HEAVY METAL POISONING

Metals differ from other toxic substances in that they are neither created nor destroyed by humans. Nevertheless, their utilization by humans influences the potential for health effects in at least two major ways: first, by environmental transport, that is, by human oranthropogenic contributions to air, water, soil, and food, and second, by altering the speciation or biochemical form of the element.*

COMPLEXATION AND CHELATIONTHERAPYComplexation is the formation of a metal ion complex in which the metal ion is associated with a charged or uncharged electron donor, referred to as a ligand. The ligand may be monodentate, bidentate, or multidentate; that is, it may attach or coordinate using one, two or more donor atoms.Chelating agents (drugs) vary in their specificity for toxic metals. Ideal chelating agents should be water-soluble, resistant to biotransformation, able to reach sites of metal storage, capable of forming nontoxic complexes with toxic metals, and of being excreted from the body; they should also have a low affinity for essential metals, particularly calcium and zinc.*

COMPLEXATION AND CHELATION THERAPYBAL (British Anti-Lewisite)-(2,3-dimercaptopropanol Or Dimercaprol)DMPS(2,3-dimercapto-1-propanesulfonic acid)DMSA(meso-2.3.-dimercaptosuccinic acid; succimer)EDTA(ethylene diamine tetraacetic acid)DTPA(diethylenetriaminepentaacetic acid)DesferrioxamineDithiocarbamate (DTC)Penicillamine and N-AcetylcysteineHemodialysis with ChelationMajor metallic toxicants:CadmiumMercuryMagnesiumLeadArsenic

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CADMIUM (Cd)Physicochemical properties: Cd is a soft, silver white metal, insoluble in water, solved in nitric acid. Its vapours are heavier than the air.Cd usage and occupational risks: used in the manufacture of plastics, alkaline accumulators, production of Cd lamps, Cd glass, galvanic coating, etc.Routes of entry: mainly by inhalation, often - by ingestion (at wet extraction of Cd). In the organism Cd is mainly bound to the metallothionein. It accumulates in liver and kidneys, and small parts in bone marrow, hypophysis, adrenal glands.

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Cd poisoningElimination - mainly by urine and less by the bile. Pathogenesis: Cd is bound to the sulphhydrate, amino- and carboxygroups and breaks the activity of some enzymes. Cd irritates directly mucous membranesCd has nephrotoxic effect.

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Rarely with occupational origin. There are two forms:Inhalation form with development of pulmonary oedemaGastrointestinal form with vomiting, nausea, gripping pains in the epigastrium, in later stages dehydration syndrome develops with hemoconcentration, convulsions, collapses, toxic hepatitis, hepatorenal syndrome, acute toxic nephropathy.

ACUTE Cd POISONING*

CHRONIC CD POISONINGCritical organs are lungs and kidneys.Respiratory system - irritative changes in the upper respiratory tract, perforation of the nasal septum, chronic rhinitis, emphysema, pulmonary fibrosis.Renal syndrome with proteinuriaHepatic syndrome - tightness and pains in the right hypochondrium, hepatomegaly, liver dysfunctional with increased liver enzymesCardiovascular syndrome - mainly functional disorders, hypertensive effectsBone syndrome: osteoporosis, osteomalacia with spontaneous fractures - at long-term exposure above 20 years

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Cd carriers without subjective symptoms but with elevated content of Cd in urineCd effect - irritative changes of the upper respiratory tract, asthenic vegetative syndrome, reticulocytosis, golden-yellowish Cd ring at the base of the teeth - Cd lines, increased Cd levels in urineStages Cd intoxication:mild: gastrointestinal syndrome, proteinuria, increased Cd levels moderate: neurasthenic syndrome, gastro-intestinal syndrome, toxic hepatitis and toxic nephropathy, increased Cd levels in urine and bloodsevere: includes the above syndromes plus bone disordersSTAGES OF CD EFFECTS*

Antidotal therapyCaNa2EDTA (calcium disodium versenate)- amp. 10% 10 ml, 1.0 g/daily during 6 days. A control on urine is performed concerning albumin and cadmium content in urine.D-penicillamin - caps. 250 mg, 2,0 g/daily for 10 days with control of blood pressure concerning the number of leucocytes and thrombocytes2. Other drugs Calcium drugs; Calcium phosphoricum, Calcium C, Calcium D, etc.Vitamins: Vit. D, Vit. C, etc.TREATMENT*

WORK ABILITY EXPERTISEIn Cd carriers - hospital treatment, vitamin therapyWhen Cd effect is established - antidote therapy is applied and temporary disabilityIn Cd intoxication permanent change of work without contact with Cd or other toxic substances is necessary. When structural damages (emphysema, hepatitis, nephropathy, bone disorders) are diagnosed an appropriate therapy is applied with permanent change of work without toxic exposure. The percent loss of working ability depends on the degree and severity poisoning and the structural organic damages.

