (Genovese et al., 2007). In addition, the administration of 2 different sub-lethal doses of a sarin surrogate, 4-nitrophenyl isopropyl methylphosphonate (NIMP), resulted in alterations of the short-term memory 1 month after intoxication, as evidenced by the NORT (Angrand et al., 2021). This phenomenon was also observed in rats chronically exposed to low dose OP pesticides, either for 14 days with CPF (Hussein et al., 2018b) or for 30 days with DFP doses superior to 0.75 mg/kg (Terry et al., 2011a). However, rats exposed to 0.25 mg/kg of DFP for 14 days did not exhibit any deficiencies when evaluated using the DSDT (Prendergast et al., 1998), suggesting that the dose and the test used could play a pivotal role in elucidating distinct facets of working memory.

Sarin inhalation at the median lethal concentration (LC₅₀) concentration resulted in deficits in working memory in surviving rats, as evidenced by the MWM test. These deficits persisted for a period of at least six months (Grauer et al., 2008). The impact of a lethal dose of soman on the working memory was observed in B6D2F1 mice 1 month after intoxication, evidenced by T-Maze (Filliat et al., 2007). The impact on working memory does not appear to be persistent over a prolonged period of time, as a partial recovery was observed 3 months following exposure in Filliat et al. study. However, using the NORT, long-term memory impairment were observed in rats 4 months following DFP injection (Rojas et al., 2016). The distinction between the two studies could be made with the species used, but also with the dose of OP used, since the dose of DFP (2.97 LD₅₀) was much higher than the dose of soman (1.2 LD₅₀) used.

### 3.1.3. Aversive memory

In Humans, the ability to recall aversive events is critical for survival; nevertheless, it can become maladaptive in psychiatric disorders.

In animal studies, the utilization of the Contextual Fear Conditioning (CFC) test constitutes a conventional approach for experimental investigation of this phenomenon. This test is based upon the principle of association between a neutral stimulus (i.e. the conditioned stimulus) and an aversive stimulus (i.e. the unconditioned stimulus). This association results in a specific fear behavioral response: freezing or escaping. This memory is characterized by its rapid and robust formation. Nevertheless, in the absence of the unconditioned stimulus, an ‘extinction’ phenomenon appears and the fear response declines.

An alteration of retention in aversive memory was evidenced up to 8 days after an exposure to a single low dose of malathion or soman (Valvassori et al., 2007; Wolthuis and Vanwersch, 1984). In contrast, a single low dose of sarin or TEPP did not result in any observable deficits (Wolthuis and Vanwersch, 1984). No deficits were detected in fear conditioning tests 3 weeks after the exposure to a single sub-lethal dose of DFP (Terry et al., 2024). However, the study's design appears to be a significant parameter, as an alteration of aversive memory was evidenced with the administration of another pesticide, triazophos (Rodrigues et al., 2020). Indeed, the exposure to a sub-lethal dose of triazophos at the end of the conditioning phase induces a deficit in aversive memory extinction, as revealed by the significant increase in the freezing time of exposed animals. Rats daily exposed to very low dose (0.02 LD₅₀) of malathion during 28 days exhibited aversive memory retention impairment shortly after the last injection (Valvassori et al., 2007). However, no impairment were observed in rats exposed to sarin or to CPF (Rosa et al., 2025; Scremin et al., 2003). This discrepancy can be attributed to the tests used, the nature of the OP, the repeated exposure protocol, or the time elapsed between the last injection and the trial.

The administration of a lethal dose of DFP has been demonstrated to result in a significant long-term impairment in fear memory (up to 2 months) (Flannery et al., 2016; Guignet et al., 2020). A reduction in freezing time in intoxicated animals during the extinction phase was
<caption>**Table 4**</caption>

Impacts of organophosphorus compounds on rodent cognitive behaviors, with particular regard to the type of test used, the exposure protocol, the doses, and the route of administration. Symbols + and – indicate post- and pre-exposure administration times (in minutes), respectively. Toxicant doses are given in mg/kg, with * representing an estimated LD₅₀ calculated from (Misik et al., 2015) or (McCollister et al., 1974) for chlorpyrifos when the exact dose was not specified in the article.

<table><thead><tr><th>Evaluation</th><th>Test</th><th>Conditions</th><th>Emergency treatment (time of administration relative to OP, dose, route of administration)</th><th>Assessment period (after the last administration)</th><th>Articles</th></tr></thead><tbody><tr><td rowspan="10">Spatial memory</td><td rowspan="10">Morris water maze</td><td>OP (dose), exposition (duration), route of administration, model</td><td></td><td></td><td></td></tr><tr><td>Sub lethal single exposure</td><td>Chlorpyrifos (250 mg/kg), single or twice (21 weeks between injections), s.c., male Wistar rats</td><td>No</td><td>21 or 26 weeks</td><td>Cañadas et al., (2005)</td></tr><tr><td rowspan="7">Sub lethal chronic exposure</td><td>Chlorpyrifos (250 mg/kg) or DFP (1,5 mg/kg, ~0.95LD<sub>50</sub>*) or parathion (15 mg/kg), single, s.c., male Wistar rats</td><td>No</td><td>72 h and 23 weeks</td><td>López-Granero et al., (2014)</td></tr><tr><td>DFP (4 mg/kg, ~0.59 LD<sub>50</sub>), single, i.p., male C57BL/6 mice</td><td>No</td><td>6 days</td><td>Terry et al., (2024)</td></tr><tr><td>Chlorpyrifos (5 mg/kg/day, ~0.03LD<sub>50</sub>*) chronic (1/day for 8 weeks), p.o. by diet, male C57BL/6 mice</td><td>No</td><td>2 months</td><td>Basaure et al., (2017)</td></tr><tr><td>VX (2.25 µg/kg/day, ~0.05 LD<sub>50</sub>) chronic (3 months), s.c., male Sprague-Dawley rats</td><td>No</td><td>3 days and 1 month</td><td>Bloch-Shilderman et al., (2008)</td></tr><tr><td>Mix of pesticides including chlorpyrifos (1.0 mg/kg, ~0.006 LD<sub>50</sub>), chronic (for 3 months), p.o. in diluted in drinking water, male Wistar rats</td><td>No</td><td>1-5 days</td><td>Ghasemnejad-Berenji et al., (2021)</td></tr><tr><td>Dichlorvos (8,8 mg/kg, ~0.1 LD<sub>50</sub>) or chlorpyrifos (14,9 mg/kg, ~0.1 LD<sub>50</sub>) or dichlorvos + chlorpyrifos, chronic (1/day for 14 days), p.o., male Wistar rats</td><td>No</td><td>14th day of treatment</td><td>Imam et al., (2018)</td></tr><tr><td>Soman (11,2 µg/kg, ~0.4 LD<sub>50</sub>), chronic (1/day for 10 days), s.c., male Hartley guinea pigs</td><td>No</td><td>7, 14 and 84 days</td><td>Johnson et al., (2008)</td></tr><tr><td rowspan="10">Object location test</td><td rowspan="10">Lethal exposure</td><td>Chlorpyrifos (5 mg/kg/day, ~0.03LD<sub>50</sub>*) chronic (1/day for 6 months), p.o. by diet, male Wistar rats</td><td>No</td><td>7 months</td><td>López-Granero et al., (2016)</td></tr><tr><td>DFP (0.05 or 0.25 mg/kg, ~0.03 or 0.16 LD<sub>50</sub>), chronic (1/day for 14 days), s.c., male Wistar rats</td><td>No</td><td>3 and 21 days</td><td>Prendergast et al., (1997)</td></tr><tr><td>DFP (0,25 mg/kg, ~0.18 LD<sub>50</sub>*) chronic (1/day for 14 days), s.c., male Wistar rats</td><td>No</td><td>2 days</td><td>Prendergast et al., (1998)</td></tr><tr><td>Chlorpyrifos (166 mg/kg (exposure 1) and 250 mg/kg (exposure 2)) or paraoxon (0.4 mg/kg (exposure 1 and 2)), twice (22 weeks between injection), s.c., male Wistar rats</td><td>No</td><td>22 and 50 weeks</td><td>Sánchez-Santed et al., 2004</td></tr><tr><td>DFP (0.25, 0.5, 0.75, and 1.0 mg/kg, ~0.16, 0.32, 0.47 and 0.63 LD<sub>50</sub>), chronic (1/day every other day for 30 days), s.c., male Wistar rats</td><td>No</td><td>8 days</td><td>Terry et al., 2011</td></tr><tr><td>DFP (0.25 or 0.75 mg/kg, 0.16 or 0.47 LD<sub>50</sub>*) or chlorpyrifos (10 or 18 mg/kg), chronic (1/day every other day for 30 days), s.c., male Wistar rats</td><td>No</td><td>140 days</td><td>Terry et al., (2012)</td></tr><tr><td>Chlorpyrifos (1, 5 or 10 mg/kg, ~0.006, 0.03 or 0.06 LD<sub>50</sub>*) chronic (1/day for 4 weeks), p.o. male Wistar rats</td><td>No</td><td>16 h</td><td>Yan et al., (2012)</td></tr><tr><td>Soman (110 µg/kg, 1.2 LD<sub>50</sub>), single, s.c., male B6D2F1/j@rj mice</td><td>Atropine methyl nitrate (< +1 min, 5 mg/kg, i.p.)</td><td>1 and 3 months</td><td>Filliat et al., (2007)</td></tr><tr><td>Soman (200 µg/kg, ~1.67 LD<sub>50</sub>*) single, s.c., male Sprague-Dawley rats</td><td>HI-6 (-30 min, 125 mg/kg, i.p.), Atropine sulfate (+1 min, 16 mg/kg, i.m.)</td><td>8 weeks</td><td>Joosen et al., (2009)</td></tr><tr><td rowspan="2">Sub lethal chronic exposure</td><td>Malathion (30 or 100 mg/kg), chronic (1/day for 15 days), s.c., male Swiss mice</td><td>No</td><td>24 h</td><td>Dos Santos et al., (2016)</td></tr><tr><td>DFP (400 µg/kg, < 0.2 LD<sub>50</sub>), chronic (1/day for 5 days), s.c., male Sprague-Dawley rats</td><td>No</td><td>3 months</td><td>Phillips andDeshpande, 2016</td></tr><tr><td>Barnes maze</td><td>Sub lethal chronic exposure</td><td>Chlorpyrifos (5 mg/kg/day, ~0.03LD<sub>50</sub>*) chronic (1/day for 8 weeks), p.o. by diet, male C57BL/6 mice</td><td>No</td><td>During the last week</td><td>Basaure et al., (2017)</td></tr></tbody></table>

