OCCUPATIONAL NEUROTOXICOSIS (INTOXICATION BY MERCURY, TETRAETHYLLEAD, MANGANESE).
INTOXICATION BY AGRICULTURE CHEMICAL POISONINGS (CHLORORGANIC COMPOUNDS, ORGANOPHOSPHORUS COMPOUNDS, MERCURIC ORGANIC COMPOUNDS, COMPOUNDS WHICH CONTAIN ARSENIC).
OCUPATIONAL NEUROTOXICOSIS (neurotoxicity and behavioural toxicity, mercury poisoning, tetraethyl lead poisoning, manganese poisoning).
NEUROTOXICITY AND BEHAVIOURAL TOXICITY
Neurotoxikosis – is an occupational intoxication, in which central and peripheral nervous system mainly affect
Neurotoxicity can be defined as any chemicallyinduced adverse effect on any aspect of the central and peripheral nervous system, including various supportive structures. From this “it follows that ‘neurotoxicity’ is associated both with various types of pathological, physiological, biochemical and neurochemical changes in the nervous system, and various types of functional and neurobehavioural changes. Obviously, neurotoxicity is not a single end-point that can be evaluated in a single test system. Pathological changes in various regions of the brain and/or clinical signs of intoxication deriving from CNS toxicity (e.g. piloerection, tremor or coma) can be monitored in the acute and repeated dose toxicity studies. Chemically-induced behavioural changes (often rather subtle effects) are more difficult to monitor. This usually requires a completely different type of testing procedure, not always familiar to a ‘traditionally’ trained toxicologist. Despite the absence of internationally accepted testing guidelines for the testing of behavioural effects in experimental animals, there are several test systems available measuring various types of subtle CNS effects (e.g. changes in the reflexive or schedule-controlled behaviours, or reduced performances in different learning and memory tasks). The whole concept of behavioural toxicology is based on the notion that behaviour is the final functional expression of the whole nervous system (indirectly including also the endocrine system and other organs). The general idea is that behavioural changes can be used as sensitive indicators of chemically-induced neurotoxicity, both in adult animals and in animals exposed in utero, or shortly after birth (‘neurobehavioural teratology’). Behavioural toxicity tests are based on changes either in an internally generated behaviour of the animals (e.g. their natural social or exploratory behaviours), or a stimulus-oriented behaviour. The latter tests are either directed towards an operant conditioned behaviour (the animals are trained to perform a task in order to avoid a punishment or to obtain a reward), or classical conditioning (the animals are learned to associate a conditioning stimulus with a reflex action). Typical responses recorded in the various types of behavioural toxicity tests are: ‘passive avoidance’; ‘auditory startle’; ‘residential maze’ and ‘walking patterns’. It is not always easy to interpret the results from behavioural neurotoxicity tests. Apart from the obvious problems associated with the functional reserve and adaptation of the nervous systems, there is also an inherent large variability in behaviour. Since neurobehavioural testing usually involves multiple testing, using multiple measurements in several different test systems, there is an obvious risk for ‘mass significance’ which sometimes can make the statistical analysis rather dubious.
Mechanisms of toxicity
Most toxicants (genotoxicants, chemical carcinogens, neurotoxicants, sensitizers, immunotoxicants, reproductive toxins, teratogens, liver poisons, etc.) induce their adverse effects by interacting with normal cellular processes. Many toxic responses are the ultimate result of cell death leading to loss of important organ functions. Other responses follow from interactions with various biochemical and physiological processes, not affecting the survival of the cells. Common mechanisms of ‘toxic action’ include receptorligand interactions, interference with cellular membrane functions, disturbed calcium homeostasis, disrupted cellular energy production, and/or reversible or irreversible binding to various proteins, nucleic acids and other ‘biomolecules’. Toxicity can be the result of one specific physiological change in a single target organ, or follow from multiple interactions at different sites, in several organs and tissues. In a review such as this, it is not possible to go into details about the mechanisms of actions underlying various types of ‘toxicological end-points’, so what follows is a brief description of some of the most important mechanisms of toxicity. Many toxicants induce their adverse effects by binding to an active site on a biologically active molecule. This molecule can be a protein (e.g. a ‘high-affinity’ receptor, a bioactivating or detoxifying enzyme, a DNA-repair enzyme, a channel protein or a transport protein), a nucleic acid (DNA or RNA), a lipid, or other macromolecules with important biological functions. A ‘receptor’ is usually referred to as a high-affinity binding site interacting with an endogenous ligand. Typical examples of such receptors are those interacting with various neurotransmittors in the CNS, and the intracellular receptors interacting with, for example, calcium or various steroid hormones. However, in a broad sense a receptor can be defined as any binding site available for a particular ligand. Toxicants interfere with both type of receptors. When a toxicant binds to a high-affinity receptor for endogenous ligands, it can either ‘activate’ the biological responses mediated by the receptor or block its function. An ‘agonist’ is an agent interacting with the receptor in the same way as the endogenous ligand. The agonist can act directly by binding to the receptor or indirectly by increasing the concentration of the endogenous ligand at the receptor (e.g. by inhibiting its degradation). Agents blocking the normal function of the receptor are known as antagonists. There are numerous examples of toxicants acting by binding to various macromolecules. For example, many genotoxic agents form various types of DNA adducts by binding covalently to DNA (increasing the risk for critical mutations). The anoxia following from the high-affinity binding between carbon monoxide and haemoglobin is another example of an adverse effect which is due to binding (in this case a non-covalent binding). ‘Metabolic poisons’ interfere with the biological activity of various enzymes (e.g. various phase I and phase II enzymes). Some toxicants do this by binding to the enzymes, thereby changing their structure. Other types of ‘metabolic poisons’ interfere with the metabolic pathways by competitive inhibition. Toxicants can also interfere with the cellular energy production. One way of doing this is to inhibit the oxidative phosphorylation in the mitochondria, interfering with the production of high-energy phosphates such as adenosine triphosphate (ATP). Other toxicants act as ‘cellular poisons’ by interfering with various membranebound functions and transport processes. Among those are many potent neurotoxins acting as ion channel blockers by binding to various channel proteins. Many toxicants form reactive intermediates during the metabolic biotransformation. The electrophilic intermediates formed can bind directly to various cellular macromolecules, but they can also induce ‘oxidative stress’ in the cells. This will eventually lead to the formation of various reactive oxygen species, including highly reactive hydroxyl radicals interacting with, for example, DNA (causing DNA damage) and unsaturated fatty acids in the cell membrane (causing lipid peroxidation). Oxidative stress has been implicated as an important factor in many biological processes, including ageing, inflammatory reactions and tumour development. Lipid peroxidation (which is associated with an increased fluidity of cell membranes, membrane disruption and cell necrosis) has been implicated as a mechanism of action for many hepatotoxic agents inducing centrilobular liver necrosis.
Clinics. Clinical pattern of acute neurointoxication is manifested by the accumulation of psycho, neurological, somatic and vegetative symptoms. At severe intoxications, consciousness is in disorder, toxic coma or acute hypoxication psychosis develops.
At chronic intoxications, changes on the side of the nervous system can be manifested through syndromes of the vegetative and vessel dystonia (dysfunction), asthenovegetative and asthenoneurotic ones. In the later stage of toxic process, there are organic changes of the nervous system – toxic encephalopathy. Disorder of peripheral sectors of the nervous system can be manifested in the form of movable, sensitive and mixed forms of toxic polyneuropathies. There is also a vegetative-sensitive form of the latter. Along the progress of neurointoxication there are two stages – functional disorder of the nervous system, which is manifested in earlier terms of the impact of poison and is characterized by the reversibility of changes, and the stage of limited changes in the central and peripheral nervous systems. Organic symptoms develop in case of long work period under unfavorable work conditions and are characterized by stable and long progressing even under conditions of the termination of the contact with the matters.
MERCURY POISONING
Mercury has been used commercially and medically for centuries. In the past it was a common constituent of many medications. It is still used in hospitals in thermometers and blood-pressure cuffs and commercially in batteries, switches, and fluorescent light bulbs. Large quantities of metallic mercury are employed as electrodes in the electrolytic production of chlorine and sodium hydroxide from saline. These uses still give rise to accidental and occupational exposures.
Mercury has been used for various purposes, including medicinal. Prehistoric cave drawings were made using cinnabar, the red ore containing mercuric sulfide. The Romans mined cinnabar (common ore of mercury) to extract mercury, and alchemists used mercury in their attempts to create gold from other metals. Today, mercury is produced as a by-product of gold and bauxite mining. Medicinal uses of mercury have included its use as a diuretic, antiseptic, skin ointment, laxative, and as a treatment of syphilis. Mercury has also been used as a poison. In an ironic illustration of the dose-related properties of mercury, the great sculptor Benvenuto Cellini, was apparently cured of a severe case of syphilis when poisoned by a sublethal dose of mercury.
Today, however, exposure of the general population comes from three major sources: fish consumption, dental amalgams, and vaccines. Each has its own characteristic form of mercury and distinctive toxicologic profile and clinical symptoms. Dental amalgams emit mercury vapor that is inhaled and absorbed into the bloodstream. Dentists and anyone with an amalgam filling are exposed to this form of mercury. Liquid metallic mercury (quicksilver) still finds its way into homes, causing a risk of poisoning from the vapor and creating major cleanup costs. Humans are also exposed to two distinct but related organic forms, methyl mercury (CH3Hg+) and ethyl mercury (CH3CH2Hg+).
Fish are the main if not the only source of methyl mercury, since it is no longer used as a fungicide. In many countries, babies are exposed to ethyl mercury through vaccination, since this form is the active ingredient of the preservative thimerosal used in vaccines. Whereas removal of certain forms of mercury, such as that in blood-pressure cuffs, will not cause increased health risks, removal of each of the three major sources described in this article entails health risks and thus poses a dilemma to the health professional. Exposure to mercury from dental amalgams and fish consumption has been a concern for decades, but the possible risk associated with thimerosal is a much newer concern. These fears have been heightened by a recent recommendation by the Environmental Protection Agency (EPA) that the allowable or safe daily intake of methyl mercury be reduced from 0.5 μg of mercury per kilogram of body weight per day, the threshold established by the World Health Organization in 1978, to 0.1 μg of mercury per kilogram per day.
† The half-life in blood is about 20 days in adults but may be as short as 7 days in infants. Chelators can remove methyl and ethyl mercury from the body; they cannot reverse the damage to the central nervous system. They may, however, prevent further deterioration.
MERCURY VAPOR FROM DENTAL AMALGAMS
Dental amalgams have been in use for over 150 years. They are inexpensive and thought to be more durable and easier to use than other types of fillings. The amalgam consists of approximately 50 % mercury combined with other metals such as silver and copper. Since their introduction, dental amalgams have been a source of controversy because of the assumed health risks of mercury. Brain, blood, and urinary concentrations correlate with the number of amalgam surfaces present. It has been estimated that 10 amalgam surfaces would raise urinary concentrations by 1 μg of mercury per liter, roughly doubling the background concentrations.
Higher urinary concentrations are found in persons who chew a great deal. For example, the long-term use of nicotine chewing gum will raise urinary concentrations close to occupational health limits. The removal of amalgam fillings can also cause temporary elevations in blood concentrations, since the process transiently increases the amount of mercury vapor inhaled.
Cases of poisoning from inhalation of mercury vapor have been recognized for centuries. Severe cases are characterized by a triad of intentional tremor, gingivitis, and erethism (Table 1). Erethism consists of bizarre behavior such as excessive shyness and even aggression. Today’s occupational exposures, such as in the dental office, are lower and may lead to mild, reversible effects on the kidney or mild cognitive changes and memory loss. Current concern arises from claims that long-term exposure to low concentrations of mercury vapor from amalgams either causes or exacerbates degenerative diseases such as amyotrophic lateral sclerosis, Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease. Speculation has been most intense with respect to Alzheimer’s disease after a report that the brains of patients with Alzheimer’s disease had elevated mercury concentrations.
MERCURY VAPOR FROM QUICKSILVER IN THE HOME
Mercury is one of two elements (bromine is the other) that are liquid at room temperature. Its elemental symbol is Hg, derived from the Greek word hydrargyrias, meaning “water silver.” This is a fitting term, since elemental mercury does resemble liquid silver. The greatest source of mercury happens to be natural. Outgassing of granite rock accounts for more than 80% of the mercury found in the atmosphere and on the earth’s surface.
