Metals are an important class of environmental toxicantsl; they are ubiquitous environmental contaminants that come from both natural and anthropogenic sources. Various toxic metals play important roles in many industrial processes and are occupational health hazards and common pollutants. The top three substances of concern due to their toxicity and likelihood of human exposure as listed under the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA, also known as Superfund) are arsenic, lead, and mercury. The toxic effects of these three metals have played a central role in the development of the field of toxicology. However, the toxic effects of low-dose chronic exposure to metals have only recently been appreciated.
Many of the toxic metals in the environment also are carcinogens (Table 67–3). In addition to toxic environmental metals, several essential metals also are toxic under conditions of overdose. Copper and especially iron are associated with toxicities, primarily targeting the liver through generation of reactive oxygen species. Toxicities from copper and iron usually result from genetic diseases that interfere with the regulation of metal absorption or excretion (e.g., Wilson's disease for copper, hemochromatosis for iron) or result from acute overdose, particularly with iron-containing medications or multivitamins. For a more comprehensive review of toxic metals, including essential metals, see Liu et al. (2008).
Table 67-3Toxic Metals with Frequent Environmental or Occupational Exposurea ||Download (.pdf) Table 67-3 Toxic Metals with Frequent Environmental or Occupational Exposurea
|METAL ||CERCLA PRIORITY ||COMMON SOURCE OF EXPOSURE ||ORGAN SYSTEMS MOST SENSITIVE TO TOXICITY ||IARC CARCINOGEN CLASSIFICATION |
|As ||1 ||Drinking water ||CV, skin, multiple other ||Group 1, carcinogenic to humans—liver, bladder, lung |
|Pb ||2 ||Paint, soil ||CNS, blood, CV, renal ||Group 2A, probably carcinogenic |
|Hg ||3 ||Air, food ||CNS, renal ||Group 2B, possibly carcinogenic (MeHg+); group 3, not classifiable (Hg0, Hg2+) |
|Cd ||7 ||Occupational, food, smoking ||Renal, respiratory ||Group 1, carcinogenic to humans—lung |
|Cr6+ ||18 ||Occupational ||Respiratory ||Group 1, carcinogenic to humans—lung |
|Be ||42 ||Occupational, water ||Respiratory ||Group 1, carcinogenic to humans—lung |
|Co ||49 ||Occupational, food, water ||Respiratory, CV ||Group 2B, possibly carcinogenic |
|Ni ||53 ||Occupational ||Respiratory, skin (allergy) ||Group 1, carcinogenic (soluble Ni compounds); group 2B, possibly carcinogenic (metallic Ni)—lung |
Not listed in Table 67–3 is the metal gold, which has its own uses and toxicities. Among heavy metals, perhaps only gold is addictive: gold has been used for centuries for relief of the itching palm, and many cannot get enough of its influence.
Exposure to lead has wide-ranging consequences for human health. Chronic exposure of populations to even very low levels of lead has major deleterious effects, which are only now beginning to be understood. It has been proposed that lead exposure contributed to the fall of the Roman Empire and that it plays a role in modern inner-city violence (Woolley, 1984; Needleman et al., 1996).
Exposure. In the U.S., paint containing lead for use in and around households was banned in 1978, while the use of tetraethyl lead in gasoline was phased out and eventually eliminated between 1976 and 1996. The economic benefit of the reduction in lead exposure due to these two measures is estimated at hundreds of billions of dollars per year (Grosse et al., 2002). Despite these bans, past use of lead carbonate and lead oxide in paint and tetraethyl lead in gasoline remain the primary sources of lead exposure. Lead is not degradable and remains throughout the environment in dust, soil, and the paint of older homes. Young children often are exposed to lead by nibbling sweet-tasting paint chips or eating dust and soil in and around older homes. Renovation or demolition of older buildings may cause substantial lead exposure. Tetraethyl lead was used as an anti-knock agent in gasoline, which resulted in high levels of lead in air pollution. Removal of lead from gasoline caused lead levels in air pollution to drop by >90% between 1982 and 2002. Lead was commonly used in plumbing and can leach into drinking water. Acidic foods and beverages dissolve lead when stored in containers with lead in their glaze or lead-soldered cans, which was a significant problem through the middle of the 20th century and remains a problem in developing countries. Lead exposure also has been traced to other sources such as lead toys, non-Western folk medicines, cosmetics, retained bullets, artists' paint pigments, ashes and fumes from painted wood, jewelers' wastes, home battery manufacture, and lead type (ATSDR, 2007b; Levin et al., 2008). Blood lead levels in the general population have steadily decreased since the 1970s. Between 1976 and 2002, mean blood levels in children 1-5 years of age dropped from 15-1.9 μg/dL. The Centers for Disease Control and Prevention (CDC) recommends screening of children at 6 months of age and the use of aggressive lead abatement for children with blood lead levels >10 μg/dL.
Occupational exposure to lead also has decreased markedly because of protective regulations. Occupational exposure generally is through inhalation of lead containing dust and lead fumes. Workers in lead smelters and in storage battery factories are at the greatest risk for lead exposure because fumes are generated and dust containing lead oxide is deposited in their environment. Other workers at risk for lead exposure are those associated with steel welding or cutting, construction, rubber and plastic industries, printing, firing ranges, radiator repair shops, and any industry where lead is flame soldered (ATSDR, 2007b).
Chemistry and Mode of Action. Lead exists in its metallic form and as divalent or tetravalent cations. Divalent lead is the primary environmental form; inorganic tetravalent lead compounds are not naturally found. Organo-lead complexes primarily occur with tetravalent lead and include the gasoline additive tetraethyl lead.
Lead toxicity results from molecular mimicry of other divalent metals (Garza et al., 2006). Lead takes the place of zinc or calcium in a number of important proteins. Because of its size and electron affinity, lead alters protein structure and can inappropriately activate or inhibit protein function. Specific molecular targets for lead are discussed below.