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<table><caption>Table 4 (continued)</caption><thead><tr><th>Evaluation</th><th>Test</th><th>Conditions</th><th>Emergency treatment (time of administration relative to OP, dose, route of administration)</th><th>Assessment period (after the last administration)</th><th>Articles</th></tr></thead><tbody><tr><td rowspan="10">Working memory</td><td>T-maze</td><td>Sub lethal chronic exposure</td><td>DFP (1 mg/kg, ~0.31 LD<sub>50</sub>*) or disulfoton (2 mg/kg), chronic (1/day for 14 days), i.p., male Long-Evans rats</td><td>No</td><td>24 h</td><td>McDonald et al., (1988)</td></tr><tr><td rowspan="3">Y-maze</td><td rowspan="2">Sub lethal single exposure</td><td>Sarin (0.8 µg/L, 1.25 µg/L or 2.5 µg/L, ~0.18 LC<sub>50</sub>*, ~0.28 LC<sub>50</sub> or ~0.56 LC<sub>50</sub>*, single, inhalation (1 h), male Wistar rats</td><td>Atropine + HI-6 (+1 min, 0.02 LD<sub>50</sub>, i.m.)</td><td>1 & 2 h, 1 day, 1-5 weeks</td><td>Kassa et al., (2001)</td></tr><tr><td>DFP (4 mg/kg, ~0.59 LD<sub>50</sub>), single, i.p., male C57BL/6 mice</td><td>No</td><td>14 days</td><td>Terry et al., (2024)</td></tr><tr><td>Sub lethal chronic exposure</td><td>Chlorpyrifos (18 mg/kg) chronic (1/day for 14 days), s.c. male Wistar rats</td><td>No</td><td>14th day of treatment</td><td>Hussein et al., 2018</td></tr><tr><td rowspan="5">Delayed stimulus discrimination task</td><td rowspan="2">Sub lethal chronic exposure</td><td>Sarin (1.25 µg/L, ~0.28 LC<sub>50</sub>), 3-time (each other day), inhalation (1 h), male Wistar rats</td><td>Atropine + HI-6 (+1 min, 0.02 LD<sub>50</sub>, i.m.)</td><td>1 & 2 h, 1 day, 1-5 weeks</td><td>Kassa et al., (2001)</td></tr><tr><td>DFP (0.25 mg/kg, ~0.18LD<sub>50</sub>), chronic (1/day for 14 days), s.c., male Wistar rats</td><td>No</td><td>9 days</td><td>Prendergast et al., (1998)</td></tr><tr><td>Morris water maze test</td><td>Lethal exposure</td><td>Sarin (34.2 ± 0.8 µg/L, 1 LCt<sub>50</sub>), single, inhalation (10 min), male Sprague-Dawley rats</td><td>No</td><td>5 weeks, 4 and 6 months</td><td>Grauer et al., (2008)</td></tr><tr><td rowspan="2">Novel object recognition test</td><td>Sub lethal single exposure</td><td>NIMP (189, 315, 441 or 567 µg/kg, 0.3, 0.5, 0.7 or 0.9 LD<sub>50</sub>), single, s.c., male Swiss mice</td><td>No</td><td>1 month</td><td>Angrand et al., (2021)</td></tr><tr><td>Sub lethal chronic exposure</td><td>Triazophos (7.5, 15, or 30 mg/kg), single, i.p. male Wistar rats</td><td>No</td><td>24 h</td><td>Rodrigues et al., (2020)</td></tr><tr><td rowspan="2">Working memory</td><td rowspan="2">Sub lethal chronic exposure</td><td>Chlorpyrifos (18 mg/kg) chronic (1/day for 14 days), s.c. male Wistar rats</td><td>No</td><td>24 h</td><td>Hussein et al., 2018</td></tr><tr><td>DFP (0.25, 0.5, 0.75, and 1.0 mg/kg, ~0.16, 0.32, 0.47 and 0.63 LD<sub>50</sub>), chronic (1/day every other day for 30 days), s.c., male Wistar rats</td><td>No</td><td>3 days</td><td>Terry et al., 2011</td></tr><tr><td rowspan="10">Radial arm maze</td><td rowspan="2">Sub lethal single exposure</td><td>DFP (9 mg/kg, ~2.81 LD<sub>50</sub>), single, i.p. male Sprague-Dawley rats</td><td>Pyridostigmine bromide (-30 min, 0.1 mg/kg, s.c.), + Atropine methylbromide (-10 min, 20 mg/kg, s.c.)</td><td>6 or 12 weeks</td><td>Rojas et al., (2016)</td></tr><tr><td>VX (0.016, 0.15, 0.30, 0.45 mg/m<sup>3</sup>), single, inhalation (1 h), male Sprague-Dawley rats</td><td>No</td><td>2 days</td><td>Genovese et al., (2007)</td></tr><tr><td rowspan="2">Sub lethal chronic exposure</td><td>VX (3.0 or 4.0 mg/m<sup>3</sup>), chronic (1/day for 2 days), inhalation (1 h), male Sprague-Dawley rats</td><td>No</td><td>2 days</td><td>Genovese et al., (2007)</td></tr><tr><td>Chlorphenvinphos (1 or 3 mg/kg, 0.1 or 0.33 LD<sub>50</sub>), single, i.p., male Wistar rats</td><td>No</td><td>24 h then every second day four times</td><td>Sočko et al., (1989)</td></tr><tr><td rowspan="2">Sub lethal chronic exposure</td><td>Soman (110 µg/kg, 1.2 LD<sub>50</sub>), single, s.c., male B6D2F1/j@rj mice</td><td>Atropine methyl nitrate (< +1 min, 5 mg/kg, i.p.)</td><td>1 and 3 months</td><td>Filliat et al., (2007)</td></tr><tr><td>Triazophos (7.5, 15, or 30 mg/kg), single, i.p. male Wistar rats</td><td>No</td><td>24 h</td><td>Rodrigues et al., (2020)</td></tr><tr><td rowspan="5">T-Maze</td><td rowspan="2">Sub lethal single exposure</td><td>DFP (4 mg/kg, ~0.59 LD<sub>50</sub>), single, i.p., male C57BL/6 mice</td><td>No</td><td>22 days</td><td>Terry et al., (2024)</td></tr><tr><td>TEPP (not more than 83.7 µg/kg, ~0.3LD<sub>50</sub> or sarin (not more than 37.2 µg/kg, ~0.3LD<sub>50</sub>) or soman (1.52 µg/kg, 0.01 LD<sub>50</sub>), single, s.c. male Wistar rats</td><td>No</td><td>30 min</td><td>Wolthuis and Vanversch, 1984</td></tr><tr><td>Lethal exposure</td><td>Chlorpyrifos (4 or 7 mg/kg), chronic (3/week for 4 weeks), i.p., male Wistar rats</td><td>No</td><td>4 days</td><td>Rosa et al., (2025)</td></tr><tr><td rowspan="2">Sub lethal single exposure</td><td>DFP (9 mg/kg, ~2.81 LD<sub>50</sub>), single, i.p. male Sprague Dawley rats</td><td>Pyridostigmine bromide (-30 min, 0.1 mg/kg, i.m.), atropine methyl nitrate (-10 min, 20 mg/kg, i.m.)</td><td>3, 7, 14, 36 days or 4, 9 and 20 days</td><td>Flannery et al., (2016)</td></tr><tr><td>Soman (74.4 µg/kg, 1.2 LD<sub>50</sub>), single, s.c. Sprague-Dawley rats</td><td>Atropine Sulfate (+1 min, 0.5 mg/kg, i.m.) + HI-6 (+1 min, 125 mg/kg, i.p.)</td><td>30 and 90 days</td><td>Miller et al., (2015)</td></tr><tr><td rowspan="2">Contextual and/or cued fear conditioning</td><td rowspan="2">Sub lethal single exposure</td><td>DFP (4 mg/kg, ~0.59 LD<sub>50</sub>), single, i.p., male C57BL/6 mice</td><td>No</td><td>22 days</td><td>Terry et al., (2024)</td></tr><tr><td>TEPP (not more than 83.7 µg/kg, ~0.3LD<sub>50</sub> or sarin (not more than 37.2 µg/kg, ~0.3LD<sub>50</sub>) or soman (1.52 µg/kg, 0.01 LD<sub>50</sub>), single, s.c. male Wistar rats</td><td>No</td><td>30 min</td><td>Wolthuis and Vanversch, 1984</td></tr><tr><td rowspan="2">Aversive memory</td><td rowspan="2">Sub lethal chronic exposure</td><td>DFP (4 mg/kg, ~0.59 LD<sub>50</sub>), single, i.p., male C57BL/6 mice</td><td>No</td><td>22 days</td><td>Terry et al., (2024)</td></tr><tr><td>TEPP (not more than 83.7 µg/kg, ~0.3LD<sub>50</sub> or sarin (not more than 37.2 µg/kg, ~0.3LD<sub>50</sub>) or soman (1.52 µg/kg, 0.01 LD<sub>50</sub>), single, s.c. male Wistar rats</td><td>No</td><td>30 min</td><td>Wolthuis and Vanversch, 1984</td></tr><tr><td rowspan="2">Sub lethal chronic exposure</td><td>Lethal exposure</td><td>DFP (9 mg/kg, ~2.81 LD<sub>50</sub>), single, i.p. male Sprague Dawley rats</td><td>No</td><td>4 days</td><td>Rosa et al., (2025)</td></tr><tr><td>Sub lethal single exposure</td><td>Soman (74.4 µg/kg, 1.2 LD<sub>50</sub>), single, s.c. Sprague-Dawley rats</td><td>No</td><td>30 and 90 days</td><td>Miller et al., (2015)</td></tr><tr><td>Inhibitory avoidance task</td><td>Sub lethal single exposure</td><td>Malathion (25, 50, 100 or 150 mg/kg, 0.02, 0.04, 0.07 or 0.11 LD<sub>50</sub> respectively), single i.p., male Wistar rats</td><td>No</td><td>1 h</td><td>Valvassori et al., (2007)</td></tr></tbody></table>

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<table><caption>Table 4 (continued)</caption><thead><tr><th>Evaluation</th><th>Test</th><th>Conditions</th><th>Emergency treatment (time of administration relative to OP, dose, route of administration)</th><th>Assessment period (after the last administration)</th><th>Articles</th></tr></thead><tbody><tr><td></td><td>Sub lethal chronic exposure</td><td>Malathion (25, 50, 100 or 150 mg/kg, 0.02, 0.04, 0.07 or 0.11 LD<sub>50</sub> respectively), chronic (1/day for 28 days), i.p., male Wistar rats</td><td>No</td><td>23 h</td><td>Valvassori et al., (2007)</td></tr><tr><td></td><td>Passive avoidance response</td><td>Sarin (62.5 µg/kg, 0.5 LD<sub>50</sub>), chronic (3days/week for 3 weeks), s.c., male Sprague-Dawley rats</td><td>No</td><td>2, 4 and 16 weeks</td><td>Scremin et al., (2003)</td></tr><tr><td></td><td>Pavlovian fear conditioning</td><td>DFP (4 mg/kg, ~2.67* LD<sub>50</sub>), single, s.c., male Sprague-Dawley rats</td><td>pyridostigmine bromide (-30 min, 0.1 mg/mg, i.m.) + Atropine sulfate (+1 min, 2 mg/kg, i.m.) + 2-PAM (+1 min, 25 mg/kg, i.m.)</td><td>34 and 64 days</td><td>Guignet et al., (2020)</td></tr><tr><td>Attention</td><td>5-Choice serial reaction time task</td><td>DFP (0.5 mg/kg, ~0.32 LD<sub>50</sub>), chronic (1/day every other day for 30 days), s.c. male Wistar rats</td><td>No</td><td>During the 30 day every other day exposure period and during the 45 following days</td><td>Terry et al., (2014)</td></tr><tr><td>Decision making</td><td>Delay-discounting task</td><td>Chlorpyrifos (250 mg/kg) or DFP (1.5 mg/kg, ~0.95LD<sub>50</sub>) or parathion (15mg/kg), single, s.c., male Wistar rats</td><td>No</td><td>10 and 30 weeks</td><td>López-Granero et al., (2014)</td></tr></tbody></table>

observed, thereby suggesting a diminution in aversive memory. Similarly, in young subjects (P21), a lethal dose of soman induced an impairment of aversive memory. However, this impairment was transient, manifesting 30 days after exposure and resolving 3 months later (Miller et al., 2015).

### 3.1.4. Attention and decision making

In the evaluation of cognitive impairment induced by OP, less attention has been given on the attention or decision-making. To our knowledge, only one study has evaluated attention deficits. In a 5-choice serial reaction time task, animals chronically exposed to DFP for 30 days exhibited deficits in visuospatial attention during the exposure period and impulsive-like behavior and/or cognitive inflexibility 45 days after the last DFP injection (Terry et al., 2014).

The assessment of impulsivity can be performed using the Delay-Discounting task. This phenomenon is revealed by the choice of the individual, which may decide between lower but more recurrent rewards or higher but rarer rewards. The first choice may be interpreted as indicative of impulsivity (Bari and Robbins, 2013; Dalley et al., 2008). However, the exposure to a single sub-lethal dose of pesticide (CPF, DFP or parathion) does not have a significant impact on impulsive choice modification 10 or 30 weeks after the intoxication (López-Granero et al., 2014).

### 3.2. Mood disorder-like behaviors affected by OP exposure

As previously outlined, exposure to OP induces alterations in mental health, notably anxiety- and depression-like behaviors. Anxiety-like behaviors have been extensively studied in animal models using tests based on approach versus avoidant paradigms, which reflect alterations in responses to stress. Depression-like symptoms are typically evaluated through paradigms that reflect anhedonia, despair, and reduced motivation.

