051001 the effect of chelation therapy with succimer

In 1991, the Food and Drug Administration li- Background
censed succimer (dimercaptosuccinic acid), the first poor children living in deteriorated urban housing, approved oral lead chelator, for use in children with are exposed to enough lead to produce cognitive im- blood lead levels of at least 45 µg per deciliter (2.2 pairment. It is not known whether treatment to re- µmol per liter).7 Succimer reduced blood lead levels duce blood lead levels prevents or reduces such im- at least as well as parenteral treatment with edetate cal- cium disodium in children with levels of 30 µg per Methods
deciliter (1.4 µmol per liter) or higher.8 Also in 1991, levels of 20 to 44 µg per deciliter (1.0 to 2.1 µmol per universal screening of children for elevated blood liter) in a randomized, placebo-controlled, double- lead levels was recommended by the Centers for Dis- blind trial of up to three 26-day courses of treatment with succimer, a lead chelator that is administered ease Control (CDC), and the threshold of concern orally. The children lived in deteriorating inner-city was lowered from 25 µg per deciliter (1.2 µmol per housing and were 12 to 33 months of age at enroll- liter) to 15 µg per deciliter (0.7 µmol per liter) — a ment; 77 percent were black, and 5 percent were His- level associated with cognitive impairment but not panic. Follow-up included tests of cognitive, motor, symptoms of lead poisoning. However, the CDC behavioral, and neuropsychological function over a made no specific recommendation about chelation therapy in children with blood lead levels of 20 to Results
During the first six months of the trial, the 44 µg per deciliter (1.0 to 2.1 µmol per liter).9 Be- mean blood lead level in the children given succimer cause of the increase in screening, the wide availabil- was 4.5 µg per deciliter (0.2 µmol per liter) lower than ity of an oral chelator, and the lack of data on lead the mean level in the children given placebo (95 per- chelation for the prevention of cognitive impair- cent confidence interval, 3.7 to 5.3 µg per deciliter [0.2to 0.3 µmol per liter]). At 36 months of follow-up, the ment, we conducted a multicenter, randomized, pla- mean IQ score of children given succimer was 1 point cebo-controlled clinical trial. Our study was designed lower than that of children given placebo, and the to test the hypothesis that children with moderate behavior of children given succimer was slightly worse blood lead levels who were given succimer would have as rated by a parent. However, the children given suc- better scores than children given placebo on a range cimer scored slightly better on the Developmental of tests measuring cognition, neuropsychological func- Neuropsychological Assessment, a battery of tests de- tion, and behavior at 36 months of follow-up.
signed to measure neuropsychological deficits thoughtto interfere with learning. All these differences were small, and none were statistically significant.
Referral and Prerandomization Activities
blood lead levels but did not improve scores on tests We accepted referrals of children 12 to 33 months of age (a range of cognition, behavior, or neuropsychological func- that includes the age at which lead levels peak) who had blood lead tion in children with blood lead levels below 45 mg per levels of 20 to 44 µg per deciliter, had no more than two main deciliter. Since succimer is as effective as any lead residences, and could be tested in English (or Spanish, at one site).
Children with blood lead levels greater than 44 µg per deciliter chelator currently available, chelation therapy is not were referred to local clinics for treatment. We measured lead levels indicated for children with these blood lead levels.
in venous blood, serum ferritin levels, blood counts, renal func- (N Engl J Med 2001;344:1421-6.)Copyright 2001 Massachusetts Medical Society.
From the National Institute of Environmental Health Sciences, Research Triangle Park, N.C. (W.J.R., N.B.R.); the Department of EnvironmentalHealth, University of Cincinnati, Cincinnati (K.N.D.); the Harvard School N children, peak blood lead levels as low as 10 to of Public Health, Boston (J.H.W., D.W.D., M.S.); the Department of Psy- 20 µg per deciliter (0.5 to 1.0 µmol per liter) are chology, Children’s Hospital of Philadelphia, Philadelphia (J.R.); the Nu-tritional Biochemistry Branch, Centers for Disease Control and Preven- associated with reduced scores on developmental tion, Atlanta (R.L.J.); the Kennedy–Krieger Institute, Baltimore (J.J.C.); tests at 4 to 10 years of age.1-5 Such blood lead and the Environmental and Occupational Health Sciences Institute, Uni- levels occur in tens of thousands of children in the versity of Medicine and Dentistry of New Jersey, Piscataway (G.G.R.). Ad- dress reprint requests to Dr. Rogan at the Epidemiology Branch, National United States each year, usually at about two years Institute of Environmental Health Sciences, A3-05, P.O. Box 12233, Re- of age. It is not known whether chelation therapy can search Triangle Park, NC 27709, or at [email protected].
