Lightening the Lead Load in Children

MARK R. ELLIS; KEVIN Y. KANE

MARK R. ELLIS, M.D., M.S.P.H., AND KEVIN Y. KANE, M.D., M.S.P.H

Am Fam Physician. 2000;62(3):545-554

A more recent article on lead poisoning in children is available.

See related patient information handout on preventing and treating lead poisoning in children, written by the authors of this article.

More than 4 percent of preschool-aged children in the United States have blood lead levels above 10 μg per dL (0.50 μmol per L), and these levels have been associated with a decline in IQ. The Centers for Disease Control and Prevention advocates the use of a screening questionnaire to identify lead exposure or toxicity in all children. Primary prevention through the removal of lead from gasoline and paint has led to a reduction of blood lead levels in children. Secondary prevention through paint hazard remediation is effective in homes that have a high lead burden. Children with lead levels of 45 to 69 μg per dL (2.15 to 3.35 μmol per L) should receive chelation therapy using succimer (DMSA) or edetate calcium disodium (CaNa2EDTA). Use of both CaNa2EDTA and dimercaprol (BAL in oil) is indicated in children with blood lead levels higher than 70 μg per dL (3.40 μmol per L). Current treatment recommendations are based on the reduction of blood lead levels, which may not represent a significant overall reduction of the lead burden. Clinical trials of existing agents are needed to determine patient-oriented outcomes, such as the effect on IQ.

Lead poisoning has been a significant public health problem for centuries. Studies conducted in the United States since 1950 have shown the adverse effects of even low levels of lead exposure. Consequently, lead poisoning is now defined as a blood lead level equal to or greater than 10 μg per dL (0.50 μmol per L).¹

In the United States, about 4.4 percent of children between one and five years of age have blood lead levels above 10 μg per dL.² Elevated levels of lead are found significantly more often in black children, children from low-income families and children who live in urban areas.² In 1995, 14 million children younger than eight years lived in housing that contained high concentrations of lead paint.¹ Other common sources of exposure include lead-soldered pipes, lead in soil, lead in dust from home-remodeling projects, lead chromate in coated electrical wire, lead-glazed ceramics, leaded crystal and lead-soldered cans manufactured in foreign countries.³

Adverse Health Effects of Lead Poisoning

Blood lead levels below 70 μg per dL (3.40 μmol per L) can result in damage to the central nervous system, kidneys and hematopoietic system. Lead toxicity is associated with a two- to three-point decrease in IQ test scores for every increase of 10 μg per dL in the blood lead level.^1,4 Elevated blood lead levels are also associated with neurodevelopmental abnormalities, including attention deficit disorder, behavioral disturbances, learning disabilities and deficits in fine and gross motor development.^4–7

Toxic effects on the central nervous system and resultant long-term neurobehavioral and cognitive deficits occur even with mildly elevated blood lead levels (10 to 25 μg per dL [0.50 to 1.20 μmol per L]).^6–8 At high blood lead levels (more than 70 μg per dL), nephropathy, neuropathy, increased intracranial pressure, seizures and death are common.^3,5

Lead toxicity is also associated with renal defects in vitamin D metabolism and microcytic anemia.^3,9

Screening Protocols

The Centers for Disease Control and Prevention (CDC) and the American Academy of Pediatrics (AAP) have addressed the societal burden of lead poisoning¹⁰ by issuing recommendations for childhood lead screening.^4,5 These recommendations include universal screening for lead poisoning in areas where at least 27 percent of houses were built before 1950 and in populations in which 12 percent or more of one- and two-year-old children have elevated blood lead levels. In all other areas, the CDC promotes targeted blood lead screening of children between six months and six years of age based on positive responses to one or more items on a screening questionnaire^3,4,11,12 (Table 1).⁵

Does your child live in or regularly visit a house that was built before 1950?†

Does your child live in or regularly visit a house built before 1978 with recent or ongoing renovations or remodeling (within the past 6 months)?

