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Heavy Metal Poisoning¶

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

Key Clinical Points¶

Activated charcoal does not bind metals and 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.
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.

1. DEFINITION & OVERVIEW¶

• Toxic Metals: Significant threat to health through both low-level environmental/occupational exposure and high-level acute exposure. • Regulatory Status: ◦ Ranked as top hazards by the U.S. Agency for Toxic Substances and Disease Registry (Arsenic, Lead, Mercury, Cadmium). ◦ Listed by the World Health Organization (WHO) as 10 chemicals of highest global concern. • Classification: ◦ Essential Trace Elements: Copper, Selenium (toxic only at high levels). ◦ Xenobiotics: Lead, Mercury (theoretically capable of exerting toxic effects at any level of exposure).

1.1 Classification of Toxic Metals¶

• Essential Trace Elements: Copper and Selenium; toxicity occurs only at high levels. • Xenobiotics: Lead and Mercury; theoretically capable of exerting toxic effects at any level of exposure.

2. EPIDEMIOLOGY¶

• Arsenic: ◦ Cancer risk: Skin, bladder, renal pelvis, ureter, kidney, liver, and lung. ◦ Cardiovascular (CV) risk: Hypertension, subclinical atherosclerosis, coronary artery stenosis, calcification, ischemic heart disease, stroke, left ventricular hypertrophy (LVH), heart failure, and peripheral artery disease (PAD). ◦ Other risks: Lung function impairment, acute respiratory tract infections, respiratory symptoms, nonmalignant lung disease mortality, neurodevelopmental delays in children, Type 2 diabetes, NAFLD, and cirrhosis. • Cadmium: ◦ Historical context: "Itai-itai" disease (1946) caused by bone toxicity leading to painful fractures. ◦ Clinical risk: Hypertension, stroke, heart failure, pulmonary inflammation, and mortality from influenza, pneumonia, and COVID-19. ◦ Cancer risk: Prostate, lung, breast, and endometrial cancer. • Lead: ◦ Cardiovascular: Hypertension, coronary artery calcifications, increased morbidity/mortality. ◦ Neurological: Hearing loss, Parkinson’s disease, amyotrophic lateral sclerosis (ALS). ◦ Reproductive: Reduced sperm health (volume, concentration, total count, viability, motility), lower birth weight, and impaired neurodevelopment in offspring. • Mercury: ◦ Neurobehavioral impacts in children; evidence of dyslipidemia and high-sensitivity C-reactive protein (hs-CRP) in adults.

2.1 Environmental Sources and Trends¶

• Arsenic: Smelting, microelectronics, wood preservatives, pesticides, herbicides, fungicides, deep-water wells (Bangladesh, Western India, China, Argentina, Chile, Mexico, USA), folk remedies, coal, and incineration products. • Lead: Manufacturing of batteries, crystal, ceramics; demolition/sanding of lead paint; stained glass; plumbing; contaminated spices/herbal remedies; recycling of batteries/e-waste. • Mercury: Long-range transport to polar regions; consumption of fish/wildlife (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, ALS, reduced sperm health, lower birth weight, neurodevelopmental performance issues in offspring.

3. ETIOLOGY & PATHOPHYSIOLOGY¶

• Exposure Routes: ◦ Inhalation: Dusts and fumes (small particles from combustion). ◦ Vapor: Mercury vapor in dental amalgams. ◦ Ingestion: Contaminated food/drink or hand-to-mouth activity (common in children). • Internal Transport & Storage: ◦ Blood is the primary transport medium. ◦ Sequestration: Bone, liver, and kidney store metals for years. ◦ Excretion: Renal clearance, gastrointestinal excretion, salivation, perspiration, exhalation, lactation, skin exfoliation, hair/nail loss. • Mechanisms of Toxicity: ◦ Enzyme inhibition; damage to subcellular organelles and DNA; covalent modification of proteins; formation of reactive oxygen species (ROS); displacement of essential metals in metal-dependent proteins. ◦ Epigenetic changes: Altered DNA methylation, dysregulated microRNAs. • Specific Metal Metabolism: ◦ Arsenic: Organic forms (arsenobetaine, arsenocholine) are non-toxic; Inorganic is readily absorbed (lung/GI); sequestered in liver, spleen, kidneys, lungs, and GI tract; biomethylation detoxifies but saturates. ◦ Cadmium: Bound by metallothionein; filtered at glomerulus but reabsorbed by proximal tubules (poorly excreted); half-life 10–30 years; binds sulfhydryl groups; competes with zinc/calcium. ◦ Lead: 95–99% sequestered in RBCs (must measure whole blood, not serum); half-life ~30 days in soft tissue; 15% in bone (>20 years); interferes with mitochondrial oxidative phosphorylation, ATPases, and calcium-dependent messengers; enhances oxidation/apoptosis. ◦ Mercury: Binds sulfhydryl groups; interferes with enzymatic processes.