As with other metals, mercury exists in multiple oxidative states, as inorganic salts, and as organic complexes [F1]. Mercury poisoning can result from vapor inhalation, ingestion, injection, or absorption through the skin.
The American Conference of Governmental Industrial Hygienists (ACGIH) has established a threshold limit for mercury vapor of 0.05 mg/m3 of air for continuous 40 hours/week exposure. Long-term chronic exposure to mercury vapor in excess of 0.05 mg/m3 of air may result in cumulative poisoning. Since mercury easily vaporizes at room temperature, the route of absorptionis often through the lungs. In humans, approximately 70% to 85% of a dose is absorbed in this manner whereas less than 3% of a dose will be absorbed dermally. If elemental mercury is ingested orally, less than 0.1% is absorbed from the gastrointestinal (GI) tract and, therefore, when orally ingested is only mildly toxic.
High levels of exposure to mercury vapor can result from the cultural and religious use of elemental mercury, including sprinkling mercury on the floor of a home or car, burning it in a candle, and mixing it with perfume. Infants and young children, whose breathing zones are closest to the floor, are at highest risk, since mercury vapor is heavy and tends to form layers close to the floor. Ingested liquid mercury passes through the gastrointestinal tract essentially unabsorbed. Centuries ago a tablespoonful of quicksilver was used to treat constipation. It arguably represents one of the first uses of gravity in medicine.
METHYL MERCURY
Organic mercury can be found in 3 forms: aryl, short, and long chain alkyl compounds. The organic mercury compounds are of great interest today because they are often found in the food chain and have been used to inhibit bacterial growth in medications. Organic mercury is also found in fungicides and industrial run-off. As a result, exposure to these materials islikely. The toxicity of these compounds depends upon the ease with which the organic moiety can dissociate from the anion. Organic mercurials are absorbed more completely from the GI tract than inorganic salts in part because they are more lipid-soluble and because they bind to sulfhydryl groups. More often, organic mercurials are absorbed from the GI tract by forming a complex with L-cysteine and crossing cell membranes on the large neutral amino acid carrier. They are also corrosive, although less corrosive than inorganic forms. Once absorbed in tissues, the aryl and long chain alkyl compounds are converted to divalent cations that possess inorganic mercury toxic properties. The short chain alkyl mercurials are readily absorbed in the GI tract (90% to 95%) and remain stable in their initial forms. Alkyl organic mercury compounds have high lipid solubility and are distributed uniformly throughout the body, accumulating in the brain, kidney, liver, hair, and skin. Organic mercurials also cross theblood-brain barrier and placenta and penetrate erythrocytes, attributing to neurological symptoms, teratogenic effects, and high blood to plasma ratio, respectively. Methylmercury has a high affinity for sulfhydryl groups, which explains its effect on enzyme dysfunction. One enzyme that is inhibited is choline acetyl transferase, which is involved in the final step of acetylcholine production. This inhibition may lead to acetylcholine deficiency, contributing to the signs and symptoms of motor dysfunction. Excretion of alkyl mercury occurs mostly in the form of feces (90%), secondary to significant enterohepatic circulation. The biological half-life of methyl mercury is approximately 65 days.
Figure 1. The Global Cycle of Mercury. Iature, mercury vapor (Hg0), a stable monatomic gas, evaporates from the earth’s surface (both soil and water) and is emitted by volcanoes (Panel A). Anthropogenic sources include emissions from coal-burning power stations and municipal incinerators. After approximately one year, mercury vapor is converted to a soluble form (Hg2+) and returned to the earth in rainwater. It may be converted back to the vapor form both in soil and in water by microorganisms and reemitted into the atmosphere. Thus, mercury may recirculate for long periods. Mercury attached to aquatic sediments is subject to microbial conversion to methyl mercury (MeHg), whereupon it enters the aquatic food chain. It reaches its highest concentrations in long-lived predatory fish, such as sharks. Panel B indicates the routes of transformation to methyl mercury as originally suggested by Jernelov. Panel C depicts the increase in mercury concentrations in feathers of fish-eating birds in Sweden. The period covered by these data corresponds approximately to the growth of industrialization in Sweden.
EXPOSURE IN ADULTS
Cases of severe, even fatal, methyl mercury poisoning date back to the 1860s in England, when such mercurials were first synthesized. Subsequent cases arose through occupational and dietary exposures. Several large outbreaks were caused by the consumption of bread mistakenly made from break in 1971 and
The brain is the primary target tissue. Adults present with paresthesias of the circumoral area and hands and feet, followed by visual-field constriction and ataxia. Neuropathological examination reveals regional destruction of neurons in the visual cortex and cerebellar granule cells. There is usually a latent period of weeks or months between exposure and the onset of symptoms.
Several studies have reported statistical associations between cardiovascular disease and mercury, mostly in the form of methyl mercury. One study found a direct relation between mercury concentrations and the risk of myocardial infarction, whereas a nested case–control study of more than 300,000 health professionals found no such association. A third study, from eastern Finland, where the consumption of saturated animal fat is high, found an association, but the authors suggested that their finding might be specific to the region. A fourth study among seven-year-old children on the Faeroe Islands found that blood pressure was increased when the blood mercury concentration was below 10 μg per liter but not when it was higher. “Contrary to expectation,” as the authors stated, “this association occurred within an exposure range characteristic of communities not depending on marine food” such as the United States. They also pointed out that “the average birth weight in this fishing community is the highest in the world and therefore the community may represent a unique setting.” Thus, firm conclusions about cause and effect cannot be yet made, since cardiovascular disease has multiple risk factors (e.g., family history, stress, dietary habits, smoking, alcohol use, diabetes, and socioeconomic status). The researchers themselves recognize this complication and use extensive statistical measures to correct for these factors. Prospective studies are needed to settle this issue.
Clinical picture.
Heavy-Metal Meals of MercuryA 28-year-old flight engineer from Singapore presented with nausea, lethargy, and tremor. He had been defecating an increasingly large quantity of silver droplets, which were identified on laboratory analysis as elemental mercury. An abdominal radiograph showed punctate opacities along the entire course of the colon. The urine mercury level was 26.1 μg per liter (130.1 nmol per liter). He required only antiemetic treatment in the hospital. For 12 weeks, the patient’s mother-in-law had provided him with a traditional Indian medicine containing elemental mercury and meals to which approximately 3 Tbs of elemental mercury had been added. The ingestion of elemental mercury is widely regarded as harmless because it is poorly absorbed. However, prolonged exposure caused by continuous oral intake of large quantities may result in systemic toxicity because the elemental mercury is volatized into a highly absorbable vapor or converted to a toxic divalent form. The patient’s lethargy, nausea, and tremor resolved within 8 weeks after the cessation of mercury consumption, and his urine mercury level decreased to 20.5 μg per liter (102.2 nmol per liter) at 4 weeks, 13.8 μg per liter (68.8 nmol per liter) at 36 weeks, and 3.3 μg per liter (16.5 nmol per liter) at 2 years.
There are acute and chronic poisonings.
A c u t e forms of poisoning with mercury under production conditions are not frequent. They can appear not only in case of permeation of a big amount of mercury into the organ is, for example, during accidents. Clinical pattern of acute intoxications develops fast and progresses rather actively. The following signs appear: sharp weakness, illness, headache, nausea, vomiting, feeling of metal taste in the mouth, and excessive salivation. Swelling and bleeding of gums and thrush can be observed. With time, pain in stomach appears, and acute asthenization takes place. In case of timely treatment, the forecast is favorable and patients recover.
C h r oi c intoxication with mercury under conditions of production can be met more frequently. First symptoms of poisoning can appear in several days as a rule after the beginning of the contact with mercury. For a long time, the disease develops without obvious symptoms.
First manifestations of the intoxication are not clear; they do not attract the attention of the patient. Sometimes, in the result of acute infection of the organism and under the impact of other unfavorable factors, the latent progressing of intoxication suddenly becomes sharp. The progressing of chronic mercurialism has three stages.
Stage I has the name of “mercuric neurasthenia. Patients complain to have headache, fast fatigability, irritation, disturbed superficial sleep, with bright dreams, which are remembered well, and drowsiness. Palpitation increased sweating, inclination to constipations, metal taste in the mouth, and excessive salivation. Gradually, these symptoms are increased, feeling of internal shivering, pain in limbs of hands and feet, and the feeling of numbness of limbs. It is very characteristic for them to have hyperesthesia no noise, bright light, and lability of mood. Memory of recent events, faces, and dates worsens; learning of new materials is more difficult. Asthenic and neurological disorders can be observed, like tremor of fingers of outstretched hands with characteristic symmetry, increase of tendon reflexes, stable red demographism, and hyperhydrosis.
Lability of pulse with the inclination to tachycardia can be observed. A number of trophic disorders take place (nail fragility, hair shedding and gingivitis). Often there are disorders of endocrine glands: dysmenorrhea, early climax, and dysfunction of thyroid gland. In case of timely release of patients from work, connected with the contact with mercury, this stage is considered a completely reverse.
Stage II of the chronic mercury intoxication has the name of “mercuric erythrism”. It can be characterized by asthenia, loss of weight, headache, sleep disorder, inclination to depression, and acute decrease of the ability to work. The so-called “mercuric erythrism develops – that is the state of increased anxiety, irritability, fear, diffidence, shyness with fast reddening of face when worrying, and inability to continue usual work in the presence of other people. From the side of neurological state, trembling of eyelids, tongue, and fingers of outstretched hands develop. Hand trembling is stable, what makes completion of work, which requires little exact movements, significantly difficult. The feeling of particular distrustfulness and suspicion; the patient concentrates much on his/her sick feeling. Often there can be seen bleeding of gums, marked gingivitis, stomatitis, and caries. It is characteristic to have copper color of gullet and soft palate. Signs of chronic gastritis, gastroenterocolitis with profuse diarrhea and intensive pain in stomach can be observed. Due to timely treatment, the majority of signs of this state disappear, though rudimentary phenomena can stay.
Stage III of chronic mercuric intoxication is called a “mercury encephalopathy”. Patients complain to have stable headache and permanent insomnia. It is very characteristic for patients in this state to have depression; however, sometimes, psychological disorders can be manifested through uninhibited anxiety and up to hysteria. There is also a syndrome of impulsive obsession, fear, visual and hearing hallucinations. With time, patients suffer from syncope, and epileptiform fits with losing consciousness and spasms. Also, psycho disorder can be manifested through the disorder of the memory, schizoid-like conditions, where hallucinatory phenomena, fears, deviation into the affective –emotional sphere, and sometimes’ emotional dullness” can be observed. Also, fast development of psychoses with the forecast of loony stage is possible.
Necrotizing nephrosis
In the neurological state, there are affections of VII and XII pairs of craniocerebral nerves according to the central type, symptoms of the affection of basal ganglia and moderate pyramidal disorders. There is asymmetry of nasolabial folds, horizontal pathological nystagmus, anisocoria and hypomia. Tendon reflexes are active, their zone is expanded, and clonus and pathological reflexes are possible. Intention tremor of fingers, which is characteristically marked, is accompanied by choreolike twitching. This state has the tendency to generalization with spreading to the head, corps and legs, and it is often starts looking like generalized hyperkinesias. Tremor of hands conditions a corresponding change of the handwriting. In rare cases, the polyneuretic syndrome with atrophy of small muscles of hands develops; and tendon reflexes decreases. Thus, clinical manifestations of mercury encephalopathy are characterized by significant psycho disorders and clear nucleuses or spread neurological indications. Neurological symptoms are accompanied by the loss of appetite, significant lost of weight, and acute general weakness.
From http://www.wellsphere.com/general-medicine-article/freya-koss/362730
Diagnosis.