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MANGANESE (Mn) POISONINGPhysicochemical properties. Mn is a grey metal, oxidized in the air, soluble in acids. It is easily bound to iron, copper, silicon, sulphur, phosphorus, etc.Use and occupational risk. It is used for the production of ferromanganese, ferrous steel, etc. Exposed to Mn are workers producing alloyed steel, welders, those engaged in non-ferrous metallurgy, mining, textile, etc.Route of entry - by inhalation, few amount by ingestion and through skin.

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BIOTRANSFORMATION AND ELIMINATION OF MNThe highest percentage of Mn in blood is in erythrocytes, tightly bound as Mn porphirine and in serum it is bound to globulin. Mn accumulates in liver, brain, kidneys, hypophysis, hair, retina, dark skin. It passes through hematoencephalic barrier and placenta.Mn is eliminated mainly by the bile and gastro-intestinal tract and significantly less by urine. *

MECHANISMS OF Mn ACTIONManganese is a neurotropic poison. It affects directly the extra pyramid structures (pallidum, substantia nigra, corpus striatum) and causes Parkinson's syndrome.It shows affinity to the thiol groups and forms complex compounds with methionine, cysteine, cystine

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Acute Mn poisoning : Chronic Mn poisoning - stages:1. Mn carriers have no subjective complaints, but only increased content of Mn in blood and urine2. Mn effect is characterized with elevated Mn absorption and asthenic vegetative syndrome with dystonia.3. Mn intoxication

CLINICAL FINDINGS*

Mn INTOXICATIONIt is divided in: a) Early stage commonly with functional disorders like astheno-vegetative syndrome, autonomic gastro-intestinal events b) Stage of microfocal symptoms with depression syndrome, coordination disorders, sensory impairments, affection of the pyramid routes, etc.c) Advanced stage: Parkinson's syndrome with increased extra pyramid muscle tone, hypokinesia and akinesia, aphonic speech and disarthria, disgraphia, most frequently micrographia, tremor, hyper salivation, hyperhydrosis, diencephalic manifistation, etc.*

DIAGNOSIS

It is based on:Objective document about occupational contact with MnIncreased levels of Mn in biological media (a correlation relationship between Mn concentrations in the air of the working environment and its content in urine) Differential diagnosis The Mn induced Parkinsonism should be differentiated from Parkinsons syndromes due to encephalitis, trauma, drugs, psychotropic medications, atherosclerosis, toxic agents - CO, Hg, Pb, parathion, etc. *

TREATMENTEtiological (antidote); -CaNa2EDTA (calcium disodium versenate) - 10% 10 ml (1,0 g) by one ampoule daily in 5% of 500 ml Glucose solution i.v. guttatim or in stream of 20-40 ml 5%, 10% of glucose solution in three consecutive days; The manganese excretion in urine is daily observed. The medication course could be repeated. -D-penicillamin (tablets of 250 mg) by 1-2 g/daily for 5 daysAntiparkinsonic drugs (dopaminergic)Vitamin therapy (Vit B1, Vit B6, Vit B12, Vit C etc.)Other symptomatic and supportive drugs*

WORK ABILITY EXPERTISEIn mild, moderate or severe stages the contact with Mn must be stopped.In mild degree the patients are able to work In moderate or severe degrees the work ability is reduced according to the clinical manifestations.Parkinson's syndrome induces completely and permanently lost work ability. *

LEAD INTOXICATIONPb - inorganic, dusts and fumes, mist Tetraethyl lead, Tetramethyl leadPb does not serve any useful biologic function in humans. Physicochemical properties of Pb: a soft malleable, blue-gray metal, with high density and soluble in acid medium. Pb occur in many ores; it is concentrated through wet grinding and flotation prior to smelting. Another source is the removing from lead scrap. Exposure limits are determined in standards. *

LEAD INTOXICATION

Risk occupations: Manufacture of storage batteries, accumulators and painting production; chemical and building industry; lead alloys (chiefly with An and Stannum) in pipes and cable sheathing, isolder and electrical applications, paints, plastics as pigment and stabilizer; Pb glazes of ceramics; in crystal glass; for shielding of radioactivity; ammunition, bronze, in blast furnace building, polygraphic, metallurgic, electronic industry, etc. Tetraethyl and tetramethyl Pb are used as antiknock agents in gasoline.