Absorption, Distribution, and Excretion. Lead exposure occurs through ingestion or inhalation. GI absorption of lead varies considerably with age and diet. Children absorb a much higher percentage of ingested lead (~40% on average) than adults (<20%). Absorption of ingested lead is drastically increased by fasting. Dietary calcium or iron deficiencies increase lead absorption, suggesting that lead is absorbed through divalent metal transporters. The absorption of inhaled lead generally is much more efficient (~90%), particularly with smaller particles. Tetraethyl lead is readily absorbed through the skin, but this is not a route of exposure for inorganic lead.
About 99% of lead in the bloodstream binds to hemoglobin. Lead initially distributes in the soft tissues, particularly in the tubular epithelium of the kidney and the liver. Over time, lead is redistributed and deposited in bone, teeth, and hair. About 95% of the adult body burden of lead is found in bone. Growing bones will accumulate higher levels of lead and can form lead lines visible by radiography. Bone lead is very slowly reabsorbed into the bloodstream, except when calcium levels are depleted, such as during pregnancy. Small quantities of lead accumulate in the brain, mostly in gray matter and the basal ganglia. Lead readily crosses the placenta.
Lead is excreted by humans primarily in the urine, although there also is some biliary excretion. The concentration of lead in urine is directly proportional to its concentration in plasma, but because most lead is in erythrocytes, only a small quantity of total lead is removed by filtration. Lead is excreted in milk and sweat and deposited in hair and nails. The serum t1/2 of lead is 1-2 months, with a steady state achieved in ~6 months. Lead accumulates in bone, where its t1/2 is estimated at 20-30 years.
Health Effects. Although the effects of high-dose lead poisoning have been known for >2000 years, the insidious toxicities of chronic low-dose lead poisoning (blood lead <20 μg/dL) have only recently been discovered. Although lead is a nonspecific toxicant, the most sensitive systems are the nervous, hematological, cardiovascular, and renal systems (Figure 67–4). Uncovering the effects of low-level lead exposure on complex health outcomes, such as neurobehavioral function and blood pressure, has been the subject of extensive research.
Heme biosynthesis and actions of lead. Lead interferes with the biosynthesis of heme at several enzymatic steps. Steps that definitely are inhibited by lead are indicated by red blocks. Steps at which lead is thought to act but where evidence is inconclusive are indicated by pink blocks.
Neurotoxic Effects. The biggest concerns with low-level lead exposure are cognitive delays and behavior changes in children (ATSDR, 2007b; Bellinger and Bellinger, 2006). The developing nervous system is very sensitive to the toxic effects of lead.
Lead interferes with the pruning of synapses, neuronal migration, and the interactions between neurons and glial cells. Together, these alterations in brain development result in decreased IQ, poor performance on exams, and behavioral problems such as distractibility, impulsivity, short attention span, and inability to follow even simple sequences of instructions. Recent studies have shown neurobehavioral deficits even with lead exposures below the CDC action level of 10 μg/dL. There is no evidence for a threshold; associations with neurobehavioral effects are evident at the lowest measurable blood lead levels (Lanphear et al., 2005). Because different areas of the brain mature at different times, the neurobehavioral changes vary between children, depending on the timing of the lead exposure. Children with very high lead levels (>70 μg/dL) are at risk for encephalopathy. Symptoms of lead-induced encephalopathy include lethargy, vomiting, irritability, anorexia, and vertigo, which can progress to ataxia, delirium, and eventually coma and death. Mortality rates for lead-induced encephalopathy are ~25%, and most survivors develop long-term sequelae such as seizures and severe cognitive deficits.
Adults also develop encephalopathy from lead exposure, although they are less sensitive than children. Encephalopathy in adults requires blood lead levels >100 μg/dL. The symptoms are similar to those observed with children. Workers chronically exposed to lead can develop neuromuscular deficits, termed lead palsy. Symptoms of lead palsy, including wrist drop and foot drop, were commonly associated with painters and other lead-exposed workers during previous eras but are very rare today. Lead induces degeneration of motor neurons, usually without affecting sensory neurons. Studies in older adults have shown associations between lead exposure and decreased performance on cognitive function tests, suggesting that lead accelerates neurodegeneration due to aging (ATSDR, 2007b).
The neurodevelopmental effects of lead primarily result from inhibition of calcium transporters and channels and altered activities of calcium responsive proteins, including PKC and calmodulin (Garza et al., 2006; Bellinger and Bellinger, 2006). These actions limit the normal activation of neurons caused by calcium release and cause inappropriate production and/or release of neurotransmitters. Lead affects almost all the neurotransmitter pathways, with the dopaminergic, cholinergic, and glutamatergic systems receiving the most attention. Neurotransmitter release and PKC signaling determine which synapses are maintained and which are lost during development. At high concentrations, lead causes disruption of membranes, including the blood-brain barrier, increasing their permeability to ions. This effect is likely responsible for encephalopathy.
Cardiovascular and Renal Effects. Low-level lead exposure increases blood pressure. Correlations between lead exposure and blood pressure extend to concentrations of lead <20 μg/dL. Although the change in blood pressure is small, ~1 mm Hg for each doubling of the blood lead concentration, a significant effect persists across a wide number of studies, and there is evidence of causality (Navas-Acien et al., 2007). Elevated blood pressure is a lasting effect of lead exposure. Adults who were exposed to lead during infancy and childhood have elevated blood pressure even in the absence of a recent exposure; thus, blood pressure correlates better to lead levels in bone than in blood (ATSDR, 2007b). Lead exposure also is associated with an increased risk of death due to cardiovascular and cerebrovascular disease (Schober et al., 2006).
The kidney is a very sensitive target of lead. Low-level lead exposure (blood levels <10 μg/dL) depresses glomerular filtration. Higher levels (>30 μg/dL) cause proteinuria and impaired transport, while very high levels (>50 μg/dL) cause permanent physical damage, including proximal tubular nephropathy and glomerulosclerosis. Impaired glomerular filtration and elevated blood pressure are closely interrelated and likely have causative effects on one another (ATSDR, 2007b).
