Different Clinical Courses for Poisoning with WHO Hazard Class Ia Organophosphates EPN, Phosphamidon, and Terbufos in Humans

PURPOSE: Extremely hazardous pesticides are classified as World Health Organization (WHO) hazard class Ia. However, data describing the clinical course of WHO class Ia OP (organophosphate) poisonings in humans are very scarce. Here, we compare the clinical features of patients who ingested hazard class Ia OPs. METHODS: This retrospective observational case study included 75 patients with a history of ingesting ethyl p-nitrophenol thio-benzene phosphonate (EPN), phosphamidon, or terbufos. The patients were divided according to the chemical formulation of the ingested OP. Data regarding mortality and the development of complications were collected and compared among groups. RESULTS: There were no differences in the baseline characteristics and severity scores at presentation between the three groups. No fatalities were observed in the terbufos group. The fatality rates in the EPN and phosphamidon groups were 11.8% and 28.6%, respectively. Patients poisoned with EPN developed respiratory failure later than those poisoned with phosphamidon and also tended to require longer mechanical ventilatory support than phosphamidon patients. The main cause of death was pneumonia in the EPN group and hypotensive shock in the phosphamidon group. Death occurred later in the EPN group than in the phosphamidon group. CONCLUSION: Even though all three drugs are classified as WHO class Ia OPs (extremely hazardous pesticides), their clinical courses and the related causes of death in humans varied. Their treatment protocols and predicted outcomes should therefore also be different based on the chemical formulation of the OP.

The Variations in Clinical Features According to Intoxicants in High Toxicity Organophosphorus Intoxication

PURPOSE: Organophosphorus (OP) pesticides are differentiated into 3 groups according to their toxicity. The differences in chemical composition of each OP pesticide determines its toxicokinetic characteristics. There are few human studies that address the clinical results of poisoning according to the OP pesticide. In this study, we aimed to examine the differences in clinical features among self-poisoning from 4 highly toxic OP pesticides. METHODS: The 4 kinds of OP poisonings included 17 cases of Dichlorvos, 17 cases of EPN, 17 cases of methidathion, and 13 cases of phosphamidon. We set primary outcomes as GCS, atropine dose required, duration of patient need for atropine, proportion who required ventilation, duration on ventilation, and the interval from ingestion to ventilation. Secondary outcomes were the proportion of OP-induced delayed neuropathy, duration of ICU stay, and proportion who required additional infusion of pralidoxime chloride (PAM). RESULTS: The EPN group required the largest amount of atropine, the longest duration of atropine use, the longest duration for support of mechanical ventilation, and the longest ICU stay. Furthermore the proportion who required additional PAM and neuropathy were in the EPN group. However, the EPN group had the longest interval from ingestion to ventilatory support. Meanwhile, the Dichlorvos group exhibited comparatively mild clinical features. CONCLUSION: Throughout this study, we found different clinical features to each OP pesticide poisoning. It can be explained by differences in chemical composition, which determined the speed of aging, the reactivation rate of OPenzyme, the metabolism, the fat solubility, and other characteristics of the pesticides.

Attenuation of phosphamidon-induced oxidative stress and immune dysfunction in rats treated with N-acetylcysteine

The effect of N-acetylcysteine, a thiolic antioxidant, on attenuation of phosphamidon-induced oxidative stress and immune dysfunction was evaluated in adult male Wistar rats weighing 200-250 g. Rats were divided into four groups, 8 animals/group, and treated with phosphamidon, N-acetylcysteine or the combination of both for 28 days. Oral administration of phosphamidon (1.74 mg/kg), an organophosphate insecticide, increased serum malondialdehyde (3.83 ± 0.18 vs 2.91 ± 0.24 nmol/mL; P < 0.05) and decreased erythrocyte superoxide dismutase (567.8 ± 24.36 vs 749.16 ± 102.61 U/gHb; P < 0.05), catalase activity (1.86 ± 0.18 vs 2.43 ± 0.08 U/gHb; P < 0.05) and whole blood glutathione levels (1.25 ± 0.21 vs 2.28 ± 0.08 mg/gHb; P < 0.05) showing phosphamidon-induced oxidative stress. Phosphamidon exposure markedly suppressed humoral immune response as assessed by antibody titer to ovalbumin (4.71 ± 0.51 vs 8.00 ± 0.12 -log2; P < 0.05), and cell-mediated immune response as assessed by leukocyte migration inhibition (25.24 ± 1.04 vs 70.8 ± 1.09%; P < 0.05) and macrophage migration inhibition (20.38 ± 0.99 vs 67.16 ± 5.30%; P < 0.05) response. Phosphamidon exposure decreased IFN-у levels (40.7 ± 3.21 vs 55.84 ± 3.02 pg/mL; P < 0.05) suggesting a profound effect of phosphamidon on cell-mediated immune response. A phosphamidon-induced increase in TNF-α level (64.19 ± 6.0 vs 23.16 ± 4.0 pg/mL; P < 0.05) suggests a contributory role of immunocytes in oxidative stress. Co-administration of N-acetylcysteine (3.5 mmol/kg, orally) with phosphamidon attenuated the adverse effects of phosphamidon. These findings suggest that oral N-acetylcysteine treatment exerts protective effect and attenuates free radical injury and immune dysfunction caused by subchronic phosphamidon exposure.

