Acute metal and metalloid toxicity is uncommon but can cause significant morbidity and mortality if unrecognized and inappropriately treated. Metals are chemical elements that possess three general properties: (1) they are a good conductor of heat and electricity, (2) they are able to form cations, and (3) they can combine with nonmetals through ionic bonds. The term heavy metal has a historical tradition in clinical medicine, but has been criticized by chemists as lacking in a precise definition or scientific merit. An alternative term, toxic metal, which also lacks firm definition, is sometimes used instead. In clinical toxicology, the following metals, noted in ascending atomic weight, are usually considered under the concept of “heavy” or “toxic” metal poisoning: beryllium, vanadium, cadmium, barium, osmium, mercury, thallium, and lead, with lead and mercury being the metals most clinically significant concerning human poisoning.

Metalloids are chemical elements with properties intermediate to those of metals and nonmetals. Although there is no precise definition, metalloids tend to have these two general properties: (1) they are semiconductors of electricity, and (2) they form amphoteric oxides. In order of ascending atomic weight, the following elements are generally considered metalloids: boron, silicon, germanium, arsenic, antimony, tellurium, and polonium; arsenic is the most clinically significant metalloid.

Exposure to either metals or nonmetals can be from (1) the pure element, (2) an organic compound containing the toxic element (defined as those compounds that contain carbon), or (3) an inorganic compound containing the element (defined as those that do not contain carbon). Depending on the metal or metalloid, potential toxicity is affected by which chemical form is responsible for the exposure.

Because of their effects on numerous enzymatic systems in the body, the metals and metalloids often present with protean manifestations primarily affecting five systems: neurologic, cardiovascular, GI, hematologic, and renal. Effects on the endocrine and reproductive systems are less clinically apparent. It is important to recognize an initial “index case” of metal poisoning to prevent others from being poisoned when the metal source is environmental or industrial (Table 203-1).

EPIDEMIOLOGY

Lead is the most common cause of chronic metal poisoning and remains a major environmental contaminant, especially in developing countries. Exposure to lead can occur from inhalation or ingestion, and both inorganic and organic forms of lead produce clinical toxicity. Nonpaint sources include foreign medications, herbal and dietary supplements, Ayurvedic medications, traditional remedies, metallic charms, and cosmetics, especially products from Asia and Africa.¹ Although no safe blood lead level has been identified, the Centers for Disease Control and Prevention reference value for an elevated level is ≥5 micrograms/dL (0.24 micromol/L).²

The United States has banned lead in household paints, gasoline, plumbing systems, food, and drink cans; created lead abatement programs; and enforced standards for industrial use of lead.^2,3 Elevated blood levels in children age 1 to 5 years old are associated with residence in urban dwellings, residence in dwellings built before 1974 (especially those built before 1946), poverty, non-Hispanic black race or ethnicity, and higher population density.⁴ Chronic lead exposure and toxicity in children is a significant public health problem because of the effect on intellectual development.⁵ Worldwide, 16% of all children are estimated to have lead levels >10 micrograms/dL (0.48 micromol/L). Common sources in low-income countries are substandard or marginal living conditions near landfills and industries such as smelters, mines, and refineries, and leaded gasoline. Child labor in highly polluted conditions is another source of exposure.⁴ In developing countries, informal recycling of used lead-acid batteries and processing of gold ore rich in lead have caused mass lead poisonings.^6,7

PHARMACOLOGY

Absorption of inorganic lead is usually via the respiratory and GI tracts; skin absorption is negligible. Dietary deficiencies in calcium, iron, copper, and zinc may contribute to increased GI absorption in children. There is usually minimal absorption of lead from bullets or shot lodged in bone or muscle, but increased absorption and toxicity have been reported when bullets or shot are in constant contact with body fluids, such as synovial fluid or cerebrospinal fluid. Absorption of organic lead can occur after inhalation, ingestion, and dermal exposure. Exposure to organic lead can occur from sniffing gasoline (see chapter 199, “Hydrocarbons and Volatile Substances”), which may contain tetraethyl lead (“leaded gasoline”). After absorption, tetraethyl lead is metabolized to inorganic lead and triethyl lead; the latter is responsible for the neurotoxicity from leaded gasoline.

Greater than 90% of the total body lead is stored in bone, where it easily exchanges with the blood. Lead can be transferred across the placenta, a process exacerbated by increased bone turnover during pregnancy. Excretion of lead occurs slowly; the biologic half-life of lead in bone has been estimated to be 30 years.