4. CLINICAL FEATURES¶

• Arsenic: ◦ Acute: Necrosis of intestinal mucosa, hemorrhagic gastroenteritis, fluid loss, hypotension, delayed cardiomyopathy, acute tubular necrosis, hemolysis. ◦ Chronic: Diabetes, vasospasm, ischemic heart disease, peripheral vascular insufficiency/gangrene, peripheral neuropathy; cancers (skin, lung, liver [angiosarcoma], bladder, kidney). ◦ Signs: Nausea, vomiting, diarrhea, abdominal pain, delirium, coma, seizures; garlicky odor on breath; hyperkeratosis, hyperpigmentation, exfoliative dermatitis, Mees' lines. • Cadmium: ◦ Acute Inhalation: Pneumonitis (4–24 h), dyspnea, cyanosis, fever, tachycardia, noncardiogenic pulmonary edema. ◦ Acute Ingestion: Nausea, vomiting, cramps, diarrhea. ◦ Chronic: Anosmia, yellowing of teeth, emphysema, microcytic hypochromic anemia (unresponsive to iron), proteinuria, β-microglobulin increase, calciuria, renal failure, osteomalacia, fractures; lung/prostate/kidney cancers. • Lead: ◦ Acute (BPb >60–80 μg/dL): Impaired neurotransmission, neuronal cell death, impaired hematopoiesis, renal tubular dysfunction. ◦ High Exposure (BPb >80–120 μg/dL): Encephalopathy with convulsions, coma, and death. ◦ Subclinical (Children, BPb 25–60 μg/dL): Anemia, mental retardation, deficits in language, motor function, balance, hearing, behavior. ◦ Chronic (Adults, BPb >40 μg/dL): Anemia, demyelinating peripheral neuropathy (motor), impaired reaction time/hearing, accelerated cognitive decline, hypertension, ECG conduction delays, interstitial nephritis, renal failure, diminished sperm counts, spontaneous abortions. ◦ Physical Exam: "Lead line" at gingiva-tooth border, pallor, wrist drop; basophilic stippling on blood smear; elevated blood protoporphyrin (free erythrocyte or zinc).

4.1 Acute vs. Chronic Toxicity¶

• Arsenic: Acute (Gastrointestinal necrosis/hemorrhage) vs. Chronic (Cancer, cardiovascular disease, neuropathy). • Cadmium: Acute (Pneumonitis/Gastroenteritis) vs. Chronic (Osteomalacia, renal failure, cancer). • Lead: Acute (Encephalopathy at >80 μg/dL) vs. Chronic (IQ loss, anemia, hypertension).

5. DIFFERENTIAL DIAGNOSIS¶

• Arsenic Differentiation: Presence of Mees' lines, garlicky breath, and hyperkeratosis. • Lead Differentiation: "Lead line" at gingiva-tooth border; basophilic stippling; IQ decline in children without other symptoms. • Cadmium Differentiation: Anosmia, yellowing of teeth, emphysema, renal failure, osteomalacia.

6. INVESTIGATIONS & DIAGNOSIS¶

Arsenic Assessment:
Evaluate 24-h urinary arsenic: >67 μmol/d or 50 μg/d (no seafood × 24 h).
If recent exposure, measure serum arsenic: >0.9 μmol/L (7 μg/dL).
Examine hair and nails for high levels.
Imaging: Radiopaque sign on abdominal x-ray; ECG findings (QRS broadening, QT prolongation, T-wave flattening).
Cadmium Assessment:
Measure serum cadmium: >500 nmol/L (5 μg/dL) for recent exposure.
Measure urinary cadmium: >100 nmol/L (10 μg/g creatinine).
Measure urinary β-microglobulin: >750 μg/g creatinine.
Lead Assessment:
Measure blood lead (BPb) in whole blood (not serum).
Identify subclinical exposure in children: BPb 25–60 μg/dL.
Identify acute encephalopathy risk: BPb >80–120 μg/dL.
Assess IQ impairment: detectable at levels down to 1 μg/dL.
Laboratory markers: Basophilic stippling, elevated blood protoporphyrin (free erythrocyte or zinc).

7. MANAGEMENT & TREATMENT¶

Arsenic Management:
Acute ingestion: Ipecac to induce vomiting → gastric lavage → activated charcoal with a cathartic.
Support: Supportive care in ICU.
Chelation (Dimercaprol): 3–5 mg/kg IM q4h × 2 days; then q6h × 1 day; then q12h × 10 days.
Alternative chelation: Oral succimer.
Lead Management:
Source Control: Identify and correct exposure sources (primary step).
Symptomatic/High Exposure: Administer oral DMSA (succimer).
Acute Toxicity: Hospitalize patient; administer IV or IM chelation with ethylenediaminetetraacetic acid calcium disodium (CaEDTA) plus dimercaprol to prevent worsening of encephalopathy.
Pregnancy Prevention: Provide 1200 mg calcium at bedtime to lower blood lead levels in pregnant women.
Thallium Management:
Administer Prussian blue orally at 250 mg/kg in divided doses to prevent absorption.
General Support:
Vitamin C: Use as a weak but natural chelating agent.
Nutritional Correction: Correct deficiencies in iron, calcium, magnesium, and zinc to lower lead absorption.