protect these children from the developmental con- *Other members of the Treatment of Lead-Exposed Children Trial Group N Engl J Med, Vol. 344, No. 19 · May 10, 2001 · www.nejm.org · 1421
The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne tion, and serum enzyme levels. We provided a vitamin and min- tional and executive, sensorimotor, visuospatial, language, and mem- eral supplement but later recalled one batch because of lead con- ory function. At 36 months of follow-up, we also administered to tamination; however, the amounts were too low to affect the chil- the parent the short form of the Conners’ Parent Rating Scale– dren’s blood lead levels.10 We inspected the children’s homes to Revised (CPRS-R).17 The CPRS-R is a 27-item scale that provides determine whether cleaning and minor repairs could be expected four behavioral indexes, of which we used the three that are appli- cable to younger children: Oppositional Index, Hyperactivity Index, Children with confirmed blood lead levels of 20 to 44 µg per and Attention-Deficit–Hyperactivity Disorder Index. We then av- deciliter who lived in housing that could be cleaned or who could eraged the CPRS-R index scores and called the average the Be- move to lead-safe housing returned for a second visit. A child was enrolled if his or her blood lead level at the time of the second visit The children were tested with a parent or guardian present be- was also 20 to 44 µg per deciliter. About half the children referred tween the hours of 9 a.m. and 4 p.m. in a quiet room. The tests to us were enrolled; most disqualifications were due to a blood lead were rescheduled if the child was acutely ill, and the child was fed if he or she had not recently eaten. The testing psychologists did We vacuumed the residences of the enrolled children (using a not know whether the children had been given succimer or pla- high-efficiency particle-arrestor vacuum cleaner), mopped floors and cebo. The IQ of the caregiver in attendance (the mother for 88 wiped walls and surfaces with a trisodium phosphate solution, made percent of the children, the father for 4 percent, and another care- minor repairs, and performed paint stabilization (by scraping loose giver for 8 percent) was assessed during one of the follow-up vis- paint and doing minor carpentry) at about the time of random- its with the short form of the Wechsler Adult Intelligence Scale– ization. The homes of 16 of the 396 children given succimer and 5 of the 384 children given placebo were never cleaned; amongthese, 3 of the children given succimer and 2 of the children giv- Statistical Analysis
en placebo were moved with their families to lead-safe housing.
Our study was designed to have 82 percent power to detect a Using supplies known to be lead-free, we collected venous blood 3-point difference between groups in the children’s mean IQ at for measurement of blood lead levels twice before randomization 36 months of follow-up at a two-sided significance level of 0.05.
and then on days 7, 28, and 42 after the beginning of each course The actual power of the study was 96 percent, because the number of treatment. The blood lead levels were measured at the Nutrition- of children with data at 36 months of follow-up was higher than al Biochemistry Branch of the CDC.11 After treatment was stopped, expected and the correlation between base-line and follow-up psy- blood lead levels were measured every three to four months. A to- chometric tests was better than expected.
tal of 780 children were enrolled; we randomly assigned 396 to suc- Nine children in the placebo group and five in the succimer cimer and 384 to placebo. Treatment assignments were stratified group attended the 36-month follow-up appointment but were according to clinical center, body-surface area, blood lead level, and unable to complete the WPPSI-R test for developmental reasons.
language (because of the tests administered in Spanish). The study So that these children could be included in the analysis, their scores was approved by the institutional review boards at the clinical cen- were imputed on the basis of the sum of scaled scores for the com- ters, the Harvard School of Public Health, the CDC, and the Na- pleted subtests or by assigning the score to the value below the low- tional Institute of Environmental Health Sciences. The parents of all est possible score for the corresponding domain. The data from the children provided written informed consent at enrollment for three children who could not be tested were treated as missing.
prerandomization activities and at the initiation of treatment for In addition, 10 children in the placebo group and 8 in the suc- cimer group completed the WPPSI-R at 18 months of follow-upbut did not attend the appointment at 36 months. For these chil- Succimer and Placebo
dren, we substituted the WPPSI-R score at 18 months of follow-up We administered succimer (Chemet) or placebo in 100-mg cap- for the score at 36 months, since the correlation between the two sules of identical appearance (both provided by McNeil Consumer test scores was 0.83 for full-scale IQ.
