This course deals with some important chemical poisons. Topics to be covered include those poisonings that either present frequently enough to merit attention or present infrequently but with serious consequences. Because exposure to chemicals can occur via a variety of routes decontamination decisions can be more complex than when dealing with pharmaceuticals. For some poisons envenomations a specific antidote is available. The selection of the appropriate antidote, the optimal dose and the indications for administration are important decisions to be made.

This module aims to cover the toxicology of following common or important chemicals used in agriculture:
• Organophosphates
• Paraquat
• Agents causing methaemoglobinaemia
• Other insecticides and herbicides

At the end of this module, students should be able to:
• Do a risk assessment of acute organophosphate exposure.
• Understand treatment of organophosphate poisoning.
• Understand the issues underlying treatment failure.
• Understand the chronic sequelae organophosphate poisoning.
• Understand the mechanism of toxicity of paraquat.
• Understand how this explains the delayed pulmonary manifestations of moderate paraquat toxicity
• List the most common clinical manifestations of poisoning with paraquat.
• Recognise situations where interventions are most likely to be useful.
• Understand the difference between a frequentist and a Bayesian approach to clinical trial evidence and how this alters what interventions you institute.
• Understand the mechanisms of methaemoglobinaemia
• Understand the basis of treatment with methylene blue
• Understand the issues underlying treatment failure
• Understand the spectrum of intoxication with insecticides and herbicides, in particular that some pesticides appear to have no direct toxic effects at all.
• Understand that aspiration of the pesticide and its solvent may be much worse than absorbing the pesticide from the GI tract, and that this should be factored into the risk assessment of performing GI decontamination.
• Describe the initial evaluation, stabilisation and treatment of organochlorine induced status epilepticus.

