Poisoning due to pyrethroids

The first pyrethroid pesticide, allethrin, was identified in 1949. Allethrin and other pyrethroids with a basic cyclopropane carboxylic ester structure are type I pyrethroids. The insecticidal activity of these synthetic pyrethroids was enhanced further by the addition of a cyano group to give alpha-cyano (type II) pyrethroids, such as cypermethrin. The finding of insecticidal activity in a group of phenylacetic 3-phenoxybenzyl esters, which lacked the cyclopropane ring but contained the alpha-cyano group (and hence were type II pyrethroids) led to the development of fenvalerate and related compounds. All pyrethroids can exist as at least four stereoisomers, each with different biological activities. They are marketed as racemic mixtures or as single isomers. In commercial formulations, the activity of pyrethroids is usually enhanced by the addition of a synergist such as piperonyl butoxide, which inhibits metabolic degradation of the active ingredient. Pyrethroids are used widely as insecticides both in the home and commercially, and in medicine for the topical treatment of scabies and headlice. In tropical countries mosquito nets are commonly soaked in solutions of deltamethrin as part of antimalarial strategies. Pyrethroids are some 2250 times more toxic to insects than mammals because insects have increased sodium channel sensitivity, smaller body size and lower body temperature. In addition, mammals are protected by poor dermal absorption and rapid metabolism to non-toxic metabolites. The mechanisms by which pyrethroids alone are toxic are complex and become more complicated when they are co-formulated with either piperonyl butoxide or an organophosphorus insecticide, or both, as these compounds inhibit pyrethroid metabolism. The main effects of pyrethroids are on sodium and chloride channels. Pyrethroids modify the gating characteristics of voltage-sensitive sodium channels to delay their closure. A protracted sodium influx (referred to as a sodium 'tail current') ensues which, if it is sufficiently large and/or long, lowers the action potential threshold and causes repetitive firing; this may be the mechanism causing paraesthesiae. At high pyrethroid concentrations, the sodium tail current may be sufficiently great to prevent further action potential generation and 'conduction block' ensues. Only low pyrethroid concentrations are necessary to modify sensory neurone function. Type II pyrethroids also decrease chloride currents through voltage-dependent chloride channels and this action probably contributes the most to the features of poisoning with type II pyrethroids. At relatively high concentrations, pyrethroids can also act on GABA-gated chloride channels, which may be responsible for the seizures seen with severe type II poisoning. Despite their extensive world-wide use, there are relatively few reports of human pyrethroid poisoning. Less than ten deaths have been reported from ingestion or following occupational exposure. Occupationally, the main route of pyrethroid absorption is through the skin. Inhalation is much less important but increases when pyrethroids are used in confined spaces. The main adverse effect of dermal exposure is paraesthesiae, presumably due to hyperactivity of cutaneous sensory nerve fibres. The face is affected most commonly and the paraesthesiae are exacerbated by sensory stimulation such as heat, sunlight, scratching, sweating or the application of water. Pyrethroid ingestion gives rise within minutes to a sore throat, nausea, vomiting and abdominal pain. There may be mouth ulceration, increased secretions and/or dysphagia. Systemic effects occur 4-48 hours after exposure. Dizziness, headache and fatigue are common, and palpitations, chest tightness and blurred vision less frequent. Coma and convulsions are the principal life-threatening features. Most patients recover within 6 days, although there were seven fatalities among 573 cases in one series and one among 48 cases in another. Management is supportive. As paraesthesiae usually resolve in 12-24 hours, specific treatment is not generally required, although topical application of dl-alpha tocopherol acetate (vitamin E) may reduce their severity.     

