Showing papers in "Toxicological Reviews in 2005"

Poisoning due to pyrethroids.

Abstract: 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 α-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 α-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 4–8 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-α tocopherol acetate (vitamin E) may reduce their severity.

Organophosphate-Induced Delayed Polyneuropathy

Abstract: Organophosphate-induced delayed polyneuropathy (OPIDP) is a rare toxicity resulting from exposure to certain organophosphorus (OP) esters. It is characterised by distal degeneration of some axons of both the peripheral and central nervous systems occurring 1-4 weeks after single or short-term exposures. Cramping muscle pain in the lower limbs, distal numbness and paraesthesiae occur, followed by progressive weakness, depression of deep tendon reflexes in the lower limbs and, in severe cases, in the upper limbs. Signs include high-stepping gait associated with bilateral foot drop and, in severe cases, quadriplegia with foot and wrist drop as well as pyramidal signs. In time, there might be significant recovery of the peripheral nerve function but, depending on the degree of pyramidal involvement, spastic ataxia may be a permanent outcome of severe OPIDP. Human and experimental data indicate that recovery is usually complete in the young. At onset, the electrophysiological changes include reduced amplitude of the compound muscle potential, increased distal latencies and normal or slightly reduced nerve conduction velocities. The progression of the disease, usually over a few days, may lead to non-excitability of the nerve with electromyographical signs of denervation. Nerve biopsies have been performed in a few cases and showed axonal degeneration with secondary demyelination. Neuropathy target esterase (NTE) is thought to be the target of OPIDP initiation. The ratio of inhibitory powers for acetylcholinesterase and NTE represents the crucial guideline for the aetiological attribution of OP-induced peripheral neuropathy. In fact, pre-marketing toxicity testing in animals selects OP insecticides with cholinergic toxicity potential much higher than that to result in OPIDP. Therefore, OPIDP may develop only after very large exposures to insecticides, causing severe cholinergic toxicity. However, this was not the case with certain triaryl phosphates that were not used as insecticides but as hydraulic fluids, lubricants and plasticisers and do not result in cholinergic toxicity. Several thousand cases of OPIDP as a result of exposure to tri-ortho-cresyl phosphate have been reported, whereas the number of cases of OPIDP as a result of OP insecticide poisoning is much lower. In this article, we mainly discuss OP pesticide poisoning, particularly when caused by chlorpyrifos, dichlorvos, isofenphos, methamidophos, mipafox, trichlorfon, trichlornat, phosphamidon/mevinphos and by certain carbamates. We also discuss case reports where neuropathies were not convincingly attributed to fenthion, malathion, omethoate/dimethoate, parathion and merphos. Finally, several observational studies on long-term, low-level exposures to OPs that sometimes reported mild, inconsistent and unexplained changes of unclear significance in peripheral nerves are briefly discussed.

Tricyclic antidepressant poisoning : cardiovascular toxicity.

Abstract: Tricyclic antidepressants remain a common cause of fatal drug poisoning as a result of their cardiovascular toxicity manifested by ECG abnormalities, arrhythmias and hypotension. Dosulepin and amitriptyline appear to be particularly toxic in overdose. The principal mechanism of toxicity is cardiac sodium channel blockade, which increases the duration of the cardiac action potential and refractory period and delays atrioventricular conduction. Electrocardiographic changes include prolongation of the PR, QRS and QT intervals, nonspecific ST segment and T wave changes, atrioventricular block, right axis deviation of the terminal 40ms vector of the QRS complex in the frontal plane (T 40ms axis) and the Brugada pattern (downsloping ST segment elevation in leads V1–V3 in association with right bundle branch block). Maximal changes in the QRS duration and the T 40ms axis are usually present within 12 hours of ingestion but may take up to a week to resolve. Sinus tachycardia is the most common arrhythmia due to anticholinergic activity and inhibition of norepinephrine uptake by tricyclic antidepressants but bradyarrhythmias (due to atrioventricular block) and tachyarrhythmias (supraventricular and ventricular) may occur. Torsade de pointes occurs uncommonly. Hypotension results from a combination of reduced myocardial contractility and reduced systemic vascular resistance due to α-adrenergic blockade. Life-threatening arrhythmias and death due to tricyclic antidepressant poisoning usually occurs within 24 hours of ingestion. Rapid deterioration is common. Level of consciousness at presentation is the most sensitive clinical predictor of serious complications. Although a QRS duration >100ms and a rightward T 40ms axis appear to be better predictors of cardiovascular toxicity than the plasma tricyclic drug concentration, they have at best moderate sensitivity and specificity for predicting complications.

