96: Lead

Industrial Applications

The low melting point and high malleability of lead made it one of the first metals smelted and used by humans. Ancient Egyptians and Hebrews used lead, and the Phoenicians established lead mines in Spain circa 2000 b.c. The Greeks and Romans released lead during the process of extracting silver from ore. Roman society found many uses for lead, including pipes, cooking utensils, and ceramic glazes, and a common practice was to use sapa, a grape syrup simmered down in lead vessels, as a sweetener and preservative.¹¹⁸ Post-industrial lead use increased dramatically, and today lead is the most widely used nonferrous metal, with global extraction on the order of 9 million tons annually.⁸² Lead is used widely for its waterproofing and electrical- and radiation-shielding properties. Use of both lead-based paint for house paint and leaded gasoline has been essentially eliminated by regulation in the United States since the 1980s, but is still a concern in many nations, and persistence of lead paint in older US homes still constitutes an enormous environmental challenge.³

History of Lead-Related Health Effects

Dioscorides, a Greek physician in the second century b.c., observed adverse cognitive effects, and Pliny cautioned the Romans of the danger of inhaled fumes from lead smelting.¹¹⁴ Modern authors have suggested that extensive use of sapa in Roman aristocratic society contributed to the downfall of Roman dominance.¹¹⁸ Lead poisoning was also recognized in American colonial times. Benjamin Franklin observed in 1763 the “dry gripes” (abdominal colic) and “dangles” (wristdrop) that afflicted tinkers, painters, and typesetters, as well as the “gripes” caused by rum distillation in leaden condensing coils.¹⁰⁵ Lead salts, particularly lead acetate (sugar of lead), were used medicinally in the early 19th century to control bleeding and diarrhea. With the 19th century Industrial Revolution, lead poisoning became a common occupational disease. The reproductive effects of lead poisoning were recognized by the turn of the 20th century, including the high rate of stillbirths, infertility, and abortions among women in the pottery industry or who were married to pottery workers.

The modern history of childhood plumbism can be traced to the recognition of lead-paint poisoning in Brisbane, Australia, in 1897.¹¹⁴ Lead poisoning was reported in American children in 1917, and by 1943, it was established that children who recovered from clinical plumbism were frequently left with neurologic sequelae and intellectual impairment. Symptomatic childhood lead poisoning was a frequent occurrence in American pediatric medical centers throughout the 1950s and 1960s, a period during which research established effective chelation therapy protocols with British anti-Lewisite (BAL) and edetate calcium disodium (CaNa₂EDTA).³⁴ From the 1970s to the present, the research thrust in childhood lead poisoning has centered on the recognition and quantification of more subtle neurocognitive impairment caused by subclinical lead poisoning.^16,115 Over this time period, the US Centers for Disease Control and Prevention (CDC) has steadily revised downward the definitions of a normal blood lead concentration (BLL) in children. The CDC definition of childhood lead poisoning was 60 μg/dL in the early 1960s, was reduced to 10 μg/dL in 1991,²² and in recent years has been further revised in light of evidence suggesting adverse cognitive effects in young children at BLLs below 10 μg/dL.²⁰ The most recent CDC Advisory Council on Childhood Lead Poisoning recommendations lower the “level of concern” to 5 μg/dL and eliminate the term “threshold,” in response to emerging data demonstrating a supralinear dose-response curve for intelligence quotient (IQ) decrement at even the lowest detectable BLLs.^8,27,79,88

Sources of Human Exposure

Numerous sources of lead exposure exist and can be generally classified as environmental, occupational, or additional (somewhat “exotic”) sources. Environmental exposures affect the entire population, particularly young children. These occur primarily by exposure to lead paint in the United States (Table 96–1). Because of its continuing impact in the United States today, lead paint exposure is further detailed here.

Lead pigments (typically lead carbonate) account for 50% by weight of many white house paints from the pre–World War II era. Since 1978, paint intended for interior or exterior residential surfaces, toys, or furniture in the United States may contain, by law, no more than 0.06% lead. However, an estimated 3 million tons of lead remain in 57 million US homes built before 1980 and painted with lead-based paint. This aging housing stock has created an enormous environmental hazard of lead exposure to children and to adult homeowners, house painters, and construction workers who become involved in sanding, scraping, and restoration of painted surfaces in these homes. Furthermore, lead-based paint is still allowed for industrial, military, marine, and some outdoor uses, such as structural components of bridges and highways; occasionally, some of this paint is inadvertently used in homes.²³ Attempts to abate lead-painted outdoor structures can pollute entire communities.⁸⁷

Although paint-derived lead exposure may result from pica in some children, most lead paint exposure in childhood relates to the crumbling, peeling, flaking, or chalking of aging paint.²² These fine paint particles are incorporated into household dust and yard soil, where ordinary childhood hand–mouth activity results in ingestion.²⁹ Seasonal variations in house dust contamination occur, with higher house dust lead concentrations and increased BLLs in exposed preschool children noted during the summer.

Adults with occupational exposures to lead constitute another large group of persons at risk. It is estimated that more than 1 million workers in the United States, employed in more than 100 occupations, are exposed to lead.¹⁴⁰ The most important route of absorption in occupational settings is inhalation of lead dust and fumes. In addition, ingestion may result when workers eat, drink, or smoke in lead dust–contaminated areas. However, the presence of lead in the workplace, per se, does not imply a significant risk of poisoning. Some types of lead-related work are more hazardous than others (Table 96–2).^140,147 For example, lead smelting can be categorized as primary (from raw ore) and secondary (reclamation, such as from used car batteries). Secondary lead production workers may be at higher risk of poisoning because this job more typically involves small, sometimes “backyard” operations that are less likely to adhere to industry safety regulations than large, well regulated primary smelters.⁴¹

For convenience, environmental and occupational or recreational lead exposures are discussed separately, although there is considerable overlap. For example, workers who fail to change lead dust–covered work clothes or shoes may bring this occupational lead hazard home and secondarily contaminate their children’s environment.¹⁴⁰

Finally, numerous additional sources of lead exposure are also reported, including contaminated folk medications or cosmetics,^19,21,89,143 imported food,⁶⁶ ingested lead foreign bodies,^102,106,172 and retained bullets.^50,94,148 Since 2010, an outbreak of lead encephalopathy from artisanal gold mining in Nigeria has claimed hundreds of lives, with the toll still growing.^11,44

Some potential exposures have raised considerable community concern and media coverage in recent years—for example, the discovery of lead contamination of some artificial turfs²³ and imported toys coated with lead paint.⁹⁵ These, too, are highlighted separately in Table 96–2.

