Evaluation of oxidative stress and genotoxicity in organophosphorus insecticide formulators

The aim of this study was to evaluate genotoxicity and oxidative stress in workers who formulate organophosphorus (OP) pesticides. In this survey, blood leukocytes and erythrocytes of a group of 21 pesticide formulating workers and an equal number of control subjects were examined for genotoxicity and oxidative stress parameters. The mean comet tail length and mean comet length were used to measure DNA damage. Lipid peroxidation level, catalase, superoxide dismutase (SOD) and glutathione peroxidase activities in erythrocytes were analysed as biomarkers of oxidative stress. In addition, the acetylcholinesterase activity was measured as a biomarker of toxicity. The average duration of employment of workers in the factory was 97 months. Results indicated that chronic exposure (multiple-dose, greater than or equal to 6 months duration) to OP pesticides was associated with increased activities of catalase, SOD and glutathione peroxidase in erythrocytes. The level of lipid peroxidation and acetylcholinesterase activity did not show any significant differences between the two groups. The results also indicated that chronic exposure to OP pesticides was associated with increased DNA damage. It is concluded that human chronic exposure to OP pesticides may result in stimulated antioxidant enzymes and increased DNA damage in the absence of depressed acetylcholinesterase levels. Routine genotoxicity monitoring concomitant to acetylcholinesterase activity in workers occupationally exposed to OP insecticides is suggested.     

The effects of acutely administered low dose sarin on cognitive behaviour and the electroencephalogram in the common marmoset.

Previous studies have suggested that administration of a clinically sign-free dose of sarin to non-human primates gives rise to subtle changes in brain electrical activity as measured by electroencephalography (EEG) several months following exposure. The functional significances of such changes are unclear. The present study monitored EEG by using implantable radiotelemetry, and also assessed the performance of complex behavioural tasks, in non-human primates for up to 15 months following exposure to a low dose of sarin. Baselines of EEG and behaviour were shown to be stable over several months in control animals. The doses of sarin administered caused erythrocyte cholinesterase inhibitions of 36.4% to 67.1%. Overall, no significant changes in EEG patterns were observed although there were increases in beta 2 amplitude which approached significance (p=0.07). No deleterious effects on performance were seen on the touchscreen mediated discrimination tasks presented from the Cambridge Neuropsychological Test Automated Battery (CANTAB). This study illustrates the validity of the approach employed and makes an important contribution to the investigation of the long-term effects of organophosphorous compounds.     

Efficacy assessment of various anticholinergic agents against topical sarin-induced miosis and visual impairment in rats

Eye exposure to the organophosphorus (OP) irreversible acetylcholinesterase inhibitor sarin results in long-term miosis and reduction in visual function. Anticholinergic drugs, such as atropine or homatropine, which are used topically in order to counter these effects may produce mydriasis and partial cycloplegia, which may worsen visual performance. This study was aimed to test the efficacy of short-acting anticholinergic drugs against sarin-induced miosis and visual impairment, which will minimally insult vision. Long-Evans rats, exposed topically to various sarin doses from 0 to 10 μg, showed a dose-dependent miosis, which returned to pre-exposure levels within 24-48 h. Tropicamide treatment rapidly widened the miotic effect to a different extent depending on time following treatment and dosage given. Cyclopentolate, however, showed a delayed response that finally widened the pupils in a dose-dependent manner. Atropine treatment showed a rapid widening of the pinpoint pupils exceeding baseline level finally causing mydriasis. Light reflex test showed that the contraction ability of the iris following atropine treatment was impaired, as opposed to the use of tropicamide which facilitated the iris contraction, similar to control. Finally, tropicamide and atropine treatments ameliorated the visual impairment, as opposed to cyclopentolate, which worsened visual performance. Considering that tropicamide treatment against sarin exposure did not cause mydriasis nor did it impair the iris contraction flexibility as a response to light, the use of this drug should be taken into consideration as a first-choice topical treatment against OP intoxication.     

