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Lancet. Author manuscript; available in PMC 2008 April 9. Published in final edited form as: doi: 10.1016/S0140-6736(05)67598-8. | PMCID: PMC2291237 UKMSID: UKMS1631 |
Differences between Organophosphorus Insecticides in Human Self-Poisoning Michael Eddleston,1,2 Peter Eyer,3 Franz Worek,4 Fahim Mohammed,2 Lalith Senarathna,2 Ludwig von Meyer,5 Edmund Juszczak,6 Ariyasena Hittarage,7 Shifa Azher,8 Wasantha Dissanayake,7 MH Rezvi Sheriff,2 Ladislaus Szinicz,4 Andrew H Dawson,9 and Nick A Buckley10 1South Asian Clinical Toxicology Research Collaboration, Centre for Tropical Medicine, University of Oxford, England 2Ox-Col Collaboration, Department of Clinical Medicine, University of Colombo, Sri Lanka 3Walther Straub Institute of Pharmacology and Toxicology, Ludwig Maximilians University, Munich, Germany 4Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany 5Institute of Legal Medicine, Ludwig Maximilians University, Munich, Germany 6Centre for Statistics in Medicine, Wolfson College, University of Oxford, England 7Anuradhapura, North Central Province, Sri Lanka 8Polonnaruwa General Hospitals, North Central Province, Sri Lanka 9Department of Clinical Medicine, University of Peradeniya, Sri Lanka 10Department of Clinical Pharmacology and Toxicology, Canberra Clinical School, ACT, Australia Background Although there are more than 100 organophosphorus (OP) insecticides, many textbooks consider OP poisoning to be a single entity, distinguished only by the OP’s lethal dose in animals. Methods We prospectively studied 802 patients with chlorpyrifos, dimethoate, or fenthion self-poisoning admitted to three Sri Lankan hospitals. Blood cholinesterase activity and OP concentration were measured to quantify both the OP and the patients’ response to OP and therapy. Clinical outcomes were recorded for each patient. Findings The poisoning syndrome varied markedly: compared to chlorpyrifos, dimethoate or fenthion produced significantly higher case fatality [chlorpyrifos 8.0%; dimethoate 23.1%, odds ratio (OR) 3.5 (95% CI 2.2-5.4); fenthion 16.2%, OR 2.2 (1.2-4.2)] and intubation rate [chlorpyrifos 15.0%; dimethoate 35.2%, OR 3.1 (2.1-4.4); fenthion 31.3%, OR 2.6 (1.6-4.2)]. Dimethoate poisoned patients died sooner than those ingesting other OPs and with refractory hypotension. Fenthion poisoning initially caused few symptoms but later caused a higher rate of respiratory paralysis. AChE inhibited by fenthion or dimethoate responded poorly to pralidoxime compared AChE inhibited by chlorpyrifos. Interpretation OP insecticide poisoning cannot be considered as a single entity. This study demonstrates major differences in clinical course and syndrome, response to oximes, and outcome for three OPs. It also shows that animal toxicity does not predict human toxicity since, although chlorpyrifos is most toxic in rats, it was least toxic in humans. Each OP should be considered as an individual poison; further studies may indicate that patients will benefit from management protocols developed for particular OPs. Organophosphorus (OP) insecticide self-poisoning is a major global health problem, 1,2 with hundreds of thousands of deaths each year. 3,4 Although the majority of deaths occur in the developing world, 4 it is also an important cause of fatal self-poisoning in developed countries. 5-7OPs inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. 8 AChE inhibition results in overstimulation of acetylcholine receptors in the autonomic nervous system, neuromuscular junction, and central nervous system (CNS). Management of severe poisoning is difficult, requiring intensive care and use of atropine and oxime cholinesterase reactivators. 9-12 In particular, management is complicated by the lack of clinical trial evidence to guide treatment, with no clear evidence for benefit from any therapies other than oxygen, atropine and diazepam. 13Textbooks, review articles, and research papers have traditionally considered acute OP poisoning to be a homogeneous entity. They do not provide specific treatment advice for particular OPs, 9-12 despite wide variation in animal toxicity, fat solubility, metabolism, selectivity for AChE over other serine esterases, side groups attached to the phosphate (diethyl or dimethyl), and speed of ageing, that may all influence severity of poisoning and response to treatment. 