Numerous investigations using acute exposure to a sub-lethal dose of OP have highlighted the rapid onset of anxiety-like behaviors following intoxication. Indeed, anxiety-like behavior was induced 30 min after a single low dose of soman or sarin exposure, as observed in the elevated plus maze (EPM) (Baille et al., 2001; Sirkka et al., 1990). Behavioral changes in handling and approach responses, vocalization, and click response were also observed 24 h after a single inhalation of soman (Bajgar et al., 2004). Short-term anxiety-like behaviors measured with EPM and open-field (OF) were observed 5 days after CPF exposure (López-Crespo et al., 2009, 2007). In contrast, no alterations in anxiety-like behavior were observed 1 h after the exposure to a single sub-lethal

dose of malathion pesticides evaluated in the OF and EPM tests (Valvassori et al., 2007). Conversely, an anxiolytic effect was observed 30 h after a single injection of ethyl octyl phosphonofluoridate (EOPF) in male Wistar rats (Ito et al., 2020a). Nevertheless, anxiety-like behaviors may be observed for a period ranging from weeks to months. Indeed, a single low dose of soman or NIMP led to an increase in anxiety behaviors from 1 to 6 months following exposure (François et al., 2022; Mamczarz et al., 2010). These long-term alterations were revealed by the OF test (Mamczarz et al., 2010) and a multipanel testing strategy combining EPM, staircase, OF, and O-maze tests to avoid any habituation (François et al., 2022). In addition, 5 months after NIMP exposure, male Swiss mice displayed reduced motivation to approach palatable food placed in the center of a square open field, indicating sustained anxiety with an onset of anhedonia (François et al., 2022).

Anhedonia, a condition characterized by a diminished capacity to experience pleasure from activities that previously provided satisfaction, is classically observed by a decline of grooming in the splash test. This behavior, with despair, are classified as depression-like behaviors, manifesting rapidly following OP exposure. For instance, an increase in immobility in the force swim test (FST), a classical indicator of despair-like behavior, was reported as early as 30 min and 12 h after exposure to a sub-lethal dose of malathion (Assini et al., 2005; Savall et al., 2020). In addition, a splash test revealed that grooming behavior was significantly reduced 12 h after exposure to malathion (Savall et al., 2020). Similarly, grooming behavior in the OF drastically decreased 45 min in male Wistar rats after exposure to a sub-lethal dose of sarin, consistent with an anhedonic-like state (Nieminen et al., 1990). However, in the same study, the behavior of rats exposed to soman was not changed (Nieminen et al., 1990), highlighting toxic difference. Delayed onset of depression-like behaviors was also reported, evidenced by increased immobility in FST observed 1 and 7 days after phosalone exposure (Aliomrani et al., 2021). Persisting immobility in FST was reported up to 4 months after single sub-lethal DFP exposure in rats (Liu et al., 2021). These results underscore the necessity of conducting exhaustive evaluations to assess the full spectrum of depressive disorders.

Chronic exposure to sub-lethal doses of sarin or VX resulted in a deficit in adaptative behavioral responses in the presence of novel paradigms (i.e., approaching pencil or environment changes) (Hulet et al., 2002; Mach et al., 2008), with persisting effects (Bloch-Shilderman et al., 2008). In addition, anxiety-like behaviors were observed in rats daily exposed to sub-lethal of soman for 3 weeks, in the EPM test 3 months after the last injection (Golime et al., 2024). However, acoustic startle reactivity was only transiently increased following sub-chronic exposure to sarin. This increase was only observed 2 weeks after the last
<caption>**Table 5**</caption>

Impacts of organophosphorus compounds on rodent mood-like behaviors, with particular regard to the type of test used, the exposure protocol, the doses, and the route of administration. Symbols: t₀ indicates the time of exposure; + and – indicate post- and pre-exposure administration, respectively. Toxicant doses are expressed in mg/kg. * denotes an estimated LD₅₀ derived from the literature, notably (Misik et al., 2015) (Maretto et al., 2012), and (McCollister et al., 1974), when the exact dose was not reported.

<table><thead><tr><th>Evaluation</th><th>Test</th><th>Conditions<br>OP (dose), exposition (duration), route of administration, model</th><th>Emergency treatment (time of administration relative to OP, dose, route of administration)</th><th>Assessment period<br>(after the last administration)</th><th>Articles</th></tr></thead><tbody><tr><td rowspan="14">Anxiety</td><td rowspan="14">Open field test<br>(square)</td><td rowspan="2">Sub lethal<br>single<br>exposure</td><td>NIMP (315 or 567 µg/kg, 0.5 or 0.9 LD₅₀), single, s.c., male Swiss mice</td><td>No</td><td>Baseline</td><td>François et al., (2022)</td></tr><tr><td>Chlorpyrifos (250 mg/kg), single, s.c., male Wistar rats</td><td>No</td><td>2, 5, 11 and 30 days</td><td>López-Crespo et al., 2007</td></tr><tr><td rowspan="2">Sub lethal<br>chronic<br>exposure</td><td>Soman (16.8 or 22.4 µg/kg, 0.6 or 0.8 LD₅₀), single, s.c., male Hartley guinea pigs</td><td>No</td><td>2 and 3 months</td><td>Mamczarz et al., (2010)</td></tr><tr><td>Malathion (25, 50, 100 or 150 mg/kg, 0.02, 0.04, 0.07 or 0.11 LD₅₀ respectively), single, i.p., male Wistar rats</td><td>No</td><td>1 h</td><td>Valvassori et al., (2007)</td></tr><tr><td>Chlorpyrifos (5 mg/kg/day, 0.03 LD₅₀*), chronic (1/day for 8 weeks), p.o., male C57BL/6 mice</td><td>No</td><td>4th weeks of treatment</td><td>Basaure et al., (2017)</td></tr><tr><td>VX (2.25 µg/kg/day, 0.05 LD₅₀), chronic (3 months), s.c., male Sprague-Dawley rats</td><td>No</td><td>3 days and 1 month</td><td>Bloch-Shilderman et al., (2008)</td></tr><tr><td rowspan="2">Lethal<br>exposure</td><td>Methamidophos (3.5 mg/kg, 0.3 LD₅₀*), chronic (1/day for 1 week), i.p., male Swiss mice</td><td>No</td><td>1 day</td><td>Do Nascimento et al., (2017)</td></tr><tr><td>Sarin (12.6, 16.8, 21, or 25.2 µg/kg, 0.3, 0.4, 0.5, or 0.6 LD₅₀), chronic (5 days/week for 2 weeks), s.c., male Hartley guinea pigs</td><td>No</td><td>4 and 6 days</td><td>Hulet et al., (2002)</td></tr><tr><td rowspan="2">Sub lethal<br>single<br>exposure</td><td>Dichlorvos (8,8 mg/kg, &lt; 1 LD₅₀) or chlorpyrifos (14,9 mg/kg, &lt; 0.1 LD₅₀) or dichlorvos + chlorpyrifos, chronic (1/day for 14 days), p.o., male Wistar rats</td><td>No</td><td>13th day of treatment</td><td>Imam et al., (2018)</td></tr><tr><td>Dichlorvos (0.0015 mg/mL, 0.1 LC₅₀), chronic (5/week for 6 weeks), inhalation (4 h), male Wistar rats</td><td>No</td><td>30th day of treatment</td><td>Reis et al., (2022)</td></tr><tr><td rowspan="2">Sub lethal<br>chronic<br>exposure</td><td>Chlorpyrifos (1 mg/kg) or Diazinon (1 mg/kg), chronic (1/day for 5 days), i.p., male Hooded-Lister rats</td><td>No</td><td>1 day</td><td>Savy et al., (2015)</td></tr><tr><td>Parathion-methyl (0.22 or 0.44 mg/kg, 0.01 or 0.02 LD₅₀), chronic (5/week for 6 weeks), p.o., male Wistar rats</td><td>No</td><td>End of the experimentation</td><td>Schulz et al., (1990)</td></tr><tr><td rowspan="2">Sub lethal<br>single<br>exposure</td><td>Malathion (25, 50, 100 or 150 mg/kg, 0.02, 0.04, 0.07 or 0.11 LD₅₀ respectively), chronic (1/day for 28 days), i.p., male Wistar rats</td><td>No</td><td>23 h</td><td>Valvassori et al., (2007)</td></tr><tr><td>DFP (9.5–12.7 mg/kg, ~ 3.3 – 4.4 LD₅₀), single, s.c., male C57BL/6-J mice</td><td>Atropine sulfate (+1 min; 0.1 mg/kg, i.m.), 2-PAM (+1 min; 25 mg/kg, i.m.)</td><td>28 days</td><td>Calsbeek et al., (2021)</td></tr><tr><td rowspan="14">Open field test<br>(circular)</td><td rowspan="2">Sub lethal<br>single<br>exposure</td><td>DFP (4 mg/kg, ~2.67 LD₅₀*), single, s.c. male Sprague-Dawley rats</td><td>Pyridostigmine bromide (-30 min; 0.1 mg/kg), atropine sulfate (+1 min; 2 mg/kg, i.m.), 2-PAM (+1 min; 25 mg/kg, i.m.)</td><td>1 and 2 months</td><td>Guignet et al., (2020)</td></tr><tr><td>Soman (74.4 µg/kg, 1.2 LD₅₀), single, s.c. male Sprague-Dawley rats</td><td>Atropine Sulfate (+1 min; 0.5 mg/kg; i.m.), HI-6 (+1 min; 125 mg/kg; i.p.)</td><td>1 and 3 months</td><td>Miller et al., (2015)</td></tr><tr><td>Sub lethal<br>chronic<br>exposure</td><td>Soman (154 µg/kg, 1.4 LD₅₀), single, s.c., male, Sprague-Dawley rats</td><td>Atropine sulfate (+20 min; 2 mg/kg, i.m.)</td><td>14 and 30 days</td><td>Prager et al., (2014)</td></tr><tr><td>NIMP (315 or 567 µg/kg, 0.5 or 0.9 LD₅₀), single, s.c., male Swiss mice</td><td>No</td><td>4 months</td><td>François et al., (2022)</td></tr><tr><td rowspan="2">Sub lethal<br>single<br>exposure</td><td>Malathion (50 or 100 mg/kg, 0.125 or 0.25 LD₅₀*), chronic (1/day for 3 days), i.p., female Wistar rats</td><td>No</td><td>1 day</td><td>Brocardo et al., (2007)</td></tr><tr><td>Malathion (30 or 100 mg/kg), chronic (1/day for 15 days), s.c., male Swiss mice</td><td>No</td><td>1 day</td><td>Dos Santos et al., (2016)</td></tr><tr><td rowspan="2">Elevated plus<br>maze</td><td>Chlorpyrifos (2.5, 5, 10 or 20 mg/kg), chronic (1/day for 10 days), s.c., male Sprague-Dawley rats</td><td>No</td><td>7 days</td><td>Chen et al., (2014)</td></tr><tr><td>Malathion (50, 100, 250 or 500 mg/kg, 0.08–0.4 LD₅₀), single, i.p., male Sprague-Dawley rats</td><td>No</td><td>30 min</td><td>Assini et al., (2005)</td></tr><tr><td rowspan="2">Sub lethal<br>single<br>exposure</td><td>Soman (30, 50 or 90 µg/kg, 0.27, 0.45 or 0.8 LD₅₀), single, s.c., male Swiss mice</td><td>No</td><td>30 min, 24 h and 7 days</td><td>Baille et al., (2001)</td></tr></tbody></table>

