By Adrienne S. Ettinger, M.P.H.

Chelation therapy for lead poisoning has been used for more than 40 years¹ to increase urinary excretion of lead in the blood and decrease total body burden. The use of chelation therapy for the treatment of elevated blood lead levels (EBLLs), however, is not without controversy. While the method of chelation is well established, the agents, dosing, and indications are seldom clear-cut. In addition, there is little evidence that the treatment of lead-exposed children improves long-term neurological outcomes that removal from the leaded environment alone would not. The introduction of a new oral chelating agent and revised guidelines from the Centers for Disease Control and Prevention (CDC), which lowered the blood lead level (BLL) of concern in children, have together reignited the debate around the treatment and management of lead poisoning in children.

Childhood lead poisoning is an entirely preventable disease; however, lead remains a primary environmental concern for children’s health. Despite substantial progress in reducing lead exposure in the United States with its removal from gasoline in the 1970s, millions of young children remain at risk for lead poisoning.² The distribution of risk varies widely within the U.S., primarily being determined by conditions of the child’s residence. Lead in paint and house dust are by far the most common sources of exposure in U.S. children.³

During the past twenty years there have been significant advances in the understanding of the absorption, distribution, retention, and toxic effects of lead.⁴ Lead is a potent neurotoxin that serves no useful purpose in the human body. There is no accurate measure of total body lead; blood lead concentration reflects only a small proportion of the total body burden. The remainder is found in large part in bone and, to a lesser degree, in soft tissues such as the brain, liver, and kidney, although differences in lead distribution have been observed at various stages of life. A greater percentage of lead in children may be found in the soft tissue compartments of the body. The primary sites of toxicity are the nervous, hematopoietic, and renal systems.

Lead is a particular hazard to young children because children absorb lead more readily than do adults. In addition, the developing nervous systems of children are more susceptible to the toxic effects of lead. Blood lead levels (BLLs) as low as 10 µg/dL have been associated with adverse health effects in young children.⁵ At high levels (> 70 µg/dL), lead can cause seizures, coma, and death. Many studies have shown a significant association between early childhood exposure to lead and decreased cognitive function, attention deficits, and behavior problems.^{6, 7, 8, 9, 10} It remains unclear whether or not these effects are reversible. Peak blood lead levels at 2 to 3 years of age are inversely associated with cognitive test scores for exposed children measured between age four to eleven years, with reported deficits of three to seven intelligence quotient (IQ) points per 10 µg/dL increase in average blood lead concentration. A recent study compared amount decline in BLL with cognitive performance and found that deficits associated with early childhood exposure to lead appear to be only partially reversible.¹¹

An estimated 890,000 children aged 1-5 years, or 4.4% of the U.S. population in that age range, have EBLLs (>10 µg/dL).¹² Elevated lead levels are largely asymptomatic making their early detection unlikely without routine screening. In 1991, CDC recommended universal screening of children less than 72 months of age for lead poisoning. All children with confirmed, venous BLLs greater than or equal to 20 µg/dL require medical and environmental evaluation. As many as 10% (89,000) of children with EBLLs fall in this range.¹³

CLINICAL PHARMACOLOGY

Lead is a bluish-white heavy metal (plumbum, Pb²⁺) which inhibits enzymes in many biochemical pathways due to its affinity for several functional groups, particularly sulfhydryl groups.¹⁴ Several agents (Table 1) are available for use in the treatment of lead toxicity. Chelating agents (Figure 1) competitively bind lead, removing it from biologically active molecules, and the complexes formed are excreted from the body. Therapy has been based on the ability of chelating agents to reverse the hematologic effects (Figure 2) of lead and to reduce the effects of lead encephalopathy. In addition to its ability to bind and therefore remove lead, an essential characteristic of an ideal lead chelator is the ability to do so in the absence of adverse effects produced by interfering with homeostasis and utilization of essential trace elements.¹⁵

The word chelate, from the Greek chele (or "claw"),¹⁶ refers to the ability to form tightly bound, nondissociable complexes with metal ions much as a claw would grasp an object. The groups attached to the central metal ion are referred to as ligands. When a ligand attaches itself to a central metal ion with the use of two or more donor atoms, it is referred to as a chelating group and the resulting ring structure is a metal chelate. This binding effectively removes the metal ions from circulation and promotes removal of any metal which is reversibly bound to enzymes and other tissue components. The metal chelate complexes are water-soluble and readily excreted in the urine.