Prevalence

Several recent national and regional surveys have evaluated current US population-based trends in BLLs and sociodemographic correlates. The CDC estimates that approximately 450,000 children aged 1 to 5 years have BLLs greater than 5 μg/dL,²⁷ the 2012 revised reference value representing primarily excessive household exposure, and that approximately 8000 adults are reported each year with BLLs greater than 24 μg/dL (typically reflecting excessive occupational exposure).¹⁷ Although such numbers are impressive, they represent a considerable decrease from prevalence rates reported in prior decades (eg, from 8.6% of children with elevated BLLs from 1988 to 1991 to 1.4% from 1999 to 2004),⁷⁷ and it is certainly the observed clinical experience that symptomatic lead poisoning in children, in particular, is far less common than it was a generation ago. Nevertheless, for young minority children and poor people who reside in the deteriorating central cities of the United States, the battle is far from won. For example, the CDC reported in 2000 that children enrolled in Medicaid had a prevalence of elevated BLLs three times greater than those not enrolled.²⁵ Refugee, immigrant, and foreign-born adopted children remain at particularly high risk,^18,89 and remarkable cases of extremely elevated BLLs (>100 μg/dL) may still be detected on routine screening.⁴⁰

Lead is a silvery-gray, soft metal ubiquitous element in the earth’s crust, with an atomic weight of 207.21 Da and an atomic number of 82. It has a low melting point, 621.3°F (327.4°C), and boils at 2948°F (1620°C) at atmospheric pressure.¹⁷¹ It occurs principally as two isotopes: ²⁰⁶Pb and ²⁰⁸Pb. Metallic lead is relatively insoluble in water and dilute acids but dissolves in nitric, acetic, and hot, concentrated sulfuric acids. In compounds, lead assumes valence states of +2 and +4. Inorganic lead compounds may be brightly colored and vary widely in water solubility; several are used extensively as pigments in paints such as lead chromate (yellow) and lead oxide (red). Lead also forms organic compounds, of which two, tetramethyl and tetraethyl lead (TEL), were used commercially as gasoline additives.⁸² These are essentially insoluble in water but readily soluble in organic ­solvents.¹⁴⁴ Lead complexes with ligands containing sulfur, oxygen, or nitrogen as electron donors. It thus forms stable complexes with several ligands common to biologic molecules, including –OH, –SH, and –NH₂. Complexes with endogenous sulfhydryl (–SH) groups are thought to be the most toxicologically important. There is no known physiologic role for lead, and thus any lead presence in human tissue represents contamination.

Toxicokinetics

Inorganic and Metallic Lead.

Absorption.

Gastrointestinal (GI) absorption is less efficient than pulmonary absorption. Adults absorb an estimated 10% to 15% of ingested lead in food, and children have a higher GI absorption rate, averaging 40% to 50%.^1,58 In animal studies, this varies by type of lead compound studied.⁶ However, it should be noted that fasting and diets deficient in iron, calcium, and zinc—factors that are frequent among groups of young children—enhance GI absorption of lead.^58,97 The role of essential trace elements in decreasing lead absorption is assumed to be a consequence of competitive absorption processes. Metallic lead is also absorbed, albeit less readily than most lead compounds.⁶ The rate of absorption of metallic lead appears to be related to particle size, total surface area, and GI tract location; whereas gastric acidity favors dissolution, the small bowel is likely the site of maximal absorption.^102,106,172

The overall absorption of inhaled lead averages 30% to 40%. Of note, both minute ventilation and the concentration of lead in air determine airborne lead exposure, so a worker engaged in vigorous physical activity will absorb considerably more lead than a person in the same atmosphere at rest. Likewise, children, having a relatively greater volume of inhaled air per unit of body size because of higher metabolic rates, are proportionally at greater risk in a given degree of atmospheric lead pollution. It is estimated that children have a 2.7-fold higher lung deposition rate of lead than do adults.¹

Cutaneous absorption of inorganic lead is low; one study found an average absorption of 0.06% through intact skin.¹⁰⁹ Soft tissue absorption of metallic lead follows exposure to retained bullets, and similar to ingested lead foreign bodies, also depends on particle size, total surface area, and location; multiple small shot and location in which particles are bathed by synovial, serosal, or spinal fluid favor a more rapid increase in BLL.^50,94,148 This is thought to be due to increased solvency of lead in organic acids, such as hyaluronic acid in synovial fluid, as well as mechanical forces from joint motion.

Transplacental lead transfer is critical in fetal and neonatal lead ­exposure. Lead readily crosses the placental barrier throughout gestation, and lead uptake is cumulative until birth.¹³¹

Distribution.

Absorbed lead enters the bloodstream, where at least 99% is bound to erythrocytes.⁵⁹ From blood, lead is distributed into both a relatively labile soft tissue pool and into a more stable bone compartment. This classic three-compartment model may be somewhat of an oversimplification. Currently, at least two bone compartments are recognized: a more labile pool in trabecular bone and a more stable pool in cortical bone. In adults, approximately 95% of the body lead burden is stored in bone versus only 70% for children. The remainder is distributed to the major soft tissue lead-storage sites, including the liver, kidney, bone marrow, and brain. Lead uptake into soft tissues occurs in a complex fashion that depends on numerous factors, including blood lead concentrations, external exposure factors, and specific tissue kinetics. Most of the toxicity associated with lead is a result of soft tissue uptake, so that the relative decrease in bone storage is another comparative disadvantage for children.

Lead in the central nervous system (CNS) is of particular toxicologic importance. Lead preferentially concentrates in gray matter and certain nuclei.⁵⁹ Fetal brain uptake is relatively higher than with postnatal exposure in animal models. The highest brain concentrations are found in the hippocampus, cerebellum, cerebral cortex, and medulla.

Unlike soft tissue storage, bone lead accumulates throughout life. Bone storage begins in utero and occurs across all ranges of exposure, so that there is no threshold for bone lead uptake.¹ Total body accumulation of lead may range from 200 to 500 mg in workers with heavy occupational exposure.⁵⁹ Bone lead is thought to be relatively metabolically inert, but it can be mobilized from the more labile compartments and contributes as much as 50% of the blood lead content. This may be of particular importance during times of rapid bone turnover such as pregnancy and lactation, in elderly persons with osteoporosis,¹⁵⁶ and in children with immobilization.¹⁰³ Lead also accumulates in the teeth, particularly the dentine of children’s teeth, a phenomenon that has been used to quantify cumulative lead exposure in young children.¹¹⁵

Excretion.

Absorbed lead that is not retained is primarily excreted in urine (approximately 65%) and bile (approximately 35%).¹ A miniscule amount is lost via sweat, hair, and nails. Children excrete less of their daily uptake than adults, with an average retention of 33% versus 1% to 4%, respectively.¹⁸² Biologic half-lives for lead are estimated as follows: blood (adults, short-term experiments), 25 days; blood (children, natural exposure), 10 months; soft tissues (adults, short-term exposure), 40 days; bone (labile, trabecular pool), 90 days; and bone (cortical, stable pool), 10 to 20 years.^1,99,132 Trace amounts of lead are also excreted in breast milk.⁷

Organic Lead.

Alkyl lead compounds are lipid soluble and have unique pharmacokinetics that are less well characterized than those of inorganic lead.⁹ Animal studies and human clinical experience with acute ingestions and leaded gasoline sniffing demonstrate TEL absorption through ingestion; inhalation; and intact skin and subsequent distribution to lipophilic tissues, including the brain.^144,164,180 TEL is metabolized to triethyl lead, which is believed to be the major toxic compound. Alkyl leads may slowly release lead as the inorganic form, with subsequent kinetics as noted above.⁹