Toxicological Aspects of the South American Herbs Cat's Claw (Uncaria tomentosa) and Maca (Lepidium meyenii) A Critical Synopsis

Abstract: Recent exceptional growth in human exposure to natural products known to originate from traditional medicine has lead to a resurgence of scientific interest in their biological effects. As a strategy for improvement of the assessment of their pharmacological and toxicological profile, scientific evidence-based approaches are being employed to appropriately evaluate composition, quality, potential medicinal activity and safety of these natural products. Using this approach, we comprehensively reviewed existing scientific evidence for known composition, medicinal uses (past and present), and documented biological effects with emphasis on clinical pharmacology and toxicology of two commonly used medicinal plants from South America with substantial human exposure from historical and current global use: Uncaria tomentosa (common name: cat's claw, and Spanish: una de gato), and Lepidium meyenii (common name: maca). Despite the geographic sourcing from remote regions of the tropical Amazon and high altitude Andean mountains, cat's claw and maca are widely available commercially in industrialised countries. Analytical characterisations of their active constituents have identified a variety of classes of compounds of toxicological, pharmacological and even nutritional interest including oxindole and indole alkaloids, flavonoids, glucosinolates, sterols, polyunsaturated fatty acids, carbolines and other compounds. The oxindole alkaloids from the root bark of cat's claw are thought to invoke its most widely sought-after medicinal effects as a herbal remedy against inflammation. We find the scientific evidence supporting this claim is not conclusive and although there exists a base of information addressing this medicinal use, it is limited in scope with some evidence accumulated from in vitro studies towards understanding possible mechanisms of action by specific oxindole alkaloids through inhibition of nuclear factor (NF)-kappaB activation. Although controlled clinical studies have demonstrated reduction in pain associated with cat's claw intake in patients with various chronic inflammatory disorders, there is insufficient clinical data overall to draw a firm conclusion for its anti-inflammatory effects. An important observation was that experimental results were often dependent upon the nature of the preparation used. It appears that the presence of unknown substances has an important role in the overall effects of cat's claw extracts is an important factor for consideration. The available animal toxicological studies did not indicate severe toxicity from oral intake of cat's claw preparations but rather were suggestive of a low potential for acute and subacute oral toxicity, and a lack of evidence to demonstrate genotoxic potential and mutagenic activity. Maca is a clear example of a herb with substantial medicinal use in traditional herbal medicine by indigenous cultures in South America since the first recorded knowledge of it in the seventeenth century. The hypocotyls of maca are the edible part of the plant used for nutritional and proposed fertility-enhancing properties. Maca has been described to possess many other medicinal properties in traditional herbal medicine but only a few of them have been well studied scientifically. Published clinical studies of maca seem to be related to its property as a nutrient, for male fertility and for energy. There are inadequate data regarding the precise mechanism of action of maca. Some studies suggest that secondary metabolites found in maca extracts are important constituents responsible for its physiological effects. Maca has been reported in the scientific literature to have a low degree of acute oral toxicity in animals and low cellular toxicity in vitro. An important finding unveiled by this review is the importance of standardisation in quality and additional basic and clinical research to scientifically validate and understand composition, biological activity, safety and risk. Development of a comprehensive pharmacological and toxicological profile through critical evaluation of existing and future experimental data, especially carefully conducted clinical studies would facilitate the scientific evidence-based approach to understanding potential biological effects of these major traditionally based herbals in current global use.

Estimates of acute pesticide poisoning in agricultural workers in less developed countries

