Clinical Toxicology (2014), 52, 538–541 Copyright © 2014 Informa Healthcare USA, Inc. ISSN: 1556-3650 print / 1556-9519 online DOI: 10.3109/15563650.2014.909933
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Organophosphate-pyrethroid combination pesticides may be associated with increased toxicity in human poisoning compared to either pesticide alone R. IYYADURAI,1 J. V. PETER,2 S. IMMANUEL,1 A. BEGUM,1 A. ZACHARIAH,1 S. JASMINE,1 and K. P. P. ABHILASH1 1Department 2Medical
of Medicine, Christian Medical College & Hospital, Vellore, Tamil Nadu, India Intensive Care Unit, Christian Medical College & Hospital, Vellore, Tamil Nadu, India
Background. Organophosphate (OP) poisoning results in significant toxicity while pyrethroid poisoning is associated with extremely low fatality. OPs can inhibit the detoxification of pyrethroid and increase the toxicity of the combination. We assessed whether mixed OP-pyrethroid poisoning impacted outcome in human poisoning. Methods. Patients were identified from a prospectively collected institutional poisoning database that incorporates demographic and outcome data of patients presenting with poisoning. Results. Of the 1177 poisoned patients admitted over 2 years, 32 presented with OP-pyrethroid (50% chlorpyrifos-5% cypermethrin mixture) poisoning (Group 1), 26 consumed 20% chlorpyrifos (Group 2), and 32 took 15% cypermethrin (Group 3). Seizures occurred in 15.6% (n ⫽ 5) with chlorpyrifos-cypermethrin poisoning, 18.8% (n ⫽ 6) with cypermethrin poisoning, and 3.9% (n ⫽ 1) with chlorpyrifos poisoning. Ventilatory requirements were 53.5% (17/32), 42.3% (11/26), and 15.7% (5/32) in Groups 1–3, respectively. Ventilator-free days (Mean ⫾ SD) was significantly lower (p ⬍ 0.006) in Group 1 (20.9 ⫾ 9.3 days) than those in Group 2 (26.1 ⫾ 4.4 days) or 3 (27.8 ⫾ 0.6). The median (inter-quartile range) hospital stay was 5.5 (4–19.5), 5 (5–6), and 1 (0.65–1.5) days, respectively, in the three groups. Four patients died in Group 1 (13%). None died in the other groups. Conclusion. Although confounded by the varying quantity of chlorpyrifos and cypermethrin in the different formulations, patients with mixed poisoning appear to have shorter ventilator-free days than patients poisoned by either of the pesticides alone. Further studies are required comparing patients poisoned by formulations with similar quantities of OP and pyrethroid or with analysis of blood pesticide concentration on admission. Keywords Pyrethroid; Organophosphorus; Combination; Insecticides; Outcome
of detoxification of pyrethroid by OP.5 Since it is unclear whether such combinations are associated with increased toxicity in humans, we undertook this study.
Introduction Pesticide poisoning is a major problem in India. Organophosphate (OP) and pyrethroid are common agents in human poisoning. Recently, OP-pyrethroid combinations such as cypermethrin-ethion, deltamethrin-triazophos, and deltamethrin-chlorpyrifos have been introduced to overcome emerging pyrethroid resistance in agricultural pests.1 Fixed dose combinations of chlorpyrifos 50% and cypermethrin 5% manufactured in China and other illegally mixed pesticides are sold in India.2 Human OP poisoning is associated with significant mortality.3 Pyrethroids, on the other hand are considered safe, although fatalities have been reported.4 However in combination, increased toxicity is postulated due to inhibition
Patients and methods This observational study was conducted at a university affiliated hospital between January 2011 and December 2012. The study was approved by the Institutional Review Board and Ethics Committee. Adult patients (ⱖ 16 years) admitted with OP or pyrethroid poisoning were identified from a prospectively collected poisoning database that is updated daily by a research officer who enrolls all patients presenting with poisoning and records demographic data, treatment, and outcomes. Compound identification (OP and pyrethroid) was made based on the container brought by the patients’ relatives. The diagnosis of OP poisoning (pure or mixed) was corroborated by low plasma pseudocholinesterase activity (⬍ 3000 U/L; reference range: 3000–8000 U/L). Assays for compound identification were not undertaken. Since different OP compounds have differential toxicity (8), we assessed the