General Mechanisms

Similar to many metals, lead is a complex xenobiotic exerting numerous pathophysiologic effects in many organ systems.⁵⁹ Furthermore, genetic polymorphism may impact on individual susceptibility to lead.¹¹⁹ Recently identified examples of such include the genes for apolipoprotein E, the vitamin D receptor, Na⁺-K⁺-ATPase, δ-aminolevulinic acid, and protein kinase C.¹⁴⁶ At the biomolecular level, lead functions in three general ways. First, its affinity for biologic electron-donor ligands, especially sulfhydryl groups, allows it to bind and impact numerous enzymatic, receptor, and structural proteins. Second, lead is chemically similar to the divalent cations calcium and zinc and interferes with numerous calcium- (and perhaps zinc-) mediated metabolic pathways, particularly in mitochondria and in second-messenger systems regulating cellular energy metabolism.⁹⁰ Lead-induced mitochondrial injury may result in apoptosis, a phenomenon particularly well studied in animal models of retinal cells.⁹⁰ Lead may function as an inhibitor or agonist of calcium-dependent processes. For example, lead inhibits neuronal voltage-sensitive calcium channels⁶ and membrane-bound Na⁺-K⁺-ATPase (adenosine triphosphatase)¹⁵⁸ but activates calcium-dependent protein kinase C.¹⁰¹ These effects adversely impact neurotransmitter function.¹⁷⁶ Third, lead exhibits mutagenic and mitogenic effects in mammalian cells in vitro and is carcinogenic in rats and mice.⁴⁵ There is mechanistic plausibility and some epidemiologic evidence for at least a facilitative role of lead in human carcinogenesis,⁷¹ and the International Agency for Research on Cancer (IARC) has assigned inorganic lead compounds a group 2A (probably carcinogenic to humans) classification.^72,155

Neurotoxicity

The neurotoxicity of lead involves multiple targets, including cerebrovascular endothelium, mitochondria, neural cell adhesion molecules, neurotransmitter and second-messenger function, regulation of apoptosis, and myelin formation.^90,133,176 Lead-induced dysfunction in several neurotransmitter systems is linked to its calcium-mimetic properties. Through blockade of calcium influx at voltage-sensitive calcium channels, lead inhibits depolarization-triggered release of acetylcholine, dopamine, and γ-amino butyric acid (GABA) but augments the background rate of spontaneous release.^{36,59,76,90,176} The dampening of the evoked neurotransmitter response in conjunction with enhanced background release results in a decreased “signal-to-noise” ratio.^56,76 In addition, lead decreases calcium currents at the N-methyl-d-aspartate (NMDA) glutamate receptor and directly activates the intracellular second-messenger protein kinase C.⁷⁶ These effects on neurotransmitter release, receptor activity, and intracellular signaling adversely affect “synaptic pruning” in the developing brain, a process by which the volume of excessive synaptic connections is selectively reduced. This disruption results in suboptimal cortical microarchitecture and function, and it particularly affects the hippocampus, an important locus of learning and memory.^56,76,176

Lead also interferes with the 78-kDa chaperone glucose-regulated protein (GRP78) in astrocytes, which may result in adverse protein conformational effects that are thought to be associated with conditions such as Alzheimer disease.¹⁷⁶ In severe cases, pathologic changes in cerebral microvasculature may result in cerebral edema and increased intracranial pressure (ICP), which are associated with the clinical syndrome of acute lead encephalopathy (Fig. 96–1). Peripheral neuropathy is a classic effect of lead poisoning in adults. The neuropathology in humans is poorly characterized. In animal models, it is associated with Schwann cell destruction, segmental demyelination, and axonal degeneration.⁵⁹ Sensory nerves are less affected than motor nerves.

Hematologic Toxicity

Lead is hematotoxic in several ways, including via potent inhibition of several enzymes in the heme biosynthetic pathway (Chap. 22 and Fig. 22–3). It also induces a defect in erythropoietin function secondary to associated kidney damage.^64,139 A shortened erythrocyte life span is caused by increased membrane fragility with resultant hemolysis. Inhibition of Na⁺-K⁺-ATPase and pyrimidine-5′-nucleotidase may impair erythrocyte membrane stability by altering energy metabolism. The inhibition of pyrimidine-5′-nucleotidase is also thought to underlie the appearance of basophilic stippling in erythrocytes, representing clumping of degraded RNA, which is normally eliminated by this enzyme¹²¹ (Fig. 96–2).

Nephrotoxicity

Functional changes associated with acute lead nephropathy include decreased energy-dependent transport, resulting in a Fanconilike syndrome of aminoaciduria, glycosuria, and phosphaturia. These changes are related to disturbed mitochondrial respiration and phosphorylation and are reversible with discontinuation of exposure or treatment.⁶¹ A pathologic finding is characteristic nuclear inclusion bodies in renal tubular cells composed of lead–protein complex. Chronic high-dose lead poisoning is associated with progressive interstitial fibrosis.⁸⁶ Lead is a renal carcinogen in rodent models, but its status in humans is uncertain.^45,59

The association of plumbism with gout (“saturnine gout”) was noted more than 100 years ago. Lead competitively decreases uric acid excretion in the distal tubule, resulting in elevated blood urate concentrations and urate crystal deposition in joints. Kidney function is virtually always impaired in patients with saturnine gout.

Cardiotoxicity

The most important manifestation of lead toxicity on the cardiovascular system is hypertension. This is likely caused by altered calcium-activated changes in contractility of vascular smooth muscle cells secondary to decreased Na⁺-K⁺-ATPase activity and stimulation of the Na⁺-Ca²⁺ exchange pump. Lead may also affect blood vessels by altering neuroendocrine input or sensitivity to such stimuli or by increasing reactive oxygen species that enhance nitric oxide inactivation.⁹³ Elevated serum renin activity is found with moderate toxicity but may be normal or decreased in chronic severe plumbism.¹⁷³ Rarely, direct cardiotoxicity is reported.^114,135,157 Animal models demonstrate increased sensitivity to norepinephrine-induced dysrhythmias and decreased myocardial contractility, protein phosphorylation, and high-energy phosphate generation.⁸³ Lead-induced impairment of intracellular calcium metabolism may impact cardiac electrophysiology.

Reproductive Toxicity

Impairment of both male and female reproductive function is associated with overt plumbism. Gametotoxic effects in animals of both sexes and chromosomal abnormalities in workers with BLLs above 60 μg/dL are reported.⁵⁹ Testicular endocrine hypofunction occurs in smelter workers with BLLs in the 60 μg/dL range.¹³⁷

Endocrine Toxicity

Reduced thyroid and adrenopituitary function are found in adult lead ­workers.^53,142 Children with elevated BLLs have a depressed secretion of human growth hormone and insulinlike growth factor.⁷⁰

Skeletal Toxicity

In addition to the importance of the skeletal system as the largest repository of lead body burden, studies suggest that bone metabolism also is adversely affected by lead.⁵⁹ Hormonal response is altered by reduced 1,25-dihydroxyvitamin D₃ concentrations and by inhibition of osteocalcin. Both new bone formation and coupling of normal osteoblast and osteoclast function may thus be impaired.⁵⁹ Bands of increased metaphyseal density on radiographs of long bones (“lead lines”) in young children with heavy lead exposure represent increased calcium deposition (not primarily lead) in the zones of provisional calcification (Fig. 96–3). Impaired bone growth and shortened stature are associated with childhood lead poisoning. Impaired calcium or cyclic adenosine monophosphate (cAMP) messenger systems may underlie these cellular effects.

Gastrointestinal Toxicity

Lead toxicity causes constipation, anorexia, and colicky abdominal pain. Although the mechanisms are not fully elucidated, theories include impaired intestinal motility, alterations in luminal ion transport, and spasmodic contraction of intestinal wall smooth muscle.^39,144

Inorganic Lead

The numerous observed lead-induced pathophysiologic effects accurately predict that the clinical manifestations of lead poisoning are diverse. These manifestations of lead toxicity are characterized into distinct acute and chronic syndromes (Tables 96–3 and 96–4). In most cases, these distinctions really describe a continuum of dose- and time-related severity. Rarely, patients with massive acute poisoning present with clinical findings that are somewhat unique but overlap considerably with cases of severe chronic plumbism. However, it should be first reemphasized that the occurrence of overt clinical effects in lead poisoning is, in most cases, the culmination of a long-term lead exposure. As the total dose increases, these effects are almost always preceded first by measurable biochemical and physiologic impairment followed, in turn, by subtle prodromal clinical effects that may only become apparent in hindsight. In general, children are considered to be more susceptible than adults to toxicity for a given measured BLL; however, the data for this primarily concern effects on the CNS.

