Assessment of the severity of organophosphate (fenitrothion) poisoning based on its serum concentration and clinical parameters.

BACKGROUND: Fenitrothion (MEP) is the most frequent cause of organophosphate pesticides (OP) poisoning in Japan, but clinical parameters to predict its severity remain uncertain. METHOD: We evaluated 26 cases (12 males and 14 females) of MEP poisoning brought to our critical care center. Regarding acute lung injury (ALI) as a hallmark complication leading to poor recovery, we divided patients into two groups: cases without ALI (Grp1, n = 14), and cases who developed ALI (Grp2, n = 12) at various points after the poisoning. Serial changes in clinical parameters and laboratory test results were compared between them. RESULTS: The median MEP concentrations on arrival (min~max) for Grp1 and Grp2 were 2.3 (0.5-5.1) and 4.6 (1.1-14.0) µg/ml, respectively. Serum pseudo-cholinesterase (PChE) levels on arrival were 21(< 10-59) U/L in Grp1 and < 10 in Grp2. Based on individual patient kinetics, we estimated MEP concentration at 2 and 24 hours after ingestion, and determined cutoff values for differentiating the two groups for each time point as 4.0 µg/ml and 0.5 µg/ml, respectively. By logistic regression analysis, two groups were distinguished with accuracy of 92.3% based on their time of arrival after ingestion and initial MEP concentration. Clinical parameters associated with ALI were days with miosis, days with PChE below 100 U/L, and days requiring administration of atropine. CONCLUSION: The severity of MEP poisoning is closely associated with both time to presentation after ingestion and initial MEP concentration. Serial monitoring of MEP concentrations in the first 24 hours is also useful in predicting the clinical course.

Monolithic spin column extraction and GC-MS for the simultaneous assay of diquat, paraquat, and fenitrothion in human serum and urine.

We present a method based on monolitic spin column extraction and gas chromatography-mass spectrometry as an analytical method for screening diquat (DQ), paraquat (PQ), and fenitrothion in serum and urine. This method is useful for clinical and forensic toxicological analyses. Recovery of DQ, PQ, and fenitrothion from serum and urine, spiked at concentrations between 0.1, 2.5, 20, and 45 µg/ml, ranged from 51.3% to 106.1%. Relative standard deviation percentages were between 3.3% and 14.8%. Detection and quantitation limits for serum and urine were 0.025 and 0.05 µg/ml, respectively, for DQ, 0.1 and 0.1 µg/ml, respectively, for PQ, and 0.025 and 0.05 µg/ml, respectively, for fenitrothion. Therefore, these compounds can be detected and quantified in the case of acute poisoning.

Effect of oral administration of fenitrothion on biochemical and hematological parameters in rats.

The aim of this study was to evaluate the effects of acute exposure to various doses of fenitrothion (FNT) on level of serum glucose, total protein, triglycerides (TG), total cholesterol (TC) and some hematological parameters. The study was conducted on 8-week-old male Wistar rats that divided into four groups (three experimental groups and one control group), were treated orally with different doses (25, 50 and 100 mg kg(-1)) of fenitrothion for 28 consecutive day. After treatment, blood samples were collected for biochemical and hematological studies. Present results demonstrated that exposed groups led to significant dose-dependent increase in serum glucose and cholesterol levels. Significant decrease was observed in some hematological parameters [Red Blood Cell (RBC) counts, Hemoglobin (Hb), Haematocrite (Ht) and Mean Corpuscular Hemoglobin (MCH) values]. Serum total protein and triglycerides were also decreased not significantly in exposed groups when compared with control. Generally, the degrees of observed variations were found to be dose dependent.

Fenitrothion, an organophosphate, affects running endurance but not aerobic capacity in fat-tailed dunnarts (Sminthopsis crassicaudata).

We measured aerobic metabolism during cold exposure and exercise performance (run duration and oxygen consumption while running at 1 m s(-1)) in the fat-tailed dunnart Sminthopsis crassicaudata, a dasyurid marsupial, before and after ingestion of 30 mg kg(-1) of fenitrothion, an organophosphate (OP) pesticide. Running endurance of OP-exposed animals was less than half that of control animals over the first 3 days after dosing and 55% of control animal endurance on day 5 post-dose. Despite these declines, peak metabolic rate at this running speed (9.3 times basal metabolic rate; BMR) was unaffected by OP exposure. Peak metabolic rate (PMR) and cumulative oxygen consumption during a 1-h exposure to conditions equivalent to -20 degrees C did not differ between OP-treated and control dunnarts, with PMR averaging 11 times BMR. We conclude that fenitrothion-induced exercise fatigue is not due to limitations in oxygen or substrate delivery to muscle or in their uptake per se, but more likely relates to decreased ability to sustain high-frequency neuromuscular function. The persistence of locomotor impairment following OP exposure in otherwise asymptomatic animals emphasizes the importance of using performance-based measures when characterising sublethal effects of pesticide exposure in an ecological context.

