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Heavy Metal Poisoning

Chapter 469 | Part 14: Poisoning, Drug Overdose, and Envenomation · Part 14 – Poisoning, Overdose & Environmental

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points

  1. Activated charcoal does not bind metals and is of limited usefulness in cases of acute metal ingestion.
  2. The first, second, third, and seventh hazards on the U.S. Agency for Toxic Substances and Disease Registry list are heavy metals: arsenic, lead, mercury, and cadmium.
  3. Low-level arsenic exposure is a risk factor for hypertension, subclinical atherosclerosis, coronary artery stenosis, and calcification.
  4. Cadmium exposure is a risk factor for cardiovascular disease, mortality, stroke, and heart failure.
  5. Lead exposure has no measurable threshold for IQ impairment; impairment appears at levels down to 1 μg/dL.
  6. Mercury binds sulfhydryl groups and interferes with a wide variety of critical enzymatic processes.
  7. Chelation therapy for chronic lead exposure remains controversial; TACT-1 showed benefit in high lead burdens, TACT-2 showed no benefit in low exposure.
  8. Mees' lines are transverse white striae of the fingernails seen in arsenic poisoning.
  9. Lead lines are seen at the gingiva-tooth border or on long bone x-rays in lead poisoning.
  10. Prussian blue prevents absorption of thallium and is given orally at 250 mg/kg in divided doses.

📑 Table of Contents

📋 Figures in This Chapter

# Type Description
1 🖼 Figure Figure / Illustration

1. DEFINITION & OVERVIEW

  • Toxic metals (hereafter referred to simply as “metals”) pose a significant threat to health through low-level as well as high level environmental and occupational exposures.
  • One indication of their importance relative to other potential hazards is their ranking by the U.S. Agency for Toxic Substances and Disease Registry, which maintains an updated list of all hazards present in toxic waste sites according to their prevalence and the severity of their toxicity.
  • The first, second, third, and seventh hazards on the list are heavy metals: arsenic, lead, mercury, and cadmium, respectively.
  • All four are also listed by the World Health Organization as among the 10 chemicals of highest concern in relation to health, globally.
  • Metals are inhaled primarily as dusts and fumes (the latter defined as tiny particles generated by combustion).
  • Metal poisoning can also result from exposure to vapors (e.g., mercury vapor in creating dental amalgams).
  • When metals are ingested in contaminated food or drink or by hand-to-mouth activity (implicated especially in children), their gastrointestinal absorption varies greatly with the specific chemical form of the metal and the nutritional status of the host.
  • Once a metal is absorbed, blood is the main medium for its transport, with the precise kinetics dependent on diffusibility, protein binding, rates of biotransformation, availability of intracellular ligands, and other factors.
  • Some organs (e.g., bone, liver, and kidney) sequester metals in relatively high concentrations for years.
  • Most metals are excreted through renal clearance and gastrointestinal excretion; some proportion is also excreted through salivation, perspiration, exhalation, lactation, skin exfoliation, and loss of hair and nails.
  • The intrinsic stability of metals facilitates tracing and measurement in biologic material, although the clinical significance of the levels measured is not always clear.
  • Some metals, such as copper and selenium, are essential to normal metabolic function as trace elements but are toxic at high levels of exposure.
  • Others, such as lead and mercury, are xenobiotic and theoretically are capable of exerting toxic effects at any level of exposure.
  • Much research is currently focused on the contribution of low-level xenobiotic metal exposure to subtle changes in health, and/or increased risks of adverse events such as heart attacks, stroke, or cancer that may have significant public health consequences given the widespread nature of their exposures.
  • Metals are well-known to be able to cause toxicity through the inhibition of enzymes, damage to subcellular organelles and DNA, covalent modification of proteins, formation of reactive oxygen species, and displacement of essential metals in metal dependent proteins.
  • Recent research has also elucidated how metals may affect DNA methylation and other changes to the epigenome, thereby resulting in altered gene expression as well as the dysregulated expression of microRNAs.
  • Genetic factors, such as polymorphisms that encode for variant enzymes with altered properties in terms of metal binding, transport, and effects, may modify the impact of metals on health.
  • Nutritional status, comorbidities, and other factors can also contribute to variations in individual susceptibility to metal effects.
  • The most important component of treatment for metal toxicity is the recognition and termination of exposure.
  • Chelating agents are used to bind metals into stable cyclic compounds with relatively low toxicity and to enhance their excretion.
  • The principal chelating agents are dimercaprol (British anti-Lewisite [BAL]), ethylenediamine tetraacetic acid (EDTA), succimer (dimercaptosuccinic acid [DMSA]), and penicillamine; their specific use depends on the metal involved and the clinical circumstances.
  • For the most part, they are reserved for treating acute, symptomatic metal toxicity.

1.1 Classification of Toxic Metals

  • Heavy metals are ranked by the U.S. Agency for Toxic Substances and Disease Registry.
  • The World Health Organization lists them among the 10 chemicals of highest concern globally.
  • Essential trace elements (copper, selenium) vs. Xenobiotics (lead, mercury).
  • Essential trace elements are toxic at high levels of exposure.
  • Xenobiotics are theoretically capable of exerting toxic effects at any level of exposure.