Laboratory Studies
Exposure to mercury and mercury compounds can be determined using blood, urine, or hair samples. The quantity of mercury in blood and urine correlates with toxicity. Samples should be collected in trace-metal-free containers. Urine mercury levels are typically less than 10 to 20 µg/24 hours. Excretion of mercury in urine is a good indicator of inorganic and elemental mercury exposure but is unreliable for organic mercury (methylmercury) because elimination occurs mostly in the feces. No absolute correlation exists between the urine mercury levels and the onset of symptoms; however, neurologic signs may be present atlevels higher than 100 µg/L. Urine concentrations of mercury greater than 800 µg/L are usually associated with death. Mercury levels in the urine also can be used to gauge the efficacy of chelation therapy. Guidelines from several occupational health groups and the WHO consider urinary excretion of mercury > 50 µg/L suggestive of significant exposure. Hair has high sulfhydryl content. Mercury forms covalent bonds with sulfur and, therefore, can be found in abundance in hair samples. However, the rate of false positive results is high with hair analysis secondary to environmental exposure. Hair analysis should not be used alone to confirm mercury toxicity or exposure. Generally, mercury concentrations in the hair do not exceed 10 mg/kg. Following moderate and severe intoxications with methylmercury, hair concentrations were 200 to 800 mg/kg and approximately 2,400 mg/kg, respectively.
In 1994, the World Health Organization recommended monitoring of hair levels of methylmercury in women of childbearing age in populations consuming >100 g/day. Maternal hair mercury concentrations >10 ppm indicate an increased risk of neurological deficits in offspring. Because methylmercury concentrates in erythrocytes elevated blood levels are seen in acute toxicity but correlation in chronic methylmercury toxicity is variable. The methylmercury blood-to-plasma ratio has been touted as a means to differentiate methylmercury and arylmercury exposure.
Arylmercury exposure is characterized by a lower blood-to-plasma ratio than observed with methylmercury exposure. Whole blood mercury levels are usually <10 µg/L (ppb) in unexposed individuals (exceptions may be individuals with a high dietary intake of fish).
Inorganic mercury redistributes to other body tissue; thus, its levels in the blood only are accurate after an acute ingestion. In general, blood levels of mercury are helpful for recent exposures and for determining if the toxicity is secondary to organic or inorganic mercury, but they are not useful for a guide to therapy.
Additional testing should include a complete blood count and serum chemistries to assess renal function and possible anemia secondary to GI hemorrhage.
Early typical symptoms: irritability, weakness, gingivitis and stomatitis. Confirmation of diagnosis is mercury determination in urine and feces. Presence of mercury in urine without proper clinical symptoms indicates a “mercury carriage”.
Treatment.
Choice of treatment depends upon the form of mercury involved. For example, elimination of the source of exposure may be sufficient following exposure to a relatively low dose of mercury vapor. As with any toxin, it is critical to obtain as much information as possible regarding the source, time, type, and mode of mercury exposure. Supportive care begins with the ABCs (airway, breathe, circulation), especially when managing the inhalation of elemental mercury and the ingestion of caustic inorganic mercury, both of which may cause the onset of airway obstruction and failure. If the patient was exposed to mercury via the skin, decontamination may involve copious irrigation of the exposed area. Aggressive hydration may be required for acute inorganic mercury ingestion because of its caustic properties, and for the same reason, one should not induce vomiting. Gastric lavage is recommended for organic ingestion, especially if the compound is observed on the abdominal radiographs. Gastric lavage with protein-containing solutions (eg, milk, egg whites, salt-poor albumin) or 5% sodium formaldehyde sulfoxylate solution may bind gastric mercury and limit its absorption. Activated charcoal is indicated for GI decontamination because it binds inorganic and organic mercury compounds to some extent.
Thiol-containing chelating agents such as dimercaprol (BAL), 2,3-dimercaptosuccinic acid (DMSA, succimer), 2,3-dimercapto-1-propane sulfonic acid (DMPS), sodium 4,5-dihydroxybenzene-1,3-disulfonate (Tiron), and penicillamine which compete with endogenous sulfhydryl groups have been used for treating mercury poisoning. In general, chelation therapy is more effective for elemental mercury than for methylmercury elimination. Newer agents such as DMSA and DMPS that can be given orally are replacing the agents such as BAL that are given by deep intramuscular injection.
A promising new chelating agent is N-acetylcysteine. Typically chelation therapy requires repeating cycles lasting for days because of the large volume of distribution, long half-life, and progressive release of mercury from tissues
Good treatment effect is caused by hydrogen sulphide bathes, which are recommended every other day for 1-0 to 12 days. Activator of ferment systems – lipamyd is recommended
In case of presence of neurasthenic syndrome, it is recommended to administer small dosages of sodium bromide (0.5 – 1 % solution) with sodium caffeine-benzol (0.1 – 0.05 %) one spoon – three times a day, antihistamine preparations (Dimedrol, suprastin and phencarol), tincture of leonury, valeriany together with small doses of caffeine. Positive effect is provided by coniferous and sea bathes, the course of 12 to 14 bathes is recommended to take every other day. If the progressing of the disease is long, patients are sent to resort centers or preventoriums of the enterprise after staying in hospital.
Hemodialysis is used in severe cases of toxicity when renal function has declined. The ability of regular hemodialysis to filter out mercury is limited because of mercury’s mode of distribution among erythrocytes and plasma. However, hemodialysis, with L-cysteine compound as a chelator, has been successful. Neostigmine may help motor function in methylmercury toxicity. This toxicity often leads to acetylcholine deficiency. Polythiol is a nonabsorbable resin that can facilitate the removal of methylmercury (short chain alkyl organic mercury), which is then excreted in the bile after enterohepatic circulation.
Verification of the ability to work. At chronic intoxication with mercury of mild stage (functional disorders of the nervous system), patients are transferred to another temporary work for the term up to two months with the provision of the sick leave. In case of the repeated intoxication, insufficient effectiveness of the treatment, and also intoxication of mean and severe degree at the appearing of the intentional tremor, transfer to the work beyond the contact with mercury is obligatory; at intoxication at the border with toxic encephalopathy, patients should receive invalidism group.
Preventive measures. Among preventive measures, first it is necessary to remember about elimination of possible sources of mercuric intoxication (correct keeping of mercury and its compounds, removal of mercury or its replacement with less toxic compounds), localization of sources of contamination of production areas and other zones with mercurous vapors, following corresponding safety norms (ventilation and sealing-in of the equipment) and rules of personal hygiene; regular demercurialization of premises, where sources of mercurous contamination are.
If mercury was spilt onto the floor, it is processed with 20 % solution of iron chloride or covered with sulfur powder. Among preventive measures, it is also necessary to mention preliminary and periodical medical examinations of workers.
TETRAETHYLLEAD POISONING
A tetraethyllead (TEL) is an oily transparent liquid which contains a 64,07 % of lead, well dissolves in organic solvents (ether, alcohol, benzol, petrol and other) and in fats. ТЕL is applied as antidetonate. A dangerous contact with TEL may occur at its producing, mixing with a fuel, at cleaning of petrol cisterns. Tetraethyllead is a strong neurotrop poison.
Pathogenesis
Tetraethyl lead is a strong neutropic and vascular poisoning. It affects all the sectors of the brain, in particular hypothalamic-pituitary system. It causes degenerative changes in liver and heart, and affects adrenal glands.
Clinical picture.
Tetraethyllead Poisoning is characterized by neurological symptoms.
Toxic affection of cerebral neurocytes
Depending on the intensiveness and the duration of the impact of tetraethyl lead onto the organism, acute or chronic poisoning can appear.
A c u t e p o i s oig. Acute intoxication is possible at significant contamination of the external environment, crashes with tetraethyle lead or with massive spilling on themselves with tetraethyle lead or ethyl liquid, as well as after the accidental swallowing of these matters.
In the initial stage (I) of acute poisoning, patients have sudden acute headache, and sometimes, vomiting, metal taste in the mouth and general weakness. Often the state of euphoria and the decrease of critics can be observed. Sleep is affected (it becomes interrupted and superficial, and is accompanied by numerous nightmares); in the sleep, patients cry, toss around the bed, jump and want to run. During the daytime, patients are gripped by the feeling of unexplained worry and fear. They are suppressed, lost and their memory is worsened. Disorders in vegetative nervous system can be found: arterial hypotonia, bradycardia, and hypothermia. The degree of severity of intoxication is determined by the expression of these symptoms. Often, patients are worried by the feeling of formication in some parts of the body – specific paresthesia.
Depending on the character of main symptoms of stage I of acute poisoning, some symptoms can be defined: predeliria, organic and asthenic ones. In prediliria symptom complex, sleep disorder dominates. Dreams are accompanied by the fear of death. It seems to patients that they are followed, tortured, and that they face death danger. Later, hypnagogic hallucinations take place when a patient falls asleep, at first, they look like episodic pictures (a patient sees faces and images of animals), and then they get the character of nightmares. Hallucinations in the period of falling asleep are forerunners of the development of psychomotor agitation.
Organic syndrome on the type of encephalopathy in comparison from predeliria is characterized by the more limited psychopathology. On the front plan, there are disorders of fronto-cerebellar system: ataxia, disorder of movement, nystagmus, and dysarthria, trembling of limbs, and sometimes, intention trembling. Acute headaches and insomnia can be observed as well.
The clinical pattern of the initial period of the acute intoxication with tetraethyl lead in its mildest forms is limited by asthenic syndromes (increased fatigability, disorder of attention, headache, and emotional unbalanced state). At mild forms of acute intoxication, the process is gradually compensated and is over with complete recovery.
Stage II – pre-culminating. In case of acute intoxications with tetraethyl lead in the majority of severe forms, the process can progress, growing into the pre-culminating stage. Delirium develops. Delirium state is the most characteristic manifestation of severe acute poisoning with tetraethyl lead. Feeling of anxiety grows. Patients are depressed, and do not trust those, who surround them. There are visual, hearing and tactile hallucinations, which have threatening character. Everything, what surrounds a patient, is treated by him as an enemy, and targeted against him or her. In the most cases, there is well marked psychomotor agitation, which develops on the background of staggering state of the awareness. Patients become aggressive. They intend to escape from hospital, and jump out of windows. During this period, certain cenestopathy and disorders of the scheme of the body can be observed, what causes the development of hallucination due to physical impact. Delirium syndrome can grow into the culmination stage.
Stage III – culminating, it develops rather actively. The most characteristic symptoms are well-marked psychomotor excitement on the background of impaired consciousness. It is very difficult to keep patients in bed; they tear linen apart, and are very aggressive. On the peak of agitation, vegetative and trophic disorders can be found, connected with the affection of higher sectors of the central nervous system. Disorders of thermal regulation are accompanied b significant increase of the body temperature; leukocitosis and lymphocytosis take place. Breathing becomes more frequent and superficial; blood pressure varies from low indicators to the high ones; as well as profuse sweating can be observed. Sometimes there is a collapse, which can lead to the death of a patient. Those, who underwent toxic psychosis, in future can have defective state of the psyche for a long period of time (emotional unbalanced state, inclination to pathological affects and intellectual degradation).
C h r oi c p o i s oig. Chronic intoxication with tetraethyl lead can be observed among people, who has been contact with small concentrations of these matters for a long period of time. In the progress of chronic poisoning, there are three consecutive stages. In general, intoxication with tetraethyl lead is referred mostly to milder ones, as well as those, which have more favorable progressing.
Initial stage (I) is characterized by asthenic complex of symptoms. Patients complain to have increased fatigability, general weakness, loss of appetite, decrease of memory and attention, disturbed sleep, and emotional instability.
On this background, there are characteristic symptoms for this stage: bradycardia, vessel hypotonia, hypothermia, increased salivation, and sweating. Sleep disorders, can be observed; nightmares take place; feeling of fear, suppressed mood, depression, and sudden emotional outbreaks can be noted. In this stage, chronic poisoning has reverse character.
Stage II of chronic intoxication with tetraethyl lead can be met rarely nowadays. The clinical pattern of the disease gets the character of encephalopathy with more stable changes in the nervous system. Trembling of hands, wobbling when walking, positive symptom of Romberg, dysarthria and nystagmus can be observed. The progress of the disease in this stage is long; patients need prolong treatment, and often, stable consequences can take place: the decrease of the intellect and the disorder of the sleep.
Stage III includes the syndrome of toxic psychosis. More often, it is the reason of the latter is the additional exogenous factor, e.g. administering of alcohol.
Among those, who underwent marked forms of chronic intoxication with tetraethyl lead, residual effects can be observed, like asthenization, sleep disorder, emotional unbalanced state, and the decrease of the ability to work. Often, these patients have fast progressing atherosclerotic process, affecting vessels of the brain and heart. On this background, hypertonic disease often develops, the progressing of which is rather severe.
Treatment.
