The heightened concern for reduction that has been occurring overof llution the past 20 – 25 years has stimenvironmental poulated active continuing research and literature on the toxicology of heavy metals. While the toxic effects of these substances is a widespread concern in the modern industrial context, Man has succeeded in poisoning himself with them repeatedly throughout recorded history. One historian/toxicologist contends that the Fall of the Roman Empire was hastened by the chronic lead poisoning experienced by the ruling classes who had water conducted through lead plumbing and drank wine from goblets which had lead/alloy composition. Virtually all metals can produce toxicity when ingested in sufficient quantities, but there are several which are especially important because either they are so pervasive, or produce toxicity at such low concentrations. When speaking of heavy metals we generally mean, lead, mercury, iron, copper, manganese, cadmium, arsenic, nickel, aluminum, silver, and beryllium.
In general heavy metals produce their toxicity by forming complexes or "ligands" with organic compounds. These modified biological molecules lose their ability to function properly, and result in malfunction or death of the affected cells. The most common groups involved in ligand formation are oxygen, sulfur, and nitrogen. When metals bind to these groups they may inactive important enzyme systems, or affect protein structure.
The following is a catalogue of some important toxic heavy metals and the pharmacologic agents and rationales used to treat them. There is a considerable cross-over in many of the toxic manifestations of the different metals, and in the agents used to treat the toxicity.
Arsenic
Arsenic sprays or gases were used during World War I trench warfare, the one favored by the British was know as Lewisite. Arsenic can produce all three types of toxcity at difference dosages, acute, sub-acute, and chronic. One sign of acute exposure is edema of the eyelids, and gastrointestinal irritation, and both central and peripheral neuropathies frequently occur. During chronic intoxication "garlic breath", skin sensitivity, dermatitis, and keratitus frequently occur. All types of arsenic exposure can cause kidney and liver damage, and in the most severe exposure there is erythrocyte hemolysis.
The first rational antidote to heavy metal intoxication was developed during World War II in anticipation of a re-initiation of gas warfare by the Germans. It was developed specifically for the British Lewisite gas and was thus known as British Anti-Lewisite, or BAL. The chemical compound is DIMERCAPROL. The rationale for its use was based on the fact that arsenic binds quite specifically to sulfur groups in the affected tissues. Dimercaprol has very active and relatively non-toxic sulfhydry groups that interact with the arsenic to inactivate it. This phenomenon is known as chelation. Chelators are the class of compounds which are used in the treatment of heavy metal intoxication. A chelator is a flexible molecule with two or more electronegative groups that can form stable co-ordinate covalent bonds with cationic metal atoms. The complexes are then excreted by the body. The efficacy of a chelator is determined in part by the number of ligands available for metal binding, in general the greater number of ligands, the more stable the chelator-metal complex. Depending on the number of metal-ligand bonds, the chelator is designated as mono- bi- or polydentate. The chelator ligands include groups such as -OH, -SH, or -NH. Dimercaprol is bidentate and forms a single heterocyclic ring with a metal ion. Unfortunately, chelators are relatively non-specific as to the metal ions they isolate, hence they also slurp up things like calcium and zinc which are vital for normal physiological function.
Dimercaprol is a colorless oily liquid with the odor of rotten eggs. It is used in the treatment of lead and mercury intoxications as well as arsenic. It is far from inocuous, producing frequent side effects of hypertension and tachycardia, as well as headache, nausea, vomiting, lacrimation, salivation, parathesia, and pain. It is generally given by intramuscular injection. Currently several other analogs are being investigated which have less toxicity and the possibility for oral administration.
The most widely used chelator is Ethylenediamine-tetra-acetic acid or EDTA. It has four ligand sites that focus on the metal atom and thus is a very efficient and stable chelator. It works well on many metals, the most notable of which are calcium, magnesium and lead. The ligand sites consist of two nitrogen and two oxygen groups. EDTA has relatively low toxicity, the major toxic response being impaired renal function. This may in fact be a result of the isolation and concentration of the toxic metal which is then excreted by the kidney in association with the EDTA. Because there is frequently a substantial difference in pH between plasma and kidney tubule, this can change the relation between chelator and metal with a consequent release of some chelated metal which then can react with the renal tissue. This is often controlled by balancing urine pH with iv infusion of bicarbonate to maintain neutral or alkaline conditions which prevent chelator dissociation. The action of EDTA is non-specific chelating many metals, but is especially valuable in treatment of lead intoxication.
Mercury and other important metal toxicant appear to have restricted access because of either "tighter" ligands to tissue sites, or primary intracellular locations which are inaccessible to EDTA.