Asymptomatic Children.

Children with elevated body lead burdens but without overt symptoms represent the largest group of persons believed to be at risk for chronic lead toxicity. The subclinical toxicity of lead in this population centers around subtle effects on growth, hearing, and neurocognitive development. This last effect, in particular, is the subject of intense research interest and scrutiny. An effort to rigorously evaluate several modern (since 1979), carefully performed studies of the association of low lead and reduced intelligence (cross-sectional studies with blood or tooth lead and prospective studies) and combine their results with a statistical meta-analysis technique is reported.¹²⁷ The overall finding was that even though the majority of individual studies failed to achieve statistical significance, in pooled analysis there was a significant inverse association between lead exposure and IQ. The magnitude was on the order of 1 to 2 IQ points for chronic BLL increases from 10 to 20 μg/dL. Since that publication, another study evaluated IQ in children from 6 months to 5 years of age and found that BLLs were inversely correlated with IQ at 3 and 5 years of age and that the magnitude of effect for all subjects was an average 4.6 point decrement in IQ for each 10 μg/dL increase in BLL. Of particular concern, this effect was even greater, with an estimated 7.4 point loss, for the subset of children in the 1 to 10 μg/dL BLL range.¹⁶ The CDC recently compiled a number of studies confirming this steeper dose response at BLLs below 10 μg/dL²⁰ and revised screening guidelines to remove the term “threshold” and lower the action BLL to 5 μg/dL, a reference value to be evaluated every 4 years based on the 97.5 percentile in most recent NHANES data.^27,88

Symptomatic Children.

Subencephalopathic symptomatic plumbism usually occurs in children 1 to 5 years of age and is associated with BLLs above 70 μg/dL but may occur with concentrations as low as 50 μg/dL. Unfortunately, common complaints in well children of this age (eg, the “terrible twos,” with functional constipation and who do not eat as much as parents expect) often overlap with the milder range of reported symptoms of lead poisoning. Frequently, parents of children diagnosed by routine blood screening recognize milder symptoms only in hindsight after chelation treatment results in clinical improvement (“it seemed as if the child was going through a phase”).⁵⁴ This is especially true currently, when symptomatic plumbism is rarely reported.^19,22 Other uncommon clinical presentations are described, including isolated seizures without encephalopathy (indistinguishable from idiopathic epilepsy), chronic hyperactive behavior disorder, isolated developmental delay, progressive loss of cortical function simulating degenerative cerebral disease, peripheral neuropathy (reported particularly in children with sickle cell hemoglobinopathy), and the occurrence of GI effects (colicky abdominal pain, vomiting, constipation) with myalgias of the trunk and proximal girdle muscles.^34,46

Acute lead encephalopathy is the most severe presentation of pediatric plumbism (Table 96–3). It may be associated with cerebral edema and increased ICP (Fig. 96–1). Encephalopathy is characterized by pernicious vomiting and apathy, bizarre behavior, loss of recently acquired developmental skills, ataxia, incoordination, seizures, altered sensorium, or coma. Physical examination may reveal papilledema, oculomotor or facial nerve palsy, diminished deep tendon reflexes, or other evidence of increased ICP.^19,178 Encephalopathy usually occurs in children ages 15 to 30 months; is associated with BLLs above 100 μg/dL, although it is reported with BLLs as low as 70 μg/dL; and tends to occur more commonly in summer months, when BLLs peak.¹²⁵ Milder but ominous findings that may portend incipient encephalopathy include anorexia, constipation, intermittent abdominal pain, sporadic vomiting, hyperirritable or aggressive behavior, periods of lethargy interspersed with lucid intervals, and decreased interest in play activities. Many such patients seek medical advice for vomiting and lethargy during the 2 to 7 days before onset of frank encephalopathy.^34,125 Physical examination of such children usually reveals no specific abnormalities.

Mortality caused by encephalopathy was 65% in the prechelation era, decreasing to below 5% with the advent of effective chelation. The incidence of permanent neurologic sequelae, including mental retardation, seizure disorder, blindness, and hemiparesis, is 25% to 30% in patients who develop encephalopathic symptoms before the onset of chelation (Fig. 96–4).³⁴

Adults.

Adults with occupational lead exposure may manifest numerous signs and symptoms representing disorders of several organ systems. Severity of symptoms correlates roughly with BLLs, although many conditions thought to be associated with low-dose chronic lead exposure are better correlated with markers of cumulative dose, such as bone lead or the cumulative blood lead index (area under the curve of BLLs ­versus time)^69,86 (Table 96–4). True acute poisoning occurs rarely, after very high inhalational,⁸² large oral,¹¹⁶ or intravenous (IV) exposures.¹¹⁷ Such patients may present with colicky abdominal pain, hepatitis, pancreatitis, hemolytic anemia, and encephalopathy over days or weeks. Most adult ­plumbism is related to chronic respiratory exposure, although some authors have used the term “acute poisoning” to include patients with such exposure whose symptoms are severe and of relatively recent onset (within 6 weeks of ­presentation) and whose exposure is relatively brief (average, one year or less).³⁸

In severe plumbism, the hallmark of toxicity is acute encephalopathy, which has been rarely reported in adults since the 1920s.³⁸ The majority of modern cases are actually not associated with occupational exposures but rather with more exotic exposures, such as ingestion of lead-­contaminated illicit “moonshine” whiskey and ethnic alternative medications.^81,161 Encephalopathy in adults is usually associated with very high BLLs (typically >150 μg/dL) and is manifested by seizures (75% of cases), obtundation, confusion, focal motor disturbances, papilledema, headaches, and optic neuritis.^104,177 In addition, adult patients with severe plumbism often manifest attacks of abdominal colic, are virtually always anemic, and are at significant risk for severe peripheral neuropathy that manifests as wristdrop and footdrop. Nephrotoxic effects may include a Fanconilike syndrome, impaired kidney function, and progressive interstitial fibrosis. Rarely, ventricular dysrhythmias are reported, and long-standing lead toxicity is associated with prolonged QT and QRS intervals.^49,135

Moderate plumbism in adults typically involves CNS, peripheral nerves, hematologic, kidney, GI, rheumatologic, endocrine or reproductive, and cardiovascular findings.^82,140,144 At BLLs above 70 μg/dL, such symptoms may include headache, memory loss, decreased libido, and insomnia. GI symptoms may include metallic taste, abdominal pain, decreased appetite, weight loss, and constipation. Abdominal guarding and tenderness are occasionally observed. Musculoskeletal and rheumatologic complaints at this stage include muscle pain and joint tenderness. Patients with saturnine gout may have typical joint findings of acute arthritis. Peripheral neuropathy may occur, primarily motor, manifesting as dominant hand or wrist weakness, numbness of the legs, paresthesias, and tremor. Many patients at this stage have mild anemia, and those with chronic exposure are at risk for nephropathy as described above.