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<table><caption>Table 5 (continued)</caption><thead><tr><th>Evaluation</th><th>Test</th><th>Conditions<br>OP (dose), exposition (duration), route of administration, model</th><th>Emergency treatment (time of administration relative to OP, dose, route of administration)</th><th>Assessment period (after the last administration)</th><th>Articles</th></tr></thead><tbody><tr><td></td><td></td><td>NIMP (315 or 567 µg/kg, 0.5 or 0.9 LD<sub>50</sub>), single, s.c., male Swiss mice</td><td>No</td><td>1 month</td><td>François et al., (2022)</td></tr><tr><td></td><td></td><td>Ethyl octylphosphonofluoridate (1, 2 or 3 mg/kg), single, i.p., male Wistar rats</td><td>No</td><td>6, 24, and 30 h</td><td>Ito et al., 2020</td></tr><tr><td></td><td></td><td>Chlorpyrifos (250 mg/kg), single, s.c., male Wistar rats</td><td>No</td><td>5 days</td><td>López-Crespo et al., 2009</td></tr><tr><td></td><td></td><td>Soman (16.8 or 22.4 µg/kg, 0.6 or 0.8 LD<sub>50</sub>), single, s.c., male Hartley guinea pigs</td><td>No</td><td>13 weeks</td><td>Mamczarz et al., (2010)</td></tr><tr><td></td><td></td><td>Sarin (12.5 or 50 µg/kg, ~0.03 or 0.11 LD<sub>50</sub>) and Soman (4 or 20 µg/kg, ~0.02 or 0.11 LD<sub>50</sub>), single, i.p., male Wistar rats</td><td>No</td><td>NA</td><td>Sirkka et al., (1990)</td></tr><tr><td></td><td></td><td>Malathion (25, 50, 100 or 150 mg/kg, 0.02, 0.04, 0.07 or 0.11 LD<sub>50</sub> respectively), single, i.p., male Wistar rats</td><td>No</td><td>1 h</td><td>Valvassori et al., (2007)</td></tr><tr><td rowspan="10">Chronic Sublethal exposure</td><td rowspan="10">Chlorpyrifos (10, 20, 40, 80 or 160 mg/kg), chronic (1/day for 1 week), s.c., male Sprague-Dawley rats</td><td>Malathion (25, 50, 100, or 250 mg/kg, 0.04–0.2 LD<sub>50</sub>), chronic (1/day for 1 week), i.p., female Wistar rats</td><td>No</td><td>30 min</td><td>Assini et al., (2005)</td></tr><tr><td>Mix of pesticides including chlorpyrifos (1.0 mg/kg, ~0.006LD<sub>50</sub>\*), chronic (for 3 months), diluted in drinking water, male Wistar rats</td><td>No</td><td>5 days</td><td>Chen et al., (2011)</td></tr><tr><td>Soman (22.5 µg/kg, 0.25 LD<sub>50</sub>), chronic (1/day for 21 days), s.c., male Wistar rats</td><td>No</td><td>1–5 days</td><td>Ghasemnejad-Berenji et al., 2021</td></tr><tr><td>Dichlorvos (8,8 mg/kg, &lt; &lt; 1 LD<sub>50</sub>) or chlorpyrifos (14,9 mg/kg, &lt; &lt; 0.1 LD<sub>50</sub>) or dichlorvos + chlorpyrifos, chronic (1/day for 14 days), p.o., male Wistar rats</td><td>No</td><td>30 and 90 days</td><td>Golime et al., (2024)</td></tr><tr><td>DFP (400 µg/kg, &lt; 0.2 LD<sub>50</sub>), chronic (1/day for 5 days), s.c., male Sprague-Dawley rats</td><td>No</td><td>13th day of treatment</td><td>Imam et al., (2018)</td></tr><tr><td>Dichlorvos (0.0015 mg/mL, 0.1 LC<sub>50</sub>), chronic (5/week for 6 weeks), inhalation (4 h), male Wistar rats</td><td>No</td><td>3 months</td><td>Phillips and Deshpande., 2016</td></tr><tr><td>Chlorpyrifos (4 or 7 mg/kg, &lt; &lt; 1 LD<sub>50</sub>\*), chronic (3/week for 4 weeks), i.p., male Wistar rats</td><td>No</td><td>30th day of treatment</td><td>Reis et al., (2022)</td></tr><tr><td>Parathion-methyl (0.22 or 0.44 mg/kg, 0.01 or 0.02 LD<sub>50</sub>), chronic (5/week for 6 weeks), p.o., male Wistar rats</td><td>No</td><td>3 days</td><td>Rosa et al., (2025)</td></tr><tr><td>Malathion (25, 50, 100 or 150 mg/kg, 0.02, 0.04, 0.07 or 0.11 LD<sub>50</sub> respectively), chronic (1/day for 28 days), i.p., male Wistar rats</td><td>No</td><td>End of the experimentation</td><td>Schulz et al., (1990)</td></tr><tr><td rowspan="3">Lethal exposure</td><td>Soman (110 µ/kg, 1.2 LD<sub>50</sub>), single, s.c., male B6D2F1 mice</td><td>Atropine methyl nitrate (+1 min, 5.0 mg/kg i.p.)</td><td>30 and 90 days</td><td>Coubard et al., (2008)</td></tr><tr><td>DFP (4 mg/kg, ~2.67 LD<sub>50</sub>\*), single, s.c. male Sprague-Dawley rats</td><td>Pyridostigmine bromide (-30 min; 0.1 mg/kg), atropine sulfate (+1 min; 2 mg/kg, i.m.), 2-PAM (+1 min; 25 mg/kg, i.m.)</td><td>1 and 2 months</td><td>Guignet et al., (2020)</td></tr><tr><td>DFP (2.5 mg/kg, ~1.58 LD<sub>50</sub>\*), single, s.c., male Sprague-Dawley rats</td><td>Atropine (+1 min; 16 mg/kg, i.p.)</td><td>6 and 27 days</td><td>Wright et al., (2010)</td></tr><tr><td>Staircase</td><td>Sublethal single exposure</td><td>NIMP (315 or 567 µg/kg, 0.5 or 0.9 LD<sub>50</sub>), single s.c., male Swiss mice</td><td>No</td><td>2 months</td><td>François et al., (2022)</td></tr><tr><td rowspan="2">Dark/light box</td><td>Sublethal single exposure</td><td>NIMP (315 or 567 µg/kg, 0.5 or 0.9 LD<sub>50</sub>), single s.c., male Swiss mice</td><td>No</td><td>3 months</td><td>François et al., (2022)</td></tr><tr><td>Lethal exposure</td><td>DFP (9.5 mg/kg, ~2.97 LD<sub>50</sub>\*), single, i.p., male Sprague-Dawley rats</td><td>Pyridostigmine bromide (-30 min, 0.1 mg/kg), atropine methylbromide (-20 min, 20 mg/kg)</td><td>1 month</td><td>Rojas et al., (2016)</td></tr><tr><td>Neophobia</td><td>Sublethal single exposure</td><td>NIMP (315 or 567 µg/kg, 0.5 or 0.9 LD<sub>50</sub>), single s.c., male Swiss mice</td><td>No</td><td>5 months</td><td>François et al., (2022)</td></tr><tr><td>Food handling-bimanual coordination</td><td>Chronic Sublethal exposure</td><td>VX (2.25 or 13.5 µg/kg, 0.05 or 0.3 LD<sub>50</sub>), chronic (1/day for a month) s.c., male Sprague-Dawley rats</td><td>No</td><td>18 days</td><td>Bloch-Shilderman et al., 2008</td></tr></tbody></table>

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<table><caption>Table 5 (continued)</caption><thead><tr><th>Evaluation</th><th>Test</th><th>Conditions</th><th>Emergency treatment (time of administration relative to OP, dose, route of administration)</th><th>Assessment period (after the last administration)</th><th>Articles</th></tr></thead><tbody><tr><td></td><td>O-maze</td><td>Sub lethal single exposure</td><td>NIMP (315 or 567 µg/kg, 0.5 or 0.9 LD<sub>50</sub>), single, s.c., male Swiss mice</td><td>No</td><td>6 months</td><td>François et al., (2022)</td></tr><tr><td></td><td>Acoustic Startle Response (ASR) test</td><td>Chronic Sub lethal exposure</td><td>Sarin (64 µg/kg, 0.4 LD<sub>50</sub>), chronic (1/day for 3 days), s.c., male C57BL/6 J mice</td><td>No</td><td>1 h (after the first dose), 1–21 days (after the last dose)</td><td>Mach et al., (2008)</td></tr><tr><td></td><td></td><td>Lethal exposure</td><td>Sarin (62.5 µg/kg, 0.5 LD<sub>50</sub>), chronic (3 days/week for 3 weeks), s.c., male Sprague-Dawley rats</td><td>No</td><td>2, 4, and 16 weeks</td><td>Scremin et al., (2003)</td></tr><tr><td></td><td>Home cage reactivity</td><td>Lethal exposure</td><td>Soman (154 µg/kg, 1.4 LD<sub>50</sub>), single, s.c., male Sprague-Dawley rats</td><td>Atropine sulfate (+20 min; 2 mg/kg, i.m.)</td><td>14 and 30 days</td><td>Prager et al., (2014)</td></tr><tr><td></td><td></td><td>Lethal exposure</td><td>DFP (9.5–12.7 mg/kg, ~ 3.3 – 4.4 LD<sub>50</sub>), single, s.c., male C57BL/6-J mice</td><td>Atropine sulfate (+1 min; 0.1 mg/kg, i.m.), 2-PAM (+1 min; 25 mg/kg, i.m.)</td><td>28 days</td><td>Calsbeek et al., (2021)</td></tr><tr><td></td><td></td><td>Lethal exposure</td><td>DFP (4 mg/kg, ~2.67* LD<sub>50</sub>), single, s.c., male Sprague-Dawley rats</td><td>Pyridostigmine bromide (~30 min, 0.1 mg/kg, i.m.), Atropine sulfate (+1 min, 2 mg/kg, i.m.), 2-PAM (+1 min, 25 mg/kg, i.m.)</td><td>1 week, 1 and 2 months</td><td>Guignet et al., (2020)</td></tr><tr><td></td><td>Behavioral scoring</td><td>Sub lethal single exposure</td><td>Soman (1.2, 1.5 or 2.7 mg/m<sup>3</sup>, 0.3, 0.4 or 0.7 LC<sub>50</sub>), single, inhalation (1 h), female guinea pig</td><td>No</td><td>1 day and 4 weeks</td><td>Bajgar et al., (2004)</td></tr><tr><td></td><td></td><td>Chronic Sub lethal exposure</td><td>Sarin (64 µg/kg, 0.4 LD<sub>50</sub>), chronic (1/day for 3 days), s.c., male C57BL/6 J mice</td><td>No</td><td>1 h (after the first dose), 1–21 days (after the last dose)</td><td>Mach et al., (2008)</td></tr><tr><td rowspan="10">Depression</td><td rowspan="10">Forced swim test</td><td>Sub lethal single exposure</td><td>Phosalone (0.6, 6, 12, 20 or 40 mg/kg, ~0.005, 0.05, 0.1, 0.16, or 0.33 LD<sub>50</sub>), single, p.o., male Swiss mice</td><td>No</td><td>3 h and 7 days</td><td>Aliomrani et al., (2021)</td></tr><tr><td>Chronic Sub lethal exposure</td><td>Malathion (50, 100, 250 or 500 mg/kg, 0.08–0.4 LD<sub>50</sub>), single, i.p., male Sprague-Dawley rats</td><td>No</td><td>30 min</td><td>Assini et al., (2005)</td></tr><tr><td>Chronic Sub lethal exposure</td><td>Malathion (25, 50, 100 and 150 mg/kg), single, i.p., male Wistar rats</td><td>No</td><td>1 h</td><td>Ramos et al., (2006)</td></tr><tr><td>Chronic Sub lethal exposure</td><td>Malathion (250 mg/kg), single, i.p., male Wistar rats</td><td>No</td><td>12 h</td><td>Savall et al., (2020)</td></tr><tr><td>Chronic Sub lethal exposure</td><td>DFP (2.0, 2.25 mg/kg), single, s.c., male Sprague-Dawley rats</td><td>No</td><td>7, 30 and 120 days</td><td>Liu et al., (2021)</td></tr><tr><td>Chronic Sub lethal exposure</td><td>Phosalone (0.6, 6, 12, or 20 mg/kg, ~0.005, 0.05, 0.1, or 0.16 LD<sub>50</sub>), chronic (1/day for 5 days), p.o., male Swiss mice</td><td>No</td><td>3 h and 7 days</td><td>Aliomrani et al., (2021)</td></tr><tr><td>Chronic Sub lethal exposure</td><td>Malathion (25, 50, 100, or 250 mg/kg, 0.04–0.2 LD<sub>50</sub>), chronic (1/day for 1 week), i.p., female Wistar rats</td><td>No</td><td>30 min</td><td>Assini et al., (2005)</td></tr><tr><td>Chronic Sub lethal exposure</td><td>Malathion (50 or 100 mg/kg, 0.125 or 0.25 LD<sub>50</sub>\*), chronic (1/day for 3 days), i.p., female Wistar rats</td><td>No</td><td>1 day</td><td>Brocardo et al., (2007)</td></tr><tr><td>Chronic Sub lethal exposure</td><td>Chlorpyrifos (10, 20, 40, 80 or 160 mg/kg, chronic (1/day for 1 week), s.c., male Sprague-Dawley rats</td><td>No</td><td>3 days</td><td>Chen et al., (2011)</td></tr><tr><td>Chronic Sub lethal exposure</td><td>Chlorpyrifos (2.5, 5, 10 or 20 mg/kg), chronic (1/day for 10 days), s.c., male Sprague-Dawley rats</td><td>No</td><td>2 days</td><td>Chen et al., (2014)</td></tr><tr><td>Chronic Sub lethal exposure</td><td>Methamidophos (1.31 or 5.25 mg/mL, 0.012 or 0.044 LD<sub>50</sub>), chronic (1 month), p.o., diluted in drinking water, male & female Swiss mice</td><td>No</td><td>28th day of treatment and 10 days</td><td>Lima et al., (2009)</td></tr><tr><td>Chronic Sub lethal exposure</td><td>DFP (400 µg/kg, < 0.2 LD<sub>50</sub>), chronic (1/day for 5 days), s.c., male Sprague-Dawley rats</td><td>No</td><td>3 months</td><td>Phillips and Deshpande, 2016</td></tr><tr><td></td><td>Tail suspension</td><td>Chronic Sub lethal exposure</td><td>Malathion (25, 50, 100 and 150 mg/kg), chronic (1/day for 28 days) i.p., male Wistar rats</td><td>No</td><td>23 h</td><td>Ramos et al., (2006)</td></tr><tr><td></td><td></td><td>Lethal exposure</td><td>DFP (2.5 mg/kg), single, s.c., male Sprague-Dawley rats</td><td>No</td><td>7, 30 and 120 days</td><td>Liu et al., (2021)</td></tr><tr><td></td><td></td><td>Lethal exposure</td><td>DFP (2.5 mg/kg, ~1.58 LD<sub>50</sub>\*), single, s.c., male Sprague-Dawley rats</td><td>Atropine (+1 min; 16 mg/kg, i.p.)</td><td>8 and 29 days</td><td>Wright et al., (2010)</td></tr><tr><td></td><td></td><td>Chronic Sub lethal exposure</td><td>Methamidophos (1.31 or 5.25 mg/mL, 0.018 or 0.07 LD<sub>50</sub>), chronic (1 month), p.o., male and female Swiss mice</td><td>No</td><td>28th day of treatment and 10 days</td><td>Lima et al., (2009)</td></tr><tr><td></td><td></td><td>Chronic Sub lethal exposure</td><td>Chlorpyrifos (10, 20, 40, 80 or 160 mg/kg, chronic (1/day for 1 week), s.c., male Sprague-Dawley rats</td><td>No</td><td>9 days</td><td>Chen et al., (2011)</td></tr></tbody></table>