Abstract: The benefits of crop protection products have to be balanced against the risks to farmers and other agricultural workers handling and applying them. The extent of acute pesticide poisoning in these workers, particularly in less developed countries, has often been based on inadequate information. A number of approaches have been taken by researchers to acquire information on pesticide poisoning. These have resulted in worldwide (global) estimates and regional, localised or field assessments. The methods include descriptive epidemiology, cross-sectional and case studies. Attempts to estimate global pesticide poisonings have often been based upon extrapolations and assumptions from chemical-related fatalities in a small number of countries; such estimates do not provide reliable data. Epidemiological studies, relying mainly on hospital and poison centre data, have been biased towards the more severe poisonings, whereas field studies indicate that occupational pesticide poisoning is associated with less severe and minor effects. Many reports do not adequately distinguish between intentional, accidental and occupational pesticide poisoning statistics or are dominated by cases of intentional (suicidal) poisoning which, by their nature, result in severe or fatal results. The majority of reports do not adequately describe whether individual cases are minor, moderate or severe poisonings. In order to assess information on acute pesticide poisoning in agricultural workers in less developed countries and to draw conclusions on the extent and severity of occupational poisoning, the most recent (post-1990) literature was reviewed. Data were also derived from the World Health Organization (WHO), United Nations Environment Programme (UNEP) and the International Labour Office (ILO). The collected information was analysed to assess the extent and severity of occupational acute pesticide poisoning in less developed countries. Occupational acute pesticide poisonings in these countries are a small proportion of overall reported poisoning and are associated with the more minor effects of pesticides. They are a small proportion (<1-4%) of the several million cases of occupational injuries and ill health in agricultural workers worldwide. However, improvements are required for the collection of acute pesticide poisoning data in less developed countries and in the verification of the circumstances of poisonings and their relative severity. There is the need to move away from further attempts to estimate global data and concentrate instead on obtaining reliable data from realistic crop protection activities.

Do corticosteroids prevent oesophageal stricture after corrosive ingestion

Abstract: The most serious complication of corrosive damage to the oesophagus besides perforation is stricture formation. The role of corticosteroids in preventing corrosive-induced strictures is controversial. This review evaluates the usefulness of corticosteroid treatment by critically assessing clinical reports published between 1991 and 2004 in the English, German, French and Spanish literature. Inclusion criteria were the presence of second- or third-degree oesophageal injuries documented by endoscopy and management involving either at least an 8-day course of corticosteroids or no steroid therapy. Ten studies with a total of 572 patients fulfilled the inclusion criteria: six studies employed corticosteroids, two studies did not use corticosteroids, and two studies compared the outcome with and without corticosteroid treatment. In those patients with second-degree burns, the incidence of stricture in the corticosteroid-treated patients was 13.8% and in the non-corticosteroid-treated patients was 6.3%. In those patients with third-degree burns, significantly worse results were found in the corticosteroid-treated group (71.0%) than in the non-corticosteroid-treated group (23.1%). As all studies did not separate second- and third-degree burns, re-analysis of the outcome was undertaken. In the 305 patients treated with corticosteroids, 35.1% developed strictures, whereas 33.3% of the 267 non-corticosteroid-treated patients developed strictures. These data suggest that systemic corticosteroids are not beneficial for second- and third-degree corrosive oesophageal burns. Therefore, the use of corticosteroids in the management of corrosive ingestions should be abandoned as they do not prevent the development of strictures and may lead to the development of serious adverse effects.

Carbon Dioxide Poisoning

Abstract: Carbon dioxide is a physiologically important gas, produced by the body as a result of cellular metabolism. It is widely used in the food industry in the carbonation of beverages, in fire extinguishers as an 'inerting' agent and in the chemical industry. Its main mode of action is as an asphyxiant, although it also exerts toxic effects at cellular level. At low concentrations, gaseous carbon dioxide appears to have little toxicological effect. At higher concentrations it leads to an increased respiratory rate, tachycardia, cardiac arrhythmias and impaired consciousness. Concentrations >10% may cause convulsions, coma and death. Solid carbon dioxide may cause burns following direct contact. If it is warmed rapidly, large amounts of carbon dioxide are generated, which can be dangerous, particularly within confined areas. The management of carbon dioxide poisoning requires the immediate removal of the casualty from the toxic environment, the administration of oxygen and appropriate supportive care. In severe cases, assisted ventilation may be required. Dry ice burns are treated similarly to other cryogenic burns, requiring thawing of the tissue and suitable analgesia. Healing may be delayed and surgical intervention may be required in severe cases.

The potential adverse health effects of dental amalgam.