PATHOPHYSIOLOGY

Lead toxicity primarily affects the nervous, cardiovascular, hematopoietic, and renal systems. In the CNS, the toxic effects of lead include (1) injuries to astrocytes, with secondary damage to the microvasculature and resultant disruption of the blood–brain barrier, cerebral edema, and increased intracranial pressure; (2) decreases in cyclic adenosine monophosphate and protein phosphorylation, which contribute to memory and learning deficits; and (3) alteration with calcium homeostasis, which leads to spontaneous and uncontrolled neurotransmitter release.⁸ In the peripheral nervous system, lead causes primary segmental demyelination, followed by secondary axonal degeneration, mostly of the motor nerves.⁹

In the cardiovascular system, small but statistically significant increases in the prevalence of hypertension and atherosclerotic vascular disease are found in individuals with elevated blood lead levels.

In the hematopoietic system, lead interferes with porphyrin metabolism, which may contribute to lead-induced anemia. Coexisting iron deficiency may act synergistically with lead toxicity to produce a more profound anemia and, in children, may be more important than lead as the cause of a microcytic anemia. Hemolytic anemia also occurs as a result of inhibition of red blood cell pyrimidine 5ʹ-nucleotidase, an enzyme responsible for clearing cellular RNA degradation products.

In the kidney, lead affects the proximal tubule, producing Fanconi’s syndrome with aminoaciduria, glycosuria, phosphaturia, and renal tubular acidosis.¹⁰ Chronic interstitial nephritis and increased uric acid levels are due to increased tubular reabsorption of urate. Chronic lead toxicity has been linked to gout and chronic renal failure.

Lead adversely affects osteoblast and osteoclast function in bone. With chronic lead exposure, increased calcium deposition at growth plates may be seen as “lead lines” on radiographs of long bones. Lead-induced adverse effects on the reproductive system include increased fetal wastage, premature rupture of membranes, depressed sperm counts, abnormal or nonmotile sperm, and sterility.

CLINICAL FEATURES

Signs and symptoms of lead toxicity vary according to the type of exposure (acute vs chronic) and, to a lesser extent, according to the age of the individual and type of lead (inorganic vs organic) involved (Table 203-2). Young children are more susceptible than adults to the effects of lead. Encephalopathy, a major cause of morbidity and mortality, may begin dramatically with seizures and coma or develop indolently over weeks to months with decreased alertness and memory progressing to mania and delirium.¹¹ Encephalopathy due to lead poisoning typically occurs in toddlers age 15 to 30 months old with blood lead levels >100 micrograms/dL (4.8 micromol/L) but has been reported with blood lead levels of 70 micrograms/dL (3.4 micromol/L) or lower.

GI and hematologic manifestations occur more frequently with acute than with chronic poisoning, and the colicky abdominal pains may be associated with concurrent hemolysis. Patients may complain of a metallic taste and, with long-term exposure, have bluish-gray gingival lead lines. Lead toxicity also causes constitutional symptoms, including arthralgias, generalized weakness, and weight loss. Delayed cognitive development can occur in infants and children whose blood lead levels are 10 micrograms/dL (0.48 micromol/L) or higher.¹² Conversely, adult and pediatric patients may be asymptomatic in the face of significantly elevated blood lead levels.

With organic lead poisoning, neurologic abnormalities predominate. Symptoms range from behavioral changes, with irritability, insomnia, restlessness, and nausea and vomiting, to tremor, chorea, convulsions, and mania.

DIAGNOSIS

Exposure history, whether occupational or environmental, related to recent travel or immigration, a hobby, or a retained lead bullet, is the most important clue in making the diagnosis. The clinician should focus on symptoms, developmental and dietary histories (in children), pica, and any house or day care remodeling. Occupational, travel, medication, dietary supplement, cosmetic, and hobby histories should be elicited for adults being evaluated and for children who may be exposed to lead secondarily from these adult activities. Toxicity due to retained lead bullets may manifest several decades after being shot. Hyperthyroidism, pregnancy, fever, reinjury, or immobilization of the affected extremity can promote lead release from these retained objects after years of dormancy. The combination of abdominal or neurologic dysfunction with a hemolysis should raise suspicion for lead toxicity. Consider the diagnosis in all children presenting with encephalopathy.