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<table><caption>Table 5 (continued)</caption><thead><tr><th>Evaluation</th><th>Test</th><th>Conditions<br>OP (dose), exposition (duration), route of administration, model</th><th>Emergency treatment (time of administration relative to OP, dose, route of administration)</th><th>Assessment period (after the last administration)</th><th>Articles</th></tr></thead><tbody><tr><td rowspan="5">Sucrose<br>preference test<br>(anhedonia)</td><td rowspan="5">Chronic Sub<br>lethal<br>exposure</td><td>Chlorpyrifos (2.5, 5, 10 or 20 mg/kg), chronic (1/day for 10 days), s.c., male Sprague-Dawley rats</td><td>No</td><td>10 days</td><td>Chen et al., (2014)</td></tr><tr><td>DFP (2.0, 2.25 mg/kg), single, s.c., male Sprague-Dawley rats</td><td>No</td><td>10, 33 and 123 days</td><td>Liu et al., (2021)</td></tr><tr><td>DFP (400 µg/kg, &lt; 0.2 LD<sub>50</sub>), chronic (1/day for 5 days), s.c., male Sprague-Dawley rats</td><td>No</td><td>3 months</td><td>Phillips and Deshpande, 2016</td></tr><tr><td>Chlorpyrifos (4 or 7 mg/kg, &lt; &lt; 1 LD<sub>50</sub>), chronic (3/week for 4 weeks), i.p., male Wistar rats</td><td>No</td><td>14th day of treatment and 2 days</td><td>Rosa et al., (2025)</td></tr><tr><td>Chlorpyrifos (1 mg/kg) or Diazinon (1 mg/kg), chronic (1/day for 5 days), i.p., male Hooded-Lister rats</td><td>No</td><td>1 day</td><td>Savy et al., (2015)</td></tr><tr><td rowspan="2">Splash Test</td><td rowspan="2">Lethal<br>exposure<br>Sub lethal<br>single<br>exposure</td><td>DFP (2.5 mg/kg), single, s.c., male Sprague-Dawley rats</td><td>No</td><td>10, 33 and 123 days</td><td>Liu et al., (2021)</td></tr><tr><td>Malathion (250 mg/kg), single, i.p., male Wistar rats</td><td>No</td><td>12 h</td><td>Savall et al., (2020)</td></tr><tr><td>Nesting test</td><td>Lethal<br>exposure</td><td>DFP (9.5–12.7 mg/kg, ~ 3.3 – 4.4 LD<sub>50</sub>), single, s.c., male C57BL/6-J mice</td><td>Atropine sulfate (+1 min; 0.1 mg/kg, i.m.), 2-PAM (+1 min; 25 mg/kg, i.m.)</td><td>28 days</td><td>Calsbeek et al., (2021)</td></tr><tr><td>Marble burying</td><td>Chronic Sub<br>lethal<br>exposure</td><td>Chlorpyrifos (1 mg/kg) or diazinon (1 mg/kg), chronic (1/day for 5 days), i.p., male Hooded-Lister rats</td><td>No</td><td>1–15 days</td><td>Savy et al., (2015)</td></tr><tr><td>Grooming<br>observation</td><td>Sub lethal<br>single<br>exposure</td><td>Sarin (12.5 or 50 µg/kg, 0.028 or 0.11 LD<sub>50</sub>), or Soman (4 or 20 µg/kg, 0.02 or 0.11 LD<sub>50</sub>), single, i.p., male Kuo Wistar rats</td><td>No</td><td>1 day</td><td>Nieminen et al., (1990)</td></tr></tbody></table>

exposure and no longer observable at 1 and 4 months (Scremin et al., 2003). Chronic exposure to pesticides has been associated with the development of anxiety-like behaviors. For instance, mice and rats exposed, respectively, to methamidophos or parathion exhibited a reduced duration of time in the center of OF, a classical indicator of anxiety (Do Nascimento et al., 2017; Schulz et al., 1990). Interestingly, a dose-dependent anxiogenic effect has been reported for malathion. Doses below 0.1 LD<sub>50</sub> did not alter behavior in the OF or the EPM (Valvassori et al., 2007), whereas higher doses (0.2 LD<sub>50</sub>) reduced the time spent in the open arms in the EPM (Assini et al., 2005). A similar dose-dependent effect was observed with CPF (Basaure et al., 2017; Chen et al., 2011; Rosa et al., 2025; Savy et al., 2015). It is noteworthy that anxiolytic effects have been observed in response to exposure to chronic CPF administration (Chen et al., 2011), and in combination with organochlorines (Ghasemnejad-Berenji et al., 2021). In addition, a delayed onset of anxiety-related behaviors was also observed after 13 days of chronic exposure to a mixture of CPF and DDVP (Imam et al., 2018), whereas chronic exposure with DDVP alone, for 6 weeks, had no effects on the OF and EPM at 1 month after the initial exposure (Reis et al., 2022). Furthermore, following chronic DFP exposure, anxiety-related behaviors were observed up to 3 months in the EPM (Phillips and Deshpande, 2016).

Depressive-like symptoms have been observed concurrently in response to chronic exposure to sub-lethal doses of pesticides. Male Hooded-Lister rats chronically exposed to CPF or diazinon, demonstrated a reduction in marble burying test that persisted up to 8 days post-exposure (Savy et al., 2015). However, chronic exposure to CPF or diazinon did not affect SPT (Rosa et al., 2025; Savy et al., 2015). These results suggest that distinct neural networks are involved in these two tests, although they both intended to assess similar affective dimensions (anhedonia). However, the interpretation and specificity of the marble burying test remain controversial. Indeed, marble burying may reflect a combination of anxiety, compulsive-like behavior, and reactivity to novelty, rather than strictly depressive-like states. A dose-dependent effect was reported after chronic exposure to CPF, with an increased immobility in FST triggered by the lower dose (10 mg/kg), and antide-

pressant-like effect of higher dose (160 mg/kg) (Chen et al., 2014, 2011). Similarly, chronic low dose exposure to different pesticides induced an increase in immobility in the FST, after exposure to methamidophos (Lima et al., 2009), malathion (Assini et al., 2005; Brocardo et al., 2007; Ramos et al., 2006), or phosalone that could last up to 7 days following the final exposure (Aliomrani et al., 2021). In a rat model of GW illness, an increased immobility in the FST was shown to persist up to 3 months after the last sub-cutaneous injection of DFP (Phillips and Deshpande, 2016). This immobility was concomitant with a reduction in SPT, indicative of persistent anhedonia. These results suggest that depressive-like effects following a chronic low dose OP exposure may endure well beyond the acute phase.

Anxious- and depressive-like behaviors were also tested in preclinical rodent models exposed to a lethal dose of OP. No anxiety-like behavior was evidenced with EPM after DFP single exposure in rats at short (6 days) or longer term (27 days) (Wright et al., 2010). In addition, 1 month after a lethal dose of DFP no significant change was observed in the light–dark box test (Rojas et al., 2016). Interestingly, an anxiolytic-like behaviors was reported in a rat epileptic model induced by DFP tested in EPM, although an increase in home cage reactivity was reported in this model at 1 week, 1 month, and 2 months post-exposure (Guignet et al., 2020). In addition, the time spent in the center of the OF was decreased 28 days after an injection of a lethal dose of DFP in mice, accompanied by an increase of home cage reactivity score (Calsbeek et al., 2021). Lethal injection of soman led to a reduction of the time spent in the center of the OF and an exaggerated acoustic startle responses 14 and 30 days after exposure (Miller et al., 2015; Prager et al., 2014). Interestingly, these effects were transient and disappeared 3 months after the poisoning (Miller et al., 2015). In contrast, the EPM test revealed the presence of persistent anxiety disorders up to 3 months following a lethal injection of soman in B6D2F1 male mice (Coubard et al., 2008).

In addition to anxiety, depressive-like behaviors were induced following DFP exposure. An increase in immobility in the FST was observed in rats exposed to high doses of DFP at 8 days and 1 month (Liu et al., 2021; Wright et al., 2010), despite no changes in the SPT (Liu et al., 2021). Additionally, a decline in nesting behavior was observed 1
<caption>**Table 6**</caption>

Impacts of organophosphorus compounds on rodent locomotion and sensory behaviors, with particular regard to the type of test used, the exposure protocol, the doses, and the route of administration. Symbols: t₀ indicates the time of exposure; + and – indicate post- and pre-exposure administration, respectively. Toxicant doses are expressed in mg/kg. * denotes an estimated LD₅₀ derived from the literature, notably (Misik et al., 2015) (Maretto et al., 2012), and (McCollister et al., 1974), when the exact dose was not reported.