Received 31 January 2014; accepted 25 March 2014. This study was presented as a poster at the Royal Australasian College of Physicians (RACP) Congress in Perth, Australia, 2013. Address correspondence to Dr. J. V. Peter, Medical Intensive Care Unit, Christian Medical College & Hospital, Vellore, Tamil Nadu 632 004, India. Tel: ⫹ 91-416-228 2693. Fax: ⫹ 91 (0416) 223 2103/223 2035. E-mail: [email protected]
538
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OP pyrethroid poisoning 539 interaction between chlorpyrifos and cypermethrin, the commonly marketed OP-pyrethroid combination. Patients were categorized as mixed chlorpyrifos-cypermethrin poisoning (Group 1), pure chlorpyrifos poisoning (Group 2), and cypermethrin poisoning (Group 3). A standardized protocol was used for treatment that included supportive care (respiratory, hemodynamic, and renal) as required and atropine for OP poisoning. Oximes were not used. Ventilator-related complications, seizures, and infections were managed as per standard protocols. Ventilator-free days (VFD), considered a more reliable indicator of ventilatory needs that also incorporates mortality, were calculated as 28 minus duration of ventilation.6 In patients who died, VFD was zero. Statistical analysis Analysis was performed using STATA® version 11. Categorical variables were summarized as frequencies (percentages) and continuous variables as mean (⫾ standard deviation [SD]). Continuous variables, not normally distributed, were summarized as median (interquartile range, IQR). Comparison of continuous variables between two groups (mixed vs. chlorpyrifos; mixed vs. cypermethrin) was performed using the t-test. For categorical variables, Fisher’s exact test was used.
Results Of the 1177 patients admitted with poisoning, 640 (54.3%) were due to pesticides of which 101 were due to pyrethroids. Thirty-two patients with mixed chlorpyrifos-cypermethrin poisoning (Group 1), 26 with chlorpyrifos poisoning (Group 2), and 32 with cypermethrin poisoning (Group 3) were included (Table 1). The characteristics of these pesticides
are given in Table 2. Of note, the concentrations of the compounds were 50% chlorpyrifos with 5% cypermethrin in the OP-pyrethroid mixture, 20% chlorpyrifos in the pure OP formulation, and 15% cypermethrin in the pure pyrethroid formulation. Salivation, Lacrimation, Urination, Defecation, Gastric cramps and Emesis (SLUDGE) symptoms dominated in OP-poisoned patients. Seizures were more frequent with cypermethrin (18.8%) and mixed chlorpyrifos-cypermethrin (15.6%) poisoning than with chlorpyrifos poisoning (3.9%). Pseudocholinesterase activity was suppressed in mixed poisoning and chlorpyrifos poisoning and normal in cypermethrin poisoning (Table 1). Atropine requirement was marginally higher (120 vs. 84 mg; p ⫽ 0.26) with mixed poisoning than with chlorpyrifos poisoning. More patients required mechanical ventilation in Group 1 (53.1%) than in Group 3 (15.7%). In Group 2, 42.3% required ventilation. The duration of ventilation was marginally higher, albeit not significant (p ⫽ 0.12), with mixed poisoning than with chlorpyrifos poisoning while it was significantly (p ⬍ 0.001) higher with mixed poisoning when compared with cypermethrin poisoning (Table 1). VFD (Mean ⫾ SD) were significantly lower (p ⬍ 0.006) in Group 1 (20.9 ⫾ 9.3 days) than those in Group 2 (26.1 ⫾ 4.4 days) or 3 (27.8 ⫾ 0.6). The median (IQR) hospital stay was 5.5 (4–19.5), 5 (5–6), and 1 (0.65–1.5) days, respectively, in the three groups. Four patients died in Group 1 (13%). None died in the other groups.