Products, Fort Washington, Pa.). We used 26-day courses of ther- We used the two-sample t-test to compare unadjusted mean apy and aimed to provide 1050 mg per square meter of body-sur- scores in the two treatment groups. We also used multiple linear face area per day for the first seven days and 700 mg per square regression analysis to adjust the mean differences for a set of base- meter per day thereafter.12 Children could receive up to three cours- line covariates chosen in advance. These covariates included the var- es of treatment; those who had blood lead levels of 15 µg per dec- iables specifically balanced by the strata used for randomization iliter or higher two weeks after the completion of a first or second (clinical center, body-surface area, blood lead level, and language course of succimer were given another course. Eighty-three percent [Spanish or English]), the caregiver’s IQ, the child’s base-line score of the children assigned to succimer required a second course, and on the Mental Development Index from the BSID-II, and a term 83 percent of those receiving a second course required a third.
for the interaction between the Mental Development Index score Children in the placebo group were assigned to retreatment to and age. For the analyses of NEPSY subscale scores, we included match the frequency of retreatment in the succimer group, within an indicator variable for the version of the test administered (age the strata used for initial randomization. If a child had a confirmed of 3 to 4 years vs. age of 5 to 12 years) and a term for the interac- blood lead level above 44 µg per deciliter, the study treatment was tion between the version and the age at testing. All analyses were stopped, and the child was referred for treatment according to the performed according to the intention-to-treat principle. Since drug usual standards of the clinical center.13 therapy was completed long before follow-up testing was per-formed, there was no need for stopping rules or interim analyses.
Developmental, Neuropsychological, and Behavioral Tests
Before treatment began, we administered to the children the Bayley Scales of Infant Development II (BSID-II),14 the current edi- Randomization, Adherence, and Retention
tion of the most widely used scales of infant development. At 18months of follow-up, if the child was still younger than 42 months The two treatment groups were balanced with re- of age, we administered the BSID-II again; if the child was 42 spect to base-line characteristics (Table 1), so the es- months of age or older, we administered the Wechsler Preschool timates of the effect of treatment are similar for the and Primary Scales of Intelligence–Revised (WPPSI-R).15 At 36 adjusted and unadjusted scores. The level of precision, months of follow-up, we administered the WPPSI-R and the De- however, is much higher for the adjusted estimates.
velopmental Neuropsychological Assessment (NEPSY),16 a batteryof tests designed to identify neuropsychological deficits that in- According to the parents’ reports, over 90 percent of terfere with learning. The NEPSY evaluates the domains of atten- the assigned doses of study drug were given. When 1422 · N Engl J Med, Vol. 344, No. 19 · May 10, 2001 · www.nejm.org
*Plus–minus values are means ±SD.
†These data were available for 361 children in the placebo group and ‡These data were available for 375 children in the placebo group and §These data were available for 335 children in the placebo group and ¶These data were available for 370 children in the placebo group and the pills were counted, about 76 percent of the cap- *Plus–minus values are means ±SD. WPPSI-R denotes the Wechsler Preschool and Primary Scales of Intelligence–Revised, NEPSY the Devel- sules had been removed from the bottles. Forty per- opmental Neuropsychological Assessment, and CPRS-R the Conners’ Par- cent of the families whose children were given succi- mer and 26 percent of the families of children given †The a priori primary outcome within each domain is indicated.
placebo reported difficulty administering the drug.
‡The CPRS-R Behavioral Index is the mean of the scores on the Opposi- tional, Hyperactivity, and Attention-Deficit–Hyperactivity Disorder Indexes.
Interruptions in the administration of the drug oc-curred at similar rates in the succimer group (30 per-cent) and the placebo group (27 percent). Of thechildren in whom administration of the drug was in-terrupted, 39 percent of those receiving succimer iliter (0.53 µmol per liter), at one week after the be- and 45 percent of those receiving placebo resumed ginning of treatment (Fig. 1). A rebound in blood lead levels in the succimer group, presumably due to Scores were obtained or imputed on the WPPSI-R lead stored in calcified tissue, began at one week and for 745 of the 780 enrolled children (96 percent), continued. At 49 days after the beginning of treat- on one or more of the NEPSY subscales for 688 (88 ment, the mean blood lead level in children given percent), and on the CPRS-R for 721 (92 percent) succimer was 72 percent of the base-line mean, as compared with 88 percent in the children given pla-cebo. Blood lead levels dropped again in the children Blood Lead Level
given second and third courses of succimer, and in We observed the largest estimated mean difference each case the levels then rebounded, whereas the mean between groups in blood lead levels, 11 µg per dec- blood levels in children given placebo declined steadi- N Engl J Med, Vol. 344, No. 19 · May 10, 2001 · www.nejm.org · 1423
The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne Figure 1. Mean Blood Lead Levels and 95 Percent Pointwise Confidence Intervals at Base Line and after the Initiation of
Treatment in Children in the Succimer and Placebo Groups.