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Occupational and Environmental ExposureInhalation (40%), and ingestion (when eating or smoking at the working place 5-10%) and through skin in contact with organic solvents containing Pb are potential routes of Pb exposure in mining particulary the more soluble carbonate and sulfate ores. Grinding and sintering operation generate high levels of Pb dust and fumes. Workers engaged in the reclamation of Pb from secondary sources have potential exposure to Pb as well as other metal contaminants. *

Occupational and Environmental ExposureExposure is a constant hazard in the manufacture of Pb batteries. Paint and pigment manufacturers are exposed to Pb additives. Painters may also be exposed, especially during fine spray-painting operations. Torch burning to remove Pb-based paints generates lead fumes. Welders and brazers may be exposed to Pb alloys fluxes, coatings. Glass-makers, pottery workers, workers in munitions plants and rifle-ranges. Environmental exposure may occur near Pb smelters due to air, soil, water contamination. From car exhausts, low-income housing, of tap water from Pb pipes in old homes.

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Absorption and Metabolism Absorption - Inhalation and ingestion are the primary routes.Metabolism In the blood stream, the majority of absorbed Pb is bound to Er. The free diffusible plasma fraction is distributed to brain, kidney, liver, skin, skeletal muscles, where it is readily exchangeable. Bone constitutes the major site of deposition of absorbed Pb, where it is incorporated into the bony matrix similar to Ca. Intracellularly, Pb binds to sulfhydryl groups and interferes with numerous cellular enzymes, including those involved in haem synthesis. This binding accounts for the presence of Pb in hair and nails. Pb also binds to mitochondrial membranes and interferes with protein and nucleic acid synthesis. *

PbBiotransformation Pb accumulates in bones, liver, kidneys, aorta, etc. During alcohol consumption, infections the accumulated Pb is released from the internal organs and manifests its toxic effect. Pb crosses the blood-brain barrier and placenta.Elimination: mainly by urine (75-80%), less by gastro-intestinal tract (about 15%) and by hairs, nails, sweat (8%).

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Pb distribution and accumulation in bones, liver, kidneys, aorta, etc. *

Excretion of PbExcretion is slow over time, primary through the kidney. Fecal excretion, sweat, and epidermal exfoliation are other routes. The half-life of Pb is long, estimated 5 - 10 years. Tetraethyl and tetramethyl Pb are converted to the trialkyl metabolites that are responsible for toxicity. The fat solubility of this compounds is responsible for the accumulation in central nervous system. Alkyl Pb compounds are ultimately converted to inorganic Pb and are excreted in the urine.

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PathogenesisAnaemia develops - acquired sideroblastic, hypochromic, hypersideremic.

directly affects Erithrocytes, destroying there structures and forms, shortening there life

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CLINICAL FINDINGS

Asthenic vegetative syndrome - functional disorders of the autonimc nervous system

Gastrointestinal syndrome - loss of appetite, metal taste, dyskinesia, nausea and development of lead colic, constipation, arterial hypertension, bradycardia, umbilical pain.*

CLINICAL FINDINGSHepatic syndrome (functional disorders of different degree up to the development of toxic hepatitis - the transition to cirrhosis is rarely met.)Encephalo-polyneurotic syndrome (paresis and paralysis, positive symptom of weakness of upper limbs).