2. EPIDEMIOLOGY

  • Arsenic, even at moderate levels of exposure, has been clearly linked with increased risks for cancer of the skin, bladder, renal pelvis, ureter, kidney, liver, and lung.
  • These risks appear to be modified by smoking, folate and selenium status, genetic traits (such as ability to methylate arsenic), and other factors.
  • Based on the accumulation of evidence, the American Heart Association concluded that low-level exposures to arsenic, lead, and cadmium are risk factors for hypertension, subclinical atherosclerosis, coronary artery stenosis, and calcification as well as ischemic heart disease and stroke, left ventricular hypertrophy and heart failure, and peripheral artery disease.
  • Recent studies in community-based populations have also generated strong evidence that arsenic exposure is a risk factor for lung function impairment, acute respiratory tract infections, respiratory symptoms, and nonmalignant lung disease mortality.
  • The association with cardiovascular disease may hold at levels of exposure in drinking water that are below the World Health Organization (WHO) provisional guideline value of 10 μg/L.
  • Evidence has also continued to build indicating that low-level arsenic is a likely cause of neurodevelopmental delays in children and likely contributes to the development of type 2 diabetes and possibly nonalcoholic fatty liver disease and cirrhosis.
  • Serious cadmium poisoning from the contamination of food and water by mining effluents in Japan contributed to the 1946 outbreak of “itai-itai” (“ouch-ouch”) disease, so named because of cadmium-induced bone toxicity that led to painful bone fractures.
  • Modest exposures from environmental contamination have been associated in a growing number of studies with lower bone density, higher incidence of fractures, and faster decline in height in both men and women, effects that may be related to cadmium’s calciuric and other toxic effects on the kidney.
  • Cadmium burdens have also been associated with an increased risk of long-term kidney graft failure, and there is evidence for synergy between the adverse impacts of cadmium and lead on kidney function.
  • Environmental exposures have also been linked to lower lung function (even after adjusting for smoking cigarettes, which contain cadmium).
  • The American Heart Association considers cadmium as a risk factor for cardiovascular disease and mortality, stroke, and heart failure.
  • Cadmium triggers pulmonary inflammation, and recent population-based studies of U.S. adults found that higher cadmium burdens are associated with higher mortality from influenza, pneumonia, and COVID-19.
  • The International Agency for Research on Cancer has classified cadmium as a known carcinogen, with evidence indicating it contributes to elevated risks of prostate, lung, breast, and endometrial cancer.
  • Overall, this growing body of research indicates that cadmium exposure is contributing significantly to morbidity and mortality rates in the general population.
  • Advances in our understanding of lead toxicity have recently benefited by the development of x-ray fluorescence (KXRF) instruments for making safe in vivo measurements of lead levels in bone, which, in turn, reflect cumulative exposure over many years, as opposed to blood lead levels, which mostly reflect recent exposure.
  • Higher levels of cumulative lead exposure in the general population are now well-established as a risk factor for chronic disease, even though blood lead levels have continued to decline in the general population over the past few decades following the removal of lead from gasoline, plumbing, solder in food cans, and other consumer products, with mean levels in the U.S. population now hovering in the 1–2 μg/dL range.
  • For example, higher bone lead levels measured by KXRF have been linked to increased risk of hypertension and accelerated declines in cognition.
  • Lead exposure at community levels has also been associated with increased risks of hearing loss, Parkinson’s disease, and amyotrophic lateral sclerosis.
  • Occupational levels of lead exposures have been consistently linked with adverse indices of sperm health, such as reduction in semen volume, sperm concentration, total sperm count, sperm vitality, and total sperm motility.
  • With respect to pregnancy-associated risks, high maternal bone lead levels were found to predict lower birth weight, head circumference, birth length, and neurodevelopmental performance in offspring by age 2 years.
  • Offspring have also been shown to have higher blood pressures at age 7–14 years, an age range at which higher blood pressures are known to predict an elevated risk of developing hypertension.
  • In a randomized trial, calcium supplementation (1200 mg daily) was found to significantly reduce the mobilization of lead from maternal bone into blood during pregnancy.
  • The toxicity of low-level organic mercury exposure (as manifested by neurobehavioral performance) is of increasing concern based on studies of the offspring of mothers who ingested mercury-contaminated fish.
  • With respect to whether the consumption of fish by women during pregnancy is good or bad for offspring neurodevelopment, balancing the trade-offs of the beneficial effects of the omega-3-fatty acids (FAs) in fish versus the adverse effects of mercury contamination in fish has led to some confusion and inconsistency in public health recommendations.
  • Overall, it would appear that it would be best for pregnant women to either limit fish consumption to those species that were known to be low in mercury contamination but high in omega-3-FAs (such as sardines or mackerel) or to avoid fish and obtain omega-3-FAs through supplements or other dietary sources.
  • Well-conducted studies have convincingly debunked the contention that ethyl mercury, used as a preservative in multiuse vaccines administered in early childhood, has played a significant role in causing neurodevelopmental problems such as autism.
  • With regard to adults, there is evidence that mercury exposure is associated with elevated markers of dyslipidemia and high-sensitivity C-reactive protein (a marker of chronic low-grade inflammation), but the direct evidence as to whether mercury exposure is associated with increased risk of hypertension and cardiovascular disease remains somewhat conflicting.
  • There is also some evidence that mercury exposure in the general population is associated with the development of diabetes, perturbations in markers of autoimmunity, and depression.
  • At this point, conclusions cannot be drawn and the clinical significance of these findings remains somewhat unclear.
  • Heavy metals pose risks to health that are especially burdensome in selected parts of the world.
  • For example, arsenic exposure from natural contamination of shallow tube wells inserted for drinking water is a major environmental problem for millions of residents in parts of Bangladesh and Western India.
  • Contamination was formerly considered only a problem with deep wells; however, the geology of this region allows most residents only a few alternatives for potable drinking water.
  • Arsenic contamination of drinking water is also a major problem in China, Argentina, Chile, Mexico, and some regions of the United States (Maine, New Hampshire, Massachusetts).
  • The global campaign to phase out leaded gasoline has concluded.
  • However, significant population exposures to lead remain, particularly in the United States with respect to older housing that contains lead paint or that receives drinking water through lead pipes, and evidence indicates that exposures are beginning to increase again in many low- and middle-income countries due to industrial pollution, the recycling of automobile batteries, electronic waste, mining, and variety of contaminated consumer products.
  • Populations living in the Arctic have been shown to have particularly high exposures to mercury and due to long-range transport patterns that concentrate mercury in the polar regions, as well as the traditional dependence of Arctic peoples on the consumption of fish and other wildlife that bioconcentrate in methylmercury.
  • Arsenic: Natural contamination of shallow tube wells (Bangladesh, Western India, China, Argentina, Chile, Mexico, US states).
  • Lead: Older housing (lead paint), lead pipes, recycling of automobile batteries, electronic waste, mining.
  • Mercury: Long-range transport patterns concentrating mercury in polar regions, consumption of fish and wildlife bioconcentrating methylmercury.
  • Cadmium: Mining effluents, food/water contamination.

