Lead Toxicity

For centuries, lead toxicity has been one of the most significant preventable causes of neurologic morbidity from an environmental toxin. A heavy metal, lead is ubiquitous in our environment but has no physiologic role in biological systems. Lead toxicity is a particularly insidious hazard with the potential of causing irreversible health effects. It interferes with a number of body functions primarily affecting the central nervous, hematopoietic, hepatic and renal system producing serious disorders. Acute toxicity is related to occupational exposure and is quite uncommon. Chronic toxicity on the other hand is much more common.

The ongoing emphasis on abatement of lead environments places added emphasis on occupational exposure to lead (eg, among workers at smelters or battery recycling plants).[1] Such exposure is a continuing problem. Whereas occupational exposure remains an occasional concern, the greatest public health issue related to lead at present is exposure of young children to decaying fragments of leaded paint. More recently, contaminated drinking water has become a cause of childhood lead exposure because of aging infrastructure.

Pediatric lead poisoning

Compared with adult lead poisoning, pediatric lead poisoning is a somewhat newer problem. First reported in the late 1800s in Australia, interest in childhood lead poisoning and its manifold clinical presentations has burgeoned. It should be noted that toxic metals, including lead, can be transmitted from a mother to her child via breast milk.[2]

Lead poisoning is probably the most important chronic environmental illness affecting modern children. Despite efforts to control it and despite apparent success in decreasing incidence, serious cases of lead poisoning still appear in hospital emergency departments (EDs), clinics, and private physicians’ offices.

In children, virtually no organ system is immune to the effects of lead poisoning. Perhaps the organ of most concern is the developing brain. Any disorganizing influence that affects an individual at a critical time in development is likely to have long-lasting effects. Such is the effect of lead on the developing brain. Effects on the brain appear to continue into the teenaged years and beyond. A high index of suspicion is necessary for physicians treating pediatric patients.

The literature suggests that significant insult to the brain of children occurs at very low levels and that medical intervention with chelation fails to reverse such effects.[3, 4, 5, 6, 7]

The major mechanism of lead toxicity is due to increased generation of reactive oxygen species (ROS) and interference with generation of antioxidants. Lead causes the generation of ROS like hydroperoxide, hydrogen peroxide, and singlet oxygen. ROS are stabilized by glutathione in the body.  Ninety percent of glutathione in the cell exists in reduced form and 10% in oxidative form, and it typically acts as an antioxidant defense mechanism. Glutathione stabilizes ROS, and after being converted (oxidizing) to glutathione disulfide, it is reduced back to GSH by glutathione reductase. Lead inactivates glutathione by binding to GSH’s sulfhydryl group, which causes GSH replenishment to become inefficient, thereby increasing oxidative stress. Lead also interferes with the activity of other antioxidant enzymes including superoxide dismutase and catalase. The increase in oxidative stress leads to cell membrane damage due to lipid peroxidation. Lead blocks the activity of 5-aminolevulinic acid dehydratase and leads to hemoglobin oxidation, which along with the lipid peroxidation can result in red cell hemolysis.[8]

Lead entering the intravascular space binds quickly to red blood cells. Lead has a half-life of approximately 30 days in the blood, from where it diffuses into the soft tissues, including the kidneys, brain, liver, and bone marrow.

Lead then diffuses into bone and is stored there for a period that corresponds to a half-life of several decades. Increased bone turnover with pregnancy, menopause, lactation, or immobilization can increase blood lead levels. Estimations of blood lead levels are more useful for diagnosing acute lead poisoning, whereas the extent of past lead exposure can be estimated by determining the body burden of lead on the basis of results from the edetate (EDTA) calcium disodium (CaNa2 EDTA) lead mobilization test.

Lead is primarily excreted in urine and bile, but the elimination rate varies, depending on the tissue that absorbed the lead. The kidney excretes lead by means of glomerular filtration and tubular secretion. Lead has bidirectional transport across the tubular epithelium. The clearance of lead ranges from 1 to 3 mL/min and is relatively independent of kidney function.

The effects of lead poisoning on the brain are manifold and include delayed or reversed development, permanent learning disabilities, seizures, coma, and even death. The long-term effect of lead exposure is maximal during the first 2 or 3 years of life, when the developing brain is in a critical formative stage.

 

The most significant lead exposure in adults usually occurs at the workplace, whereas for children, other forms of environmental exposure are more important. Although lead toxicity can occur after a single event, it is usually a result of chronic exposure.

Workplace exposure

Sites and occupations associated with lead exposure include pipe cutting, lead mining and ore crushing, lead and copper smelting, welding operations, construction, the rubber industry, the plastic industry, radiator repair, battery manufacturing, soldering of lead products, the printing industry, glass manufacture, organic lead production, solid waste combustion, frit manufacture, and paint and pigment manufacture. Persons employed in these occupations may also expose family members to lead by transporting lead dust from the workplace to their homes.

Other environmental exposure

Exposure from lead-based paint was significant among children in the past. Although lead was banned from use in residential paint, it continues to be used in nonresidential settings, and as a result of its past use, lead paint can still be found in many older homes.

Leaded gasoline contaminates the atmosphere. Although lead has been removed from gasoline in Western countries, leaded gasoline continues to be used in the developing world. Huffing of leaded gasoline (ie, deeply inhaling fumes to achieve a “high”) could also cause poisoning.

Food has been an important source of lead exposure. Surface contamination of homegrown vegetables, storage cans with lead solder seams (banned in 1991), and kitchenware are sources of lead contamination in food. Strong animal evidence suggests that malnutrition is highly significantly associated with increased levels of blood lead.[9]

Water is an important source of lead poisoning. Lead from the atmosphere may contaminate bodies of water[10]  and equally important, the leaching of lead from water pipes may cause poisoning. Although use of lead pipes (largely replaced by copper or polyvinyl pipes) has declined considerably since the 1950s, old public water systems continue to have networks that include lead piping. Because the use of lead-based soldering of copper pipes was permitted until 1986, homes with copper plumbing may also have substantial lead in the water. In May 2015, at least 28 children under the age of five were killed by drinking stream water contaminated with lead in Nigeria's Niger state.[11]

One of the worst public waterworks failures occurred in Flint, Michigan causing widespread lead poisoning. In 2014, Flint changed sourcing water from Lake Huron to the Flint River to save money. The corrosion-control treatments required by the Environmental Protection Agency were not followed for unknown reasons and increased amounts of chlorine were added to the water due to bacterial contamination. This made the water very corrosive and caused leaching of lead from the aging water system pipes. In six of nine city wards, the water in 20% to 32% of the homes had a lead concentration greter than15 μg per liter. The 90th percentile was 25 μg per liter, and in some samples the lead concentration exceeded 1000 μg per liter (www.FlintWaterStudy.org).[4] The incidence of children with elevated blood lead concentrations (greater than the reference value of 5 μg per deciliter) increased from 2.4% to 4.9% between 2013 and 2015. The increase was greatest, from 4.0% to 10.6%, among children in neighborhoods with the highest lead concentrations in water.[12]

Some hobbies are associated with exposures to lead. These hobbies may include making bullets, making fishing-weights, soldering, indoor firearm shooting, and remodeling older homes.