Discussion This study suggests that, in human poisoning, mixed OPcypermethrin poisoning may be associated with shorter VFD when compared with chlorpyrifos or cypermethrin poisoning. None of the patients with cypermethrin or chlorpyrifos
Table 1. Demographics, clinical features, and outcome of patients with mixed (chlorpyrifos and pyrethroid) poisoning, chlorpyrifos poisoning, and cypermethrin poisoning. Variable Age, Mean (SD) Male, n (%) Volume ingested, Mean (SD) ml Seizures Salivation Pseudocholinesterase, Median, IQR Need for ventilation, n (%) Ventilation duration^, Median, IQR days Ventilation free days, Mean (SD) Hospital length of stay, Median, IQR Total atropine used, Median, IQR Died/Alive (%)
Mixed (n ⫽ 32)
Chlorpyrifos (n ⫽ 26)
P value‡
Mixed (n ⫽ 32)
Cypermethrin (n ⫽ 32)
P value‡‡
29.9 (8.4) 24 (75%) 78.3 (54.2) 5 (15.6%) 32 (100%) 93 (68.5–135) 17 (53.1%) 2 (0–8) 20.9 (9.3) 5.5 (4–19.5) 120 (72–366) 4/32 (13%)
30.1 (12.3) 18 (69%) 69.1 (42.9)† 1 (3.9%) 26 (100%) 70 (53–103) 11 (42.3%) 0 (0–1) 26.1 (4.4) 5 (5–6) 84 (72–120) 0/26 (0%)
0.53 0.77 0.25 0.21 – 0.25 0.44 0.12 0.006* 0.5 0.26 0.12
29.9 (8.4) 24 (75%) 78.3 (54.2) 5 (15.6%) 32 (100%) 93 (68.5–135) 17 (53.1%) 2 (0–8) 20.9 (9.3) 5.5 (4–19.5) 120 (72–366) 4/32 (13%)
31.3 20 (62.5%) 73.7 (74.1)†† 6 (18.8%) 0 (0%) 6797 (5438–9063) 5 (15.7%) 0 (0–0) 27.8 (0.6) 1 (0.65–1.5) 0 (0–0) 0/32 (0%)
0.31 0.42 0.40 1.0 ⬍ 0.001* ⬍ 0.001* 0.003* ⬍ 0.001* ⬍ 0.001* ⬍ 0.001* ⬍ 0.001* 0.11
SD, Standard deviation; IQR, interquartile range; n ⫽ number of patients ˆDuration of ventilation counted as zero in those who were not ventilated. ‡P values are for comparisons between mixed group (chlorpyrifos with cypermethrin combination) and chlorpyrifos group. ‡‡P values are for comparisons between mixed group (chlorpyrifos and cypermethrin combination) and cypermethrin group. †Data available only on 22 patients. ††Data available on 31 patients. *Significant results. Copyright © Informa Healthcare USA, Inc. 2014
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Table 2. Characteristics of the compounds implicated in poisoning.
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Characteristic
Chlorpyrifos with cypermethrin
Chlorpyrifos
Chlorpyrifos Cypermethrin Emulsifier A
50% w/w 5% w/w Blend of calcium salt of alkyl benzene sulfonic acid and polyethanoxy ether of nonyl phenol (5.6% w/w)
Emulsifier B Solvent
Blend of calcium salt of alkyl benzene sulfonic acid and polyethanoxy propoxy ether of fatty alcohol (2.4% w/w) Aromatic hydrocarbon 37%
Other ingredients Sold as
– 100 mL, 250 mL, 500 mL, 1 L
Cypermethrin
20% m/m Nil Alkyl phenol ethoxylate/ Alkyl aryl sulfonate (6% m/m) –
Nil 15% w/w Mixture of anionic alkylaryl sulfonate and non-anionic ethylene ether (10% w/w) –
Aromax petroleum solvent (72.5%) – 100 mL, 250 mL, 500 mL, and 1 L
Naphtha (74%) Masking fragrance (1%) 100 mL, 250 mL, 500 mL, and 1 L
Chemical structure
poisoning died, while 4 patients with mixed chlorpyrifoscypermethrin poisoning died. These results however need to be interpreted in the context of the differential concentration of the individual compounds (20% chlorpyrifos; 15% cypermethrin) as compared with the mixture (50% chlorpyrifos-5% cypermethrin). Chlorpyrifos is a WHO class II insecticide considered moderately toxic to humans.7 Chlorpyrifos poisoning is associated with early respiratory paralysis and delayed recovery.8 Case fatality with chlorpyrifos is 5.8–8%.3,9 In the current series, none of the patients with chlorpyrifos poisoning died. Cypermethrin, a synthetic (Type II) pyrethroid acts on voltage-gated sodium and chloride channels in contrast to Type I pyrethroids that predominantly delay the closure of sodium channels.4 Pyrethroids are 2250 times more toxic to insects than humans.4 The mammalian resistance to pyrethroid toxicity is due to the capacity for ester hydrolysis leading to rapid detoxification. Carboxylesterase inhibitors such as OPs may enhance the toxicity of pyrethroid by inhibiting detoxification.5 Seizures were more frequent with pyrethroid poisoning. Even in those with mixed poisoning, seizures did not persist. In mixed poisoning, the biochemical mechanism of toxicity should have resulted in potentiation of pyrethroid toxicity