14The system used most widely for differentiating OPs is a World Health Organization (WHO) method based on toxicity in rats after oral dosing. 15 This scheme was developed for occupational poisoning but has been used to ban pesticides that cause frequently deaths from self-poisoning 16 and to identify highly toxic pesticides. 9,11,17,18 The aim of this study was to determine whether OPs differ in the form and severity of poisoning they cause and whether the WHO classification system accurately predicts toxicity in humans. Patients Patients were seen on admission to three Sri Lankan hospitals as part of a cohort study of acute self-poisoning that started 31st March 2002 in Anuradhapura, 4th June 2002 in Polonnaruwa, and 23rd November 2002 in Kurunegala. Patients were seen until 19th February 2003 in Kurunegala and 25th May 2004 in Anuradhapura and Polonnaruwa. Patients were included in this study if they had a history of chlorpyrifos, dimethoate or fenthion ingestion as indicated by the patient or relatives, the transferring doctor, or the pesticide bottle. Patients who ingested more than one OP or other poisons in addition to the OP (except for alcohol) were excluded from the analysis. Patients remained under the care of the consultant physicians. Management protocols were agreed between the ward doctors and study team. Decisions about intubation and transfer of patients to intensive care were made by the medical team independently of the study doctors. All decisions were made on the basis of the patient’s clinical condition and did not reflect the particular OP ingested. Atropine was administered as required following a standard protocol. 19 Symptomatic patients received pralidoxime chloride 1g bolus followed by further bolus doses of 1g q6h for 1-3 days as determined by the consultant physician. Once stable, patients or their relatives were approached concerning recruitment to a RCT of activated charcoal that was nested into the cohort. All patients, whether recruited to the RCT or not, were seen regularly by full time study doctors at least every three hours and more according to clinical need. Patients were also seen on a study ward round twice each day (0830, 2030) at which time their condition was recorded in a handheld Compaq iPAQ computer using a specifically written database. Significant events (intubation, seizures, death) were recorded at the time of the event. The patients’ condition over the previous 12hrs was reviewed at each ward round. Patients were first managed on the medical ward. Seriously ill patients, as judged by the ward’s medical staff, were transferred to the intensive care unit (ICU) as a bed became available. Each hospital had 2-8 ICU beds for medical patients; many were filled with OP poisoning patients 20 and there was always difficulty in obtaining a bed. Criteria for intubation were tidal volume less than 180ml/breath using a Wright’s respirometer, respiratory rate less than 10 breaths/minute, or failure of a Guedel airway to preserve airway function. Arterial blood gas measurements were not available to guide therapy. Hypotensive patients, not responding to atropine and fluid resuscitation, were treated with dopamine plus dobutamine as necessary. Norepinephrine and epinephrine infusions were not used in the study hospitals; bolus epinephrine was only administered for cardiac arrests. Treatment was started on the ward in all cases and continued in the ICU as bed availability permitted. Ethics approval was obtained from the Oxfordshire Clinical Research Ethics Committee, UK, and the Faculty of Medicine Ethics Committee, Colombo University, Sri Lanka. Toxicological analysis Blood samples were taken from a subset of patients recruited to the RCT and used to validate the history taken from the whole cohort. Admission plasma samples (taken a median time post-ingestion of 3-4 hours for all three OPs) were assayed for BuChE activity (to confirm exposure) and OP concentration in 433 patients (240 chlorpyrifos, 136 dimethoate, 57 fenthion) recruited to the RCT. Using 50% reduction of BuChE as a cut off, significant poisoning was found in 90.7% of chlorpyrifos, 77.7% of dimethoate, and 83% of fenthion patients. Among these patients, the alleged OP was detected in the plasma of 95.5% of chlorpyrifos, 85.3% of dimethoate, and 95.2% of fenthion patients. Red cell AChE levels were assayed in serial samples taken from 90 consecutive symptomatic patients in the RCT (57 with chlorpyrifos, dimethoate or fenthion) during two periods (9th May to 10th July 2002 and 2nd December to 26th December 2002). Lab assay capacity limited the number of samples that could be handled and determined the relatively short period of sampling while automated analyses were being set up. For measurement of AChE, a 0.2ml EDTA blood sample was diluted at the bedside into 4ml of cooled saline and frozen to -20C. Plasma was separated, frozen at -20C, and sent to Munich with matched AChE samples for analysis. AChE activity was determined according to a modified Ellman method. 