In the absence of treatment, following removal from exposure decline in blood lead concentration occurs relatively rapidly, followed by a slow continued decline over several months to years. Chelation therapy is administered in order to increase the rate of excretion of lead in the short term, by upwards of 25 to 30 times normal, which may otherwise take months to years. The effectiveness of chelating agents is associated with their ability to reduce concentrations of lead in the metabolically-active (mobile) compartments.¹⁷ It is assumed that the rapid reduction in blood lead along with the removal of the child from the source of exposure will improve long-term outcomes. However, the improvement of biochemical markers may be transient as BLLs rebound in most children within days of completion of treatment.¹⁸ Lead chelation is known to reduce blood lead concentrations acutely, but the levels may rebound to as much as 70% of baseline within weeks to months after treatment, often requiring repeated courses of treatment. Children with higher initial BLLs have been shown to have greater declines compared to children with lower blood lead initially, with or without treatment.¹⁹

During chelation, lead is removed from the blood and soft tissue components and, upon discontinuation of treatment, is redistributed from the bony compartment to the blood and soft tissues.²⁰ This may explain the rebound effect observed following chelation. Chelating agents are likely to be most useful in patients with acute lead poisoning as the greatest percentage of lead will be in the blood or soft tissue compartment where it is accessible by the chelating agent. Combinations of therapies may be necessary to provoke the maximum excretion of body lead stores, while preserving essential elements and cell functions.^{21, 22}

Historically, chelation therapy was reserved for only the most severe, symptomatic cases of lead poisoning with BLLs in the range of 100 µg/dL or greater.²³ However, as the number of cases of severe, life-threatening lead poisoning have decreased and knowledge about the harmful effects of lower levels has increased, BLLs at which chelation therapy is indicated have declined.²⁴ While acute lead encephalopathy is largely a disease for the pediatric history books, BLLs above 70 µg/dL in children (and all symptomatic lead poisoning, regardless of blood lead level) are deemed medical emergencies. BLLs greater than 70 µg/dL usually involve hospitalization for parenteral chelation therapy as patients require intensive monitoring. It is generally agreed upon that levels between 45-69 µg/dL require medical and environmental management, usually including chelation therapy after the blood lead level has been confirmed. The treatment of BLLs less than 45 µg/dL is less definitive and remains a point of contention among experts in the field.

Chelating agents are chosen to maximize potential benefits while minimizing harmful side effects. Currently, there are two parenteral and two oral agents used for the chelation of lead in children (Table 2).²⁵ It should be noted that among the oral agents one (d-Penicillamine) is not labeled for use in the treatment of lead poisoning and the other (succimer) is labeled for use only at BLLs greater than or equal to 45 µg/dL in children. There are many reports advocating these products for "off-label" use.^{26, 27, 28, 29}

Patients undergoing chelation therapy require intensive monitoring for changes in blood cell counts, hepatic enzymes, and serum electrolytes. Most of the associated effects are transient and values return to normal upon completion of treatment. The need for prolonged treatment, often involving multiple courses of drug, makes hemodynamic stability essential. After one full course of treatment, a period of re-equilibration should be allowed, after which time another BLL should be obtained.³⁰ Subsequent therapy should be based on this determination.

British Anti-Lewisite (BAL), or generic dimercaprol, was first used in WWII as an antidote for arsenic poisoning and proved to be useful in lead intoxication. BAL, because it is diluted in oil, is administered only using deep intramuscular injection every four hours and is therefore extremely painful and difficult to administer especially in children. Calcium disodium edetate (CaNa₂EDTA), first reported in 1952, may be administered intravenously by slow infusion over several hours. CaNa₂EDTA increases urinary excretion of lead and reverses inhibition of aminolevulinic acid (ALA) dehydratase (a heme pathway enzyme). In children, BAL may be administered with CaNa₂EDTA to maximize efficiency and minimize toxicity of both agents.³¹

Until recently, many pediatricians relied on Pb-mobilization testing (EDTA provocation or "challenge" test) to determine which asymptomatic children should go on to receive a full course of chelation therapy. When given a single dose of CaNa₂ETDA, patients who responded with evidence of substantial elimination of lead were deemed appropriate candidates for chelation therapy.³² This is one of many clinically-tested but unsubstantiated strategies for management of childhood lead poisoning. The practice presumed to assess total body burden of lead by mobilizing the lead from tissue by chelation and involved several false assumptions which may have resulted in the misclassification of "responders."³³ Given these and other practical factors, the CaNa₂EDTA/Pb-mobilization test is now considered obsolete.