Clinical Characteristics of Acute Dichlorvos Poisoning in Korea

Purpose: Dichlorvos has been in widespread use as an organophosphate (OP) insecticide compound. The purpose of this study was to access the epidemiology and clinical features of dichlorvos in Korea. Methods: This was a 38 multi-center prospective study of dichlorvos poisoning using surveys, a structural reporting system and review of hospital records from August 2005 to July 2006. A total of 54 patients with acute dichlorvos poisoning on a national basis were enrolled. We analyzed the epidemiologic characteristics and clinical manifestations of dichlorvos poisoning. In addition, the clinical features of dichlorvos poisoning were compared with others OP compounds. Results: During the study period, compounds involving pure OP poisoning were dichlorvos (22.7%), methidathion (8.4%), and phosphamidon (6.7%). In acute dichlorvos poisoning, all ingestion routes were oral. Intentional poisoning involved 74.1% of cases. The common initial complaints involved gastrointestinal (64.8%), systemic (61.1%), central or peripheral nervous system (53.7%), and respiratory symptoms (50.0%). The median arrival time to hospital after dichlorvos poisoning was 2.6 hours and mean hospitalization duration was 7.1 days. 2-PAM was administered in 35 patients in mean doses of 6.3 g/day intravenously. Atropine was administered in 30 patients with a mean dose of 62.8 mg/day (maximal 240 mg/day). Overall mortality rate for dichlorvos poisonings were 14.8% (8/54). Immediate causes for death included sudden cardiac arrest or ventricular dysrhythmias (50%), multi-organ failure (25%), acute renal failure (12.5%), and unknown causes (12.5%). Conclusion: When compared to previous reports, dichlorvos poisoning displayed relatively moderate severity. The presence of a lower GCS score, altered mental status, serious dysrhythmias, systemic shock, acute renal failure, and respiratory complications upon presentation were associated with a more serious and fatal poisoning.

Effect of phosphamidon on the testes of albino rats: a histological study.

The present study shows the qualitative and quantitative histological changes in testes of albino rats treated with two doses of phosphamidon 35 and 50 parts per million(ppm) for 1 month time period. Rats were treated by drinking water containing 35 ppm (low dose) and 50ppm (high dose) concentration of phosphamidon for 30 days. After 30 days, they were sacrificed, the testes were fixed in vivo and were taken out. The histological slides of these testes were prepared and were studied under light microscope. The decrease in the weight of testes and diameter of seminiferous tubules, increase in the interstitial space, the decrease in the numbers of germ cells and supporting cells, Cytoplasmic vacuolization of the germ cells, distortion of seminiferous tubules were the findings of present study. phosphamidon seems to be toxic on male reproductive system if exposed for prolong period. The awareness regarding the impact of phosphamidon should be given to farmer and they should be encouraged to practice biological means to control pests and herbs instead of these harmful chemical compounds.

Immunotoxicity of phosphamidon following subchronic exposure in albino rats.

