Mercury Hazards to Living Organisms - Chapter 4 docx

37 C HAPTER 4 Mercury Poisoning and Treatment The toxicity of mercury has been recognized since antiquity (Hook and Hewitt, 1986). No other metal demonstrates the diversity of effects caused by different biochemical forms than does mercury (Goyer, 1986). Toxicologically, there are three forms of mercury: (1) elemental mercury, (2) inorganic mercury compounds, and (3) organomercurials (Goyer, 1986). Among the various forms of mercury and its compounds, elemental mercury in the form of vapor, mercuric mercury, and methylmercury have the greatest toxicological potential (Satoh, 1995). Metallic or elemental mercury volatilizes to mercury vapor at ambient air temperatures, and most human exposure is by inhalation. Mercury vapor is lipid soluble, readily diffuses across the alveolar membranes, and concentrates in erythrocytes and the central nervous system. Inorganic mercury salts can be divalent (mercuric) or monovalent (mercurous). Gastrointestinal (GI) absorption of inorganic salts of mer- cury from food is less than 15.0% in mice and about 7.0% in a study of human volunteers; however, methylmercury absorption in the GI tract is 90.0 to 95.0%. Methylmercury, when compared to inorganic mercury compounds, is about 5 times more soluble in erythrocytes than in plasma, and about 250 times more abundant in hair than in blood (Goyer, 1986). 4.1 POISONING The primary mode of action of both inorganic and organic mercury compounds is associated with interference of membrane permeability and enzyme reactions through binding of mercuric ion to sulfhydryl groups, although organomercurials can penetrate membranes more readily (Norton, 1986). Early accounts of acute and chronic mercury poisoning and their treatment follow (Anon., 1948); however, it is cautioned that treatment should be under the guidance of a physician. 4.1.1 Elemental Mercury Metallic or elemental mercury volatilizes to mercury vapor at ambient air temperatures, and most human exposure is by way of inhalation (Goyer, 1986). The saturated vapor pressure at 20.0 ° C is 13.2 mg/m 3 . This value far exceeds the threshold limited value (TLV) of 0.05 mg/m 3 ; accordingly, mercury intoxication due to inhalation of the vapor readily occurs in various occupational and environmental situations (Satoh, 1995). Mercury vapor readily diffuses across the alveolar mem- brane and is lipid soluble so that it has an affinity for the central nervous system and red blood cells. Metallic mercury, unlike mercury vapor, is only slowly absorbed by the GI tract (0.01%) at a rate related to the vaporization of the elemental mercury and is of negligible toxicological significance (Goyer, 1986). © 2006 by Taylor & Francis Group, LLC 38 MERCURY HAZARDS TO LIVING ORGANISMS Inhaled mercury vapor (Hg o ) is readily oxidized via the catalase–H 2 O 2 complex and converted to Hg 2+ , mainly in liver and erythrocytes (Satoh, 1995). Although this reaction is rapid, some Hg o crosses the blood–brain barrier and accumulates to a greater extent than does Hg 2+ after ionic mercury exposure. Because Hg 2+ is reduced to Hg o , there is probably an oxidation-reduction cycle of mercury in the body (Satoh, 1995). In typical Hg o vapor poisonings, excessive bronchitis and bronchiolitis occur within a few hours after heavy exposure, that is, direct inhalation of mercury vapor generated by heating metallic mercury (Satoh, 1995). This is followed by pneumonitis and respiratory distress, excitability, and tremors. If the amount inhaled is sufficiently large, renal failure will develop. In one Japanese factory producing sulfuric acid using Hg o in the process, a few of the workers died of respiratory distress associated with renal failure (Satoh, 1995). Moderate and repeated exposure results in classical mercury poisoning (Satoh, 1995). Inhalation of mercury vapor, if not fatal, is associated with an acute, corrosive bronchitis, interstitial pneumonitis, tremors, and increased excitability (Goyer, 1986). With chronic exposure to mercury vapor, the major effects are on the central nervous system. Early signs are nonspecific and have been termed “micromercurialism” or “asthenic- vegetative syndrome” (Goyer, 1986). Micromercurialism is characterized by weakness, fatigue, anorexia, weight loss, and GI disturbance (Satoh, 1995). This syndrome is characterized clinically by at least three of the following: tremors, thyroid enlargement, increased radioiodine uptake by thyroid, tachycardia, unstable pulse, dermographism, gingivitis, changes in blood chemistry, and increased excretion of mercury in urine (Goyer, 