Poisoning due to pyrethrins

The pyrethrins have a long and fascinating history. They were derived from dried chrysanthemum flower heads that were found to have pesticidal activity centuries ago. They comprise a complex mixture of six main chemicals. Commercial formulations usually contain piperonyl butoxide, which inhibits metabolic degradation of the active ingredients. Pyrethrins are readily absorbed from the gut and respiratory tract but poorly absorbed through skin. The active components are rapidly and extensively metabolised in the liver. Pyrethrins probably act on sodium channels resulting in nervous system overactivity. The possibility that they also induce hypersensitivity, which may be fatal when the respiratory tract is involved, has been debated for many years. A few clinical reports support this suggestion but the limited epidemiological evidence available is against it. The number of reports of toxicity caused by pyrethrins has greatly decreased over recent years. The pyrethrins are generally of low acute toxicity but convulsions may occur if substantial amounts are ingested. Two deaths from acute asthma have been attributed to pyrethrins and clinical reports suggest that they may also cause a variety of forms of dermatitis. Ocular exposure has resulted in corneal erosions. Management of pyrethrin toxicity is supportive and symptomatic.     

Poisoning due to Pyrethrins

The pyrethrins have a long and fascinating history. They were derived from dried chrysanthemum flower heads that were found to have pesticidal activity centuries ago. They comprise a complex mixture of six main chemicals. Commercial formulations usually contain piperonyl butoxide, which inhibits metabolic degradation of the active ingredients. Pyrethrins are readily absorbed from the gut and respiratory tract but poorly absorbed through skin. The active components are rapidly and extensively metabolised in the liver. Pyrethrins probably act on sodium channels resulting in nervous system overactivity. The possibility that they also induce hypersensitivity, which may be fatal when the respiratory tract is involved, has been debated for many years. A few clinical reports support this suggestion but the limited epidemiological evidence available is against it. The number of reports of toxicity caused by pyrethrins has greatly decreased over recent years. The pyrethrins are generally of low acute toxicity but convulsions may occur if substantial amounts are ingested. Two deaths from acute asthma have been attributed to pyrethrins and clinical reports suggest that they may also cause a variety of forms of dermatitis. Ocular exposure has resulted in corneal erosions. Management of pyrethrin toxicity is supportive and symptomatic.     

Poisoning due to chlorophenoxy herbicides

Chlorophenoxy herbicides are used widely for the control of broad-leaved weeds. They exhibit a variety of mechanisms of toxicity including dose-dependent cell membrane damage, uncoupling of oxidative phosphorylation and disruption of acetylcoenzyme A metabolism. Following ingestion, vomiting, abdominal pain, diarrhoea and, occasionally, gastrointestinal haemorrhage are early effects. Hypotension, which is common, is due predominantly to intravascular volume loss, although vasodilation and direct myocardial toxicity may also contribute. Coma, hypertonia, hyperreflexia, ataxia, nystagmus, miosis, hallucinations, convulsions, fasciculation and paralysis may then ensue. Hypoventilation is commonly secondary to CNS depression, but respiratory muscle weakness is a factor in the development of respiratory failure in some patients. Myopathic symptoms including limb muscle weakness, loss of tendon reflexes, myotonia and increased creatine kinase activity have been observed. Metabolic acidosis, rhabdomyolysis, renal failure, increased aminotransferase activities, pyrexia and hyperventilation have been reported. Substantial dermal exposure to 2,4-dichlorophenoxy acetic acid (2,4-D) has led occasionally to systemic features including mild gastrointestinal irritation and progressive mixed sensorimotor peripheral neuropathy. Mild, transient gastrointestinal and peripheral neuromuscular symptoms have occurred after occupational inhalation exposure. In addition to supportive care, urine alkalinization with high-flow urine output will enhance herbicide elimination and should be considered in all seriously poisoned patients. Haemodialysis produces similar herbicide clearances to urine alkalinization without the need for urine pH manipulation and the administration of substantial amounts of intravenous fluid in an already compromised patient.     

Poisoning due to urea herbicides

Urea herbicides, which act by inhibiting photosynthesis, were introduced in 1952 and are now used as pre- and post-emergence herbicides for general weed control in agricultural and non-agricultural practices. Urea herbicides are generally of low acute toxicity and severe poisoning is only likely following ingestion when nausea, vomiting, diarrhoea and abdominal pain may occur. As urea herbicides are metabolised to aniline derivatives, which are potent oxidants of haemoglobin, methaemoglobinaemia (18-80%) has been documented, as well as haemolysis. Treatment is supportive and symptomatic. Methylthioninium chloride (methylene blue) 1-2mg (the dose depending on the severity of features) should be administered intravenously over 5-10 minutes if there are symptoms consistent with methaemoglobinaemia and/or a methaemoglobin concentration >30%.     

