Pharmacology of Murcury
Mercury
Mercury was an important constituent of drugs for centuries as an ingredient in many diuretics, antibacterials, antiseptics, skin ointments, and laxatives. More specific, effective, and safer modes of therapy now have replaced the mercurials, and drug-induced mercury poisoning has become rare. However, mercury has a number of important industrial uses (Table 65-2), and poisoning from occupational exposure and environmental pollution continues to be an area of concern. There have been epidemics of mercury poisoning among wildlife and human populations in many countries. With very few exceptions and for numerous reasons, such outbreaks were misdiagnosed for months or even years. Reasons for these tragic delays included the insidious onset of the affliction, vagueness of early clinical signs, and the medical profession's unfamiliarity with the disease (Gerstner and Huff, 1977).
Chemical Forms and Sources of Mercury. With regard to the toxicity of mercury, three major chemical forms of the metal must be distinguished: mercury vapor (elemental mercury), salts of mercury, and organic mercurials. Table 65-3 indicates the estimated daily retention of various forms of mercury from various sources.
Elemental mercury is the most volatile of the metal's inorganic forms. Human exposure to mercury vapor is mainly occupational. Extraction of gold with mercury and then heating the amalgam to drive off the mercury is a technique that has been used extensively by gold miners and still is used today in some developing countries. Chronic exposure to mercury in ambient air after inadvertent mercury spills in poorly ventilated rooms, often scientific laboratories, can produce toxic effects. Mercury vapor also can be released from silver-amalgam dental restorations. In fact, this is the main source of mercury exposure to the general population, but the amount of mercury released does not appear to be of significance for human health (Eley and Cox, 1993) except for allergic contact eczema seen in a few individuals.
Salts of mercury exist in two states of oxidation¾as monovalent mercurous salts or as divalent mercuric salts. Mercurous chloride (Hg2Cl2), or calomel, the best-known mercurous compound, was used in some skin creams as an antiseptic and was employed as a diuretic and cathartic. Mercuric salts are the more irritating and acutely toxic form of the met al. Mercuric nitrate was a common industrial hazard in the felt-hat industry more than 400 years ago. Occupational exposure produced neurological and behavioral changes depicted by the Mad Hatter in Lewis Carroll's Alice's Adventures in Wonderland. Mercuric chloride (Hg2Cl2), once a widely used antiseptic, also was used commonly for suicidal purposes. Mercuric salts still are employed widely in industry, and industrial discharge into rivers has introduced mercury into the environment in many parts of the world. The main industrial uses of inorganic mercury today are in chloralkali production and in electronics. Other uses of the metal include the manufacturing of plastics, fungicides, and germicides and the formulation of amalgams in dentistry.
The organomercurials in use today contain mercury with one covalent bond to a carbon atom. Members of this heterogeneous group of compounds have varying abilities to produce toxic effects. The alkylmercury salts are by far the most dangerous of these compounds; methylmercury is the most common. Alkylmercury salts have been used widely as fungicides and have produced toxic effects in humans. Major incidents of human poisoning from the inadvertent consumption of mercury-treated seed grain have occurred in Iraq, Pakistan, Ghana, and Guatemala. The most catastrophic outbreak occurred in Iraq in 1972. During the fall of 1971, Iraq imported large quantities of seed (wheat and barley) treated with methylmercury and distributed the grain for spring planting. Despite official warnings, the grain was ground into flour and made into bread. As a result, 6530 victims were hospitalized, and 500 died (Bakir et al., 1973, 1980).
Minamata disease also was due to methylmercury. In the Japanese town of Minamata, the major industry was a chemical plant that emptied its effluent directly into Minamata Bay. The chemical plant used inorganic mercury as a catalyst, and some of it was methylated before it entered the bay. In addition, microorganisms can convert inorganic mercury to methylmercury; the compound then is taken up rapidly by plankton algae and is concentrated in fish via the food chain. Residents of Minamata who consumed fish as a large portion of their diet were the first to be poisoned. Eventually, 121 persons were poisoned, and 46 died (McAlpine and Araki, 1958; Smith and Smith, 1975; Tamashiro et al., 1985). In the United States, human poisonings have resulted from ingestion of meat from pigs fed grain treated with an organomercurial fungicide. Because of concerns about methylmercury accumulation in fish, the Food and Drug Administration (FDA) recommends that pregnant or nursing women, women of childbearing age, and young children avoid eating large fish (e.g., shark, swordfish, king mackerel, and tilefish) and limit their intake of albacore tuna to 6 ounces per week.
In other instances, exposure to mercury was intentional. For example, thimerosal (CH3CH2¾Hg¾S¾C6H4¾COOH) has been used as an antibacterial additive to biologics and vaccines since the 1930s. However, concerns about the possibility of health risks from thimerosal in vaccines have been debated, especially the possibility that the ethylmercury thiosalicylate preservative in hepatitis B immunoglobulin (HBIG) could release ethylmercury and cause severe mercury intoxication (Lowell et al., 1996; Ball et al., 2001). These concerns were based on the assumption that ethylmercury, for which there is limited toxicologic information, is toxicologically similar to its close chemical relative, methyl mercury (CH3¾Hg+), about which much is known (Clarkson, 2002).