<table><thead><tr><th>Evaluation</th><th>Test</th><th>Conditions</th><th>Emergency treatment (time of administration relative to OP, dose, route of administration)</th><th>Assessment period (after the last administration)</th><th>Articles</th></tr></thead><tbody><tr><td rowspan="15">Locomotion</td><td rowspan="15">Open field</td><td>Sub lethal single exposure</td><td></td><td></td><td></td></tr><tr><td>Sarin (27.2 µg/L, 0.8 Lct<sub>50</sub>), single, inhalation (10 min), male Sprague-Dawley rats</td><td>No</td><td>1 and 6 months</td><td>Allon et al., (2011)</td></tr><tr><td>Malathion (50, 100, 250 or 500 mg/kg, 0.08–0.4 LD<sub>50</sub>), single, i.p., female Wistar rats</td><td>No</td><td>30 min</td><td>Assini et al., (2005)</td></tr><tr><td>DFP (2.0, 2.25 mg/kg), single, s.c., male Sprague-Dawley rats</td><td>No</td><td>5, 28 and 118 days</td><td>Liu et al., (2021)</td></tr><tr><td>Sarin (12.5 or 50 µg/kg, 0.028 or 0.11 LD<sub>50</sub>), or Soman (4 or 20 µg/kg, 0.02 or 0.11 LD<sub>50</sub>), single, i.p., male Kuo Wistar rats</td><td>No</td><td>1 day</td><td>Nieminen et al., (1990)</td></tr><tr><td>Soman (50 or 85 µg/kg, ~0.42 or 0.71 LD<sub>50</sub>\*), single, s.c., male Sprague-Dawley rats</td><td>No</td><td>4 weeks</td><td>Raffaele et al., 1987</td></tr><tr><td>Soman (25 µg/kg, 0.6 LD<sub>50</sub>\*), single, i.v., male ICR mice</td><td>No</td><td>5, 10, 20, 30, 50, 110, 230, 410 min, 1 and 4 days</td><td>Reynolds et al., (1985)</td></tr><tr><td>Tabun (100, 122, 144, 168 or 198 µg/kg, ~0.4, 0.45, 0.6, 0.7 or 0.8 LD<sub>50</sub>\*), single, s.c., male Sprague-Dawley-derived rats</td><td>No</td><td>30 min</td><td>Romano and Landauer, (1986)</td></tr><tr><td>Malathion (250 mg/kg, 0.6 LD<sub>50</sub>\*), single, i.p., male Wistar rats</td><td>No</td><td>12 h</td><td>Savall et al., (2020)</td></tr><tr><td>Chlorphenvinphos (1 mg/kg or 3 mg/kg, 0.1 or 0.33 LD<sub>50</sub>), single, i.p., male Wistar rats</td><td>No</td><td>3 h then for 2 weeks</td><td>Sočko et al., (1989)</td></tr><tr><td>Dichlorvos (3 mg/kg), chronic (1/day for 10 days), i.p., Charles Foster strain rats</td><td>No</td><td>Each day of intoxication over 4 h</td><td>Ali et al., (1980)</td></tr><tr><td>Malathion (25, 50, 100, 250 mg/kg, 0.04–0.2 LD<sub>50</sub>), chronic (1/day for 1 week), i.p., female Wistar rats</td><td>No</td><td>30 min</td><td>Assini et al., (2005)</td></tr><tr><td>VX (2.25 µg/kg/day, 0.05 LD<sub>50</sub>), chronic (3 months), s.c., male Sprague-Dawley rats</td><td>No</td><td>3 days and 1 month</td><td>Bloch-Shilderman et al., (2008)</td></tr><tr><td>Malathion (50 or 100 mg/kg, 0.125 or 0.25 LD<sub>50</sub>\*), chronic (1/day for 3 days), i.p., female Wistar rats</td><td>No</td><td>1 day</td><td>Brocardo et al., (2007)</td></tr><tr><td>Chlorpyrifos (2.5, 5, 10 or 20 mg/kg), chronic (1/day for 10 days), s.c., male Sprague-Dawley rats</td><td>No</td><td>1 week</td><td>Chen et al., (2014)</td></tr><tr><td>Sarin (64 µg/kg, 0.4 LD<sub>50</sub>), chronic (1/day for 3 days), s.c., male C57BL/6 J mice</td><td>No</td><td>1 h, 1, 7, 14 and 21 days</td><td>Mach et al., (2008)</td></tr><tr><td>DFP (0.05, 0.25 or 0.5 mg/kg, ~0.03, 0.16 or 0.32 LD<sub>50</sub>\*), chronic (1/day for 14 days), s.c., male Wistar rats</td><td>No</td><td>5 min after each injection</td><td>Prendergast et al., (1997)</td></tr><tr><td>Chlorpyrifos (4 or 7 mg/kg, &lt; &lt; 1 LD<sub>50</sub>\*), chronic (3/week for 4 weeks), i.p., male Wistar rats</td><td>No</td><td>3 days</td><td>Rosa et al., (2025)</td></tr><tr><td>Sarin (62.5 µg/kg, 0.5 LD<sub>50</sub>), chronic (3 days/week for 3 weeks), s.c., male Sprague-Dawley rats</td><td>No</td><td>2, 4, and 16 weeks</td><td>Scremin et al., (2003)</td></tr><tr><td>Chlorphenvinphos (0.5 or 1 mg/kg, 0.05 or 0.1 LD<sub>50</sub>), chronic (1/day, 5 days/week for 2 weeks), i.p., male Wistar rats</td><td>No</td><td>1, 3 and 6 weeks</td><td>Sočko et al., (1999)</td></tr><tr><td>DFP (0.25, 0.5, 0.75 and 1 mg/kg, ~0.16, 0.32, 0.47, and 0.63 LD<sub>50</sub>\*), chronic (every other day for 30-day period), s.c., male Wistar rats</td><td>No</td><td>8th and 22nd day of exposure, 7 days</td><td>Terry et al., 2011</td></tr><tr><td>Chlorpyrifos (1, 5 or 10 mg/kg, ~0.006, 0.03, 0.02 LD<sub>50</sub>\*), chronic (1/day for 4 weeks), p.o., male Wistar rats</td><td>No</td><td>1 day</td><td>Yan et al., (2012)</td></tr><tr><td>Lethal exposure</td><td></td><td>Soman (80–280 µg/kg, 1–3.5 LD<sub>50</sub>), single, s.c., male Wistar rats</td><td>Physostigmine (-30 min, 150 µg/kg, i.m.) + artane (-30 min, 2 mg/kg, i.m.)</td><td>2 and 9 days</td><td>Buccafusco et al., (1990)</td></tr></tbody></table>

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<table><caption>Table 6 (continued)</caption><thead><tr><th>Evaluation</th><th>Test</th><th>Conditions<br>OP (dose), exposition (duration), route of administration, model</th><th>Emergency treatment (time of administration relative to OP, dose, route of administration)</th><th>Assessment period (after the last administration)</th><th>Articles</th></tr></thead><tbody><tr><td rowspan="12"></td><td rowspan="2">Elevated-plus maze</td><td>Lethal<br>exposure</td><td>DFP (9.5–12.7 mg/kg, ~ 3.3 – 4.4 LD<sub>50</sub>), single, s.c., male C57BL/6-J mice</td><td>Atropine sulfate (+ 1 min; 0.1 mg/kg, i.m.), 2-PAM (+ 1 min; 25 mg/kg, i.m.)</td><td>27 days</td><td>Calsbeek et al., (2021)</td></tr><tr><td>Actophotometer</td><td>Dichlorvos (200 mg/kg), single, s.c., or Monocrotophos (20 mg/kg), single, p.o., male Wistar rats</td><td>No</td><td>5, 28 and 118 days</td><td>Liu et al., (2021)</td></tr><tr><td rowspan="2">Nocturne home cage<br>activity</td><td>Lethal<br>exposure</td><td>DFP (2.5 mg/kg, ~1.58 LD<sub>50</sub>\*), single, s.c., male Sprague-Dawley rats</td><td>Atropine methyl nitrate (+ 1 min, 5.0 mg/kg i.p.)</td><td>30 and 90 days</td><td>López-Crespo et al., 2007</td></tr><tr><td>Figure-eight maze</td><td>Chlorpyrifos (0, 10, 30, 60 or 100 mg/kg), single, p.o., male Long-Evans rats</td><td>Atropine (-20 min, 20 mg/kg i.p.), 2-PAM (-20 min, 100 mg/kg i.p.)</td><td>28 days</td><td>Coubard et al., (2008)<br>Masoud et al., (2011)</td></tr><tr><td rowspan="2">Animex activity<br>meter</td><td>Sub lethal<br>chronic<br>exposure</td><td>Dichlorvos (3 mg/kg), chronic (1/day for 10 days), i.p., Charles Foster strain rats</td><td>No</td><td>Each day of intoxication over 4 h</td><td>Ali et al., (1980)</td></tr><tr><td>Phenotyper</td><td>DFP (4 mg/kg, ~0.59 LD<sub>50</sub>), single, i.p., male C57BL/6 mice</td><td>No</td><td>20–23 days</td><td>Terry et al., (2024)</td></tr><tr><td rowspan="12">Motor<br>coordination</td><td rowspan="2">Rotarod</td><td>Sub lethal<br>single<br>exposure</td><td>Soman (1.2, 1.5 or 2.7 mg/m<sup>3</sup>, 0.3, 0.4 or 0.7 LC<sub>50</sub>), single, inhalation (1 h), female guinea pig</td><td>No</td><td>1 day and 4 weeks</td><td>Bajgar et al., (2004)</td></tr><tr><td>Sub lethal<br>single<br>exposure</td><td>Tabun (100, 122, 144, 168 or 198 µg/kg, ~0.4, 0.45, 0.6, 0.7 or 0.8 LD<sub>50</sub>\*), single, s.c., male Sprague-Dawley-derived rats</td><td>No</td><td>30 min</td><td>Romano and Landauer, (1986)</td></tr><tr><td rowspan="12">Grip test</td><td rowspan="2">Hanging wire test</td><td>Sub lethal<br>chronic<br>exposure</td><td>Malathion (250 mg/kg), single, i.p., male Wistar rats</td><td>No</td><td>12 h</td><td>Savall et al., (2020)</td></tr><tr><td>Horizontal bar test</td><td>Sarin (12.5 or 50 µg/kg, ~0.03 or 0.11 LD<sub>50</sub>\*), single, i.p., male Wistar rats</td><td>No</td><td>NA</td><td>Sirkka et al., (1990)</td></tr><tr><td rowspan="12">Muscle<br>weakness</td><td rowspan="2">Sub lethal<br>chronic<br>exposure</td><td>DFP (3 mg/kg ~0.9 LD<sub>50</sub>\*), single, i.p., male and female DBA, CH3 and C57 mice</td><td>No</td><td>0.25, 0.5, 1, 2, 3, 4, 5 and 6 h</td><td>Smolen et al., 1986</td></tr><tr><td>DFP (4 mg/kg, ~0.59 LD<sub>50</sub>), single, i.p., male C57BL/6 mice</td><td>No</td><td>17–18 days</td><td>Terry et al., (2024)</td></tr><tr><td rowspan="2">Sub lethal<br>chronic<br>exposure</td><td>Soman (22.5 µg/kg, 0.25 LD<sub>50</sub>), chronic (1/day for 21 days), s.c., male Wistar rats</td><td>No</td><td>30 and 90 days</td><td>Golime et al., (2024)</td></tr><tr><td>Methamidophos (1.31 or 5.25 mg/mL, 0.018 or 0.07 LD<sub>50</sub>), chronic (1 month), diluted in drinking water, male Swiss mice</td><td>No</td><td>28th day of exposure and 11 days</td><td>Lima et al., (2009)</td></tr><tr><td rowspan="2">Sub lethal<br>chronic<br>exposure</td><td>Chlorpyrifos (2.5, 10 or 18 mg/kg, ~ 0.0625, 0.25 or 0.45 LD<sub>50</sub>\*), chronic (every other day over 30 days), by water, male Wistar rats</td><td>No</td><td>16th and 30th day of exposure, 4 and 14 days</td><td>Terry et al., (2007)</td></tr><tr><td>DFP (0.25, 0.5, 0.75 and 1 mg/kg, ~0.16, 0.32, 0.47, and 0.63 LD<sub>50</sub>\*), chronic (every other day for 30-day period), s.c., male Wistar rats</td><td>No</td><td>16th and 30th day of exposure, 4 and 14 days</td><td>Terry et al., 2011</td></tr><tr><td rowspan="2">Sub lethal<br>chronic<br>exposure</td><td>Chlorpyrifos (1, 5 or 10 mg/kg, ~ 0.006, 0.03, 0.02 LD<sub>50</sub>\*), chronic (1/day for 4 weeks), p.o., male Wistar rats</td><td>No</td><td>1 day</td><td>Yan et al., (2012)</td></tr><tr><td>Soman (110 µg/kg, 1.2 LD<sub>50</sub>), single, s.c., male B6D2F1/j@rj mice</td><td>Atropine methyl nitrate (+ 1 min, 5.0 mg/kg, i.p.)</td><td>1, 2, 3, 6, 9, 13, 20, 27, 34, 48, 62, 76, and 90 days</td><td>Filliat et al., (2007)</td></tr><tr><td rowspan="2">Sub lethal<br>single<br>exposure</td><td>DFP (4 mg/kg, ~0.59 LD<sub>50</sub>), single, i.p., male C57BL/6 mice</td><td>No</td><td>15 days</td><td>Terry et al., (2024)</td></tr><tr><td>Sarin (12.5 or 50 µg/kg, ~0.03 or 0.11 LD<sub>50</sub>\*), single, i.p., male Wistar rats</td><td>No</td><td>NA</td><td>Sirkka et al., (1990)</td></tr><tr><td rowspan="2">Sub lethal<br>single<br>exposure</td><td>Soman (100 and 150 µg/kg, <1 LD<sub>50</sub>), single, i.m., Sprague-Dawley rats</td><td>No</td><td>1, 2 and 3 weeks</td><td>Haggerty et al., (1986)</td></tr><tr><td>DFP (4 mg/kg, ~0.59 LD<sub>50</sub>), single, i.p., male C57BL/6 mice</td><td>No</td><td>16 days</td><td>Terry et al., (2024)</td></tr><tr><td rowspan="2">Sub lethal<br>single<br>exposure</td><td>NIMP (315 µg/kg, 0.5 LD<sub>50</sub>), single, s.c., male Swiss mice</td><td>No</td><td>1–6 months</td><td>Champault et al., (2026)</td></tr></tbody></table>