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CLINICAL FINDINGSEye disorders Blood syndrome (sideroblastic anaemia, reticulocytosis, increased number of basophile stippled erythrocytes).Cardio-vascular syndrome (bradycardia, hypotonia, early atherosclerosis with myocardial disorders)Stigmata of Pb intoxication: typical distinct Pb line in the gum a grey blue pigmentation of the gum especially near carious teeth; Pb face with pale grey colour as a result of skin vessels spasm)*

STAGES OF LEAD POISONINGLead carriers - preclinical stage without complaints, but gum changes, higher Pb content in blood and urine, increased daily urine content of lead.Lead effect asthenic vegetative and blood syndrome.Mild degree - blood syndrome, gastro-intestinal syndrome dyskinesia of the biliary and intestinal tracts, spastic colitis, functional liver disorders, and no lead colic.Moderate degree - blood syndrome, toxic hepatitis, gastro-intestinal disorders including lead colic, Pb polyneuropathy.Severe degree Pb encephalopathy - epilepsy, toxic hepatitis, gastro-intestinal - lead colic, motor form of polyneuropathy, anemia*

DIAGNOSIS

Occupational risk with lead exposure

Laboratory constellation with increased content of Pb in blood and urine, reticulocytosis, increased number of basophilic stippled erythrocytes.*

Essentials of DiagnosisInorganic Pb- acute effects:Abnormal pain (collic)EncephalopathyHemolysisAcute renal failure*

Essentials of DiagnosisInorganic Pb- chronic effects:AnemiaPeripheral neuropathy (Nerve conduction studies may reveal delayed motor conduction velocities even without overt peripheral neuropathy )Fatigue and astheniaArthralgias and myalgiasNeurobehavioral disorders and chronic encephalopathy Gout and gouty nephropathy Chronic renal failure Proximal renal injury may result in aminoaciduria, glucosuria, phosphaturia, hyperuricemia. Liver involvement may be suggested by mild elevations of serum aminotransferases.

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Alkyl lead compounds:Fatigue HeadacheNausea and vomitingNeuropsychiatric complaints (memory loss, difficulty in concentrating)Delirium, seizures, coma

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Laboratory findingsAnemia is a frequent manifestation.It is usually normochromatic. Normal Fe-levels in sera.Increased red cells turnover and frank hemolysispresent, with basophilic stippling of the Er and reticulocytosis.*

Laboratory findingsBlood lead levels are an indication of recent exposure (days or weeks). The current standard requires that Pb levels be maintained < 40g/dLAltered haem synthesis, evidenced by an increase in protoporphyrin measured as either free erythrocyte protoporphyrin (FEP) begins when blood Pb levels exceed 40 g/ dL. The enzyme Delta-aminolevulinic acid dehydratese (delta-ALAD) is inhibited by Pb and Delta-aminolevulinic acid is increased the urine test.

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Laboratory findingsMeasurement of chelatable Pb may assist in the diagnosis; CaNa2 EDTA (Calcium disodium versenate) Pbmobilization test is an indication of the total body burden and, when abnormally high, suggests that chelation therapy should be initiated.A 24-hour urine (using the proper acid-washed polypropylene bottles) is collected for Pb before and after i.v. giving a CaNa2 EDTA dose of 30 mg/kg body weight.; infusion over 1h in 250 mL of 20% dextrose.

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Medical examination of lead - exposed workers1. Medical and occupational history (focusing on Pb exposure history) 2. Physical examination (focusing on gums, gastrointestinal, hematologic, renal, reproductive problems. 3. Blood pressure measurement 4. Blood testing: Blood lead level; Protoporphyrin; Haemoglobin; Hematocrit; Peripheral smear; Serum iron; Serum creatinine; ASAT; ALAT; Delta-aminolevulinic acid in urine 5. Neurological examination (focusing on neurological problems) 6. Psychological tests

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TREATMENTThe first step is removal from exposure.The decision about whether chelation therapy.Symptomatic therapy1.Etiological (Antidote)CaNa2EDTA - 10% of 10 ml amp in serum or glucose solution by 1,0 g daily i. v. during three consecutive days. This course may be repeated two times with three days break if the Pb exposure is high.In the administration of therapy with CaNa2EDTA the following is observed: content of iron, zinc, copper in urine, possible presence of proteinuria.*

TREATMENTSuccimer (chemet) caps. 350 mg - 2,1 g/daily at equal administrations per 8 hours during 5 days, after that the dose is reduced to 1,4 e/daily, Therapy course - 7 to 10 days (at lower degree of lead exposure). It is obligatorily to determine the levelD-penicillamin (Cuprenil) tabl. 250 mg, 2,0 g daily in four applications. Therapy course - 7 days. An (preventive therapy). BAL (2,3-dimercaptopropanol) is also a clinically useful chelating agent.2.Spasmolitics as an additional therapy at lead colics (Atropine sulf., Buscolysin, Spasmalgon etc.), hepatoprotective therapy (levulose solutions, Carsil 3x2 tabl. etc.), etc.3.Vitamin therapy (Vit B1, Vit B6, Vit C)