Inhibition and recovery of maternal and foetal cholinesterase enzymes following fenitrothion administration in CD rats.

The purpose of this study was to characterize tissue esterase activity and blood fenitrothion concentrations in the rat dam and foetus following in-utero exposure to the organophosphate insecticide fenitrothion. Time-mated, 8-week-old rats were gavaged on gestation day 19 with 0, 5, or 25 mg fenitrothion kg-1. Fenitrothion was absorbed rapidly from the gastrointestinal tract, with peak maternal and foetal blood levels observed 0.5-1.0 h after dosing. Fenitrothion concentrations in maternal and foetal blood were virtually identical and demonstrated a non-linear dose-response relationship. Acetylcholinesterase and carboxylesterase activities in maternal liver and blood and in foetal liver and brain decreased within 30-60 min of fenitrothion exposure. Esterase inhibition occurred at a fenitrothion dose (5 mg kg-1) that has not been previously associated with reproductive toxicity, suggesting that esterase inhibition should be considered as the critical effect in risk assessments for this pesticide.

[Serum fenitrothion concentration and toxic symptom in acute intoxication patients].

The serum drug concentrations were measured by HPLC or GC/MS in 15 patients of acute fenitrothion (MEP), an organophosphorus insecticide, intoxication. There was no fatal case. The patients were admitted 0.5 approximately 12 hours after the ingestion of 5 approximately 50g MEP. The range of serum MEP concentrations were from undetectable level (< 0.01 microg/mL) to 9.73 microg/mL. Toxic symptoms were correlated with the serum MEP levels. About < 7 microg/mL of the serum MEP levels associated with mild cases and about > 7 microg/mL associated with serious cases. The elimination curves in mild cases were successfully simulated by the one-compartment model and the elimination half-lives (T1/2) were 9.9 +/- 7.7hr (mean +/- S.D.). The serum MEP concentrations declined below the detectable level in 48hr. The elimination curves in two serious cases were successfully simulated by the two-compartment model. The T1/2 in the alpha phase were 5.3hr and 6.7hr (under the direct hemoperfusion), and the T1/2 in the beta phase were 35hr and 52hr. The serum MEP concentrations declined below the detectable level in 300hr.

A rat model to evaluate the pesticide permeability and stress effects of protective clothing.

No animal model exists for testing the suitability of a protective garment before actual application in humans. The animal testing model is valuable in particular as the assessment of permeability of hazardous chemicals in humans cannot be easily performed due to possible toxicity to test subjects. We explored a rat model by designing a protective garment to fit rats, and then examining pesticide permeability and physiological responses. When nongarmented rats were exercised in a treadmill, there were increases in heart rate, mean arterial pressure and body temperature. The increases in heart rate and body temperature were further augmented by wearing the protective garment. Fenitrothion, an organophosphate insecticide, was detected in plasma after application on the dorsal area in plasma of nongarmented and garmented (comparable to regular human work clothes) rats. Plasma acetylcholine esterase activity was decreased, suggesting intoxication in these animals. Fenitrothion intoxication was not observed in rats wearing a protective garment. In humans, heart rate and body temperature augmentation were also observed when wearing a protective garment. This result suggests that the present rat model provides a useful assessment of chemical permeability and stress effects of protective garments.

Severe fenitrothion poisoning complicated by rhabdomyolysis in psychiatric patient.

Non-traumatic rhabdomyolysis associated with organophosphate intoxication has not been generally reported. We report here in a severe case of fenitrothion poisoning complicated by rhabdomyolysis. A 43-year-old woman ingested approximately 100 ml of fenitrothion emulsion (50%) in an attempt to commit suicide. On day 3 after admission, her creatine phosphokinase (CPK) peaked at 47,762 IU/L. She received supportive treatment included sodium bicarbonate and fluid resuscitation. However, muscarinic symptoms including excessive miosis and salivation developed on day 5 when her CPK levels decreased. The delay in cholinergic symptoms might have been due to the trihexyphenidyl she took with the antipsychotic drugs. Fortunately, the present patient recovered from the acute cholinergic crisis, and acute renal failure was prevented by early diagnosis. This is a case of organophosphate poisoning complicated by rhabdomyolysis in a psychiatric patient. The masking of acute cholinergic symptoms should be taken into consideration in such patients.