Valproate monotherapy in juvenile myoclonic epilepsy: dose-related effects on electroencephalographic and other neurophysiologic tests

A neurophysiologic test battery (consisting of a 24-hour, seven-channel electroencephalogram [EEG], EEG spectral analysis, multiple sleep latency test, visual evoked potentials, critical flicker fusion, and visual contrast sensitivity) was administered twice to 16 patients with juvenile myoclonic epilepsy (JME) in a double-blind, randomized, crossover study comparing two daily doses of sodium valproate (VPA), 1000 mg and 2000 mg. Clinical observation time was 6 months for each dose. Mean total VPA concentration during low-dose treatment was 470.4 mmol/L and during high-dose treatment was 700.0 mmol/L. Ten patients had seizures during low-dose treatment, but only three of these showed spike-wave activity on EEGs. During high-dose treatment, nine patients had seizures; five of these had spike-wave activity. EEG power spectrum did not change between doses. The other tests also showed no change between doses. Our results suggested that EEG and our selection of other neurophysiologic tests were of limited value for monitoring seizure frequency and clinical effects of VPA.     

Efficacy assessment of a combined anticholinergic and oxime treatment against topical sarin-induced miosis and visual impairment in rats

Background and Purpose

Eye exposure to the organophosphorus (OP) irreversible cholinesterase inhibitor sarin results in long-term miosis and impaired visual function. We have previously shown that tropicamide is better at ameliorating this insult than topical atropine or cyclopentolate. However, to minimize side effects associated with repeated tropicamide applications and high treatment doses, we evaluated the effects of oximes (ChE re-activators) alone and combined with tropicamide at ameliorating OP-induced ocular impairments.

Experimental approach

Rats were topically exposed to sarin, followed by topical treatment with various oximes alone or in combination with tropicamide. Pupil width and light reflex were measured by an infrared-based digital photograph system, while visual performance was assessed by employing the cueing version of the Morris water maze (MWM).

Key Results

Oxime treatment following sarin ocular exposure induced a slow persistent pupil widening with efficacy in the order of HLö-7 > HI-6 > obidoxime = TMB-4 = MMB-4. In the light reflex test, the ability of the iris to contract following oxime treatment was mostly impaired at 1 h and was back to normal at 4 h following sarin exposure. All oxime treatments ameliorated the sarin-induced visual impairment as tested in the visual task (MWM). The combined topical treatment of tropicamide with an oxime induced a rapid improvement in pupil widening, light reflex and visual performance, and enabled a reduction in tropicamide dose.

Conclusions and Implications

The use of tropicamide combined with an oxime should be considered as the topical treatment of choice against the toxic effects of ocular OP exposure.     

Low levels of sarin affect the EEG in marmoset monkeys: a pilot study

The main purpose of this pilot study was to estimate the lowest observable adverse effect level (LOAEL) for the electroencephalogram (EEG) upon long-term, low-level exposure of vehicle-pretreated and pyridostigmine-pretreated marmoset monkeys to sarin vapour. This is the C.t value (t=5 h) of exposure at which the EEG becomes significantly different from that resulting from air exposure of the same animals. The LOAELs for effects on the EEG in vehicle- and pyridostigmine-pretreated marmosets appeared to be 0.2 and 0.1 mg min m(-3), respectively. Comparatively, the latter LOAEL values are at least an order of magnitude lower than the previously established LOAEL for miosis and only 2-5 times higher than the lowest observable effect level (LOEL) of bound sarin in blood.The second aim of the study was to analyse the EEG of the same marmosets again during a 5-h exposure to air 1 year after exposure to sarin vapour. All the marmosets still demonstrated significant (P <0.05) EEG differences. In most vehicle-pretreated marmosets the energy (microV2) per EEG band was higher than that observed 1 year earlier, which might indicate that neurons had become more sensitive to excitation. This phenomenon was less pronounced in pyridostigmine-pretreated animals. Visual examination of the EEG records revealed clear bursts of alpha frequencies (ca. 9 Hz), resembling sleep-spindles, that were present more frequently in both groups of exposed marmosets than in naive animals. These late changes in spindle oscillation might be the result of changes in the cholinergic system due to exposure to sarin vapour 1 year previously. In conclusion, EEG abnormalities persisting for more than 1 year may occur in humans during long-term (5 h) exposure to subclinical levels of sarin that are not detectable by the currently fielded alarm systems.     

Cyclopentolate in treatment of sarin miosis

1. Six young male volunteers were exposed to sarin vapour (isopropyl methyl phosphonofluoridate) at a concentration of 0.5 mg/m(3) for 30 min (concentration time (Ct) 15 (mg min)/m(3)).2. The resulting clinical syndrome was treated by instilling 0.06 ml of a 1% solution of cyclopentolate into the conjunctival sac.3. Visual acuity, retinoscopy, objective and subjective refraction and pupil sizes were noted before the trial, after exposure to sarin and after treatment with cyclopentolate.4. No appreciable difference was demonstrated between the control objective retinoscopy values and those obtained after cyclopentolate treatment of the clinical syndrome induced by sarin. Reduced near visual acuity was observed in some subjects treated with cyclopentolate as compared with acuity after exposure to sarin alone, considered to be due to the partial cycloplegia produced by treatment. Visual acuity after exposure to sarin alone was improved in some instances by the miosis produced.5. It is suggested that unless full dark adaptation is a consideration, treatment of the ophthalmic condition resulting from exposure to this dosage of sarin should be reserved for those experiencing distressing ocular symptoms.     