1. Davies JOJ, Eddleston M, Buckley NA.Predicting outcome in acute organophosphorus poisoning with a poison severity score or the Glasgow coma scale.QJM 2008; 101: 371-9 (fulltext)
2. Eddleston M, Dawson A, Karalliedde L, et al. Early management after self-poisoning with an organophosphorus or carbamate pesticide - a treatment protocol for junior doctors. Crit Care. 2004;8:R391-R397.(fulltext)
3. Michael Eddleston, Nick A Buckley, Peter Eyer, Andrew H Dawson Management of acute organophosphorus pesticide poisoning Lancet 2008; 371: 597–607 (fulltext)
4. Roberts DM, Aaron C. Management of acute organophosphorus pesticide poisoning. BMJ 2007;334;629-634 (fulltext)
5. Pawar KS, Bhoite RR, Pillay CP, Chavan SC, Malshikare DS, Garad SG.Continuous pralidoxime infusion versus repeated bolus injection to treat organophosphorus pesticide poisoning: a randomised controlled trial.Lancet. 2006 Dec 16;368(9553):2136-41.(fulltext)
6. Buckley NA, Karalliedde L, Dawson A, Senanayake N, Eddleston M. Where is the evidence for treatments used in pesticide poisoning? Is clinical toxicology fiddling while the developing world burns? J Toxicol Clin Toxicol. 2004;42(1):113-6.(fulltext)
7. Eddleston M, Szinicz L, Eyer P, Buckley N. Oximes in acute organophosphorus pesticide poisoning: a systematic review of clinical trials. QJM. 2002;95:275-283. (fulltext)
8. Eddleston M, Eyer P, Worek F, Mohamed F, Senarathna L, von Meyer L, Juszczak E, Hittarage A, Azhar S, Dissanayake W, Sheriff MH, Szinicz L, Dawson AH, Buckley NA. Differences between organophosphorus insecticides in human self-poisoning: a
   prospective cohort study.Lancet. 2005 Oct 22-28;366(9495):1452-9. (fulltext 1) (fulltext 2)
9. Lin JL, Leu ML, Liu YC, Chen GH. A prospective clinical trial of pulse therapy with glucocorticoid and cyclophosphamide in moderate to severe paraquat-poisoned patients. Am J Respir Crit Care Med 1999; 59:357–60.(fulltext)
10. Eddleston M, Wilks MF, Buckley NA. Prospects for treatment of paraquat-induced lung fibrosis with immunosuppressive drugs and the need for better prediction of outcome: a systematic review. QJM. 2003;96:809-24.(fulltext)
11. Dinis-Oliveira RJ, Duarte JA, Sánchez-Navarro A, Remião F, Bastos ML, Carvalho F. Paraquat poisonings: mechanisms of lung toxicity, clinical features, and treatment.Crit Rev Toxicol. 2008;38(1):13-71
12. Wilks MF, Fernando R, Ariyananda PL, Eddleston M, Berry DJ, Tomenson JA,Buckley NA, Jayamanne S, Gunnell D, Dawson A.
13. Improvement in survival after paraquat ingestion following introduction of a new formulation in Sri Lanka.PLoS Med. 2008 Feb;5(2):e49. (fulltext)
14. Wright RO, Lewander WJ, Woolf AD. Methemoglobinemia: Etiology, pharmacology, and clinical management. Ann Emerg Med 1999;34:646-656.
15. Prasad R, Singh R, Mishra OP, Pandey M. Dapsone induced methemoglobinemia : Intermittent vs continuous intravenous methylene blue therapy.Indian J Pediatr. 2008 Mar;75(3):245-7 (fulltext)
16. Maric P, Ali SS, Heron LG, Rosenfeld D, Greenwood M. Methaemoglobinaemia following ingestion of a commonly available food additive.Med J Aust. 2008 Feb 4;188(3):156-8.(fulltext)
17. Bradberry SM. Occupational Methaemoglobinaemia: Mechanisms of Production, Features, Diagnosis and Management Including the Use of Methylene Blue. Toxicol Rev. 2003;22;13-27.
18. Prchal JT, Gregg XT. Red cell enzymes.Hematology Am Soc Hematol Educ Program. 2005:19-23 (fulltext)
19. Eddleston M, Rajapakse M, Roberts D, et al. Severe propanil [N-(3,4-dichlorophenyl) propan-amide] pesticide self-poisoning. J Toxicol Clin Toxicol. 2002,40:847-854. (fulltext)
20. Sorensen FW, Gregersen M. Rapid lethal intoxication caused by the herbicide glyphosate-trimesium (Touchdown). Hum Exp Toxicol. 1999;18:735-7.
21. Stella J, Ryan M. Glyphosate herbicide formulation: a potentially lethal ingestion. Emerg Med Australasia. 2004;16:235-9.
22. Bradberry SM, Proudfoot AT, Vale JA. Glyphosate poisoning.Toxicol Rev. 2004;23(3):159-67.
23. Wu IW, Lin JL, Cheng ET. Acute poisoning with the neonicotinoid insecticide imidacloprid in N-methyl pyrrolidone. J Toxicol Clin Toxicol. 2001;39:617-21.
24. Roberts D, Seneviratne R, Mohamed F, et al. Deliberate self-poisoning with the chlorphenoxy herbicide 4-chloro-2-methylphenoxyacetic acid (MCPA). AAnn Emerg Med. 2005 Sep;46(3):275-84 (fulltext)
25. Roberts D, Dissanayake W, Sheriff MHR, Eddleston M. Refractory status epilepticus following self-poisoning with the organochlorine pesticide endosulfan. J Clin Neurosci 2004, 11: 760-762.
26. Karatas AD, Aygun D, Baydin A. Characteristics of endosulfan poisoning: a study of 23 cases.Singapore Med J. 2006 Dec;47(12):1030-2. (fulltext)
27. Mohamed F, Senarathna L, Anwar S, et al. Acute human self-poisoning with the N-phenyl-pyrazole insecticide fipronil – a GABA-gated chloride channel blocking pesticide. J Toxicol Clin Toxicol 2004, 42: 955-963.(fulltext)
28. Koren G, Matsui D, Bailey B.DEET-based insect repellents: safety implications for children and pregnant and lactating women.CMAJ. 2003 Aug 5;169(3):209-12 (fulltext)
29. Goodyer L, Behrens RH.Short report: The safety and toxicity of insect repellents.Am J Trop Med Hyg. 1998 Aug;59(2):323-4.(fulltext)

While politicians raise concerns about weapons of mass destruction and threats of chemical attack, the reality is that at least 300 000 people die from deliberate self-poisoning with organophosphates each year in Asia. Most published guidelines on treatment are generated in developed countries by authors with limited direct experience of organophosphate toxicity. There does not seem to be a significant difference in case fatality rates between the developed and developing world. Within this class of compounds there is considerable pharmacokinetic and pharmacodynamic diversity which leads to a number of differences in the clinical course of poisoning for various compounds and response to treatment. Supportive care and atropine are established treatments; most other treatments engender some controversy.