Does your child have a sibling or playmate who has or did have lead poisoning?

The American Academy of Family Physicians recommends lead screening at 12 months of age in infants who meet the following criteria¹³:

Residence in a community with a high or undefined prevalence of lead levels requiring intervention.
Residence in or frequent visits to a home built before 1950 that has dilapidated paint or has recently undergone or is undergoing renovation or remodeling.
Close contact with a person who has an elevated blood lead level.
Residence near a lead industry or heavy traffic.
Residence with a person whose hobby or job involves lead exposure.
Use of lead-based pottery.
Use of traditional remedies that contain lead.

Universal blood lead screening is somewhat controversial.¹⁴ Physicians should check with the local health department to determine if universal screening is necessary in that geographic area. When possible, venous blood samples should be used for initial screening. If capillary (fingerstick) blood testing is used initially, values above 10 μg per dL should be confirmed with a venous sample (Table 2).⁴

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Prevention Strategies

PRIMARY PREVENTION

Strategies for the primary prevention of lead poisoning have only been implemented within the past 25 years. One such measure, the Environmental Protection Agency's mandated removal of lead from gasoline, resulted in a 73 percent decrease in gasoline-related lead consumption between 1975 and 1984. This action coincided with a 37 percent reduction in blood lead levels from 1976 through 1980. A second major primary prevention strategy, the removal of lead from paint, was mandated in 1978. Cost benefits for the removal of lead from gasoline and paint have been reported.¹⁵

Additional primary prevention strategies have been proposed by the U.S. Department of Health and Human Services and have been endorsed by the CDC.¹⁶

SECONDARY PREVENTION

Secondary prevention of lead poisoning includes family education, high-efficiency particulate air (HEPA) vacuums, interior dust abatement, soil abatement and residential paint hazard remediation. The efficacies of environmental lead removal techniques are reviewed in Table 3.

Intervention	Relative efficacy	Comments
Residential paint hazard remediation	B	Most efficacious in homes where children have preabatement blood levels higher than 35 μg per dL (1.70 μmol per L)
		Risk of transiently elevated blood lead levels during remediation
High-efficiency particulate air (HEPA) vacuuming	C	Probably requires frequent intervention (more than 20 times per year)
Interior dust abatement	C	Inconsistent evidence to support efficacy, although efficacy was recently demonstrated for combined use of interior dust abatement and HEPA vacuuming
		Probably requires frequent intervention (more than 20 times per year)
Soil abatement	D	Associated with very small reductions in blood lead levels (less than 2.7 μg per dL [0.15 μmol per L])

In one study,¹⁷ researchers visited families and provided literature on lead poisoning, information on behaviors that increase the potential for lead exposure, instructions on proper nail care and diet for children, and suggestions for the removal of peeling paint. These interventions were associated with a 40 percent decline in blood lead levels over one year in children who had an average initial blood lead level of 15 μg per dL (0.70 μmol per L). Because the study did not report the frequency of paint removal in these homes, the effect of education as a sole intervention is uncertain.

HEPA vacuums retain lead-containing particles that slip through the filters of conventional vacuum cleaners.¹⁸ Dust control strategies include the use of an all-purpose cleaner or detergent solution to wipe or mop the floors, walls and horizontal surfaces of lead-contaminated dwellings. Most studies have not found HEPA vacuuming and dust control measures to be efficacious,^18,19 although one recent randomized, controlled trial²⁰ of these methods demonstrated a 34 percent reduction in the blood lead levels of children whose homes were treated 20 or more times during a one-year period.

Soil abatement is accomplished by removing the top 15 cm (6 in) of soil from the yard, covering the exposed subsurface with geotextile fabric and then replacing the top layer with 20 cm (8 in) of clean soil and ground cover.³ This intervention has been associated with a decline in blood lead levels of only 0.8 to 2.7 μg per dL (0.05 to 0.15 μmol per L) in children with low to moderate baseline lead levels.^21,22 Based on study findings, soil abatement is an expensive and low-yield intervention in most children with low-level lead exposure.