In January 1991, the U.S. Food and Drug Administration (FDA) approved succimer (Chemet ^® McNeil Consumer Products Company),³⁴ as an orphan drug for treatment of lead poisoning in children with BLLs 45 µg/dL or greater. While this agent was new as a legitimate prescription drug, the orally active, water soluble analogue of dimercaprol had been known for many years and used for a variety of other toxic metal exposures in experimental and overseas settings. Succimer has several advantages over other available agents, including minimal effects on levels of essential elements, equal or better reductions in blood lead levels, and minimal overall toxicity. While oral administration allows for outpatient treatment, additional considerations of patient compliance and monitoring of the patient and the environment must be taken into account. Hospitalization using parenteral agents affords the added benefit of increased ability to monitor adherence to therapy regimens, blood enzyme levels and adverse reactions. In addition, it allows for removal of the child from the leaded environment while lead hazard reduction activities may occur in the home. However, this "benefit" may be at severe "cost" to the family. These issues must be addressed when deciding on the proper course of treatment.

There is little information about the extent of utilization of the various agents for treatment of childhood lead exposure. A 1992 survey demonstrated widely varying approaches to treatment of childhood lead poisoning both in regard to the criteria for using chelation and the choice of treatment used.³⁵ Although CDC and the American Academy of Pediatrics (AAP) do not recommend chelation (outside of ongoing clinical trials) for BLLs less than 45 µg/dL and 25 µg/dL respectively, surveillance data from ten states indicate chelation therapy occurring at BLLs as low as 11 µg/dL.³⁶

The most important factor in the management of pediatric plumbism is to reduce the child’s exposure to lead. Chelation has been shown to increase lead absorption,³⁷ so the removal of the child from the leaded environment is an essential part of chelation therapy. Iron and calcium deficiency have also been shown to increase lead absorption.³⁸ Particular attention should be given to nutritional status; adjuvant vitamin and mineral supplementation is not indicated and should be considered prior to initiation or upon completion of chelation. Chelation therapy is not a substitute for environmental remediation or preventing exposure to lead and no agent should be used prophylactically.³⁹

Concerns about the safety of chelation have focused on experimental evidence in animals and on clinical experience. The recommended doses for use in children are empiric and have been based both on body weight (mg/kg) and surface area (mg/m²). One study noted that the dose calculations differ, in some cases, by as much as two times depending on the child’s age.⁴⁰

When deciding to treat a child for lead exposure, careful consideration of the risks versus anticipated benefits is needed; all of the agents have associated adverse reactions, some of which are not inconsequential.

Toxicological effects of lead chelators include the depletion of some essential elements and other adverse reactions (Table 3). Almost 50% of patients given BAL experience some serious side effects. CaNa₂EDTA is a relatively nonspecific chelator which causes clinically significant depletion of essential elements including zinc, magnesium, copper, calcium, and iron. As it does not enter cells, CaNa₂EDTA only removes extracellular lead and, if administered orally, promotes uptake of lead from the gut. When used alone, it may aggravate symptoms associated with lead encephalopathy by causing redistribution of lead to the brain.⁴¹ Combination therapy using an initial dose of BAL followed by a full course of CaNa₂EDTA has proven to reduce the occurrence of side effects. Penicillamine is used only in the "d" isomer form because "l" isomer and racemic mixture have higher incidence of adverse effects. Penicillamine is contraindicated in patients with penicillin sensitivity and is itself associated with allergic-type reactions (33% of patients).⁴² Besides not being approved for use in the treatment of lead poisoning, the relative lack of specificity for lead tends to limit the usefulness of this drug. Succimer, which can be given orally with few side effects, is more specific to lead and does not cause depletion of essential minerals. The most common adverse events attributable to succimer are gastrointestinal, possibly due to the strong mercaptan odor. Transient elevations in serum transaminases have been observed in about 10% of patients.^{43, 44, 45} The drug has been fairly well-tolerated in its limited use and has a wider therapeutic index than the other drugs currently used for lead intoxication.

Prior to the use of chelation therapy for lead intoxication, lead enchephalopathy had a 60% fatality rate.⁴⁶ In the 1960's, when BAL and EDTA were used, the fatality rate was about 30%.⁴⁷

Timely intervention with chelating agents, along with the removal of the child from the leaded environment, prevents progression of the disease and improves clinical outcome for severely- poisoned children. Once the need for chelation therapy has been determined, the choice of agent may be based on the contraindications for use in the particular child and the likely compliance with therapy regimens. Clearly, in some patients, the benefits outweigh the risks.