Mild plumbism may manifest as minor CNS findings, such as changes in mood and cognition. Subtle abnormalities detectable by careful neuropsychiatric testing are found in both adults and children with modest elevations in BLLs and include impaired memory span, rapid motor tapping, visual motor coordination, and grip strength.³⁸ Studies document ­abnormal psychometrics and nerve conduction in workers recently exposed to lead as BLLs increased to above 30 μg/dL.⁹⁸ Early psychiatric effects, manifesting at BLLs of 40 to 70 μg/dL, include increased tiredness at the end of the day, disinterest in leisure time pursuits, falling asleep easily, moodiness, and irritability. The physical examination is usually normal,⁴¹ or hypertension may be present. A bluish-purple gingival lead line (Burton line), representing lead sulfide precipitation in patients with poor dentition, is described rarely. One author described grayish stippling of the retina circumferential to the optic disk,¹⁶⁰ but other authors dispute this finding.¹²²

Effects on reproductive function may also be apparent in this range of exposure. Historically, infertility and stillbirths were common among heavily exposed women lead workers. More recent studies found reduced sperm counts, impaired motility, and abnormal morphology in men who work in the battery industry with BLLs above 40 μg/dL⁵ and increased incidence of menstrual irregularity and spontaneous abortion in lead-exposed women who worked in China⁷⁵ and Mexico.¹⁰ Prematurity is more common in children of pregnancies associated with elevated maternal BLLs.¹¹³

Increased blood pressure is probably the most prevalent adverse health effect observed from lead toxicity in adults. Epidemiologic studies document significant associations between hypertension and body lead burdens. The association is particularly strong for adult men ages 40 to 59 years, with an approximate 1.5 to 3.0 mm Hg increase in systolic pressure for every doubling of BLL beginning at 7 μg/dL.^126,167 Additional studies correlate body lead burden with several other disorders of aging, including a decline in cognitive ability,^147,154 essential tremor,⁴³ cardiovascular and cerebrovascular events,^73,86,108 electrocardiographic abnormalities,³⁰ chronic renal dysfunction,^86,93 osteoporosis,¹⁵ and cataract prevalence.¹⁴⁵

Organic Lead

Clinical symptoms of TEL toxicity are usually nonspecific initially and include insomnia and emotional instability.^9,144 Nausea, vomiting, and anorexia may occur. The patient may exhibit tremor and increased deep tendon reflexes. In more severe cases, these symptoms progress to encephalopathy with delusions, hallucinations, and hyperactivity, which may resolve or deteriorate to coma and, occasionally, death. Severely ill patients may also develop liver and kidney injury. Because many reported patients were exposed via intentional abuse of leaded gasoline, much of the literature reporting this syndrome may be confounded by accompanying volatile hydrocarbon toxicity.¹⁶⁴ Of note, in contrast to inorganic lead poisoning, patients with significant TEL toxicity do not consistently manifest hematologic abnormalities or elevations of heme synthesis pathway biomarkers. In addition, significant neurotoxicity may occur at BLLs considerably lower than those typically associated with inorganic lead poisoning.⁶⁷ A case report details the clinical course of a 13 year-old boy who unintentionally ingested a mouthful of fuel stabilizer containing 80% to 90% TEL. He developed progressive tremor, weakness, hallucinations, myoclonus, and hyperreflexia and required mechanical ventilation for 2 days and prolonged hospitalization for management of persistent hallucinations, weakness, dysphagia, and urinary and fecal incontinence. His BLL peaked on the third day after ingestion at only 62 μg/dL.¹⁸⁰

Clinical Diagnosis in Symptomatic Patients

For all patients in whom plumbism is considered based on clinical manifestations, the medical evaluation should first include a comprehensive medical history. Further inquiry should elicit environmental, occupational, or recreational sources of exposure as detailed earlier (Tables 96–1 and 96–2). Plumbism is more likely in a child between the ages of 1 and 5 years with prior plumbism or noted elevated BLLs; history of pica or acute unintentional ingestions;⁶⁵ aural, nasal, or esophageal foreign bodies;¹⁷⁹ history of iron-deficiency anemia; residence in a pre-1960s–built home, especially with deteriorated paint, or one that has undergone recent remodeling; family history of lead poisoning; or foreign-born status.^3,32,181 Affected children may manifest persistent vomiting, lethargy, irritability, clumsiness, or loss of recently acquired developmental skills; afebrile seizures; or evidence of child abuse or neglect.^52,149 In adults, the history should focus on occupational and recreational activities that might involve lead exposure (Table 96–2), a history of plumbism, and gunshot wounds with retained bullets.

The differential diagnosis of plumbism is broad. Adult patients may be misdiagnosed as having carpal tunnel syndrome, Guillain-Barré syndrome, sickle cell crisis, acute appendicitis, renal colic, or infectious encephalitis. Children are often initially considered to have viral gastroenteritis or even to have insidious symptoms passed off as a difficult developmental phase.

A patient who presents to the emergency department with potential lead encephalopathy presents the physician with a dilemma: severe lead toxicity requires urgent diagnosis, but confirmatory blood lead assays are not usually rapidly available.¹²⁰ For adults, a history of occupational exposure is often available from medical records or family members, and lead encephalopathy can be strongly considered with positive supportive laboratory findings such as anemia, basophilic stippling, elevated erythrocyte protoporphyrin (especially >250 μg/dL, sometimes available on an urgent basis), and abnormal urinalysis. In this context, it might be appropriate to institute presumptive chelation therapy while awaiting a BLL. In children, a similar indication for presumptive treatment would be suggested by a constellation of clinical features and ancillary studies, such as age 1 to 5 years, a prodromal illness of several days to weeks duration (suggestive of milder lead-related symptoms), history of pica and source of lead exposure, the laboratory features noted above (which are equally helpful in young children), radiologic findings of dense metaphyseal “lead lines” at wrists or knees (Fig. 96–3), or evidence of recent pica for ingested foreign bodies or lead paint particles on abdominal radiographs (Figs. 96–5 and 96–6). Radiographic confirmation of retained bullets or shrapnel may be relevant in patients of any age (Fig. 96–7).^{50,94,148,153} In both adults and children, the decision to institute empiric chelation treatment should not deter additional emergent diagnostic efforts to exclude or to confirm other important entities while BLLs are pending. An important consideration in this context may be the suspicion of an acute, potentially treatable CNS infection (eg, bacterial meningitis or herpetic encephalitis). Lumbar puncture may be dangerous in patients with severe lead encephalopathy because of the risk of cerebral herniation.³⁵ If immediate lumbar puncture is thought to be essential, a computed tomography scan should be first obtained to determine cerebral edema, midline shift, or other evidence of high risk for herniation. If a lumbar puncture is performed, the minimal amount of fluid necessary for diagnosis (<1 mL) should be removed using a small-gauge needle.

Laboratory Evaluation

In patients suspected of having plumbism, laboratory testing is used to augment the evaluation of both lead exposure and lead toxicity. The whole BLL is the principal measure of lead exposure available in clinical practice, reflecting both recent and remote exposure. In any patient suspected of symptomatic plumbism, whole blood should be collected by venipuncture into special lead-free evacuated tubes. The BLL is typically determined by atomic absorption spectrophotometry. For asymptomatic children, BLL screening is often performed by capillary blood testing for convenience; however, venous confirmation of elevated capillary lead concentrations, unless extremely high (eg, ≥70 μg/dL) or unless the patient is clearly symptomatic, is still considered mandatory before chelation or other significant interventions. Hair and urine lead concentrations have no clinical utility. The erythrocyte protoporphyrin concentration reflects inhibition of the heme synthesis pathway (Chap. 22) and was used as a screening tool in the past, but it is no longer considered sufficiently sensitive. The erythrocyte protoporphyrin concentration test may still be useful for tracking response to therapy and in distinguishing acute from chronic lead poisoning; as an adjunct to the emergency diagnosis of symptomatic plumbism if emergent BLL determination is not available; and, rarely, in the evaluation of suspected factitious ­plumbism. Routine serum chemistries, kidney function tests, liver function tests, urinalysis, and complete blood count are indicated in patients who are symptomatic or about to undergo chelation therapy. Radiographic studies may reveal retained bullets (Fig. 96–7) or recent lead ingestion. Abdominal radiographs may reveal lead paint chips or other ingested lead foreign material (Figs. 96–5 and 96–6). The finding of “lead lines,” metaphyseal densities at the ends of long bones in young children, may substantiate a clinical diagnosis of plumbism before BLLs are available (Fig. 96–3), although dense metaphyseal bands are rarely caused by other causes, including other metals (arsenic, bismuth, and ­mercury), healing rickets, and recovery from scurvy.^130,180