Paint hazard remediation entails removing lead paint from surfaces 1.5 m (5 ft) or less above the ground or covering lead paint on these surfaces, and removing loose paint from other surfaces in the living area.²¹ This intervention has been associated with an 18 to 23 percent decline in the blood lead levels of children with baseline lead levels of 25 μg per dL or higher.^23,24 The greatest effect of paint hazard remediation is seen in children with preabatement blood lead levels of 35 μg per dL (1.70 μmol per L) or higher.²⁴

Paint hazard remediation in homes having a low lead burden has not been found to result in a clinically significant decline in blood lead levels. In fact, the intervention may actually increase blood lead levels.^21,23

New statutes have curtailed abatement techniques thought to be associated with transient increases in residents' blood lead levels during remediation. These techniques include dry abrasive blasting and on-site use of methylene chloride or propane torches.²⁵

Pharmacologic Treatment

If a child is found to have a significantly elevated blood lead level (greater than 45 μg per dL [2.15 μmol per L]), chelation therapy should be considered (Tables 2⁴ and 4²⁶ ). Specific treatment recommendations are based on the measured blood lead level. Available chelation agents include the following:

Dimercaprol, or BAL (British anti-lewisite) in oil.
Edetate disodium calcium, or CaNa2EDTA (calcium disodium salt of ethyl-enediaminetetraacetic acid [EDTA]).
Succimer, or DMSA (2,3-dimercaptosuccinic acid).
Penicillamine (Cuprimine). Note that the U.S. Food and Drug Administration (FDA) has not labeled penicillamine for the treatment of lead poisoning.

The efficacies of pharmacologic treatments for lead poisoning are reviewed in Table 5.

Blood lead level,μg per dL (μmol per L)	Intervention
< 25 (1.20)	Environmental intervention
25 to 44 (1.20 to 2.10)	Aggressive environmental intervention
25 to 44 (1.20 to 2.10)	Consider oral chelation therapy if blood lead levels persist in this range after environmental intervention.
45 to 69 (2.15 to 3.35)	Before chelation therapy is initiated, obtain an abdominal radiograph to look for enteral lead; if lead is present, consider bowel decontamination as an adjunct to treatment.
	If no signs of encephalopathy are present, succimer, or DMSA, may be given in a dosage of 30 mg per kg per day for 5 days, followed by 20 mg per kg per day for 14 days; consider hospitalization to monitor for side effects of chelation therapy and to start environmental abatement.
	Alternative therapy: inpatient treatment with edetate disodium calcium, or
	CaNa2EDTA, in a dosage of 25 mg per kg per day for 5 days
> 70 (3.40)	If signs of encephalopathy are present, obtain a consultation; admit the child to an intensive care unit for treatment of increased intracranial pressure, monitoring of mental status and hemodynamic stability, osmotic therapy and drug therapy, in addition to chelation therapy.
	Initiate chelation therapy with dimercaprol, or BAL, administered intramuscularly in a dosage of 25 mg per kg per day divided into six doses.
	After the second dose of BAL (4 hours after the first dose), immediately administer CaNa2EDTA, 50 mg per kg per day in a single dose given intravenously during several hours or as a continuous slow infusion.*
	Continue treatment with BAL and CaNa2EDTA for at least 72 hours.
	After initial treatment, parenteral therapy with CaNa2EDTA and BAL or with CaNa2EDTA alone may be continued for a total of 5 days.