1986). With increasing exposure, the symptoms include tremors of the fingers, eyelids, and lips, and may progress to generalized trembling of the entire body and violent chronic spasms of the arms and legs. This is accompanied by changes in personality and behavior, with loss of memory, increased excitability, severe depression, delirium, and hallucination. Another characteristic feature of mercury toxicity is severe salivation (Goyer, 1986). Tremors, increased excitability, and gingivitis have been recognized historically as the major manifestation of mercury poisoning from inhalation of mercury vapor and exposure in the fur, felt, and hat industry to mercuric nitrate (Goldwater, 1972). Effects of mercury vapor exposure prevail long after cessation of exposure, although typical symptoms such as tremors, gingivitis, and salivation usually disappear quickly (Satoh, 1995). Residual effects due to previous exposure have been documented in workers with a peak urinary mercury concentration greater than 0.6 mg/L; neurobehavioral disturbances were observed in these workers 20 to 35 years post exposure (Satoh, 1995). 4.1.2 Inorganic Mercurials Inorganic mercury salts can be divalent (mercuric) or monovalent (mercurous). Chronic exposure to low levels of inorganic mercury compounds is associated with psychological changes including abnormal irritability (erethismas mercurialis), colored mercury compounds in the anterior lens capsule of the eye (mercurialentis), tremors, and excessive salivation (Norton, 1986). Inorganic forms of mercury are corrosive and produce symptoms that include metallic taste, burning, irritation, salivation, vomiting, diarrhea, upper GI tract edema, abdominal pain, and hemorrhage (Rumack and Lovejoy, 1986). These effects are seen acutely and may subside with subsequent lower GI tract ulceration. Large ingestion of the mercurial salts may produce kidney ingestion, such as nephrosis, oliguria, and anuria (Rumack and Lovejoy, 1986). 4.1.2.1 Mercuric Mercury Acute poisoning by mercurials usually occurs in the case of mercuric perchlorides, with intense gastrointestinal inflammation, vomiting, diarrhea, and extreme collapse. Treatment is usually with albumin, which forms an insoluble compound with the perchloride (Anon., 1948). Chronic poison- ing, or mercurialism, is marked by tenderness of the teeth while eating and offensive breath. Later, © 2006 by Taylor & Francis Group, LLC MERCURY POISONING AND TREATMENT 39 the gums become inflamed, salivary glands are swollen and tender, and saliva pours from the mouth. The teeth may become loose and fall out. The symptoms are aggravated until the tongue and mouth ulcerate, the jaw bone necroses, hemorrhages occur in various parts of the body, and death results from anemia, septic inflammation, or exhaustion. Treatment includes administration of potassium iodide in low, repeated doses (Anon., 1948). Chronic exposure to low levels of inorganic mercuric compounds produces tremors, excess salivation, and psychological changes characterized by irritability and excitement (Norton, 1986). Collectively, this is often described as the “mad hatter syndrome” (Rumack and Lovejoy, 1986). Mercuric mercury (Hg 2+ ) is a potentially toxic chemical, although it is poorly absorbed by the GI tract and other body parts (Satoh, 1995). Accidental or suicidal ingestion of mercuric chloride or other mercuric salts produces corrosive ulceration, bleeding, necrosis of the intestinal tract and is usually accompanied by shock and circulatory collapse (Goyer, 1986). If the patient survives the gastrointestinal damage, renal failure may occur within 24 hours owing to necrosis of the proximal tubular epithelium followed by diminished secretion of urine and kidney pathology. These may be followed by ultrastructural changes consistent with irreversible cell injury. Regeneration of the tubular lining is possible if the patient can be maintained by dialysis (Goyer, 1986). The pathogenesis of chronic mercury kidney damage has two phases: an early phase with antibasement membrane glomerulonephritis, followed by a superimposed immune-complex glom- erulonephritis (Roman-Franco et al., 1978). The pathogenesis of the nephropathy in humans appears similar, although early glomerular nephritis may progress to an interstitial immune-complex nephri- tis (Tubbs et al., 1982). Injection of mercuric chloride produces necrosis of kidney epithelium (Gritzka and Trump, 1968). Cellular changes include fragmentation of the plasma membrane, disruption of cytoplasmic membranes, loss of ribosomes, and mitochondrial swelling; however, all of these changes are associated with renal cell necrosis from a variety of insults. High doses of mercuric chloride are directly toxic to renal tubular lining cells and chronic low-level doses to mercuric salts may induce an immunologic glomerular disease that is the most common form of mercury- induced nephropathy. Chronic mercury-induced kidney damage seldom occurs in the absence of detectable damage to the nervous system (Gritzka and Trump, 1968). Although kidneys contain the highest concentrations of mercury following exposure to inorganic mercury salts and mercury vapor, it is emphasized that organomercurials concentrate in the posterior cortex of the brain (Goyer, 1986). 