2.2 Cardiovascular and Neurodevelopmental Risks

  • Arsenic: Hypertension, subclinical atherosclerosis, coronary artery stenosis, calcification, ischemic heart disease, stroke, LVH, heart failure, peripheral artery disease, lung function impairment, neurodevelopmental delays, type 2 diabetes, NAFLD, cirrhosis.
  • Cadmium: Hypertension, stroke, heart failure, pulmonary inflammation, mortality from influenza/pneumonia/COVID-19, prostate/lung/breast/endometrial cancer.
  • Lead: Hypertension, coronary artery calcifications, increased cardiovascular morbidity and mortality, hearing loss, Parkinson’s disease, amyotrophic lateral sclerosis, reduced sperm health, lower birth weight, neurodevelopmental performance issues in offspring.

3. ETIOLOGY & PATHOPHYSIOLOGY

  • Metals are inhaled primarily as dusts and fumes (the latter defined as tiny particles generated by combustion).
  • Metal poisoning can also result from exposure to vapors (e.g., mercury vapor in creating dental amalgams).
  • When metals are ingested in contaminated food or drink or by hand-to-mouth activity (implicated especially in children), their gastrointestinal absorption varies greatly with the specific chemical form of the metal and the nutritional status of the host.
  • Once a metal is absorbed, blood is the main medium for its transport, with the precise kinetics dependent on diffusibility, protein binding, rates of biotransformation, availability of intracellular ligands, and other factors.
  • Some organs (e.g., bone, liver, and kidney) sequester metals in relatively high concentrations for years.
  • Most metals are excreted through renal clearance and gastrointestinal excretion; some proportion is also excreted through salivation, perspiration, exhalation, lactation, skin exfoliation, and loss of hair and nails.
  • The intrinsic stability of metals facilitates tracing and measurement in biologic material, although the clinical significance of the levels measured is not always clear.
  • Some metals, such as copper and selenium, are essential to normal metabolic function as trace elements but are toxic at high levels of exposure.
  • Others, such as lead and mercury, are xenobiotic and theoretically are capable of exerting toxic effects at any level of exposure.
  • Metals are well-known to be able to cause toxicity through the inhibition of enzymes, damage to subcellular organelles and DNA, covalent modification of proteins, formation of reactive oxygen species, and displacement of essential metals in metal dependent proteins.
  • Recent research has also elucidated how metals may affect DNA methylation and other changes to the epigenome, thereby resulting in altered gene expression as well as the dysregulated expression of microRNAs.
  • Genetic factors, such as polymorphisms that encode for variant enzymes with altered properties in terms of metal binding, transport, and effects, may modify the impact of metals on health.
  • Nutritional status, comorbidities, and other factors can also contribute to variations in individual susceptibility to metal effects.

3.1 Mechanisms of Toxicity

  • Enzyme inhibition.
  • Damage to subcellular organelles and DNA.
  • Covalent modification of proteins.
  • Formation of reactive oxygen species.
  • Displacement of essential metals in metal dependent proteins.
  • DNA methylation and epigenome changes.
  • Dysregulated expression of microRNAs.

3.2 Specific Metal Metabolism

  • Arsenic: Organic arsenic (arsenobetaine, arsenocholine) is ingested in seafood and fish, but is nontoxic; inorganic arsenic is readily absorbed (lung and GI); sequesters in liver, spleen, kidneys, lungs, and GI tract; residues persist in skin, hair, and nails; biomethylation results in detoxification, but this process saturates.
  • Cadmium: Absorbed through ingestion or inhalation; bound by metallothionein, filtered at the glomerulus, reabsorbed by proximal tubules (thus, minor excreted). Biologic half-life: 10–30 y. Binds to cellular sulfhydryl groups, competes with zinc, calcium for binding sites. Concentrates in liver and kidneys.
  • Lead: Absorbed through ingestion or inhalation; organic lead (e.g., tetraethyl lead) absorbed dermally. In blood, 95–99% sequestered in RBCs—thus, must measure lead in whole blood (not serum). Distributed widely in soft tissue, with half-life ~30 days; 15% of dose sequestered in bone with half-life of >20 years. Excreted mostly in urine, but also appears in other fluids including breast milk. Interferes with mitochondrial oxidative phosphorylation, ATPases, calcium-dependent messengers; enhances oxidation and cell apoptosis.
  • Mercury: Elemental mercury (Hg) is not well absorbed; however, it will volatilize into highly absorbable vapor. Inorganic mercury is absorbed through the gut and skin. Organic mercury is well absorbed through inhalation and ingestion. Elemental and organic mercury cross the blood-brain barrier and placenta. Mercury is excreted in urine and feces and has a half-life of ~60 days; binds to metallothionein, which provides some detoxification benefit. Mercury binds sulfhydryl groups and interferes with a wide variety of critical enzymatic processes.