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PREVENTIONTechnological prevention - automation and pressurization of the production processes, local and general ventilation, wet cleaning, use of personal protective equipment. Regular conduction of preliminary and periodic medical check-ups.Workplace hygiene (Clean areas for eating, no smoking, showering and cleaning of work)Technological and machine innovations Ventilation in working roomsMedical prevention Medical examinations and laboratory tests for workers (periods are according laws and standards)Medical examinations before accepting in the work place (new labours)

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MERCURY POISONING (Hg)Physicochemical properties. Hg is a liquid metal Its vapours are seven times heavier than the air, they are easily volatile.

Portal of entry in the organism - by inhalation and skin contact, rarely - ingestion (when eating or smoking the working places)

Usage and occupational risk: in production of mercury and quartz lamps, amalgams, manufacture of thermometers, barometers, manometers ,etc. *

Biotransformation. Hg is bound to erythrocytes. It can also be found in the blood plasma. It is a cumulative poison, mostly accumulates in kidneys and liver, where bounds to low-molecular-weight protein - metallothionein. Hg crosses the blood-brain barrier and placenta. It has affinity to the sulfhydryl groups of the cellular enzymes and proteins.

Elimination: mainly in urine, feces, and few amounts in sweat.

Mechanism of action: Hg is a neurotropic poison. *

CLINICAL FINDINGSHigh levels of mercury in urine Asthenic vegetative syndrome - headache, vertigo, decreased work ability, feeling of fear, insomnia, memory loss, increased anger, tremor of hands, the so-called mercury erethism, psychogenic and cerebellum manifestations.Polyneuropathy and encephalopathy may also occur.*

CLINICAL FINDINGSGastro-intestinal syndrome: unpleasant, sweetish, metal taste in the mouth, increased salivation - up to a few litres in the twenty-four-hour period - the so-called mercury ptyalism; in other cases, on the contrary a dry mouth is observed; abdominal pain, vomiting, nausea - chronic gastritis and colitis. The Hg pharyngitis - the so-called Kussmaul's sign or throat. Inflammatory processes in the oral cavity are manifested - gingivitis, stomatitis. A Hg line - bluish purple pigmentation from Hg sulphide may be present on the teeth or gums. -*

CLINICAL FINDINGSCardio-vascular syndrome - it has most frequently functional character - cardialgia, tachycardia, etc.Renal syndrome - mercury nephrosis and glomerulonephritis may also occur.Skin damage - on the bare parts of the body chronic dermatitis or eczema may develop.Eye disorders - Atkinson's syndrome - the colour of the cornea is changed to dark pink-brown.

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Stages of mercury poisoning1. Mercury carrier - in the urine increased content of Hg, mercury line on the gums and no objective clinical findings.2. Mercury effect - asthenic vegetative, neurotic syndrome with changes in the oral cavity, increased level of Hg in urine, inhibited activity of carboanhydrase. nervous system effects,.3. Micromercurism - expressed manifestations of tremor, disorders of coordination, gastrointestinal syndrome, strongly inhibited activity of the carboanhydrase4. Severe degree - organic disorders of the central nervous system, encephalopathy*

Diagnosis. Differential diagnosis Diagnosis - proved occupational risk, clinical course of the intoxication, Atkinson's syndrome, mercury content in urine.Differential diagnosis. The differential diagnosis is with the diseases of the nervous, gastro-intestinal systems, renal diseases with non-occupational origin. *

TREATMENT1.Antidote (Unithiol - 5 ml amp. by 1 amp. daily, a treatment course from 5 to 10daysSuccimer (caps. 350 mg by 2,1 g/daily at equal administrations per 8 hours during 5 days. Depending on the excretion of mercury in urine, the dose of Succimer can be reduced to 1,4 g/daily, 2 times per 12 hours during 2 weeks.The therapy with Succimer is an alternative to that with Unithiol. A therapy with Succimer can be applied after treatment with Unithiol, but not earlier than 4 weeks from the Unithiol administration. *