The exact mechanisms for the cardiovascular and renal effects of lead are not known. The cardiovascular effects of lead are thought to involve the production of reactive oxygen species by lead, through an unknown mechanism. Reactive oxygen species react with nitric oxide, which may contribute to the elevated blood pressure by reducing NO-induced vasodilation and contribute to cardiovascular toxicity through the formation of highly reactive peroxynitrite (Vaziri and Khan, 2007). Lead also forms inclusion bodies with various proteins, including metallothionein, in the kidney. The formation of these bodies greatly increases intracellular lead concentrations in the kidney but appears to be protective. It is not known how lead reduces glomerular filtration rate, although there is evidence that lead targets kidney mitochondria and may interfere with the electron transport chain (ATSDR, 2007b).
Hematological Effects. Chronic lead intoxication is associated with hypochromic microcytic anemia, which is observed more frequently in children and is morphologically similar to iron-deficient anemia. The anemia is thought to result from both decreased erythrocyte life span and inhibition of several enzymes involved in heme synthesis, which is observed at very low lead levels (Figure 67–5).
Manifestations of lead toxicity associated with varying concentrations of lead in the blood of children and adults. δ-ALA, δ-aminolevulinate.
Inhibition of γ-aminolevulinate (γ-ALA) dehydratase and ferrochelatase is well documented. Ferrochelatase is responsible for incorporating the ferrous ion into protoporphyrin IX to form heme. When ferrochelatase is inhibited by lead, zinc is incorporated in place of iron, resulting in zinc-protoporphyrin, which is highly fluorescent and diagnostic of lead poisoning. γ-ALA dehydratase is the most sensitive of these enzymes to inhibition by lead; very low levels of lead increase urinary excretion of γ-ALA. Lead also causes both immunosuppression and increased inflammation, primarily through changes in helper T-cell and macrophage signaling (Dietert and Piepenbrink, 2006).
Gastrointestinal Effects. Lead affects the smooth muscle of the gut, producing intestinal symptoms that are an early sign of high-level exposure to the metal. The abdominal syndrome often begins with a persistent metallic taste, mild anorexia, muscle discomfort, malaise, headache, and usually constipation. Occasionally, diarrhea replaces constipation. As intoxication advances, symptoms worsen and include intestinal spasms that cause severe intestinal pain (lead cholic). Intravenous calcium gluconate can relieve this pain.
Carcinogenesis. IARC recently upgraded lead to "probably carcinogenic to humans" (group 2A; IARC, 2006). Epidemiological studies have shown associations between lead exposure and cancers of the lung, brain, kidney, and stomach. Rodents exposed to lead develop kidney tumors, and some rats develop gliomas. Lead is not mutagenic but increases clastogenic events. The mechanism of lead carcinogenesis is unknown but may result from inhibition of DNA binding zinc-finger proteins, including those involved in DNA repair and synthesis (Silbergeld, 2003). Lead is a good example of a non-genotoxic carcinogen.
Treatment. The most important response to lead poisoning is removal of the source of lead exposure. Supportive measures should be undertaken to relieve symptoms.
Chelation therapy is warranted for children and adults with high blood lead levels (>45 μg/dL and >70 μg/dL, respectively) and/or acute symptoms of lead poisoning (Ibrahim et al., 2006). Although chelation therapy is effective at lowering blood lead levels and relieving immediate symptoms, it does not reduce the chronic effects of lead beyond the benefit of lead abatement alone (Rogan et al., 2001). In rats, chelators enhance mobilization of lead from the soft tissues to the brain and may increase the adverse neurodevelopmental effects of lead (Andersen and Aaseth, 2002).
Mercury is a unique metal in that it is a liquid at room temperature. Because of its capacity to amalgamate with other metals, mercury has been used industrially since ancient Greece, and mercury's toxicity was noted by Hippocrates. Mercury also was used as a therapeutic drug for several centuries. Indeed, its use for the treatment of syphilis inspired Paracelsus' observation that "the dose makes the poison," one of the central concepts of toxicology, and also gave rise to the cautionary expression, "A night with Venus, a year with Mercury." Toxicities from occupational exposure to mercury have been known for a long time. For instance, the phrase "mad as a hatter" originated from the exposure of hatters to metallic mercury vapor during production of felt for hats using mercury nitrate (Goldwater, 1972). While the phrase likely inspired the character of the Mad Hatter in Alice in Wonderland, his symptoms are not consistent with mercury exposure.
Exposure. Inorganic mercury cations and metallic mercury are found in the Earth's crust, and mercury vapor is released naturally into the environment through volcanic activity and off-gassing from soils. Mercury also enters the atmosphere through human activities such as combustion of fossil fuels. Once in the air, metallic mercury is photo-oxidized to inorganic mercury, which can then be deposited in aquatic environments in rain. Microorganisms can then conjugate inorganic mercury to form methyl mercury. Methyl mercury concentrates in lipids and will bioaccumulate up the food chain so that concentrations in aquatic organisms at the top of the food chain, such as swordfish or sharks, are quite high (Figure 67–6; ATSDR, 1999).
The primary source of exposure to metallic mercury in the general population is vaporization of mercury in dental amalgam, which often contains >50% Hg0 mixed with silver and other metals. This release is enhanced by chewing. There also is limited exposure through broken thermometers and other mercury-containing devices. Human exposure to organic mercury primarily is through the consumption of fish. Other foods contain inorganic mercury at low levels (ATSDR, 1999).
Workers are exposed to metallic and inorganic mercury, most commonly though exposure to vapors. The highest risk for exposure is in the chloralkali industry (i.e., bleach) and in other chemical processes in which mercury is used as a catalyst. Mercury is a component of many devices, including alkaline batteries, fluorescent bulbs, thermometers, and scientific equipment, and exposure occurs during the production of these devices. Dentists also are exposed to mercury from amalgam. Mercury can be used to extract gold during mining, which results in substantial occupational exposure, because the last step involves vaporization of the mercury. This process is still commonly used in developing countries. Mercuric salts are used as pigments in paints (ATSDR,1999).
Mercury salts were once found in a number of medications, including antiseptics, antidiuretics, skin-lightening creams, and laxatives. Most of these uses have been replaced by safer and more effective drugs. Thimerosal is an antimicrobial agent used as a preservative in vaccines. Its use is controversial because it releases ethyl mercury, which is chemically similar to methyl mercury. Due to the concerns of some parents that thimerosal might be a cause of autism, the American Academy of Pediatrics and the U.S. Public Health Service issued a call for its replacement in vaccines to improve the prevalence of vaccination (Ball et al., 2001). However, studies have not found an association between thimerosal use in vaccines and negative outcomes, and it is still used in influenza vaccines (Heron and Golding, 2004).