Finally, two measures of cumulative lead exposure are available. X-ray fluorescence technology measures bone lead, and thus indirectly estimates total body lead burden. The cumulative blood lead index, derived from several BLLs measured over the presumed course of lifetime lead exposure, calculated as an area under the concentration curve, is also described.⁶⁹ Both techniques are used in research studies of issues concerning past chronic lead exposure and a variety of current health outcomes.^68,85,175

Although outside the scope of this discussion, screening is an essential public health practice for the prevention of severe plumbism in both ­children and adults from high-risk settings. Table 96–5 outlines the current CDC^20,26,27 pediatric recommendations, which also are endorsed by the American Academy of Pediatrics.³ Likewise, the Occupational Safety and Health Administration (OSHA) maintains a lead standard for US workers formulated to reduce workplace exposure to lead, decrease symptomatic lead poisoning, and provide quality medical care to workers with elevated BLLs.^{168,169,170, and 171} Table 96–6A summarizes the OSHA-mandated action BLL values for worker notification, removal, and reinstatement. An expert panel convened by the Association of Occupational and Environmental Clinics published an alternative set of health-based management recommendations for lead exposed workers. The authors propose that their recommendations are more reflective of recent research linking adverse health outcomes to chronic, low-dose lead exposure.⁸⁶ These guidelines are summarized in Table 96–6B.

There are several caveats about the management of patients with lead poisoning. First, the most important aspect of treatment is removal from further exposure to lead. Unfortunately, effective implementation of this therapy is often beyond the control of the clinician but rather depends on a complex interplay of public health, social, and political actions. Currently, the ability to control exposure is generally more applicable to adults with occupational exposures than to children exposed to residential hazards. Second, in children for whom some residual lead exposure potentially continues, optimization of nutritional status is vital in order to minimize absorption. Finally, pharmacologic therapy with chelators, although a mainstay of therapy for symptomatic patients, is an inexact science, with numerous unanswered questions despite almost 50 years of clinical use.^2,4,85 The rationale for chelation therapy of lead poisoned patients is that chelators complex with lead, forming a chelate that is excreted in urine, feces, or both. Chelation therapy increases lead excretion, reduces blood concentrations, and reverses hematologic markers of toxicity during therapy. Reports from the 1950s found symptomatic improvement in adults chelated for lead colic.¹⁷⁴ The institution of effective combination chelation treatment of childhood lead encephalopathy in the 1960s contributed to the dramatic decline in mortality and morbidity of that devastating degree of plumbism.³⁴ However, the same era saw major advances in pediatric critical care in general and medical management of increased ICP in particular. The situation of chelation therapy for asymptomatic patients with mildly to moderately increased body burdens of lead is even less clear, and many questions regarding efficacy and safety remain.^32,60,85,124 To date, long-term reduction of target tissue lead content or reversal of toxicity is not demonstrated in human trials.^42,102,138

Decreasing Exposure

All patients with significantly elevated BLLs warrant identification of the lead exposure source, and specific environmental and medical interventions, or both (Table 96–7). In adults, this usually involves worksite changes.^41,86,144 The risk of occupational lead exposure correlates with several factors that contribute to the occurrence of respirable lead fumes or dust particles in the worksite atmosphere.¹⁴⁴ First, there are hazards inherent in the work process itself, including high temperatures; significant aerosol, dust, or fume production; and a less mechanized workplace (with resulting greater “hands-on” employee exposure). Second, the adequacy of dust elimination, such as local and general ventilation, is critical. The third category is that of worksite and personal hygiene, including proper use of protective clothes and equipment, and thorough housekeeping. Remedial actions might include improvements in ventilation, modification of personal hygiene habits, and optimal use of respiratory apparatus. It is vital to prohibit smoking, eating, and drinking in a lead exposed work area. Work clothes should be changed after each shift and should not be lockered together with street clothes.

In patients with plumbism caused by retained bullets, surgical removal of this lead source should be considered.^28,94,107Table 96–7 also summarizes several specific educational guidelines that may be offered to parents of lead-exposed children.^3,14,22 Overarching principles include home lead paint abatement (done preferably by professionals, with the family out of the home), home dust reduction techniques, decreasing soil lead exposure, and nutritional evaluation and counseling. Patients manifesting iron deficiency should be treated, and for others, a diet sufficient in trace nutrients, particularly iron and calcium (which may decrease lead absorption) and vitamin C (which may enhance renal lead excretion) is likely of value.³ Clinicians who have primary responsibility for children with elevated BLLs should refer to the exhaustive monograph developed by the CDC, which details such pediatric case management.²²

Occasionally, children may require urgent GI decontamination to reduce ongoing acute lead exposure. Patients with large burdens of lead paint chips may benefit from prompt institution of whole-bowel irrigation (WBI) (Fig. 94–6) (Antidotes in Depth: A2). The presence of ingested lead foreign bodies is a unique situation that requires careful individualization of management. Several case reports document rapid absorption, with significantly elevated BLLs measured within 24 hours of ingestion in some cases. Such patients warrant baseline BLL determination and frequent repeat BLLs, with consideration for prompt endoscopic removal, particularly with gastric location and increasing BLLs.^106,112,172 Proton pump inhibitor and prokinetic therapy are recommended for gastric foreign bodies in an effort to decrease gastric acidity, retention time, and resultant lead ­dissolution.⁵¹ WBI may be an adjunct for more distally located foreign bodies but has not been uniformly successful. Endoscopic or surgical removal may be indicated with delayed passage of foreign bodies, inability to tolerate WBI due to intestinal obstruction, or rapid elevations in BLL soon after foreign body ingestion.^51,112,172 The issue of concomitant chelation therapy in patients with significant GI lead burdens is addressed in the following section.