A study by the FDA determined that that there is a significant safety margin incorporated into all the acceptable mercury exposure limits. Furthermore, there are no data or evidence of any harm caused by the level of exposure that some children may have encountered in following the existing immunization schedule. Nevertheless, the availability of vaccines with alternate preservatives led to a statement calling forremoval of allvaccines containing thimerosal (Joint Statement of the American Academy of Pediatrics and the United States Public Health Service, 1999; Ball et al., 2001). This practice remains in place today, even though subsequent studies have failed to demonstrate any health risk associated with vaccines containing thiomerosal (Verstraeten et al., 2003; Heron et al., 2004).
Chemistry and Mechanism of Action. Mercury readily forms covalent bonds with sulfur, and it is this property that accounts for most of the biological properties of the met al. When the sulfur is in the form of sulfhydryl groups, divalent mercury replaces the hydrogen atom to form mercaptides, X¾Hg¾SR and Hg(SR)2, where X is an electronegative radical and R is protein. Organic mercurials form mercaptides of the type R¾Hg¾SR'. Even in low concentrations, mercurials are capable of inactivating sulfhydryl groups of enzymes and thus interfering with cellular metabolism and function. The affinity of mercury for thiols provides the basis for treatment of mercury poisoning with such agents as dimercaprol and penicillamine. Mercury also combines with phosphoryl, carboxyl, amide, and amine groups.
Absorption, Biotransformation, Distribution, and Excretion. Elemental Mercury. Elemental mercury is not particularly toxic when ingested because of very low absorption from the GI tract; this is due to the formation of droplets and because the metal in this form cannot react with biologically important molecules. However, inhaled mercury vapor is completely absorbed by the lung and then is oxidized to the divalent mercuric cation by catalase in the erythrocytes (Magos et al., 1978). Within a few hours, the deposition of inhaled mercury vapor resembles that after ingestion of mercuric salts, with one important difference: Because mercury vapor crosses membranes much more readily than does divalent mercury, a significant amount of the vapor enters the brain before it is oxidized. CNS toxicity is thus more prominent after exposure to mercury vapor than to divalent forms of the metal.
Inorganic Salts of Mercury. The soluble inorganic mercuric salts (Hg2+) gain access to the circulation when taken orally. GI absorption is approximately 10% to 15% of that ingested, and a considerable portion of the Hg2+ may remain bound to the alimentary mucosa and the intestinal contents. Insoluble inorganic mercurous compounds, such as calomel (Hg2Cl2), may undergo some oxidation to soluble compounds that are more readily absorbed. Inorganic mercury has a markedly nonuniform distribution after absorption. The highest concentration of Hg2+ is found in the kidneys, where the metal is retained longer than in other tissues. Concentrations of inorganic mercury are similar in whole blood and plasma. Inorganic mercurials do not readily pass across the blood-brain barrier or the placenta. The metal is excreted in the urine and feces with a half-life of about 60 days (Friberg and Vostal, 1972); studies in laboratory animals indicate that fecal excretion is quantitatively more important (Klaassen, 1975).
Organic Mercurials. Organic mercurials are absorbed more completely from the GI tract than are the inorganic salts because they are more lipid soluble and less corrosive to the intestinal mucosa. Their uptake and distribution are depicted in Figure 65-3A . More than 90% of methylmercury is absorbed from the human GI tract. The organic mercurials cross the blood-brain barrier and the placenta and thus produce more neurological and teratogenic effects than do the inorganic salts. Methylmercury combines with cysteine to form a structure similar to methionine, and the complex is transported by the large neutral amino acid carrier present in capillary endothelial cells (Clarkson, 1987) (Figure 65-3B). Organic mercurials are distributed more uniformly to the various tissues than are the inorganic salts (Klaassen, 1975). A significant portion of the body burden of organic mercurials is in the red blood cells. The ratio of the concentration of organomercurial in erythrocytes to that in plasma varies with the compound; for methylmercury, it approximates 20:1 (Kershaw et al., 1980). Mercury concentrates in hair because of its high sulfhydryl content. The carbon-mercury bond of some organic mercurials is cleaved after absorption; with methylmercury, the cleavage is quite slow, and the inorganic mercury formed is not thought to play a major role in methylmercury toxicity. Aryl mercurials, such as mercurophen, usually contain a labile mercury-carbon bond; their toxicity is similar to that of inorganic mercury. Methylmercury in humans is excreted mainly in the feces in the form of a glutathione conjugate; less than 10% of a dose appears in urine (Bakir et al., 1980). The half-life of methylmercury in the blood of humans is between 40 and 105 days (Bakir et al., 1973).