21 Reactivatability of RBC-AChE (ageing) and BuChE were assessed as described. The within-run precision of native and 94% inhibited AChE was 0.95 and 4.24 CV%, respectively. 21Organophosphates in plasma were quantified by reversed phase HPLC after n-hexane extraction along with an internal standard (chlorpyrifos and fenthion) or deproteinisation with trichloroacetic acid (dimethoate) with UV detection at 288 and 200 nm, respectively. The recoveries, CVs and LOQs for chlorpyrifos (10 μM), fenthion (10 μM) and dimethoate (100 μM) in spiked plasma samples were 75% (CV 3.7%, LOQ 0.1 μM), 77% (CV 3.8%, LOQ 0.1 μM) and 97% (CV 2.1%, LOQ 1 μM), respectively. Statistics The primary data analysis was performed in SPSS for Windows 22 and Stata. 23 Demographic factors and clinical characteristics were summarised using counts (percentages) for categorical variables and the median (interquartile range [IQR]) for non-normally distributed continuous variables. Case fatality (and need for intubation) in the dimethoate and fenthion groups was compared with chlorpyrifos by calculating odds ratios and 95% confidence intervals (CI). CIs were calculated using the recommended Wilson method, CIA software. 24 We used logistic regression models to investigate the effects of age, gender, and charcoal administration on mortality. Between 31 March 2002 to 26 May 2004, 5585 poisoned patients were reviewed on admission to the adult medical wards. 1193/5585 (21.4%) had a history of OP insecticide self-poisoning. All were approached for recruitment to an RCT of activated charcoal. 937 (78.5%) were recruited. The RCT was stopped in October 2004 after the planned final interim analysis showed no effect of either single or multiple dose activated charcoal on death. 25Variable toxicity with the common OP insecticides Two-thirds of OP-poisoned patients (802/1193; 67.2%) reported ingesting one of three OPs: 439 chlorpyrifos (36.8%), 264 dimethoate (22.1%), and 99 fenthion (8.3%). The groups were similar at baseline ( table 1). 147 patients (12.3%) ingested unknown cholinesterase inhibitors while 244 (20.5%) ingested other OPs or more than one OP. | Table 1Demographic and admission characteristics following admission to hospital with self-poisoning by OP |
There were clear differences in human poisoning caused by the OPs ( table 2) despite similar rat toxicities and their classification as WHO Class II moderately hazardous pesticides. 15 Dimethoate or fenthion poisoning was more severe than chlorpyrifos poisoning: the case fatality for chlorpyrifos was 35/439 (8.0%; 95% confidence intervals 5.8 to 10.9), dimethoate 61/264 (23.1%; 18.4 to 28.6), fenthion 16/99 (16.2%; 10.2 to 24.7). The odds ratio [OR] (95% CI) of death after dimethoate or fenthion compared to chlorpyrifos was 3.5 (2.2 to 5.4) and 2.2 (1.2 to 4.2), respectively. | Table 2Outcomes following admission to hospital with self-poisoning by OP (plus admission characteristics for fatalities) |
The need for intubation was more common with dimethoate and fenthion ( table 2); the proportion of patients requiring intubation with chlorpyrifos was 66/439 (15.0%; 12.0 to 18.7), dimethoate 93/264 (35.2%; 29.7 to 41.2), and fenthion 31/99 (31.3%; 23.0 to 41.0). The OR for intubation for dimethoate and fenthion compared to chlorpyrifos was 3.1 (2.1 to 4.4) and 2.6 (1.6 to 4.2), respectively. Seizures were rare for all three OPs: chlorpyrifos 8/439 (1.8%; 0.79 to 3.56), dimethoate 0/264 (0%; 0.0 to 1.4), and fenthion 5/99 (5.1%; 1.7 to 11.4). Timing and mode of death The mode and timing of death differed markedly between OPs. Matched times of ingestion and death were available for 107/112 patients who died (95.5%; table 2). Median time to death varied from 24 hrs with dimethoate, to 82 hrs with chlorpyrifos, and 192 hrs with fenthion ( and table 2). Three deaths from ingesting chlorpyrifos (3/33; 