Chemistry and Mode of Action. There are three general forms of mercury of concern to human health. Metallic, or elemental, mercury (Hg0) is the liquid metal found in thermometers and dental amalgam; it is quite volatile, and exposure is often to the vapor form. Inorganic mercury can be either monovalent (mercurous, Hg1+) or divalent (mercuric, Hg2+) and forms a variety of salts. Organic mercury compounds consist of divalent mercury complexed with one or occasionally two alkyl groups. The organic mercury compound of most concern is methyl mercury (MeHg+), which is formed environmentally from inorganic mercury by aquatic microorganisms.
Both Hg2+ and MeHg+ readily form covalent bonds with sulfur, which causes most of the biological effects of mercury. At very low concentrations, mercury reacts with sulfhydryl residues on proteins and disrupts their functions. Given the large numbers of proteins with important cysteines, determination of the specific mechanism for cellular dysfunction has been difficult, and there are probably multiple pathways affected. One of these pathways involves the generation of oxidative stress in cells. Also, microtubules are particularly sensitive to the toxic effects of mercury, which disrupts their formation and can catalyze their disassembly (Clarkson, 2002). There also may be an autoimmune component to mercury toxicity.
Absorption, Distribution, Biotransformation, and Excretion. Hg0 vapor is readily absorbed through the lungs (~70-80%), but GI absorption of metallic mercury is negligible. Once absorbed, Hg0 distributes throughout the body and crosses membranes such as the blood-brain barrier and the placenta via diffusion. Hg0 is oxidized by catalase in the erythrocytes and other cells to form Hg2+. Shortly after exposure, some Hg0 is eliminated in exhaled air. After a few hours, distribution and elimination of Hg0 resemble the properties of Hg2+. After exposure to Hg0 vapor, it is oxidized to Hg2+ and retained in the brain (ATSDR, 1999).
GI absorption of mercury salts varies depending on the individual and on the particular salt and averages ~10-15%. Hg1+ will form Hg0 or Hg2+ in the presence of sulfhydryl groups. Hg2+ primarily is excreted in the urine and feces; a small amount also can be reduced to Hg0 and exhaled. With acute exposure, the fecal pathway predominates, but following chronic exposure, urinary excretion becomes more important. All forms of mercury also are excreted in sweat and breast milk and deposited in hair and nails. The t1/2 for inorganic mercury is approximately 1-2 months (ATSDR, 1999).
Orally ingested MeHg+ is almost completely absorbed from the GI tract. MeHg+ readily crosses the blood-brain barrier and the placenta and distributes fairly evenly to the tissues, although concentrations are highest in the kidneys (ATSDR, 1999). MeHg+ can be demethylated to form inorganic Hg2+. The liver and kidney exhibit the highest rates of demethylation, but this also occurs in the brain. MeHg+ is excreted in the urine and feces, with the fecal pathway dominating. The t1/2 for MeHg+ is ~2 months. The pharmacokinetic properties of MeHg+ are thought to result from molecular mimicry. Complexes between MeHg+ and cysteine resemble methionine and can be recognized by transporters for that amino acid and taken across membranes (Ballatori, 2002).
Mobilization of mercury in the environment. Metallic mercury (Hg0) is vaporized from the Earth's surface both naturally and through human activities such as burning coal. In the atmosphere, Hg0 is oxidized to form divalent inorganic mercury (Hg2+). Hg2+ then falls to the surface in rain. Aquatic bacteria can methylate Hg2+ to form methyl mercury (MeHg+). MeHg+ in plankton is consumed by fish. Because of its lipophilicity, MeHg+ bioaccumulates up the food chain.
Metallic Mercury. Inhalation of high levels of mercury vapor over a short duration is acutely toxic to the lung. Respiratory symptoms of mercury exposure start with cough and tightness in the chest and can progress to interstitial pneumonitis and severely compromised respiratory function. Other initial symptoms include weakness, chills, metallic taste, nausea, vomiting, diarrhea, and dyspnea. Acute exposure to high doses of mercury also is toxic to the CNS, with symptoms similar to those of chronic exposure (Figure 67–7).
The concentration of mercury vapor in the air and related concentrations of mercury in urine are associated with a variety of toxic effects.
Toxicity to the nervous system is the primary concern with chronic exposure to mercury vapor. Mercury vapor induces characteristic CNS symptoms that are consistent across patients exposed to mercury over short or long periods. These symptoms include tremors (particularly of the hands), emotional lability (irritability, shyness, loss of confidence, and nervousness), insomnia, memory loss, muscular atrophy, weakness, paresthesia, and cognitive deficits. These symptoms intensify and become irreversible, with increases in duration and concentration of exposure. Other common symptoms of chronic mercury exposure include tachycardia, labile pulse, severe salivation, and gingivitis. Prolonged exposure to mercury also causes kidney damage.
Inorganic Salts of Mercury. Ingestion of Hg2+ salts is intensely irritating to the GI tract, leading to vomiting, diarrhea, and abdominal pain. The kidney is the primary target of both valence states of inorganic mercury. Acute exposure to mercury salts (typically in suicide attempts) leads to tubular necrosis, resulting in decreased urine output and often acute renal failure. Chronic exposures also target the kidney, with glomerular injury predominating.
Organic Mercury. The CNS is the primary target of methyl mercury toxicity. Two incidents of high-dose exposure to methyl mercury provide much of our knowledge regarding methyl mercury poisoning. One was in fishing villages surrounding the heavily polluted Minamata Bay in Japan, and the other was in Iraq, where grains treated with methyl mercury were accidentally consumed. Symptoms of methyl mercury exposure include visual disturbances, ataxia, paresthesia, fatigue, hearing loss, slurring of speech, cognitive deficits, muscle tremor, movement disorders, and, following severe exposure, paralysis and death. The developing nervous system exhibits increased sensitivity to methyl mercury. Children exposed in utero can develop severe symptoms, including mental retardation and neuromuscular deficits, even in the absence of symptoms in the mother. In adults, methyl mercury causes focused lesions in specific areas of the brain, while the brains of children exposed in utero sustain widespread damage (Clarkson, 2002).