Toxicity. Elemental Mercury. Short-term exposure to the vapor of elemental mercury may produce symptoms within several hours, including weakness, chills, metallic taste, nausea, vomiting, diarrhea, dyspnea, cough, and a feeling of tightness in the chest. Pulmonary toxicity may progress to an interstitial pneumonitis with severe compromise of respiratory function. Recovery, although usually complete, may be complicated by residual interstitial fibrosis.
Chronic exposure to mercury vapor produces a more insidious form of toxicity that is dominated by neurological effects (Friberg and Vostal, 1972). The syndrome, termed the asthenic vegetative syndrome, consists of neurasthenic symptoms in addition to three or more of the following findings: goiter, increased uptake of radioiodine by the thyroid, tachycardia, labile pulse, gingivitis, dermographia, and increased mercury in the urine (Goyer and Clarkson, 2001). With continued exposure to mercury vapor, tremor becomes noticeable, and psychological changes consist of depression, irritability, excessive shyness, insomnia, reduced self-confidence, emotional instability, forgetfulness, confusion, impatience, and vasomotor disturbances (such as excessive perspiration and uncontrolled blushing, which together are referred to as erethism). Common features of intoxication from mercury vapor are severe salivation and gingivitis. The triad of increased excitability, tremors, and gingivitis has been recognized historically as the major manifestation of exposure to mercury vapor when mercury nitrate was used in the fur, felt, and hat industries. Renal dysfunction also has been reported to result from long-term industrial exposure to mercury vapor. The concentrations of mercury vapor in the air and mercury in urine that are associated with the various effects are shown in Figure 65-4.
Inorganic Salts of Mercury. Inorganic ionic mercury (e.g., mercuric chloride) can produce severe acute toxicity. Precipitation of mucous membrane proteins by mercuric salts results in an ashen-gray appearance of the mucosa of the mouth, pharynx, and intestine and also causes intense pain, which may be accompanied by vomiting. The vomiting is perceived to be protective because it removes unabsorbed mercury from the stomach; assuming that the patient is awake and alert, vomiting should not be inhibited. The local corrosive effect of ionic inorganic mercury on the GI mucosa results in severe hematochezia with evidence of mucosal sloughing in the stool. Hypovolemic shock and death can occur in the absence of proper treatment, which can overcome the local effects of inorganic mercury.
Systemic toxicity may begin within a few hours of exposure to mercury and last for days. A strong metallic taste is followed by stomatitis with gingival irritation, foul breath, and loosening of the teeth. The most serious and frequent systemic effect of inorganic mercury is renal toxicity. Acute tubular necrosis occurs after short-term exposure, leading to oliguria or anuria. Renal injury also follows long-term exposure to inorganic mercury, where glomerular injury predominates. This results from direct effects on the glomerular basement membrane and later indirect effects mediated by immune complexes (Goyer and Clarkson, 2001).
The symptom complex of acrodynia (pink disease) also commonly follows chronic exposure to inorganic mercury ions. Acrodynia is an erythema of the extremities, chest, and face with photophobia, diaphoresis, anorexia, tachycardia, and either constipation or diarrhea. This symptom complex is seen almost exclusively after ingestion of mercury and is believed to be the result of a hypersensitivity reaction (Matheson et al., 1980).
Organic Mercurials. Most human toxicological data about organic mercury concern methylmercury and have been collected as the unfortunate result of large-scale accidental exposures. Symptoms of exposure to methylmercury are mainly neurological and consist of visual disturbance (scotoma and visual-field constriction), ataxia, paresthesias, neurasthenia, hearing loss, dysarthria, mental deterioration, muscle tremor, movement disorders, and with severe exposure, paralysis and death (Table 65-4). Effects of methylmercury on the fetus can occur even when the mother is asymptomatic; mental retardation and neuromuscular deficits have been observed.
Diagnosis of Mercury Poisoning. A history of exposure to mercury, either industrial or environmental, is obviously valuable in making the diagnosis of mercury poisoning. Otherwise, clinical suspicions can be confirmed by laboratory analysis. The upper limit of a nontoxic concentration of mercury in blood generally is considered to be 3 to 4 mg/dl (0.15 to 0.20 mM). A concentration of mercury in blood in excess of 4 mg/dl (0.20 mM) is unexpected in normal, healthy adults and suggests the need for environmental evaluation and medical examination to assess the possibility of adverse health effects. Because methylmercury is concentrated in erythrocytes and inorganic mercury is not, the distribution of total mercury between red blood cells and plasma may indicate whether the patient has been poisoned with inorganic or organic mercury. Measurement of total mercury in red blood cells gives a better estimate of the body burden of methylmercury than it does for inorganic mercury. A rough guide to the relationship between concentrations of mercury in blood and the frequency of symptoms that result from exposure to methylmercury is shown in Table 65-4. Concentrations of mercury in plasma provide a better index of the body burden of inorganic mercury, but the relationship between body burden and the concentration of inorganic mercury in plasma is not well documented. This may relate to the importance of timing of measurement of the blood sample relative to the last exposure to mercury. The relationship between the concentration of inorganic mercury in blood and toxicity also depends on the form of exposure. For example, exposure to vapor results in concentrations in brain approximately 10 times higher than those that follow an equivalent dose of inorganic mercuric salts.