Soil contaminated with lead can be an important source of lead exposure. Such soil contamination may occur surrounding lead smelters and around older homes with deterioration of exterior surfaces.

Moonshine ethanol (ie, illegally distilled corn whiskey) made in lead-containing vessels, such as discarded automobile radiators, has been associated with lead poisoning and even local epidemics.[13]

Topical agents that contain lead, such as kohl and surma, may be ingested accidentally.

Several reports exist of lead poisoning that develops as the result of absorption of lead from retained bullet or shrapnel fragments. Bullets located in areas bathed by fluids are more likely to dissolve, while those embedded in soft tissues are likely to be walled off by inflammation.

An incidental finding of bullet or shrapnel fragments on an x-ray should prompt consideration of possible elevated lead levels, though most of these cases occur only with intra-articular fragments. Of particular concern is a retained bullet in the spine, an area where removal is often considered too dangerous to attempt.[14]

Familial factors

Frequently, 1 or 2 children in a family develop more lead poisoning than other siblings. This observation may be related to age, activity, or genetics. Identical twins seem to have concordant lead levels and biologic evidence of lead’s effects, but this is less likely to be the case with fraternal twins.

For further information on etiology, see Pathophysiology and Etiology of Lead Toxicity.

United States statistics

Children are more likely than adults to have elevated blood lead levels (BLLs). More hand-to-mouth behavior and better gastrointestinal absorption of lead are some factors contributing to higher BLLs in children. In fact, lead poisoning is said to be the most common environmental illness of children in the United States. The incidence varies with age, socioeconomic status, the population of a given community, race, and the age of the home.

No blood level of lead is safe. In 1991, the CDC defined BLLs of ≥10 µg/dL as the "level of concern" for children aged 1–5 years. However, in May 2012, the CDC accepted the recommendations of its Advisory Committee on Childhood Lead Poisoning Prevention that the term "level of concern" be replaced with an upper reference interval value defined as the 97.5th percentile of BLLs in US children aged 1–5 years from two consecutive cycles of NHANES (National Health and Nutritional Examination Survey). The current upper reference interval value of the 97.5th percentile of the distribution of the combined 2007–2008 and 2009–2010 cycles of NHANES was calculated as 5 µg/dL.[15]

There has been a remarkable decline in BLLs in children over the past 30 years. Data from the 1976–1980 cycle of NHANES indicated that an estimated 88% of children aged 1–5 years had BLLs ≥10 µg/dL. Since then, the percentage has fallen sharply, to 4.4% during 1991–1994 (NHANES III), to 1.6% during 1999–2002, and to 0.8% during 2007–2010.[16] The percentage of children aged 1–5 years with BLLs ≥5 µg/dL from the 2007–2010 NHANES cycle was 2.6% or approximately 535,000 US children. Despite progress in reducing BLLs among children in this age group overall, long-standing disparities persist. The geometric mean BLLs (GM BLLs) among younger children, those belonging to poor families, and those enrolled in Medicaid were significantly higher compared with their older, more affluent counterparts, while the GM BLLs for non-Hispanic black children were significantly higher compared with either non-Hispanic white or Mexican American children.

Generally, adults develop lead poisoning as the result of an occupational exposure or from exposure through a hobby.

Adult Blood Lead Epidemiology and Surveillance (ABLES) is a program that works with states to accurately measure trends in work-related adult BLLs, to better target interventions and prevent lead exposures. The National Institute for Occupational Safety and Health (NIOSH) in 2015 designated 5 µg/dl of whole blood, in a venous blood sample, as the reference BLL for adults. A BLL ≥5 µg/dL is considered abnormal. The US Occupational Safety and Health Administration (OSHA) Lead Standards require workers to be removed from lead exposure when BLLs are equal or greater than 50 µg/dL (construction industry) or 60 µg/dL (general industry) and allow workers to return to work when the BLL is less than 40 µg/dL.

Data from the NHANES show that the average BLL (geometric mean) of all adults in the United States in 2009–2010 was 1.2 µg/dL. Over the last 18 years, a 54% decrease in the national prevalence rates of BLL ≥25 μg/dL has been documented using ABLES surveillance data. In 1994, the rate was 14.0 employed adults per 100,000; in 2011, the rate was reduced to 6.4. In 2010, 40 state ABLES programs that provided data reported 31,081 adults with BLLs ≥10 μg/dL. Among these, 8,793 had BLLs ≥25 μg/dL, and 1,388 had BLLs ≥40 μg/dL. Overall, the national prevalence rate of BLLs ≥10 μg/dL declined from 26.6 adults per 100,000 employed in 2010 (among 37 states) to 20.4 in 2013 (among 29 reporting states).[17]

The highest numbers of workers exposed to lead with BLLs of 25 µg/dL or greater included employees in the storage battery manufacturing and lead and zinc ore mining industries, according to the ABLES report.[18]

International statistics

Lead poisoning has been reported in almost every country on earth. Blood lead levels are higher in developing countries because of continued use or later phaseout of leaded gasoline and paint. Occupational exposure in these countries is higher as well. In particular, the old “iron-curtain” countries had less strict guidelines for occupational and environmental exposures than other places in the world; thus, exposures there were common.

Age-related demographics

Young children who are independently mobile are at greatest neurologic risk from chronic exposure to low or moderate levels of lead. From the time children are able to crawl until they enter school, they are at risk of ingesting lead-containing dust. Although this sometimes is associated with pica and intentional ingestion of paint chips, lead poisoning often occurs without such behavior. Children may also be at risk for lead toxicity if folk remedies are used or if their parents, siblings, or caregivers are involved in lead-related occupations.

Children younger than 3 years are at the greatest risk for lead poisoning. This is because these children are most likely to put things containing lead into their mouths and because their brains are rapidly developing and are most vulnerable to any disorganizing influence. However, physicians and other health care professionals must be aware that lead poisoning can occur in children of any age.

Adults are now believed to be affected at a lower level of exposure than was once assumed. This has sparked renewed interest in occupational exposure to lead and its consequences. Careful attention must be paid to the occupations of adults who present with uncommon peculiar symptoms and signs.