A case of serious organophosphate poisoning treated by percutaneus cardiopulmonary support.

We report a case of respiratory arrest, refractory circulatory collapse, and severe hypothermia following ingestion of an organophosphate insecticide. In addition to conventional management, including mechanical ventilation, administration of vasopressors, enteral lavage, charcoal hemoperfusion and administration of antidotes, extracorporeal cardiopulmonary support in the form of percutaneous cardiopulmonary support was successfully employed. Percutaneous cardiopulmonary support may be used for severe but potentially reversible pulmonary or cardiovascular toxicity induced by organophosphates as well as complicated severe hypothermia.

Bioconcentration and excretion of fenitrothion in the brain of the eel (Anguilla anguilla).

The bioconcentration of fenitrothion in the brain of the european eel (Anguilla anguilla) and its posterior elimination have been studied. Animals were exposed to a sublethal concentration of fenitrothion (0.04 mg/L) for 96 hours in a flow-through test system. After this pesticide exposure, animals were transferred to clean water for 72 hours more. Bioconcentration and elimination processes of fenitrothion were studied in blood and brain. This insecticide showed a strong tendency to bioconcentrate into selected tissues. A steady-state was observed in blood in few hours. Highest accumulation was detected in brain, where any steady-state could be observed. Elimination started rapidly from both tissues when a recovery period was allowed. Elimination kinetics were adjusted to one-compartment model. K2 of 0.015 and 0.044 hr-1 were calculated for fenitrothion in blood and brain. These K2 values were related with a relatively short half-live of fenitrothion in the analyzed tissues; probably due to the low biotransformation rate of this toxicant in the european eel. That fact would protect the animals against many biotransformation products even more toxic than the parent fenitrothion.

Determination of organophosphorous pesticides in biological samples of acute poisoning by HPLC with diode-array detector.

We have developed a simple and rapid method for measuring 11 organophosphorous pesticides (dichlorvos, methidathion, salithion, malathion, fenitrothion, fenthion, parathion, diazinon, ethylthiometon, O-ethyl O-(4-nitrophenyl)phenylphosphonothioate (EPN) and chlorpyrifos) and one metabolite (3-methyl-4-nitrophenol) of fenitrothion in serum and urine of acute poisoning patients by HPLC with a diode-array detector. An aliquot of the biological sample after deproteinization by acetonitrile was injected into C18 column using acetonitrile-water as a mobile phase. The detection limits in serum and urine ranged from 0.05 to 6.8 micrograms/ml at a wavelength of 230 nm. This method was successfully applied to two actual cases of acute poisoning.

Relapse and elevation of blood urea nitrogen in acute fenitrothion and malathion poisoning.

We observed 6 patients with severe fenitrothion and/or malathion poisoning necessitating artificial ventilation and intensive care monitoring. Three developed relapse following acute cholinergic crisis. In these patients the blood urea nitrogen (BUN) abnormally elevated before the development of relapse and the initial high concentration of plasma organophosphate (OP) decreased only gradually. However, the patients who did not develop relapse showed no elevation of BUN and a relatively low concentration of plasma OP. This observation was confirmed in a retrospective search of 14 patients. In addition, erythrocyte cholinesterase (EChE) activities were more helpful to diagnose the development of relapse than plasma cholinesterase activities. Therefore, careful monitoring of BUN in addition to plasma OP concentration may be useful to predict the development of relapse.

Intermediate syndrome in acute fenitrothion poisoning.