If an organophosphate poisoning comes to your hospital, get apprehensive and get out of bed. Read on.

1. To be able to do a risk assessment of acute organophosphate exposure.
2. Consider variables which may affect the risk assessment.
3. Understand treatment of organophosphate poisoning.
4. Understand the issues underlying treatment failure.
5. Understand the chronic sequelae organophosphate poisoning.

1. WikiTox Organophosphates
2. Davies JOJ, Eddleston M, Buckley NA.Predicting outcome in acute organophosphorus poisoning with a poison severity score or the Glasgow coma scale.QJM 2008; 101: 371-9 (fulltext)
3. Eddleston M, Dawson A, Karalliedde L, et al. Early management after self-poisoning with an organophosphorus or carbamate pesticide - a treatment protocol for junior doctors. Crit Care. 2004;8:R391-R397.(fulltext)
4. Michael Eddleston, Nick A Buckley, Peter Eyer, Andrew H Dawson Management of acute organophosphorus pesticide poisoning Lancet 2008; 371: 597–607 (fulltext)

1. Roberts DM, Aaron C. Management of acute organophosphorus pesticide poisoning. BMJ 2007;334;629-634 (fulltext)
2. Pawar KS, Bhoite RR, Pillay CP, Chavan SC, Malshikare DS, Garad SG.Continuous pralidoxime infusion versus repeated bolus injection to treat organophosphorus pesticide poisoning: a randomised controlled trial.Lancet. 2006 Dec 16;368(9553):2136-41.(fulltext)
3. Buckley NA, Karalliedde L, Dawson A, Senanayake N, Eddleston M. Where is the evidence for treatments used in pesticide poisoning? Is clinical toxicology fiddling while the developing world burns? J Toxicol Clin Toxicol. 2004;42(1):113-6.(fulltext)
4. Eddleston M, Szinicz L, Eyer P, Buckley N. Oximes in acute organophosphorus pesticide poisoning: a systematic review of clinical trials. QJM. 2002;95:275-283. (fulltext)
5. Eddleston M, Eyer P, Worek F, Mohamed F, Senarathna L, von Meyer L, Juszczak E, Hittarage A, Azhar S, Dissanayake W, Sheriff MH, Szinicz L, Dawson AH, Buckley NA. Differences between organophosphorus insecticides in human self-poisoning: a
   prospective cohort study.Lancet. 2005 Oct 22-28;366(9495):1452-9. (fulltext 1) (fulltext 2)
6. Darren M Roberts and Cynthia K Aaron, “Management of acute organophosphorus pesticide poisoning,” BMJ (Clinical Research Ed.) 334, no. 7594 (March 24, 2007): 629-634. Fulltext
7. Nick A Buckley et al., “Oximes for acute organophosphate pesticide poisoning,” Cochrane Database of Systematic Reviews (Online) 2 (2011): CD005085. Fulltext
8. Pradeepa Jayawardane et al., “The spectrum of intermediate syndrome following acute organophosphate poisoning: a prospective cohort study from Sri Lanka,” PLoS Medicine 5, no. 7 (July 15, 2008): e147. Fulltext
9. Michael Eddleston et al., “Pralidoxime in acute organophosphorus insecticide poisoning–a randomised controlled trial,” PLoS Medicine 6, no. 6 (June 30, 2009): e1000104. Freetext

Link to Problems for Discussion

Paraquat is widely used around the world as a low cost and effective herbicide. However, it has one of the highest fatality rates of any poisoning, with around 70% of ingestions being lethal. Paraquat is a good example of an agent that causes oxidative stress. Treatments aimed at combating this mechanism have had very limited success in animals, and human data are inconclusive or lacking. There have also been a large number of attempts to develop tests or algorithms that predict outcome but with moderate success.

Most cases of paraquat poisoning result from deliberate self-harm but unintentional poisoning can occur when it has been stored incorrectly. Death has also occurred following large dermal exposure and intravenous administration.

Diquat is, like paraquat, a dipyridyl herbicide. Some formulations contain a mixture of both compounds. Diquat and paraquat have similar toxicity. Unlike paraquat, diquat is not accumulated by the lungs and has a half-life in the lung 5 times shorter than paraquat. Therefore, diquat produces less pulmonary injury and fibrosis.