The concentration of mercury in the urine also has been used as a measure of the body burden of the met al. The normal upper limit for excretion of mercury in urine is 5 mg/L. There is a linear relationship between plasma concentration and urinary excretion of mercury after exposure to vapor; in contrast, the excretion of mercury in urine is a poor indicator of the amount of methylmercury in the blood because it is eliminated mainly in feces (Bakir et al., 1980).
Hair is rich in sulfhydryl groups, and the concentration of mercury in hair is about 300 times that in blood. Human hair grows about 20 cm a year, and a history of exposure may be obtained by analysis of different segments of hair.
Treatment of Mercury Poisoning. Measurement of the concentration of mercury in blood should be performed as soon as possible after poisoning with any form of the met al.
Elemental Mercury Vapor. Therapeutic measures include immediate termination of exposure and close monitoring of pulmonary status. Short-term respiratory support may be necessary. Chelation therapy, as described below for inorganic mercury, should be initiated immediately and continued as indicated by the clinical condition and the concentrations of mercury in blood and urine.
Inorganic Mercury. Prompt attention to fluid and electrolyte balance and hematological status is of critical importance in moderate-to-severe oral exposures. Emesis can be induced if the patient is awake and alert, although emesis should not be induced where there is corrosive injury. If ingestion of mercury is more than 30 to 60 minutes before treatment, emesis may have little efficacy. With corrosive agents, endoscopic evaluation may be warranted, and coagulation parameters are important. Activated charcoal is recommended by some, although it lacks proven efficacy. Administration of charcoal may make endoscopy difficult or impossible.
Chelation Therapy. Chelation therapy with dimercaprol (for high-level exposures or symptomatic patients) or penicillamine (for low-level exposures or asymptomatic patients) is used routinely to treat poisoning with either inorganic or elemental mercury. Recommended treatment includes dimercaprol 5 mg/kg intramuscularly initially, followed by 2.5 mg/kg intramuscularly every 12 to 24 hours for 10 days. Penicillamine (250 mg orally every 6 hours) may be used alone or following treatment with dimercaprol. The duration of chelation therapy will vary, and progress can be monitored by following concentrations of mercury in urine and blood. The orally effective chelator succimer appears to be an effective chelator for mercury (Campbell et al., 1986; Fournier et al., 1988; Bluhm et al., 1992), although it has not been approved by the FDA for this purpose.
The dimercaprol-mercury chelate is excreted into both bile and urine, whereas the penicillamine-mercury chelate is excreted only into urine. Thus penicillamine should be used with extreme caution when renal function is impaired. In fact, hemodialysis may be necessary in the poisoned patient whose renal function declines. Chelators still may be used because the dimercaprol-mercury complex is removed by dialysis (Giunta et al., 1983).
Organic Mercury. The short-chain organic mercurials, especially methylmercury, are the most difficult forms of mercury to mobilize from the body presumably because of their poor reactivity with chelating agents. Dimercaprol is contraindicated in methylmercury poisoning because it increases brain concentrations of methylmercury in experimental animals. Although penicillamine facilitates the removal of methylmercury from the body, it is not clinically efficacious, and large doses (2 g/day) are needed (Bakir et al., 1980). During the initial 1 to 3 days of administration of penicillamine, the concentration of mercury in the blood increases before it decreases, probably reflecting the mobilization of metal from tissues to blood at a rate more rapid than that for excretion of mercury into urine and feces.
Methylmercury compounds undergo extensive enterohepatic recirculation in experimental animals. Therefore, introduction of a nonabsorbable mercury-binding substance into the intestinal tract should facilitate their removal from the body. A polythiol resin has been used for this purpose in humans and appears to be effective (Bakir et al., 1973). The resin has certain advantages over penicillamine. It does not cause redistribution of mercury in the body with a subsequent increase in the concentration of mercury in blood, and it has fewer adverse effects than do sulfhydryl agents that are absorbed. Clinical experience with various treatments for methylmercury poisoning in Iraq indicates that penicillamine, N-acetylpenicillamine, and an oral nonabsorbable thiol resin all can reduce blood concentrations of mercury; however, clinical improvement was not clearly related to reduction of the body burden of methylmercury (Bakir et al., 1980).
Conventional hemodialysis is of little value in the treatment of methylmercury poisoning because methylmercury concentrates in erythrocytes, and little is contained in the plasma. However, it has been shown that L -cysteine can be infused into the arterial blood entering the dialyzer to convert methylmercury into a diffusible form. Both free cysteine and the methylmercury-cysteine complex form in the blood and then diffuse across the membrane into the dialysate. This method has been shown to be effective in humans (Al-Abbasi et al., 1978). Studies in animals indicate that succimer may be more effective than cysteine in this regard (Kostyniak, 1982).