4. CLINICAL FEATURES

  • Arsenic: Acute arsenic poisoning results in necrosis of intestinal mucosa with hemorrhagic gastroenteritis, fluid loss, hypotension, delayed cardiomyopathy, acute tubular necrosis, and hemolysis. Chronic arsenic exposure causes diabetes, vasospasm, ischemic heart disease, peripheral vascular insufficiency and gangrene, peripheral neuropathy, and cancer of skin, lung, liver (angiosarcoma), bladder, and kidney. Lethal dose: 120–200 mg (adults); 2 mg/kg (children).
  • Cadmium: Acute cadmium inhalation causes pneumonitis after 4–24 h; acute dyspnea, cyanosis, fever, tachycardia, nausea, noncardiogenic pulmonary edema. With ingestion: nausea, vomiting, cramps, diarrhea. Chronic exposure causes anosmia, yellowing of teeth, emphysema, bone pain, fractures with osteomalacia. Chronic exposure causes lower bone density, higher incidence of fractures, faster decline in height, ischemic heart disease and stroke, lung, prostate, and kidney cancers.
  • Lead: Acute exposure with blood lead levels (BPb) of >60–80 μg/dL can cause impaired neurotransmission and neuronal cell death (with central and peripheral nervous system effects); impaired hematopoiesis and renal tubular dysfunction. At higher levels of exposure (e.g., BPb >80–120 μg/dL), acute encephalopathy with convulsions, coma, and death may occur. Subclinical exposures in children (BPb 25–60 μg/dL) are associated with anemia; mental retardation; and deficits in language, motor function, balance, hearing, behavior, and school performance. Impairment of IQ appears to occur at even lower levels of exposure with no measurable threshold above the limit of detection in most assays of 1 μg/dL. In adults, chronic subclinical exposures (BPb >40 μg/dL) are associated with an increased risk of anemia, demyelinating peripheral neuropathy (mainly motor), impairments of reaction time and hearing, accelerated declines in cognition, hypertension, ECG conduction delays, hypertension, higher risk of cardiovascular disease and death, interstitial nephritis and chronic renal failure, diminished sperm counts, and spontaneous abortions.
  • Mercury: Acute inhalation of Hg vapor causes pneumonitis and noncardiogenic pulmonary edema leading to death. Chronic exposure to metallic mercury vapor produces a characteristic mercurial erethism: excitability, memory loss, insomnia, timidity, and delirium (“mad as a hatter”). On neurobehavioral tests: decreased motor speed, visual scanning, verbal and visual memory, visuomotor coordination. Lower exposures impair renal function, motor speed, memory, coordination. Acute ingestion of inorganic mercury causes gastroenteritis, the nephritic syndrome, or acute renal failure, hypertension, tachycardia, and cardiovascular collapse, with death at a dose of 10–42 mg/kg. Chronic inorganic mercury exposure causes CNS toxicity (mercurial erethism), lower exposures impair renal function, motor speed, memory, coordination. Children exposed to mercury in any form may develop acrodynia (“pink disease”): flushing, itching, swelling, excessive salivation or perspiration, irritability, weakness, morbilliform rashes, desquamation of palms and soles. Chronic inorganic mercury exposure causes CNS toxicity (mercurial erethism), lower exposures impair renal function, motor speed, memory, coordination.
  • Other Metals: Aluminum contributes to the encephalopathy in patients with severe renal disease, who are undergoing dialysis. High levels of aluminum are found in the neurofibrillary tangles in the cerebral cortex and hippocampus of patients with Alzheimer’s disease, as well as in the drinking water and soil of areas with an unusually high incidence of Alzheimer’s. Hexavalent chromium is corrosive and sensitizing. Workers in the chromate and chrome pigment production industries have consistently had a greater risk of lung cancer. The introduction of cobalt chloride as a fortifier in beer led to outbreaks of fatal cardiomyopathy among heavy consumers, a condition that has also recently been reported in conjunction with the cobalt exposure associated with metal implants used in hip arthroplasty. Occupational exposure (e.g., of miners, dry-battery manufacturers, and arc welders) to manganese (Mn) can cause a parkinsonian syndrome within 1–2 years, including gait disorders; postural instability; a masked, expressionless face; tremor; and psychiatric symptoms. In contrast to typical cases of Parkinson’s disease, manganese-induced parkinsonism is nonresponsive to treatment with L-dopa. With the introduction of methylcyclopentadienyl manganese tricarbonyl (MMT) as a gasoline additive, there is concern for the toxic potential of environmental manganese exposure. Some epidemiologic studies have found an association between the prevalence of parkinsonian disorders and estimated manganese exposures emitted by local ferroalloy industries; others have found evidence suggesting that manganese may interfere with early childhood neurodevelopment in ways similar to that of lead. Manganese toxicity is clearly associated with dopaminergic dysfunction, and its toxicity is likely influenced by age, gender, ethnicity, genetics, and preexisting medical conditions. Nickel exposure induces an allergic response, and inhalation of nickel compounds with low aqueous solubility (e.g., nickel subsulfide and nickel oxide) in occupational settings is associated with an increased risk of lung cancer. Overexposure to selenium may cause local irritation of the respiratory system and eyes, gastrointestinal irritation, liver inflammation, loss of hair, depigmentation, and peripheral nerve damage. Workers exposed to certain organic forms of tin (particularly trimethyl and triethyl derivatives) have developed psychomotor disturbances, including tremor, convulsions, hallucinations, and psychotic behavior. Thallium, which is a component of some insecticides, metal alloys, and fireworks, is absorbed through the skin as well as by ingestion and inhalation. Severe poisoning follows a single ingested dose of >1 g or >8 mg/kg. Nausea and vomiting, abdominal pain, and hematemesis precede confusion, psychosis, organic brain syndrome, and coma. Thallium is radiopaque.

4.1 Acute vs. Chronic Toxicity

  • Arsenic: Acute (GI necrosis, cardiomyopathy, ATN, hemolysis) vs. Chronic (Diabetes, vasospasm, neuropathy, cancer).
  • Cadmium: Acute (Pneumonitis, GI) vs. Chronic (Osteomalacia, kidney failure, cancer).
  • Lead: Acute (Encephalopathy, convulsions) vs. Chronic (Neuropathy, anemia, renal failure, CV disease).
  • Mercury: Acute (Pneumonitis, GI) vs. Chronic (Erethism, renal, fetal).
  • Other Metals: Aluminum (Dialysis encephalopathy), Chromium (Lung cancer), Cobalt (Cardiomyopathy), Manganese (Parkinsonism), Nickel (Lung cancer), Selenium (Irritation), Tin (Psychomotor), Thallium (Coma).