1. Understand the mechanism of toxicity of paraquat.
2. Understand how this explains the delayed pulmonary manifestations of moderate paraquat toxicity
3. List the most common clinical manifestations of poisoning with paraquat.
4. Recognise situations where interventions are most likely to be useful.
5. Understand the difference between a frequentist and a Bayesian approach to clinical trial evidence and how this alters what interventions you institute.

1. WikiTox Paraquat
2. Lin JL, Leu ML, Liu YC, Chen GH. A prospective clinical trial of pulse therapy with glucocorticoid and cyclophosphamide in moderate to severe paraquat-poisoned patients. Am J Respir Crit Care Med 1999; 59:357–60.(fulltext)
3. Eddleston M, Wilks MF, Buckley NA. Prospects for treatment of paraquat-induced lung fibrosis with immunosuppressive drugs and the need for better prediction of outcome: a systematic review. QJM. 2003;96:809-24.(fulltext)
4. Dinis-Oliveira RJ, Duarte JA, Sánchez-Navarro A, Remião F, Bastos ML, Carvalho F. Paraquat poisonings: mechanisms of lung toxicity, clinical features, and treatment.Crit Rev Toxicol. 2008;38(1):13-71
5. Wilks MF, Fernando R, Ariyananda PL, Eddleston M, Berry DJ, Tomenson JA,Buckley NA, Jayamanne S, Gunnell D, Dawson A.
6. Improvement in survival after paraquat ingestion following introduction of a new formulation in Sri Lanka.PLoS Med. 2008 Feb;5(2):e49. (fulltext)

Link to Problems for Discussion

'Doctor, the patient is a curious blue.’
‘Ah, then we had better give them the curious blue medicine.’

Methaemoglobin is occasionally produced therapeutically and is probably seen more commonly from recreational amyl nitrate use. There is a wide range of drugs and chemicals that can cause the oxidative stress that transforms Fe+++ to Fe++, causing the patient to appear cyanosed, altering the oxygen carrying capacity and turning blood to a chocolate-brown colour.

1. Understand the mechanisms of methaemoglobinaemia
2. Understand the basis of treatment with methylene blue
3. Understand the issues underlying treatment failure

1. WikiTox Methaemoglobinaemia
2. Wikitox Methaemoglobin
3. Wright RO, Lewander WJ, Woolf AD. Methemoglobinemia: Etiology, pharmacology, and clinical management. Ann Emerg Med 1999;34:646-656.
4. Prasad R, Singh R, Mishra OP, Pandey M. Dapsone induced methemoglobinemia : Intermittent vs continuous intravenous methylene blue therapy.Indian J Pediatr. 2008 Mar;75(3):245-7 (fulltext)
5. Maric P, Ali SS, Heron LG, Rosenfeld D, Greenwood M. Methaemoglobinaemia following ingestion of a commonly available food additive.Med J Aust. 2008 Feb 4;188(3):156-8.(fulltext)
6. Bradberry SM. Occupational Methaemoglobinaemia: Mechanisms of Production, Features, Diagnosis and Management Including the Use of Methylene Blue. Toxicol Rev. 2003;22;13-27.
7. Prchal JT, Gregg XT. Red cell enzymes.Hematology Am Soc Hematol Educ Program. 2005:19-23 (fulltext)
8. Eddleston M, Rajapakse M, Roberts D, et al. Severe propanil [N-(3,4-dichlorophenyl) propan-amide] pesticide self-poisoning. J Toxicol Clin Toxicol. 2002,40:847-854. (fulltext)

Link to Problems for Discussion

There are an estimated 300,000 deaths annually from pesticide self-poisoning in the Asia-Pacific region. The great majority of deaths are caused by three classes of pesticide: organophosphorus compounds, paraquat, and aluminium phosphide. Organochlorine pesticides were once important causes of fatal poisoning but their replacement by organophosphorus insecticides in agricultural practice has reduced the number of deaths they cause. There are numerous other pesticides in use globally – many of them appear to be relatively harmless after overdose.

Organophosphorus pesticides, propanil and paraquat are covered separately; this section looks at poisoning with other insecticides and herbicides.