Sex-related demographics

Because of occupational exposures, men have higher lead levels than women. No sex difference in incidence is reported in children.

Racial differences in incidence

Although no compelling evidence exists that any particular race is biologically predisposed to lead toxicity, covariant conditions such as poor nutrition and lower socioeconomic status clearly are associated with chronic lead poisoning.

Certain populations, such as African American children and new immigrants living in homes with decaying lead-based paint in low-income urban centers, are at increased risk of lead poisoning. The NHANES III data have shown higher lead levels among non-Hispanic blacks and Mexican Americans. Whether this translates into a higher incidence of lead nephropathy among these persons is not known.

Overall, black non-Hispanic children appear to have the greatest risk of developing lead poisoning. The NHANES figures for 1997 reveal a prevalence rate of 21.9% among black non-Hispanic children living in homes built before 1946, a rate of 13.7% in those living in homes built in 1946-1973, and a rate of 3.4% in those living in homes built subsequent to 1973.

This compares to a prevalence of 13%, 2.3%, and 1.6% among Mexican-American children and 5.6%, 1.4%, and 1.5% among white non-Hispanic children living in homes built before 1946, living in homes built in 1946-1973, and living in homes built subsequent to 1973, respectively.

An analysis of trends in blood lead levels over the past 20 years shows that, although the overall geometric mean blood lead level in children has dropped dramatically, disparities still exist, causing increased risk to certain populations. The factors of living in older housing, poverty, age, and being non-Hispanic black places a child at risk for elevated blood lead levels.[19]

Essentially, 2 syndromes of lead poisoning exist, depending on exposure: one syndrome is associated with acute or subacute high-level lead exposure, and the other is associated with chronic low-level lead exposure.

With exposure to high levels of lead, patients develop lethargy, progressing to coma and seizures. Death is uncommon with appropriate medical management. Long-term sequelae depend on the duration, as well as the amount, of exposure. Acute lead nephropathy is usually completely reversible with chelation therapy. Deaths may result from the elevated intracranial pressure (ICP) associated with lead encephalopathy.

With chronic exposure to low or moderate levels of lead, subacute symptoms develop. Patients with chronic lead nephropathy may have a progressive decline in kidney function and eventually require renal replacement therapy.

Mortality related to lead toxicity is rare today. However, morbidity remains common. Because lead is an enzymatic poison, it perturbs multiple essential bodily functions, producing a wide array of symptoms and signs.

Adults generally do not develop central effects but may develop distal motor neuropathies. Some reports document an increase in depressive disorders, aggressive behavior, and other maladaptive affective disorders in adult patients with lead poisoning. Men with lead poisoning tend to have lower sperm counts and may experience frank impotence; women have an increase in miscarriages and smaller babies.

In the pediatric population, fatalities associated with lead encephalopathy were reported in the 1960s. Today, with aggressive management of ICP, these deaths are preventable. Occasional cases of acute lead encephalopathy still occur, and these often result in severe neurologic damage. Mounting evidence suggests that lead poisoning in childhood produces a long-term problem with learning, intelligence, and earning power. Asymptomatic lead poisoning has a far better prognosis.

In cooperation with local health departments, the physician should educate families about the following:

• Causes and effects of lead poisoning

• Relationship between blood lead level and anticipated medical or neuropsychological problems

• Importance of follow-up or serial blood lead level determinations to monitor effects of treatment and environmental lead abatement

• Identifying and eliminating possible sources of lead exposure

• Increased lead absorption in patients with iron-deficiency anemia

• Local resources about lead exposure and treatment

All patients must be educated in lead avoidance. The termination of exposure to lead is imperative. In particular, workers should be educated regarding the health risks of lead and sources that may cause poisoning.

A good, substantial diet is important; lead absorption is increased when a diet rich in fats is consumed. Also, diets low in iron, calcium, and vitamin C increase the likelihood of lead absorption and resultant lead poisoning. Dietary fiber helps promote good peristalsis and decreases the opportunity for lead absorption; thus, at least 15 g of dietary fiber is suggested for children each day.

The clinical presentation varies widely, depending upon the age at exposure, the amount of exposure, and the duration of exposure. Organic lead, because of its higher lipid solubility, causes greater toxicity and affects the neurological system predominantly. Younger patients tend to be affected more than older children and adults, because lead is absorbed from the gastrointestinal (GI) tract of children more effectively than from that of adults.

Neurological Toxicity

The neurological system is most vulnerable to lead toxicity.  Children are more likely to develop central nervous system toxicity while the peripheral nervous system is more often affected in adults.

The manifestations in children include temperamental lability, irritability, behavioral changes, hyperactivity or decreased activity, loss of developmental milestones and language delay. Lower IQ and ADHD like symptoms may be present. Severe toxicity can cause delirium, convulsions and encephalopathy. Depression and anxiety are more common in patients. Lead causes demyelination of the peripheral nervous system and the abnormalities mostly affect the extensor motor nerves and may result in hand and foot drop.

Hematological Toxicity

Anemia may develop with lead poisoning due to impaired synthesis of heme, hemolysis of red cells and shortened red cell survival. Anemia is usually mild and is more commonly seen in adults.

Gastrointestinal Toxicity

Patients may develop lead colic, nausea, vomiting and anorexia.  Occasionally, some patients with acute poisoning can develop severe diarrhea and dehydration.

Renal Toxicity

Acute nephropathy manifests with tubular defects, which may include phosphaturia, glucosuria and amino aciduria. This combination of tubular defects is referred to a Fanconi’s syndrome. Chronic lead nephropathy is characterized histologically by chronic interstitial nephritis and is frequently associated with hypertension and gout. Furthermore, lead exposure, at much lower levels than those causing lead nephropathy, acts as a cofactor with more established renal risk factors to increase the risk of chronic kidney disease, development of end-stage kidney disease, and the rate of progression. Adverse renal effects have been reported at mean blood lead levels of less than 5 µg/dL. Cumulative lead dose has also been associated with worse renal function.

Cardiovascular Toxicity

Lead exposure has been associated with the development of hypertension. The development of hypertension may be secondary to oxidative stress or an association with chronic nephropathy. Studies have also documented an association between lead toxicity and cardiovascular disease and stroke.

Reproductive Effects

In men, lead causes a reduction in libido, abnormal spermatogenesis, chromosomal damage and infertility. Women experience an increase in the incidence of stillbirth, miscarriage, pregnancy induced hypertension and prematurity.