Fenitrothion has been reported as one of the organophosphates causing so called "intermediate syndrome"--clinical entity of still unclear reasons. That is why we decided to perform a retrospective examination of oral intoxication with this compound. Clinical course of 16 cases were analysed. Clinical state on admission, AChE activity and pesticide concentration in blood were considered. Gastric lavage, atropine and oximes were included in the treatment. 6 patients died in the period of 5 to 22 days (mean 11.8) from poison intake. All 6 revealed slight signs of poisoning at the time of admission (first 24th). AChE was moderately inhibited. Patients' clinical state was deteriorating and AChE activity was decreasing during next 48 h even though oximes therapy was applied. Intubation and mechanical ventilation was required. Fenitrothion concentration in blood varied from 470 to 8350 ng/ml (mean 2823 ng/ml). In 3 fatal cases toxicological examination of autopsy tissue was done. High fenitrothion concentration was found in adipose tissue and also in the brain. In the group of 10 recovered patients "intermediate syndrome" was not observed in 3 only. AChE activity returned to normal quickly. Fenitrothion concentration ranged from 96 to 360 ng/ml (mean 202 ng/ml). In the remaining 7 clinical state became worse during next 48-72 hours after temporary improvement. Respiratory failure and increasing AChE activity inhibition were major signs. Fenitrothion concentration varied from 180 to 3020 ng/ml (mean 1690 ng/ml). AChE inhibition persisted even for 30 days from poisoning.

Determination of atropine in biological specimens by high-performance liquid chromatography.

A sensitive and selective method for the determination of atropine in biological specimens has been developed. Samples alkalinized with sodium hydroxide were extracted with dichloromethane, and the organic phase was evaporated in a water-bath at 50 degrees C for ca. 10 min. The residue was dissolved in the mobile phase and injected into a reversed-phase column (TSK gel ODS-120A). The retention time for atropine could be varied by changing either the acetonitrile-water ratio in the mobile phase or the pH of the mobile phase. Acetonitrile-water (2:8, v/v) containing 6 mM phosphoric acid was used as mobile phase. Samples of 200 microliters or less were injected into the chromatography and measured at 215 nm. The recoveries of atropine added to drug-free specimens were satisfactory with coefficients of variation of 4% or less. Ninety-two compounds tested did not interfere with the assay of atropine. The method has been applied for monitoring atropine concentrations in cases of organophosphate and drug poisoning.

Determination of dimethoate in blood and hemoperfusion cartridge following ingestion of formothion: a case study.

A 57-year-old male who had ingested not more than 22 g of formothion was semicomatose on admission to hospital, approximately 1.5 h after ingestion. Dimethoate, a hydrolyzed formothion, was found in blood samples collected from the patient and in the charcoal column in the direct hemoperfusion cartridge which was used 6 to 7.5 h after ingestion. It was extracted and purified by Extrelut column extraction. A gas chromatograph, equipped with a flame photometric detector and a gas chromatograph-mass spectrometer, were used to detect and confirm the presence of dimethoate. The blood dimethoate concentrations which were taken approximately 1.5 and 6 h after ingestion were 21.4 and 12.7 micrograms/g, respectively. A blood dimethoate concentration of 21.4 micrograms/g would appear to indicate a high level of formothion intoxication. The total amount of dimethoate found in the charcoal column used was 15 mg.

[Screening of drugs and chemicals by wide-bore capillary gas chromatography. II. Detection of drugs and chemicals in the blood].

This paper describes the detection limit for 23 drugs and chemicals in the blood by means of a screening method that uses a gas chromatographic system equipped with a wide-bore capillary column and a nitrogen phosphorus detector. The detection limit by this method was determined as being 1 mm of peak height at the detector's range of 100 and 8 of attenuation. Using this scale, the absolute detection limit was in the range of 1 pg for malathion and sumithion to 1 ng for meprobamate. The detection limit of drugs and chemicals in the blood was 5 ng/ml for sumithion to 8 micrograms/ml for meprobamate. Therefore, this screening method is able to detect the presence of drugs even a therapeutic-level dosages, with the exception of compounds such as haloperidol, which have extremely low therapeutic dosage levels.

[Delayed Sumithion intoxication].

A case of delayed Sumithion (fenitrothion) intoxication is reported. A 52-year-old man ingested 10 ml of Sumithion in order to commit suicide with alcohol and triazoram. Several hours later, he was admitted to our hospital because of clouding consciousness. On admission, he was somnolent, but had no other symptoms, especially suggested organophosphorus intoxication. After 40 hours, fasciculation and salivation, which are early symptoms of organophosphorus intoxication, gradually appeared. The concentration of Sumithion in the blood was measured during the course and its metabolism was represented phalmacokineticaly by a 2-compartment model. The retarded metabolism of the Sumithion was suggested by this model. It is considered that the retarded metabolism of Sumithion caused the delayed intoxication.