PENICILLAMINE is the only important chelator which can be administered orally. It is prepared by hydrolytic degradation of penicillin and only the D-isomer is recommended for clinical use.
It is an effective chelator of copper, mercury, lead, and zinc promoting their excretion in the urine, ligands forming with the sulfhydryl, amine, and possibly the carboxyl group. The major toxicity is related to inhibition of pyridoxal dependent enzymes, and it is usual to supplement patients with pyridoxine to compensate for this effect. Individuals with sensitivity to penicillin will also react to penicillamine. Penicillamine is often used in conjunction with EDTA to treat lead and mercury intoxication, especially because of the oral administration property. The major use of the drug other than for heavy metal poisoning is the treatment of Wilson's disease. This hereditary disorder in|volves a storage defect in the handling of copper. Normal individuals have plasma protein which is the transport mechanism (and storage depot) for copper. This protein is defective in Wilson's patients and the copper cumulates producing neurotoxicity. Since these individuals must be treated throughout their life to keep copper levels within normal limits the low toxicity and oral route of administra|tion of d-penicillamine are especially useful. In addition penicillamine is used in the treatment of rheumatoid arthritis. Here the mechanism is obscure but probably involves a reduction of inflammatory response by reduction of tissue calcium and magnesium levels.
DEFEROXAMINE is a very specific naturally occuring chelator. It is synthesized by a streptomyces organism, and has a specific high affinity for iron, with virtually no effect on calcium and magnesium. It is the agent of choice for treatment of iron intoxication, which mainly occurs in small children who get into their parents supplement pills. Full-blown acute iron intoxication can produce GI damage, with convulsions and coma. Since the mortality for untreated severe iron intoxication is about 50%, and the use of deferoxamine in these types of cases produces significant increases in survival, it is an important and useful drug. It is also used in the treatment of relatively rare iron storage disorder analogous to Wilson's disease.
LEAD
Depending on one's location on the face of the planet, the food and water supply as well as the air we breath expose us to lead. Areas of particular risk are places where the drinking water is obtained from geologic strata with significant lead content. Areas which have deposits of gold, zinc, and other economically useful metals, also have lead as an ore contaminant and the "tailings" of the mining and purification of the ore often have a very high lead content. Before the systematic reduction of lead content in regular gasoline, the lead in the atmosphere in high automobile traffic areas was hazardous especially to small children. In old houses in which lead based paints were used there is a risk of toddlers consuming flaking paint chips with high lead content. This was a particular problem in the "slums" of large cities in the US till the ecologic consciousness was raised in the 60's and 70's. There are probably many old houses in Newfoundland with lead paint in their interiors, and there are known to be many communities with significant lead, zinc, and manganese concentrations in the ground water.
In most individuals there is a "lead balance", that is one excretes as much as they take in, and the tissue levels are below the concentrations which result in pathological changes. However an increase in the rate of intake will result in accumulation or a "positive lead balance". Since lead is chemically very similar to calcium, it is handled by the body as if it were calcium. Thus the first place to which it is transported is to the plasma and the membrane sites in soft tissues. It is then distributed to the other sites where calcium plays an important role, most notably in the teeth of developing children and in bone at all ages.
Acute toxicity:
Following ingestion of a large amount of lead, there will be direct tissue interaction. This includes tissue dessication, mucosal tissue damage in the GI tract, and convulsion possibly resulting in death. The most sensitive system is the hematopoietic (blood forming) system, with hypochromic microcytic anemia common. The biosynthesis of hemes in general is deranged by the presence of lead. All actively dividing cells are especially susceptible, hence acute intoxication has major potential for GI and renal mucosal damage. In addition there is a high risk of neurological damage. With acute lead poisoning use of intravenous EDTA is the preferred treatment modality, often supplemented with oral penicillamine, and sometimes with intramuscular injections of dimercaprol.
Chronic Lead Intoxication:
With a gradual build-up of a positive lead balance there is no sudden onset of symptoms as seen with acute poisoning. The initial symptoms include clumsiness, ataxia, vertigo, irritability and insomnia. In affected children, they are often considered "slow", the real basis for the difficulty is not recognized. As the lead levels rise, hyper-excitability is seen. Confusion, delerium and convulsions may occur in some cases, while in others there is progressive lethargy leading to a comatose state.
One of the earliest diagnostic signs present is the appearance of "lead lines" at the gingival border in the mouth. This occurs because the lead following calcium pathways is secreted with the saliva. It then is involved in a reaction with oral bacteria which produce sulfides. The lead reacts with these compounds to form a purplish, or black lead sulfide deposit which precipitates in the region of highest concentration, the "protected area" at the gingival border. Other metals also produce this phenomenon, but with differing colors for the deposit.