Mercury was an important constituent of drugs for centuries as an ingredient in many diuretics, antibacterials, antiseptics, skin ointments, and laxatives. More specific, effective, and safer modes of therapy now have replaced the mercurials, and drug-induced mercury poisoning has become rare. However, mercury has a number of important industrial uses (Table 65-2), and poisoning from occupational exposure and environmental pollution continues to be an area of concern. There have been epidemics of mercury poisoning among wildlife and human populations in many countries. With very few exceptions and for numerous reasons, such outbreaks were misdiagnosed for months or even years. Reasons for these tragic delays included the insidious onset of the affliction, vagueness of early clinical signs, and the medical profession's unfamiliarity with the disease (Gerstner and Huff, 1977).
Chemical Forms and Sources of Mercury. With regard to the toxicity of mercury, three major chemical forms of the metal must be distinguished: mercury vapor (elemental mercury), salts of mercury, and organic mercurials. Table 65-3 indicates the estimated daily retention of various forms of mercury from various sources.
Elemental mercury is the most volatile of the metal's inorganic forms. Human exposure to mercury vapor is mainly occupational. Extraction of gold with mercury and then heating the amalgam to drive off the mercury is a technique that has been used extensively by gold miners and still is used today in some developing countries. Chronic exposure to mercury in ambient air after inadvertent mercury spills in poorly ventilated rooms, often scientific laboratories, can produce toxic effects. Mercury vapor also can be released from silver-amalgam dental restorations. In fact, this is the main source of mercury exposure to the general population, but the amount of mercury released does not appear to be of significance for human health (Eley and Cox, 1993) except for allergic contact eczema seen in a few individuals.
Salts of mercury exist in two states of oxidation¾as monovalent mercurous salts or as divalent mercuric salts. Mercurous chloride (Hg2Cl2), or calomel, the best-known mercurous compound, was used in some skin creams as an antiseptic and was employed as a diuretic and cathartic. Mercuric salts are the more irritating and acutely toxic form of the met al. Mercuric nitrate was a common industrial hazard in the felt-hat industry more than 400 years ago. Occupational exposure produced neurological and behavioral changes depicted by the Mad Hatter in Lewis Carroll's Alice's Adventures in Wonderland. Mercuric chloride (Hg2Cl2), once a widely used antiseptic, also was used commonly for suicidal purposes. Mercuric salts still are employed widely in industry, and industrial discharge into rivers has introduced mercury into the environment in many parts of the world. The main industrial uses of inorganic mercury today are in chloralkali production and in electronics. Other uses of the metal include the manufacturing of plastics, fungicides, and germicides and the formulation of amalgams in dentistry.
The organomercurials in use today contain mercury with one covalent bond to a carbon atom. Members of this heterogeneous group of compounds have varying abilities to produce toxic effects. The alkylmercury salts are by far the most dangerous of these compounds; methylmercury is the most common. Alkylmercury salts have been used widely as fungicides and have produced toxic effects in humans. Major incidents of human poisoning from the inadvertent consumption of mercury-treated seed grain have occurred in Iraq, Pakistan, Ghana, and Guatemala. The most catastrophic outbreak occurred in Iraq in 1972. During the fall of 1971, Iraq imported large quantities of seed (wheat and barley) treated with methylmercury and distributed the grain for spring planting. Despite official warnings, the grain was ground into flour and made into bread. As a result, 6530 victims were hospitalized, and 500 died (Bakir et al., 1973, 1980).
Minamata disease also was due to methylmercury. In the Japanese town of Minamata, the major industry was a chemical plant that emptied its effluent directly into Minamata Bay. The chemical plant used inorganic mercury as a catalyst, and some of it was methylated before it entered the bay. In addition, microorganisms can convert inorganic mercury to methylmercury; the compound then is taken up rapidly by plankton algae and is concentrated in fish via the food chain. Residents of Minamata who consumed fish as a large portion of their diet were the first to be poisoned. Eventually, 121 persons were poisoned, and 46 died (McAlpine and Araki, 1958; Smith and Smith, 1975; Tamashiro et al., 1985). In the United States, human poisonings have resulted from ingestion of meat from pigs fed grain treated with an organomercurial fungicide. Because of concerns about methylmercury accumulation in fish, the Food and Drug Administration (FDA) recommends that pregnant or nursing women, women of childbearing age, and young children avoid eating large fish (e.g., shark, swordfish, king mackerel, and tilefish) and limit their intake of albacore tuna to 6 ounces per week.
In other instances, exposure to mercury was intentional. For example, thimerosal (CH3CH2¾Hg¾S¾C6H4¾COOH) has been used as an antibacterial additive to biologics and vaccines since the 1930s. However, concerns about the possibility of health risks from thimerosal in vaccines have been debated, especially the possibility that the ethylmercury thiosalicylate preservative in hepatitis B immunoglobulin (HBIG) could release ethylmercury and cause severe mercury intoxication (Lowell et al., 1996; Ball et al., 2001). These concerns were based on the assumption that ethylmercury, for which there is limited toxicologic information, is toxicologically similar to its close chemical relative, methyl mercury (CH3¾Hg+), about which much is known (Clarkson, 2002).