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<table><caption>Table 6 (continued)</caption><thead><tr><th>Evaluation</th><th>Test</th><th>Conditions<br>OP (dose), exposition (duration), route of<br>administration, model</th><th>Emergency treatment (time of<br>administration relative to OP,<br>dose, route of administration)</th><th>Assessment period (after<br>the last administration)</th><th>Articles</th></tr></thead><tbody><tr><td rowspan="12">Sensory<br>systems</td><td rowspan="4">Hanging wire test</td><td><strong>Sub lethal<br>chronic<br>exposure</strong></td><td>Chlorpyrifos (2.5 mg/kg), chronic<br>(1/weekday for 38 days), s.c., male Wistar<br>rats<br><br>Chlorpyrifos (2.5, 10 or 18 mg/kg, ~<br>0.0625, 0.25 or 0.45 LD<sub>50</sub>°), chronic<br>(every other day over 30 days), by water,<br>male Wistar rats<br><br>DFP (0.25, 0.5, 0.75 and 1 mg/kg, ~0.16,<br>0.32, 0.47, and 0.63 LD<sub>50</sub>°), chronic<br>(every other day for 30-day period), s.c.,<br>male Wistar rats<br><br>Chlorpyrifos (1, 5 or 10 mg/kg, ~ 0.006,<br>0.03, 0.02 LD<sub>50</sub>°) chronic (1/day for 4<br>weeks), p.o., male Wistar rats</td><td>No</td><td>1/weekday during the first<br>week, 1/week until the<br>end of exposure, 5 days<br><br>7th and 14th, 21st and<br>28th day of treatment, 6<br>and 13 days</td><td>Terry et al.,<br>(2003)<br><br>Terry et al.,<br>(2007)</td></tr><tr><td><strong>Sub lethal<br>single<br>exposure</strong></td><td>DFP (4 mg/kg, ~0.59 LD<sub>50</sub>°), single, i.p.,<br>male C57BL/6 mice</td><td>No</td><td>7th and 14th, 21st and<br>28th day of treatment, 6<br>and 13 days</td><td>Terry et al.,<br>2011</td></tr><tr><td>Hot Plate</td><td><strong>Sub lethal<br>single<br>exposure</strong></td><td>Soman (100 µg/kg and 150 µg/kg, &lt;1<br>LD<sub>50</sub>°), single, i.m., Sprague-Dawley rats<br><br>Soman (40-80 mg/kg, 0.5 LD<sub>50</sub> to 0.9<br>LD<sub>50</sub>°), single, i.m., rats</td><td>No</td><td>1 day</td><td>Yan et al.,<br>(2012)</td></tr><tr><td><strong>Sub lethal<br>chronic<br>exposure</strong></td><td>Chlorphenvinphos (0.5 or 1 mg/kg, 0.05<br>or 0.1 LD<sub>50</sub>°), chronic (1/day 5 days/week<br>for 2 weeks), i.p., male Wistar rats</td><td>No</td><td>15 days</td><td>Terry et al.,<br>(2024)</td></tr><tr><td>Tail Flick</td><td><strong>Sub lethal<br>single<br>exposure</strong></td><td>Soman (40-80 mg/kg, 0.5 LD<sub>50</sub>° to 0.9<br>LD<sub>50</sub>°), single, i.m., rats</td><td>No</td><td>1, 2 and 3 weeks</td><td>Haggerty et al.,<br>(1986)</td></tr><tr><td>Electronic Von Frey</td><td><strong>Sub lethal<br>single<br>exposure</strong></td><td>Soman (35 µg/kg, ~0.7 LD<sub>50</sub>°), chronic<br>(1/day for 3 days, then 3/week to reach 22<br>injections), s.c., Sprague-Dawley rats</td><td>No</td><td>1 day</td><td>Romano et al.,<br>(1985)<br><br>Sočko et al.,<br>(1999)</td></tr><tr><td>Acetone test</td><td><strong>Sub lethal<br>single<br>exposure</strong></td><td>NIMP (315 µg/kg, 0.5 LD<sub>50</sub>°), single, s.c.,<br>male Swiss mice</td><td>No</td><td>1, 3 and 6 weeks</td><td>Romano et al.,<br>(1985)</td></tr><tr><td>Distortion product<br>otoacoustic<br>emissions</td><td><strong>Sub lethal<br>single<br>exposure</strong></td><td>NIMP (315 µg/kg, 0.5 LD<sub>50</sub>°), single, s.c.,<br>male Swiss mice</td><td>No</td><td>1 day</td><td>Russell et al.,<br>(1986)</td></tr><tr><td></td><td></td><td>NIMP (315 µg/kg, 0.5 LD<sub>50</sub>°), single, s.c.,<br>male Swiss mice</td><td>No</td><td>1-6 months</td><td>Champault et<br>al., (2026)</td></tr><tr><td></td><td></td><td>Soman (70 µg/kg), single, s.c., male<br>Wistar rats</td><td>No</td><td>4 h to 1 day</td><td>Carpentier et<br>al., (2010)</td></tr><tr><td></td><td></td><td>Soman (45 µg/kg, 0.5 LD<sub>50</sub>°), single, s.c.,<br>male Wistar rats</td><td>No</td><td>4 h to 1 day</td><td>Job et al.,<br>(2007)</td></tr></tbody></table>

month after DFP exposure in C57BL/6 mice (Calsbeek et al., 2021), indicative despair onset.

### 3.3. Locomotor dysfunctions and sensorimotor changes induced by OP exposure

Motor and sensory modifications have been reported in preclinical studies concerning the neurobehavioral consequences of OP exposure. These deficits may indicate more extensive damage to motor pathways, neuromuscular junctions, or sensorimotor integration systems, particularly with high doses or repeated exposure. Locomotor activity is commonly assessed using the OF, rotarod, or horizontal bar tests. The OF test is particularly sensitive to hypoactivity, which is characterized by decreased distance traveled or increased immobility time. The rotarod and horizontal bar tests evaluate motor coordination, gait, and balance based on the number of failures and the time it takes to complete or quit the test. An overview of the behavioral tools used to assess these domains is provided in Table 3.

A transient reduction in spontaneous activity is observed within minutes to hours after acute sub-lethal exposure to NA like soman, sarin or tabun. This hypolocomotion typically emerges within 30 min and can last up to 24 h following NA exposure (Bajgar et al., 2004; Nieminen et al., 1990; Reynolds et al., 1985; Romano and Landauer, 1986). A similar transient decrease in activity has been reported with OP pesticides, such as CPF and malathion (Assini et al., 2005; Nostrandt et al., 1997), but could persist several days for sub-lethal dose of DFP (Liu et al., 2021) or CVP (Sočko et al., 1989). However, no detectable

locomotor or coordination deficits were found in the first hours following malathion injection in rats (Savall et al., 2020). In addition, ambulation in phenotyper was not affected 3 weeks after DFP exposure in mice (Terry et al., 2024). Nevertheless, the decline in spontaneous activity does not necessarily occur with motor coordination problems. For instance, in a comparative study (Sirkka et al., 1990), male Wistar rats exposed to sarin exhibited an increased latency to complete the horizontal bar test, while soman had no effect, suggesting compound-specific differences in neuromotor integration. It is noteworthy that neither agent impaired motor coordination tested in rotarod performance in the Sirkka et al.'s study. However, a transient impairment of motor coordination was observed following DFP exposure in 3 different strains of mice, without difference between male and female (Smolen et al., 1986). Indeed, mice exposed to were unable to complete the rotarod test within 2 h following intoxication, but recovered by 4 h post-intoxication. Hyperlocomotion was induced 1 week after soman exposure (Raffaele et al., 1987), and was also observed up to 6 months following sarin intoxication (Allon et al., 2011).

Similarly, chronic exposure induces variable locomotor effects depending on the specific OP, the duration of the exposure and the dose. For instance, Charles Foster rats exposed to DDVP exhibited a persistent reduction in locomotion in OF from day 1 throughout the 10 days of exposure (Ali et al., 1980). In addition, using an automated system to record motor activity, a significant decrease in gross and fine movements was apparent on the third day following the initial exposure. This decline in motor activity was persistent and exhibited a tendency to normalize after 7 days, correlating with the brain monoamine changes
induced by chronic DDVP exposure (Ali et al., 1980). Similarly, tran-
sient OF hypolocomotion has been observed in response to chronic ex-
posure to CVP (Sočko et al., 1999), malathion (Assini et al., 2005;
Brocardo et al., 2007), and CPF (Rosa et al., 2025). Conversely, no loco-
motors effects were observed with chronic exposure to CPF (Chen et al.,
2014; Yan et al., 2012). It is noteworthy that diametrically opposed ef-
fects on locomotion were observed after 14 days of exposure to DFP.
Male Wistar rats exposed to the lower dose (50 µg/kg) exhibited hyper-
locomotion; rats exposed to 250 µg/kg exhibited transient hypolocomo-
tion; and rats exposed to 250 µg/kg exhibited persistent hypolocomo-
tion (Prendergast et al., 1997). However, the nature of the DFP in expo-
sure protocols poses a significant challenge, as locomotor disturbances
are only observed at a dose of 1 mg/kg for 30 days of exposure, for the
same rat strain and sex (Terry et al., 2011b). Motor coordination tested
in rotarod, was also not altered after chronic exposure to CPF (Terry et
al., 2007) or metamidophos (Lima et al., 2009). NA appeared to elicit
more pronounced and enduring effects: VX (Bloch-Shilderman et al.,
2008), and sarin (Mach et al., 2008; Scremin et al., 2003) have been
shown to reduce activity for days or weeks, with rotarod performance
also impaired after soman (Golime et al., 2024) exposure.

Rats exposed to lethal doses of OP pesticides (DFP, DDVP, Monocro-
tophos), exhibited a reduction in spontaneous activity that could persist
several days after the poisoning (Liu et al., 2021; Masoud et al., 2011;
Wright et al., 2010). Similarly, the rotarod test revealed a transient im-
pairment in motor coordination that persisted up to 18 days following
DFP exposure. Similarly, male Wistar rates exposed to soman
(Buccafusco et al., 1990) or CPF (López-Crespo et al., 2007) exhibited
reduced OF activity at 48 h, with deficits persisting up to 13 days in ro-
tarod test (Filliat et al., 2007). Long-term impairments in locomotor ac-
tivity were observed (Calsbeek et al., 2021) and 3 months after soman
exposure. Indeed, mice showed increased immobility and decreased
vertical exploration behavior in the EPM (Coubard et al., 2008). How-
ever, the EPM test is not particularly pertinent to evaluate locomotor
deficit, and the persistent anxiety observed in these animals could ex-
plain the decreased locomotion and rearing behaviors.