沙丁胺醇过量致中毒

1例30岁男性患者因与家属争吵后自服沙丁胺醇约300片（2mg／片）后急诊入院,自述有头晕、头痛、目眩、心悸及口干等。予催吐、导泻、口服药用炭片吸附毒物,纠正电解质紊乱及维持酸碱平衡,血液灌流联合血液透析等治疗。3d后症状好转出院。7d后随访,患者无不适。     

吗啡控释片应用不当导致中毒

硫酸吗啡控释片(美施康定),是临床普遍应用的三阶梯止痛药,整片口服才能达到控释的目的,疗效可维持12h。现报告1例因应用不当导致中毒的病例。患者女,50岁。因右乳癌术后1年余,多发肝转移,多发骨转移,疼痛3月余,神志不清4h,于2003年12月13日22:05来我院急诊。家属诉患者当晚服用美施康定时将1片30mg的美施康定掰碎服用,2h后出现昏睡,意识不清。查体:T36.5℃,P102次/min,R12次/min、BP128/72mmHg(1mmHg=0.133kPa)。昏睡状,呼之不应。双侧瞳孔缩小,直径1mm。双肺呼吸音粗,未闻及啰音訡T检查未见异常。考虑为吗啡中毒,予吸氧,纳洛酮0.4mg…     

Poisoning due to class IA antiarrhythmic drugs. Quinidine, procainamide and disopyramide

Quinidine, procainamide and disopyramide are antiarrhythmic drugs in the class 1A category. These drugs have a low toxic to therapeutic ratio, and their use is associated with a number of serious adverse effects during long term therapy and life-threatening sequelae following acute overdose. Class 1A agents inhibit the fast inward sodium current and decrease the maximum rate of rise and amplitude of the cardiac action potential. Prolonged Q-T interval and, to a lesser extent, QRS duration may be observed at therapeutic concentrations of quinidine. With increasing plasma concentrations, progressive depression of automaticity and conduction velocity occur. 'Quinidine syncope' (a transient loss of consciousness due to paroxysmal ventricular tachycardia, frequently of the torsade de pointes type) occurs with therapeutic dosing, often in the first few days of therapy. Extracardiac adverse effects of quinidine include potentially intolerable gastrointestinal effects and hypersensitivity reactions such as fever, rash, blood dyscrasias and hepatitis. Procainamide produces electrophysiological changes that are similar to those of quinidine, although Q-T interval prolongation with the former is less pronounced at therapeutic concentrations. Hypersensitivity reactions including fever, rash and (more seriously) agranulocytosis are associated with procainamide, and a frequent adverse effect requiring cessation of therapy is the development of systemic lupus erythematosus. Of the 3 drugs, disopyramide has the most pronounced negative inotropic effects, which are especially significant in patients with pre-existing left ventricular dysfunction. As with quinidine, unexpected 'disopyramide syncope' at therapeutic concentrations has been described. Anticholinergic side effects are common with this drug and may require cessation of therapy. Disopyramide therapy may unpredictably induce severe hypoglycaemia. Severe intoxication with the class 1A agents may result from acute accidental or intentional overdose, or from accumulation of the drugs during long term therapy. Acute overdose can result in severe disturbances of cardiac conduction and hypotension, frequently accompanied by central nervous system toxicity. Decreased renal function can cause significant accumulation of procainamide and its active metabolite acecainide (N-acetyl-procainamide), resulting in severe intoxication. Mild to moderate renal dysfunction is less likely to lead to quinidine or disopyramide intoxication, unless renal failure is severe or concurrent hepatic dysfunction is present. Management of acute intoxication with class 1A drugs includes gut decontamination with provision of respiratory support and treatment of seizures as needed. Hypertonic sodium bicarbonate, by antagonising the inhibitory effect of quinidine on sodium conductance, may reverse many or all manifestations of cardiovascular toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)     

Poisoning due to calcium antagonists. Experience with verapamil, diltiazem and nifedipine.