9%) and four from dimethoate (4/60; 7%) occurred within six hrs of ingestion due to the acute cholinergic effects of the poisoning. In contrast, no fenthion poisoned patients died within 24hrs of ingestion. Unlike chlorpyrifos and fenthion poisoning, many deaths in dimethoate poisoned patients (35/60; 58%) occurred 12-48hrs after ingestion from refractory hypotensive shock (). Most presented with low GCS, poor respiratory function requiring mechanical ventilation, and hypotension requiring vasopressers and atropine. Patients with fatal fenthion poisoning were often asymptomatic on admission. They initially required little atropine but some then developed recurrent cholinergic crises requiring atropine and/or exhibited peripheral respiratory failure. No chlorpyrifos or dimethoate poisoned patients who had mild symptoms on presentation died from delayed respiratory arrest. Deaths from fenthion (10/14, 71%) or chlorpyrifos (14/33, 42%) often occurred late, after five days, due to complications of long term ventilation or the respiratory or neurological complications of events that occurred before admission. Such late deaths were uncommon with dimethoate (4/60, 7%). Reasons for the variable human toxicity The differential toxicity is unlikely to be due to patient differences since the groups were similar ( table 1) except for a marginal excess of men taking chlorpyrifos. However, this should increase the chlorpyrifos case fatality since deaths are more common in men. 26 Indeed, logistic regression analysis adjusting for gender, age, and charcoal administration increased the OR of death for dimethoate and fenthion, compared to chlorpyrifos, to 4.34 (2.66 to 7.09) and 3.17 (1.58 to 6.34), respectively. There were clear differences on admission in the condition of patients who died ( table 2). Patients with dimethoate poisoning were more ill than those ingesting fenthion or chlorpyrifos. Seven of 16 (44%) fatal fenthion cases and 6/35 (17%) fatal chlorpyrifos cases had a normal GCS on admission; only 2/61 (3%) fatal dimethoate cases had a normal GCS. 61% of dimethoate and 40% of chlorpyrifos cases had a GCS of 3/15 on admission; only 13% of fenthion cases had this GCS. Differences between OP insecticides We wondered whether the variable toxicity might be due to the formulation of the OPs and therefore investigated how each OP was prepared. We were unable to find any notable differences. Each was sold as 100-400 mls of an emulsifiable concentrate with 40-50% active ingredients ( table 3). 40-50% xylene solvent was used for each OP; however, some chlorpyrifos and dimethoate formulators replaced part of the xylene with cyclohexanone or petroleum fractions. | Table 3Characteristics of the three OP insecticides |
Differences between the OPs themselves might therefore account for the differential toxicity. The OPs differ in their chemistry - in particular, dimethoate and fenthion are dimethyl OPs while chlorpyrifos is a diethyl OP (, table 3). We assessed whether differential inhibition of cholinesterases or response to oximes might explain the variable toxicity. Differences in the human response to OP and therapy Selecting only patients with significant poisoning (BuChE <3000mU/ml and detectable OP), median BuChE on admission was lower after chlorpyrifos (33.5) and fenthion (0.0) than dimethoate (1129; table 2). Remarkably, despite the lesser BuChE inhibition by dimethoate, its median concentration was far higher (355.5μM) than fenthion or chlorpyrifos (4.86μM, 1.28μM). We serially sampled all 32 patients with chlorpyrifos (18), dimethoate (10) and fenthion (4) self-poisoning who had BuChE <3000mU/ml and AChE measured at <300mU/μmolHb on admission. BuChE, red cell AChE, AChE aging, and plasma OP concentrations were assayed before and after giving an initial 1g dose of pralidoxime. Quite different responses to OP and oxime were apparent (representative cases are shown in ). Median AChE level on admission in these patients was similar for all three OPs (normal 600mU/μmolHb; chlorpyrifos 63.5, dimethoate 69.0, fenthion 64.2; table 2). This contrasts markedly with BuChE activity that was very low with chlorpyrifos and fenthion but not dimethoate. There were clear differences in response to pralidoxime. By one hour, median AChE levels in chlorpyrifos poisoning had increased by 328mU compared to only 41mU and 4mU with dimethoate and fenthion ( table 2). At 12hrs, median AChE was 249mU