Abstract: There is significant public concern about the potential health effects of exposure to mercury vapour (Hg0) released from dental amalgam restorations. The purpose of this article is to provide information about the toxicokinetics of Hg0, evaluate the findings from the recent scientific and medical literature, and identify research gaps that when filled may definitively support or refute the hypothesis that dental amalgam causes adverse health effects. Dental amalgam is a widely used restorative dental material that was introduced over 150 years ago. Most standard dental amalgam formulations contain approximately 50% elemental mercury. Experimental evidence consistently demonstrates that Hg0 is released from dental amalgam restorations and is absorbed by the human body. Numerous studies report positive correlations between the number of dental amalgam restorations or surfaces and urine mercury concentrations in non-occupationally exposed individuals. Although of public concern, it is currently unclear what adverse health effects are caused by the levels of Hg0 released from this restoration material. Historically, studies of occupationally exposed individuals have provided consistent information about the relationship between exposure to Hg0 and adverse effects reflecting both nervous system and renal dysfunction. Workers are usually exposed to substantially higher Hg0 levels than individuals with dental amalgam restorations and are typically exposed 8 hours per day for 20–30 years, whereas persons with dental amalgam restorations are exposed 24 hours per day over some portion of a lifetime. This review has uncovered no convincing evidence pointing to any adverse health effects that are attributable to dental amalgam restorations besides hypersensitivity in some individuals.

Hyperbaric oxygen for carbon monoxide poisoning: A systematic review and critical analysis of the evidence

Abstract: Poisoning with carbon monoxide (CO) is an important cause of unintentional and intentional injury worldwide. Hyperbaric oxygen (HBO) enhances CO elimination and has been postulated to reduce the incidence of neurological sequelae. These observations have led some clinicians to use HBO for selected patients with CO poisoning, although there is considerable variability in clinical practice. This article assesses the effectiveness of HBO compared with normobaric oxygen (NBO) for the prevention of neurological sequelae in patients with acute CO poisoning. The following databases were searched: MEDLINE (1966 to present), EMBASE (1980 to present), and the Controlled Trials Register of the Cochrane Collaboration, supplemented by a manual review of bibliographies of identified articles and discussion with recognised content experts. All randomised controlled trials involving people acutely poisoned with CO, regardless of severity, were examined. The primary analysis included all trials from which data could be extracted. Sensitivity analysis examined trials with better validity (defined using the validated instrument of Jadad) and those enrolling more severely poisoned patients. Two reviewers independently extracted from each trial, including information on the number of randomised patients, types of participants, the dose and duration of the intervention, and the prevalence of neurological sequelae at follow-up. A pooled odds ratio (OR) for the presence of neurological symptoms at 1-month follow-up was calculated using a random effects model. Bayesian models were also investigated to illustrate the degree of certainty about clinical effectiveness. Eight randomised controlled trials were identified. Two had no evaluable data and were excluded. The remaining trials were of varying quality and two have been published only as abstracts. The severity of CO poisoning varied among trials. At 1-month follow-up after treatment, sequelae possibly related to CO poisoning were present in 242 of 761 patients (36.1%) treated with NBO, compared with 259 of 718 patients (31.8%) treated with HBO. Restricting the analysis to the trials with the highest quality scores or those that enrolled all patients regardless of severity did not change the lack of statistical significance in the outcome of the pooled analysis. We found empiric evidence of multiple biases that operated to inflate the benefit of HBO in two positive trials. In contrast, the interpretation of negative trials was hampered by low rates of follow-up, unusual interventions for control patients and inclusion of less severely poisoned patients. Collectively, these limitations may have led negative trials to overlook a real and substantial benefit of HBO (type II error). There is conflicting evidence regarding the efficacy of HBO treatment for patients with CO poisoning. Methodological shortcomings are evident in all published trials, with empiric evidence of bias in some, particularly those that suggest a benefit of HBO. Bayesian analysis further illustrates the uncertainty about a meaningful clinical benefit. Consequently, firm guidelines regarding the use of HBO for patients with CO poisoning cannot be established. Further research is needed to better define the role of HBO, if any, in the treatment of CO poisoning. Such research should not exclude patients with severe poisoning, have a primary outcome that is clinically meaningful and have oversight from an independent data monitoring and ethics committee.

Analytical toxicology: guidelines for sample collection postmortem.