Effect of subchronic doses of phosphamidon exposure on humoral and cell mediated immune (CMI) responses were studied in male albino rats using SRBC, ovalbumin and KLH as antigens. Humoral immune responses were assessed by estimating antibody titre against antigen and splenic plaque forming cells (PFC) assay. CMI responses were studied by using leucocyte migration inhibition (LMI), macrophage migration inhibition (MMI) and delayed type hypersensitivity (DTH) response. Results obtained in the present study revealed marked suppression of humoral and CMI responses in a dose dependent pattern. Hence, suppression of immune responses by phosphamidon even at subchronic doses is clearly an important aspect for its safety evaluation.

Influence of the organophosphorus insecticide phosphamidon on lentic water.

The inland freshwater resources are being increasingly subjected to heavy stress as a result of indiscriminate dumping of industrial wastes, domestic sewage and agricultural run-off causing deterioration of the water quality and adverse impact on aquatic biota. Pesticides drained to the aquatic environment are primarily of agricultural origin. Phosphamidon (widely used organophosphate pesticide in paddy field) significantly reduced dissolved oxygen (DO) at 1.8 mg/l exposure and reduced alkalinity at 0.9 and 1.8 mg/l. Hardness also reduced gradually but not significantly. Free carbondioxide was increased significantly at 1.8 mg/l of the insecticide compared to control. The insecticide had no influence on pH and temperature. There was maximum reduction of phytoplankton and zooplankton population at 1.8 mg/l of phosphamidon. Though gradual reduction of plankton community was also noticed at different lower concentrations of pesticides but in case of phytoplankton an abrupt reduction (about 50% of the control) was observed. The normal behaviour and feeding rate of air breathing teleost, Channa punctatus was also hampered. Therefore, phosphamidon even at low concentrations may create disorders in the aquatic ecosystem.

Effect of dimecron on the blood parameters of Heteropneustes fossilis.

The effects of an organophosphate insecticide. dimecron. has been studied on certain haematological parameters, viz., haemoglobin concentration, RBC number, haematocrit, O2 carrying capacity of blood, etc. of Heteropneustes fossilis following exposures to the LC50 for 24 h and 96 h and 1/10 and 1/50 parts of 96 h LC50 for 90 days. There was a significant decrease in the Hb%, RBC number, HCt% and O2 carrying capcity of blood. But, there was significant increase in the MCH and MCV values following both acute and chronic exposures. The results indicate possible induction of anaemia in the exposed fish.

Intermediate Myasthenia Syndrome Following Organophosphate Intoxication

BACKGROUND: Intermediate myasthenia syndrome(IMS) is thought to have clinical importance because it may cause sudden respiratory failure during the recovery phase of a cholinergic crisis of organophosphate poisoning. We designed this study to identify the prevalence, the inducing agent, clinical predictor, and the proposed treatment of IMS. METHODS: Patients who had admitted with the diagnosis of acute organophosphate poisoning from 1992 to 1998 at two teaching hospitals were enrolled in this study. We selected the cases of IMS based on a review of medical records using modified He's criteria. RESULTS: Twelve(12) out of 110 patients with acute organophosphate poisoning were diagnosed for a prevalence at 10.9%. The drug inducing IMS were identified as dichlorvos, fenthion, EPN, methidathion, and phosphamidon. The occurrence of IMS was not related to either the initial treatment with atropine and pralidoxime, or the level of serum cholinesterase. Complications were pneumonia, sepsis, pancreatitis, and pseudomembranous colitis, etc. Eleven(11) patients were discharged without sequelae, and one patient was discharged as a hopeless care. CONCLUSION: This study suggests that IMS is not rare, so close observation is required to detect IMS in organophosphate-poisoning patients. Also, more studies are required to find predictors and treatments.

Male reproductive toxicity of phosphamidon: histopathological changes in epididymis.

Phosphamidon, a neurotoxic insecticide, was tested for male reproductive toxicity with special reference to the epididymis. The insecticide was fed to Wistar strain male albino rat at 35 ppm concentration in drinking water ad libitum for 30 days. After vascular perfusion, thin slices of caput and cauda epididymidis were embedded in plastic, cut at 1 micron thickness and stained in toluidine blue for light microscopic observation. Principal cells of the caput epididymidis were vacuolarized and seen to pinch off fragments apically. In the proximal cauda the clear cells increased in height and in the size of the secondary lysosomal granules. In the distal cauda the clear cells appeared swollen out of proportion. Phosphamidon appears to affect the principal cells indirectly through its toxic effect on the Leydig cells; the clear cells of the cauda appear to be directly vulnerable to the toxic action of the pesticide.