The effects of low-dose methyl mercury exposure from routine consumption of fish are difficult to assess due to the opposing beneficial effects of ω-3 fatty acids found in fish oils, and studies have produced discrepant results (Grandjean et al., 1999; Myers et al., 2003; Myers et al., 2007).
Treatment. With exposure to metallic mercury, termination of exposure is critical and respiratory support may be required. Emesis may be used within 30-60 minutes of exposure to inorganic mercury, provided the patient is awake and alert and there is no corrosive injury. Maintenance of electrolyte balance and fluids is important for patients exposed to inorganic mercury. Chelation therapy is beneficial in patients with acute inorganic or metallic mercury exposure. There are limited treatment options for methyl mercury. Chelation therapy does not provide clinical benefits, and several chelators potentiate the toxic effects of methyl mercury (Rush, 2008). Nonabsorbed thiol resins may be beneficial by preventing reabsorption of methyl mercury from the GI tract.
Because of the conflicting effects of mercury and ω-3 fatty acids, there is considerable controversy regarding the restriction of fish intake in women of reproductive age and children. The EPA recommends limiting fish intake to 12 oz (two meals) per week. Many experts feel this recommendation is too conservative, and the FDA is considering revising their recommendation to state that the benefits of fish consumption outweigh the risks. The recommendation that women consume fish that is lower in mercury content (i.e., canned light tuna, salmon, pollock, catfish) and avoid top predators, such as swordfish, shark, and tilefish, is not controversial.
Arsenic is a metalloid that is common in rocks and soil. Arsenic compounds have been used for >2400 years as both therapeutic agents and poisons. In the late 19th century, Robert Ehrlich coined the terms "magic bullet" and "chemotherapy" to describe his work using the organic arsenic compound arsphenamine for the treatment of syphilis. The use of arsenic in drugs has been mostly phased out, but arsenic trioxide (ATO) is still used as an effective chemotherapy agent for acute promyelocytic leukemia (see Chapter 63).
Exposure. The primary source of exposure to arsenic is through drinking water. Arsenic naturally leaches out of soil and rocks into well and spring water (Mead, 2005). Levels of arsenic in drinking water average 2 μg/L (ppb) in the U.S. but can be >50 μg/L (five times the EPA standard) in private well water, particularly in California, Nevada, and Arizona. Drinking water from other parts of the world where well water has been promoted to prevent waterborne illness, particularly Taiwan, China, Argentina, Chile, Bangladesh, and eastern India, sometimes is contaminated with much higher levels of arsenic (sometimes several hundred micrograms per liter), and widespread poisonings have resulted (Figure 67–8). Studies in Bangladesh found that ~40% of water samples from across the country were contaminated with >50 μg/L of arsenic, and some samples had far higher levels (Mead, 2005; Chowdhury et al., 1999; BGS and DPHE, 2001). Arsenic also can enter the environment through human activities such as the use of arsenic-containing pesticides, mining, and burning of coal. Food, particularly seafood, often is contaminated with arsenic. Arsenic in seafood exists primarily as organic compounds (i.e., arsenobetaine) that are much less toxic than inorganic arsenic. The average daily human intake of arsenic is 10 μg/day, almost exclusively from food and water.
Before 2003, >90% of arsenic used in the U.S. was as a preservative in pressure-treated wood, but the lumber industry has voluntarily replaced arsenic with other preservatives. Arsenic-treated wood is thought to be safe unless burned (Hall, 2002). The major source of occupational exposure to arsenic is in the production and use of organic arsenicals as herbicides and insecticides. Exposure to metallic arsenic, arsine, arsenic trioxide, and gallium arsenide also occurs in high-tech industries, such as the manufacture of computer chips and semiconductors.
Chemistry and Mode of Action. Arsenic exists in its elemental form and trivalent (arsenites/arsenious acid) and pentavalent (arsenates/arsenic acid) states. Arsine is a gaseous hydride of trivalent arsenic that exhibits toxicities that are distinct from other forms. Organic compounds containing either valence state of arsenic are formed in animals. The toxicity of a given arsenical is related to the rate of its clearance from the body and its ability to concentrate in tissues. In general, toxicity increases in the sequence: organic arsenicals < As5+ < As3+ < arsine gas (AsH3).
Like mercury, trivalent arsenic compounds form covalent bonds with sulfhydryl groups. The pyruvate dehydrogenase system is particularly sensitive to inhibition by trivalent arsenicals because the two sulfhydryl groups of lipoic acid react with arsenic to form a six-membered ring. Inorganic arsenate (pentavalent) inhibits the electron transport chain. It is thought that arsenate competitively substitutes for phosphate during the formation of adenosine triphosphate, forming an unstable arsenate ester that is rapidly hydrolyzed.
Absorption, Distribution, Biotransformation, and Excretion. The absorption of arsenic compounds is directly related to their solubility. Poorly water-soluble forms such as arsenic sulfide, lead arsenate, and arsenic trioxide are not well absorbed. Water-soluble arsenic compounds are readily absorbed from both inhalation and ingestion. GI absorption of arsenic dissolved in drinking water is >90% (ATSDR, 2007a).
At low doses, arsenic is fairly evenly distributed throughout the tissues of the body. Nails and hair, due to their high sulfhydryl content, exhibit high concentrations of arsenic. After an acute high dose of arsenic (i.e., fatal poisoning), arsenic is preferentially deposited in the liver and, to a lesser extent, kidney, with elevated levels also observed in the muscle, heart, spleen, pancreas, lungs, and cerebellum. Arsenic readily crosses the placenta and blood-brain barrier.
Arsenic undergoes biotransformation in humans and animals (Figure 67–9). Trivalent compounds can be oxidized back to pentavalent compounds, but there is no evidence for demethylation of methylated arsenicals. Biotransformation of arsenic varies greatly across species, with humans excreting much higher levels of monomethyl-arsenic (MMA) compounds than most other animals (ATSDR, 2007a). Because the pentavalent methylated arsenic compounds have greatly reduced toxicity, the methylation pathway was long thought to be a detoxification pathway. However, the trivalent methylated arsenicals actually are more toxic than inorganic arsenite, due to an increased affinity for sulfhydryl groups, and formation of MMAIII now is considered a bioactivation pathway (Aposhian and Aposhian, 2006).