At acute intoxication, it is recommended to have the following: complete rest, hypnotic from the group of barbiturates. At sudden excitement – intramuscular injections of 10 ml of 10 % solution of hexenal are recommended. Then, administering of 2 % solution of barbital in the microenema (50 ml) is recommended. Intramuscular administering of barbamyl (5 – 10 ml of 5 % solution), intravenous or intramuscular administering of 25 % solution of magnesium sulfate (5 to 10 ml).
Intravenous administering of 40 % solution of glucose (20 ml) with ascorbic acid (300 to 500 mg) and vitamin B1 (40 to
When tetraethyl lead gets to the skin, affected areas should be immediately washed with the help of kerosene or petrol, and then with warm water with soap. It is also necessary to change clothes and underwear.
In case of chronic poisoning and if vegeto-asthenic syndrome takes place: intravenous injections of 40 % solution of glucose (20 ml) with ascorbic acid (300 mg), intramuscular injections of 10 ml of 10 % solution of calcium gluconate (10 to 12 injections), and biogenic stimulators are recommended. At vascular hypotonia: vitamin B1 (40 to 50 mg) intravenously is recommended. At hypertensia: intramuscular injections of magnesium sulfate in the dosage of 5 ml of 25 % solution (15 injections).
Verification of the ability to work. At the initial stage of intoxication – temporary inability to work (occupational sick leave) is issued. Return to work can be only under condition of positive results of treatment and improvement of work conditions. At moderately marked stage – return to work where contact with ethyl petrol is possible is prohibited. Stable restriction of the ability to work (occupational invalidism) and rational job are recommended. Marked stage – the ability to work is strictly restricted or lost (invalidism of group II and III).
Preventive measures. Strict keeping to the stated sanitary and hygienic rules: prohibition of filling machines manually with buckets, sucking in benzene through a hose with the help of mouth, washing hands and clothes in ethyl petrol, keeping to rules of personal hygiene and regulation of feeding during the work, as well as keeping clothes and washing uniform only at the enterprise. Meals should be rich in lecithin. It is necessary to conduct preliminary and periodical medical examinations of workers.
MANGANESE POISONING.
The occupational manganese poisoning occurs among workers who work on the manganese mines, in metallurgical industry at steel making, special alloys producing (ferromanganese – to 80 % of manganese, mirror cast-iron – to 15 % of manganese), at making of electrodes and gumboils which are used for the electric welding, in chemical and lacquer-paint industry, in agriculture (stain of seed for stimulation of plant growth), in rubber industry. Most dangerous is ground and sifting of pound ore, because a lot of small disperse dust of manganese appear.
Into the organism manganese penetrates through the organs of breathing, rarer through a gastrointestinal tract and skin. The oxides of manganese are quickly absorbed. In blood manganese circulates as an unsteady complex with plasma proteins. Manganese is deposited in bones, cerebrum, parenchyma organs. It is excreted from the organism with feces and urine. Manganese may cause bronchial asthma and eczema because of its allergic influence.
Pathogenesis.
Manganese, as a microelement, takes part in biological processes of organism. It influences on metabolic processes, depresses cholinesterase activity , affects metabolism of serotonin. At the protracted and systematic getting into the organism it has a direct influence oervous tissue, and causes vascular violations, increase capillary permeability. It changes activity of enzymes of nervous cells, depresses the biosynthesis of catecholamines, intensifies protein metabolism. The action of manganese is divided into two phases.
The first phase – cholinergic – is characterized by predominance of cholinergic influence.
Second phase – phase of areactivity – injury of acetylcholinoreactive structures.
A manganese influences on the function of thyroid, cardiovascular system, gastrointestinal tract, liver and other.
Pathways Leading to Pain in Peripheral Neuropathy
Clinical picture.
The first clinical indicators of intoxication are often come across in several years of the contact with manganese and its compounds, but it can take place within a shorter period of time (6 to 9 months). Later clinical forms of neucrotoxicosis are possible (in several years after the termination of the contact with manganese).
There are three stages of chronic poisoning with manganese.
Stage I, functional disorders of the nervous system are characteristic: asthenia, drowse, paresthesia and mild weakness in limbs; symptoms of dysfunction of the vegetative nervous system: increased hyperhidrosis and salivation; and vegetative-sensitive polyneuritis. They can be expressed through neurological microsymptoms: mild hypomimia, muscle hypotonia, increased tendon reflexes and hypostesia on the polyneuritic types. Relative change in the psychological activity is characteristic: the decrease of the activity, narrowing of the circle of interests, reduction of memory and attention to the disease, and the increase of the psycho asthenia.
Changes in psyche usually follow neurological symptoms of poisons. There can be sings of inhibition of the function of gonads, thyroid glands, disorder of functions of the liver and gastrointestinal tract. Diagnostics of Stage I of the intoxication through the absence of clear symptoms is more difficult. Besides, the transition to Stage I into Stage II sometimes pass very fast. Besides, such sick people should be under thorough observation.
Stage II of chronic intoxication with manganese is called the stage of the initial toxic encephalopathy. At this stage, marked asthenic syndrome is formed; apathy and drowse develop. Neurological indicators of extrapyramidal insufficiency can be revealed: hypomimia, sensitive bradykinesia, pro-and retropulsion, muscle dystonia with the increase of muscular tonus of some muscles. Sings of polyneuritis, paresthesia in lungs is more expressed and walking up and down stairs is more complicated. Inhibition of the functions of gonads, and adrenal glands is characteristic. Functional disorders of liver and gastrointestinal tract can be observed.
Stage III of poisoning with manganese – manganese Parkinsonism. For this stage, it is characteristic to have severe disorders when moving: mask-like face, dysarthria, disorder of handwriting, “cock” walking (walking on tiptoes, conditioned by the contraction of flexor muscles of foot) or spastic-paretic with foot paresis, rough pro- and retropulsation. All the movements are slow and difficult. Muscle tone is observed, mostly in legs; muscle hypotonia or dystonia can be often observed as well. Tendon reflexes are increased according to the pyramidal type, and polyneuretic type of hypoesthesia can be noted.
A different feature of manganese Parkinsonism is specific psycho disorders: patients are in euphoria, attitude to the disease is reduced or absent, and periodically they have violent emotions (weeping or laughter). Combination of euphoria, laughter and wobbly walking creates the impression of alcoholic intoxication or imbecility. Gradually, the circle of interests of the patient reduces, they become indifferent (symptom of the so-called affective flattening), and general intellect reduces as well. Change of handwriting is specific to it as well; it becomes illegible with the tendency to small image of letters (symptom of micrography).
Handwriting in different stages of manganese poisoning
Sometimes, symptoms, which are rather characteristic to intoxication, are absent. However, the general feature of various symptoms of manganese intoxication is the disorder of plastic tone of muscles with its advantage in some muscle groups. Thus, neurological pattern of manganese intoxication is mostly characterized by the syndrome of Parkinsonism; however, it is not completely covered by it. Presence of the affection of cranial nerves, pyramidal insufficiency, and frequent affection of peripheral nervous system enable to talk about toxic encephalomyelopolyneuritis.
Sometimes, in spite of the termination of the contact with manganese, phenomena of Parkinsonism progress, in particular during the nearest 2 to 3 years.
Clinic of Stage III of manganese intoxication is close to postencephalitic Parkinsonism. At differentiated diagnostics, it is necessary to take into consideration the data of anamnesis (contact with manganese, absence of acute beginning with fever, changes in the blood pattern, double vision, strabismus, and fits of “gaze spasms”. It is also necessary to remember that manganese Parkinsonism has the tendency of faster development, than the postencephalitic one.
Manganese Parkinsonism Toxic hepatitis. Stage of yellow dystrophy
(“cock” walking)
Chronic manganese intoxication among electric welders is characterized by specific clinical progressing. Asthenic syndrome is more expressed. Manifestation of extra pyramidal insufficiency is also possible. Changes as to muscles often manifest through dystonia, component of clinical symptoms is the development of specific polyneuretic syndrome on the background of general asthezation. However, with the development of the pathological process, it is possible to observe merging with extrapyramidal insufficiency. Clinical manifestation of manganese intoxication of electric welders has mild progressing. Tendency to variation of the arterial blood pressure can be observed, often patients complain to have pain of pressing character in the heart. Often, palpitation and lability of pulse and dullness of heart tones can be observed; and in a number of cases – sinus arrhythmia as well as the decrease of the contraction of the heart ability.
Diagnosis.
Special attention is paid to early diagnosis of chronic manganese poisoning. It’s necessary to find out a professional route, sanitary description of labor conditions (manganese concentration in the workplace, duration of contact during work day, experience of work, influence of other harmful professional factors), to analyse results of biochemical investigations (level of manganese in blood, urine, saliva, milk).
A decline of patient activity, dormancy of psychical processes, insufficient critical relation to the state of organism predetermine the late appeal of patients for medical help.
Treatment:
Already in early stages of the diseases, patients with chronic manganese intoxication should be prescribed vitamins B1. Thiamine chloride should be administered intravenously or intramuscularly in the dosage of 1 ml of 5 % solution. It is expedient to use vitamins B1 and B6 together.
With more marked signs of intoxication, it is recommended to administer intravenously 0.5 % solution of Novocain in the dosage of 5 ml. Administering of Novocain should be alternated with hypodermic injections of 0.5 % solution of proserin or neostigmine, starting with 0.3 to 0.8 ml. The treatment course is 15 days. Good therapeutic effect is provided by the preparation of benzotropine, as it causes cholinergic action, and improves synaptic transmission.
At rigid bradykinetic syndrome, it is recommended to use mitandan, which also possesses cholinergic activity. The preparation is recommended to take in the dosage of 0.1 g twice or three times a day. The treatment course duration might be from one to three months. Due to the fact that with manganese intoxication, the content of dopamine decreases, it is better to utilize 1-dihydroxyphenylalanine. Levodopa goes through blood-brain barrier, in bazal ganglia; it is turned into dopamine and reduces hypokinesia and rigidity of muscles. It can be administered inside after meals, starting with the dosage of
To increase the resistance of the organism, it is recommended to administer intravenously 5 ml of 5 % solution of ascorbic acid together with 20 ml of 40 % solution of glucose. Both in the initial stage of intoxication, and at micro-organic affections of the nervous system, positive effect is rendered by radon, pine needle, and chamber galvanic bathes.
There is also information on utilization of complexing agents, and in particular EDTA (ethylenediaminetetraacetic acid) at manganese.
Verification of the ability to work. In case of suspicion of intoxication with manganese, it is recommended to have temporary transfer to another job position for the term of a months and a half with the provision of the occupational certificate and with medical supervision. All patients with chronic intoxication should be immediately removed from work where the contact with manganese and its compounds is possible. At stage I of the intoxication, patients beyond the contact with manganese keep their ability to work and thus are subject to rational job placement. In cases, when the transfer to another job might have negative impact onto the qualification or the amount of the occupational activity, patients should receive group III of the occupational invalidism.
Patients with chronic intoxication with manganese of Stage II due to significant decrease of the ability to work or its complete loss are subject to transfer to group III or II of the occupational invalidism (depending on the degree of the functional disorders).
At Stage III of intoxication, patients are considered completely incapable to work and receive Group II or I of invalidism. It is necessary to take into consideration that sometimes, progressing of the process can start in several years after the termination of the contact with manganese. All the patients with chronic intoxication with manganese are subjects to regular dynamic medical check-up.
Preventive measures. It is reduced to the complete sealing-in of production processes, decrease of dust creation, keeping to rules of personal hygiene (utilization of respirators, having meal outside the production premises and frequent change of a uniform), as well as the conduct of periodical medical examinations.
INTOXICATION BY AGRICULTURE CHEMICAL POISONINGS (CHLORORGANIC COMPOUNDS, ORGANOPHOSPHORUS COMPOUNDS, MERCURIC ORGANIC COMPOUNDS, COMPOUNDS WHICH CONTAIN ARSENIC).
OCCUPATIONAL HAZARDS OF AGRICULTURAL WORKERS
Occupational health in agriculture sector is a new concept. From the standpoint of capital investment and number of persons employed, agriculture may be termed as “big industry”. Agricultural workers have a multitude of health problems – a fact which is often forgotten because of the widespread misconception that occupational health is mainly concerned with industry and industrialised countries. The health problems of workers in agriculture may be enumerated as below.