Children

No pathognomonic symptoms exist. When symptoms do occur, they are typically nonspecific. Consider lead poisoning whenever a small child presents with peculiar symptoms that do not match any particular disease entity. Common nonspecific symptoms include the following:

• Temperamental lability, irritability, behavioral changes

• Hyperactivity or decreased activity

• Loss of developmental milestones, language delay

More significant exposure to lead may cause symptoms in children that are more likely to lead to a medical evaluation. They are as follows:

• Abdominal pain, loss of appetite, vomiting, constipation

• Headache, ataxia, somnolence

• Lethargy, seizures, stupor, coma

The presence of fever does not rule out the diagnosis, which still must be given full consideration.

Inquiries should be made regarding possible sources of lead exposure. For example, query families about the condition of the home, the presence of peeling or cracking paint and plaster, the occupations or hobbies of the family members, and the presence of industry in the immediate vicinity.

Determine the approximate age of the home. Homes built from 1920 to 1950 are more likely to contain lead pigment-based paint than newer homes. Houses built after 1978 are unlikely to contain lead-pigmented paints. Lead contamination still may be present in plumbing fixtures, but the lead dose in plumbing fixtures is an order of magnitude less than that of paint.

Determine whether the home contains any lead-based kitchen utensils, pottery, or imported toys. In addition, inquire about other homes where the child stays, and determine whether a parent is working as a painter or renovator or in a battery factory, shooting range, or other workplace where that lead is used.

Ask about exposure to foods and additives produced outside the United States. Some spices or food coloring may also contain lead pigments, and some candies have been reported to be contaminated with lead. Also ask about the use of herbal folk remedies. Hispanic and Asian families occasionally use herbal folk remedies that may contain lead.

Investigate the patient’s past medical history, including developmental milestones or delays, hygiene, pica, and previous exposure to lead. Evidence suggests that delayed weaning is associated with excessive pica and lead poisoning. It is commonly found that lead-poisoned children are bottle-fed for protracted periods. Inquire about the patient’s siblings (eg, ages, developmental history, school performance, and blood lead levels [BLLLs] if known).

Adults

In adults, similar symptoms may develop, although cognitive changes may be discerned more easily, especially since exposures are more typically acute. In addition, adults with chronic exposure may develop other symptoms, such as the following:

• Weakness of extensor muscles (eg, foot drop, wrist drop)

• Delirium, hallucinations

Adults with lead poisoning frequently have sleep disorders. They may be hypersomnolent or have difficulty falling asleep at the appropriate time.

A meticulous environmental history is necessary in patients with suspected lead exposure. Depending on whether it is tailored to children or adults, it should include the following information:

Inquire about present and recent residences, including the location, age, and condition of the building; any history of renovations, inspections, or deleading programs; and any analyses of indoor and outdoor surfaces, water, and soil (if available). Ask about practices concerning changing of clothes and the presence of any work areas in the home.

In adults, obtaining a careful occupational and hobby history is important. More than 900 occupations have been associated with cases of lead poisoning. Always ask patients not just the name of their job but also the duties the job entails. This may uncover an obvious cause of exposure.

A history of ingesting illicit liquor may be an important clue to the etiology of lead poisoning. According to a study from a large urban emergency department (ED) involving patients who reported ingesting “moonshine” sometime during the previous 5 years, 51% had elevated BLLs, and 31% had BLLS in the very elevated range (ie, ≥ 50 µg/dL).[20]

Additionally, numerous reports document lead poisoning resulting from retained bullet or shrapnel fragments; thus, a history of military or other penetrating trauma may be important.

Subtle changes in cognitive performance are not identified easily on physical examination. Careful mental status examination may detect changes in more severe cases, while formal neuropsychological testing may be needed to detect changes in other cases.

A child with lead toxicity is frequently iron deficient and pale because of anemia. The child may be either hyperactive or lethargic.

Impaired fine-motor coordination[21] or subtle visual-spatial impairment may be seen. In adults, chronic distal motor neuropathy (eg, foot drop or wrist drop) may be seen with decreased reflexes and weakness of extensor muscles; sensory function is relatively spared (see the image below). This is a classic, though not very common, presentation of occupational lead toxicity.

It is important to evaluate the patient for papilledema, cranial nerve abnormalities, and signs of increased intracranial pressure (ICP). Cranial nerve involvement, particularly involvement of the optic nerve, is not uncommon. Chronic lead exposure has been shown to cause optic neuritis and blindness.[22]

Lead lines appearing on gingival tissue (see the image below) are very unusual in children. The dentition of children does not promote poor enough hygiene to produce pyorrhea and the subsequent precipitation of lead sulfide. Adults with poor dental hygiene may demonstrate this characteristic finding in any heavy metal poisoning.

A report indicates that relative hypertension is related to elevated lead levels, but this finding has never been duplicated.

Lead exposure can precipitate a gout attack. The patient should be observed for joint changes suggestive of acute arthritis. In patients with history of penetrating or military trauma, gunshot wounds must be identified.

Lead poisoning, with or without encephalopathy, may result in neurologic, renal, hepatic, or cardiac damage. All organ systems may be potentially damaged by lead. A possibility that symptoms may progress with chelation exists, and the treating physician must be prepared to manage them. Such complications may consist of syndrome of inappropriate excretion of antidiuretic hormone (SIADH), increased ICP, renal impairment from the chelated lead complex, and hypertension.

Nervous system

Neuropsychiatric problems, impaired cognition, learning difficulties, and antisocial behavior are described in both children and adults.

Peripherally, lead selectively affects motor axons, causing segmental demyelination and axonal degeneration. The upper extremities are affected more often than the lower extremities, and extensors are affected more often than flexors. Hand drop and foot drop are common manifestations of axonopathy.

Kidneys

An increased prevalence of renal adenocarcinoma is reported among lead workers. Variability in individual susceptibility may be explained by differences in lead-binding proteins.

Anemia

Inhibition of enzymes in the heme synthetic pathway, including aminolevulinic acid synthase, delta-aminolevulinic acid dehydratase (ALAD), and ferrochelatase, causes anemia. With kidney disease, erythropoietin production is impaired and thus causes anemia.

Bones

Lead can interfere with bone development, leading to the formation of lead lines at bone metaphyses. These lines represent periods of growth arrest, not lead toxicity per se.

Lead interferes with the conversion of 25-hydroxy vitamin D to 1,25-dihydroxy vitamin D and causes rickets or osteomalacia. Patients with Fanconi syndrome may develop vitamin D–resistant rickets.

Reproductive system

Lead is a known reproductive toxin. In males, it causes reductions in sperm count and fertility. In females, it increases the risk of spontaneous abortions, stillbirths, and preterm births. Offspring may experience lead poisoning in utero and may have developmental delay. Research has demonstrated that these reproductive effects occur at relatively low levels of exposure, even those previously considered safe. Skeletal lead may be mobilized during pregnancy and lactation and can be transported to the fetus or the neonate.