Changes of acetylcholinesterase activity after long-term exposure to sarin vapors in rats

In our study, rats were exposed to sarin vapors for 240 min at four different concentrations (0.30, 0.43, 0.58 and 0.82 microg/L) in a whole-body inhalation chamber. The acetylcholinesterase activity (AChE, EC 3.1.1.7) was measured in the whole blood, frontal cortex (FC), pontomedullar area (PM) and basal ganglia (BG). Convulsions and hypersalivation were observed in only one animal of the group exposed to the highest sarin concentration. The decrease in blood AChE activity was significant in all animals exposed to sarin vapors. The highest inhibition of AChE activity (61%) was determined in animals exposed to sarin vapors at a concentration of 0.82 microg/L. In the PM, AChE activity was decreased in all experimental groups, significantly only in the group exposed to sarin vapors at a concentration of 0.58 microg/L. Our results show that in long-term exposure to low concentrations of sarin, the significant decrease in AChE activity in the blood is followed by significant changes of AChE activity in the PM only. This part of the brain seems to be more sensitive than the FC or BG.     

Transient and reversible nephrotoxicity of sarin in rats

Organophosphate (OP) poisoning, which inhibits cholinesterase activity, leads to severe cholinergic symptoms. Effective and quick management of these symptoms is considered critical to the clinical outcome. Acute renal damage following exposure to OP insecticides has been reported. Similar complications might occur following exposure to OP nerve agents, however, this subject has been studied only sporadically. In the present study, the effect of the nerve agent sarin on renal function was examined in rats. A single dose of sarin ( approximately 0.9 LD(50)) led to a significant reduction (of 45%) in renal function during the first 2 days post exposure, as exhibited by evaluation of the glomerular filtration rate, through measuring the clearance of ( 99m)Tc-DTPA. The urine volume was reduced by 50%, the urine specific gravity increased to 104% of the control value and massive hematuria and glucosuria were recorded 24-48 h post exposure. In addition, around 60% decrease in urine electrolytes was monitored during the first 2 days following exposure, with a recovery after 8 days. Post mortem gross inspection of the bladder, 24 h post exposure, revealed severe edema and hemorrhage. Treatment with the muscarinic antagonist atropine and the oxime TMB-4, at excessive doses administered 1 min post exposure, did not prevent most renal impairments. It has been concluded that sarin caused an acute renal dysfunction, possibly accompanied by bladder damage. These impairments were reversible, recovered spontaneously within 3-8 days, and were probably related to the state of shock and hypovolemia caused by the poisoning. However, if renal impairments are left unattended, they might contribute to the overall toxic manifestation and as a result aggravate the clinical state of intoxicated casualties.     

EEG spectra,behavioral states and motor activity in rats exposed to acetylcholinesterase inhibitor chlorpyrifos

Exposure to organophosphates (OP) has been associated with sleep disorders such as insomnia and "excessive dreaming." The central mechanisms of these effects are not well understood. OPs inhibit acetylcholinesterase (AChE) activity, leading to a hyperactivity of the brain cholinergic systems that are involved in sleep regulation. We studied alterations in the EEG, behavioral states, motor activity and core temperature in rats orally administered with 10 or 40 mg/kg of the OP insecticide chlorpyrifos (CHP). Occipital EEG, motor activity and core temperature were recorded with telemetric transmitters. Behavioral sleep-wake states were visually scored. Both doses of CHP produced alterations of the EEG (decrease in power of sigma/beta and increase in slow theta and fast gamma bands) characteristic of arousal. EEG alterations were consistent with behavioral changes such as an increase in wakefulness and a decrease in sleep. Waking immobility was a prevalent behavior. We did not detect any overt signs of CHP toxicity, such as an abnormal posture or gait, suggesting that reduced locomotion can be a result of central effects of CHP (such as activation of cholinergic motor inhibitory system) rather than peripheral (such as an impairment of neuromuscular function). Changes in the EEG and behavior occurred independently of the decrease in core temperature. Increased wakefulness together with reduced motor activity after exposure to CHP seems to be a result of hyperactivity in brain cholinergic neuronal networks.     