Elimination of arsenicals by humans primarily is in the urine, although some is also excreted in feces, sweat, hair, nails, skin, and exhaled air. Compared to most other toxic metals, arsenic is excreted quickly, with a t1/2 of 1-3 days. In humans, ingested inorganic arsenic in urine is a mixture of 10-30% inorganic arsenicals, 10-20% monomethylated forms, and 60-80% dimethylated forms.
Arsenic in drinking water. (A) World map demonstrating regions where there is increased arsenic exposure in drinking water. (B) Map of Bangladesh demonstrating arsenic concentrations in drinking water in samples from wells across the country. (Adapted from BGS and DPHE, 2001. This report was produced by the British Geological Survey and the Department of Public Health Engineering (Bangladesh) undertaking a project funded by the UK Department for International Development.)
Metabolism of arsenic. GSH, reduced glutathione; GSSG, oxidized glutathione; SAM, S-adenosyl-l-methionine; SAH, S-adenosyl-l-homocysteine. AS3MT, arsenite methyltransferase; MMAV, monomethylarsonic acid; MMAIII, monomethylarsonous acid; DMAV, dimethyl arsinic acid.
Health Effects. With the exception of arsine gas (which is discussed later in "Arsine Gas"), the various forms of inorganic arsenic exhibit similar toxic effects. Inorganic arsenic exhibits a broad range of toxicities and has been associated with effects on every organ system tested, although some systems are much more sensitive than others (ATSDR, 2007a). Humans also are exposed to large organic arsenic compounds in fish, which are relatively nontoxic. Humans are the most sensitive species to the toxic effects of inorganic arsenic. Acute exposure to large doses of arsenic (>70-180 mg) often is fatal. Death immediately following arsenic poisoning typically is the result of its effects on the heart and GI tract. Death sometimes occurs later as a result of arsenic's combined effect on multiple organs.
Cardiovascular System. Acute and chronic arsenic exposure cause myocardial depolarization, cardiac arrhythmias, and ischemic heart disease; these are known side effects of arsenic trioxide for the treatment of leukemia. Chronic exposure to arsenic causes peripheral vascular disease, the most dramatic example of which is "blackfoot disease," a condition characterized by cyanosis of the extremities, particularly the feet, progressing to gangrene. Blackfoot disease is endemic in regions of Taiwan, with arsenic levels of between 170 and 800 μg/L. Arsenic dilates capillaries and increases their permeability. This causes edema after acute exposures and is likely responsible for peripheral vascular disease following chronic exposure.
Skin. The skin is very sensitive to chronic arsenic exposure. Dermal symptoms often are diagnostic of arsenic exposure. Arsenic induces hyperkeratinization of the skin (including formation of multiple corns or warts), particularly of the palms of the hands and the soles of the feet. It also causes areas of hyperpigmentation interspersed with spots of hypopigmentation. These symptoms can be observed in individuals exposed to drinking water with arsenic concentrations of at least 100 μg/L and are typical in those chronically exposed to much higher levels. Hyperpigmentation can be observed after 6 months of exposure, while hyperkeratinization takes years. Children are more likely to develop these effects than adults. The mechanism of arsenic-induced changes to the skin is unknown, partly because these effects are not seen in other animals (Mead, 2005; ATSDR, 2007a).
GI Tract. Acute or subacute exposure to high-dose arsenic by ingestion is associated with GI symptoms ranging from mild cramping, diarrhea, and vomiting to GI hemorrhaging and death. GI symptoms are caused by increased capillary permeability, leading to fluid loss. At higher doses, fluid forms vesicles that can burst, leading to inflammation and necrosis of the submucosa and then rupture of the intestinal wall. GI symptoms are not observed with chronic exposure to lower levels of arsenic.
Nervous System. Acute high-dose arsenic exposure causes encephalopathy in rare cases, with symptoms that can include headache, lethargy, mental confusion, hallucination, seizures, and coma. However, the most common neurological effect of acute or subacute arsenic exposure is peripheral neuropathy involving both sensory and motor neurons. This effect is characterized by the loss of sensation in the hands and feet (a stocking and glove distribution). This often is followed by muscle weakness. Neuropathy occurs several days after exposure to arsenic and can be reversible following cessation of exposure, although recovery usually is not complete. Arsenic exposure may cause intellectual deficits in children. Wasserman et al. (2007) observed a negative association between arsenic levels in drinking water and performance on intelligence tests.
Other Non-Cancer Toxicities. Acute and chronic arsenic exposures induce anemia and leukopenia. Arsenic likely causes both direct cytotoxic effects on blood cells and suppression of erythropoiesis through bone marrow toxicity. Arsenic also may inhibit heme synthesis. In the liver, arsenic causes fatty infiltrations, central necrosis, and cirrhosis of varying severity. The action of arsenic on renal capillaries, tubules, and glomeruli can cause severe kidney damage. Inhaled arsenic is irritating to the lungs, and ingested arsenic may induce bronchitis progressing to bronchopneumonia in some individuals. Chronic exposure to arsenic is associated with an increased risk of diabetes.
Carcinogenesis. Arsenic compounds were among the first recognized human carcinogens. At the end of the 19th century, Hutchinson observed that patients receiving arsenic-containing drugs had an increased occurrence of skin tumors. Epidemiological studies performed in regions with very high arsenic levels in drinking water consistently observe substantially increased rates of skin cancer (squamous cell and basal cell carcinomas), bladder cancer, and lung cancer. There also are associations between arsenic exposure and other cancers, including liver, kidney, and prostate tumors. Inhalation exposure to arsenic in occupational settings causes lung cancer. IARC classifies arsenic as "carcinogenic to humans (group 1)."
The developing fetus and young children may be at increased risk of arsenic carcinogenesis, because humans exposed to arsenic in utero and in early childhood have a greatly elevated risk of lung cancer (Smith et al., 2006). Studies in rodents also have observed increased cancer risks from in utero exposure and suggest that the second trimester of pregnancy represents a critical susceptibility window (Waalkes et al., 2007).