Abstract: The reliability and relevance of any analytical toxicology result is determined in the first instance by the nature and integrity of the specimen(s) submitted for analysis. This article provides guidelines for sample collection, labelling, transport and storage, especially regarding specimens obtained during a postmortem examination. Blood (5 mL) should be taken from two distinct peripheral sites, preferably left and right femoral veins, taking care not to draw blood from more central vessels. Urine (if available), vitreous humour (separate samples from each eye), a representative portion of stomach contents, and liver (10-20 g, right lobe) are amongst other important specimens. A preservative (sodium fluoride, 0.5-2% weight by volume (w/v) should be added to a portion of the blood sample/the sample from one vein, and to urine. Leave a small (10-20% headspace) in tubes containing liquids if they are likely to be frozen. Precautions to minimise the possibility of cross-contamination of biological specimens must be taken, especially if volatile poison(s) may be involved. If death occurred in hospital, any residual antemortem samples should be sought as a matter of urgency. Hair/nail collection should be considered if chronic exposure is suspected, for example, in deaths possibly related to drug abuse. A lock of hair the width of a pen tied at the root end is required for a comprehensive drug screen. The value of providing as full a clinical/occupational/circumstantial history as possible together with a copy of the postmortem report (when available) and of implementing chain-of-custody procedures when submitting samples for analysis cannot be over-emphasised.

Management of the cardiovascular complications of tricyclic antidepressant poisoning : role of sodium bicarbonate.

Abstract: Experimental studies suggest that both alkalinisation and sodium loading are effective in reducing cardiotoxicity independently. Species and experimental differences may explain why sodium bicarbonate appears to work by sodium loading in some studies and by a pH change in others. In the only case series, the administration of intravenous sodium bicarbonate to achieve a systemic pH of 7.5–7.55 reduced QRS prolongation, reversed hypotension (although colloid was also given) and improved mental status in patients with moderate to severe tricyclic antidepressant poisoning. This clinical study supports the use of sodium bicarbonate in the management of the cardiovascular complications of tricyclic antidepressant poisoning. However, the clinical indications and dosing recommendations remain to be clarified.

Tricyclic antidepressant poisoning : central nervous system effects and management.

Abstract: All tricyclic drugs are potentially able to cause the main acute CNS toxic syndromes of coma and convulsions. Dosulepin (dothiepin) seems more likely to cause convulsions than other drugs in this class, and amitriptyline also appears a more toxic tricyclic agent. Coma is the most useful sign indicative of toxic risk and appears to predict severe toxic complications (fits and arrhythmias) more reliably than ECG changes. Prophylactic therapy against convulsions has not been shown to be effective. Use of an anticholinesterase (physostigmine) is not recommended for management of coma. There is no good evidence base to support a particular anticonvulsant.

Interpretation of Analytical Toxicology Results in Life and at Postmortem

Abstract: Interpretation of analytical toxicology results from live patients is sometimes difficult. Possible factors may be related to: (i) the nature of the poison(s) present; (ii) sample collection, transport and storage; (iii) the analytical methodology used; (iv) the circumstances of exposure; (v) mechanical factors such as trauma or inhalation of stomach contents; and (vi) pharmacological factors such as tolerance or synergy. In some circumstances, detection of a drug or other poison may suffice to prove exposure. At the other extreme, the interpretation of individual measurements may be simplified by regulation. Examples here include whole blood alcohol (ethanol) in regard to driving a motor vehicle and blood lead assays performed to assess occupational exposure. With pharmaceuticals, the plasma or serum concentrations of drugs and metabolites attained during treatment often provide a basis for the interpretation of quantitative measurements. With illicit drugs, comparative information from casework may be all that is available. Postmortem toxicology is an especially complex area since changes in the composition of fluids such as blood depending on the site of collection from the body and the time elapsed since death, amongst other factors, may influence the result obtained. This review presents information to assist in the interpretation of analytical results, especially regarding postmortem toxicology. Collection and analysis of not only peripheral blood, but also other fluids/tissues is usually important in postmortem work. Alcohol, for example, can be either lost from, or produced in, blood especially if there has been significant trauma, hence measurements in urine or vitreous humour are needed to confirm the reliability of a blood result. Measurement of metabolites may also be valuable in individual cases.

Poisoning due to pyrethrins.

Abstract: 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.

Is Electric Arc Welding Linked to Manganism or Parkinson’s Disease?