The criterion standard is a whole blood lead level (BLL). Any BLL greater than 5 µg/dL is considered positive and consequential. Patients with BLLs between 10 and 20 µg/dL require removal from the exposure, repeated testing, and follow-up.

A free erythrocyte protoporphyrin (FEP) level may be useful in demonstrating the degree of biological abnormalities that exist. Significantly elevated BLLs are associated with a microcytic anemia. Iron deficiency, also associated with anemia, may produce an elevation of FEP, confounding the significance of FEP measurement.

Workup guidelines for the use of investigative studies in patients with different BLLs (see below) are based on the recommendations from the Centers for Disease Control and Prevention (CDC) Advisory Committee on Childhood Lead Poisoning Preventions, the National Center of Environmental Health/Agency for Toxic Substances and Disease Registry, and the American Academy of Pediatrics Committee on Environmental Health.[23, 24, 25, 26, 27]

Imaging studies are ordered as appropriate.

Lead may produce subtle nephrogenic effects, which, if unappreciated, may lead to treatment failures or complications. For example, a child may appear to have a mild degree of dehydration based on decreased urine output, increased urine specific gravity, and poor appetite while actually suffering from the syndrome of inappropriate excretion of antidiuretic hormone (SIADH). Such patients have hypo-osmolar hyponatremia and, in fact, are often treated with fluid restriction.

Blood lead level

Although not an accurate measure of the whole-body burden of lead, the BLL is a reasonable approximation of lead exposure,[28] in that levels decline in a predictable manner after removal from the source of lead.

Capillary (ie, fingerstick) blood levels do provide a reliable measurement if performed correctly, though samples improperly collected may be contaminated by lead dust on the skin or from the collecting equipment. The blood must be drawn in an anticoagulated tube and one certified to be lead-free. Confirmation of BLL needs a venous blood sample. Trace metal tubes and anticoagulated tubes are available, but aside from certified tubes, they all tend to give high-biased levels. Because of laboratory limitations, the result may not be immediately available at all institutions.

Testing criteria

Most children with elevated blood lead levels demonstrate few, if any, symptoms that immediately suggest lead poisoning. For this reason, the CDC advocates obtaining blood lead levels in children at ages 1 and 2 if they meet any of the criteria noted below. In addition, children aged 3-5 years who have not previously been tested and meet any of the criteria below should be tested.[25, 26] The criteria are as follows:

• Eligible for or receiving Medicaid, or WIC benefits

• Living in a ZIP determined to be high-risk on the basis of age of housing and other factors

• Living in or regularly visiting a house or daycare center built before 1950

• Living in or regularly visiting a house that was built before 1978 with peeling or chipping paint or that has recent (within the last 6 months), ongoing, or planned renovation

• Living with or regularly visiting a sibling, housemate, or playmate with lead poisoning

• Living with an adult whose job or hobby involves exposure to lead

• Living near an active lead smelter, battery recycling plant, or other industry likely to release lead

Free erythrocyte protoporphyrin (FEP) level or zinc protoporphyrin (ZPP)

Lead inhibits enzymes involved in hemoglobin synthesis and causes elevated FEP and ZPP levels. A FEP or ZPP level may be useful in demonstrating the degree of biologic abnormalities that exist.

FEP and ZPP levels can also be used to help distinguish recent acute lead exposure from chronic exposure. If FEP in normal in the context of high blood lead levels, the exposure is more likely acute; if both are elevated, the exposure is more likely chronic. FEP and ZPP elevation lags behind the blood lead elevation that causes it.

Other blood studies

Lead toxicity causes a hypochromic microcytic anemia and basophilic stippling of red blood cells. Hypochromia and microcytosis are typically seen in iron-deficiency anemia, which often coexists with lead toxicity. Assessing iron storage status (ferritin) in all cases of lead poisoning is important. In pregnant women, some evidence suggests that lead also causes a decrease in erythropoietin production and a depression in red blood cell (RBC) production. Lead is a surface-acting poison and may produce increased RBC fragility and acute hemolytic anemia (see the image below).

A chemistry profile including renal studies, liver studies, and a uric acid is advisable. Children often have low uric acid levels and leak uric acid into their urine. Adults, because of the disturbance of enzymatic aminohydrolases, manifest elevated uric acid levels and, possibly, clinical gout.

Abdomen

Obtain a radiograph of the abdomen in children with suspected elevated lead levels. In selected cases, abdominal radiographs may demonstrate lead-containing paint chips or other lead-containing objects (see the image below). Retained lead objects within the gastrointestinal (GI) tract are an acute emergency and should prompt referral for potential removal. A radiograph also helps guide therapy aimed at preventing further absorption through GI decontamination.

Long bones

Radiographs of the long bones in growing children may reveal the characteristic lead lines. These lines, actually growth arrest lines, are not pathognomonic but are associated with BLLs higher than 40 µg/dL over a protracted period (see the image below). A radiodensity in the distal metaphyseal plate is a frequent occurrence in children with chronic lead poisoning of a moderate degree. These findings are unlikely to be observed in adults.

The classic findings of lead lines on radiographs of long bones are rarely seen, because most cases of lead poisoning in children are due to exposures to low or moderate amounts of lead. Obtaining radiographs in search of lead lines is not recommended by the CDC.

In general, neuroimaging (eg, with magnetic resonance imaging [MRI] or computed tomography [CT]) does not play an important role in the diagnosis of lead poisoning. However, cerebral edema and microhemorrhages may be seen in patients presenting with acute encephalopathy on both CT and MRI. With chronic exposure to lead, patchy calcifications may be seen. Atrophy and white matter changes may be present with chronic exposures.

Atre et al reported a case of lead encephalopathy with MRI findings of symmetric occipital lobe lesions that were bright on T2-weighted and fluid-attenuated inversion recovery images and hypointense on T1-weighted images.[29] These lesions disappeared after chelation therapy with clinical laboratory improvement.

Electroencephalography

Findings from electroencephalography (EEG) may be normal or may show nonspecific findings; they generally are not helpful in the diagnosis.

Lumbar puncture

A lumbar puncture (spinal tap) may be needed for evaluation of patients with altered mental status. However, it is contraindicated in patients with lead encephalopathy, because of the possible risk of herniation resulting from elevated intracranial pressure (ICP).

Provocative chelation test

A provocative chelation test may provide additional information (eg, total-body burden). It should not be done in acute lead poisoning because of the potential of precipitating or worsening encephalopathy. Urine is collected after administering a dose of a chelation agent. Edetate (EDTA) calcium disodium (CaNa2 EDTA) is the most commonly used chelator for this test.