with protracted seizures and coma. Instead we observed predominant SLUDGE symptoms and prolonged respiratory weakness suggesting potentiation of OP toxicity rather than ongoing pyrethroid toxicity. The pesticide concentrations and the ratio of the mixtures provide insights on this (Table 2). In the only published series on mixed OP-pyrethroid poisoning that included 8 patients, predominant pyrethroid effects of choreo-athetosis, excessive salivation and seizures were observed without bradycardia or high atropine requirements.2 In contrast, in our study, although seizures were more frequent with mixed chlorpyrifos-cypermethrin poisoning than with chlorpyrifos poisoning, the dominant effects were
that of chlorpyrifos. This is not surprising as the concentration of chlorpyrifos was higher (50%) in the mixture than the pure formulation (20%). Further, the OP-pyrethroid ratio of 10:1 for chlorpyrifos-cypermethrin as compared with 1:4 for methyl parathion: lambda-cyalothrin may also explain the dominance of OP manifestations in our study and pyrethroid manifestations in the earlier study.2 In a study of farmers with pure and mixed OP-pyrethroid exposure, the inhibitory effect on acetylcholinesterase was induced to a similar extent by the OP component of the mixture as with the single OP formulation.10 Serial chlorpyrifos levels and butyrylcholinesterase activity may have helped establish the persistence of OP in the circulation with prolongation of symptoms. However this was not done and this limits the inferences.
Conclusions Chlorpyrifos-cypermethrin combination pesticides, in the currently marketed concentrations may be more toxic than chlorpyrifos alone. Given the limitations highlighted earlier, further study is warranted. Although such combinations are used to combat the increasing resistance among pests, the potential for higher toxicity to humans should encourage the search for agents with a better safety profile.
Declaration of interest The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.
References 1. Martin T, Ochou OG, Vaissayre M, Fournier D. Organophosphorus insecticides synergize pyrethroids in the resistant strain of cotton bollworm, Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae) from West Africa. J Econ Entomol 2003; 96:468–474. Clinical Toxicology vol. 52 no. 5 2014
Clinical Toxicology Downloaded from informahealthcare.com by Biblioteka Uniwersytetu Warszawskiego on 01/21/15 For personal use only.
OP pyrethroid poisoning 541 2. Tripathi M, Pandey R, Ambesh SP, Pandey M. A mixture of organophosphate and pyrethroid intoxication requiring intensive care unit admission: a diagnostic dilemma and therapeutic approach. Anaesth Analg 2006; 103:410–412. 3. Peter JV, Jerobin J, Nair A, Bennett A, Samuel P, Chrispal A, et al. Clinical profile and outcome of patients hospitalized with dimethyl and diethyl organophosphate poisoning. Clin Toxicol (Phila) 2010; 48:916–923. 4. Bradberry SM, Cage SA, Proudfoot AT, Vale JA. Poisoning due to pyrethroids. Toxicol Rev 2005; 24:93–106. 5. Hernandez AF, Parron T, Tsatsakis AM, Requena M, Alarcon R, Lopez-Guarnido O. Toxic effects of pesticide mixtures at a molecular level: their relevance to human health. Toxicology 2013; 307: 136–145. 6. Schoenfeld DA, Bernard GR. Statistical evaluation of ventilatorfree days as an efficacy measure in clinical trials of treatments for
Copyright © Informa Healthcare USA, Inc. 2014
7.
8.
9.
10.
acute respiratory distress syndrome. Crit Care Med 2002; 30: 1772–1777. Peter JV, Jerobin J, Nair A, Bennett A. Is there a relationship between the WHO hazard classification of organophosphate pesticide and outcomes in suicidal human poisoning with commercial organophosphate formulations? Regul Toxicol Pharmacol 2010; 57:99–102. Eddleston M, Mohamed F, Davies JO, Eyer P, Worek F, Sheriff MH, Buckley NA. Respiratory failure in acute organophosphate pesticide self-poisoning. QJM 2006; 99:513–522. Eddleston M, Eyer P, Worek F, Mohamed F, Senarathna L, von Meyer L, et al. Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet 2005; 366:1452–1459. He F, Chen S, Tang X, Gan W, Tao B, Wen B. Biological monitoring of combined exposure to organophosphates and pyrethroids. Toxicol Lett 2002; 134:119–124.