A study by the FDA determined that that there is a significant safety margin incorporated into all the acceptable mercury exposure limits. Furthermore, there are no data or evidence of any harm caused by the level of exposure that some children may have encountered in following the existing immunization schedule. Nevertheless, the availability of vaccines with alternate preservatives led to a statement calling forremoval of allvaccines containing thimerosal (Joint Statement of the American Academy of Pediatrics and the United States Public Health Service, 1999; Ball et al., 2001). This practice remains in place today, even though subsequent studies have failed to demonstrate any health risk associated with vaccines containing thiomerosal (Verstraeten et al., 2003; Heron et al., 2004).
Chemistry and Mechanism of Action. Mercury readily forms covalent bonds with sulfur, and it is this property that accounts for most of the biological properties of the met al. When the sulfur is in the form of sulfhydryl groups, divalent mercury replaces the hydrogen atom to form mercaptides, X¾Hg¾SR and Hg(SR)2, where X is an electronegative radical and R is protein. Organic mercurials form mercaptides of the type R¾Hg¾SR'. Even in low concentrations, mercurials are capable of inactivating sulfhydryl groups of enzymes and thus interfering with cellular metabolism and function. The affinity of mercury for thiols provides the basis for treatment of mercury poisoning with such agents as dimercaprol and penicillamine. Mercury also combines with phosphoryl, carboxyl, amide, and amine groups.
Absorption, Biotransformation, Distribution, and Excretion. Elemental Mercury. Elemental mercury is not particularly toxic when ingested because of very low absorption from the GI tract; this is due to the formation of droplets and because the metal in this form cannot react with biologically important molecules. However, inhaled mercury vapor is completely absorbed by the lung and then is oxidized to the divalent mercuric cation by catalase in the erythrocytes (Magos et al., 1978). Within a few hours, the deposition of inhaled mercury vapor resembles that after ingestion of mercuric salts, with one important difference: Because mercury vapor crosses membranes much more readily than does divalent mercury, a significant amount of the vapor enters the brain before it is oxidized. CNS toxicity is thus more prominent after exposure to mercury vapor than to divalent forms of the metal.
Inorganic Salts of Mercury. The soluble inorganic mercuric salts (Hg2+) gain access to the circulation when taken orally. GI absorption is approximately 10% to 15% of that ingested, and a considerable portion of the Hg2+ may remain bound to the alimentary mucosa and the intestinal contents. Insoluble inorganic mercurous compounds, such as calomel (Hg2Cl2), may undergo some oxidation to soluble compounds that are more readily absorbed. Inorganic mercury has a markedly nonuniform distribution after absorption. The highest concentration of Hg2+ is found in the kidneys, where the metal is retained longer than in other tissues. Concentrations of inorganic mercury are similar in whole blood and plasma. Inorganic mercurials do not readily pass across the blood-brain barrier or the placenta. The metal is excreted in the urine and feces with a half-life of about 60 days (Friberg and Vostal, 1972); studies in laboratory animals indicate that fecal excretion is quantitatively more important (Klaassen, 1975).
Organic Mercurials. Organic mercurials are absorbed more completely from the GI tract than are the inorganic salts because they are more lipid soluble and less corrosive to the intestinal mucosa. Their uptake and distribution are depicted in Figure 65-3A . More than 90% of methylmercury is absorbed from the human GI tract. The organic mercurials cross the blood-brain barrier and the placenta and thus produce more neurological and teratogenic effects than do the inorganic salts. Methylmercury combines with cysteine to form a structure similar to methionine, and the complex is transported by the large neutral amino acid carrier present in capillary endothelial cells (Clarkson, 1987) (Figure 65-3B). Organic mercurials are distributed more uniformly to the various tissues than are the inorganic salts (Klaassen, 1975). A significant portion of the body burden of organic mercurials is in the red blood cells. The ratio of the concentration of organomercurial in erythrocytes to that in plasma varies with the compound; for methylmercury, it approximates 20:1 (Kershaw et al., 1980). Mercury concentrates in hair because of its high sulfhydryl content. The carbon-mercury bond of some organic mercurials is cleaved after absorption; with methylmercury, the cleavage is quite slow, and the inorganic mercury formed is not thought to play a major role in methylmercury toxicity. Aryl mercurials, such as mercurophen, usually contain a labile mercury-carbon bond; their toxicity is similar to that of inorganic mercury. Methylmercury in humans is excreted mainly in the feces in the form of a glutathione conjugate; less than 10% of a dose appears in urine (Bakir et al., 1980). The half-life of methylmercury in the blood of humans is between 40 and 105 days (Bakir et al., 1973).