Neuropsychological testing

Formal neuropsychological testing provides the best measure of a patient’s cognitive impairment. This is effective in tracking improvement in attention, visual-spatial abnormalities, and memory as a result of treatment and in establishing the extent and nature of long-term impairment.

The most important step in treatment is to prevent further exposure to lead. Accurate assessment of environmental and occupational exposure is essential. Modifying children’s behavior to decrease hand-to-mouth activity is beneficial.

Children

Recommended actions based on BLLs are provided below.[30] Capillary BLL levels need to be confirmed with venous blood draws. The urgency of the confirmation is dependent on the BLL. Levels of 40–59 µg/dl require confirmation in 48 hrs, BLLs between 60 and 69 µg/dl require confirmation in 24 hrs, and higher levels require immediate confirmation.

BLL < 5 µg/dL

Share results with family. Perform routine assessment of nutritional, physical, and mental development and assess risk factors for iron deficiency. Families should be provided with anticipatory guidance about common sources of environmental lead exposure. Repeat BLL in 6–12 months if the child is at high risk for lead exposure or if risk profile increases. For children initially screened before 12 months of age, consider retesting in 3–6 months for children at high risk.

BLLs between 5 and 9 µg/dL

Routine assessment of nutritional and developmental milestones, environmental assessment to identify potential sources of lead exposure, and nutritional counseling related to calcium and iron intake and have follow up BLLs. 

BLLs between 10 and 19 µg/dl

A home visit to identify potential sources of lead exposure in addition to the above are required. Consider checking blood iron levels and repeat BLLs within 3 months.

BLLs between 20 and 44 µg/dl

In addition to the above, patients require neurodevelopmental assessment, assessment of blood iron levels, and abdominal X-rays with bowel decontamination if indicated. Patients with BLL 20–24 µg/dl should have BLL checked in 1 to 3 months. If BLL is between 25 and 44 µg/dl, then retesting must be done within one month.

BLLs ranging from 45 to 69 µg/dl

Such levels warrant medical treatment with oral chelation therapy and environmental assessment and remediation within 48 hours. If a lead-safe environment cannot be assured, then the subjects should be hospitalized.

BLLs greater than 70 µg/dL

These levels are considered medical emergencies, regardless of whether neurologic symptoms are present. The risk of encephalopathy is high and treatment is required. However, lead levels should be reviewed in the context of the clinical examination and history. For example, a child may swallow a lead foreign body, show a documented BLL higher than 70 µg/dL within 2 days, and still have a low total-body burden (the lead would be predominantly within the blood compartment in this scenario). Encephalopathy would not be expected in this scenario. However, a child who chronically ingests lead paint dust may have a lower BLL but a much higher total-body burden and may subsequently exhibit neurologic findings (in this scenario, the lead has had time to redistribute amongst all the compartments).

Adults

The recommendations for management of adults are summarized below:[31]

BLL < 5 µg/dl: No action needed.

BLL 5–9 µg/dl: Discuss health risks and reduce exposure during pregnancy

BLL 10–19 µg/dl: Discuss health risks, decrease exposure, monitor BLL and remove from exposure for pregnancy, certain medical conditions, and long term risks.

BLL 20–29 µg/dl: Remove from exposure during pregnancy, remove from exposure if repeat BLL in 4 weeks remains > 20 µg/dl and an annual lead medical exam is recommended.

BLL 30–49 µg/dl: Remove from exposure and provide prompt medical evaluation

BLL 50–79 µg/dl: Remove from exposure. Provide prompt medical evaluation and consider chelation with significant symptoms

BLL> 80 µg/dl: Remove from exposure and provide urgent medical evaluation. Chelation may be indicated.[31]

The US Occupational Safety and Health Administration (OSHA) has recommendations for occupational lead exposure. Under these guidelines, the permissible exposure limit is 50 µg/m3 for an 8-hour, time-weighted average. Workers with blood lead levels (BLLs) of 60 µg/dL or higher must be removed from the workplace. Additionally, employees should be removed from the workplace if the average of their last 3 BLLs is 50 µg/dL or higher. Individuals with BLLs of 40 µg/dL or higher must undergo medical evaluation.[32]

Medical treatment (ie, chelation therapy) is but one element of a comprehensive treatment plan for exposure to lead; removal of the source of lead exposure is more important. The interventions described below relate to chelation therapy for the most severe cases of lead poisoning. Chelation is of only transient benefit in the patient whose source of lead exposure has not been identified and removed.

Chelation therapy, especially in the setting of encephalopathy, can be complicated. If appropriate facilities for treatment are not available, consider transfer to an institution that is capable of managing an encephalopathic patient and also has a provider experienced in lead poisoning and chelation therapy. Ideally, children should be treated in specialized pediatric intensive care units.

Chelation agents

Succimer is a water-soluble, oral chelating agent that is appropriate for use with BLLs higher than 45 µg/dL.[22, 33]  In a retrospective study from Nigeria, chelation therapy using dimercaptosuccinic acid (DMSA) lowered blood lead levels in children with severe lead poisoning.[34]

D-penicillamine is a second-line oral chelating agent, although it is not approved by the US Food and Drug Administration (FDA) for use in lead poisoning.

Edetate (EDTA) calcium disodium (CaNa2 EDTA) is a parenteral chelating agent. It should never be used as the sole agent in patients manifesting with lead encephalopathy, because it does not cross the blood-brain barrier and can potentially lead to exacerbation of lead encephalopathy; dimercaprol, which does cross the blood-brain barrier, should be administered first. Life-threatening hypocalcemia has been reported when disodium EDTA was inadvertently substituted for CaNa2 EDTA.

Dimercaprol (also referred to as British antilewisite [BAL]) is another parenteral chelating agent recommended as an agent of first choice for patients with lead encephalopathy. With high BLLs (ie, > 100 µg/dL), it is used in conjunction with CaNa2 EDTA.

Acute lead poisoning and nephropathy

In the acute setting, if suggestive radiopacities are observed on a plain radiograph of the abdomen, gastric lavage, cathartics, or whole bowel irrigation may be used to limit lead absorption.

With acute lead poisoning, the indications for chelation therapy are well defined. Institute chelation therapy in children with BLLs of 45 µg/dL or higher. Treat children whose BLLs are 70 µg/dL or higher as medical emergencies.

Succimer and penicillamine may be given orally. Penicillamine may be used when blood lead levels are 25-40 µg/dL, especially with a negative CaNa2 EDTA mobilization test result. Succimer may be an alternative; its main indication is in persons whose BLLs are 45 µg/dL or higher.

Intravenous (IV) therapy is preferable for persons with BLLs of 70 µg/dL or higher. Use the combination of dimercaprol and CaNa2 EDTA with BLLs of 70 µg/dL or higher and in the presence of lead encephalopathy.