The squares in the upper left are the base-line values, which were measured about nine days before treatment wasinitiated (shaded squares indicate the succimer group, and open squares the placebo group). Means for the curves werecalculated by locally weighted regression. The broken vertical line marks one week after randomization, which is thefirst time blood lead levels were measured after the initiation of treatment. (Adapted from the Treatment of Lead-ExposedChildren Trial Group13 with the permission of the publisher.) ly but slowly. One year after treatment began, the cimer and 10 percent of those given placebo. There difference in mean blood lead levels between the two was no significant excess of any other category of groups had largely disappeared. The mean blood lead symptoms, individual symptom, or laboratory abnor- level of the children treated with succimer was lower mality in either group.13 (Full data are available on the by 4.5 µg per deciliter (95 percent confidence inter- study Web site at http://dir.niehs.nih.gov/direb/ val, 3.7 to 5.3 µg per deciliter [0.2 µmol per liter; tlc1/home.htm). We monitored the children’s growth 95 percent confidence interval, 0.2 to 0.3 µmol per and found that those given succimer had grown 0.25 liter]) than the mean level of the children given pla- cm (95 percent confidence interval, 0.05 to 0.45) cebo over the 6 months after the initiation of treat- less than those given placebo over 12 months of fol- ment, and lower by 2.7 µg per deciliter (95 percent low-up and 0.35 cm (95 percent confidence interval, confidence interval, 1.9 to 3.5 µg per deciliter [0.1 0.05 to 0.72) less over 34 months of follow-up.
µmol per liter; 95 percent confidence interval, 0.1 to0.2 µmol per liter]) over the 12 months after the Intelligence, Neuropsychological Development,
and Behavior
Unadjusted mean scores on the WPPSI-R, NEPSY, Safety Monitoring
and CPRS-R were similar in the two treatment groups Of 10 children who were receiving succimer when (Table 2). After adjustment for the variables listed in their blood lead levels exceeded 44 µg per deciliter, the Statistical Analysis section above, the mean full- 9 were hospitalized for treatment; of 7 children who scale IQ score on the WPPSI-R for children given were receiving placebo when their blood lead levels succimer was 1.1 points (95 percent confidence in- exceeded 44 µg per deciliter, 4 were hospitalized.
terval for the difference, ¡2.6 to 0.5) lower than Five of the children given succimer and none of those that for children given placebo (Fig. 2). The children given placebo were hospitalized for trauma, with no given succimer scored slightly higher on four of the common pattern or site of injury. A history of trau- five domains of the NEPSY; the differences did not ma or evidence of trauma on physical examination vary according to age at testing. For the CPRS-R, was noted for 15 percent of the children given suc- the behavioral index was 1.2 points (95 percent con- 1424 · N Engl J Med, Vol. 344, No. 19 · May 10, 2001 · www.nejm.org
Figure 2. Difference in Adjusted Mean Scores on the WPPSI-R, NEPSY, and CPRS-R Scales between the Children Given Succimer
and Those Given Placebo 36 Months after the Initiation of Treatment.
Diamonds in the upper, shaded half of the graph represent differences in scores that favor the children given succimer. I bars are 95percent confidence intervals for the difference in means. For the Wechsler Preschool and Primary Scales of Intelligence–Revised(WPPSI-R), PIQ denotes performance IQ, VIQ verbal IQ, and FSIQ full-scale IQ. For the Developmental Neuropsychological Assessment(NEPSY) subscales, Attention denotes attentional and executive function, Language language function, Sensorimotor sensorimotorfunction, Visuospatial visuospatial function, and Memory memory function. For the Conners’ Parent Rating Scale–Revised (CPRS-R),OI denotes the Oppositional Index, HI the Hyperactivity Index, ADHD the Attention-Deficit–Hyperactivity Disorder Index, and BI theBehavioral Index, an average of the preceding indexes. Asterisks denote variables for which there were a priori hypotheses.