(1) ZOONOTIC DISEASES : The close contact of the agricultural worker with animals or their products increases the likelihood of his contracting certain zoonotic diseases such as brucellosis, anthrax, leptospirosis, tetanus, tuberculosis (bovine) and Q fever. The extent of the occupational occurrence of these diseases in most parts of the world is not known.
(2) ACCIDENTS: Agricultural accidents are becoming more frequent, even in developing countries, as a result of the increasing use of agricultural machinery. Insect and snake bites are an additional health problem in
3) TOXIC HAZARDS: Chemicals are being used increasingly in agriculture either as fertilizers, insecticides or pesticides. Agricultural workers are exposed to toxic hazards from these chemicals. Associated factors such as malnutrition and parasitic infestation may increase susceptibility to poisoning at relatively low levels of exposure.
(4) PHYSICAL HAZARDS: The agricultural worker may be exposed to extremes of climatiс conditions such as temperature, humidity, solar radiation, which may impose additional stresses upon him. He may also have to tolerate excessive noise and vibrations, inadequate ventilation and the necessity of working in uncomfortable positions for long periods of time.
(5)RESPIRATORY DISEASES: Exposure to dusts of grains, rice husks, coconut fibres, tea, tobacco, cotton, hay and wood are common where these products are grown. The resulting diseases – e.g., byssinosis, bagassosis, farmer’s lung and occupational asthma, appear to be widespread.
Pesticides
Pesticide spraying
Pesticide exposures cause disorders varying from straightforward topical irritant reactions, such as those to synthetic pyrethroid insecticides, to complex systemic illness, such as that resulting from cholinesterase inhibition by organophosphate pesticides. The acute illness syndromes associated with pesticides most commonly encountered by clinicians are illustrated here by cases reported to the California Pesticide Illness Surveillance Program. The issues raised include asthma associated with exposure to contaminants in organophosphate insecticides, systemic toxicity of ingested pyrethroids (in children), and illnesses associated with spills or misuse of fumigants.
More than 1000 chemical compounds, biological agents, and physical agents, marketed as multiple formulations and brand names, are used around the world as insecticides, fungicides, herbicides, rodenticides, and antimicrobial compounds (panel 1).
Panel 1: Chemical structural categories of pesticides
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Insecticides
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Organochlorines, organophosphates, carbamates, pyrethrins, synthetic pyrethroids, nicotine, rotenone, microbiological (Bacillus thuringiensis) |
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Herbicides
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Trichloro/dichlorophenoxyherbicides, urea derivatives, carbamates, triazines, glyphosate |
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Fungicides
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Carbamates, organophosphates, miscellaneous compounds including captan, captofol, pentachlorophenol, iprodione, elemental sulphur
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Antimicrobials
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Triazine-S-triones, chlorine-releasing agents, chlorine, dichloronitrobenzene
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Rodenticides
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Coumadin and derivatives, long-acting and short-acting anticoagulants, strychnine, sodium fluoroacetate
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Organophosphates and N-methyl carbamates
Organophosphates and N-methyl carbamates are the pesticides that most commonly cause systemic illness. The specific materials most frequently encountered depend on the nature of the application and local use patterns. The majority of illnesses in agricultural workers during this period (1379) were associated with high-toxicity organophosphates (mevinphos, methomyl, methamidophos, oxydemeton, and parathion), and also with moderately toxic compounds (dimethoate and phosalone). Organophosphates poison the nervous system by inhibiting the enzyme-catalysed breakdown of the neurotransmitter acetylcholine. This inhibition results in overstimulation of the parts of the nervous system that contain acetylcholine—muscarinic post-ganglionic fibres of the parasympathetic nervous system (which control secretions of the respiratory and gastrointestinal tracts and heart rate), sweat glands in the sympathetic nervous system, preganglionic fibres in the sympathetic nervous system, and skeletal muscle. The acronym MUDDLES (miosis, urination, diarrhoea, diaphoresis, lacrimation, excitation of central nervous system [CNS], salivation) is a helpful way to remember the principal effects of cholinesterase inhibitors. Organophosphate-induced bradycardia can be severe and may cause episodes of dizziness and syncope. N-methyl-carbamate insecticides have effects similar to those of the organophosphates, but they are of much shorter duration. Athough patients may have symptoms for 1–2 weeks after organophosphate poisoning, most patients with carbamate poisoning recover within 24 h. N-methylcarbamate poisoning is more readily reversible, since the complex between the cholinesterase enzyme and carbamate insecticides readily breaks down (panel 2). It is not necessary for new enzyme to be synthesised for normal functioning to be restored. Thus, cholinesterase depression due to carbamates is more difficult to detect than that due to organophosphates. Many organophosphates are also associated with irritation of the skin and upper respiratory tract (panel 2). The agents producing odour and irritant effects associated with most organophosphates are thought to be lowmolecular- weight mercaptans and sulphides. Monitoring studies of communities near applications of the cotton defoliant tributyl phosphorothioate have shown, for example, concentrations of butyl mercaptan of 0·29–9·93 parts per billion (well above the odour thresholds for mercaptans) compared with concentrations of the active ingredient of 0–0·034 parts per trillion. Athough the odourproducing agents associated with organophosphates can give rise to characteristic irritant symptoms, they can also provoke non-specific symptoms,8 such as headache and nausea. Most of the irritation is confined to the upper airways, but occasional complaints of organophosphateassociated wheezing and chest tightness have been reported. These cases need careful investigation, because bronchoconstriction can result from systemic poisoning as well as from airway irritation. A few cases of persistently reactive airways independent of cholinesterase inhibition have been reported after organophosphate exposure. The most serious non-cholinesterase-related effect of organophosphates is a delayed neuropathy that presents 7–14 days after exposure. This disorder has been principally associated with a handful of organophosphate compounds that have a high affinity for and inhibit neuropathy target enzyme. These include compounds no longer used, such as leptophos and EPN. Most organophosphates can induce delayed neuropathy after massive intoxication, but none of those currently used worldwide preferentially inhibit neuropathy target enzyme at doses that do not also cause cholinesterase inhibition. The intermediate syndrome reported by Senanayake and Karalliedde is distinguished from delayed neuropathy by onset within 24–96 h after recovery from acute cholinergic crisis, tendency for the cranial nerves and proximal muscles to be affected, and tetanic fade instead of denervation potentials on electromyography. Recovery was also faster, occurring over 4–18 days rather than 6–12 months as is typical of delayed neuropathy. The controversy over whether neurobehavioural effects persist after recovery from organophosphate poisoning has continued for 30 years. There have been reports of deficits in memory and abstraction on test batteries and subclinical decreases in vibrotactile sensitivity in workers recovering from organophosphate poisoning, but results of clinical and neurological examinations were normal. Among workers who apply organophospates but have not suffered poisoning episodes, some studies have shown similar types of subclinical neurobehavioural deficits and subclinical electroencephalographic abnormalities, whereas others had largely negative results. Identification of the active ingredient involved in a pesticide exposure is essential and is the best done from a product label or material data safety sheet. Trade references (such as the Farm Chemicals Handbook published annually by Meister Publishing, Willoughby, Ohio, USA) provide a means of identifying agricultural pesticides from their tradenames; organophosphates and carbamates can be identified from listing of atropine or pralidoxime as antidotes in the pesticide dictionary section of this handbook. An online source of information is the pesticide label database. Clinicians should be aware also that the “active ingredient” on a pesticide label relates only to activity against the species to be targeted by the substance (eg, insect, nematode); many of the inactive ingredients (eg, petroleum distillates) can also have harmful effects on human beings. Diagnosis of acute organophosphate poisoning is based on a history of exposure and a blood test of red-cell and plasma cholinesterase. When organophosphate poisoning is strongly suspected (eg, an illness outbreak or a group of workers routinely handling organophosphates), a test result within the laboratory normal range is not sufficient to rule out poisoning, given the wide range of normal values in the population.
CLINICAL FEATURES OF ORGANOPHOSPHORUS PESTICIDE POISONING (Patients usually present with features of parasympathetic overstimulation. A few might show signs of sympathetic stimulation, including tachycardia. However, tachycardia can also be caused by hypovolaemia, hypoxia, previous doses of atropine, and alcohol withdrawal. Respiratory failure can be due to bronchospasm, bronchorrhoea (both reversible with atropine), and dysfunction of neuromuscular junctions and the CNS) Appropriate diagnosis can be made by comparison with a baseline value, by doing serial follow-up tests, or by testing for regeneration of the native acetycholinesterase enzyme in vitro after treatment of a blood sample with the cholinesterase antidote pralidoxime. There is no clear evidence as to what degree of cholinesterase inhibition is necessary to produce symptomatic illness. Variation in the degree of inhibition required to produce symptoms is related to the rate of inhibition. Diagnosis of delayed neuropathy may be established by means of nerve conduction tests and characteristic onset of symptoms after substantial exposure to an organophosphate. No specific tests are available for diagnosis of chronic neurobehavioural effects of organophosphates in individual cases. Reactive airways can be diagnosed by means of methacholine challenge tests, but association with organophosphate exposure in individual cases may be difficult to establish. For illness that does not require admission to hospital (about 73% of definite or probable organophosphate poisonings reported in California), decontamination of the skin may be the main treatment required.
Principles of therapy (From: Management of acute organophosphorus pesticide poisoning. – Michael Eddleston, Nick A Buckley, Peter Eyer, Andrew H Dawson. – Lance t 2008; 371: 597–607; www.thelancet.com)
Treatment includes resuscitation of patients and giving oxygen, a muscarinic antagonist (usually atropine),fluids, and an acetylcholinesterase reactivator (an oxime that reactivates acetylcholinesterase by removal of the phosphate group). Respiratory support is given as necessary. Gastric decontamination should be considered only after the patient has been fully resuscitated and stabilised. Patients must be carefully observed after stabilisation for changes in atropine needs, worsening respiratory function because of intermediate syndrome, and recurrent cholinergic features occurring with fat-soluble organophosphorus. Few randomised trials of such poisoning have been done; consequently the evidence base is restricted. Both atropine and oximes were introduced into clinical practice rapidly in the 1950s without clinical trials. As a result, we do not know the ideal regimens for either therapy. Trials of other interventions are hindered because the best way to give the core treatments has not yet been determined and is highly variable in practice. This variability interferes with development of a widely accepted study protocol and limits the external validity of study results.
Summary of treatment
Return to work that does not involve organophosphate exposure is appropriate in the absence of significant impairment. No reexposure should be allowed until cholinesterase activities have returned to baseline values. Treatment with an antidote is usually reserved for patients who need hospital admission. Atropine reverses muscarinic symptoms of organophosphate poisoning for short periods (mean pharmacological half-life 70 min. Intravenous doses of 1–2 mg can be used. Doses may be titrated to maintain clear breath sounds and a heart rate of 80–100 beats per min.
(From: Management of acute organophosphorus pesticide poisoning. – Michael Eddleston, Nick A Buckley, Peter Eyer, Andrew H Dawson. – Lance t 2008; 371: 597–607; www.thelancet.com)
Intoxication by arsenic connections
extremely complex because it can exist in metallic form, can be in trivalent and pentavalent state (charge of 3+ or 5+), and can be organic or inorganic
widely distributed iature (variety of forms)
Environmental fate:
found in surface and groundwater through runoff
accumulates in plants if soil conditions are right
bioaccumulates in aquatic ecosystems (so fish consumption is a source)
Sources of As
smelting of gold, silver, copper, lead and zinc ores
combustion of fossil fuels
agricultural uses as herbicides and fungicides, as insecticides for staining of seed, destroying the pests of garden cultures, rice fields, malarial mosquito maggots and for a fight against rodents
cigarette smoke
occupational: largest source is manufacture of pesticides and herbicides
Arsenic Toxicity Mechanisms
binds to sulfhydryl groups (and disulfide groups), disrupts sulfhydryl-containing enzymes (As (III))
¡ inhibits pyruvate and succinate oxidation pathways and the tricarboxylic acid cycle, causing impaired gluconeogenesis, and redu ced oxidative phosphorylation
÷ targets ubiquitous enzyme reactions, so affects nearly all organ systems
substitution for phosphorus in biochemical reactions
¡ Replacing the stable phosphorus anion in phosphate with the less stable As(V) anion leads to rapid hydrolysis of high-energy bonds in compounds such as ATP. That leads to loss of high-energy phosphate bonds and effectively “uncouples” oxidative phosphorylation.
The catarrhal form of acute intoxication
· appear from the hit of the aerosol of arsenic on the mycoses of eyes and breathing organs.