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Organophosphate-pyrethroid combination pesticides may be associated with increased toxicity in human poisoning compared to either pesticide alone R. IYYADURAI,1 J. V. PETER,2 S. IMMANUEL,1 A. BEGUM,1 A. ZACHARIAH,1 S. JASMINE,1 and K. P. P. ABHILASH1 1Department 2Medical
of Medicine, Christian Medical College & Hospital, Vellore, Tamil Nadu, India Intensive Care Unit, Christian Medical College & Hospital, Vellore, Tamil Nadu, India
Background. Organophosphate (OP) poisoning results in significant toxicity while pyrethroid poisoning is associated with extremely low fatality. OPs can inhibit the detoxification of pyrethroid and increase the toxicity of the combination. We assessed whether mixed OP-pyrethroid poisoning impacted outcome in human poisoning. Methods. Patients were identified from a prospectively collected institutional poisoning database that incorporates demographic and outcome data of patients presenting with poisoning. Results. Of the 1177 poisoned patients admitted over 2 years, 32 presented with OP-pyrethroid (50% chlorpyrifos-5% cypermethrin mixture) poisoning (Group 1), 26 consumed 20% chlorpyrifos (Group 2), and 32 took 15% cypermethrin (Group 3). Seizures occurred in 15.6% (n ⫽ 5) with chlorpyrifos-cypermethrin poisoning, 18.8% (n ⫽ 6) with cypermethrin poisoning, and 3.9% (n ⫽ 1) with chlorpyrifos poisoning. Ventilatory requirements were 53.5% (17/32), 42.3% (11/26), and 15.7% (5/32) in Groups 1–3, respectively. Ventilator-free days (Mean ⫾ SD) was significantly lower (p ⬍ 0.006) in Group 1 (20.9 ⫾ 9.3 days) than those in Group 2 (26.1 ⫾ 4.4 days) or 3 (27.8 ⫾ 0.6). The median (inter-quartile range) hospital stay was 5.5 (4–19.5), 5 (5–6), and 1 (0.65–1.5) days, respectively, in the three groups. Four patients died in Group 1 (13%). None died in the other groups. Conclusion. Although confounded by the varying quantity of chlorpyrifos and cypermethrin in the different formulations, patients with mixed poisoning appear to have shorter ventilator-free days than patients poisoned by either of the pesticides alone. Further studies are required comparing patients poisoned by formulations with similar quantities of OP and pyrethroid or with analysis of blood pesticide concentration on admission. Keywords Pyrethroid; Organophosphorus; Combination; Insecticides; Outcome
of detoxification of pyrethroid by OP.5 Since it is unclear whether such combinations are associated with increased toxicity in humans, we undertook this study.
Introduction Pesticide poisoning is a major problem in India. Organophosphate (OP) and pyrethroid are common agents in human poisoning. Recently, OP-pyrethroid combinations such as cypermethrin-ethion, deltamethrin-triazophos, and deltamethrin-chlorpyrifos have been introduced to overcome emerging pyrethroid resistance in agricultural pests.1 Fixed dose combinations of chlorpyrifos 50% and cypermethrin 5% manufactured in China and other illegally mixed pesticides are sold in India.2 Human OP poisoning is associated with significant mortality.3 Pyrethroids, on the other hand are considered safe, although fatalities have been reported.4 However in combination, increased toxicity is postulated due to inhibition
Patients and methods This observational study was conducted at a university affiliated hospital between January 2011 and December 2012. The study was approved by the Institutional Review Board and Ethics Committee. Adult patients (ⱖ 16 years) admitted with OP or pyrethroid poisoning were identified from a prospectively collected poisoning database that is updated daily by a research officer who enrolls all patients presenting with poisoning and records demographic data, treatment, and outcomes. Compound identification (OP and pyrethroid) was made based on the container brought by the patients’ relatives. The diagnosis of OP poisoning (pure or mixed) was corroborated by low plasma pseudocholinesterase activity (⬍ 3000 U/L; reference range: 3000–8000 U/L). Assays for compound identification were not undertaken. Since different OP compounds have differential toxicity (8), we assessed the