fidence interval for the difference, ¡0.5 to 2.8) ed 10 µg per deciliter only briefly, and the mean dif- higher (i.e., worse) in children given succimer. None ference was 4.5 µg per deciliter (0.2 µmol per liter) of these differences approached statistical signifi- during the six months after the initiation of treat- cance. Adjustment had little effect on the estimates ment. Thus, it could be that the failure of our study of the differences in means, as would be expected to demonstrate a difference in test scores is due to the given the similarity of the groups at base line (Table 2 small difference in blood lead levels that we observed.
and Fig. 2). When we excluded the 32 children for However, succimer is as effective as any chelating agent whom we imputed the WPPSI-R scores or substitut- currently available, and we used it for 26 days per ed the scores obtained at 18 months, the estimates course rather than the usual 19 days. We also used were very similar; for adjusted full-scale IQ scores, the (higher) loading dose for the first seven days, rath- the difference (succimer scores minus placebo scores) er than the first five days, of each course, with the with imputation was –1.1 (95 percent confidence in- dose calculated according to body-surface area rather terval for the difference, ¡2.6 to 0.5), and without than weight.20 When the pills were counted, 76 per- imputation it was –1.3 (95 percent confidence inter- cent were gone, so adherence to therapy was as high val for the difference, ¡2.8 to 0.1).
as has been reported among children in trials lastinglonger than a week.21,22 We believe it is unlikely that DISCUSSION
another chelation regimen would have been more Our study was a randomized trial of chelation ther- apy in children exposed to lead that was designed to Ruff et al.23 treated children with blood lead levels examine developmental end points. Treatment with of 25 to 55 µg per deciliter (1.2 to 2.6 µmol per succimer did not lead to better scores on cognitive, liter) using parenteral edetate calcium disodium as a neuropsychological, or behavioral tests than placebo.
chelation agent. Chelation was not randomly assigned Observational data suggest that the effect on IQ but was used when clinically indicated and had no of an increase in the blood lead level from 10 to 20 relation to blood lead level or IQ at follow-up. How- µg per deciliter is a decrease of about 2 to 3 points.19 ever, the children whose blood lead levels fell the The difference in blood lead levels between the chil- most had the greatest improvement in IQ. The non- dren given succimer and those given placebo exceed- randomized design of the study by Ruff et al. made N Engl J Med, Vol. 344, No. 19 · May 10, 2001 · www.nejm.org · 1425
The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne it difficult to control for environmental and parent- the Cincinnati Lead Study cohort at age 4 years. Neurotoxicol Teratol ing differences that might lead to both larger drops 1991;13:203-11.
2. McMichael AJ, Baghurst PA, Wigg NR , Vimpani GV, Robertson EF,
in blood lead levels and increased IQ, and the six- Roberts RJ. Port Pirie Cohort Study: environmental exposure to lead and month follow-up period was relatively short. How- children’s abilities at the age of four years. N Engl J Med 1988;319:468-75.
ever, Australian children whose blood lead levels fell 3. Bellinger D, Sloman J, Leviton A, Rabinowitz M, Needleman HL, Wa-
more quickly as toddlers had higher IQ scores at seven ternaux C. Low-level lead exposure and children’s cognitive function in the years of age.24 The children in our study completed preschool years. Pediatrics 1991;87:219-27. [Erratum, Pediatrics 1994;93:A28.] their 36 months of follow-up at about five years of 4. Dietrich KN, Berger OG, Succop PA, Hammond PB, Bornschein
age and are now being evaluated at seven years of age.
RL. The developmental consequences of low to moderate prenatal and Unless a more positive outcome becomes appar- postnatal lead exposure: intellectual attainment in the Cincinnati Lead Study Cohort following school entry. Neurotoxicol Teratol 1993;15:37- ent at seven years of age, these results suggest that drug therapy should be used with caution in young 5. Bellinger DC, Stiles KM, Needleman HL. Low-level lead exposure, in-
telligence and academic achievement: a long-term follow-up study. Pediat-
children with blood lead levels below 45 µg per dec- iliter. The treatment in our study did not reduce the 6. Pirkle JL, Kaufman RB, Brody DJ, Hickman T, Gunter EW, Paschal
number of children whose blood lead levels exceeded DC. Exposure of the U.S. population to lead, 1991-1994. Environ Health Perspect 1998;106:745-50.