Protective efficacy of catalytic bioscavenger, paraoxonase 1 against sarin and soman exposure in guinea pigs

Human paraoxonase 1 (PON1) has been portrayed as a catalytic bioscavenger which can hydrolyze large amounts of chemical warfare nerve agents (CWNAs) and organophosphate (OP) pesticides compared to the stoichiometric bioscavengers such as butyrylcholinesterase. We evaluated the protective efficacy of purified human and rabbit serum PON1 against nerve agents sarin and soman in guinea pigs. Catalytically active PON1 purified from human and rabbit serum was intravenously injected to guinea pigs, which were 30 min later exposed to 1.2 × LCt₅₀ sarin or soman using a microinstillation inhalation exposure technology. Pre-treatment with 5 units of purified human and rabbit serum PON1 showed mild to moderate increase in the activity of blood PON1, but significantly increased the survival rate with reduced symptoms of CWNA exposure. Although PON1 is expected to be catalytic, sarin and soman exposure resulted in a significant reduction in blood PON1 activity. However, the blood levels of PON1 in pre-treated animals after exposure to nerve agent were higher than that of untreated control animals. The activity of blood acetylcholinesterase and butyrylcholinesterase and brain acetylcholinesterase was significantly higher in PON1 pre-treated animals and were highly correlated with the survival rate. Blood O₂ saturation, pulse rate and respiratory dynamics were normalized in animals treated with PON1 compared to controls. These results demonstrate that purified human and rabbit serum PON1 significantly protect against sarin and soman exposure in guinea pigs and support the development of PON1 as a catalytic bioscavenger for protection against lethal exposure to CWNAs.     

Neuropsychiatric evaluation in subjects chronically exposed to organophosphate pesticides.

Long-term exposure to low levels of organophosphate pesticides (OP) may produce neuropsychiatric symptoms. We performed clinical, neuropsychiatric, and laboratory evaluations of 37 workers involved in family agriculture of tobacco from southern Brazil who had been exposed to OP for 3 months, and in 25 of these workers, after 3 months without exposure to OP. Plasma acetylcholinesterase activity levels of all subjects were within the normal range (3.2 to 9.0 U/l) and were not different between on- and off-exposure periods (4.7 +/- 0.9 and 4.5 +/- 1.1 U/l, respectively). Clinically significant extrapyramidal symptoms were present in 12 of 25 subjects, which is unexpected in such a population. There was a significant reduction of extrapyramidal symptoms after 3 months without exposure to OP, but 10 subjects still had significant parkinsonism. Mini-mental and word span scores were within the expected range for this population and were not influenced by exposure to OP. Eighteen of the 37 subjects (48%) had current psychiatric diagnoses in the first interview (13 with generalized anxiety disorder and 8 with major depression). Among the 25 subjects who completed both evaluations, the total number of current psychiatric diagnoses, after 3 months without using OP, dropped from 24 to 13 and the number of affected individuals with any psychiatric diagnosis dropped from 11 to 7. In conclusion, this study reinforces the need for parameters other than acetylcholinesterase activity to monitor for chronic consequences of chronic low-dose OP exposure, and it suggests that subjects have not only transient motor and psychiatric consequences while exposed, but may also develop enduring extrapyramidal symptoms.     

Elevated frequency of sister chromatid exchanges of lymphocytes in sarin-exposed victims of the Tokyo sarin disaster 3 years after the event

We previously reported that the frequency of sister chromatid exchanges (SCEs) among victims of the Tokyo subway sarin disaster was significantly higher than that of controls 2-3 months after the disaster. It has been reported that the victims were also exposed to the by-products generated during sarin synthesis, i.e., diisopropyl methylphosphonate (DIMP), diethyl methylphosphonate (DEMP) and N,N-diethylaniline (DEA) during the disaster and we previously found that DIMP, DEMP and DEA induced a significant SCE increase in human lymphocytes in vitro. To monitor the genetic aftereffects of the sarin exposure, SCEs of peripheral blood lymphocytes were measured in fire fighters and police officers involved in the disaster 3 years after the event. We found that the frequency of SCEs was still significantly higher in the exposed subjects than the controls, suggesting a risk of the genetic aftereffects of the sarin exposure. We further found a significant positive correlation between the frequency of SCEs and the inhibition of serum cholinesterase activity in the exposed subjects, suggesting that the elevated frequency of SCEs is related to the sarin exposure. On the other hand, there was no significant difference in natural killer activity between the exposed and the controls.     