– appearance of weakness, dizziness, nausea, vomit, by sweetish taste in a mouse, feeling of fear, shaking, and painful cramps;
– there are an irritation and sharp hyperemia of mucosas of overhead respiratory tracts and eyes that shows up burning of eyes, tearing, cold, sneezing, edema of mucus of nose, cough, sometimes with hemoptysis and pain in thorax;
– the signs of heart insufficiency, astenovegetative syndrome, and also symptoms of defect of gastrointestinal tract, appear later.
Gastrointestinal form
· at the casual hit of poison in a gastrointestinal tract.
· metallic taste appears in a mouth, dryness, swallowing, incessant vomit (the masses of vomits have a garlic smell), acute abdomen pain, diarrhea.
· the amount of urine diminishes;
· the loss of liquid conduces to acute dehydration of organism;
· an acute weakness, dizziness, develops, sometimes fainting fit, decrease the temperature of body and arterial blood pressure goes down, the collapse state develops;
Chronic intoxication
q meets in persons, which long time contact in the terms of productions with pair or dust of connections of arsenic, which get to the organism through respiratory tracts or skin.
q absence of appetite, hypersalivation, periodic nausea and vomit, stomach pain, violation of stool;
q pains in a nose and throat, hoarseness, cough, cold, nose-bleeds, rhinitis, tracheitis, bronchitis;
q rush appears on a skin, ulcers and psilosis;
heavy violations of metabolism result in considerable weight loss, defect of liver, kidneys, appearance of anemia.
Clinical picture
Typical findings are skin and nail changes, such as hyperkeratosis, hyperpigmentation, exfoliative dermatitis, and Mees’ lines (transverse white striae of the fingernails); sensory and motor polyneuritis manifesting as numbness and tingling in a “stocking-glove” distribution, distal weakness, and quadriplegia; and inflammation of the respiratory mucosa.Epidemiologic evidence has linked chronic consumption of water containing arsenic at concentrations in the range of 10 to 1820 ppb with vasospasm and peripheral vascular insufficiency culminating in “blackfoot disease – a gangrenous condition affecting the extremities. Chronic arsenic exposure has also been associated with a greatly elevated risk of skin cancer and possibly of cancers of the lung, liver (angiosarcoma), bladder, kidney, and colon
Source: http://manbir–online.com/diseases/arsenic.htm
Diagnostic criteria of Chronic arsenicosis.
1. At least 6 months exposure to arsenic levels of greater than 50 mg/L or exposure of high arsenic level from food and air.
2. Dermatological features characteristic of chronic arsenicosis.
3. Non carcinomatous manifestations : Weakness, chronic lung disease, non cirrhotic portal fibrosis of liver with/without portal hypertension, peripheral neuropathy, peripheral vascular disease, non pitting edema of feet/ hand.
4. Cancers : Bowens disease, Squamous cell carcinoma, Basal cell carcinoma at multiple sites, occurring in unexposed parts of the body.
5. Arsenic level in hair and nail above 1 mg/kg and 1.08 mg/kg respectively and/or arsenic level in urine, above 50 mg/L (without any history of taking seafood).
Dermatological criteria and grading of severity of chronic arsenic toxicity
Grade I
|
Grade I |
Mild |
a) Diffuse melanosis. b) Suspicious spotty depigmentation / pigmentation over trunk /limbs. c) Mild diffuse thickening of soles and palms |
|
Grade II |
Moderate |
a) Definite spotty pigmentation / depigmentation on the trunk and limbs, bilaterally distributed. b) Severe diffuse thickening (with/without wart like nodules of the palms and soles) |
|
Grade III |
Severe |
a) Definite spotty pigmentation/depigmentation as above with few blotchy pigmented/depigmented macular patches over trunks or limbs. b) Pigmentation involving the undersurface of tongue and/or buccal mucosa. c) Larger nodules over thickened palms and soles occasionally over dorsal aspect of hands and feet. Diffuse verrucous lesions of the soles with cracks and fissures and keratotic horns over palms/soles. |
Source: http://www.who.int/water_sanitation_health/dwq/arsenicun4.pdf Guha Mazumder , (In press)
Laboratory investigation.
When acute arsenic poisoning is suspected, an x-ray of the abdomen may reveal ingested arsenic, which is radiopaque. The serum arsenic level may exceed 0.9 umol/L (7 ug/dL); however, arsenic is rapidly cleared from the blood. Electrocardiographic findings may include QRS complex broadening, QT prolongation, ST-segment depression, T-wave flattening, and multifocal ventricular tachycardia. Urinary arsenic should be measured in 24-h specimens collected after 48 h of abstinence from seafood ingestion; normally, levels of total urinary arsenic excretion are less than 0.67 umol/d (50 ug/d).Arsenic may be detected in the hair and nails for months after exposure.Abnormal liver function, anemia, leukocytosis or leukopenia, proteinuria, and hematuria may be detected.Electromyography may reveal features similar to those of Guillain-Barre syndrome.
Basophilic stippling in peripheral smear
Treatment.
Vomiting should be induced in the alert patient with acute arsenic ingestion.
Gastric lavage may be useful; activated charcoal with a cathartic (such as sorbitol) may be tried.
Aggressive therapy with intravenous fluid and electrolyte replacement in an intensive-care setting may be life-saving.
Dimercaprol is the chelating agent of choice and is administered intramuscularly at an initial dose of 3 to 5 mg/kg on the following schedule: every 4 hr for 2 days, every 6 hr on the third day, and every 12 hr thereafter for 10 days. (An oral chelating agent may be substituted). Succimer is sometimes an effective alternative, particularly if adverse reactions to dimercaprol develop (such as nausea, vomiting, headache, increased blood pressure, and convulsions). In cases of renal failure, doses should be adjusted carefully, and hemodialysis may be needed to remove the chelating agent-arsenic complex. Arsine gas poisoning should be treated supportively with the goals of maintaining renal function and circulating red-cell mass.
Intoxication by chlorine organic connections.
Chlorinated hydrocarbon (organochlorine) insecticides, solvents, and fumigants are widely used around the world. This class comprises a variety of compounds containing carbon, hydrogen, and chlorine. These compounds can be highly toxic, and the overwhelming majority have been universally banned because of their unacceptably slow degradation and subsequent bioaccumulation and toxicity.[1]Among the more notable, dichlorodiphenyltrichloroethane (DDT) is an organochlorine pesticide and its invention won Paul Müller the 1948 Nobel Prize in Physiology or Medicine
5 groups of organochlorines insecticides
Dichlorodiphenyltrichloroethane (DDT) and analogues (eg, dicofol, methoxychlor)
Hexachlorocyclohexane (ie, benzene hexachloride) and isomers (eg, lindane, gamma-hexachlorocyclohexane)
Cyclodienes (eg, endosulfan, chlordane, heptachlor, aldrin, dieldrin, endrin, isobenzan)
Chlordecone, kelevan, and mirex
Toxaphene
Organochlorines insecticides in the food chain.
Mechanism of toxicity
Toxicity in humans is largely due to stimulation of the central nervous system. Cyclodienes (such as endosulfan), hexachlorocyclohexanes (such as lindane), and toxaphene predominately are GABA antagonists and inhibit calcium ion influx, but also may inhibit Ca- and Mg-ATPase, causing calcium ion accumulation at neuronal endplates, thereby causing sustained release of excitatory neurotransmitters. DDT affects potassium and voltage-dependent sodium channels. These changes can result in agitation, confusion, and seizures. Cardiac effects have been attributed to sensitization of the myocardium to circulating catecholamines.
Some of the more volatile organochlorines can be inhaled while in vapor form or swallowed while in liquid form. Inhalation of toxic vapors or aspiration of liquid after ingestion may lead to atelectasis, bronchospasm, hypoxia, and a chemical pneumonitis. In severe cases, this can lead to acute lung injury (ALI), hemorrhage, and necrosis of lung tissue. In liquid form, they are easily absorbed through the skin and GI tract.
Clinical presentation
CNS excitation and depression are the primary effects observed from organochlorine toxicity; therefore, the patient may appear agitated, lethargic, intoxicated, or even unconscious. Organochlorines lower the seizure threshold, which may precipitate seizure activity. Initial euphoria with auditory or visual hallucinations and perceptual disturbances are common in the setting of acute toxicity. Patients may have pulmonary complaints or may be in severe respiratory distress. Cardiac dysrhythmias may complicate the initial clinical presentation.
Other symptoms include the following:
Pulmonary – Cough, shortness of breath
Dermatological – Skin rash
Gastrointestinal – Nausea, vomiting, diarrhea, and abdominal pain
Nervous system – Headache, dizziness, or paresthesias of the face, tongue, and extremities
Physical examinations findings depends on type of exposure:
Ingestions
Nausea and vomiting
Confusion, tremor, myoclonus, coma, and seizures
Respiratory depression or failure
Unusual odor – Toxaphene may have a turpentine-like odor. Endosulfan may have a sulfur odor
Skin absorption or inhalation
Ear, nose, and throat irritation
Blurred vision
Cough
Acute lung injury (ALI)
Dermatitis
Chronic exposure (meets in persons who constantly contact with chlorine organic connections: workers of compositions and enterprises from the production of chemical poisonings)
Anorexia
Hepatotoxicity
Renal toxicity
CNS disturbances
Skin irritation
Physical findings
Pulmonary – Increased A-a gradient, hypoxemia
Cardiovascular – Sinus tachycardia or bradycardia, QT prolongation, nonspecific ST-segment changes
Gastrointestinal – Transaminitis and hyperbilirubinemia
Hematological – Leukocytosis and prolonged activated partial thromboplastin time (aPTT)
Renal – Acidemia, azotemia, creatinine elevation, hyperkalemia
Prehospital Care
Dermal decontamination is a priority. Remove clothes.
Wash skin with soap and water.
Provide oxygen and supportive care as necessary
GI decontamination and elimination
Treatment
GI Decontaminant Activated charcoal is emergency treatment in poisoning caused by drugs and chemicals. The network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. It does not dissolve in water.
For maximum effect, administer within 30 minutes of ingesting poison.
Multiple dose activated charcoal (MDAC) may be administered at 10-
Bile acid sequestrants These binding agents are used in the treatment of hypercholesterolemia and have been noted to bind certain lipid-soluble drugs and enterohepatically recycled drugs.
Cholestyramine forms a nonabsorbable complex with bile acids in the intestine, which, in turn, inhibits enterohepatic reuptake of intestinal bile salts.
Benzodiazepines
Mainstay of treatment for hydrocarbon insecticide–induced seizures.
Lorazepam (Ativan) Rate of injection should not exceed 2 mg/min. May be administered IM if unable to obtain IV access.
Midazolam (Versed) Used as alternative in termination of refractory status epilepticus. Because water soluble, takes approximately 3 times longer than diazepam to peak EEG effects. Thus, clinician must wait 2-3 min to fully evaluate sedative effects before initiating procedure or repeating dose.
Diazepam (Valium) Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA.
Anticonvulsants. Additional options include pentobarbital or propofol for seizure control if status epilepticus does not respond to benzodiazepines or phenytoin or fosphenytoin.
Intoxication by mercury organic connections
They are high enough bactericidal and fungicides characteristics and at staining does not have a negative influence on a corn, seed of vegetable and technical crops of bobs. That’s why they are basic pesticides that are used for staining of seed. The organic mercury compounds are of great interest today because they are often found in the food chain and have been used to inhibit bacterial growth in medications. Organic mercury is also found in fungicides and industrial run-off.