The mechanism of arsenic carcinogenesis is poorly understood. Arsenic is an unusual carcinogen in that evidence for human carcinogenesis is much stronger than for carcinogenesis in laboratory animals. Arsenic does not directly damage DNA; rather, arsenic is thought to work through changes in gene expression, DNA methylation, inhibition of DNA repair, generation of oxidative stress, and/or altered signal transduction pathways (Salnikow and Zhitkovich, 2008; Hartwig et al., 2002). Arsenic compounds can act as tumor promoters or co-carcinogens in rodents, particularly when combined with ultraviolet light (Burns et al., 2004). In humans, exposure to arsenic potentiates lung tumorigenesis from tobacco smoke. Smokers in regions with high concentrations of arsenic in the drinking water have a 5-fold increased risk of cancer over smokers living in low arsenic regions (Ferreccio et al., 2000). Arsenic co-carcinogenesis may involve inhibition of proteins involved in nucleotide excision repair (Salnikow and Zhitkovich, 2008; Hartwig et al., 2002). Arsenic also has endocrine-disrupting activities on several nuclear steroid hormone receptors, enhancing hormone-dependent transcription at very low concentrations and inhibiting it at slightly higher levels (Bodwell et al., 2006).
Arsine Gas. Arsine gas, formed by electrolytic or metallic reduction of arsenic, is a rare cause of industrial poisonings. Arsine induces rapid and often fatal hemolysis, which probably results from arsine combining with hemoglobin and reacting with oxygen. A few hours after exposure, patients can develop headache, anorexia, vomiting, paresthesia, abdominal pain, chills, hemoglobinuria, bilirubinemia, and anuria. Jaundice appears after 24 hours. Arsine induces renal toxicities that can progress to kidney failure. Approximately 25% of cases of arsine exposure result in death.
Treatment. Following acute exposure to arsenic, stabilize the patient and prevent further absorption of the poison. Close monitoring of fluid levels is important because arsenic can cause fatal hypovolemic shock. Chelation therapy is effective following short-term exposure to arsenic but has very little or no benefit in chronically exposed individuals. Exchange transfusion to restore blood cells and remove arsenic often is warranted following arsine gas exposure (Ibrahim et al., 2006).
Cadmium was discovered in 1817 and first used industrially in the mid-20th century. Cadmium is resistant to corrosion and exhibits useful electrochemical properties, which has led to its use in electroplating, galvanization, plastics, paint pigments, and nickel-cadmium batteries.
Exposure. In the general population, the primary source of exposure to cadmium is through food, with an estimated average daily intake of 50 μg/day. Cadmium also is found in tobacco; a cigarette contains 1-2 μg of cadmium (Jarup and Akesson, 2009). Workers in smelters and other metal-processing industries can be exposed to high levels of cadmium, particularly by inhalation.
Chemistry and Mode of Action. Cadmium exists as a divalent cation and does not undergo oxidation-reduction reactions. There are no covalent organometallic complexes of cadmium of toxicological significance. The mechanism of cadmium toxicity is not fully understood. Like lead and other divalent metals, cadmium can replace zinc in zinc-finger domains of proteins and disrupt them. Through an unknown mechanism, cadmium induces formation of reactive oxygen species, resulting in lipid peroxidation and glutathione depletion. Cadmium also upregulates inflammatory cytokines and may disrupt the beneficial effects of nitric oxide.
Absorption, Distribution, and Excretion. Cadmium is not well absorbed from the GI tract (1.5-5%) but is better absorbed via inhalation (~10%). Cadmium primarily distributes first to the liver and later the kidney, with those two organs accounting for 50% of the absorbed dose. Cadmium distributes fairly evenly to other tissues, but unlike other heavy metals, little cadmium crosses the blood-brain barrier or the placenta. Cadmium primarily is excreted in the urine and exhibits a t1/2 of 10-30 years (ATSDR, 2008a).
Toxicity. Acute cadmium toxicity primarily is due to local irritation along the absorption route. Inhaled cadmium causes respiratory tract irritation with severe, early pneumonitis accompanied by chest pains, nausea, dizziness, and diarrhea. Toxicity may progress to fatal pulmonary edema. Ingested cadmium induces nausea, vomiting, salivation, diarrhea, and abdominal cramps; the vomitus and diarrhea often are bloody.
Symptoms of chronic cadmium toxicity vary by exposure route. The lung is an important target of inhaled cadmium, while the kidney is a major target of cadmium from both inhalation and ingestion.
Cadmium bound to metallothionein is transported to the kidney, where it can be released. The initial toxic effect of cadmium on the kidney is increased excretion of small-molecular-weight proteins, especially β2 microglobulin and retinol-binding protein. Cadmium also causes glomerular injury, with a resulting decrease in filtration. Chronic occupational exposure to cadmium is associated with an increased risk of renal failure and death. There is no evidence for a threshold level for cadmium's effects on the kidney; cadmium levels consistent with normal dietary exposure can cause renal toxicity, including a reduction in glomerular filtration rate and creatinine clearance (Jarup and Akesson, 2009).
Workers with long-term inhalation exposure to cadmium exhibit decreased lung function. Symptoms initially include bronchitis and fibrosis of the lung, leading to emphysema. The exact cause of cadmium-induced lung toxicity is not known but may result from inhibition of the synthesis of α1 antitrypsin. Chronic obstructive pulmonary disease causes increased mortality in cadmium-exposed workers.
When accompanied by vitamin D deficiency, cadmium exposure increases the risks for fractures and osteoporosis. This may be an effect of cadmium interfering with calcium and phosphate regulation due to its renal toxicity.
Carcinogenicity. Chronic occupational exposure to inhaled cadmium increases the risk of developing lung cancer (IARC, 1993; NTP, 2004). The mechanism of cadmium carcinogenesis is not fully understood. Cadmium causes chromosomal aberrations in exposed workers and treated animals and human cells. It also increases mutations and impairs DNA repair in human cells (NTP, 2004). Cadmium substitutes for zinc in DNA repair proteins and polymerases and may inhibit nucleotide excision repair, base excision repair, and the DNA polymerase responsible for repairing single-strand breaks (Hartwig et al., 2002). There is evidence that cadmium also alters cell signaling pathways and disrupts cellular controls of proliferation (Waisberg et al., 2003). Thus, cadmium acts as a non-genotoxic carcinogen.