Received 31 January 2014; accepted 25 March 2014. This study was presented as a poster at the Royal Australasian College of Physicians (RACP) Congress in Perth, Australia, 2013. Address correspondence to Dr. J. V. Peter, Medical Intensive Care Unit, Christian Medical College & Hospital, Vellore, Tamil Nadu 632 004, India. Tel: ⫹ 91-416-228 2693. Fax: ⫹ 91 (0416) 223 2103/223 2035. E-mail: [email protected]
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OP pyrethroid poisoning 539 interaction between chlorpyrifos and cypermethrin, the commonly marketed OP-pyrethroid combination. Patients were categorized as mixed chlorpyrifos-cypermethrin poisoning (Group 1), pure chlorpyrifos poisoning (Group 2), and cypermethrin poisoning (Group 3). A standardized protocol was used for treatment that included supportive care (respiratory, hemodynamic, and renal) as required and atropine for OP poisoning. Oximes were not used. Ventilator-related complications, seizures, and infections were managed as per standard protocols. Ventilator-free days (VFD), considered a more reliable indicator of ventilatory needs that also incorporates mortality, were calculated as 28 minus duration of ventilation.6 In patients who died, VFD was zero. Statistical analysis Analysis was performed using STATA® version 11. Categorical variables were summarized as frequencies (percentages) and continuous variables as mean (⫾ standard deviation [SD]). Continuous variables, not normally distributed, were summarized as median (interquartile range, IQR). Comparison of continuous variables between two groups (mixed vs. chlorpyrifos; mixed vs. cypermethrin) was performed using the t-test. For categorical variables, Fisher’s exact test was used.
Results Of the 1177 patients admitted with poisoning, 640 (54.3%) were due to pesticides of which 101 were due to pyrethroids. Thirty-two patients with mixed chlorpyrifos-cypermethrin poisoning (Group 1), 26 with chlorpyrifos poisoning (Group 2), and 32 with cypermethrin poisoning (Group 3) were included (Table 1). The characteristics of these pesticides
are given in Table 2. Of note, the concentrations of the compounds were 50% chlorpyrifos with 5% cypermethrin in the OP-pyrethroid mixture, 20% chlorpyrifos in the pure OP formulation, and 15% cypermethrin in the pure pyrethroid formulation. Salivation, Lacrimation, Urination, Defecation, Gastric cramps and Emesis (SLUDGE) symptoms dominated in OP-poisoned patients. Seizures were more frequent with cypermethrin (18.8%) and mixed chlorpyrifos-cypermethrin (15.6%) poisoning than with chlorpyrifos poisoning (3.9%). Pseudocholinesterase activity was suppressed in mixed poisoning and chlorpyrifos poisoning and normal in cypermethrin poisoning (Table 1). Atropine requirement was marginally higher (120 vs. 84 mg; p ⫽ 0.26) with mixed poisoning than with chlorpyrifos poisoning. More patients required mechanical ventilation in Group 1 (53.1%) than in Group 3 (15.7%). In Group 2, 42.3% required ventilation. The duration of ventilation was marginally higher, albeit not significant (p ⫽ 0.12), with mixed poisoning than with chlorpyrifos poisoning while it was significantly (p ⬍ 0.001) higher with mixed poisoning when compared with cypermethrin poisoning (Table 1). VFD (Mean ⫾ SD) were significantly lower (p ⬍ 0.006) in Group 1 (20.9 ⫾ 9.3 days) than those in Group 2 (26.1 ⫾ 4.4 days) or 3 (27.8 ⫾ 0.6). The median (IQR) hospital stay was 5.5 (4–19.5), 5 (5–6), and 1 (0.65–1.5) days, respectively, in the three groups. Four patients died in Group 1 (13%). None died in the other groups.