Benefits of chelation therapy in symptomatic lead poisoning are well established.⁴⁸ An additional recognized benefit of chelation therapy is to halt the progression to symptomatic disease in children with substantially-elevated BLLs who are otherwise asymptomatic. Although therapeutic benefit is "obvious" in frank lead poisoning, its usefulness and efficacy in the treatment of low-level, chronic exposure to lead in children is unproven.

Lead chelation is known to reduce blood lead concentrations acutely, but the levels may rebound within weeks to months after treatment, often requiring repeated courses of treatment. The presumed effectiveness of chelation as a treatment for chronic low-level exposure is based on animal models, clinical experience, and historical trends. The efficacy of chelating agents in reversing or modifying the adverse neurobehavioral effects at all BLLs in asymptomatic children, however, is all but unknown. The long-term effects of treatment with succimer in children with moderately elevated (20-44 µg/dL) BLLs is the focus of an ongoing multicenter randomized trial sponsored by the National Institute of Environmental Health Sciences,⁴⁹ though results are many years away.

Management of children with elevated lead levels is complex and often complicated with issues of follow-up testing, medical treatment, environmental intervention, developmental referrals, and coordination of care. Without proper attention to environmental factors, often out of the jurisdiction of the physician, treatment is unlikely to benefit and may actually harm the child. Given the lack of data on improvement of long-term outcomes associated with any type of chelation and the lack of safety data to exclude rare but potentially severe side effects in newer agents, widespread use of chelation therapy for low-level exposures does not seem warranted at this time.

Chelation therapy is not a substitute for environmental remediation or preventing exposure to lead. While it is widely recognized a shift to efforts of primary prevention of lead exposure is needed, screening and medical management of lead-exposed children will remain critically important until the sources of lead are eliminated. Routine screening of children at risk for lead exposure combined with parental education and increased awareness to lead hazards would be beneficial in reducing further exposure among children with low lead levels. The treatment and management of lead-exposed children requires a thorough medical evaluation, environmental intervention, and sound clinical judgement. Strategies for treating children with elevated blood lead levels and for assessing the effects of these treatments are urgently needed.

1. Chisholm JJ, Jr., Harrison HE. The treatment of acute lead encephalopathy in children. Pediatrics 1957;19:2-20.
2. Committee on Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations. Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations. Washington, D.C., National Research Council, National Academy Press, 1993.

3. Office of Pollution Prevention and Toxics. Report on the National Survey of Lead-Based Paint in Housing: base report. Washington, D.C., U.S. Environmental Protection Agency, Office of Pollution Prevention and Toxics, 1995.
4. A New Look at Childhood Lead Toxicity, Proceedings of the Conference on Childhood Lead Toxicity: June 1990, Chicago. Comtact Corporation, 1991.
5. Centers for Disease Control. Preventing lead poisoning in young children: a statement by the Centers for Disease Control. Atlanta, U.S. Department of Health and Human Services, Public Health Service, 1991.
6. Needleman HL, et al. Deficits in psychologic and classroom performance of children with elevated dentine lead levels. N Engl J Med 1979;300:689-95.
7. Bellinger D, et al. Longitudinal analyses of prenatal and postnatal lead exposure and early cognitive development. N Engl J Med 1987;316:1037-43.
8. Needleman HL, et al. The long-term effects of exposure to low doses of lead in childhood: An 11-year follow-up report. N Engl J Med 1990;322:83-8.
9. Needleman HL, Gatsonis CA. Low-level lead exposure and the IQ of children: A meta-analysis of modern studies. JAMA 1990;263:673-8.
10. Dietrich KN, et al. The developmental consequences of low to moderate prenatal and postnatal lead exposure: intellectual attainment in the Cincinnati lead study cohort following school entry. Neurotox Teratol 1993;15:37-44.
11. Tong S, et al. Declining blood lead levels and changes in cognitive function during childhood: the Port Pirie cohort study. JAMA 1998; 280(22):1915-9.