Abstract: Manganese and its inorganic compounds are widely used in many industries and have been accepted as occupational neurotoxins that have caused a distinct and disabling clinical entity, manganism, in several types of work, notably where exposure is by way of dust. There is inconclusive and inconsistent evidence that, in these occupations, subclinical neurological effects, detectable only by neurobehavioural studies, may be caused by low doses. This has prompted a re-evaluation of occupational exposure limits. Some countries, including the UK, already demand much higher levels of protection against exposure than 5 years ago. Welding is the most common source of occupational exposure as manganese is an essential component of steel and so its compounds are inevitable components of fume emitted from steel welding processes. There it is found in respirable particles, often as complex oxides (spinels), sometimes within a core protected by a silicon oxide shell - as distinct from the much simpler form of particle formed by disintegration in processes such as mining and ore milling where manganism has been diagnosed convincingly. Millions of workers are at risk of exposure to manganese-containing compounds in fumes from electric arc welding of steel. In recent years it has been asserted that neurological and neurobehavioural disorders may develop consequent to exposure to steel welding fumes and that employment as a welder is associated with the unusually early onset of Parkinson's disease. Causal relationships have been postulated. Welders have been recorded as having been exposed to high levels of manganese-containing fume, especially where they have worked in confined, unventilated spaces, although this appears from limited data to be the exception rather than the rule. Even then the dose received is generally less than in mining or ore crushing. When care is taken to exclude exposures from hardfacing and burning and cutting arc processes, where manganese may form a high percentage of the fume, manganese compounds usually form a relatively low percentage of the composition of welding fume particles, 65 years. It has been suggested, on flawed and contested evidence, not that welding causes the disease but rather that employment as a welder carries with it the risk of developing this disease at a younger age than if that trade had not been followed. Manganese in welding fume has been nominated as the neurotoxin. This may be biologically feasible if manganese destroys insufficient receptor cells to produce clinical manganism but sufficient to enhance the effects of a reduced supply of dopamine to give the manifestations of already developing idiopathic Parkinson's disease earlier in the course of destruction of the substantia nigra than if all receptors were intact.

Air pollution and the heart : cardiovascular effects and mechanisms.

Abstract: There has been increasing awareness in recent years of the adverse cardiovascular effects of ambient air pollution. The recent publication of a statement from the Expert Panel on Population and Prevention Science of the American Heart Association has highlighted this issue. It has been appreciated for several decades that major pollution episodes, such as that associated with the London Fog of 1952, are responsible for increased numbers of deaths and most of these are due to cardiorespiratory causes. Realisation of this prompted government and environmental health initiatives to reduce emissions through establishing air quality standards. Previously, the major sources of air pollution were related to domestic coal burning and industry. However, the pattern of emissions in modern developed countries has changed, resulting in a pollution mixture of different composition to that on which early air quality standards were based. Even current 'lower' levels of air pollution have been shown consistently to be associated with adverse health effects. Over the past two decades, a wealth of epidemiological studies have considered both long- and short-term health effects of air pollution. Although the relative risk of respiratory disease in relation to air pollution exposure seems to be higher than that of cardiovascular disease, the latter are of greater absolute significance in population terms. A number of hypotheses have been proposed in order to explain the observed associations, and recent research efforts have focused on examining the mechanisms underlying the effects. It is suggested that certain subgroups of the population such as the elderly or those with pre-existing cardiorespiratory disease may be more susceptible to the effects of air pollution, and analysis of survival data from cohort studies supports this observation.

The management of tricyclic antidepressant poisoning : the role of gut decontamination, extracorporeal procedures and fab antibody fragments.

Abstract: Although there have been descriptive, uncontrolled clinical reports of removal of tablet debris by gastric lavage, there have been no clinical studies that have demonstrated that this has any impact on outcome in patients with tricyclic antidepressant (TCA) poisoning. There is also the possibility that lavage may increase drug absorption by pushing tablets into the small intestine. Furthermore, gastric lavage in patients with TCA poisoning may induce hypoxia and a tachycardia potentially increasing the risk of severe complications such as arrhythmias and convulsions. In view of the paucity of evidence that gastric lavage removes a significant amount of drug and the risk of complications associated with the procedure, the routine use of gastric lavage in the management of patients with TCA poisoning is not appropriate.

Poisoning due to urea herbicides

Abstract: 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%.

A clinical and pharmacoeconomic justification for intravenous acetylcysteine : A US perspective