In adults, consider chelation therapy for patients with blood lead levels BLLs of 70 µg/dL or higher. Also consider chelation therapy in symptomatic adults with BLLs exceeding 50 µg/dL. Available chelation agents for adults are dimercaprol and CaNa2 EDTA; penicillamine and succimer do not have US Food and Drug Administration (FDA) approval for this application, although they are effective treatments.

Chelation therapy reverses Fanconi syndrome, transient hypertension, and tubular structural changes observed on histopathology findings.

Chronic lead nephropathy

Patients with chronic lead nephropathy, in the absence of marked interstitial fibrosis and with only minimal impairment in kidney function, may respond to chelation therapy.

Extremely limited data are available regarding the benefits of chelation therapy with documented lead nephropathy. In 1979, Wedeen et al treated patients with occupational lead nephropathy and found a 20% improvement in the GFR in 4 of 8 patients given EDTA 3 times a week for 6-50 months.[35] The reported improvements in kidney function could be from reversal of acute-on-chronic lead nephropathy.

Lin and coworkers from Taiwan performed 3 well-designed studies addressing populations of patients with high-normal BLLs and chronic kidney disease.[36, 37, 38]

The first of these studies included 32 subjects with chronic kidney disease (serum creatinine level [SCr] of 1.5-4 mg/dL) and mildly elevated body lead burden (lead excretion value of 150-600 µg with the 3-D CaNa2 EDTA lead mobilization test). Subjects were randomly assigned to receive EDTA chelation therapy or placebo weekly for 2 months and were followed for an additional 12 months. The reciprocal of serum creatinine (1/SCr) versus time data suggested that using chelation may slow the progression of renal disease.

The second study described the results of chelation therapy in 36 subjects (24 study group subjects and 12 controls) with serum creatinine values of 1.5-4 mg/dL and high-normal bone lead burden. This time, chelation therapy with CaNa2 EDTA was administered weekly for 3 months. In the treated group, creatinine clearance improved by as much as 10.2% at 1 year, whereas in the control group, kidney function declined by as much as 11%.

The third study included 202 subjects who were followed for 2 years. In this study, 64 patients with a high-normal body lead burden (urinary lead excretion > 80 µg and < 600 µg after 1 g of CaNa2 EDTA infusion) and SCr lower than 4.2 mg/dL were randomized to chelation or placebo.

In the initial 3 months, the chelation group received 1 g of CaNa2 EDTA every week, and the controls received placebo. In the ensuing 24 months, repeated chelation therapy was administered weekly to patients with a high-normal lead burden unless, on repeated testing, the body lead burden fell below 60 µg.

The glomerular filtration ate (GFR) increased by 11.9% (+3.4 mL/min) in the chelation group at the end of the initial 3 months, whereas it fell by 3.6% (-1 mL/min) in the control group. Thereafter, no further improvement in the GFR was observed in these patients. At the end of 27 months, the mean change in GFR was +2.1 mL/min in the chelation group and -6 mL/min in the control group over the 27-month study.

These studies suggest that in patients with an increased lead burden, chelation with small doses of CaNa2 EDTA at longer intervals might be safe for treating chronic kidney disease. However, repeated and chronic exposure to CaNa2 EDTA may create its own nephrotoxicity; therefore, use caution when deciding to institute chelation therapy. Exclude other causes of kidney disease, and define an endpoint of therapy, such as normalization of the CaNa2 EDTA test results or improvement in kidney function.

Supplementary measures

Closely monitor cardiovascular and mental status in patients with lead poisoning. Maintain an adequate urine output. Assess renal and hepatic functions.

Diphenhydramine may help alleviate the adverse effects of dimercaprol. Iron supplementation should be avoided in patients receiving dimercaprol chelation therapy because dimercaprol forms a complex with iron, leading to toxicity.

The diet should be adequate in energy (caloric) intake and replete in calcium, zinc, and iron. Data from the Normative Aging Study suggest that low dietary intake of vitamin D may increase accumulation of lead in bones, whereas low dietary intake of vitamin C and iron may increase lead levels in blood in subjects who range in age from middle-aged to elderly.

Similar data associate calcium and iron deficiency with lead absorption in children. Although no studies have specifically addressed treatment of lead exposure with calcium and iron supplementation, it is a logical therapy to help limit the absorption of lead.

Primary

The 2010 Healthy People objective to eliminate childhood lead poisoning can be achieved through primary prevention. Pediatricians and family practitioners provide a fundamental role with anticipatory guidance about potential sources of lead exposure and its hazards for the development of children.

A successful primary prevention should focus on the 2 main exposure sources for children in the United States: lead in housing and nonessential uses of lead in certain products, such as imported and domestically manufactured toys, eating and drinking utensils, cosmetics, and traditional medicines.

Environmental measures for prevention of lead toxicity include abatement of lead paint usage, removal of lead from gasoline, and removal of lead solder from cans. Lead abatement in dwellings must be performed by skilled and experienced workers.

For adults, occupational measures focus on engineering controls, such as isolation by containment and local exhaust systems, personal protective equipment (eg, respirators), and good work practices. Workers should be educated regarding the health risks of lead and sources that may cause poisoning.

OSHA standards should be followed in the workplace. These standards for permissible exposure limit lead in the workplace to a maximum of 50 µg/m3 of air averaged over an 8-hour period. Medical surveillance is indicated when workers are exposed to lead levels exceeding 30 µg/m3 for more than 30 days a year (regardless of respiratory protection).

Secondary

Efforts to prevent lead poisoning have focused primarily on secondary prevention because the cost of primary prevention in the form of environmental inspection and abatement of all homes and other sources of lead is prohibitive. This focus does not reflect the true importance of primary prevention.

Secondary prevention focuses on the early detection of lead poisoning. The CDC has devised screening criteria to determine which children are at high risk for lead poisoning; screening of BLLs should be carried out according to these criteria (see Workup). Medical evaluation, treatment, and environmental and public health follow-up are essential in individuals with elevated BLLs.

Consultation with a toxicologist and a nephrologist is appropriate. Medical toxicology services can typically be located by contacting a local poison center.

All occupational exposures must be reported to OSHA. The local or county health departments responsible for monitoring children with lead toxicity, should be informed about patients with elevated lead levels or those undergoing medical treatment, so that they may initiate appropriate environmental evaluation and lead abatement.

Many local health departments have programs for appropriate lead screening of children, in cooperation with local pediatricians. Stressing the need for screening in any patient at risk (because of housing, industrial, ethnic, recreational concerns) is important. Repairs of older homes must be done carefully to avoid lead exposure. Proper lead abatement in older homes prevents future exposure to lead and, thus, prevents further lead poisoning.