The calcium antagonists are a heterogeneous class of drugs which block the inward movement of calcium into cells through 'slow channels' from extracellular sites. By inhibiting phase 0 depolarisation in cardiac pacemaker cells and phase 2 plateau in myocardium, and by depressing calcium ion flux in smooth muscle cells of blood vessels, these agents may exert profound effects on the cardiovascular system, particularly in susceptible individuals or in overdose. Sinus node depression, impaired atrioventricular (AV) conduction, depressed myocardial contractility, and peripheral vasodilatation may result. Pharmacokinetic features of calcium antagonists include rapid and complete absorption from the gastrointestinal tract, with extensive first-pass hepatic metabolism yielding generally low bioavailability. The volume of distribution is generally large and protein binding is high. Elimination is almost entirely by the liver. Impaired renal function does not affect pharmacokinetics. Verapamil is the most potent inhibitor of cardiac conduction and contractility, with diltiazem also showing such effects. Nifedipine is the most potent vasodilator, but only occasionally impairs the sinus node or AV conduction. Significant pharmacodynamic effects are common during combination therapy with calcium antagonists, especially verapamil and beta-blockers. Verapamil may significantly elevate serum digoxin concentrations and may exert additive negative effects on chronotropism and dromotropism when this combination is used. Overdoses of calcium entry blockers are becoming more frequent and reflect an extension of the known pharmacodynamic profile of these agents. Typical features include confusion or lethargy, hypotension, sinus node depression and cardiac conduction defects. Onset of symptoms may be delayed if a sustained release preparation is ingested. Management of calcium antagonist overdose includes gut decontamination with lavage and activated charcoal. All symptomatic patients and patients with a history of ingesting a sustained release preparation should be admitted for ECG monitoring. If bradycardia and/or conduction defects contribute to hypotension, atropine or isoprenaline (isoproterenol) may accelerate the ventricular rate. Transvenous pacing may be required. Depressed myocardial contractility usually responds well to calcium chloride or calcium gluconate administration, but further inotropic support may be required. Peripheral vasodilation should be managed with intravenous fluids and a pressor agent such as dopamine or norepinephrine (noradrenaline).     

Poisoning of an urban family due to misapplication of household organophosphate and carbamate pesticides.

A case report of an urban family who experienced excessive exposure to organophosphate and carbamate pesticides is presented. All three family members developed symptoms that were compatible with cholinesterase inhibition: headache, lightheadedness, wheezing, shortness of breath, nausea, and fatigue. Serial measurement of red blood cell and serum cholinesterases soon after exposure and during subsequent months confirmed the diagnosis of pesticide poisoning. This report demonstrates that the misapplication of pesticides commonly used in residences in urban areas can cause acute pesticide poisoning and demonstrates the usefulness of repeated measurements of cholinesterase during the post-exposure period in establishing the correct diagnosis.     

Cytotoxicity,Cytogenotoxicity and Allergenicity Tests on Certain Pyrethroids

ABSTRACT

Pyrethroids are potent synthetic insecticides which have been increasingly employed in recent years. Such compounds have been shown to bind covalently to hepatic proteins. Covalent binding is often associated with toxic effects. Possible cytotoxic, cytogenotoxic and allergenic effects could be due to covalent binding of these compounds and/or their metabolites to endogenous macromolecules. In the present paper we examine possible cytotoxic effects of certain pyrethroids on human lymphocytes and L 1210 lymphoblastoid mouse cells, cytogenotoxic effects with micronuclei test and allergenic effects with Magnusson and mast cell degranulation tests.

Under our experimental conditions, the tested compounds showed neither acute cytotoxic nor cytogenotoxic effects, though, Cismethrin presented slight antimitotic effects statistically different to those with the control.

Slight allergenic character of Cismethrin, Bioresmethrin and Deltamethrin was revealed by Magnusson and mast cell degranulation tests.     

Pyrethroids and piperonyl-butoxide affect human T-lymphocytes in vitro.