Intervention	Relative efficacy	Comments
Edetate disodium calcium, or CaNa2EDTA	A	Only agent demonstrating improvement in IQ test scores
Edetate disodium calcium, or CaNa2EDTA	A	Risk of renal toxicity
Succimer, or DMSA	B	Only oral agent indicated for the treatment of lead poisoning (blood lead levels of 45 to 69 μg per dL [2.15 to 3.35 μmol per L])
Succimer, or DMSA	B	Efficacy is currently being assessed in children with moderate lead toxicity (blood lead levels of 20 to 44 μg per dL [0.95 to 2.10 μmol per L]).
Dimercaprol, or BAL	B	Chelates lead in the brain
Dimercaprol, or BAL	B	Recommended in combination with CaNa2EDTA for children with blood lead levels higher than 70 μg per dL (3.40 μmol per L)
Penicillamine (Cuprimine)	B	Not labeled by the U.S. Food and Drug Administration for the treatment of lead poisoning
		Risk of nephrotoxicity
		Because of toxicity, this agent should be used only when treatment with DMSA, CaNa2EDTA and/or BAL is contraindicated.

DIMERCAPROL (BAL)

Dimercaprol, or BAL, binds with lead and is excreted in bile and urine. In children with blood lead levels exceeding 70 μg per dL, BAL is used in combination with CaNa2EDTA to chelate lead in the brain. BAL is mixed in peanut oil. The dosage is 25 mg per kg per day given intramuscularly in six divided doses (4.16 mg per kg per injection) for two to five days.¹⁶, ²⁶

Common side effects of BAL include mild febrile reactions, mild elevation of liver transaminase levels, nausea and vomiting, headache, conjunctivitis, lacrimation, rhinorrhea and salivation.¹⁶ To avoid a possible toxic reaction, iron supplementation for lead-caused anemia should be deferred until BAL therapy has been completed.²⁶

BAL treatment is contraindicated in patients with peanut allergies. This chelation agent can cause hemolysis in patients with glucose-6-phosphatase deficiency.¹⁶

EDETATE DISODIUM CALCIUM (CANA2EDTA)

Edetate disodium calcium, or CaNa2EDTA, binds with extracellular lead and increases urinary lead excretion. This chelation agent should not be confused with disodium edetate (NaEDTA), which can cause fatal hypocalcemia.²⁶

CaNa2EDTA is recommended as monotherapy for the treatment of children with blood lead levels between 45 and 69 μg per dL (2.15 and 3.35 μmol per L). It is also recommended for use in combination with BAL for the treatment of blood lead levels higher than 70 μg per dL.¹⁶, ²⁶

The appropriate dosage of CaNa2EDTA is 25 to 50 mg per kg per day for five days, depending on the initial blood lead level.¹⁶, ²⁶ This agent is usually given intravenously in a solution of less than 0.5 percent dextrose and water or in a 0.9 percent saline solution. Slow infusion of CaNa2EDTA over four hours is indicated because rapid infusion may precipitate encephalopathy. Intramuscular administration is possible but causes extreme pain if CaNa2EDTA is not mixed with procaine.

Common side effects of CaNa2EDTA therapy include proteinuria, urinary sedimentation and transient elevations of blood urea nitrogen, creatinine and liver enzyme levels. Adequate hydration is essential when CaNa2EDTA is used, and patients should be monitored closely for signs of renal toxicity and oliguria.¹⁶

The findings of several studies support the use of CaNa2EDTA in children with blood lead levels above 45 μg per dL.^27,28 Perhaps the most important of these investigations is a prospective study in 154 children who had initial blood lead levels of 25 to 55 μg per dL (1.20 to 2.65 μmol per L).²⁷ This study compared the use of CaNa2EDTA therapy plus home lead abatement with the sole use of home lead abatement. The investigators found that the children treated with CaNa2EDTA had a one-point increase in IQ test scores over six months for every 3 μg per dL (0.15 μmol per L) decrease in blood lead levels. Whether such a minimal increase in IQ test scores has any functional significance remains to be seen.

SUCCIMER (DMSA)

Succimer, or DMSA, is the only available oral agent for lead chelation. This agent is approved for use in children with blood lead levels of 45 to 69 μg per dL. The recommended dosage is 10 mg per kg taken every eight hours for five days, then every 12 hours for two weeks. Multiple courses may be given, with a minimum of two weeks between courses.¹⁶, ²⁶

Drawbacks of succimer therapy include a “rotten egg” sulfur odor, abdominal pain, nausea and vomiting, diarrhea, and possible elevation of hepatic transaminase levels.³ Like any chelation agent, DMSA should be given with aggressive home lead abatement to avoid continued lead toxicity.¹⁶

Because DMSA therapy has been associated with 43 to 60 percent reductions in blood lead levels,^29,30 the outlook is favorable for its use in children with low-level lead poisoning. DMSA has fared well in studies comparing it to other chelation agents.