Discussion This study suggests that, in human poisoning, mixed OPcypermethrin poisoning may be associated with shorter VFD when compared with chlorpyrifos or cypermethrin poisoning. None of the patients with cypermethrin or chlorpyrifos
Table 1. Demographics, clinical features, and outcome of patients with mixed (chlorpyrifos and pyrethroid) poisoning, chlorpyrifos poisoning, and cypermethrin poisoning. Variable Age, Mean (SD) Male, n (%) Volume ingested, Mean (SD) ml Seizures Salivation Pseudocholinesterase, Median, IQR Need for ventilation, n (%) Ventilation duration^, Median, IQR days Ventilation free days, Mean (SD) Hospital length of stay, Median, IQR Total atropine used, Median, IQR Died/Alive (%)
Mixed (n ⫽ 32)
Chlorpyrifos (n ⫽ 26)
P value‡
Mixed (n ⫽ 32)
Cypermethrin (n ⫽ 32)
P value‡‡
29.9 (8.4) 24 (75%) 78.3 (54.2) 5 (15.6%) 32 (100%) 93 (68.5–135) 17 (53.1%) 2 (0–8) 20.9 (9.3) 5.5 (4–19.5) 120 (72–366) 4/32 (13%)
30.1 (12.3) 18 (69%) 69.1 (42.9)† 1 (3.9%) 26 (100%) 70 (53–103) 11 (42.3%) 0 (0–1) 26.1 (4.4) 5 (5–6) 84 (72–120) 0/26 (0%)
0.53 0.77 0.25 0.21 – 0.25 0.44 0.12 0.006* 0.5 0.26 0.12
29.9 (8.4) 24 (75%) 78.3 (54.2) 5 (15.6%) 32 (100%) 93 (68.5–135) 17 (53.1%) 2 (0–8) 20.9 (9.3) 5.5 (4–19.5) 120 (72–366) 4/32 (13%)
31.3 20 (62.5%) 73.7 (74.1)†† 6 (18.8%) 0 (0%) 6797 (5438–9063) 5 (15.7%) 0 (0–0) 27.8 (0.6) 1 (0.65–1.5) 0 (0–0) 0/32 (0%)
0.31 0.42 0.40 1.0 ⬍ 0.001* ⬍ 0.001* 0.003* ⬍ 0.001* ⬍ 0.001* ⬍ 0.001* ⬍ 0.001* 0.11
SD, Standard deviation; IQR, interquartile range; n ⫽ number of patients ˆDuration of ventilation counted as zero in those who were not ventilated. ‡P values are for comparisons between mixed group (chlorpyrifos with cypermethrin combination) and chlorpyrifos group. ‡‡P values are for comparisons between mixed group (chlorpyrifos and cypermethrin combination) and cypermethrin group. †Data available only on 22 patients. ††Data available on 31 patients. *Significant results. Copyright © Informa Healthcare USA, Inc. 2014
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Table 2. Characteristics of the compounds implicated in poisoning.
Clinical Toxicology Downloaded from informahealthcare.com by Biblioteka Uniwersytetu Warszawskiego on 01/21/15 For personal use only.
Characteristic
Chlorpyrifos with cypermethrin
Chlorpyrifos
Chlorpyrifos Cypermethrin Emulsifier A
50% w/w 5% w/w Blend of calcium salt of alkyl benzene sulfonic acid and polyethanoxy ether of nonyl phenol (5.6% w/w)
Emulsifier B Solvent
Blend of calcium salt of alkyl benzene sulfonic acid and polyethanoxy propoxy ether of fatty alcohol (2.4% w/w) Aromatic hydrocarbon 37%
Other ingredients Sold as
– 100 mL, 250 mL, 500 mL, 1 L
Cypermethrin
20% m/m Nil Alkyl phenol ethoxylate/ Alkyl aryl sulfonate (6% m/m) –
Nil 15% w/w Mixture of anionic alkylaryl sulfonate and non-anionic ethylene ether (10% w/w) –
Aromax petroleum solvent (72.5%) – 100 mL, 250 mL, 500 mL, and 1 L
Naphtha (74%) Masking fragrance (1%) 100 mL, 250 mL, 500 mL, and 1 L
Chemical structure
poisoning died, while 4 patients with mixed chlorpyrifoscypermethrin poisoning died. These results however need to be interpreted in the context of the differential concentration of the individual compounds (20% chlorpyrifos; 15% cypermethrin) as compared with the mixture (50% chlorpyrifos-5% cypermethrin). Chlorpyrifos is a WHO class II insecticide considered moderately toxic to humans.7 Chlorpyrifos poisoning is associated with early respiratory paralysis and delayed recovery.8 Case fatality with chlorpyrifos is 5.8–8%.3,9 In the current series, none of the patients with chlorpyrifos poisoning died. Cypermethrin, a synthetic (Type II) pyrethroid acts on voltage-gated sodium and chloride channels in contrast to Type I pyrethroids that predominantly delay the closure of sodium channels.4 Pyrethroids are 2250 times more toxic to insects than humans.4 The mammalian resistance to pyrethroid toxicity is due to the capacity for ester hydrolysis leading to rapid detoxification. Carboxylesterase inhibitors such as OPs may enhance the toxicity of pyrethroid by inhibiting detoxification.5 Seizures were more frequent with pyrethroid poisoning. Even in those with mixed poisoning, seizures did not persist. In mixed poisoning, the biochemical