Interaction of organophosphorus insecticides phosphamidon & malathion on lipid profile & acetylcholinesterase activity in human erythrocyte membrane.

The organophosphorus insecticides phosphamidon and malathion were found to inhibit the activity of human acetylcholinesterase in vitro, in the human erythrocyte membrane. Lineweaver-Burk analysis indicated that the insecticide induced inhibition of acetylcholinesterase activity was uncompetitive in nature. The total lipid, cholesterol and phospholipid contents of erythrocyte membranes were reduced following phosphamidon and technical malathion treatment, while the level of lipid peroxidation was raised following malathion treatment.

Acetylhomocysteine thiolactone protection against phosphamidon-induced alteration of regional superoxide dismutase activity in the central nervous system and its correlation with altered lipid peroxidation.

Phosphamidon intoxication (2 mg/kg body wt./day for 7 days) inhibited SOD activity, but enhanced the lipid peroxidation in various CNS regions. Administration of cithiolone (8 mg/kg body wt./day, ip for 7 days), however, elevated SOD activity and depleted lipid peroxidation. Interestingly, no significant change was observed either in SOD activity or in lipid peroxidation following simultaneous administration of phosphamidon and cithiolone.

Effects of organophosphorus insecticide phosphomidon on antioxidant defence components of human erythrocyte and plasma.

Effect of organophosphorus insecticide, phosphomidon (250 and 500 ppm) on human erythrocyte and plasma were studied in vitro to get insight into the cellular antioxidant defence mechanism and malondialdehyde formation. The antioxidant defence system of erythrocyte was altered as evident by depression of glutathione reductase, glucose 6 phosphate dehydrogenase, whereas the level of reduced glutathione, glutathione peroxidase, glutathione-S-transferase, superoxidedismutase and catalase were stimulated. In the case of plasma fraction, glutathione reductase, glutathione peroxidase, glutathione-s-transferase, glucose-6-phosphate dehydrogenase, superoxide dismutase and levels of reduced glutathione were significantly depressed and the malondialdehyde formation and catalase activity were elevated indicating the less adaptive response of plasma to protect it from oxidative damage.

Individual and combined toxicity of common pesticides to teleost Puntius conchonius Hamilton.

Individual and combined toxicity of three pesticides, endosulfan, phosphamidon, and aldicarb was evaluated in P. conchonius. The 48 hr LC50 was 21.36 and 446.5 ppm respectively for endosulfan and phosphamidon. When tested jointly, 48 hr LC50 for different ratios of these pesticides were 0.332 (IE:3P), 0.224 (IE:1P), and 0.178 ppm (3E:1P). The cotoxicity coefficients for these combinations were 1793, 3986, and 10009, respectively. An equitoxic mixture of endosulfan, phosphamidon, and aldicarb yielded a 48 hr LC50 of 130.5 ppm. An enhanced toxic impact is indicated when the pesticides are present together rather than as individual compounds.

Regional alterations in the monoamine levels, monoamine oxidase activity & neurobehavioural effects in rats treated with Dimecron (phosphamidon).

Monoamine levels, MAO activity and neurobehavioral perturbations were studied in albino rats intoxicated with Dimecron i.e., phosphamidon (2.0 mg/kg b wt, ip x 7 days). Open field behaviour (OFB) of the rats was examined thrice a day for seven days. Significant depletion in DA, NE and 5-HT, and enhancement of MAO were found in various regions of the central nervous system (CNS) on the 7th day. Daily decrease was observed in ambulation, rearing and preening responses, with maximum decrement on the seventh day of Dimecron intoxication.

Acute neurobehavioural toxicity of phosphamindon and its drug-induced alteration.

Phosphamidon, a systemic organophosphate insecticide, (1.4 mg/kg - dose 1/4th of LD50 given ip), produced several autonomic, neurological and behavioral effects in mice with peak effects being at 15 min. Similar dose in rats also abolished conditioned avoidance response. Pre-treatment with atropine, iproniazid, alpha-methyl-p-tyrosine, p-chlorophenylalanine or thiosemicarbazide reduce many of these effects. This suggests that phosphamidon toxicity involves the central cholinergic, adrenergic, serotonergic and GABAergic systems in addition to peripheral cholinergic effects.