above admission for chlorpyrifos compared to -27mU and -22mU for dimethoate and fenthion. Significant ageing had already occurred on admission for dimethoate and fenthion with a median of 72% and 70% of AChE aged; in contrast, only 19% of chlorpyrifos-inhibited AChE was aged ( table 2). Ageing continued until a median of 85% and 86% of dimethoate and fenthion inhibited AChE had aged at 12hrs; pralidoxime partially prevented further aging in chlorpyrifos poisoning. Complete aging occurred by 24hrs in most cases of dimethoate and fenthion poisoning (), making oximes thereafter completely ineffective. OP insecticide self-poisoning is a major global public health problem, causing hundreds of thousands of deaths each year. 3,4 Current treatment is only partially effective, with case fatality often greater than 10% in even the best ICUs. Part of the problem is that there is little evidence on which to base therapy. 27 But another is that all OPs have been grouped together, with no attempt being made to develop OP specific management protocols. Although the basic mechanism of toxicity is thought to be the same for all OPs, this study found major differences in the clinical course of humans poisoned by three particular OPs despite identical treatment. The differences are fundamentally important for management. The study also shows that the relative human toxicity of OPs may not be related to animal toxicity. The widely used approach of differentiating OPs according to their animal LD50 did not accord with human toxicity and is probably of limited value in risk assessment or management of acute human poisoning. Dimethoate poisoning produced a different clinical syndrome to the other OPs. Some patients were deeply unconscious on admission despite having AChE >10-20% of normal. Most textbooks suggest that greater AChE inhibition is required for severe clinical features of poisoning. Severely poisoned patients were hypotensive on admission and died from refractory hypotension while being ventilated. The reason for this different presentation is not known 28,29 but may be related to the very high blood concentration of this aliphatic OP. The high plasma dimethoate concentration is probably due to the low fat solubility of dimethoate ( table 3) causing a much lower volume of distribution for dimethoate compared to the two other fat soluble OPs. The majority of fenthion deaths and many chlorpyrifos deaths occurred after several days of ventilation in ICU. The deaths were often due to complications of pesticide aspiration and hypoxic brain injury before hospital admission or the sudden respiratory arrest of the intermediate syndrome, in addition to the complications of long term ventilation. The rate of onset for each OP will determine whether respiratory arrests occur pre-hospital or after several days in hospital. The known toxicology of the solvents, 30 and the predominant use of xylene for all three OPs, makes it unlikely that solvents were responsible for the variable toxicity. We were unable to find any evidence that differences in the formulations’ taste and palatability might explain the differences in toxicity. In the absence of conclusive clinical trial data, there has been extensive debate about the effectiveness of oximes in OP poisoning. 31-33 Asian doctors have reported no benefit from pralidoxime; 34,35 however, a 250mg bolus of obidoxime (equivalent to pralidoxime 2g) clearly reactivates AChE inhibited by the diethyl OP parathion. 5,31,36 We found that patients poisoned by one diethyl OP responded well to pralidoxime while those poisoned by two dimethyl OPs responded poorly. This suggests that uncertainty about oxime effectiveness is likely to be due to confounding from studying OPs as a group rather than individual compounds. The dose of pralidoxime used was lower than the current WHO recommended dose. 37 We do not think that this was responsible for its poor efficacy in dimethoate or fenthion poisoning - studies in Munich with obidoxime 250mg have also shown a poor effect in dimethoate poisoning, with complete aging occurring within 20hrs (see in ref 31). The failure of pralidoxime to reactivate dimethoate-inhibited AChE did not appear to be due to its high blood concentration since a similar failure was noted with fenthion which has a 100-fold lower concentration. The low dose did appear to be sub-optimal for chlorpyrifos poisoning, allowing some AChE to become