Structures, physical, and chemical properties of organic mercury compounds Organic mercury can be found in 3 forms: aryl, short, and long chain alkyl compounds. The organic mercury compounds are of great interest today because they are often found in the food chain and have been used to inhibit bacterial growth in medications. Organic mercury is also found in fungicides and industrial run-off. As a result, exposure to these materials islikely. The toxicity of these compounds depends upon the ease with which the organic moiety can dissociate from the anion. Organic mercurials are absorbed more completely from the GI tract than inorganic salts in part because they are more lipid-soluble and because they bind to sulfhydryl groups. More often, organic mercurials are absorbed from the GI tract by forming a complex with L-cysteine and crossing cell membranes on the large neutral amino acid carrier. They are also corrosive, although less corrosive than inorganic forms. Once absorbed in tissues, the aryl and long chain alkyl compounds are converted to divalent cations that possess inorganic mercury toxic properties. The short chain alkyl mercurials are readily absorbed in the GI tract (90% to 95%) and remain stable in their initial forms. Alkyl organic mercury compounds have high lipid solubility and are distributed uniformly throughout the body, accumulating in the brain, kidney, liver, hair, and skin. Organic mercurials also cross theblood-brain barrier and placenta and penetrate erythrocytes, attributing to neurological symptoms, teratogenic effects, and high blood to plasma ratio, respectively. Methylmercury has a high affinity for sulfhydryl groups, which explains its effect on enzyme dysfunction. One enzyme that is inhibited is choline acetyl transferase, which is involved in the final step of acetylcholine production. This inhibition may lead to acetylcholine deficiency, contributing to the signs and symptoms of motor dysfunction. Excretion of alkyl mercury occurs mostly in the form of feces (90%), secondary to significant enterohepatic circulation. The biological half-life of methyl mercury is approximately 65 days.
Simplified version of the mercury biogeochemical Cycle. This cycle consists of three phases – terrestrial, oceanic and atmospheric. The major pathways into the atmosphere from natural offgassing by earth movements and volcanoes are depicted on the left along with the varied emissions from industrial activities and disposal of products in which mercury is a component. Inorganic mercury compounds become widely dispersed in the atmosphere and are subjected to repeated deposition and resuspension both over the ocean and over land.
In the process of this cycling some of the mercury (Hg0) is oxidized in the presence of ozone, oxygen and moisture to form ionic mercury (Hg++) which is highly water soluble and readily incorporates into rain drops. This ionic mercury (Hg++) is carried by rainwater into soil and sediment containing bacteria, algae, fungi and other organisms. These organisms react with mercury, converting some of it back to its gaseous elemental state for re-release into the atmosphere. Depending upon the conditions and the organisms present in soil and sediment the inorganic mercury can be converted or methylated into organic mercury. The organic mercury (methylmercury MeHg+, and dimethylmercury DMeHg) has the capacity to penetrate through cell membranes and react with essential proteins, amino acids and nucleic acids within the cells. In this form it is highly toxic and capable of being incorporated into the aquatic organisms that are part of the food chain of higher animals. These methylmercury compounds with their capacity to bioaccumulate and biomagnify can compromise the health of higher organisms. This inadvertent exposure to elemental and organic mercury in the environment poses a serious threat to humans as well as wildlife.
The dominant route of exposure to methylmercury is through the ingestion of fish. Most fish, both freshwater and salt-water, contain methylmercury. While the GI tract is the primary route of absorption, methylmercury can be absorbed through the skin and the lungs as well. Once absorbed into the circulation, methylmercury enters erythrocytes where more than 90% will be found bound to hemoglobin. Lesser amounts will be bound to plasma proteins. About 10% of the burden of methylmercury is found in the brain where it slowly undergoes demethylation to aninorganic mercuric form. Methylmercury readily crosses the placenta to the fetus, where deposition within the developing fetal brain can occur. In the brain, methylmercury causes focal necrosis of neurons and destruction of glial cells and is toxic to the cerebral and cerebellar cortex.
Symptoms of exposure to organic mercury compounds are similar to those found following exposure with elemental mercury: ataxia, tremors, unsteady gait, and illegible handwriting. Slurred speech may also occur as muscle tone of the facial muscles is lost. Acrodynia, known as Pink Disease and considered to be a mercury allergy, presents with erythema of the palms and soles, edema of the hands and feet, desquamating rash, hair loss pruritus, di- phoresis, tachycardia, hypertension, photophobia, irritability, anorexia, insomniapoor muscle tone, and constipation or diarrhea. Acrodynia typically presents in only a small percentage of those exposed to inorganic mercury and is an indicator of widespread disease. It was more prevalent when mercury-containing teething powders were used or when diapers werewashed with detergents or fungicides conaining mercury. Organic mercury poisoning usually results from ingestion of contaminated food, particularly fish. The long chain and aryl forms of organic mercury have similar characteristics of inorganic mercury toxicity. Organic mercury targets specific sites in the brain, including the cerebral cortex (especially visual cortex), motor and sensory centers (precentral and postcentral cortex), auditory center (temporal cortex), and cerebellum. The onset of symptoms is delayed (days to weeks) after exposure. Organic mercury targets enzymes, and the depletion of these en- zymes must occur before the onset of symptoms. Symptoms related to toxicity are typically neurological, such as visual disturbance (eg, scotomata, visual field constriction), ataxia, paresthesias (early signs), hearing loss, dysarthria, mental deterioration, muscle tremor, movement disorders, and, with severe exposure, paralysis and death. All forms of mercury are toxic to the fetus, but methylmercury most readily passes through the placenta. Even with an asymptomatic patient, maternal exposure can lead to spontaneous abortion or retardation
A diagnosis based on the special clinical picture and information of anamnesis, which specify on a contact with mercury organic connections. The important diagnostic sign of intoxication is a presence of mercury in blood, urine, and at heavy intoxications – in a cerebrospinal liquid.
Treatment
To wash a stomach and enterosorbtion;
– Antidote – Unitiol, intramuscular 5 % solution on a chart: in first days 3-4 times in 6-8 hours, on the second days 2-3 times, on third-seven days 1-2 times per a day;
– Intravenous enter 10 ml of 30 % solution of thiosulphate of sodium.
– During acidosis intravenous we give 200 ml of 3-5 % solution of hidrocarbonate of sodium.
– Symptomatic therapy.
– Hemotransfusion, hemodialysis.
– During chronic intoxication – Unitiol, the vitamins of group B, ascorbic acid, and also symptomatic therapy and procedures of physical therapies.
Urinary Calcium Oxalate Crystals
in Ethylene Glycol Intoxication
Case example. А 73-year-old man presented with a self-inflicted stab wound to the abdomen. A plasma ethanol level of 27 mg per deciliter was found on preliminary toxicologic screening; the results of chemical analyses were normal. No internal injuries were found on exploratory laparotomy. Eight hours postoperatively, the patient became confused and was intubated because of respiratory distress. Arterial blood gas measurements showed a pH of 6.91, partial pressure of carbon dioxide of
hemodialysis
Scheme hemodialysis perfoming
Shortterm treatment included fomepizole and continuous hemodialysis, but the patient remained on long-term hemodialysis for two months after hospital discharge.
Hydrofluoric Acid Burn
A 45-year-old healthy man was involved in demolishing an industrial plant in which glass had been etched
Case example. А 45-year-old healthy man was involved in demolishing an industrial plant in which glass had been etched. He was exposed to a reservoir of 70% hydrofluoric acid while repairing a pipeline. He was admitted to the intensive care unit for second-degree and third-degree burns from hydrofluoric acid affecting 30% of his body-surface area, including both hands, both forearms, the chest, back, scalp, and neck. After penetrating tissue, hydrofluoric acid dissociates into hydrogen and fluoride ions, of which particularly fluoride is toxic. Since fluoride ions are inactivated by means of precipitation with calcium and magnesium, the infusion of calcium and magnesium is considered a therapy in patients with hydrofluoric acid burns. In this patient, magnesium was infused intravenously, and calcium was infused intravenously and intraarterially (through the brachial artery) and was applied topically to the burned skin. The blood magnesium level was always within the normal range during substitution therapy. Blood levels of ionized calcium were initially elevated to up to 1.75 mmol per liter but were within the normal range after 36 to 48 hours. As a result of this intense calcium and magnesium therapy, cutaneous calcification developed on the fingertips by 36 to 48 hours, as well as on the dorsal and palmar aspects of the hand (Panels A and B, respectively). Three months later, the patient had regained an almost full range of motion, was free of symptoms, and had a good aesthetic result.
Ethylene Glycol Poisoning
Urine Fluorescence in Ethylene Glycol Poisoning
Case example. A 38-year-old man presented to the emergency department after reportedly ingesting antifreeze. He appeared to be intoxicated and was agitated and combative; chemical sedation was induced. Initial laboratory studies revealed a pH of 7.0, an anion gap of 22 mmol per liter, and an osmolar gap of 79 mOsm. It was noted that the patient’s urine fluoresced under ultraviolet light (in the basin on the left), as compared with a negative control (in the basin on the right), which shows the purple reflection of the ultraviolet light (arrow). The patient received fomepizole, thiamine, folate, pyridoxine, and bicarbonate; he subsequently underwent hemodialysis. Laboratory studies revealed that his ethylene glycol level had been 222 mg per deciliter when the treatment began. His recovery was uneventful. Fluorescein is a fluorescent dye added to antifreeze preparations to aid in the detection of radiator leaks. In addition to the history and elevated osmolar and anion gaps, the fluorescence of urine under ultraviolet light may aid in the early identification of ethylene glycol poisoning. False negative and false positive results may occur. For example, many containers, such as urine collection bags, may be characterized by native fluorescence.
BITES OF VENOMOUS SNAKES
АPPROXIMATELY 15 percent of the 3000 species of snakes found worldwide are considered to be dangerous to humans (Table 1). The last comprehensive survey of snake-venom poisoning, completed in the late 1950s, documented an average of 45,000 snakebites annually in the United States, 8000 of them by venomous snakes. During the past three years, the American Association of Poison Control Centers has reported an annual average of 6000 snakebites in the United States, 2000 of them by venomous snakes. Since reporting is not mandatory, many snakebites go unreported. Some victims do not seek treatment, and some treating physicians do not consult with a poison-control center. The true incidence of bites by venomous snakes in the United States is probably 7000 to 8000 per year, of which 5 or 6 result in death. The eastern and western diamondback rattlesnakes account for most fatalities. Deaths typically occur in children, in the elderly, and in victims to whom antivenom is not given, is given after a delay, or is administered in insufficient quantities. Typically, victims are male and between 17 and 27 years of age. Ninety-eight percent of bites are on extremities, most often the hands or arms, and result from deliberate attempts to handle, harm, or kill the snake. Most bites occur between April and September, when snakes are active and humans are outdoors. Alcohol intoxication of the victim is a factor in many envenomations. The majority of bites in the United States occur in the southwestern part of the country — in part because of the near-decimation of rattlesnake populations in the eastern United States.
Few bites are now associated with agricultural activities, and more bites result from deliberate exposure to captive native and non-native snakes. This article focuses on the management and treatment of bites from venomous snakes encountered in North America; however, the principles of management apply to patients with bites seen in medical facilities worldwide.
VENOMOUS SNAKES
Of the approximately 120 species of snakes indigenous to the United States, approximately 20 are venomous. All are pit vipers (rattlesnakes, cottonmouths, and copperheads), with the exception of the coral snake, the only other native venomous snake (Fig.). At least one species of venomous snake has been identified in every state except Alaska, Maine, and Hawaii. Minton described the management of 54 bites from at least 29 species of non-native venomous snakes that were kept in zoos or by amateur or professional collectors. The most common species was the cobra, which is perceived as the quintessential deadly snake. Cobras remain popular with zoos as well as with amateur snake keepers and are readily available in the animal trade.
Venomous Snakes of North America. Panel A shows an eastern diamondback rattlesnake (Crotalus adamanteus), Panel B a western diamondback rattlesnake (C. atrox), Panel C a timber rattlesnake (C. Horridus), Panel D a cottonmouth (Agkistrodon piscivorus ), Panel E a copperhead (A. Contortix), and Panel F an eastern coral snake (Micrurus fulvius fulvius). (Photos in Panels A, B, and F courtesy of James Harrison, Kentucky Reptile Zoo.)
VENOMOUS OR NONVENOMOUS?
Definitive diagnosis of snake-venom poisoning requires positive identification of the snake and clinical manifestations of envenomation. Although the snake is rarely available for identification, it may be brought into the health care facility — alive or dead, whole or in parts — for identification. Snake parts should not be handled directly, since the bite reflex in recently killed or decapitated snakes remains intact, rendering them capable of inflicting a bite. Specific characteristics of pit vipers and nonvenomous snakes aid in their identification. Herpetologists from zoos or aquariums may be available to assist with positive identification. In the assessment of a reported bite from a venomous snake, one must distinguish the bite from that of a nonvenomous snake or another animal (e.g., a rat) and from puncture wounds caused by inanimate objects. In the absence of positive identification, objective signs and symptoms of envenomation become the primary focus of diagnosis.