TREATMENTNa thiosulfuricum (10-20% - 10 ml, therapy course of 5 days. It is applied in the absence of Unithiol and Succimer.2.Vitamin therapy (Vit Bu Vit B6, Vit C).3. Symptomatic treatment - in the early phases tranquilizers, in more advanced stages - antidepressants, neurotrophics, vessel dilators). *

Arsenic poisoningArsenic is released during the smelting process of copper, zinc, tin, and lead

It is an irritant to the skin and may cause eczematous dermatitis and arsenical keratosis usually on the palms and soles on contact Chronic toxic effects include megaloblastic bone marrow suppression and liver enlargement

Normal blood concentration is 223 g/L and urine levels are 550 g/d.

Biological monitoring of arsenic is usually conducted by measuring total arsenic in the hair, nails, or urine*

Arsenic poisoningArsenic is particularly difficult to characterize as a single element because its chemistry is so complex and there are many different arsenic compounds. It may be trivalent or pentavalent and is widely distributed in nature. The most common inorganic trivalent arsenic compounds are arsenic trioxide, sodium arsenite, and arsenic trichloride. Pentavalent inorganic compounds are arsenic pentoxide, arsenic acid, and arsenates, such as lead arsenate and calcium arsenate. Organic compounds may also be trivalent or pentavalent, such as arsanilic acid, or may even occur in methylated forms as a consequance of biomethylation by organisms in soil, fresh water, and seawater.*

ToxicokineticsAbout 80 to 90 percent of a single dose of arsenite[As(III) or arsenate As(V)] has been shown to be absorbed from the gastrointestinal tract of humans and experimental animals.Arsenic compounds of low solubility (e.g., arsenic selenide,lead arsenide, and gallium arsenide) are absorbed less efficiently than dissolved arsenicSkin can be a route of exposure to arsenic, and systemic toxicity has been reported in persons having extensive acute dermal contact with solutions of inorganic arsenic*

Biotransformation The metabolism and potential for toxicity of arsenic is complicated by in vivo transformation of inorganic forms by methylation to monomethyl arsenic (MMA) and dimethyl arsenic (DMA). The methylation of arsenic compounds involves both oxidation states of the element. The liver is the major site for methylation. A substantial fraction of absorbed As(V) is rapidly reduced to AS(III), most of which is then methylated to MMA or DMA.*

Mechanisms of ToxicityIt has been known for some years that trivalent compounds of arsenic are the principal toxic forms and that pentavalent arsenic compounds have little effect on enzyme activity. A number of sulfhydryl-containing proteins and enzyme systems have been found to be altered by exposure to arsenic.Some of these can be reversed by addition of an excess of a monothiol such as glutathione.*

ToxicologyIngestion of large doses (70 to 180 mg) of arsenic may be fatal. Symptoms of acute illness, possibly leading to death,consist of fever, anorexia, hepatomegaly, melanosis, and cardiac arrhythmia, with changes in electrocardiograph results that may point to eventual cardiovascular failure. Other features include upper respiratory tract symptoms, peripheral neuropathy, and gastrointestinal, cardiovascular, and hematopoietic effects. Acute ingestion may be suspected from damage to mucous membranes, such as irritation, vesicle formation, and even sloughing.*

Reproductive Effects and TeratogenicityHigh doses of inorganic arsenic compounds given to pregnant experimental animals produced various malformations, somewhat dependent on time and route of administration, in fetuses and offspring. However, no such effects have been noted in humans with excessive occupational exposures to arsenic compounds. Arsenic readily crosses the placenta in women without known exposure to arsenic.*

CarcinogenicityIn humans, chronic exposure to arsenic induces a series of characteristic changes in skin epithelium, proceeding from hyperpigmentation to hyperkeratosis.Diffuse or spotted hyperpigmentation, the initial nonmalignant cutaneous effect, can first appear within 6 months to 3 years of chronic ingestion at concentrations in excess of approximately 0.4 mg/kg/day.*

TreatmentTreatment is symptomatic, with particular attention to fluid volume replacement and support of blood pressure with pressor agents. For acute symptoms, dimercaprol may be given (3 mg/kg intramuscularly every 4 hours) until symptoms subside, followed by oral penicillamine. Succimer(2,3-dimercaptosuccinic acid) is also thought to be effective. For chronic exposures, dimercaprol and/or penicillamine may also be used*