Synthetic pyrethroids are increasingly used as insecticides and are claimed to have a relatively low human toxicity. The aim of this study was to examine the in vitro effects of the synthetic pyrethroid S-bioallethrin alone and in combination with the common synergist piperonyl-butoxide (PBO) on human blood lymphocytes and basophils in atopic individuals and non-atopic control subjects. S-bioallethrin and PBO also caused inhibition of lymphocyte proliferation (MTT-test) after a 72-h culture period in a concentration dependent manner. In contrast to the MTT-measurements the combined agents are more effective in inhibiting interleukin-4 (IL-4)- and interferon-gamma (IFN-gamma)-production. The regulatory IL-4/IFN-gamma balance showed a significant difference between atopic and non-atopic subjects after a culture period of 24-48 h in the presence of micromolar S-bioallethrin (P < 0.001). Furthermore S-bioallethrin, PBO and the combined agents induced histamine release from human basophils. Although this effect was little compared to histamine liberators like FMLP and anti-IgE, the response to S-bioallethrin and PBO was significantly different in atopic donors compared with non-atopics (P < 0.01). In scratch test experiments 4 of 18 tested atopic volunteers showed positive reaction (wheals and flares) to S-bioallethrin and permethrin, whereas no reaction could be measured in the control group (age-matched). These findings demonstrate the immuno- and allergo-toxicological properties of the synthetic pyrethroid S-bioallethrin combined with the synergistic PBO using this in vitro approach with human lymphocytes and basophils.     

Glyphosate Poisoning

Glyphosate is used extensively as a non-selective herbicide by both professional applicators and consumers and its use is likely to increase further as it is one of the first herbicides against which crops have been genetically modified to increase their tolerance. Commercial glyphosate-based formulations most commonly range from concentrates containing 41% or more glyphosate to 1% glyphosate formulations marketed for domestic use. They generally consist of an aqueous mixture of the isopropylamine (IPA) salt of glyphosate, a surfactant, and various minor components including anti-foaming and colour agents, biocides and inorganic ions to produce pH adjustment. The mechanisms of toxicity of glyphosate formulations are complicated. Not only is glyphosate used as five different salts but commercial formulations of it contain surfactants, which vary in nature and concentration. As a result, human poisoning with this herbicide is not with the active ingredient alone but with complex and variable mixtures. Therefore, It is difficult to separate the toxicity of glyphosate from that of the formulation as a whole or to determine the contribution of surfactants to overall toxicity. Experimental studies suggest that the toxicity of the surfactant, polyoxyethyleneamine (POEA), is greater than the toxicity of glyphosate alone and commercial formulations alone. There is insufficient evidence to conclude that glyphosate preparations containing POEA are more toxic than those containing alternative surfactants. Although surfactants probably contribute to the acute toxicity of glyphosate formulations, the weight of evidence is against surfactants potentiating the toxicity of glyphosate. Accidental ingestion of glyphosate formulations is generally associated with only mild, transient, gastrointestinal features. Most reported cases have followed the deliberate ingestion of the concentrated formulation of Roundup®¹ (41% glyphosate as the IPA salt and 15% POEA). There is a reasonable correlation between the amount ingested and the likelihood of serious systemic sequelae or death. Advancing age is also associated with a less favourable prognosis. Ingestion of >85mL of the concentrated formulation is likely to cause significant toxicity in adults. Gastrointestinal corrosive effects, with mouth, throat and epigastric pain and dysphagia are common. Renal and hepatic impairment are also frequent and usually reflect reduced organ perfusion. Respiratory distress, impaired consciousness, pulmonary oedema, infiltration on chest x-ray, shock, arrythmias, renal failure requiring haemodialysis, metabolic acidosis and hyperkalaemia may supervene in severe cases. Bradycardia and ventricular arrhythmias are often present pre-terminally. Dermal exposure to ready-to-use glyphosate formulations can cause irritation and photo-contact dermatitis has been reported occasionally; these effects are probably due to the preservative Proxel® (benzisothiazolin-3-one). Severe skin burns are very rare. Inhalation is a minor route of exposure but spray mist may cause oral or nasal discomfort, an unpleasant taste in the mouth, tingling and throat irritation. Eye exposure may lead to mild conjunctivitis, and superficial corneal injury is possible if irrigation is delayed or inadequate. Management is symptomatic and supportive, and skin decontamination with soap and water after removal of contaminated clothing should be undertaken in cases of dermal exposure.     