Chelation Therapy

The indications for and specifics of chelation therapy are determined by the age of the patient, the BLL, and clinical symptomatology (Table 96–8). Three chelators are currently recommended as drugs of choice for the treatment of lead poisoning: BAL (Antidotes in Depth: A25) and CaNa₂EDTA (Antidotes in Depth: A27) are used parenterally for more severe cases, and succimer (Antidotes in Depth: A26) is available for oral therapy. A fourth drug, d-penicillamine, has been used orally for patients with mild to moderate excess lead burdens. Unfortunately, d-penicillamine has a toxicity profile that includes life-­threatening hematologic disorders and reversible, but serious, dermatologic and kidney effects; consequently, since 1991, its role in lead poisoning treatment at most centers has been largely replaced by succimer. Currently, the American Academy of Pediatrics recommends d-penicillamine use only when unacceptable adverse reactions to both succimer and CaNa₂EDTA occur, and it remains important to continue chelation.^2,3

Chelation is not a panacea for lead poisoning. It is a relatively inef­ficient process, with a typical course of therapy decreasing body content of metal by only 1% to 2%.^85,111 Furthermore, there is little evidence that ­chelators have significant access to critical sites in target organs, particularly in the brain.³⁷ Assumptions that reducing BLL will improve subtle neurocognitive dysfunction or other subclinical organ toxicity are appealing theoretically but unproven.^42,138

Children

Lead encephalopathy is an acute life-threatening emergency and should be treated under the guidance of a multidisciplinary team in the intensive care unit of a hospital experienced in the management of critically ill children. Encephalopathy requires treatment by combination parenteral chelation therapy with maximum-dose BAL and CaNa₂EDTA along with meticulous supportive care.^2,22,34 Such combination therapy has a dramatic effect on decreasing BLL—to 50% or less of baseline within 15 hours and to 75% to 80% of baseline by 48 to 72 hours. It is far superior to monotherapy with CaNa₂EDTA in this regard.³⁴

Chelation is instituted with 450 mg/m²/d (or 25 mg/kg/d) of intramuscular (IM) BAL in six divided doses.^2,22 The second dose of BAL is given 4 hours later followed immediately by IV CaNa₂EDTA, in maximum concentration of 0.5% solution, at 1500 mg/m²/d (or 50 mg/kg/d) as a continuous infusion or in divided-dose infusions over several hours.^2,22,125 The delay in initiating CaNa₂EDTA infusion is based on past observations of clinical deterioration in encephalopathic patients treated with CaNa₂EDTA alone.^2,34 Therapy is typically continued with both agents for 5 days, although in milder cases with prompt resolution of encephalopathy and decrease of BLL to below 50 μg/dL, BAL may be discontinued after 3 days, with continuation of CaNa₂EDTA alone for 2 more days.

The presence of radiopaque material in the GI tract on radiography has raised concern that parenteral chelation might enhance absorption of residual gut lead. This issue is not settled fully,^32,78 but most experts advocate initiation of parenteral chelation without delay in seriously symptomatic patients. It seems reasonable to simultaneously attempt whole bowel irrigation with a polyethylene glycol preparation.² One case report described the successful use of chelation therapy begun with parenteral BAL and CaNa₂EDTA and then enteral succimer (initiated after 3 days of WBI) for a child with lead encephalopathy and an extraordinarily high BLL of 550 µg/dL.⁵⁷ This issue applies as well to ingested lead foreign bodies, as noted above.^106,112,172 Generally, oral fluids, feedings, and medications are withheld for at least the first several days. Careful provision of adequate IV fluids optimizes kidney function while avoiding overhydration and the risk of exacerbating cerebral edema. The occurrence of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) may be associated with lead encephalopathy,^34,163 so urine volume, specific gravity, and serum electrolytes should be closely monitored, especially as fluids are gradually liberalized with clinical improvement (Chap. 19). In the context of lead encephalopathy, this approach would need to be tempered by the requirement for maintaining good urine output to optimize chelation efficacy.

Seizure control is usually accomplished with benzodiazepines. Ongoing anticonvulsant therapy is typically continued with phenytoin or phenobarbital. Rarely, continuous infusions of midazolam or high-dose pentobarbital therapy may be necessary.¹⁷⁸

Modern approaches to the management of cerebral edema and increased ICP have not been critically evaluated in the context of lead encephalopathy. Lumbar puncture should probably be avoided if lead encephalopathy is highly suspected and acute infectious processes are not. Of note, repeated lumbar puncture was used as an adjunct to the treatment of lead encephalopathy associated with increased ICP in the 1950s but was complicated by proximate death when signs of impending herniation were present.³⁵ It seems reasonable that measures such as prevention of hypoxia and hypercarbia with tracheal intubation and controlled ventilation, seizure treatment and prophylaxis, maintenance of adequate cerebral perfusion pressure, mild hyperventilation with PCO₂ of 30 to 35 mm Hg, and neutral head positioning with elevation of the head of the bed to 30 degrees might have a salutary effect at minimal risk of increased iatrogenic morbidity.^2,162 Mannitol administration may prove beneficial in deteriorating patients and has been particularly suggested as an adjunctive therapy when cerebral edema is complicated by SIADH or impaired kidney function.³⁴ Whether more aggressive measures, such as acute hyperventilation for impending herniation, ICP monitoring, drainage of ventricular cerebrospinal fluid, decompressive craniectomy, induced hypothermia, or barbiturate coma would decrease mortality or morbidity further is unknown.

For children with milder effects or who are asymptomatic with BLL greater than 70 μg/dL, chelation with a two-drug regimen similar to that used for encephalopathy is recommended. It is likely that this group of patients will require only 2 to 3 days of BAL in addition to 5 days of CaNa₂EDTA. Some authors have suggested that asymptomatic patients in this group, particularly those with BLLs below 100 μg/dL, might also be adequately treated with CaNa₂EDTA alone,¹⁸¹ succimer plus CaNa₂EDTA, or even succimer alone, most recently a large cohort of 1193 Nigerian children with moderate to severe lead poisoning were managed with succimer alone. Although data concerning long term efficacy is still emerging, this appears to be a safe alternative if circumstances preclude standard two drug chelation.^164a Intensive care monitoring may be prudent for such patients as well, at least during the initiation of chelation therapy.¹¹¹

Chelation therapy is widely recommended for asymptomatic children with BLLs between 45 and 70 μg/dL.^2,4,22,111 Children without overt symptoms may be treated with succimer alone, which has documented efficacy in lowering BLLs and short-term safety since its approval by the Food and Drug Administration in 1991.^63,91 Succimer is initiated at 30 mg/kg/d (or 1050 mg/m²/d) orally in three divided doses; this is continued for 5 days and then decreased to 20 mg/kg/d (or 700 mg/m²/d) in two divided doses for 14 additional days.^2,62 The original data establishing this empiric dosing regimen were based on body surface area rather than weight.⁶² For younger children, the alternative dosing by body weight results in suboptimal dosing.¹³⁶ Although the ability to chelate children orally with succimer makes it tempting to prescribe routinely for outpatient therapy and some animal evidence suggests succimer does not enhance enteral lead absorption,⁸⁰ clinical reports suggest that children must be protected from continued lead exposure during succimer chelation.^31,33 Home abatement and reinspection should be accomplished before initiation of ambulatory succimer therapy; if this is not feasible, hospitalization is still warranted. Alternative regimens (for rare patients with succimer intolerance or allergy or because of parental noncompliance) include parenteral chelation with CaNa₂EDTA at 25 mg/kg/d for 5 days.²

After initial chelation therapy, decisions to repeat treatment are based on clinical symptoms and follow-up BLLs. Patients with encephalopathy or any severe symptoms or with an initial BLL above 100 μg/dL often require repeated courses of treatment. It is suggested that at least 2 days elapse before restarting chelation. The precise regimen and dosing of chelating agents are determined by ongoing symptomatology and the repeat BLLs (Table 96–8). A third course of chelation should rarely be necessary sooner than 5 to 7 days after the second course ends.¹²⁵ For patients with milder degrees of plumbism (eg, asymptomatic, initial BLL <70 μg/dL), it is reasonable to allow 10 to 14 days of reequilibration before restarting treatment.²