mechanism of toxicity should have resulted in potentiation of pyrethroid toxicity with protracted seizures and coma. Instead we observed predominant SLUDGE symptoms and prolonged respiratory weakness suggesting potentiation of OP toxicity rather than ongoing pyrethroid toxicity. The pesticide concentrations and the ratio of the mixtures provide insights on this (Table 2). In the only published series on mixed OP-pyrethroid poisoning that included 8 patients, predominant pyrethroid effects of choreo-athetosis, excessive salivation and seizures were observed without bradycardia or high atropine requirements.2 In contrast, in our study, although seizures were more frequent with mixed chlorpyrifos-cypermethrin poisoning than with chlorpyrifos poisoning, the dominant effects were
that of chlorpyrifos. This is not surprising as the concentration of chlorpyrifos was higher (50%) in the mixture than the pure formulation (20%). Further, the OP-pyrethroid ratio of 10:1 for chlorpyrifos-cypermethrin as compared with 1:4 for methyl parathion: lambda-cyalothrin may also explain the dominance of OP manifestations in our study and pyrethroid manifestations in the earlier study.2 In a study of farmers with pure and mixed OP-pyrethroid exposure, the inhibitory effect on acetylcholinesterase was induced to a similar extent by the OP component of the mixture as with the single OP formulation.10 Serial chlorpyrifos levels and butyrylcholinesterase activity may have helped establish the persistence of OP in the circulation with prolongation of symptoms. However this was not done and this limits the inferences.
Conclusions Chlorpyrifos-cypermethrin combination pesticides, in the currently marketed concentrations may be more toxic than chlorpyrifos alone. Given the limitations highlighted earlier, further study is warranted. Although such combinations are used to combat the increasing resistance among pests, the potential for higher toxicity to humans should encourage the search for agents with a better safety profile.
Declaration of interest The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.
References 1. Martin T, Ochou OG, Vaissayre M, Fournier D. Organophosphorus insecticides synergize pyrethroids in the resistant strain of cotton bollworm, Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae) from West Africa. J Econ Entomol 2003; 96:468–474. Clinical Toxicology vol. 52 no. 5 2014
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OP pyrethroid poisoning 541 2. Tripathi M, Pandey R, Ambesh SP, Pandey M. A mixture of organophosphate and pyrethroid intoxication requiring intensive care unit admission: a diagnostic dilemma and therapeutic approach. Anaesth Analg 2006; 103:410–412. 3. Peter JV, Jerobin J, Nair A, Bennett A, Samuel P, Chrispal A, et al. Clinical profile and outcome of patients hospitalized with dimethyl and diethyl organophosphate poisoning. Clin Toxicol (Phila) 2010; 48:916–923. 4. Bradberry SM, Cage SA, Proudfoot AT, Vale JA. Poisoning due to pyrethroids. Toxicol Rev 2005; 24:93–106. 5. Hernandez AF, Parron T, Tsatsakis AM, Requena M, Alarcon R, Lopez-Guarnido O. Toxic effects of pesticide mixtures at a molecular level: their relevance to human health. Toxicology 2013; 307: 136–145. 6. Schoenfeld DA, Bernard GR. Statistical evaluation of ventilatorfree days as an efficacy measure in clinical trials of treatments for
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7.
8.
9.
10.
acute respiratory distress syndrome. Crit Care Med 2002; 30: 1772–1777. Peter JV, Jerobin J, Nair A, Bennett A. Is there a relationship between the WHO hazard classification of organophosphate pesticide and outcomes in suicidal human poisoning with commercial organophosphate formulations? Regul Toxicol Pharmacol 2010; 57:99–102. Eddleston M, Mohamed F, Davies JO, Eyer P, Worek F, Sheriff MH, Buckley NA. Respiratory failure in acute organophosphate pesticide self-poisoning. QJM 2006; 99:513–522. Eddleston M, Eyer P, Worek F, Mohamed F, Senarathna L, von Meyer L, et al. Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet 2005; 366:1452–1459. He F, Chen S, Tang X, Gan W, Tao B, Wen B. Biological monitoring of combined exposure to organophosphates and pyrethroids. Toxicol Lett 2002; 134:119–124.