Pentachlorophenol Poisoning

Despite being banned in many countries and having its use severely restricted in others, pentachlorophenol (PCP) remains an important pesticide from a toxicological perspective. It is a stable and persistent compound. In humans it is readily absorbed by ingestion and inhalation but is less well absorbed dermally. Its distribution is limited, its metabolism extensive and it is eliminated only slowly. Assessment of the toxicity of PCP is confounded by the presence of contaminants known to cause effects identical to those attributed to PCP. However, severe exposure by any route may result in an acute and occasionally fatal illness that bears all the hallmarks of being mediated by uncoupling of oxidative phosphorylation. Tachycardia, tachypnoea, sweating, altered consciousness, hyperthermia, convulsions and early onset of marked rigor (if death occurs) are the most notable features. Pulmonary oedema, intravascular haemolysis, pancreatitis, jaundice and acute renal failure have been reported. There is no antidote and no adequate data to support the use of repeat-dose oral cholestyramine, forced diuresis or urine alkalinisation as effective methods of enhancing PCP elimination in poisoned humans. Supportive care and vigorous management of hyperthermia should produce a satisfactory outcome. Chronic occupational exposure to PCP may produce a syndrome similar to acute systemic poisoning, together with conjunctivitis and irritation of the upper respiratory and oral mucosae. Long-term exposure has also been reported to result in chronic fatigue or neuropsychiatric features in combination with skin infections (including chloracne), chronic respiratory symptoms, neuralgic pains in the legs, and impaired fertility and hypothyroidism secondary to endocrine disruption. PCP is a weak mutagen but the available data for humans are insufficient to classify it more strongly than as a probable carcinogen.     

Ricin Poisoning

Ricin is a naturally occurring toxin derived from the beans of the castor oil plant Ricinus communis. It is considered a potential chemical weapon. Ricin binds to cell surface carbohydrates, is internalised then causes cell death by inhibiting protein synthesis. Oral absorption is poor and absorption through intact skin most unlikely; the most hazardous routes of exposure being inhalation and injection. Features of toxicity mainly reflect damage to cells of the reticuloendothelial system, with fluid and protein loss, bleeding, oedema and impaired cellular defence against endogenous toxins. It has been estimated that in man, the lethal dose by inhalation (breathing in solid or liquid particles) and injection (into muscle or vein) is approximately 5–10 µg/kg, that is 350–700µg for a 70kg adult. Death has ensued within hours of deliberate subcutaneous injection. Management is supportive. Prophylactic immunisation against ricin toxicity is a developing research initiative, although presently not a realistic option in a civilian context.     

Paraquat Poisoning

This paper deals with the development of methods for the detection and determination of the weed-killer, paraquat, in body fluids (urine, blood, gastric aspirate, dialysates) and tissues. These have been obtained from 6 cases of paraquat poisoning (2 of which were fatal) admitted to hospital and from several other negative cases. A specific colour reaction is described for the detection and determination of paraquat. Thus when sodium hydrogen carbonate followed by sodium dithionite is added to the test solution, a blue colour is produced. The detection limit is about 1 microgram/ml. Following admission to hospital shortly after the ingestion of paraquat, the reaction can be applied directly to diluted urine and diluted (filtered) gastric aspirate. Paraquat can be detected in small quantities in urine for quite a long period after ingestion. It is necessary, however, to use a column of a cation exchange resin to achieve concentration and also to remove any interfering substances. Under these conditions, it is preferable to assess the absorbance of the blue colour on a recording spectrophotometer. The concentration of paraquat in the blood serum is extremely low and only detectable shortly after ingestion. It has been extremely difficult to detect any traces of paraquat in dialysates (haemo- and peritoneal). Depending on the interval of time between ingestion and death, paraquat may be detected in some tissues e. g. liver and kidney. Using the cation exchange resin technique, paraquat in quantities of 50 to 100 micrograms added to 100 ml of urine can be recovered with an accuracy of 86 to 91 %.