Toxicity from inorganic lead can be treated with chelators, but organic lead compounds such as tetra-ethyl lead produces a similar symptomology, but cannot be treated with these agents because they already have formed strong ligands with their organic constituents. The alkyl lead eventually is converted to inorganic lead, which can be treated with the chelators.
MERCURY
Mercury can combine with a methyl group to become methyl mercury. This form of mercury is found in a variety of environmental pollution situations and can produce a range of toxicities. Elemental mercury is less labile but produces a similar set of toxic manifestations.
Acute toxicity:
Organic or inorganic mercury can both precipitate protein in a local reaction. In the GI tract, acute poisoning produces a sloughing away of the mucosa to an extent where pieces of the intestinal mucosa can be found in the stools. This produces a large loss of fluids and electrolytes. Mercury also breaks down barriers in the capillaries. This results in edema throughout the body. A range of neurological toxicities are also common. These include lethargy (at low doses), excitement, hyper-reflexia, and tremor.
Chronic toxicity:
Often a psychotic state resulting in hyper-excitability. The expression 'Mad as a Hatter' originates from the hat-makers of the 19th century who were chronically exposed to mercury compounds used in making felt hats. The CNS effects are slowing or incompletely reversible. In chronic intoxication there is mercury line at the gingival border similar to the "lead line". Mercury is especially poisonous to rapidly growing tissue. A common effect is deterioration of alveolar bone in the jaw, with a subsequent loosening of the teeth. There are also substantial liver and kidney toxicity because of mucosal degeneration.
Mercury can be chelated in the peripheral tissues with EDTA and penicillamine. Even though the plasma levels can be reduced very efficiently, mercury forms alkyl ligands in the tissues. This is especially persistent in CNS tissue. Recovery from mercury poisoning can require months or years even with efficient chelator treatment, and is often incomplete.
MANGANESE
This heavy metal is frequently associated with iron deposits, and in fact the strata underlying Conception Bay providing the basis for the Wabana mines has a very rich manganese content. This metal is known to block Calcium channels, and with chronic intoxication results in CNS dopamine depletion. This latter condition duplicates almost all the symptomology of Parkinson's Disease, and is treated with some success using typical anti-Parkinson drugs. While the concentration in the surface water does not exceed official public health limits, it is in the high range of acceptable levels. It would be interesting to see if the epidemiology of Parkinsons syndrome in that locality is different from regions in the province with lower manganese concentrations. Manganese excretion can be facilitated by the use of chelator therapy, but it is not as easily managed as lead or mercury, because it is further down the list of chelator affinities
. In general heavy metals produce their toxicity by forming complexes or "ligands" with organic compounds. These modified biological molecules lose their ability to function properly, and result in malfunction or death of the affected cells. The most common groups involved in ligand formation are oxygen, sulfur, and nitrogen. When metals bind to these groups they may inactive important enzyme systems, or affect protein structure.
The following is a catalogue of some important toxic heavy metals and the pharmacologic agents and rationales used to treat them. There is a considerable cross-over in many of the toxic manifestations of the different metals, and in the agents used to treat the toxicity.
Arsenic
Arsenic sprays or gases were used during World War I trench warfare, the one favored by the British was know as Lewisite. Arsenic can produce all three types of toxcity at difference dosages, acute, sub-acute, and chronic. One sign of acute exposure is edema of the eyelids, and gastrointestinal irritation, and both central and peripheral neuropathies frequently occur. During chronic intoxication "garlic breath", skin sensitivity, dermatitis, and keratitus frequently occur. All types of arsenic exposure can cause kidney and liver damage, and in the most severe exposure there is erythrocyte hemolysis.
The first rational antidote to heavy metal intoxication was developed during World War II in anticipation of a re-initiation of gas warfare by the Germans. It was developed specifically for the British Lewisite gas and was thus known as British Anti-Lewisite, or BAL. The chemical compound is DIMERCAPROL. The rationale for its use was based on the fact that arsenic binds quite specifically to sulfur groups in the affected tissues. Dimercaprol has very active and relatively non-toxic sulfhydry groups that interact with the arsenic to inactivate it. This phenomenon is known as chelation. Chelators are the class of compounds which are used in the treatment of heavy metal intoxication. A chelator is a flexible molecule with two or more electronegative groups that can form stable co-ordinate covalent bonds with cationic metal atoms. The complexes are then excreted by the body. The efficacy of a chelator is determined in part by the number of ligands available for metal binding, in general the greater number of ligands, the more stable the chelator-metal complex. Depending on the number of metal-ligand bonds, the chelator is designated as mono- bi- or polydentate. The chelator ligands include groups such as -OH, -SH, or -NH. Dimercaprol is bidentate and forms a single heterocyclic ring with a metal ion. Unfortunately, chelators are relatively non-specific as to the metal ions they isolate, hence they also slurp up things like calcium and zinc which are vital for normal physiological function.