4.1.2.2 Mercurous Mercury Mercurous (Hg + ) mercury compounds are unstable and easily break down to Hg o and Hg 2+ (Satoh, 1995). Mercurous compounds are less corrosive and less toxic than mercuric compounds, probably because they are less soluble (Rumack and Lovejoy, 1986). Calomel — a mercurous chloride-containing powder with a long history of medical use — is known to be responsible for acrodynia or “pink-disease” in children when used as a teething powder (Matheson et al., 1980). This is probably a hypersensitivity response by skin to mercurous salts, producing vasodilation, hyperkeratosis, and excessive sweating. Afflicted children had fever, pink- colored rashes, swollen spleen and lymph nodes, and hyperkeratosis and swelling of fingers. Effects were independent of dose and are thought to be a hypersensitivity reaction (Matheson et al., 1980). 4.1.3 Organomercurials Among the organomercurials, alkylmercurials — especially methylmercurials (CH 3 Hg + ) — are the most environmentally and ecologically significant (Satoh, 1995). Methylmercury is naturally pro- duced from inorganic mercury by microbial activity; methylmercurials are lipid soluble and readily cross blood–brain and placental barriers (Satoh, 1995). The sensitivity of the developing brain to methylmercury is due to placental transfer of lipophilic methylmercury to the central nervous system © 2006 by Taylor & Francis Group, LLC 40 MERCURY HAZARDS TO LIVING ORGANISMS (CNS) (Campbell et al., 1992). The blood–brain barrier is incomplete during the first year of life in humans, and methylmercury can cross this barrier during that time (Rodier, 1995). Phenylmer- curials (C 6 H 5 Hg + ) and methoxyethyl mercurials (CH 3 OC 2 H 4 Hg + ) have been used as fungicides and pesticides and readily transform into inorganic mercurials in living organisms with toxic properties similar to those of inorganic mercurials (Satoh, 1995). Ingestion of organomercurials, such as ethylmercury, may produce symptoms of nausea, vom- iting, abdominal pain, and diarrhea, but in most cases the main toxicity is neurologic involvement presenting with paresthesias, visual disturbances, mental disturbances, hallucinations, ataxia, hear- ing defects, stupor, coma, and death (Rumack and Lovejoy, 1986). Symptoms may occur for several weeks after exposure. Exposure and poisoning can occur after ingestion of mercury-contaminated seafoods, grains, or inhalation of vaporized organomercurials (Rumack and Lovejoy, 1986). The toxic signs of alkylmercury compounds, such as methylmercury, are different than those of inorganic mercurials owing to greater penetration of the organomercurials into the brain (Norton, 1986). Methylmercury causes necrosis of the granule cell layer of the cerebellum, which is asso- ciated with carbohydrate metabolism and kidney disorders. Focal atrophy of the cortex, with sensory disturbances, ataxia, and dysarthria, is found after methylmercury intoxication. The emotional changes and autonomous nervous system involvement with inorganic mercury compounds are not seen with organomercurials (Norton, 1986). Sensory nerve fibers are selectively damaged (Norton, 1986). The primary mode of action of both inorganic and organic mercury compounds may be interference with membrane permeability and enzyme actions by binding of mercuric ion to sulfhydryl groups. Small neurons in the CNS are more likely to be damaged than large neurons in the same area by methylmercury (Norton, 1986). The major clinical features of methylmercury toxicity are neurologic, consisting of pares- thesia, ataxia, dysarthria, and deafness, appearing in that order (Roizin et al., 1977). The main pathologic features include degeneration and necrosis of neurons in focal areas of the cerebral cortex and in the granular layer of the cerebellum. Studies of both inorganic- and organic-mercury- related neuropathy show degeneration of primary sensory ganglion cells. Lesion distribution in the CNS suggests that mercury damages small nerve cells in the cerebellum and visual cortex (Roizin et al., 1977). Methylmercuric chloride, as an environmental pollutant, has produced renal damage in humans and animals through inhibition of mitochondrial and other enzyme systems (Hook and Hewitt, 1986). 