45 µg per deciliter and did not improve the cogni- 7. Nightingale SL. Succimer (DMSA) approved for severe lead poisoning.
tive, behavioral, or neuropsychological outcome 36 months later. The regimen is expensive and a signif- 8. Graziano JH, Lolacono NJ, Meyer P. Dose response study of oral
2,3-dimercaptosuccinic acid in children with elevated blood lead concen-
icant burden on the families. In addition, the slight slowing of linear growth and the evidence of more 9. Preventing lead poisoning in young children: a statement by the Cen-
ters for Disease Control — October 1991. 4th rev. Atlanta: Centers for
frequent trauma in children receiving succimer are not reassuring. Since lead poisoning and its sequelae are 10. Rogan WJ, Ragan NB, Damokosh AI, et al. Recall of a lead-contam-
entirely preventable, our inability to demonstrate effec- inated vitamin and mineral supplement in a clinical trial. Pharmacoepide-miol Drug Saf 1999;8:343-50.
tive treatment lends further impetus to efforts to pro- 11. Miller DT, Paschal DC, Gunter EW, Stroud PE, D’Angelo J. Determi-
tect children from exposure to lead in the first place.
nation of lead in blood using electrothermal atomisation atomic absorption spectrometry with a L’vov platform and matrix modifier. Analyst 1987;112:1701-4.
Supported by contracts and intra-agency agreements with the National 12. The Treatment of Lead-exposed Children (TLC) trial: design and re-
Institute of Environmental Health Sciences in cooperation with the Office cruitment for a study of the effect of oral chelation on growth and devel- of Research on Minority Health at the National Institutes of Health and opment in toddlers. Paediatr Perinat Epidemiol 1998;12:313-33.
the Centers for Disease Control and Prevention.
13. Treatment of Lead-exposed Children (TLC) Trial Group. Safety and
Presented in part at the National Lead Grantee Conference of the Cen- efficacy of succimer in toddlers with blood lead levels of 20-44 microg/dl. ters for Disease Control and Prevention, Atlanta, December 11, 2000, and at the Society of Toxicology meeting, San Francisco, March 27, 2001.
14. Bayley N. Bayley Scales of Infant Development: manual. 2nd ed. San
Antonio, Tex.: Psychological Corporation, 1993.
We are indebted to T. Shaffer, Program Support Center, Depart- 15. Wechsler D. Wechsler Preschool and Primary Scales of Intelligence
ment of Health and Human Services, Perry Point, Md., and to E. manual. Rev. San Antonio, Tex.: Psychological Corporation, 1989.
16. Korkman M, Kirk U, Kemp S. NEPSY: a developmental neuropsycho-
Helzner, McNeil Consumer Products, Fort Washington, Pa. logical assessment: manual. San Antonio, Tex.: Psychological Corporation, 1998.
17. Conners CK. Conners’ Rating Scales: technical manual. Rev. North
The following persons also participated in the study: J.R. Serwint, Johns Tonawanda, N.Y.: Multi-Health Systems, 1997.
Hopkins Hospital, Baltimore; M. Brophy, C.T. Davoli, M.R. Farfel, and 18. Silverstein AB. Two- and four-subtest short forms of the WAIS-R:
G.W. Goldstein, Kennedy Krieger Institute, Baltimore; J. Rubin, University a closer look at validity and reliability. J Clin Psychol 1985;41:95-7.
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S. Wilkins, University of Cincinnati Medical Center, Cincinnati; G. May- telligence: a systematic review of the epidemiological evidence. BMJ 1994; nard-Wentzel and M.E. Mortensen (to 1994), Children’s Hospital of Co- lumbus, Columbus, Ohio; S. Adubato, M. Elsafty, M. Heenehan, A. Shef- 20. Rhoads GG, Rogan WJ. Treatment of lead-exposed children. Pediat-
fet, A. Ty (to 1997), and R.P. Wedeen, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark; C. Camp- 21. Jonasson G, Carlsen KH, Sodal A, Jonasson C, Mowinckel P. Patient
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1. Dietrich KN, Succop RA, Berger OG, Hammond PB, Bornschein RL.
Lead exposure and the cognitive development of urban preschool children:
Copyright 2001 Massachusetts Medical Society.
1426 · N Engl J Med, Vol. 344, No. 19 · May 10, 2001 · www.nejm.org

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