The definitive diagnosis rests on finding an elevated blood lead level, with or without symptoms. The blood lead level is the best single test for evaluating lead toxicity, and levels at or >5 micrograms/dL (0.24 micromol/L) are considered elevated in children. Screening may be performed on fingerstick capillary blood, but because of the potential for environmental lead contamination, elevated levels always should be confirmed on a venous blood sample.¹³ The edetate calcium disodium provocation test and testing for erythrocyte protoporphyrin (e.g., free erythrocyte protoporphyrin, zinc protoporphyrin) are no longer recommended.

Although it is important to order a blood lead level for confirmatory diagnosis and assistance in monitoring therapy, the laboratory turnaround time for results may be days. Diagnostic studies in the ED should therefore focus on evaluation for anemia and examination of radiographs for evidence of lead exposure.

The anemia from lead toxicity can be normocytic or microcytic, possibly with evidence of hemolysis, such as an elevated reticulocyte count and increased serum-free hemoglobin. Basophilic stippling in red blood cells from impaired clearing of cellular RNA degradation products is sometimes seen in lead-poisoned patients. This finding is nonspecific for lead toxicity; it is also found in arsenic toxicity, sideroblastic anemia, and the thalassemias. Anemia and basophilic stippling occur variably, and their absence does not exclude lead toxicity.

Following acute or subacute ingestion of lead, abdominal radiographs may show radiopaque material in the GI tract. In children, radiographs of long bones, especially of the knee, may reveal horizontal, metaphyseal “lead lines,” which represent failure of bone remodeling rather than deposition of lead.

The differential diagnosis of lead toxicity includes causes of encephalopathy, such as Wernicke’s encephalopathy; withdrawal from ethanol and other sedative-hypnotic drugs; meningitis; encephalitis; human immunodeficiency virus infection; intracerebral hemorrhage; hypoglycemia; severe fluid and electrolyte imbalances; hypoxia; arsenic, thallium, and mercury toxicity; and poisoning with cyclic antidepressants, anticholinergic drugs, ethylene glycol, or carbon monoxide. The abdominal pains of lead toxicity can mimic sickle cell crisis, the hepatic porphyrias, and even appendicitis. Chronic lead toxicity can mimic major depression, hypothyroidism, polyneuritis, gout, iron deficiency anemia, and learning disability.

TREATMENT

Patients with appropriate signs and symptoms and an elevated blood lead level are classified as lead toxic and should be treated.

Lead-induced encephalopathy is rare but causes serious morbidity and mortality. In severely toxic patients, standard life support measures should be instituted. Seizures are treated with benzodiazepines and general anesthesia, if necessary. Lumbar puncture may precipitate cerebral herniation and should be performed carefully, if at all, with the removal of only a small amount of cerebrospinal fluid. If lead encephalopathy is suspected, initiate chelation therapy promptly (i.e., in the ED) without waiting for the results of a blood lead level (Table 203-3). If abdominal films demonstrate radiopaque flecks consistent with lead, whole-bowel irrigation with a polyethylene glycol electrolyte solution should be instituted. Larger lead bodies, such as fishing sinkers and jewelry, may require endoscopic or surgical removal.

Chelation therapy for lead toxicity uses dimercaprol (previously known as British anti-Lewisite), edetate calcium disodium (sometimes abbreviated CaNa₂-EDTA), and succimer (also known as dimercaptosuccinic acid) (Table 203-3). Another chelating agent, penicillamine, has not received approval for use in the treatment of lead toxicity by the U.S. Food and Drug Administration, but there is published experience demonstrating benefit, and penicillamine is used in Europe for lead poisoning. The chelation dosing schedules are guided by the blood lead levels, the presence or absence of symptoms, and the age of the patient. Adverse side effects from chelation therapy are common, and consultation with a medical toxicologist is recommended to assist in management.

Dimercaprol crosses the blood–brain barrier and is indicated when neurotoxicity or high blood lead levels are present. Dimercaprol is administered IM and is typically used with edetate calcium disodium to prevent lead from being transported into the brain. The diluent for dimercaprol includes peanut oil, and therefore, dimercaprol should be used with great caution in patients with peanut allergy. Side effects of dimercaprol include hypertension; fever, pain, and sterile abscess at injection site; nausea; vomiting; diarrhea; abdominal pain; headache; lacrimation; rhinorrhea; and hemolysis in glucose-6-phosphate dehydrogenase–deficient patients. Side effects with dimercaprol are dose dependent and occur in up to 65% of treated patients using recommended doses.