Comparison of Venomous Snakes (Pit Vipers) and Nonvenomous Snakes
SYSTEMIC SYMPTOMS AND SIGNS
The most common reaction to snakebite is terror, which may cause nausea, vomiting, diarrhea, syncope, tachycardia, and cold, clammy skin. Many people believe that any bite from a venomous snake will result in envenomation; in fact, 25 percent of all pitviper bites are “dry” and do not result in envenomation. Autonomic reactions related to terror must be differentiated from systemic manifestations of envenomation. Common characteristics of pit-viper bites include the presence of one or more fang marks, including puncture wounds and scratches. Local findings emerge within 30 to 60 minutes after most pit-viper envenomations. These findings include pain, edema, erythema, or ecchymosis at the site of the bite and in adjacent tissues. Localized pain is usually felt immediately and occurs in more than 90 percent of envenomations. An exception is envenomation by the Mojave rattlesnake, which may cause little or no pain. Edema from small-vessel injury usually appears within 30 minutes but may not become apparent for several hours. Bullae (serous or hemorrhagic) may be noted within several hours after the envenomation. There may be signs of lymphangitis, with tender regional lymph nodes and warmth in the injured body part. An ecchymosis may appear over the site of the bite within three to six hours after a bite by a rattlesnake (except the Mojave rattlesnake); ecchymoses are less common after copperhead bites. Early systemic manifestations usually include nausea, vomiting, perioral paresthesia, tingling of the fingertips and toes, myokymia, lethargy, and weakness. Victims may describe a “rubbery,” “minty,” or “metallic” taste after envenomation by some species of rattlesnake. More severe systemic effects include hypotension, tachypnea, respiratory distress, severe tachycardia, and altered sensorium. Bites by rattlesnakes may result in a consumptive coagulopathy manifested by a prolonged or unmeasurable international normalized ratio (prothrombin time) and activated partial-thromboplastin time, hypofibrinogenemia, the presence of fibrin-degradation products, or a platelet count of less than 20,000 per cubic millimeter. Pit-viper venom increases the permeability of the capillary membranes, resulting in the extravasation of electrolytes, albumin, and red cells into the envenomated site. This process may also occur in the lungs, myocardium, kidneys, peritoneum, and rarely, the central nervous system. Altered permeability of red-cell membranes may result in hemolysis. Edema, hypoalbuminemia, and hemoconcentration are followed by pooling of blood and fluids in the microcirculation, resulting in hypovolemic shock and lactic acidosis. Renal failure may result from hypotension, intravascular hemolysis, a syndrome resembling disseminated intravascular coagulation, or nephrotoxic effects of components of venom. General guidelines are available to help the physician assess the severity of envenomations by North American pit vipers (Table 2). The ultimate severity of a bite from any venomous snake depends on the size and species of the snake, the amount and degree of toxicity of the venom injected, the location of the bite, the first-aid treatments provided, the timing of definitive treatment, the presence or absence of underlying medical conditions, and the unique susceptibility of the victim to the venom. Coral-snake envenomations produce little or no pain but may result in tremors, marked salivation, and changes in mental status, including drowsiness and euphoria. The neurologic manifestations are usually cranial-nerve palsies evidenced by ptosis, dysarthria, dysphagia, dyspnea, and respiratory paralysis. The onset of neurotoxic effects may be delayed up to 12 hours. Once manifestations appear, it may not be possible to prevent further effects or reverse the changes that have already occurred.
PHARMACOLOGY OF VENOMS
Snake venoms are chemically complex mixtures of proteins ranging from 6 to 100 kD. Many of the proteins have enzymatic properties (Table 3). Although enzymes contribute to the deleterious effects of the venom, the lethal components may be the smaller lowmolecular-weight polypeptides. The quantity, lethality, and composition vary with the species and age of the snake, the geographic location, and the time of year. Venom is highly stable and is resistant to temperature changes, drying, and drugs.
Electron microscopy has demonstrated that these proteins damage endothelial cells of vascular walls, causing blebs in the endothelium, dilating the perinuclear space, and breaking down the plasma membrane. The peptides in venom appear to bind to multiple receptor sites in the prey. Components of pit-viper venom affect almost every organ system; therefore, it is inaccurate to label a venom as a “neurotoxin,” a “hemotoxin,” a “cardiotoxin,” or a “myotoxin.” The most deleterious effects are seen in the cardiovascular, hematologic, respiratory, and nervous systems.
TREATMENT
Treatment in the Field
After a bite from any venomous snake, the victim should be moved beyond striking distance, placed at rest, kept warm, and transported immediately to the nearest medical facility. The injured part of the body should be immobilized in a functional position below the level of the heart. Rings, watches, and constrictive clothing should be removed, and no stimulants should be administered. Previously recommended first-aid measures such as tourniquets, incision and suction, cryotherapy, and electric-shock therapy are strongly discouraged. Paramedical personnel should focus on support of the airway and breathing, administration of oxygen, establishment of intravenous access in an unaffected extremity, and transportation of the victim to the nearest medical facility. If a tourniquet or constriction band has been placed as first aid, it should be left in place until the victim is evaluated in the hospital and, if appropriate, until infusion of antivenom is initiated.
Treatment in the Emergency Department
Victims of bites from venomous snakes require aggressive supportive care and sometimes the administration of antivenom. Once airway, breathing, and circulation have been established, a rapid, detailed history should be obtained. Key points include the time of the bite, a general description of the snake, first-aid measures used, coexisting medical conditions, drug and food allergies, allergy to horse or sheep products, and history of snakebite and consequent therapy. The physical examination should be complete, with special attention to the cardiovascular, pulmonary, and neurologic systems. The bite should be examined for fang or tooth marks and scratches, edema, erythema, and ecchymoses. During initial evaluation, base-line circumferential measurements at several points above and below the site of the bite should be documented. Measurements at the same sites should be repeated and documented every 15 to 20 minutes until local progression (swelling) subsides. The time should be marked with an indelible marker at the advancing edge of swelling to serve as an index of local progression and a guide for the administration of antivenom. Base-line laboratory studies should include a complete blood count with platelet count, coagulation profile (international normalized ratio [prothrombin time], activated partial-thromboplastin time, and fibrinogen level), measurement of fibrin degradation products, electrolytes, blood urea nitrogen, and serum creatinine, and urinalysis. Laboratory studies should be repeated after each infusion of antivenom. In addition, testing such as measurement of creatine kinase, blood typing with cross-matching, chest radiography, and electrocardiography may be indicated on the basis of the victim’s age or medical history or the severity of the envenomation.21 Immunization against tetanus should be administered if indicated by the patient’s history. Since manifestations of envenomation can be delayed, particularly with the bites of Mojave rattlesnakes, it is recommended that all patients with pitviper bites be observed in the emergency department for a minimum of eight hours. If no clinical or laboratory manifestations have presented during this time, the patient may be discharged. A mild envenomation syndrome at one hour could progress to a severe syndrome within several hours and, without continuous observation, lead to death. Monitoring in an intensive care unit is recommended for all patients treated with antivenom. There have beeo controlled trials to establish the efficacy of pretreatment with epinephrine, histamine H1- and H2-receptor blockers, or corticosteroids. Although we do not recommend pretreatment, some experts pretreat routinely. Envenomations by copperheads are not considered to be as toxic as rattlesnake or cottonmouth bites and rarely require treatment; however, severe envenomations left untreated in children or elderly persons may result in death. Victims of bites by snakes confirmed to be coral snakes should be treated immediately with coral-snake antivenom. However, if the snake has not been found, victims of bites by snakes suspected to be coral snakes should be admitted to the hospital for 12 hours of observation, since the effects of envenomation may develop precipitously hours after a snakebite and are not easily reversed.13 Local necrosis and coagulopathy are not seen in persons with coral-snake envenomation. Because coral-snake venom has a potent neurotoxic component, monitoring should focus oeuropathic symptoms. Patients require frequent assessment of oxygen saturation and ventilatory function. Ventilatory support may be required. The bites of non-native venomous snakes present their own challenge. When this type of emergency arises, expert consultation should be sought through a poison-control center or local zoo. Specific antivenoms are available to treat envenomations by most exotic snakes.
ANTIVENOMS
Antivenin (Crotalidae) Polyvalent (ACP), Wyeth, was introduced in the United States in 1954 and contributed to a remarkable decrease in the rate of mortality from crotaline (pit-viper) snakebites — from an estimated 5 to 25 percent in the 19th century to less than 0.5 percent today.23 According to ESI Lederle, the manufacturer, production of antivenoms for the bites of both crotaline and coral snakes is being discontinued. Another antivenom for bites of crotaline snakes, Crotalidae Polyvalent Immune Fab (Ovine) (FabAV), is now available. The two antivenoms are compared in Table 4. FabAV is a mixed, monospecific, polyvalent antivenom produced by immunizing sheep with the venoms of crotaline snakes. In animal testing, the new product was, on average, 5.2 times as potent as ACP (range, 3.0 to 11.7 times as potent). FabAV has been evaluated in two prospective trials in which a snakebite severity score was used to document objectively the severity of envenomation.
An unexpected observation during the first clinical trial was the recurrence of effects of venom after the completion of FabAV treatment.25 Recurrence was defined as the return of any venom-related effect after that abnormality had resolved. Limb swelling recurred in some patients within 18 hours after treatment ended, and recurrence of hypofibrinogenemia was found in one patient during a follow-up visit seven days after treatment was completed. On the basis of the findings of the second trial, a dosing schedule was established that effectively prevented recurrence. The schedule requires the administration of a loading dose of FabAV and, once initial control has been achieved, three maintenance doses 6, 12, and 18 hours later.
Safety
Products of animal serum can produce adverse reactions ranging from rash to death. Anaphylaxis or anaphylactoid reactions may occur during infusion or may be delayed, as in serum sickness. According to retrospective reports, the incidence of acute reactions to ACP ranges from 23 percent to 56 percent. The incidence of acute reactions to FabAV in clinical trials was 14 percent. The incidence of serum sickness in reaction to ACP, according to retrospective reports, ranges from 18 percent to 86 percent.31,32 In the only prospective study of reactions to ACP, serum sickness developed in six of eight patients. The overall rate of serum sickness after the administration of FabAV was 16 percent; this rate has been lower in initial clinical experience.
Clinical Use
In the United States, indications for the use of antivenom have not been defined rigorously. After rattlesnake bites, the indications include progressive effects of venom, such as worsening local injury (pain, swelling, and ecchymosis), coagulopathy, or systemic effects (hypotension and altered mental status). Early administration of antivenom binds venom components, thereby reversing some manifestations of envenomation, such as hypotension and coagulopathy, and preventing further progression of local manifestations. FabAV is administered according to the principle that initial control should be established, followed by scheduled therapy (Fig. 3). Control is defined as the reversal or marked attenuation of all effects of venom. In most reported cases, 8 to 12 vials were sufficient to establish initial control, but 22 vials were needed in one case. FabAV is a lyophilized antivenom. Each dose must be reconstituted and then diluted to a volume of 250 ml in a crystalloid fluid before being administered. The initial dose is given by slow infusion for the first 10 minutes, and the infusion of the rest of the dose is completed over the course of 1 hour.
COMPLICATIONS OF ENVENOMATION AND TREATMENT
It is inadvisable to attempt to correct a coagulopathy until sufficient quantities of neutralizing antivenom have been administered. The consumptive coagulopathy seen with rattlesnake envenomations is unresponsive to heparin and the replacement of coagulation factors (i.e., with fresh-frozen plasma) or other blood components while unneutralized components of venom are circulating. Treatment with coagulation factors or blood components adds more substrate for unneutralized venom, thus increasing the levels of degradation products, which are also anticoagulant. Opioid analgesics should be avoided if the venom is known to have neurotoxic components (as do, for example, the venoms of coral snakes, Mojave rattlesnakes, and cobras), so as to avoid masking neurotoxic effects. Wound infections are rare after pit-viper bites; therefore, the prophylactic use of antibiotics is not recommended. Antibiotics should be administered if there is clinical and microbiologic evidence of wound infection. Severe envenomations by rattlesnakes may be associated with increased compartment pressure. The local reaction to envenomation, manifested as marked swelling, tenderness, tenseness, hypesthesia, and pain, may mimic a true compartment syndrome. In cases of suspected compartment syndrome, clinical diagnosis requires objective evidence of elevations in compartment pressure to more than
References
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