4.2 Specific Clinical Signs

  • Mees' lines: Transverse white striae of the fingernails (Arsenic).
  • Lead lines: At the gingiva-tooth border or on long bone x-rays (Lead).
  • Acrodynia: Flushing, itching, swelling, excessive salivation or perspiration, irritability, weakness, morbilliform rashes, desquamation of palms and soles (Mercury).
  • Pink disease: Flushing, itching, swelling, excessive salivation or perspiration, irritability, weakness, morbilliform rashes, desquamation of palms and soles (Mercury).
  • Mad as a hatter: Excitability, memory loss, insomnia, timidity, and delirium (Mercury).
  • Basophilic stippling: Lab test finding (Lead).
  • Elevated blood protoporphyrin level: Lab test finding (Lead).

5. DIFFERENTIAL DIAGNOSIS

  • Heavy metal poisoning must be distinguished from other causes of similar clinical presentations.
  • Arsenic: Differentiate from other causes of GI necrosis, cardiomyopathy, and neuropathy.
  • Cadmium: Differentiate from other causes of osteomalacia, kidney failure, and lung cancer.
  • Lead: Differentiate from other causes of anemia, neuropathy, and cognitive decline.
  • Mercury: Differentiate from other causes of erethism, renal failure, and fetal neurotoxicity.
  • Other Metals: Differentiate from other causes of encephalopathy (Aluminum), lung cancer (Chromium, Nickel), cardiomyopathy (Cobalt), parkinsonism (Manganese), and psychosis (Thallium, Tin).
  • Key distinguishing features include specific exposure history, characteristic clinical signs (Mees' lines, Lead lines), and specific lab findings (elevated blood/urine metal levels, specific ECG changes, basophilic stippling).

5.1 Distinguishing Features by Metal

  • Arsenic: GI necrosis, Mees' lines, ECG changes (QRS broadening, QT prolongation).
  • Cadmium: Osteomalacia, kidney failure, lung cancer, anosmia.
  • Lead: Anemia, basophilic stippling, lead lines, cognitive decline, hypertension.
  • Mercury: Erethism, tremor, renal failure, acrodynia.
  • Aluminum: Dialysis encephalopathy.
  • Chromium: Lung cancer (hexavalent).
  • Cobalt: Cardiomyopathy.
  • Manganese: Parkinsonism (nonresponsive to L-dopa).
  • Nickel: Lung cancer, allergic response.
  • Selenium: Irritation, liver inflammation, hair loss.
  • Tin: Psychomotor disturbances.
  • Thallium: Coma, psychosis, radiopaque.

6. INVESTIGATIONS & DIAGNOSIS

  • Diagnosis relies on identification of exposure sources and specific lab/imaging findings.
  • Arsenic: Radiopaque sign on abdominal x-ray; ECG–QRS broadening, QT prolongation, ST depression, T-wave flattening; 24-h urinary arsenic >67 μmol/d or 50 μg/d; (no seafood × 24 h); if recent exposure, serum arsenic >0.9 μmol/L (7 μg/dL). High arsenic in hair or nails.
  • Cadmium: Urinary cadmium >100 nmol/L (10 μg/g creatinine) or >750 μg/g creatinine (but urinary β-microglobulin also increased in other renal diseases such as pyelonephritis). Urinary cadmium >500 nmol/L (5 μg/dL).
  • Lead: Identification and correction of exposure sources are critical. In the United States, most states ask or require primary care physicians and/or laboratories to report all BPbs to the appropriate health agency. In the highly exposed individual with symptoms, chelation is recommended with oral DMSA (succimer); if acutely toxic, hospitalization and IV or IM chelation with ethylenediaminetetraacetic acid calcium disodium (CaEDTA) may be required, with the addition of dimercaprol to prevent worsening of encephalopathy. Screening of all U.S. children when they begin to crawl (~6 months) is recommended by the CDC; source identification and intervention is begun if the BPb >3.5 μg/dL. In adults, acute exposure causes similar symptoms as in children as well as headaches, arthralgias, myalgias, depression, impaired short-term memory, loss of libido. Physical examination may reveal a “lead line” at the gingiva-tooth border, pallor, wrist drop, and cognitive dysfunction (e.g., declines on the mini-mental state exam); lab tests may reveal a normocytic, normochromic anemia, basophilic stippling, an elevated blood protoporphyrin level (free erythrocyte or zinc), and motor delays on nerve conduction. U.S. OSHA requires regular testing of lead-exposed workers with removal if BPb >40 μg/dL. Newer guidelines have been proposed recommending that BPb be maintained at 20 μg/dL, and monitoring of cumulative exposure parameters.
  • Mercury: Children exposed to mercury in any form may develop acrodynia (“pink disease”). Chronic inorganic mercury exposure causes CNS toxicity (mercurial erethism), lower exposures impair renal function, motor speed, memory, coordination. Mild exposures during pregnancy (from fish consumption) are associated with declines in neurobehavioral performance in offspring. Organic mercury exposure is best measured by levels in blood (if recent) or hair (if chronic); CNS toxicity in children may derive from fetal exposures associated with maternal hair Hg >30 nmol/g (6 μg/g).
  • Other Metals: Aluminum (High levels in neurofibrillary tangles), Chromium (Lung cancer risk), Cobalt (Cardiomyopathy), Manganese (Parkinsonism), Nickel (Lung cancer), Selenium (Irritation), Tin (Psychomotor), Thallium (Radiopaque).