All patients treated for lead poisoning require extensive outpatient follow-up. The intent of such follow-up is to avoid further exposure to lead and to maintain lead levels in the acceptable range.

After chelation, the blood lead level should be rechecked in 7–21 days to determine whether repeat chelation therapy is required. Chelation therapy, either oral or intravenous, may be continued in an outpatient setting if indicated. Carefully monitor kidney and liver function during therapy.

Assess the source of lead. Involvement of the local health department can assist in this regard. Do not discharge patients from the hospital until they can go to a lead-free environment. Children in particular should not be allowed to return to a lead-contaminated environment; if they are exposed to more lead, their lead levels will rapidly rise again.

There is a general belief, probably incorrect, that once chelation is terminated, BLLs will rebound rapidly. Numerous publications have discussed the effect of lead stored in bone.[39, 40, 41, 42, 43, 18] In the light of the known kinetics of lead in the body and the reports of expected decreases in lead level over time, this would not appear to be expected, because the half-life of lead in bone is measured in years. Thus, significant elevations in BLL after termination of chelation should be considered probable reexposure.

The mainstay of treatment is chelation therapy. Chelation agents contain sulfhydryl groups that bind or chelate lead, and the resulting complex is excreted either renally or hepatically. The chelation agents succimer and penicillamine are given orally, whereas dimercaprol and edetate (EDTA) calcium disodium (CaNa2 EDTA) are administered parenterally.

These agents reduce body stores of lead. Reducing blood lead levels also may mobilize skeletal stores of lead. Therefore, caution must be exercised in using chelation agents, both because of their adverse effects and because of their ability to mobilize lead.

Dimercaptopropanesulfonic acid (DPMS) has received much attention worldwide, but it is not yet available in the United States, except under special FDA Investigational New Drug (IND) permits. In Europe and Asia, DPMS has become the drug of choice for most heavy metal intoxications. It is available both in an oral form and in a water-based parenteral form.

Class Summary

Antidotes are used to prevent intoxication resulting from lead poisoning. These agents bind lead in the vascular compartment and prevent it from reaching the end organs of toxicity. Chelators promote the excretion of lead.

Succimer (Chemet)

Succimer, or meso 2,3-dimercaptosuccinic acid (DMSA), is an analogue of dimercaprol used in lead poisoning. It has high sensitivity for lead, but its ability to chelate essential trace metals is low. It is available as capsules of 100 mg. Succimer is generally well tolerated after oral (PO) administration and produces a linear dose-dependent reduction in serum lead concentration. It forms a water-soluble chelate with heavy metals and is excreted in urine. It produces plumburesis approaching that achieved with the combination of CaNa2EDTA and dimercaprol.

In January 1991, succimer became the only drug approved by the US Food and Drug Administration (FDA) specifically for lead chelation in children and the only drug approved to treat a specific laboratory test—namely, a blood lead level (BLL) higher than 45 µg/dL (2.17 mmol/L). It has been shown to be an effective oral chelator.

Although never a substitute for careful environmental controls, succimer produces a rapid decline in lead level and reverses many of the biochemical indicators of toxicity. It is not currently licensed for use in adults. Although experience suggests that this agent is safe and effective, its use must be considered carefully. Adults exposed from an occupational source must be carefully excluded from further exposure.

Patients with extremely high lead levels may experience abnormalities in gastrointestinal (GI) motility; thus, the absorption of succimer may be unpredictable or erratic. Use of this agent in patients with lead levels higher than 60 µg/dL has not been carefully studied. Therefore, consideration should be given to the use of parenteral therapy until lead levels drop below this value.

Edetate calcium disodium

CaNa2EDTA is nearly the perfect chelator. It is water-soluble, can be administered either intravenously (IV) or intramuscularly (IM), allows lead to be renally eliminated, is not metabolized, and has few toxic effects. Its main limitation is that it removes lead from extracellular spaces only.

CaNa2EDTA should generally be given IV, diluted to a concentration of less than 0.5% in 5% dextrose in water (D5W) or isotonic saline. In patient with acute lead encephalopathy and increased intracranial pressure, dilution to concentration of less than 3.0% may be necessary, or the IM route may be preferred to limit fluids. Ideally, the first dose of dimercaprol should be given at least 4 hours before CaNa2EDTA. Note that CaNa2EDTA initially may aggravate symptoms of lead toxicity because of its mobilization of stored lead.

CaNa2EDTA may induce central nervous system (CNS) toxicity if BAL therapy is not initiated first when blood lead levels are higher than 70 µg/dL in children or 100 µg/dL in adults and in encephalopathy. To prevent hypocalcemia, only CaNa2EDTA should be used for chelation in heavy metal toxicity.

When CaNa2EDTA is given IM, the same daily dose is used, divided into 2-6 doses. IM preparations of CaNa2EDTA are extremely irritating to muscle and intensely painful. Lidocaine or procaine with the IM preparation lessens the pain.

Dimercaprol (BAL in Oil)

Dimercaprol (British antilewisite [BAL], or 2,3-dimercapto-1-propanol) was the first chelator used in encephalopathic individuals and is the drug of choice for treatment of lead toxicity. It is a chelating agent for intracellular and extracellular lead that and diffuses into red blood cells (RBCs) and rapidly crosses the blood-brain barrier. Sulfhydryl groups combine with ions of heavy metals to form soluble, nontoxic complexes that are excreted renally. Dimercaprol is excreted primarily in bile, making it an agent that can be used in patients with renal failure.

Combination therapy with dimercaprol and CaNa2EDTA is recommended in all cases of severe, acute intoxication (eg, BLL > 100 µg/dL), particularly when encephalopathy is present. Dimercaprol is administered IM every 4 hours, mixed in a peanut oil base; therefore, it should not be used in patients allergic to peanuts. In very severely poisoned patients, the dose is increased to 7 mg/kg, with great caution.

Adverse effects are fever, pain at the injection site, nausea, vomiting, headache, and sterile abscess formation.

D-penicillamine (Cuprimine, Depen Titratabs)

D-penicillamine (3-mercapto-D-valine), a second-line oral chelating agent, is a hydrolysis product of penicillin that is FDA-approved for the treatment of Wilson disease and cystinosis. It has been used as an oral chelator of lead for 30 years but has never been licensed for this indication by the FDA.

Penicillamine is effective orally and has few adverse effects. It can be administered over an extended period (weeks to months) for children with lead levels below 45 µg/dL. Penicillamine is available as capsules of 125 mg and 250 mg. Pyridoxine supplementation is required. Adjust the dose for patients with compromised renal function.