Dimercaprol is a colorless oily liquid with the odor of rotten eggs. It is used in the treatment of lead and mercury intoxications as well as arsenic. It is far from inocuous, producing frequent side effects of hypertension and tachycardia, as well as headache, nausea, vomiting, lacrimation, salivation, parathesia, and pain. It is generally given by intramuscular injection. Currently several other analogs are being investigated which have less toxicity and the possibility for oral administration.
The most widely used chelator is Ethylenediamine-tetra-acetic acid or EDTA. It has four ligand sites that focus on the metal atom and thus is a very efficient and stable chelator. It works well on many metals, the most notable of which are calcium, magnesium and lead. The ligand sites consist of two nitrogen and two oxygen groups. EDTA has relatively low toxicity, the major toxic response being impaired renal function. This may in fact be a result of the isolation and concentration of the toxic metal which is then excreted by the kidney in association with the EDTA. Because there is frequently a substantial difference in pH between plasma and kidney tubule, this can change the relation between chelator and metal with a consequent release of some chelated metal which then can react with the renal tissue. This is often controlled by balancing urine pH with iv infusion of bicarbonate to maintain neutral or alkaline conditions which prevent chelator dissociation. The action of EDTA is non-specific chelating many metals, but is especially valuable in treatment of lead intoxication.
Mercury and other important metal toxicant appear to have restricted access because of either "tighter" ligands to tissue sites, or primary intracellular locations which are inaccessible to EDTA.
PENICILLAMINE is the only important chelator which can be administered orally. It is prepared by hydrolytic degradation of penicillin and only the D-isomer is recommended for clinical use.
It is an effective chelator of copper, mercury, lead, and zinc promoting their excretion in the urine, ligands forming with the sulfhydryl, amine, and possibly the carboxyl group. The major toxicity is related to inhibition of pyridoxal dependent enzymes, and it is usual to supplement patients with pyridoxine to compensate for this effect. Individuals with sensitivity to penicillin will also react to penicillamine. Penicillamine is often used in conjunction with EDTA to treat lead and mercury intoxication, especially because of the oral administration property. The major use of the drug other than for heavy metal poisoning is the treatment of Wilson's disease. This hereditary disorder in|volves a storage defect in the handling of copper. Normal individuals have plasma protein which is the transport mechanism (and storage depot) for copper. This protein is defective in Wilson's patients and the copper cumulates producing neurotoxicity. Since these individuals must be treated throughout their life to keep copper levels within normal limits the low toxicity and oral route of administra|tion of d-penicillamine are especially useful. In addition penicillamine is used in the treatment of rheumatoid arthritis. Here the mechanism is obscure but probably involves a reduction of inflammatory response by reduction of tissue calcium and magnesium levels.
DEFEROXAMINE is a very specific naturally occuring chelator. It is synthesized by a streptomyces organism, and has a specific high affinity for iron, with virtually no effect on calcium and magnesium. It is the agent of choice for treatment of iron intoxication, which mainly occurs in small children who get into their parents supplement pills. Full-blown acute iron intoxication can produce GI damage, with convulsions and coma. Since the mortality for untreated severe iron intoxication is about 50%, and the use of deferoxamine in these types of cases produces significant increases in survival, it is an important and useful drug. It is also used in the treatment of relatively rare iron storage disorder analogous to Wilson's disease.
LEAD
Depending on one's location on the face of the planet, the food and water supply as well as the air we breath expose us to lead. Areas of particular risk are places where the drinking water is obtained from geologic strata with significant lead content. Areas which have deposits of gold, zinc, and other economically useful metals, also have lead as an ore contaminant and the "tailings" of the mining and purification of the ore often have a very high lead content. Before the systematic reduction of lead content in regular gasoline, the lead in the atmosphere in high automobile traffic areas was hazardous especially to small children. In old houses in which lead based paints were used there is a risk of toddlers consuming flaking paint chips with high lead content. This was a particular problem in the "slums" of large cities in the US till the ecologic consciousness was raised in the 60's and 70's. There are probably many old houses in Newfoundland with lead paint in their interiors, and there are known to be many communities with significant lead, zinc, and manganese concentrations in the ground water.