6.1 Diagnostic Criteria and Cutoffs

  • Arsenic: 24-h urinary arsenic >67 μmol/d or 50 μg/d; serum arsenic >0.9 μmol/L (7 μg/dL) if recent exposure.
  • Cadmium: Urinary cadmium >100 nmol/L (10 μg/g creatinine) or >750 μg/g creatinine.
  • Lead: BPb >80 μg/dL (acute encephalopathy); BPb >60–80 μg/dL (impaired neurotransmission); BPb >40 μg/dL (subclinical declines in IQ); BPb >3.5 μg/dL (intervention recommended).
  • Mercury: Hair Hg >30 nmol/g (6 μg/g) for CNS toxicity in children.

6.2 Imaging and Lab Findings

  • Arsenic: Radiopaque sign on abdominal x-ray.
  • Lead: Lead lines on long bone x-rays; epiphyseal plate “lead lines” on primary care x-rays.
  • Lead: Normocytic, normochromic anemia; basophilic stippling; elevated blood protoporphyrin level.
  • Mercury: CNS toxicity measured by blood (recent) or hair (chronic).
  • Thallium: Radiopaque.

7. MANAGEMENT & TREATMENT

  • The most important component of treatment for metal toxicity is the recognition and termination of exposure.
  • Chelating agents are used to bind metals into stable cyclic compounds with relatively low toxicity and to enhance their excretion.
  • The principal chelating agents are dimercaprol (British anti-Lewisite [BAL]), ethylenediamine tetraacetic acid (EDTA), succimer (dimercaptosuccinic acid [DMSA]), and penicillamine; their specific use depends on the metal involved and the clinical circumstances.
  • For the most part, they are reserved for treating acute, symptomatic metal toxicity.
  • Activated charcoal does not bind metals and thus is of limited usefulness in cases of acute metal ingestion.
  • Arsenic: If acute ingestion, ipecac to induce vomiting, gastric lavage, activated charcoal with a cathartic. Supportive care in ICU. Dimercaprol 3–5 mg/kg IM q4h × 2 days; q6h × 1 day, then q12h × 10 days; alternative: oral succimer.
  • Cadmium: There is no effective treatment for cadmium poisoning (chelation not useful; dimercaprol can exacerbate nephrotoxicity). Avoidance of further exposure, supportive therapy, vitamin D for osteomalacia.
  • Lead: Identification and correction of exposure sources are critical. In the United States, most states ask or require primary care physicians and/or laboratories to report all BPbs to the appropriate health agency. In the highly exposed individual with symptoms, chelation is recommended with oral DMSA (succimer); if acutely toxic, hospitalization and IV or IM chelation with ethylenediaminetetraacetic acid calcium disodium (CaEDTA) may be required, with the addition of dimercaprol to prevent worsening of encephalopathy. A large multicenter randomized trial of chelation showed no improvement in measures of intelligence among children with asymptomatic lead exposure (e.g., BPb 20–40 μg/dL). It is possible but remains unclear whether chelation among adults with chronic lead exposure may improve cardiovascular outcomes. Correction of dietary deficiencies in iron, calcium, magnesium, and zinc will lower lead absorption and may also improve toxicity. Vitamin C is a weak but natural chelating agent. Calcium supplements (1200 mg at bedtime) have been shown to lower blood lead levels in pregnant women.
  • Mercury: Treat acute ingestion of mercuric salts with induced emesis or gastric lavage and polythiol resins (to bind mercury in the GI tract). Chelate with dimercaprol (up to 24 mg/kg per day IM in divided doses), DMSA (succimer), or penicillamine, with 5-day courses separated by several days of rest. If renal failure occurs, treat with peritoneal dialysis, hemodialysis, complexing hemodialysis and extracorporeal regional complexing hemodialysis and succimer. High exposure during pregnancy result in a >20-μg increase in 24-h urine after a 2-g dose of succimer.
  • Other Metals: Aluminum (No specific chelation mentioned for dialysis encephalopathy in text). Chromium (No specific treatment mentioned). Cobalt (No specific treatment mentioned). Manganese (No specific treatment mentioned). Nickel (No specific treatment mentioned). Selenium (No specific treatment mentioned). Tin (No specific treatment mentioned). Thallium: Induced emesis or gastric lavage is indicated within 4–6 h of acute ingestion; Prussian blue prevents absorption and is given orally at 250 mg/kg in divided doses. Unlike other types of metal poisoning, thallium poisoning may be less severe when activated charcoal is used to interrupt its enterohepatic circulation. Other measures include forced diuresis, treatment with potassium chloride (which promotes renal excretion of thallium), and peritoneal dialysis. Chelation therapy remains the treatment of choice for most toxic metals in the setting of severe acute clinical poisoning. However, the use of chelation for treating chronic diseases remains controversial, in part because of the lack of evidence from rigorous randomized clinical trials. One area for which there is moderate evidence is the use of chelation in patients with higher than average levels of accumulated lead burdens as a means of improving kidney function. The results from a series of randomized trials conducted in Taiwan suggest that among individuals with mildly elevated lead burdens (defined as between 150 and 600 μg of lead per 72-h urine upon an EDTA mobilization test [1 g EDTA]), weekly calcium disodium EDTA chelation treatments for between 2 and 27 months can improve renal function outcomes, both individuals with and without type 2 diabetes. The Trial to Assess Chelation Therapy (TACT-1), a multicenter, double-blind, placebo-controlled, prospective randomized trial funded by the National Institutes of Health of 1708 patients aged ≥50 years who had experienced a myocardial infarction (MI), found that a protocol of repeated intravenous chelation with disodium EDTA, compared with placebo, modestly but significantly reduced the risk of adverse cardiovascular outcomes, many of which were revascularization procedures. The effect was particularly pronounced among those with concurrent diabetes. However, the trial did not include rigorous measures of exposure to lead or other metals or any selection criteria based on metals exposure. By contrast, the recently released results of the TACT-2 trial, which reproduced the TACT-1 protocol with the addition of measures of metals, did not show benefit. However, the metals exposure levels among subjects was very low, likely reflecting the known decline in metals exposure over time in a study conducted more than 10 years after TACT-1, and it remains unclear whether chelation has a role in treating individuals with significant chronic metals exposure.