12. Update: Blood Lead Levels - United States, 1991-1994. Centers for Disease Control and Prevention, MMWR 1997;46(7):141-6. Errata in: MMWR 1997;46(26):607.
13. U.S. Preventive Services Task Force. Guide to clinical preventive services, 2^nd ed., Williams & Wilkins, Baltimore, 1996.
14. Graziano JH. Validity of lead exposure markers in diagnosis and surveillance. Clin Chem 1994;40(7):1387-90.
15. Goyer RA, et al. Role of chelating agents for prevention, intervention, and treatment of exposures to toxic metals. Environ Health Perspect 1995; 103(11):1048-52.
16. Thomas CA, ed., Taber’s Cyclopedic Medical Dictionary 15^th edition. F.A. Davis Company, New York, 1985.
17. Chisholm JJ, Jr. Chelation therapy in children with subclinical plumbism. Pediatrics 1974;53(3):441-3.
18. Marcus AH. Multicompartment kinetic models for lead. Environ Res 1985;36:459-72.
19. Markowitz ME, et al. Effects of calcium disodium versenate (CaNa₂EDTA) chelation in moderate childhood lead poisoning. Pediatrics 1993;92(2):265-71.
20. Schutz A, et al. Chelatable lead versus lead in human trabecular bone and compact bone. Sci Tot Environ 1987;61:201-9.
21. Cory-Slechta DA. Mobilization of lead over the course of DMSA chelation therapy and long-term efficacy. J Pharm Exp Ther 1988;246(1):84-91.
22. Chisholm JJ, Jr., BAL, EDTA, DMSA, and DMPS in the treatment of lead poisoning in children, Clin Toxicol 1992; 30(4):493-504.
23. Chisholm JJ, Jr. The use of chelating agents in the treatment of acute and chronic lead intoxication in childhood. J of Pediatrics 1968;73(1):1-38.
24. Chisholm JJ, Jr. Evaluation of the potential role of chelation therapy in treatment of low to moderate lead exposures. Environ Health Perspect 1990; 89:67-74.
25. American Academy of Pediatrics, Committee on Drugs. Treatment Guidelines for Lead Exposure in Children, Policy Statement. Pediatrics 1995;96(1):155-60.
26. Liebelt EL, Shannon MW. Oral chelators for childhood lead poisoning. Pediatric Ann 1994;23(11):616-26.
27. Shannon MW, et al. Efficacy and toxicity of d-penicillamine in low-level lead poisoning. J Pediatr 1988;112:799-804.
28. Besunder JB, et al. Short-term efficacy of oral dimercaptosuccinic acid in children with low to moderate lead intoxication. Pediatrics 1995;96(4):683-7.
29. Liebelt EL, et al. Efficacy of oral meso-2,3-dimercaptosuccinic acid therapy for low-level childhood plumbism. J Pediatr 1994;124:313-7.
30. AAP, 1995.
31. Glotzer DE. Management of childhood lead poisoning: strategies for chelation. Pediatric Ann 1994;23(11):607-15.
32. Piomelli S, et al. Management of childhood lead poisoning. J Pediatr 1984;105:523-32.
33. Graziano JH. Conceptual and practical advances in the measurement and clinical management of lead toxicity. Neurotoxicology 1993;14(2-3):219-23.
34. Chemet ^TM [succimer], 100mg capsule, Product information package insert. McNeil Consumer Products Company, Fort Washington, PA; 1991.
35. Glotzer DE, Bauchner H. Management of childhood lead poisoning: a survey. Pediatrics 1992; 89(4):614-8.
36. Unpublished data. CDC Childhood Blood Lead Surveillance Program. Centers for Disease Control and Prevention. Atlanta, 1998.
37. CDC, 1991.
38. Barltrop D, Khoo HE. The influence of nutritional factors on lead absorption. Postgrad Med 1975;51:795-800.
39. Bowden CA, Krenzelok EP. Clinical applications of commonly used contemporary antidotes: A U.S. perspective. Drug Saf 1997; 16(1):9-47.
40. Rhoads GG, Rogan WJ. Treatment of lead-exposed children. (letter) Pediatrics 1996;98(1):162-3.
41. Cory- Slechta DA, et al. Mobilization and redistribution of lead over the course of CaEDTA chelation therapy. J Pharmacol Exp Ther 1987;243:804-13.
42. Shannon, 1988.
43. Graziano JH, et al. Controlled study of meso-2,3-dimercaptosuccinic acid for the management of childhood lead intoxication. J Pediatr 1992;120:133-9.
44. Graziano JH, et al. Dose-response study of oral 2,3-dimercaptosuccinic acid in children with elevated blood lead concentrations. J Pediatr 1988;113:751-7.
45. Graziano JH, et al. Role of 2,3-dimercaptosuccinic acid in the treatment of heavy metal poisoning. Med Toxicol 1986;1:155-62.
46. Chisholm, 1957.
47. Chisholm, 1967, 1974.
48. Bowden, 1997.
49. Treatment of Lead-exposed Children Trial Group, The Treatment of Lead-exposed Children (TLC) trial: design and recruitment for a study of the effect of oral chelation on growth and development in toddlers. Paediatr Perinat Epidemiol 1998; 12: 313-333.