4.2 MERCURY TREATMENT Treatment of mercury-poisoned victims is complex, and should be supervised by a physician. Therapy of mercury poisoning is directed toward lowering the concentration of mercury at the critical organ or site of injury (Berlin, 1979). For the most severe cases, particularly with acute renal failure, hemodialysis together with infusion of mercury-chelating agents such as cysteine and penicillamine is warranted. For less severe cases of inorganic mercury poisoning, chelation with BAL (dimercaprol) is recommended. Chelation therapy, however, is not effective for poisoning with organomercurials. In those cases, oral administration of a nonabsorbable thiol resin that binds mercury and enhances intestinal excretion, or surgical establishment of gallbladder drainage have proven satisfactory (Berlin, 1979). Treatment usually consists of emesis or lavage, followed by administration of activated charcoal and a saline cathartic (Rumack and Lovejoy, 1986). Cow’s milk may be given to help precipitate the mercury compound. Blood and urine levels of mercury may be useful in determining whether chelating agents, such as D-penicillamine or BAL (dimercaprol) should be administered. D-penicillamine is given at 250.0 mg orally, four times daily in adults. For children, D-penicillamine is given at 100.0 mg/kg body weight daily to a maximum recommended dose of 1000 mg daily for 3 to 10 days © 2006 by Taylor & Francis Group, LLC MERCURY POISONING AND TREATMENT 41 with continuous monitoring of mercury urinary excretion. In patients unable to tolerate penicil- lamine, BAL can be administered at a dose of 3.0 to 5.0 mg/kg body weight (BW) every 4 h by deep intramuscular (im) injection for the first 2 days, then 2.5 to 3.0 mg/kg BW im every 6 h for 2 days, followed by 2.5 to 3.0 mg/kg BW im every 12 h for 1 week. Adverse reactions associated with BAL, such as skin eruptions (urticaria), can often be controlled with antihistamines such as diphenylhydramine. The development of renal failure contraindicates use of penicillamine because the kidney is the main excretory route for penicillamine. BAL therapy can be used cautiously despite renal failure because BAL is excreted in the bile; however, BAL toxicity, which consists of fever, rash, hypertension, and CNS stimulation must be closely monitored. Dialysis is not recommended because it does not remove chelated or free mercury (Rumack and Lovejoy, 1986). Mercury-antagonistic and mercury-protectant drugs and compounds now include 2,3-dimercap- topropanol, polythiol resins, selenium salts, thiamin, vitamin E, metallothionein-like proteins, and sulfhydryl agents (Magos and Webb, 1979; Elhassani, 1983; Siegel et al., 1991; USPHS, 1994; Caurent et al., 1996). Thiols (R-SH), which compete with mercury for protein binding sites, are the most important antagonists of inorganic mercury salts, and have been used extensively in attempts to counteract mercury poisoning in humans (Das et al., 1982). Thiamin was the most effective of the Group VIB derivatives (which includes sulfur, selenium, and tellurium) in protecting against organomercury poisoning in higher animals (Siegel et al., 1991). The protective action of selenium (Se) against adverse or lethal effects induced by inorganic or organic mercury salts is documented for algae, aquatic invertebrates, fish, birds, and mammals (Magos and Webb, 1979; Heisinger, 1979; Chang et al., 1981; Lawrence and Holoka, 1981; Das et al., 1982; Gotsis, 1982; Satoh et al., 1985; Eisler, 1987; Goede and Wolterbeek, 1994; Paulsson and Lundbergh, 1989; USPHS, 1994; Caurent et al., 1996; Kim et al., 1996a, 1996b). For example, selenium, as sodium selenite, that was introduced into a nonacidified mercury-contaminated lake in Sweden to concentrations of 3.0 to 5.0 µg Se/L (from 0.4 µg Se/L) and sustained at this level for 3 years resulted in declines of 50.0 to 85.0% in mercury concentrations in fish muscle (Paulsson and Lundbergh, 1989). The mercury-protective effect of selenium is attributed to competition by selenium for mercury-binding sites associated with toxicity, formation of a Hg-Se complex that diverts mercury from sensitive targets, and prevention of oxidative damage by increasing the amount of selenium available to the selenium-dependent enzyme glutathione peroxidase (USPHS, 1994). In seabirds, an