7.1 Chelating Agents and Dosing

  • Dimercaprol (BAL): 3–5 mg/kg IM q4h × 2 days; q6h × 1 day, then q12h × 10 days (Arsenic). Up to 24 mg/kg per day IM in divided doses (Mercury).
  • Succimer (DMSA): Oral alternative for Arsenic. 5-day courses separated by several days of rest (Mercury).
  • CaEDTA: IV or IM chelation for acute lead toxicity. Weekly calcium disodium EDTA chelation treatments for between 2 and 27 months (Lead).
  • Penicillamine: Alternative for Mercury.
  • Prussian blue: Prevents absorption of Thallium. Given orally at 250 mg/kg in divided doses.
  • Vitamin C: Weak but natural chelating agent (Lead).
  • Calcium supplements: 1200 mg at bedtime (Lead, pregnant women).
  • Potassium chloride: Promotes renal excretion of Thallium.

7.2 Supportive and Dietary Measures

  • Arsenic: Supportive care in ICU.
  • Cadmium: Avoidance of further exposure, supportive therapy, vitamin D for osteomalacia.
  • Lead: Correction of dietary deficiencies in iron, calcium, magnesium, and zinc will lower lead absorption and may also improve toxicity.
  • Mercury: Limit fish consumption to those species known to be low in mercury contamination but high in omega-3-FAs (such as sardines or mackerel) or to avoid fish and obtain omega-3-FAs through supplements or other dietary sources.
  • Thallium: Forced diuresis, peritoneal dialysis.

8. PROGNOSIS & COMPLICATIONS

  • Arsenic: Increased risks for cancer of the skin, bladder, renal pelvis, ureter, kidney, liver, and lung. Risks modified by smoking, folate and selenium status, genetic traits. Low-level exposures are risk factors for hypertension, subclinical atherosclerosis, coronary artery stenosis, and calcification as well as ischemic heart disease and stroke, left ventricular hypertrophy and heart failure, and peripheral artery disease. Arsenic exposure is a risk factor for lung function impairment, acute respiratory tract infections, respiratory symptoms, and nonmalignant lung disease mortality. Low-level arsenic is a likely cause of neurodevelopmental delays in children and likely contributes to the development of type 2 diabetes and possibly nonalcoholic fatty liver disease and cirrhosis.
  • Cadmium: Associated with lower bone density, higher incidence of fractures, faster decline in height, ischemic heart disease and stroke, lung, prostate, and kidney cancers. Cadmium exposure is contributing significantly to morbidity and mortality rates in the general population. Cadmium burdens have also been associated with an increased risk of long-term kidney graft failure, and there is evidence for synergy between the adverse impacts of cadmium and lead on kidney function.
  • Lead: Higher bone lead levels measured by KXRF have been linked to increased risk of hypertension and accelerated declines in cognition. Lead exposure at community levels has also been associated with increased risks of hearing loss, Parkinson’s disease, and amyotrophic lateral sclerosis. Occupational levels of lead exposures have been consistently linked with adverse indices of sperm health, such as reduction in semen volume, sperm concentration, total sperm count, sperm vitality, and total sperm motility. With respect to pregnancy-associated risks, high maternal bone lead levels were found to predict lower birth weight, head circumference, birth length, and neurodevelopmental performance in offspring by age 2 years. Offspring have also been shown to have higher blood pressures at age 7–14 years, an age range at which higher blood pressures are known to predict an elevated risk of developing hypertension.
  • Mercury: High exposure during pregnancy result in a >20-μg increase in 24-h urine after a 2-g dose of succimer. High exposure during pregnancy causes derangement of fetal neuronal migration resulting in severe mental retardation. Organic mercury exposure is best measured by levels in blood (if recent) or hair (if chronic); CNS toxicity in children may derive from fetal exposures associated with maternal hair Hg >30 nmol/g (6 μg/g). Mild exposures during pregnancy (from fish consumption) are associated with declines in neurobehavioral performance in offspring.
  • Other Metals: Aluminum (Encephalopathy in dialysis patients). Chromium (Lung cancer). Cobalt (Cardiomyopathy). Manganese (Parkinsonism). Nickel (Lung cancer). Selenium (Irritation, liver inflammation). Tin (Psychomotor disturbances). Thallium (Coma, psychosis).

8.1 Cardiovascular and Renal Complications

  • Arsenic: Hypertension, subclinical atherosclerosis, coronary artery stenosis, calcification, ischemic heart disease, stroke, LVH, heart failure, peripheral artery disease.
  • Cadmium: Hypertension, stroke, heart failure, ischemic heart disease, kidney graft failure, synergy with lead on kidney function.
  • Lead: Hypertension, coronary artery calcifications, increased cardiovascular morbidity and mortality, interstitial nephritis, chronic renal failure, diminished sperm counts, spontaneous abortions.

8.2 Neurodevelopmental and Cancer Risks

  • Arsenic: Cancer of skin, bladder, renal pelvis, ureter, kidney, liver, lung. Neurodevelopmental delays in children. Type 2 diabetes, NAFLD, cirrhosis.
  • Cadmium: Lung, prostate, kidney, breast, endometrial cancer. Lower bone density, higher incidence of fractures.
  • Lead: Mental retardation, deficits in language, motor function, balance, hearing, behavior, school performance. Impairment of IQ. Parkinson’s disease, amyotrophic lateral sclerosis.
  • Mercury: Severe mental retardation (high exposure during pregnancy). Declines in neurobehavioral performance in offspring.