To complete the evaluation of locomotion, muscle strength assess-
ments have frequently been conducted. Despite the fact that the grip-
test remains the most frequently utilized assay for the evaluation of
muscular strength, other methods, such as the hanging wire, are also
employed to score muscular resistance. The majority of the studies us-
ing OP pesticides, whether chronically or acutely exposed, have not evi-
denced any deficiency in strength (Terry et al., 2007, 2024; Yan et al.,
2012). Similarly, the hanging wire test demonstrated no change in mus-
cle strength/resistance following acute DFP exposure (Terry et al.,
2024). However, chronic exposure to DFP at 1 mg/kg a transient mus-
cle weakness in grip test (Terry et al., 2011b). Similarly, a transient
deficit in both hindlimb and forelimb strength was reported after
chronic exposure to CPF 40 days after the initial exposure (Terry et al.,
2003). Interestingly, acute exposure to sub-lethal or lethal doses of so-
man has been shown to result in a significant loss of grip strength that
persists for several days, without recovery (Filliat et al., 2007; Haggerty
et al., 1986). In addition, Swiss mice exposed to sub-lethal dose of NIMP
(0.5 LD₅₀) exhibited long-term muscle weakness in grip test (Champault
et al., 2026).

Only a limited number of studies have specifically examined sensory
deficits following exposure to OP. For instance, chronic exposure to
CVP did not alter pain sensitivity, as measured in the hot plate test
(Sočko et al., 1999). However, the latency of the paw-lick response to
heat was found to increase after footshock, and was found to persist
longer than in unexposed rats (Sočko et al., 1999). In studies involving
NA, soman has been reported to cause sensory dysfunction with dose-
dependent effect (Romano et al., 1985). In addition, acute or sub-
chronic soman exposures increased hot plate response latency, indica-
tive of hypoalgesia, with both nociceptive and perceptual thresholds re-
maining elevated for up to 7 days post-exposure (Haggerty et al., 1986;

Russell et al., 1986). Furthermore, sub-lethal exposure to NIMP induced a transient cold-thermal allodynia and a persistent mechanical allodynia up to 6 months, without locomotion deficit in OF (Champault et al., 2026). Two studies have been conducted to examine the auditory disturbances following exposure to soman. The monitoring of the hearing function of rats exposed to moderate doses (50 and 70 µg/kg) of soman revealed a temporary reduction in cochlear function, which reflected the severity of intoxication (Carpentier et al., 2010; Job et al., 2007).

4. Non-exhaustive overview of behavioral paradigms used for therapeutic evaluations following OP intoxication: from lethal to sub-lethal exposures

4.1. *Methodological insights*

In summary, substantial variability is observed in the occurrence,
severity and onset of neurobehavioral impairments, depending on the
type of OP, the administered dose, the route of exposure and the murine
models. It is imperative to note that the administration of a high dose of
OP frequently results in the onset of epileptic seizures and, in certain
cases, the progression to status epilepticus (SE). While epilepsy is
known to disrupt cognitive functions (Chin and Scharfman, 2013; Kleen
et al., 2010), its development in OP preclinical models complicate inter-
pretation of behavioral disturbances. Therefore, it is essential to dis-
criminate the direct effects of OP on behavioral changes from those
caused by seizure induced by exposure to high doses of OP. The inter-
pretation of behavioral data is contingent upon the design of the study,
the selection of the tests and their combination, and the use of con-
trolled parameters. To validate a given biological hypothesis, converg-
ing evidence from different behavioral tests must be obtained. How-
ever, behavioral evaluations enhance the translational value of experi-
mental models and facilitate the detection of long-term neurofunctional
consequences and quantification of therapeutic benefit over time. Be-
havioral assessments are also essential for the detection of delayed or
subtle deficits, thereby enabling longitudinal follow-up.

4.2. *High-dose exposure: seizure-centric approaches and their limitations*

High dose OP intoxication models are frequently utilized to evaluate
emergency treatments intended to arrest seizures and reduce acute neu-
rotoxicity. Oxime prodrugs, including pro-2-PAM, various anticonvul-
sants, and varying doses of atropine or other anti-muscarinic agents,
have been evaluated in the optimization of therapeutic treatments.
Combination therapies involving midazolam with ketamine or val-
proate have demonstrated superior protection against cognitive deficits
when compared to monotherapies (Lumley et al., 2021; Niquet et al.,
2020; Reddy et al., 2020). Similarly, adjustments in atropine and di-
zepam dosing have also influenced behavioral recovery. For instance,
increasing the doses of atropine combined with diazepam can improve
fear memory performance following a lethal exposure to soman
(Philippens et al., 1992). In addition to the standard therapy, the cen-
tral alpha 2 noradrenergic receptor agonist clonidine was capable of in-
hibiting soman-induced short term locomotor impairment (Buccafusco
et al., 1990). A recent study reported that a diet supplemented with
saracatinib, a Src inhibitor, can reduce long-term locomotor impair-
ments and anxiety, and attenuate the severity of SRS in male and female
rat models of epilepsy induced by soman exposure (Massey et al.,
2025).

Other approaches aim to modulate the excitatory neurotransmis-
sion. The AMPA receptor antagonist LY293558 provided more effective
seizure control and neuroprotection than diazepam. In particular, it im-
proved anxiety-related outcomes, as shown by increased time spent in
the center zone of the OF test and reduced amplitude of the acoustic
startle response (Apland et al., 2018), reduced anxiety in OF
(Figueiredo et al., 2025) as well as enhanced locomotor activity and
rearing behavior and preserved the aversive memory (Miller et al., 2015). When combined with caramiphen, this strategy conferred full protection against seizures and neuropathology, allowing for rapid restoration of normal behavioral profiles and persist over the time (Figueiredo et al., 2025). However, the NMDA receptor antagonist MK-801 did not improve spatial memory following six months of daily exposure to CPF in the diet (López-Granero et al., 2016).

Countermeasures targeting oxidative stress, a well-established con-
sequence of both OP intoxication and prolonged SE, has emerged as a
key therapeutic target. Co-administration of antioxidants alongside an-
ticonvulsants, such as 1400 W (Putra et al., 2020b, 2024), diapocynin
(Putra et al., 2020a), or AEOL10150 (Liang et al., 2024), has shown
some efficacy in preserving cognitive and motor functions (Liang et al.,
2024; Putra et al., 2024, 2020b). Notably, AEOL10150 improved anxi-
ety-related behavior in the OF test, as evidenced by increased time
spent in the center zone (Liang et al., 2024).

OP intoxication can also be counteracted by the adrenergic system. In the central nervous system, the A₁ Adenosine Receptor (A₁AR) is expressed and is involved in many functions like sleep, pain, locomotion (Borea et al., 2018). The use of an agonist of the A₁AR improves cognitive performances after a lethal exposure when the compound was associated with the classical treatment (Meads et al., 2021). Unfortunately, other behavioral components were not assessed.

4.3. *Sub-lethal exposure and comprehensive therapeutic strategies*

Sub-lethal exposure preclinical models offer a more accurate repre-
sentation of long-term functional impairments relevant to chronic low
dose exposure scenarios, such as those seen in pesticide applications or
delayed consequences of NA use. These models are essential for assess-
ing the chronic neurotoxic effects of OP and the efficacy of interven-
tions that target broader or delayed pathophysiological processes.

Oxidative stress contributes also to neurotoxicity following expo-
sure to sub-lethal dose of OP. For example, mitigating oxidative stress
with kaempferol during chronic exposure to CPF reduced neuronal
damage and preserved both working and cognitive memories, as evalu-
ated in the Y-maze and NORT (Hussein et al., 2018a). In addition,
Crataegus oxyacantha extract or vitamins C and E have been utilized in
the treatment of rats exposed to a mixture of pesticides, including
deltamethrin and CPF. Both antioxidant treatments significantly re-
duced immobility time in OF and attenuated anxious behaviors in EPM
induced by the pesticides (Saoudi et al., 2019). These findings under-
score the potential neuroprotective effects of antioxidants in counter-
acting OP neurotoxicity.

As previously described, psychiatric-like effects such as depressive
behavior have also been evaluated in OP-exposed models. Research has
demonstrated that exposure to phosalone or malathion results in in-
creased immobility in the FST, a response that can be reversed by
scopolamine (Aliomrani et al., 2021), or zinc supplementation
(Brocardo et al., 2007). Furthermore, research on malathion-induced
neurobehavioral deficits has demonstrated the therapeutic potential of
a novel oxime, (3Z)-5-Chloro-3-(hydroxyimino)indolin-2-one (Cl-HIN).
When administered during malathion exposure, Cl-HIN prevented de-
pressive-like behaviors by decreasing immobility time in the FST and
normalizing grooming behavior in the splash test without affecting lo-
comotor activity (Savall et al., 2020).

Finally, it has been demonstrated that anxious behaviors induced by
a single injection of EOPF could be prevented by the co-administration
of cannabinoid receptor inverse agonist (SLV-319) in rats (Ito et al.,
2020b). These results underscore the potential for counteracting the ef-
fects of OP exposure by targeting the endocannabinoid system.

5. Conclusion

In order to develop specific countermeasures that address the long-
term effects of OP exposure, it is important to consider that the individ-
uals may be exposed to various levels of OP through pesticide use, sui-
cide attempts, terrorist attacks, or armed conflict. Victims exposed to
sub-lethal doses may experience serious neurological sequelae with on-
set times ranging from several hours to several years, not all fully attrib-
utable to the sole toxic effect of the OP. As previously stated, victims of
OP exposure should follow up over long periods in order to detect mi-
nor changes in behavior, EEG or neuropsychological parameters (Eyer,
1995). Preclinical rodent models have provided critical insights into the
long-term behavioral effects of OP exposure, and they remain central to
therapeutic evaluation. However, the majority of studies utilize acute
epileptic or degenerative models, which provide minimal information
regarding chronic outcomes or the efficacy of delayed treatment. The
future development of animal models to study long-term effects should
integrate the available data from human exposures, as well as the ef-
fects of other stressors, such as psychological stress and multiple toxic
exposures. Furthermore, the development of novel therapeutic strate-
gies should be directed towards the evaluation of immediate interven-
tions and deferred treatments over an extended period of time, with the
objective of substantiating their effectiveness. These considerations will
lead to the development of more translationally relevant models, which
will integrate chronicity, environmental influences, and delayed thera-
peutic windows.

Funding

This work was supported by the French Ministry of Armed Forces: Direction Générale de l'Armement (DGA), and Service de Santé des Armées (SSA), grants #NBC-5-C-4211 and NBC-5-C-2513. It was also supported the ANR grant #ANR-22-CE-39-0007 (NeuroTarget) and ANR-24-CE-39-2094-01 (Minotor), Astrid ANR grant # ANR-22-ASTR-0022 (B-BOP). The Agence de l'Innovation de Defense (AID) supported the PhD grant of Alexandre CHAMPAULT. Funding sources had no involvement in study design, collection, analysis or interpretation of data, or decision to publish.

CRediT authorship contribution statement

Rosalie BEL: Conception, data analysis and interpretation, writing original draft, writing review and editing. Alexandre CHAMPAULT: Conception, data analysis and interpretation, writing original draft, writing review and editing. Frédéric DORANDEU: Scientific validation, writing review and editing. Karine THIBAULT: Design, funding acquisition, data analysis and interpretation, writing original draft, writing review and editing. Gregory DAL BO: Design, funding acquisition, data analysis and interpretation, writing original draft, writing review and editing. All authors have approved the version to be submitted.

Uncited reference

(Ghanei1 et al., 2010).

Declaration of Competing Interest

The authors declare the following financial interests/personal rela-
tionships which may be considered as potential competing interests:
Karine THIBAULT and Gregory DAL BO report financial support was
provided by French National Research Agency. Alexandre CHAM-
PAULT reports financial support was provided by French Government
Defense Innovation Agency. Karine THIBAULT and Gregory DAL BO re-
port financial support was provided by General Directorate of Arma-
ments. Funding sources had no involvement in study design, collection, analysis or interpretation of data, or decision to publish.

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