Toxicity. Elemental Mercury. Short-term exposure to the vapor of elemental mercury may produce symptoms within several hours, including weakness, chills, metallic taste, nausea, vomiting, diarrhea, dyspnea, cough, and a feeling of tightness in the chest. Pulmonary toxicity may progress to an interstitial pneumonitis with severe compromise of respiratory function. Recovery, although usually complete, may be complicated by residual interstitial fibrosis.
Chronic exposure to mercury vapor produces a more insidious form of toxicity that is dominated by neurological effects (Friberg and Vostal, 1972). The syndrome, termed the asthenic vegetative syndrome, consists of neurasthenic symptoms in addition to three or more of the following findings: goiter, increased uptake of radioiodine by the thyroid, tachycardia, labile pulse, gingivitis, dermographia, and increased mercury in the urine (Goyer and Clarkson, 2001). With continued exposure to mercury vapor, tremor becomes noticeable, and psychological changes consist of depression, irritability, excessive shyness, insomnia, reduced self-confidence, emotional instability, forgetfulness, confusion, impatience, and vasomotor disturbances (such as excessive perspiration and uncontrolled blushing, which together are referred to as erethism). Common features of intoxication from mercury vapor are severe salivation and gingivitis. The triad of increased excitability, tremors, and gingivitis has been recognized historically as the major manifestation of exposure to mercury vapor when mercury nitrate was used in the fur, felt, and hat industries. Renal dysfunction also has been reported to result from long-term industrial exposure to mercury vapor. The concentrations of mercury vapor in the air and mercury in urine that are associated with the various effects are shown in Figure 65-4.
Inorganic Salts of Mercury. Inorganic ionic mercury (e.g., mercuric chloride) can produce severe acute toxicity. Precipitation of mucous membrane proteins by mercuric salts results in an ashen-gray appearance of the mucosa of the mouth, pharynx, and intestine and also causes intense pain, which may be accompanied by vomiting. The vomiting is perceived to be protective because it removes unabsorbed mercury from the stomach; assuming that the patient is awake and alert, vomiting should not be inhibited. The local corrosive effect of ionic inorganic mercury on the GI mucosa results in severe hematochezia with evidence of mucosal sloughing in the stool. Hypovolemic shock and death can occur in the absence of proper treatment, which can overcome the local effects of inorganic mercury.
Systemic toxicity may begin within a few hours of exposure to mercury and last for days. A strong metallic taste is followed by stomatitis with gingival irritation, foul breath, and loosening of the teeth. The most serious and frequent systemic effect of inorganic mercury is renal toxicity. Acute tubular necrosis occurs after short-term exposure, leading to oliguria or anuria. Renal injury also follows long-term exposure to inorganic mercury, where glomerular injury predominates. This results from direct effects on the glomerular basement membrane and later indirect effects mediated by immune complexes (Goyer and Clarkson, 2001).
The symptom complex of acrodynia (pink disease) also commonly follows chronic exposure to inorganic mercury ions. Acrodynia is an erythema of the extremities, chest, and face with photophobia, diaphoresis, anorexia, tachycardia, and either constipation or diarrhea. This symptom complex is seen almost exclusively after ingestion of mercury and is believed to be the result of a hypersensitivity reaction (Matheson et al., 1980).
Organic Mercurials. Most human toxicological data about organic mercury concern methylmercury and have been collected as the unfortunate result of large-scale accidental exposures. Symptoms of exposure to methylmercury are mainly neurological and consist of visual disturbance (scotoma and visual-field constriction), ataxia, paresthesias, neurasthenia, hearing loss, dysarthria, mental deterioration, muscle tremor, movement disorders, and with severe exposure, paralysis and death (Table 65-4). Effects of methylmercury on the fetus can occur even when the mother is asymptomatic; mental retardation and neuromuscular deficits have been observed.
Diagnosis of Mercury Poisoning. A history of exposure to mercury, either industrial or environmental, is obviously valuable in making the diagnosis of mercury poisoning. Otherwise, clinical suspicions can be confirmed by laboratory analysis. The upper limit of a nontoxic concentration of mercury in blood generally is considered to be 3 to 4 mg/dl (0.15 to 0.20 mM). A concentration of mercury in blood in excess of 4 mg/dl (0.20 mM) is unexpected in normal, healthy adults and suggests the need for environmental evaluation and medical examination to assess the possibility of adverse health effects. Because methylmercury is concentrated in erythrocytes and inorganic mercury is not, the distribution of total mercury between red blood cells and plasma may indicate whether the patient has been poisoned with inorganic or organic mercury. Measurement of total mercury in red blood cells gives a better estimate of the body burden of methylmercury than it does for inorganic mercury. A rough guide to the relationship between concentrations of mercury in blood and the frequency of symptoms that result from exposure to methylmercury is shown in Table 65-4. Concentrations of mercury in plasma provide a better index of the body burden of inorganic mercury, but the relationship between body burden and the concentration of inorganic mercury in plasma is not well documented. This may relate to the importance of timing of measurement of the blood sample relative to the last exposure to mercury. The relationship between the concentration of inorganic mercury in blood and toxicity also depends on the form of exposure. For example, exposure to vapor results in concentrations in brain approximately 10 times higher than those that follow an equivalent dose of inorganic mercuric salts.