In most individuals there is a "lead balance", that is one excretes as much as they take in, and the tissue levels are below the concentrations which result in pathological changes. However an increase in the rate of intake will result in accumulation or a "positive lead balance". Since lead is chemically very similar to calcium, it is handled by the body as if it were calcium. Thus the first place to which it is transported is to the plasma and the membrane sites in soft tissues. It is then distributed to the other sites where calcium plays an important role, most notably in the teeth of developing children and in bone at all ages.
Acute toxicity:
Following ingestion of a large amount of lead, there will be direct tissue interaction. This includes tissue dessication, mucosal tissue damage in the GI tract, and convulsion possibly resulting in death. The most sensitive system is the hematopoietic (blood forming) system, with hypochromic microcytic anemia common. The biosynthesis of hemes in general is deranged by the presence of lead. All actively dividing cells are especially susceptible, hence acute intoxication has major potential for GI and renal mucosal damage. In addition there is a high risk of neurological damage. With acute lead poisoning use of intravenous EDTA is the preferred treatment modality, often supplemented with oral penicillamine, and sometimes with intramuscular injections of dimercaprol.
Chronic Lead Intoxication:
With a gradual build-up of a positive lead balance there is no sudden onset of symptoms as seen with acute poisoning. The initial symptoms include clumsiness, ataxia, vertigo, irritability and insomnia. In affected children, they are often considered "slow", the real basis for the difficulty is not recognized. As the lead levels rise, hyper-excitability is seen. Confusion, delerium and convulsions may occur in some cases, while in others there is progressive lethargy leading to a comatose state.
One of the earliest diagnostic signs present is the appearance of "lead lines" at the gingival border in the mouth. This occurs because the lead following calcium pathways is secreted with the saliva. It then is involved in a reaction with oral bacteria which produce sulfides. The lead reacts with these compounds to form a purplish, or black lead sulfide deposit which precipitates in the region of highest concentration, the "protected area" at the gingival border. Other metals also produce this phenomenon, but with differing colors for the deposit.
Toxicity from inorganic lead can be treated with chelators, but organic lead compounds such as tetra-ethyl lead produces a similar symptomology, but cannot be treated with these agents because they already have formed strong ligands with their organic constituents. The alkyl lead eventually is converted to inorganic lead, which can be treated with the chelators.
MERCURY
Mercury can combine with a methyl group to become methyl mercury. This form of mercury is found in a variety of environmental pollution situations and can produce a range of toxicities. Elemental mercury is less labile but produces a similar set of toxic manifestations.
Acute toxicity:
Organic or inorganic mercury can both precipitate protein in a local reaction. In the GI tract, acute poisoning produces a sloughing away of the mucosa to an extent where pieces of the intestinal mucosa can be found in the stools. This produces a large loss of fluids and electrolytes. Mercury also breaks down barriers in the capillaries. This results in edema throughout the body. A range of neurological toxicities are also common. These include lethargy (at low doses), excitement, hyper-reflexia, and tremor.
Chronic toxicity:
Often a psychotic state resulting in hyper-excitability. The expression 'Mad as a Hatter' originates from the hat-makers of the 19th century who were chronically exposed to mercury compounds used in making felt hats. The CNS effects are slowing or incompletely reversible. In chronic intoxication there is mercury line at the gingival border similar to the "lead line". Mercury is especially poisonous to rapidly growing tissue. A common effect is deterioration of alveolar bone in the jaw, with a subsequent loosening of the teeth. There are also substantial liver and kidney toxicity because of mucosal degeneration.
Mercury can be chelated in the peripheral tissues with EDTA and penicillamine. Even though the plasma levels can be reduced very efficiently, mercury forms alkyl ligands in the tissues. This is especially persistent in CNS tissue. Recovery from mercury poisoning can require months or years even with efficient chelator treatment, and is often incomplete.
MANGANESE
This heavy metal is frequently associated with iron deposits, and in fact the strata underlying Conception Bay providing the basis for the Wabana mines has a very rich manganese content. This metal is known to block Calcium channels, and with chronic intoxication results in CNS dopamine depletion. This latter condition duplicates almost all the symptomology of Parkinson's Disease, and is treated with some success using typical anti-Parkinson drugs. While the concentration in the surface water does not exceed official public health limits, it is in the high range of acceptable levels. It would be interesting to see if the epidemiology of Parkinsons syndrome in that locality is different from regions in the province with lower manganese concentrations. Manganese excretion can be facilitated by the use of chelator therapy, but it is not as easily managed as lead or mercury, because it is further down the list of chelator affinities