re-inhibited and aged after the initial response. High dose oxime infusions in Germany were effective at obtaining sustained AChE reactivation and slowing aging with the diethyl parathion (compare with in ref 31). However, the fact that our patients received only low doses of pralidoxime does not explain the differences in human toxicity. Higher doses may have further decreased the toxicity and mortality of chlorpyrifos poisoning, but are unlikely to have markedly benefited fenthion and dimethoate poisoned patients. Admission AChE or BuChE levels cannot be used to predict outcome or severity. There was variability between OPs in the degree of inhibition of BuChE and AChE on admission ,. BuChE values were zero for many symptomatic chlorpyrifos and fenthion poisoned patients but often above 20% for severe dimethoate poisoning cases. The rate of AChE inhibition also differed between OPs, being rapid with chlorpyrifos such that the nadir AChE value occurred on admission. In contrast, the nadir AChE value in dimethoate and fenthion poisoning occurred after 12-24hrs (). This is likely to be due to variation in the speed of conversion of the thion ‘pro-poisons’ into active oxons and their rate of AChE inhibition. 38Some textbooks state that the onset of symptoms is delayed with thions compared to oxons that do not require activation. However, the variation in time to nadir AChE with these OPs indicates that it is not so simple. Furthermore, patients poisoned with the thion parathion can be unconscious within 30 minutes of ingestion indicating rapid activation. 36A limitation of this study is that a blood sample was not available from all patients to prove the identity of the OP ingested. However, samples were available for 54% of patients and in those with inhibited BuChE (indicating significant poisoning) the reported OP was detected in 85-95% of patients. This suggests that the history was effective for identification of the ingested OP. We chose not to exclude patients without detectable OP in the blood since we did not have blood samples for all patients and would therefore have introduced bias. This finding of significant clinical differences between OPs is important for pesticide regulation and clinical trials. Previously, regulatory decisions have sometimes been based on the WHO classification by animal toxicity. 16 However, if these findings can be generalised to all dimethyl or diethyl OPs, it may be safer to have human poisoning with slowly activated diethyl thion OPs that respond well to oximes than with dimethyl OPs that are difficult to treat, irrespective of their animal toxicity. Earlier trials of pralidoxime are confounded by the presence of both dimethyl and diethyl OPs, some of which might not respond to oximes. 31 Future trials will need to identify the OPs taken by each patient. Pralidoxime was not efficacious in reactivating AChE inhibited by the dimethyl OPs dimethoate and fenthion. More research is required to determine whether this is a general property of dimethyl OPs. Possible public health responses include banning OPs that do not respond to oximes 39 and developing new therapies that allow oximes to work better. Finally, management guidelines for OP poisoning do not differentiate between individual pesticides. This work suggests that it is not adequate to consider it as a homogeneous entity. The variable clinical syndromes and differential response to oximes suggest that future studies may lay the ground work for developing specific management protocols for individual OPs. We thank the directors, consultant physicians, medical and nursing staff of the study hospitals for their support, Mike Clarke for advice and permission to publish, Gamini Manuweera and Sumith Jayakody for information on solvents; Flemming Konradsen, Horst Thiermann and Cynthia Aaron for critical review, Renate Heilmair, Bodo Pfeiffer and Elisabeth Topoll for technical assistance, and the Ox-Col study doctors for their immensely valuable work. ME thanks David Warrell for his patient mentoring. ME is a Wellcome Trust Career Development Fellow; this work was funded by grant 063560MA from the Wellcome’s Tropical Interest Group to ME. The South Asian Clinical Toxicology Research Collaboration (SACTRC) is funded by the Wellcome Trust/ National Health and Medical Research Council International Collaborative Research Grant 071669MA. 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