Treatment. Treatment of cadmium poisoning is symptomatic. Patients suffering from inhaled cadmium may require respiratory support. Patients suffering from kidney failure due to cadmium poisoning may require a transplant. There is no evidence for clinical benefit from chelation therapy following cadmium poisoning, and chelation therapy may result in adverse effects (ATSDR, 2008a).
Chromium is an industrially important metal used in a number of alloys, particularly stainless steel, which contains at least 11% chromium. Chromium can be oxidized to multiple valence states, with trivalent (CrIII) and hexavalent chromium (CrVI) being the two forms of biological importance. Chromium exists almost exclusively as the trivalent form in nature, and CrIII is an essential metal involved in the regulation of glucose metabolism. CrVI is thought to be responsible for the toxic effects of chromium exposure (ATSDR, 2008b).
Exposure. Exposure to chromium in the general population primarily is through the ingestion of food, although there also is exposure from drinking water and air. Workers are exposed to chromium during chromate production, stainless steel production and welding, chromium plating, ferrochrome alloy and chrome pigment production, and in tanning industries (Ashley et al., 2003). Exposure usually is to a mixture of CrIII and CrVI, except in chromium plating, which usually uses CrVI, and tanning, where CrIII is used.
Chemistry and Mode of Action. Chromium occurs in its metallic state or in any valence state between divalent and hexavalent. CrIII is the most stable and common form. CrVI is corrosive and is readily reduced to lower valence states. The primary reason for the different toxicological properties of CrIII and CrVI is thought to be differences in their absorption and distribution. Hexavalent chromate resembles sulfate and phosphate and can be taken across membranes by anion transporters. Once inside the cell, CrVI undergoes a series of reduction steps, ultimately forming CrIII, which is thought to cause most of the toxic effects. Trivalent chromium readily forms covalent interactions with DNA. Hexavalent chromium also induces oxidative stress and hypersensitivity reactions.
Absorption, Distribution, Biotransformation, and Excretion. Absorption of inhaled chromium depends on its solubility, valence state, and particle size. Smaller particles are better deposited in the lungs. Absorption into the bloodstream of hexavalent and soluble forms is higher than the trivalent or insoluble forms, with the remainder often retained in the lungs. Approximately 50-85% of inhaled CrVI particles (<5 μm) are absorbed. Absorption of ingested chromium is <10%. Soluble CrVI compounds are better absorbed from the GI tract than other forms. CrVI crosses membranes by facilitated transport, while CrIII crosses by diffusion. CrVI is distributed to all of the tissues and crosses the placenta. The highest levels are attained in the liver, kidney, and bone; CrVI also is retained in erythrocytes, bound tightly to hemoglobin and other ligands. Excretion primarily is through urine, with small amounts also excreted in bile and breast milk and deposited in hair and nails. The t1/2 of ingested CrVI is ~40 hours, while the t1/2 of CrIII is ~10 hours, reflecting the enhanced tissue retention of CrVI (ATSDR, 2008b).
Toxicity. Acute exposure to very high doses of chromium causes death via damage to multiple organs, particularly the kidney, where it causes tubular and glomerular damage. Chronic low-dose chromium exposure primarily causes toxicity at the site of contact. Workers exposed to inhaled chromium develop symptoms of lung and upper respiratory tract irritation, including epistaxis, chronic rhinorrhea, nasal itching and soreness, nasal mucosal atrophy, perforations and ulceration of the nasal septum, bronchitis, pneumonoconiosis, decreased pulmonary function, and pneumonia. Chronic exposure to chromium via ingestion, including after mucociliary clearance of inhaled particles, causes symptoms of GI irritation such as oral ulcer, diarrhea, abdominal pain, indigestion, and vomiting. CrVI is a dermal irritant and can cause ulceration or burns. Following low-dose exposure by any route, some individuals become sensitized to chromium and develop allergic dermatitis following dermal exposure to chromium, including products containing metallic chromium. Chromium-sensitized workers often also develop asthma following inhalation exposure (ATSDR, 2008b).
Carcinogenicity. CrVI compounds are known human carcinogens (group 1; IARC, 1990). There is insufficient evidence for carcinogenesis from metallic and trivalent chromium (group 3). Workers exposed to CrVI via inhalation have elevated incidence of and mortality from lung and nasal cancer. Environmental exposure to CrVI in drinking water increases the risk of developing stomach cancer. Based on animal studies, the most potent carcinogenic compounds are slightly soluble CrVI compounds.
There are multiple potential mechanisms for chromium carcinogenicity (Salnikow and Zhitkovich, 2008). After uptake into cells, reduction of CrVI to CrIII occurs with concomitant oxidation of cellular molecules. Ascorbate is the primary reductant, but other molecules, including glutathione, lipids, proteins, and DNA, also can be oxidized. CrIII forms a large number of covalent DNA adducts, primarily at the phosphate backbone. The most common DNA adducts are either binary (DNA-CrIII) adducts or cross-links to small molecules such as ascorbate and glutathione. The DNA adducts are not very mutagenic and are repaired by nucleotide excision repair. It is thought that the high level of nucleotide excision repair activity following chromium exposure contributes to carcinogenesis, either by preventing repair of mutagenic lesions formed by other carcinogens or through the formation of single-strand breaks due to incomplete repair. Chromium also forms toxic cross-links between DNA and protein. Chronic inflammation due to chromium-induced irritation also may promote tumor formation.
Treatment. There are no standard protocols for treatment of acute chromium poisoning. One approach that has shown promise in rodents is the use of reductants such as ascorbate, glutathione, or N-acetylcysteine to reduce CrVI to CrIII after exposure but before absorption to limit bioavailability (ATSDR, 2008b). These compounds and EDTA also increase urinary excretion of chromium after high-dose exposure, particularly if given soon enough to prevent uptake into cells. Exchange transfusion to remove chromium from plasma and erythrocytes may be beneficial.