Correspondence

Chelation Therapy in Children Exposed to Lead

N Engl J Med 2001; 345:1212-1213October 18, 2001

Article

To the Editor:

Rogan et al. (May 10 issue)1 conclude that chelation therapy with succimer for children with lead levels of 20 to 44 μg per deciliter is valueless. However, an important methodologic weakness of their study is that succimer therapy failed to achieve a timely, enduring reduction in the lead level, producing a difference in blood lead levels between treatment groups of only 2.7 μg per deciliter over a one-year period. There is no evidence (e.g., measurement of erythrocyte protoporphyrin) that succimer effected any significant reduction in the body burden of lead. The authors assert without reference that there is no better chelator than succimer. However, efficacy has been reported with penicillamine2-4 and with 2,3-dimercaptopropane-1-sulfonate.5 Finally, the authors ignore the other toxic effects of lead poisoning that can be reversed by chelation — e.g., normalization of 1,25-dihydroxyvitamin D, δ-aminolevulinic acid dehydratase, and erythrocyte protoporphyrin activity.6 Collectively, these shortcomings leave open the possibility that individualized case management for children with lead poisoning may have a role in treatment, which may in some cases include chelation therapy.

Michael Shannon, M.D.
Children's Hospital, Boston, MA 02115
michael.shannon@tch.harvard.edu

Alan Woolf, M.D., M.P.H.
Harvard Medical School, Boston, MA 02115

Helen Binns, M.D.
Children's Memorial Hospital, Chicago, IL 60614

6 References

1
Rogan WJ, Dietrich KN, Ware JH, et al. The effect of chelation therapy with succimer on neuropsychological development in children exposed to lead. N Engl J Med 2001;344:1421-1426
Full Text | Web of Science | Medline

2
Marcus SM. Experience with D-penicillamine in treating lead poisoning. Vet Hum Toxicol 1982;24:18-20
Medline

3
Shannon M, Graef J, Lovejoy FH Jr. Efficacy and toxicity of D-penicillamine in low-level lead poisoning. J Pediatr 1988;112:799-804
CrossRef | Web of Science | Medline

4
Shannon M, Grace A, Graef JW. Use of penicillamine in children with small lead burdens. N Engl J Med 1989;321:979-980
Web of Science | Medline

5
Chisolm JJ Jr, Thomas DJ. Use of 2,3-dimercaptopropane-1-sulfonate in treatment of lead poisoning in children. J Pharm Exp Ther 1985;235:665-669
Web of Science | Medline

6
Rosen JF, Chesney RW, Hamstra A, DeLuca HF, Mahaffey KR. Reduction in 1,25-dihydroxyvitamin D in children with increased lead absorption. N Engl J Med 1980;302:1128-1131
Full Text | Web of Science | Medline

To the Editor:

Rogan et al. cite a meta-analysis by Pocock et al.1 demonstrating the association between increased blood lead level and decreased IQ. They do not, however, reveal the conclusion of the authors of the meta-analysis: “However, the inherent limitations of observational epidemiology in pinpointing the reasons for this association mean that uncertainty remains as to the real impact that lead makes on children's neuropsychological development.”

Given this uncertainty, a very reasonable explanation for the findings in the study by Rogan et al. — i.e., that lowering blood lead levels did not improve scores on tests of cognition, behavior, or neuropsychological function — is that lead exposure was not responsible for impairment in the first place. This possibility was not even broached by the authors.

David E. Mandelbaum, M.D., Ph.D.
University of Medicine and Dentistry of New Jersey–, Robert Wood Johnson Medical School, New Brunswick, NJ 08901

1 References

1
Pocock SJ, Smith M, Baghurst P. Environmental lead and children's intelligence: a systematic review of the epidemiological evidence. BMJ 1994;309:1189-1197
CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Shannon et al. propose the use of other oral chelating agents and the treatment of biochemical responses to lead exposure. We evaluated the use of penicillamine when we planned our trial and came to the same conclusion that the American Academy of Pediatrics did: “The overall toxicity profile of penicillamine relegates it to a third-line agent, indicated only when unacceptable reactions have occurred to succimer and CaNa2EDTA.”1 We are not aware of any controlled, long-term data on the reduction of any measure of lead exposure by penicillamine. Concurrent, preferably randomized controls are necessary because of the strong effects of age on blood lead levels, as seen in our study. Similarly, studies showing the efficacy of chelation for protoporphyria2 and abnormalities of vitamin D metabolism3 have not been randomized, controlled trials, and their results are consistent with regression to the mean or spontaneous resolution as the blood lead level falls. As for 2,3-dimercaptopropane-1-sulfonate, it is not commercially available in the United States.

Mandelbaum is of course correct in saying that if lead does no damage, then treating lead exposure will do no good. For the purposes of both public health and clinical trials, however, we think that the debate about whether lead causes cognitive deficits at relatively low levels of exposure is settled. Major organizations, including the Centers for Disease Control and Prevention4 and the World Health Organization,5 treat the association as causal. Lead is the best studied of the environmental chemical agents thought to produce cognitive deficits at commonly encountered levels, with a huge clinical and laboratory literature showing unquestionable neurotoxicity. The only question is the dose at which the toxic effects become measurable. The relation between lead and neurotoxicity was sufficiently established that we and our advisors thought that a trial attempting to reduce or prevent lead-associated cognitive deficits by means of chelation was needed, and we still believe that to have been true.

We note with sadness the death of our senior colleague, J. Julian Chisholm, Jr., on June 20, 2001.

Walter J. Rogan, M.D.
National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709
rogan@niehs.nih.gov

Thomas R. Shaffer
Department of Health and Human Services, Perry Point, MD 21902

Kim N. Dietrich, Ph.D.
University of Cincinnati, Cincinnati, OH 45267

for the Treatment of Lead-Exposed Children Trial Investigators

5 References

1
American Academy of Pediatrics Committee on Drugs. Treatment guidelines for lead exposure in children. Pediatrics 1995;96:Part 1:155-160
Web of Science | Medline

2
Marcus SM. Experience with D-penicillamine in treating lead poisoning. Vet Hum Toxicol 1982;24:18-20
Medline

3
Rosen JF, Chesney RW, Hamstra A, DeLuca H, Mahaffey KR. Reduction in 1,25-dihydroxyvitamin D in children with increased lead absorption. N Engl J Med 1980;302:1128-1131
Full Text | Web of Science | Medline

4
Screening young children for lead poisoning: guidance for state and local public health officials. Atlanta: Centers for Disease Control and Prevention, 1997.