Abstract: Paracetamol (acetaminophen) poisoning remains the most common exposure reported to US poison information centres and the leading cause of poisoning-related fatalities, despite the availability of an effective antidote, acetylcysteine. Oral acetylcysteine solution has been approved for the management of acetaminophen poisoning in the US for four decades. Until the recent approval of intravenous acetylcysteine in the US, it was necessary to compound the oral solution for intravenous administration. The effectiveness and tolerability of oral and intravenous acetylcysteine for the prevention of hepatotoxicity induced by paracetamol poisoning are well established in the literature. Intravenous acetylcysteine may be preferred over oral administration based on improved tolerability, ease of administration and the shortened course of therapy (20 hours intravenous vs 72 hours oral). The two intravenous acetylcysteine regimens documented in the literature, 48 hours and 20 hours, have similar efficacy when started within 8-10 hours of ingestion. Although there are no legal concerns with continuing the routine compounding of the oral solution to an intravenous product, new standards for pharmacy compounding of sterile preparations set forth by the US Pharmacopoeia highlight that the risk of compounding products for intravenous use must be assessed carefully. Changing the route of administration of a sterile oral solution to an intravenous preparation, when a commercial sterile and pyrogen-free product is available, may not be advisable. The best cost-containment strategies must be used for introduction of the more costly sterile, pyrogen-free intravenous acetylcysteine formulation by hospitals and healthcare systems. The intravenous acetylcysteine product is more cost effective when given for 20 hours than other treatment protocols based on the costs of acetylcysteine and hospitalisation. If used per protocol, the 20-hour intravenous acetylcysteine regimen may decrease hospital length of stay, thereby, offsetting the increased drug cost. Data conflict on the efficacy and administration of intravenous acetylcysteine for off-label uses, such as radiographic contrast media-induced nephropathy prevention and reperfusion in orthotopic liver transplantation. The costs for the intravenous formulation for these indications is significantly higher than use of the oral formulation for oral administration in radiographic contrast media-induced nephropathy prevention and compounded for intravenous use in orthotopic liver transplantation. The oral solution should be retained by healthcare systems for oral and inhalation applications, such as respiratory conditions, oral administration for radiographic contrast media nephropathy prevention, or the use of the 72-hour oral protocol to treat paracetamol poisoning, when the intravenous preparation cannot be used.

Treatment of US crotalidae bites: comparisons of serum and globulin-based polyvalent and antigen-binding fragment antivenins.

Abstract: In the US, two antivenins are marketed for the treatment of snake envenomation. The horse-derived serum-globulin-based Antivenin (Crotalidae) Polyvalent (ACP) has been available since 1954. There are few data on the efficacy and incidence of adverse events that occur following the administration of ACP. Most of the data are retrospective, anecdotal, or case reports. In 2000, ovine-derived serum-globulin-based ACP (Crofab®) became available. Crofab® is said to cause fewer reactions than ACP, but there are few comparative data to substantiate this claim. Although both antivenins ameliorate the systemic symptoms following snake envenomation, the efficacy of either antivenin in decreasing oedema and swelling is unknown for a number of reasons. Clinical trials are small and have not included control arms. The degree of oedema, as well as the efficacy of the antivenin in decreasing oedema, may depend on the genera of the snake (usually unknown) that envenomated the patient. This article compares available data on clinical aspects of the two antivenins. More prospective data are needed to determine the comparative efficacy of the two antivenins, or the efficacy of Crofab® in preventing tissue oedema. There are still unanswered questions regarding the optimal dosing regimen of Crofab®.

Resolving disputes about toxicological risks during military conflict : the US Gulf War experience.

Abstract: In the last 15 years, the US and UK have fought two major wars in the Persian Gulf region. Controversy has arisen over the nature and causes of health problems among military veterans of these two wars. Toxic exposures have been hypothesised to cause the majority of the long-term health problems experienced by veterans of the 1991 Gulf War. The assessment of these toxic exposures and the resolution of controversy about their health effects provide a unique case study for understanding how toxicological disputes are settled in the US. Neither clinical examination of ill war veterans nor scientific research studies have been sufficient to answer contentious questions about toxic exposures. Numerous expert review panels have also been unable to resolve these controversies except for the US National Academy of Sciences Institute of Medicine (IOM). The IOM has conducted exhaustive and independent investigations based on peer-reviewed scientific literature related to potential health risks during the two Gulf Wars. In four recent studies, IOM committees identified a wide range of previously documented illnesses associated with common occupational and environmental exposures after considering thousands of relevant publications; however, they did not identify a new medical syndrome or a specific toxic exposure that caused widespread health problems among Gulf War veterans. These IOM studies have, therefore, added little to our basic knowledge of environmental hazards because most of the health effects were well known. Nevertheless, this expert review process, which is on-going, has been generally acceptable to a wide range of competing interests because the findings of the IOM have been perceived as scientifically credible and independent, and because none of the postulated toxicological risks have been completely ruled-out as possible causes of ill health among veterans.