The management of asymptomatic children with BLLs of 20 to 44 μg/dL is controversial.^{31,100,110,166} The National Institutes of Health–sponsored Treatment of Lead-exposed Children (TLC) trial found only modest efficacy of succimer in reducing BLL. Furthermore, at 3 years postenrollment, no benefit was noted in treated patients on measures of cognition, neuropsychiatric function, or behavior.¹³⁸ This large study enrolled 780 children in a multicenter, randomized, placebo-controlled, double-blind trial, but it still has been criticized, particularly for using a single chelator and having failed to lower BLL significantly over time between treated and control groups.¹⁵¹ Of note, small but statistically significant decrements in growth velocity were noted in the treatment group, which might reflect trace mineral depletion.¹²⁴ Since its initial publication, the primary findings of the TLC trial on lack of cognitive improvement were confirmed in a 7 year follow-up study.⁴² In addition,a reanalysis of the original data found that decreasing blood concentrations did correlate with improved cognitive scores over the initial 36 month trial period (~4 IQ points for each 10 μg/dL decrease in BLL), but only in the placebo group.⁹⁶ Nevertheless, there may still be potential indications for occasional chelation treatment in this group, including BLLs at the higher end of the range (eg, 35–44 μg/dL), especially if BLLs remain the same or increase over several months after rigorous environmental controls are instituted, in younger children (eg, younger than 2 years), in children with evidence of biochemical toxicity (an elevated erythrocyte protoporphyrin concentration, after iron supplementation, if necessary), or any hint of subtle symptoms. Currently, the CDC¹⁹ and the American Academy of Pediatrics^2,3 recommend aggressive environmental and nutritional interventions with close monitoring of blood lead concentrations, without routine chelation therapy, for such children.

BLLs of 5 to 19 μg/dL are defined by the CDC as representing excessive exposure to lead but not requiring chelation therapy. Close monitoring (for the 5–14 μg/dL range) and careful environmental investigation and interventions as necessary (particularly for the 15–19 μg/dL range) are appropriate and sufficient.^2,3,22 The educational approaches outlined earlier should be included in the case management of all children with even modestly elevated lead levels (Table 96–7).

Adults

General Considerations.

The first principle in the treatment of adults with lead poisoning is that chelation therapy may not substitute for adherence to OSHA lead standards at the worksite and should never be given prophylactically.^41,82 In addition to the guidelines for decreasing lead exposure noted earlier, chelation therapy is indicated for adults with significant symptoms (encephalopathy, abdominal colic, severe arthralgias, or myalgias), evidence of target organ damage (neuropathy or nephropathy), and possibly in asymptomatic workers with markedly elevated BLLs or ­evidence of biochemical toxicity.^{86,134,144,150}Table 96–8 outlines suggested chelation therapy regimens for adults. For encephalopathic adult patients, our practice is to recommend combined BAL and CaNa₂EDTA therapy, just as for ­children, although some clinicians suggest that adults with severe lead ­poisoning may be successfully treated with CaNa₂EDTA alone in doses of 2 to 4 g/d by continuous IV ­infusion.⁸⁴ Recent reports support the use of succimer in adult patients with mild to moderate plumbism after environmental and occupational remedies have been instituted.^92,128 Chelation therapy should also be considered in the perioperative period for patients undergoing surgical removal of retained bullets or débridement of adjacent lead-contaminated tissue.^94,107,148­Treatment of patients with acute TEL toxicity is largely supportive, with sedation as necessary. For patients seen soon after a large-volume ingestion, nasogastric suction, with airway protection as needed, may be warranted. In general, chelation therapy for TEL toxicity is associated with enhanced lead excretion¹² but has not been found to be clinically efficacious.^144,164,180 However, for symptomatic, especially encephalopathic patients with very elevated BLLs (in whom there may be a significant component of metabolically derived inorganic lead toxicity), we recommend chelation therapy.

Pregnancy, Neonatal, and Lactation Issues.

An area of particular concern in the management of adult plumbism involves decisions regarding therapy during pregnancy. As noted previously, lead freely passes the placental barrier and accumulates in the fetus throughout gestation. Chelation therapy during early pregnancy poses theoretical problems of teratogenicity, particularly that caused by enhanced excretion of potentially vital trace elements, or translocation of lead from mother to fetus (Antidotes in Depth: A25, A26, and A27). Symptomatic pregnant women with elevated BLLs certainly warrant chelation therapy, regardless of these concerns. Additionally, of some reassurance regarding fetal health, a case series and 25 year literature review of lead poisoning during pregnancy found no reports of chelation-associated birth defects in the handful of published cases.¹⁵² It should be noted that despite decreases in maternal BLL with chelation therapy, newborn BLLs may be considerably higher and, in some cases, may approximate the pretreatment maternal BLL, implying limited efficacy for in utero fetal chelation. However, in these cases, the hemoglobin concentration of the newborn was generally much higher than that of the mother, and thus some of the maternal–neonatal difference in BLL may simply reflect this difference in hemoglobin concentration and hence total blood lead content. In general, there currently seems little support for routine chelation therapy in pregnant women who would not otherwise warrant treatment based on their own symptoms or degree of elevated BLL. Calcium carbonate supplementation may be considered because its use is associated with decreased bone resorption during pregnancy and thus possibly lessened fetal lead exposure.⁷⁴

Postnatally, infant BLLs may decline over time without chelation, but this occurs very slowly.¹⁴¹ In two reported neonates exposed to prenatal maternal chelation who were then monitored for 2 weeks postpartum, the BLL remained stable or increased until chelation therapy was instituted.^123,165 In two additional cases of neonates whose mothers were not treated prepartum, BLLs also remained stable or increased for 17 days to 3 weeks.^55,159 Thus, postpartum chelation therapy is warranted for neonates, depending on BLLs, as per the guidelines described above for older children. Exchange transfusion might be considered for neonates with extremely elevated BLLs.¹³ Succimer chelation therapy was used for one neonate with presumed organic lead exposure via maternal gasoline sniffing.¹²⁹

Lastly, the issue of allowing mothers with elevated BLLs to breastfeed their infants may arise. Breast milk from heavily exposed mothers may be a potential source of lead exposure and may require lead concentration analysis before breastfeeding can be safely recommended.^7,48 One small case series found that breast milk from two women with BLLs of 34 and 29 μg/dL, respectively, had clinically insignificant lead content (<0.01 μg/mL).⁷ Breast milk analysis may be warranted in some cases, particularly with BLLs of 35 μg/dL or greater, before safely advising continued nursing. Despite these considerations, the majority of women without excessive lead exposure should still be encouraged to breastfeed. Of note, one study has found that a relatively simple intervention, calcium supplementation (1200 mg/d of elemental calcium as calcium carbonate), reduces breast milk lead ­content by 5% to 10%.⁴⁷

• Lead is a widely distributed element that has long been used by humans for a variety of purposes, including waterproofing; electrical and radiation shielding; and the production of ammunitions, paints, plastics, ceramics, glass, and explosives.

• Lead poisoning, or plumbism, has an equally long history, but today it is primarily manifest in young children exposed to deteriorated lead paint and as an occupational toxic exposure for adult workers.

• Lead causes multiorgan toxicity, affecting especially the hematologic and neurologic systems in patients of all ages and causing hypertension in adults. This may result in a broad spectrum of clinical effects ranging from subtle neurocognitive effects to vague constitutional symptoms to acute encephalopathy, intracranial hypertension, cerebral edema, and death.

• The mainstays of treatment are removal from exposure. Chelationtherapy is reserved for patients with symptoms or significantly ­elevated body lead burdens. Defining a group of asymptomatic patients that will benefit from chelation therapy has been difficult and controversial.

• Parenteral chelation with CaNa₂EDTA and BAL is efficacious in lowering BLLs and reducing mortality and morbidity from severe lead poisoning. Succimer, an oral chelator, also has efficacy in reducing BLLs in asymptomatic children, although the neurocognitive benefit of doing so is unproven.

References