• Organophosphorus compounds
• Carbamates
• Organochlorines (cyclodienes [eg. endosulfan] and cycloalkanes [eg. lindane])
• Pyrethroids (eg. permethrin)
• Neonicotinoids (eg. imidacloprid)
• N-phenylpyrazole insecticides (eg. fipronil)
• N,N-Diethyl-m-toluamide (DEET)

• Dipyridyl compounds (paraquat, diquat)
• Glyphosate
• Chlorphenoxy compounds (eg 2,4-D, MCPA)
• Propanil

There are several other relatively new classes of pesticides for which we currently have very little human toxicity data. Many of them are likely to be relatively harmless to humans in self-poisoning.

Significant acute exposure to insecticides or herbicides usually results in one of several clinical syndromes:
1. Cholinergic over-activity or crisis (OPs, carbamates)
2. Seizures (organochlorines, N-phenylpyrazoles)
3. Multiorgan failure or lung fibrosis (dipyridyls)
4. Muscle damage producing renal damage (chlorphenoxy compounds)
5. Methaemoglobinaemia (propanil)
6. Effects of the surfactant (probably true for glyphosate, in particular)
7. Aspiration pneumonia
8. No effect (some newer classes of pesticides)

1. Understand the spectrum of intoxication with insecticides and herbicides, in particular that some pesticides appear to have no direct toxic effects at all.
2. Understand that aspiration of the pesticide and its solvent may be much worse than absorbing the pesticide from the GI tract, and that this should be factored into the risk assessment of performing GI decontamination.
3. Understand the value of careful observation.
4. Describe the initial evaluation, stabilisation and treatment of organochlorine induced status epilepticus.

1. Eddleston M, Rajapakse M, Roberts D, et al. Severe propanil [N-(3,4-dichlorophenyl) propan-amide] pesticide self-poisoning. J Toxicol Clin Toxicol. 2002,40:847-854. (fulltext)
2. Sorensen FW, Gregersen M. Rapid lethal intoxication caused by the herbicide glyphosate-trimesium (Touchdown). Hum Exp Toxicol. 1999;18:735-7.
3. Stella J, Ryan M. Glyphosate herbicide formulation: a potentially lethal ingestion. Emerg Med Australasia. 2004;16:235-9.
4. Bradberry SM, Proudfoot AT, Vale JA. Glyphosate poisoning.Toxicol Rev. 2004;23(3):159-67.
5. Wu IW, Lin JL, Cheng ET. Acute poisoning with the neonicotinoid insecticide imidacloprid in N-methyl pyrrolidone. J Toxicol Clin Toxicol. 2001;39:617-21.
6. Roberts D, Seneviratne R, Mohamed F, et al. Deliberate self-poisoning with the chlorphenoxy herbicide 4-chloro-2-methylphenoxyacetic acid (MCPA). AAnn Emerg Med. 2005 Sep;46(3):275-84 (fulltext)
7. Roberts D, Dissanayake W, Sheriff MHR, Eddleston M. Refractory status epilepticus following self-poisoning with the organochlorine pesticide endosulfan. J Clin Neurosci 2004, 11: 760-762.
8. Karatas AD, Aygun D, Baydin A. Characteristics of endosulfan poisoning: a study of 23 cases.Singapore Med J. 2006 Dec;47(12):1030-2. (fulltext)
9. Mohamed F, Senarathna L, Anwar S, et al. Acute human self-poisoning with the N-phenyl-pyrazole insecticide fipronil – a GABA-gated chloride channel blocking pesticide. J Toxicol Clin Toxicol 2004, 42: 955-963.(fulltext)
10. Koren G, Matsui D, Bailey B.DEET-based insect repellents: safety implications for children and pregnant and lactating women.CMAJ. 2003 Aug 5;169(3):209-12 (fulltext)
11. Goodyer L, Behrens RH.Short report: The safety and toxicity of insect repellents.Am J Trop Med Hyg. 1998 Aug;59(2):323-4.(fulltext)
12. WikiTox Other insecticides and Herbicides This links to multiple pesticide monographs
13. WikiTox Chlorphenoxy Herbicides
14. Propanil
15. WikiTox Glyphosate
16. WikiTox Organochlorines
17. WikiTox Pyrethrins and pyrethroids
18. WikiTox N-phenylpyrazole insecticides (eg. fipronil)

Link to Problems for Discussion