One retrospective study³¹ that compared children treated with BAL and CaNa2EDTA and children treated with DMSA and CaNa2EDTA found a comparable reduction in post-treatment blood lead levels in the two groups but fewer adverse treatment effects in the DMSA group. In two small, noncontrolled clinical trials^32,33 comparing the use of DMSA and CaNa2EDTA in children with initial blood lead levels of 31 to 69 μg per dL (1.50 to 3.35 μmol per L), high-dose DMSA therapy reduced mean blood lead levels by 61 to 77 percent over five days. In both studies, the blood lead levels of the children treated with CaNa2EDTA declined by about 45 percent.^32,33

In contrast, a recently published randomized, controlled trial of DMSA versus placebo in conjunction with environmental remediation in children who had baseline blood lead levels of 30 to 45 μg per dL (1.45 to 2.15 μmol per L) found similar reductions in lead levels after six months.³⁴ However, this study of 39 children may have lacked the power to detect a statistical difference between the DMSA and placebo groups.

Based on research and experience, the CDC and AAP recommend succimer therapy for children with blood lead levels above 45 μg per dL. Although some health centers use DMSA in children with lower levels of lead poisoning, the scientific literature demonstrating the efficacy of this agent at lower levels is inconclusive.

We believe that succimer should not be given routinely to children with blood lead levels below 45 μg per dL, although there may be a place for its use on a case-by-case basis in coordination with a pediatric specialist. A large randomized, controlled trial is currently in progress to assess the efficacy of DMSA in children with moderately elevated lead levels (20 to 44 μg per dL [0.95 to 2.10 μmol per L]).³⁵ The findings of the study may lend support to the use of succimer in children with lower blood lead levels.

PENICILLAMINE

Although the FDA has not labeled penicillamine for the treatment of lead poisoning, one retrospective study³⁶ found that this agent reduced blood lead levels by 33 percent in children with initial levels of 25 to 40 μg per dL (1.20 to 1.95 μmol per L).

Adverse effects of penicillamine include rash, leukopenia, thrombocytopenia, hematuria, proteinuria, eosinophilia, elevated liver enzyme levels and nephrotoxicity. Because of the toxicity of penicillamine, the AAP recommends that this agent be used to treat lead poisoning “only when unacceptable reactions have occurred to DMSA and CaNa2EDTA and continued therapy is considered important.”^26(p158)

If penicillamine is used, the appropriate dosage is 20 to 30 mg per kg per day in divided doses taken for up to several months. Children should be started on a small dose that is gradually increased. Complete blood count and urinalysis should be monitored routinely throughout treatment. Penicillamine therapy is contraindicated in children with known penicillin allergy.¹⁶

Management of Lead Toxicity

Children with elevated blood lead levels should undergo clinical evaluation (Table 6).⁵ The proper management of children with blood lead levels higher than 10 μg per dL is based on the relative degree of the elevation. The CDC recommends a coordinated program of follow-up screening, education, case management, environmental investigation, lead hazard control and clinical evaluation.¹⁶ The AAP recommendations, summarized in Tables 2⁴ and 4,²⁶ differ only slightly from the CDC recommendations.