equivalent molar ratio of 1:1 between total mercury and selenium was found in livers of individual seabirds that contained more than 100.0 mg Hg/kg DW; this relation was unclear in other individuals, which had relatively low mercury levels (Kim et al., 1996a, 1996b). The selenium-protective mechanism in birds is explained by a strong binding between mercury and selenium, possibly by the formation of a selenocystamine–methylmercury complex (CH 3 HgSeCH 2 CH 2 NH 3 + ), mercury binding to sele- nocysteine residues (CH 3 HgSeCH 2 CH(NH 3 )(COO)•H 2 O), the formation of insoluble mercuric selenide (HgSe), or binding of mercury to SeH residues of selenoproteins, notably metallothioneins with thiols replaced by SeH (Goede and Wolterbeek, 1994). However, high selenium concentrations in tissues of marine wading birds do not have their origin in elevated levels of mercury. The Se:Hg ratio in marine wading birds from the Wadden Sea is 32:1 and greatly exceeds the 1:1 ratio found when selenium is accumulated to detoxify mercury (Goede and Wolterbeek, 1994). In marine mammals and humans, selenium and mercury concentrations are closely related, almost linearly in a 1:1 molar ratio (Eisler, 1987). The molar ratio between mercury and selenium in marine mammals suggests that the major mechanism of detoxification is through the formation of a complex Hg–Se that leads to mercury demethylation (Caurent et al., 1996). The site of this process is the liver in which mercury appeared mainly as inorganic; whereas in the muscle, the percent of organic to total mercury was much higher. Detoxification is limited in lactating female whales, and some- times in all the individuals of one school (Caurent et al., 1996). Selenium does not, however, protect against mercury-induced birth defects, such as cleft palate in mice (USPHS, 1994). It is clear that more research is needed on mercury protectants. © 2006 by Taylor & Francis Group, LLC 42 MERCURY HAZARDS TO LIVING ORGANISMS 4.3 SUMMARY Both inorganic and organomercurials interfere with membrane permeability and enzyme reactions through binding of mercuric ion to sulfhydryl groups; organomercurials usually penetrate mem- branes more readily. Symptoms of acute and chronic mercury poisoning caused by elemental mercury, mercuric mercury, mercurous mercury, and organomercurial compounds are listed, mech- anisms of action discussed, and treatment regimes prescribed. For elemental mercury, inhalation of Hg o is the primary toxicological route. Inhaled Hg o vapor is readily oxidized within the body, mainly in liver and erythrocytes, and converted to Hg 2+ . Neurobehavioral disturbances were observed in some Hg o vapor poisoning cases 20 to 35 years after exposure. For inorganic mercuric compounds, exposure routes include inhalation and ingestion, with primary damage to the renal system. Mercurous (Hg + ) mercury compounds are unstable and degrade to Hg o and Hg 2+ . Mercurous compounds are less corrosive and less toxic than mercuric compounds and this could be associated with their comparatively low solubility. Among the organomercurials, methylmercury compounds (CH 3 Hg + ) are the most significant toxicologically because they are produced naturally from inor- ganic mercury by microbial activity and are lipid soluble, thus readily crossing blood–brain and placental barriers. Ingestion is the main route of administration for methylmercurials and the primary target organs are brain and other neurologic tissues. Treatment of mercury-poisoned victims is complex and should be supervised by a physician. Therapy is directed to lowering the mercury concentration at the critical organ or site of injury through emesis, lavage, cathartics, administration of activated charcoal and various mercury chelat- ing agents, and — in the most severe cases — dialysis. 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Toxicological Profile for Mercury (Update), TP-93/10. U.S. PHS, Agen. Toxic Substances Dis. Registry, Atlanta, GA. 366 pp. © 2006 by Taylor & Francis Group, LLC . developing brain to methylmercury is due to placental transfer of lipophilic methylmercury to the central nervous system © 2006 by Taylor & Francis Group, LLC 40 MERCURY HAZARDS TO LIVING ORGANISMS (CNS). LLC 38 MERCURY HAZARDS TO LIVING ORGANISMS Inhaled mercury vapor (Hg o ) is readily oxidized via the catalase–H 2 O 2 complex and converted to Hg 2+ , mainly in liver and erythrocytes (Satoh,. for 3 to 10 days © 2006 by Taylor & Francis Group, LLC MERCURY POISONING AND TREATMENT 41 with continuous monitoring of mercury urinary excretion. In patients unable to tolerate penicil- lamine,