Changes in sleep and wakefulness following single and repeated exposures to toluene vapor in rats

Male rats with indwelling electrodes for electroencephalographic (EEG), electromyographic (EMG) and electrooculographic (EOG) recordings were exposed via inhalation to 900 ppm and 2700 ppm toluene vapor continuously for a 8-h period or repeatedly for 3 weeks at a rate of 8 h/day and 5 days/week. Rats exposed to a clean airstream under the same exposure schedules served as controls. Polygraphic recordings were made on 3 consecutive days after cessation of the single 8-h and repeated 3-week exposures to 900 ppm and 2700 ppm toluene vapor or clean airstream. Amounts of time spent in wakefulness (W), slow-wave sleep (SWS) and paradoxical sleep (PS) were quantified by visual inspection of the polygraphic records. Single exposure to toluene produced a prolonged PS latency and a long-lasting increase in SWS at the expense of depressed W, whereas repeated exposures prolonged both SWS and PS latencies, abolished the initial increase of SWS and increased the light-phase level of W on Days 1 and 2. The prolonged PS latency and the decreased light-phase PS on Day 2 induced by single exposure to toluene still persisted after repeated exposures. There were no statistically significant differences in attenuation of brain and blood toluene levels between single and repeated exposures to toluene vapor of 900 ppm and 2700 ppm.     

Organophosphorus pesticide exposure decreases sperm quality: association between sperm parameters and urinary pesticide levels

Several studies have suggested that human semen quality has declined over the past decades and some of them have associated it with occupational exposure to pesticides. However, most of these studies have not been associated with a reliable exposure level and have been designed mostly as cross-sectional studies. The present work evaluates, in a longitudinal follow-up study, the effect of organophosphate pesticides (OP) at three occupational exposure levels on semen quality. In addition, the study examined the association between OP urinary levels and sperm parameters in exposed and unexposed workers. A total of 139 semen samples from 52 volunteers were assessed. Urinary OP levels were measured by gas-liquid chromatography.The results revealed that the poorest semen quality was found among the subjects with the highest OP exposure and the highest urinary OP levels. Seasonal variations in sperm concentration and sperm count were registered.The results showed a significant decrease in total sperm count among subjects with the highest exposure to OP. Further studies assessing the effects of OP on male reproductive health should be controlled by the variability in human sperm parameters, sperm seasonality, spermatogenesis time and the changing OP exposure level in men highly exposed to OP.     

The effect of organophosphorus compounds on serum pseudocholinesterase levels in a group of industrial workers.

This paper presents the findings of a study of serum pseudocholinesterase activity in a group of 36 industrial workers chronically exposed to organophosphorus (OP) compounds. The mean pseudocholinesterase level of the workers was significantly lower than that of 36 other workers without a history of similar exposure. Although there was a high incidence of clinical features suggestive of OP compound toxicity in the exposed workers, no significant correlation between serum pseudocholinesterase levels and clinical symptoms and signs was found. Six exposed workers, found to have low serum pseudocholinesterase levels, were transferred for 6 months to work areas which did not involve OP exposure, whereupon their levels rose significantly back to the normal range.     

Sleep and wake after benzodiazepine hypnotics: a 20-hour EEG comparison of lormetazepam and flunitrazepam

In an electropharmacokinetic study, the effects of lormetazepam and flunitrazepam were compared by the means of a sleep EEG and waking EEG during the following daytime. At a 1-week interval, 6 normal subjects received at random either 2 mg lormetazepam or 2 mg flunitrazepam in a double-blind, crossover fashion. Sleep EEG was recorded throughout the night; 6-min EEG samples were recorded every hour during 10 hours on the following daytime for spectral analysis. Night sleep after flunitrazepam showed lower Stage IV sleep than after lormetazepam. During daytime, only flunitrazepam induced an increased percentage of beta 2 frequencies, which remained above baseline up to 10 hours after awakening, indicating a prolonged impregnation time. This study permitted comparison of the relative intensity and duration of these two benzodiazepines: lormetazepam appeared to be a short-acting hypnotic while flunitrazepam displayed longer modification of the brain electrical activity.     

Success of pyridostigmine, physostigmine, eptastigmine and phosphotriesterase treatments in acute sarin intoxication.