The concentration of mercury in the urine also has been used as a measure of the body burden of the met al. The normal upper limit for excretion of mercury in urine is 5 mg/L. There is a linear relationship between plasma concentration and urinary excretion of mercury after exposure to vapor; in contrast, the excretion of mercury in urine is a poor indicator of the amount of methylmercury in the blood because it is eliminated mainly in feces (Bakir et al., 1980).
Hair is rich in sulfhydryl groups, and the concentration of mercury in hair is about 300 times that in blood. Human hair grows about 20 cm a year, and a history of exposure may be obtained by analysis of different segments of hair.
Treatment of Mercury Poisoning. Measurement of the concentration of mercury in blood should be performed as soon as possible after poisoning with any form of the met al.
Elemental Mercury Vapor. Therapeutic measures include immediate termination of exposure and close monitoring of pulmonary status. Short-term respiratory support may be necessary. Chelation therapy, as described below for inorganic mercury, should be initiated immediately and continued as indicated by the clinical condition and the concentrations of mercury in blood and urine.
Inorganic Mercury. Prompt attention to fluid and electrolyte balance and hematological status is of critical importance in moderate-to-severe oral exposures. Emesis can be induced if the patient is awake and alert, although emesis should not be induced where there is corrosive injury. If ingestion of mercury is more than 30 to 60 minutes before treatment, emesis may have little efficacy. With corrosive agents, endoscopic evaluation may be warranted, and coagulation parameters are important. Activated charcoal is recommended by some, although it lacks proven efficacy. Administration of charcoal may make endoscopy difficult or impossible.
Chelation Therapy. Chelation therapy with dimercaprol (for high-level exposures or symptomatic patients) or penicillamine (for low-level exposures or asymptomatic patients) is used routinely to treat poisoning with either inorganic or elemental mercury. Recommended treatment includes dimercaprol 5 mg/kg intramuscularly initially, followed by 2.5 mg/kg intramuscularly every 12 to 24 hours for 10 days. Penicillamine (250 mg orally every 6 hours) may be used alone or following treatment with dimercaprol. The duration of chelation therapy will vary, and progress can be monitored by following concentrations of mercury in urine and blood. The orally effective chelator succimer appears to be an effective chelator for mercury (Campbell et al., 1986; Fournier et al., 1988; Bluhm et al., 1992), although it has not been approved by the FDA for this purpose.
The dimercaprol-mercury chelate is excreted into both bile and urine, whereas the penicillamine-mercury chelate is excreted only into urine. Thus penicillamine should be used with extreme caution when renal function is impaired. In fact, hemodialysis may be necessary in the poisoned patient whose renal function declines. Chelators still may be used because the dimercaprol-mercury complex is removed by dialysis (Giunta et al., 1983).
Organic Mercury. The short-chain organic mercurials, especially methylmercury, are the most difficult forms of mercury to mobilize from the body presumably because of their poor reactivity with chelating agents. Dimercaprol is contraindicated in methylmercury poisoning because it increases brain concentrations of methylmercury in experimental animals. Although penicillamine facilitates the removal of methylmercury from the body, it is not clinically efficacious, and large doses (2 g/day) are needed (Bakir et al., 1980). During the initial 1 to 3 days of administration of penicillamine, the concentration of mercury in the blood increases before it decreases, probably reflecting the mobilization of metal from tissues to blood at a rate more rapid than that for excretion of mercury into urine and feces.
Methylmercury compounds undergo extensive enterohepatic recirculation in experimental animals. Therefore, introduction of a nonabsorbable mercury-binding substance into the intestinal tract should facilitate their removal from the body. A polythiol resin has been used for this purpose in humans and appears to be effective (Bakir et al., 1973). The resin has certain advantages over penicillamine. It does not cause redistribution of mercury in the body with a subsequent increase in the concentration of mercury in blood, and it has fewer adverse effects than do sulfhydryl agents that are absorbed. Clinical experience with various treatments for methylmercury poisoning in Iraq indicates that penicillamine, N-acetylpenicillamine, and an oral nonabsorbable thiol resin all can reduce blood concentrations of mercury; however, clinical improvement was not clearly related to reduction of the body burden of methylmercury (Bakir et al., 1980).
Conventional hemodialysis is of little value in the treatment of methylmercury poisoning because methylmercury concentrates in erythrocytes, and little is contained in the plasma. However, it has been shown that L -cysteine can be infused into the arterial blood entering the dialyzer to convert methylmercury into a diffusible form. Both free cysteine and the methylmercury-cysteine complex form in the blood and then diffuse across the membrane into the dialysate. This method has been shown to be effective in humans (Al-Abbasi et al., 1978). Studies in animals indicate that succimer may be more effective than cysteine in this regard (Kostyniak, 1982).
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