9. SPECIAL CONSIDERATIONS

  • Pregnancy: Pregnant women should either limit fish consumption to those species that were known to be low in mercury contamination but high in omega-3-FAs (such as sardines or mackerel) or to avoid fish and obtain omega-3-FAs through supplements or other dietary sources. Calcium supplementation (1200 mg daily) was found to significantly reduce the mobilization of lead from maternal bone into blood during pregnancy. Calcium supplements (1200 mg at bedtime) have been shown to lower blood lead levels in pregnant women.
  • Pediatrics: Screening of all U.S. children when they begin to crawl (~6 months) is recommended by the CDC; source identification and intervention is begun if the BPb >3.5 μg/dL. A large multicenter randomized trial of chelation showed no improvement in measures of intelligence among children with asymptomatic lead exposure (e.g., BPb 20–40 μg/dL).
  • Elderly: TACT-1 trial included patients aged ≥50 years who had experienced a myocardial infarction (MI).
  • Renal Impairment: Cadmium burdens have also been associated with an increased risk of long-term kidney graft failure. If renal failure occurs in mercury poisoning, treat with peritoneal dialysis, hemodialysis, complexing hemodialysis and extracorporeal regional complexing hemodialysis and succimer. Aluminum contributes to the encephalopathy in patients with severe renal disease, who are undergoing dialysis.
  • Occupational: U.S. OSHA requires regular testing of lead-exposed workers with removal if BPb >40 μg/dL. Newer guidelines have been proposed recommending that BPb be maintained at 20 μg/dL, and monitoring of cumulative exposure parameters. Occupational exposure (e.g., of miners, dry-battery manufacturers, and arc welders) to manganese (Mn) can cause a parkinsonian syndrome within 1–2 years. Workers in the chromate and chrome pigment production industries have consistently had a greater risk of lung cancer. The introduction of cobalt chloride as a fortifier in beer led to outbreaks of fatal cardiomyopathy among heavy consumers, a condition that has also recently been reported in conjunction with the cobalt exposure associated with metal implants used in hip arthroplasty.

9.1 Pregnancy and Fetal Exposure

  • Fish consumption: Limit to low mercury species (sardines, mackerel) or avoid fish and obtain omega-3-FAs through supplements.
  • Lead: Calcium supplementation (1200 mg daily) reduces mobilization of lead from maternal bone into blood during pregnancy.
  • Mercury: High exposure during pregnancy causes derangement of fetal neuronal migration resulting in severe mental retardation.
  • Vaccines: Well-conducted studies have convincingly debunked the contention that ethyl mercury, used as a preservative in multiuse vaccines administered in early childhood, has played a significant role in causing neurodevelopmental problems such as autism.

9.2 Occupational Safety

  • Lead: U.S. OSHA requires regular testing of lead-exposed workers with removal if BPb >40 μg/dL.
  • Manganese: Occupational exposure (miners, dry-battery manufacturers, arc welders) can cause parkinsonian syndrome within 1–2 years.
  • Chromium: Workers in chromate and chrome pigment production industries have consistently had a greater risk of lung cancer.
  • Cobalt: Introduction of cobalt chloride as a fortifier in beer led to outbreaks of fatal cardiomyopathy among heavy consumers.
  • Nickel: Inhalation of nickel compounds with low aqueous solubility in occupational settings is associated with an increased risk of lung cancer.

10. KEY PEARLS & CLINICAL TRAPS

  • Activated charcoal does not bind metals and thus is of limited usefulness in cases of acute metal ingestion.
  • The first, second, third, and seventh hazards on the U.S. Agency for Toxic Substances and Disease Registry list are heavy metals: arsenic, lead, mercury, and cadmium, respectively.
  • Low-level arsenic exposure is a risk factor for hypertension, subclinical atherosclerosis, coronary artery stenosis, and calcification.
  • Cadmium exposure is a risk factor for cardiovascular disease, mortality, stroke, and heart failure.
  • Lead exposure has no measurable threshold for IQ impairment; impairment appears at levels down to 1 μg/dL.
  • Mercury binds sulfhydryl groups and interferes with a wide variety of critical enzymatic processes.
  • Chelation therapy for chronic lead exposure remains controversial; TACT-1 showed benefit in high lead burdens, TACT-2 showed no benefit in low exposure.
  • Mees' lines are transverse white striae of the fingernails seen in arsenic poisoning.
  • Lead lines are seen at the gingiva-tooth border or on long bone x-rays in lead poisoning.
  • Prussian blue prevents absorption of thallium and is given orally at 250 mg/kg in divided doses.

10.1 Diagnostic Pitfalls

  • Activated charcoal is of limited usefulness in cases of acute metal ingestion.
  • Blood lead levels mostly reflect recent exposure; bone lead levels reflect cumulative exposure over many years.
  • Urinary cadmium >100 nmol/L (10 μg/g creatinine) or >750 μg/g creatinine (but urinary β-microglobulin also increased in other renal diseases such as pyelonephritis).
  • Screening of all U.S. children when they begin to crawl (~6 months) is recommended by the CDC; source identification and intervention is begun if the BPb >3.5 μg/dL.

10.2 Treatment Controversies

  • Chelation therapy for chronic diseases remains controversial.
  • Use of chelation for treating chronic diseases remains controversial, in part because of the lack of evidence from rigorous randomized clinical trials.
  • TACT-1 showed benefit in high lead burdens, TACT-2 showed no benefit in low exposure.
  • It is possible but remains unclear whether chelation among adults with chronic lead exposure may improve cardiovascular outcomes.

Figures & Illustrations

Reproduced from Harrison's 22nd Edition.

Figure 1

| Comprehensive Summary Table of Heavy Metal Poisoning: Sources, Metabolism,...

Caption: Figure 469-1 | Comprehensive Summary Table of Heavy Metal Poisoning: Sources, Metabolism, Toxicity, Diagnosis, and Treatment for Arsenic, Cadmium, Lead, and Mercury.

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.