The acute toxicity of organophosphorus (OP) compounds in mammals is due to their irreversible inhibition of acetylcholinesterase (AChE) in the nervous system, which leads to increased synaptic acetylcholine levels. The protective actions of intravenously (i.v.) administered pyridostigmine, physostigmine, eptastigmine, and an organophosphate hydrolase, phosphotriesterase, in acute sarin intoxication were studied in mice. The acute intragastric (i.g.) toxicity (LD50) of sarin with and without the pretreatments was tested by the up-and-down method. The mice received pyridostigmine (0.06 mg/kg body weight), physostigmine (0.09 mg/kg body weight), the physostigmine derivative eptastigmine (0.90 mg/kg body weight) or phosphotriesterase (104 U/g, 10.7 microg/g body weight) 10 min prior to the i.g. administration of sarin. Physostigmine was also administered with phosphotriesterase. Phosphotriesterase was the most effective antidote in sarin intoxication. The LD50 value for sarin increased 3.4-fold in mice receiving phosphotriesterase. Physostigmine was the most effective carbamate in sarin exposure. The protective ratios of physostigmine and pyridostigmine were 1.5- and 1.2-1.3-fold, respectively. Eptastigmine did not give any protection against sarin toxicity. Both the phosphotriesterase and physostigmine treatments protected the brain AChE activities measured 24 h after sarin exposure. In phosphotriesterase and physostigmine-treated mice, a 4- and 2-fold higher sarin dose, respectively, was needed to cause a 50% inhibition of brain AChE activity. Moreover, the combination of phosphotriesterase-physostigmine increased the LD50 value for sarin 4.3-fold. The animals pretreated with phosphotriesterase-ephysostigmine tolerated four times the lethal dose in control animals, furthermore their survival time was 2-3 h in comparison to 20 min in controls. In conclusion, phosphotriesterase and physostigmine were the most effective treatments against sarin intoxication. However, eptastigmine did not provide any protection against sarin toxicity.     

Toxic effects of sarin in rats at three months following single or repeated low-level inhalation exposure

Male albino Wistar rats were once or repeatedly exposed to three various low concentrations of sarin for 60 min. in the inhalation chamber. The clinical status of control as well as sarin-poisoned rats was tested 3 months after exposure to sarin using biochemical, haematological, neurophysiological, behavioural and immunotoxicological methods. While biochemical and haematological parameters, including the activities of cholinesterases in erythrocytes, plasma and various organs (brain, diaphragm), did not differ from the control values regardless of the sarin concentration used, few signs of sarin-induced neurotoxicity and immunotoxicity in sarin-poisoned rats were demonstrated. This was especially true when the single exposure of rats to non-convulsive symptomatic concentration and repeated exposure of rats to clinically asymptomatic concentration of sarin was used. In rats repeatedly poisoned with clinically asymptomatic concentrations of sarin, the alteration of the gait characterized by ataxia, the increase in the stereotyped behaviour, the increase in the excitability of the central nervous system following the administration of the convulsive drug pentamethylenetetrazol were observed. In rats poisoned with non-convulsive symptomatic concentration of sarin, the subtle supression of spontaneous, as well as lipopolysaccharides-stimulated, proliferation of spleen lymphocytes and the bactericidal activity of peritoneal macrophages was primarily observed besides the signs of neurotoxicity. Our findings confirm that both non-convulsive symptomatic and clinically asymptomatic concentrations of sarin can only cause very few, subtle long-term signs of neurotoxicity and immunotoxicity in sarin-poisoned rats when the rats were exposed to asymptomatic sarin concentrations repeatedly.     

A long-term study of the effects of diazinon on sleep, the electrocorticogram and cognitive behaviour in common marmosets

The long-term sequelae of exposure to low doses of organophosphate compounds are ill defined, with effects variously reported on a range of indices of central nervous system functions such as sleep, cognitive performance and electroencephalogram (EEG). These indices were examined in common marmosets exposed to a range of doses of the organophosphorous sheep dip, diazinon. Cognitive performance was assessed by means of elements from the Cambridge Neuropsychological Test Automated Battery (CANTAB), and radiotelemetry techniques were employed to monitor the electrocorticogram and sleep patterns. Data were collected for 12 months following intramuscular administration of a single dose of diazinon (10, 90 or 130 mg.kg (-1)) or vehicle. Although high levels of erythrocyte acetylcholinesterase (AChE) inhibition (up to 82%) and short-term changes in sleep patterns were seen, there was no evidence of biologically significant long-term changes in any measures. The effects of multiple exposures, impurities or mixtures of OP compounds remain to be investigated.