8. PROGNOSIS & COMPLICATIONS¶

• Arsenic: Cancer (skin, lung, liver [angiosarcoma], bladder, kidney); cardiovascular failure; peripheral gangrene. • Cadmium: Chronic renal failure; osteomalacia and fractures; pulmonary inflammation. • Lead: Neurodevelopmental delay in children; hypertension; cardiovascular morbidity; impaired reproduction. • Mercury: CNS toxicity; renal impairment.

9. SPECIAL CONSIDERATIONS¶

• Pregnancy and Fetal Exposure: 1. Mercury: Balance omega-3 benefits vs. mercury risk; recommend low-mercury/high-omega-3 fish (sardines, mackerel) or supplements. 2. Lead: Calcium 1200 mg at bedtime reduces lead mobilization from bone to blood. • Occupational Safety: 1. Lead: OSHA requires reporting and removal if BPb >40 μg/dL; newer guidelines suggest removal if BPb >20 μg/dL.

10. KEY PEARLS & CLINICAL TRAPS¶

• Chelation Agents: Dimercaprol (BAL), EDTA, Succimer (DMSA), and Penicillamine. • Lead IQ Threshold: No measurable threshold for impairment above 1 μg/dL. • Arsenic Markers: Mees' lines (nails) and garlicky breath. • Cadmium Marker: β-microglobulin in urine as a marker of renal damage. • Thallium Treatment: Prussian blue (250 mg/kg). • Lead Source Control: Identification and correction of exposure sources is the critical first step.

Reference Tables¶

TABLE 469-1 Heavy Metals¶

Harrison's 22e, p.3700

MAIN SOURCES	METABOLISM	TOXICITY	DIAGNOSIS	TREATMENT
Arsenic
Smelting and microelectronics industries; wood preservatives, pesticides, herbicides, fungicides; contaminant of deep- water wells; folk remedies; and coal; incineration of these products.	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.	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).	Nausea, vomiting, diarrhea, abdominal pain, delirium, coma, seizures; garlicky odor on breath; hyperkeratosis, hyperpigmentation, exfoliative dermatitis, and Mees’ lines (transverse white striae of the fingernails); sensory and motor polyneuritis, distal weakness. 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.	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
Absorbed through ingestion or inhalation; bound by metallothionein, filtered at the glomerulus, but reabsorbed by proximal tubules (thus, poorly excreted). Biologic half-life: 10–30 y. Binds cellular sulfhydryl groups, competes with zinc, calcium for binding sites. Concentrates in liver and kidneys.	Acute cadmium inhalation causes pneumonitis after 4–24 h; acute ingestion causes gastroenteritis. Chronic exposure causes anosmia, yellowing of teeth, emphysema, minor LFT elevations, microcytic hypochromic anemia unresponsive to iron therapy, proteinuria, increased urinary β-microglobulin, 2 calciuria, leading to chronic renal failure, osteomalacia, and fractures, ischemic heart disease and stroke. Cadmium exposure now known to cause lung, prostate, and kidney cancers.	With inhalation: pleuritic chest pain, dyspnea, cyanosis, fever, tachycardia, nausea, noncardiogenic pulmonary edema. With ingestion: nausea, vomiting, cramps, diarrhea. Bone pain, fractures with osteomalacia. If recent exposure, serum cadmium >500 nmol/L (5 μg/dL). Urinary cadmium >100 nmol/L (10 μg/g creatinine) and/or urinary β-microglobulin 2 >750 μg/g creatinine (but urinary β-microglobulin also increased 2 in other renal diseases such as pyelonephritis).
Lead
Manufacturing of auto batteries, lead crystal, ceramics, fishing weights, etc.; demolition or sanding of lead-painted houses, bridges; stained glass making, plumbing, soldering; environmental exposure to paint chips, house dust (in homes built <1975), firing ranges (from bullet dust), food or water from improperly glazed ceramics or lead-contaminated cookware; lead pipes and plumbing; contaminated spices, herbal remedies, candies; exposure to environmental pollution from the combustion of leaded fuels, recycling of automobile batteries and electronic waste.	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.	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.	Abdominal pain, irritability, lethargy, anorexia, anemia, Fanconi’s syndrome, pyuria, azotemia in children with blood lead level (BPb) >80 μg/dL; may also see epiphyseal plate “lead lines” on long bone x-rays. Convulsions, coma at BPb >120 μg/dL. Clinically-apparent neurodevelopmental delays can be seen at BPb of 40–80 μg/dL with sub- clinical declines in IQ expected at lower levels of BPb down to 1 μg/dL. 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 <10 μg/dL, removal of workers if BPb >20 μg/dL, and monitoring of cumulative exposure parameters.	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.