Medical history

Symptoms

Developmental history

Mouthing activities (e.g., pica)

Previous blood lead level measurements

Family history of lead poisoning

Environmental history

Age, condition and ongoing remodeling or repainting of primary residence and other places where the child spends time (including day care centers)

Other local sources of potential lead exposure (e.g., industrial facilities, construction sites)

Potential lead exposure relating to occupations or hobbies of adults

Nutritional history

Dietary history (including participation in food stamps program and WIC [Women, Infants and Children])

Iron status

Physical examination

Neurologic evaluation

Assessment of psychologic and language development

BLOOD LEAD LEVELS OF 10 TO 19 μG PER DL

For children with blood lead levels between 10 and 19 μg per dL (0.5 to 0.9 μmol per L), the CDC recommends nonpharmacologic interventions. Family education should include information on sources of lead exposure, potential adverse health effects, good nutrition and control of lead dust.

BLOOD LEAD LEVELS OF 20 TO 44 μG PER DL

For children with blood lead levels between 20 to 44 μg per dL, strategies recommended by the CDC include case management by a qualified social worker, clinical management, environmental assessment and lead hazard control.⁵ Local health departments are valuable resources for providing lead education, coordinating home inspections and helping with financial assistance or home relocation. Appropriate medical management involves a thorough clinical evaluation and possible cautious use of chelation therapy in children with refractory blood lead levels.

BLOOD LEAD LEVELS OF 45 TO 69 μG PER DL

The CDC and AAP support the use of chelation therapy in children with blood lead levels between 45 and 69 μg per dL. The CDC recommends CaNa2EDTA monotherapy.¹⁶ The recommended dosage is 25 mg per kg per day given by continuous infusion or in divided doses for no more than five days, with regular monitoring of blood electrolyte levels and renal and hepatic function during treatment.²⁶ A second course of CaNa2EDTA may be given if the blood lead level rebounds to 45 μg per dL within seven to 14 days after treatment.

In children without encephalopathy, the AAP supports the use of DMSA for the treatment of blood lead levels of 45 to 69 μg per dL. The recommended dosage is 30 mg per kg per day for five days, followed by 20 mg per kg per day for 14 days.²⁶

Hospitalization may be warranted initially to monitor side effects and implement proper environmental lead abatement.²⁶

BLOOD LEAD LEVELS GREATER THAN 70 μG PER DL

Children with blood lead levels higher than 70 μg per dL, with or without encephalopathy, should be hospitalized and started on immediate chelation therapy. The CDC and the AAP recommend combined treatment with CaNa2EDTA and BAL.^16,26

The recommended dosage of BAL is 25 mg per kg per day given in divided doses every four hours. The first dose of BAL should be administered at least four hours before the first dose of CaNa2EDTA because CaNa2EDTA alone may aggravate symptoms and BAL chelates the lead in brain tissue. The dosage of CaNa2EDTA is 50 mg per kg per day in a single dose given intravenously over several hours or by continuous infusion.^16,26

The CDC recommends initial treatment with both BAL and CaNa2EDTA for five days. Blood lead levels should be monitored after this treatment. A second course of CaNa2EDTA alone is recommended if blood lead levels rebound to 45 to 69 μg per dL; the use of CaNa2EDTA in combination with BAL is recommended for rebound blood lead levels higher than 70 μg per dL. The CDC recommends waiting five to seven days between the end of the first course and the beginning of a second course. After another five-day waiting period, a third course of CaNa2EDTA alone may be needed if blood lead levels rebound to higher than 45 μg per dL within 48 hours of the second course.¹⁶

The AAP recommendations differ slightly. According to the AAP, BAL can be stopped after a minimum of three days of initial treatment. CaNa2EDTA is then continued alone for the full five-day course.²⁶

Challenges in Lead Poisoning Management

The management of lead poisoning remains challenging. Lead has a long half-life and is absorbed into bone and other tissues. Post-treatment rebound of blood lead levels is problematic, and questions remain about the duration of chelation therapy that is necessary to provide a clinically meaningful reduction in the overall body lead burden. Only one study,²⁷ using CaNa2EDTA, has shown a modest increase in IQ six months after treatment, and this outcome has not been demonstrated for all chelation agents. Other neuro-behavioral outcomes of treatment also need to be studied. The CDC has emphasized the importance of addressing these challenges and has called for future research in the area of lead poisoning management.⁵

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